2013_rrc4

ISSN: 1583-2996

President: Ioan M. ComanPresident elect: Gabriel Tatu-ChiţoiuFormer president: Dan E. DeleanuVice-presidents: Dragoş Vinereanu

Radu CiudinSecretary: Bogdan A. PopescuTreasurer: Ovidiu ChioncelMembers: Eduard Apetrei Şerban Bălănescu Mircea Cinteză Marian Croitoru Dan Gaiţă Daniel Gherasim Ioana Ghiorghiu Carmen Ginghină Adriana Ilieşiu Daniel Lighezan

Florin MituCălin PopRadu VătăşescuDragoş Vinereanu

THE ROMANIAN SOCIETY OF CARDIOLOGY BOARD

EDITORIAL STAFF

Editor-in chiefEduard Apetrei

Deputy EditorCarmen Ginghină

EditorsRadu CăpâlneanuCezar Macarie

Founding editorCostin Carp

Associate editorsMihaela RuginăRuxandra JurcuţBogdan A. PopescuCostel Matei

EDITORIAL BOARD

Şerban Bălănescu - Bucureşti Luigi Paolo Badano - Italia Ion V. Bruckner - BucureştiAlexandru Câmpeanu - BucureştiGheorghe Cerin - ItaliaMircea Cinteză - BucureştiRadu Ciudin - BucureştiD. V. Cokkinos - GreciaIoan Mircea Coman - BucureştiG. Andrei Dan - BucureştiDan Deleanu - BucureştiGenevieve Derumeaux - FranţaDoina Dimulescu - BucureştiMaria Dorobanţu - BucureştiŞtefan Iosif Drăgulescu - TimişoaraGuy Fontaine - FranţaAlan Fraser - AngliaCătălina Arsenescu-Georgescu - Iaşi

Mihai Gheorghiade - USALeonida Gherasim - BucureştiAurel Grosu - Chişinău,R. MoldovaAssen R. Goudev - BulgariaAnthony Heagerty - MareaBritanieAlexandru Ioan - BucureştiDan Dominic Ionescu -CraiovaGabriel Kamensky - SlovaciaAndre Keren - IsraelMichel Komajda, FranţaGiuseppe Mancia - ItaliaIoan Maniţiu - SibiuAthanasios Manolis - GreciaMartin S. Martin - SUAGerald A. Maurer - AustriaŞerban Mihăileanu - FranţaTiberiu Nanea, Bucureşti

Gian Luigi Nicolosi - ItaliaPeter Nilsson - SuediaNour Olinic - Cluj-NapocaFausto Pinto - PortugaliaCălin Pop - Baia MareJosep Redon - SpaniaWillem J. Remme - OlandaMichal Tendera - PoloniaIon Ţintoiu - BucureştiPanagiotis Vardas - GreciaMargus Viigimaa - EstoniaDragoş Vinereanu - BucureştiMarius Vintilă - BucureştiDumitru Zdrenghea -Cluj-Napoca

Issue editorBogdan A. Popescu

SecretaryMihaela Sălăgean

TECHNICAL INFORMATIONResponsibility for the contents of the published articles falls entirely on the authors. Opinions, ideas, results of studies published in the Ro-manian Journal of Cardiology are those of the authors and do not refl ect the position and politics of the Romanian Society of Cardiology. No part of this publication can be reproduced, registered, transmitted under any form or means (electronic, mechanic, photocopied, recorded) without the previous written permission of the editor.All rights reserved to the Romanian Society of CardiologyContact: Societatea Română de Cardiologie Str. Avrig nr. 63, Sector 2, Bucureşti Tel./Fax: +40.21.250 01 00, +40.21.250 50 86, +40.21.250 50 87; E-mail: offi [email protected]

"Carol Davila" University of Medicine and Pharmacy, Bucharest,"CC Iliescu" Department of Cardiology - A short history 315E. Apetrei

Investigation of patients’ adherence to Angiotensin II ReceptorBlockers drug treatment for hypertensive patients in primary medicalcare (I ADHERE) 323D. Gherasim, M. Iurciuc, C. Voiculet, A. Giuca, V. Petrescu, F. Maghiar, A. Gherghina, A.Tase, C. Ginghină

Th e study of vascular reactivity on the ascending aorta aft er aorticcoarctation corrective surgery 332I. A. Ghiorghiu, M. E. Iancu, M. Ş erban, C. Ginghină

Almanac 2013: acute coronary syndromes 339P. Meier, A. J. Lansky, A. Baumbach

Almanac 2013: heart failure 348A. L. Clark

Almanac 2013: cardiac arrhythmias and pacing – an editorial overviewof selected research that has driven recent advances in clinical cardiology 354R. Liew

Fostering Diff usion of Scientifi c Contents of National SocietiesCardiovascular Journals: Th e New ESC Search Engine 367F. Alfonso, L. Gonçalves, F. Pinto, A. Timmis, H. Hector, G. Ambrosio, P. Vardas

Surprising awakening of a sleeping heart 376A. Scridon, R. C. Ș erban, A. Elkahlout, M. Opriș , D. Dobreanu

Endovascular treatment in a case of transplant renal artery stenosis 381A. Bucș a, C. Bucș a, C. Matei, C. Chirion, M. Croitoru

Echocardiography - Complex cardiac malformation in a young pregnant woman 384O. Nă stase, R. Enache, B. A. Popescu, C. Ginghină , R. Jurcuţ

Vascular Doppler - Ultrasound imaging of a bilateral carotid bodyparaganglioma 387R. O. Darabont

Updates in Cardiology 390

National and international cardiology agenda 2014 396

Reviewers 2013 399

Instructions for authors 400

Vol. 23, No. 4, 2013

ORIGINAL ARTICLES

REVIEWS

CASE PRESENTATIONS

IMAGES IN CARDIOLOGY

UPDATES IN CARDIOLOGY

AGENDA

REVIEWERS

INSTRUCTIONS FOR AUTHORS

THE WORLD OF CARDIOLOGY

Universitatea de Medicină și Farmacie "Carol Davila” București,Clinica de Cardiologie "CC Iliescu" – Scurt istoric 315E. Apetrei

Evaluarea complianţei la tratamentul cu blocanţi ai receptorilor deangiotensină II la pacienţii hipertensivi în centrele de medicinăprimară (I ADHERE) 323D. Gherasim, M. Iurciuc, C. Voiculet, A. Giuca, V. Petrescu, F. Maghiar, A. Gherghina, A.Tase, C. Ginghină

Studiul reactivității vasculare la nivelul aortei ascendente post corecția coarctației de aortă 332I. A. Ghiorghiu, M. E. Iancu, M. Şerban, C. Ginghină

Almanac 2013: sindroame coronariene acute 339P. Meier, A. J. Lansky, A. Baumbach

Almanac 2013: insufi ciența cardiacă 348A. L. Clark

Almanac 2013: aritmii cardiace și cardiostimularea 354R. Liew

Fostering Diff usion of Scientifi c Contents of National SocietiesCardiovascular Journals: Th e New ESC Search Engine 367F. Alfonso, L. Gonçalves, F. Pinto, A. Timmis, H. Hector, G. Ambrosio, P. Vardas

Trezirea surprinzătoare a unei inimi adormite 376A. Scridon, R. C. Ș erban, A. Elkahlout, M. Opriș , D. Dobreanu

Tratamentul endovascular în cazul stenozelor de arteră renalăposttransplant 381A. Bucș a, C. Bucș a, C. Matei, C. Chirion, M. Croitoru

Ecocardiografi e - Malformație cardiacă complexă la o gravidă tânără 384O. Nă stase, R. Enache, B. A. Popescu, C. Ginghină , R. Jurcuţ

Doppler vascular - Imagini ecografi ce în tumora glomică carotidiană bilaterală 387R. O. Darabont

Actualităţi în cardiologie 390

Calendarul manifestărilor științifi ce cardiologice 2013 396

Referenți 2013 399

Instrucţiuni pentru autori 400

PREZENTÃRI DE CAZ

REFERATE

ARTICOLE ORIGINALE

AGENDA

REFERENÞI

INSTRUCÞIUNI PENTRU AUTORI

IMAGINI ÎN CARDIOLOGIE

Vol. XXII, Nr. 1, 2007

Vol. 23, No. 4, 2013

ACTUALITÃÞI ÎN CARDIOLOGIE

DIN LUMEA CARDIOLOGIEI

Romanian Journal of Cardiology | Vol. 23, No. 4, 2013

THE WORLD OF CARDIOLOGY

"CC Iliescu" Department of Cardiology - A short historyEduard Apetrei

Cardiology was defi ned as a separate medical speci-alty in our country faster than in other countries,

in the 1960’. A crucial role in this was played by the founder of Romanian cardiology, Prof. Dr. CC Iliescu.

Th e fi rst cardiology clinic in Romania was founded in 1959 and it was named Th e ASCAR Cardiology Cli-nic.

Th e clinic was part of the Faculty for the Training and Specialization of Doctors and Pharmacists (FPSMF), within the Medicine and Pharmacy Institute - Bucha-rest. Th e faculty for Training and Specialization was founded in 1958 by turning the Institute for Training and Specialization for Doctors and Pharmacists (de-pendant on the Ministry of Health) - founded in 1952 - into a Faculty. Th e newly founded faculty was naturally included in the Institute for Medicine and Pharmacy, Bucharest.

Th e one who strived and fi nally succeeded in foun-ding this school was Prof. Dr. Constantin C. Iliescu. He was then named head of the clinic, occupying this position until 1962, when he retired. Th e cardiology clinic was named ASCAR Cardiology Clinic because it was within the ASCAR Hospital (CARdiac Assistan-ce – ASistenta CARdiacilor). Th e ASCAR institution was founded in 1945. A centre for the care of cardiac patients was a novelty not only for Romania, but for the entire world. It was the fi rst institution of its kind in Europe, and the second in the entire world.

Besides the care for cardiovascular diseases it was also necessary to train doctors and specialists in car-diology for the entire country. Th us, the ASCAR cli-nic had a determining role in contouring cardiology in Romania. In the fi rst year the clinic held specialization courses in cardiology for internal medicine specialists and later, for pediatricians. Th e duration of the courses was 9 months and 120 doctors graduated until 1965. In this way a cardiology network was created all around the country.

It is important to note that during this period, Prof. Iliescu used to visit newly inaugurated cardiology de-partments in order to see how the medical activity is being managed and to give an impulse through his pre-sence. I can remember such a visit from 1963, from the Onesti hospital, where Dr. Florin Anghelescu, a fresh

graduate of the specialization courses, was working. I resident in internal medicine there during that year and this visit determined me to choose cardiology as a specialization. During the same period, 30 day cour-ses for the initiation and study of the electrocardiogram were organized. During the 1965/1966 academic year the speciality in for perfecting various areas of cardio-logy was launched. Th us, a few areas such as congenital diseases, valvulopathies, ischemic heart diseases cardi-omyopathy and later, phonocardiography were intro-duced in this program. Th ese 1-2 month courses’ goal was to refresh the existing know ledge and train specia-lists in the diff erent subspecialties of cardiology. 3 week electrocardiography courses were also held in other centres in the country, such as Sibiu, Slatina, Craiova. Starting with 1965, internal medicine interns (nowa-days residents) were allowed to participate to these co-urses, in order to become cardiologists. I am one of the graduates of this fi rst course organized for interns. Th e 9 month specialization courses respected the following schedule: in the beginning a few introductory noti-ons about the anatomy of the heart and large vessels, cardiovascular physiopathology, cardiovascular semi-ology and clinical examination. Th is was followed by a period dedicated to learning electrocardiogram (5 hours/day - without clinical activity) - 3 weeks; pho-nocardiography - 2 weeks; radiology - 10 days. Th en, clinical activity was resumed and theory classes were held daily at 13:00 hours, except for Wednesdays, whi-ch were reserved to the presentation of a clinical case. Th e clinical cases presentation was done by a resident, respecting the exam methodology: 20 minutes to exa-minate the patients, 20 minutes to structure the case, 20 minutes for the presentation (this methodology is now well known and still applied). Th e second participant/resident (afore named) made diff erent comments and remarks in completion to the presentation, followed by questions and discussions with the colleagues in the class. Th e theoretical courses were held by the pro-fessor and lecturers. Some courses were assigned to the “little ones”. Professor Iliescu, or one of the lectu-rers (L. Kleinerman and E. Viciu), took part in these courses held by the assistants. Th e course was followed by a private discussion “behind closed doors” with 2

Eduard Apetrei"CC Iliescu" Department of Cardiology - A short history

Romanian Journal of CardiologyVol. 23, No. 4, 2013

partners. Th e course was analyzed regarding the way it was structured, correctness of the disseminated infor-mation, whether or not it was updated information and how the course should be. Th ese lessons cannot be for-gotten and it would be important if they were repeated nowadays. During the training period the participants worked for 5 months in the patient wards (ASCAR had 3 sections, with a total of 120 beds) and 2 month in the ambulatory (this had 8 consultation rooms). Every Saturday, in the ambulatory, Prof. Iliescu commented on some particular cases and paid great attention to how the charts were completed. Every case had a chart and congenital heart diseases and cardiac failure had special charts. Th is summed up to 110.000 charts. Th e doctors were encouraged to go with the patients to the electrocardiography laboratories (there were 3 such la-boratories, 2 in the ambulatory and one for the patient wards), to the phonocardiography laboratories, radio-logy or heart catheterism. Regular testing was perfor-med throughout the training period (especially ECG, Phono and later echocardiography) in order to evalua-te the participants. Tests were also administered at the beginning of the training period, in order to assess the level of those entering the course. Th is made possible a comparison between the level of knowledge at the be-ginning and at the end of the training course. At the end of the course a committee appointed by the Health Ministry was appointed and the graduates who passed the examination (they usually passed) became specia-list in cardiology. Some of the trainees were also invol-ved in the clinic’s scientifi c activity, which was mostly concentrated on congenital heart diseases - clinical and hemodynamic studies, valvulopathies, arrhythmias (one of Prof. Iliescu’s greatest passions), myocardial infarction, arterial hypertension (I have forgotten to mention that in the ambulatory there was a special ca-binet for patients with arterial hypertension). During this period the members of the clinic published a series of monographies: Infectious Endocarditis, cardiovas-cular functional exploration, Cardiomyopathies, Mitral Stenosis, Chronic Pulmonary Heart Disease, Arterial Hypertension etc (see Annex). Th e cardiology clinic and the whole of ASCAR rapidly became the centre of national education in cardiology, the place of origin for the cardiology network, the place where specialists were trained and methodology books were elaborated for training purposes. During this time, respecting the model of the hospital ASCAR several subsidiaries were inaugurated in Timisoara, Craiova and many cardio-logy departments were founded all around the coun-

try. Th e ASCAR cardiology clinic was visited by many personalities from the world of cardiology, such as Paul Dudley White - the patriarch of american cardiology, De Bakey, L.Turner, Eliot Corday, O.Abbott, R.Bing, A.De Maria, etc. PD White wrote in the ASCAR Hono-ur Book: “ASCAR is performing a pioneering activity in the vital fi eld of preventing heart diseases”. In 1960 the cardiology clinic had the following confi guration: Prof. Dr. CC Iliescu head of clinic, Associate professor Dr. Lazar Kleinerman, Associate Professor Emil Viciu, Dr. Matei Iliescu - lecturer, Dr. Radian Petrescu - assistant, Dr. Georgeta Domocos - assistant, Dr. Constantin Ba-ciu - assistant, Dr. Paul Iacobini - assistant. Prof. Dr. CC Iliescu was also chairman of the newly founded Cardi-ology subsection of subsection of the Internal Medici-ne Section of the Medical Sciences Societies in Roma-nia. In 1962 the subsection becomes an independent section, named the Cardiology Society - chairman, Dr. Petronela Vintila - secretary. Starting with 1961, annu-al cardiology conferences are being organized. A great role in the organization of these conferences was pla-yed by the Cardiology Clinic and ASCAR Hospital. In the future, most of the presidents and secretaries of the Cardiology Societies will come from this clinic.

Between 1962 and 1966 the clinic was ran by Associ-ate Professor L. Kleinerman and by Associate Professor Emil Viciu (they ran the clinic alternatively). During this period the didactic activity aimed at training doc-tors continued, new laboratories were created (like the hemodynamics laboratory - led by Associate Prof. Klei-nerman) and the electrocardiography laboratories were expanded - Dr. I Loebel wrote the fi rst romanian book on electrocardiography, Dr. P Dumitru, Dr. Olga Du-

Figure 1. Prof. CC Iliescu and some of his collaborators (1974)From left to right: Dr. C Parlog, Dr. R. Enescu, Dr. Hortensia Cionca, Dr. Anca Iliescu, Dr. P Andreescu, Dr. Maria Moman, Dr. Lucia Serafi m, Dr. Munteanu.



mitrescu. Associate Prof. Viciu continued the studies on clinical and experimental electrocardiography, fi na-lized with the editing, in collaboration with Dr. B Fotia-de and Dr. R Zamfi rescu of a comprehensive treaty on electrocardiography. In 1964, the fi rst coronary intensi-ve care unit in Romania was inaugurated (by Prof. C. C. Iliescu), the fi rst electrical conversions were performed and the fi rst Romanian built pacemaker (built by Eng. Goldis, Dr. D. Draghici si Dr. Gh. Bunghez - 1965) was implanted.

In 1966 Prof. A Moga was named head of the clinic. He came from Cluj to occupy the function of health minister (1966 - 1969). During this period the clinic had the following componence: Aurel Moga - pro-fessor, head of clinic; Lazar Kleinerman - associate pro-fessor; Emil Viciu – associate professor, Matei Iliescu - lecturer, Ion Orha - lecturer, Radian Petrescu - assis-tant professor, Georgeta Domocos - assistant professor, Constantin Baciu - assistant professor, Paul Iacobini- assistant professor, Oprisan Alexandrina - preparator, Eduard Apetrei-preparator.

Dr. Ion Orha - lecturer and Dr. Niculae Stancioiu - Prof. Moga’s PhD student, were also transferred from Cluj. Dr. N Stancioiu was later appointed assistant pro-

fessor and in 1974 he became lecturer. Dr. N. Stancioiu activated in the clinic until 1981 when he was trans-ferred to Cluj as Assistant Professor, initially in a Me-dical clinic and soon aft er, in the newly founded Car-diology clinic, due to personal eff orts (the Cardiology clinic from Cluj was the second Cardiology clinic in the country). In the fi rst few months aft er he became head of the clinic, Prof. A Moga presented the idea of turning the Cardiology clinic into an Internal Medicine Clinic, specialized in Cardiology. He was probably considering the model of the Cluj clinic where he activated until he came to Bucharest and where (and why hide the fact) he was worshiped by his collaborators, being one of the most well-known medical personalities in Romania. Despite all the infl uence he had at that time, as Health minister and then, President of the Romanian Medical Sciences Academy (until 1974) he did not succeed in fulfi lling his plan. Prof. Iliescu was still active, he came to the clinic every day and still had enough infl uence to oppose such a project, unwanted by the entire staff .

Cardiology was rapidly evolving towards indepen-dence from Internal Medicine.

In this period, due to the eff orts of Dr. I Orha exerci-se testing for coronary patients was started and the re-habilitation program was initiated. In the beginning the eff ort tests were done at the Center for Sports Medicine and then, in our clinic. Aft er the death of Prof. Moga in 1973, Assistant Prof. L. Kleinerman became once more the head of the clinic. Th e ASCAR Cardiology clinic functioned since its foundation in the ASCAR building in Cosmonauts Square (nowadays Lahovary Square). Due to the “eff orts” of some personalities from the romanian medical world with political inclinations the Cardiology clinic and the entire ASCAR hospital were relocated in 1976 in the Fundeni Hospital. It is im-portant to note that next to the ASCAR building there was a space destinated (and all plans were made and approved) for a new building, in order to expand the ambulatory and include a Cardiovascular surgery cli-nic. Th e plans were app roved and the construction was ready to begin. During this period the head of the clinic was Associate Professor L. Kleinerman, a good doctor and teacher and Dr. C. Parlog was manager of the AS-CAR hospital. Th ey accepted the relocation of the clinic without great opposition, but during those times not much could be done if a decision was made “at the top”. Th e clinic’s relocation also had positive aspects, but we are not going to discuss this matter in this article.

At the time of its relocation to Fundeni Hospital the clinic had the following confi guration: Assoc. Prof. L Kleinerman - head of clinic, Dr. Matei Iliescu - leturer,

Figure 2. Prof. C.C. IliescuTh e painting is now in the Meeting Room of the University of Medicine, Bucharest.



Dr. Ion Orha - lecturer, Dr.Radian Petrescu - lecturer, Dr. Georgeta Domocos - assistant, Dr. Petre Dumitru - assistant, Dr. Alexandrina Oprisan - assistant, Dr. Edu-ard Apetrei - assistant, Dr.Niculae Stancioiu - assistant.

Along with the relocation the clinic received a new name: Th e Fundeni Cardiology Clinic. Th e clinic con-tinued its didactic activities within the Faculty for the Training and Specialization of Doctors and Pharma-cists (FPSMF). Assoc. Prof. L. Kleinerman retires in 1976, the same year when the clinic was relocated to Fundeni and Dr. Matei Iliescu - lecturer is appointed to run the clinic. During those years academic promo-tions were “frozen”, so many doctors were blocked in the same positions for many years. Th is was also the case of Dr. Matei Iliescu. He competently ran the clinic for almost 2 years, in a slightly hostile atmosphere (2 other lecturers were working in the clinic), but the ge-neral activity of the clinic did not suff er. Didactic acti-vities went on without any impediments. In 1978 Prof. Costin Carp was put in charge of the clinic. He came from the Caritas hospital. Although Prof. Costin Carp was not a collaborator of CC Iliescu and he had never worked in ASCAR, he managed to run the clinic in the ASCAR spirit, ensuring without a doubt, its continuity. During this period the clinic continued to consolidate its position as a training and specialization center. Most specialists working in Cardiology or cardiology subfi -elds, such as echocardiography, phonocardiography or invasive cardiology were trained in the Fundeni clinic. Prof. C. Carp was a very good clinician and he mana-ged in a relatively short period of time to impose pro-fessionalism, sobriety and responsibility in the medical act. Th e medical act could not suff er from any political intervention. Th en, as today, politicians (“the party”) wanted to control everything (it was also a very diffi -cult period), but this desire was not fulfi lled regarding the medical fi eld. Medical research was continued in the fi elds of epidemiology and rehabilitation (depart-ment led by Dr. I. Orha - this department took part in international programs such as the OMS program for myocardial infarction or the MONICA program), ar-rhythmias (one of Prof. Carp’s favorite preoccupations), valvulopathies, cardiomyopathies, congenital diseases, arterial hypertension, etc. New diagnostic methods are introduced - initiated and developed by members of the clinic (an example is echocardiography - Dr. E. Apetrei). Th e fi rst echocardiography cours in Romania are organized starting with 1982 and then, our clinic organizes National Symposiums on echocardiography, beginning with 1984.

Our involvement in the international cardiology sce-ne is increasingly higher because of the eff orts and sti-mulation of Prof. Dr. C. Carp.

In Romania, the Fundeni Cardiology Clinic plays an important role in the reorganization of the Romanian Society of Cardiology and in 1990 Prof. Carp is elected president of the Society of Cardiology and Dr. E. Ape-trei is elected secretary.

Aft er Prof. Carp’s retirement in 1992 his position as head of the Fundeni Cardiology Clinic becomes vacant and is occupied aft er public competition by Conf. Dr. E. Apetrei.

In 1993 the academic staff of the Cardiology Clinic consisted of: Prof. Dr. Eduard Apetrei – head of clinic, Prof Dr. Costin Carp - consulting professor, Assoc. Prof. Dr. Radian Petrescu, Dr.Petre Dumitru - assistant professor, Dr. Ioana Stoian - assistant professor, R Ciu-din- assistant professor, I Coman - assistant professor.

Assoc. Prof. Dr. I. Orha moved in 1991 at the Flo-reasca Emergency Hospital as a Professor, head of the Medical Clinic. Th e didactic activities concerning trai-ning and specialization continued without interrup-tion. Courses for resident doctors respect a program recommended by the European Union of Medical Spe-cialties (UEMS) - Section Cardiology (Prof. E. Apetrei was in the board of this European forum between 1994 and 2011 and Prof. Dr. Carmen Ginghina is a member of this board since 2011). New courses were introduced - transesophageal echocardiography - 2002, vascular Doppler ultrasound - 2003, invasive cardiology - 2002. A totasl of 6-8 specialization courses are organized each year. A course of echocardiography was organized in Milan for 1 month in 1994 and 1995, with the support of Dr. Faletra. 24 cardiologists from the clinic and from other cardiology clinics in the country participated, to this training period. In 1993 the university courses for medical students were introduced for the fi rst time in the clinic. At fi rst 3 series of students were taught here each year, but later only 2series were accepted (the cli-nic was overcrowded with residents and specialists). Shorter specialization courses were introduced (7 days and even 2 days, in week-ends). Attendance for these courses is still high. Th e clinic was visited by numerous personalities coming here for conferences, courses, de-bates, new methods of treatment. Some of the members of the clinic (Dr. R. Ciudin, Dr. I. Coman, Dr. A Mereu-ta, Dr. C. Matei) went abroad for specialization courses, facilitating the introduction of new diagnostic methods and treatment. Research continues, books and cardio-logy treaties are written (see Annex 1). Th e Cardiology Clinic becomes in 2001 a CENTER FOR EXCELLEN-



Adrian Mereuta Assistant Professor, Dr. Monica Rota-reasa Assistant Professor, Dr. Matei Costel preparator.

In 2002 a second Professor’s position is opened and Assoc. Prof. C. Macarie occupies it aft er an open com-petition. In 2003 a third position of Professor is opened and is occupied by Assoc. Prof. Dr. Carmen Ginghi-na, aft er a public competition. In October 2003 Prof. Dr. E. Apetrei retires and Prof. Dr. C. Macarie becomes the head of Fundeni cardiology Clinic. Aft er 1 year, elections are organized in order to choose the heads of clinics for the entire University of Medicine and Pharmacy and Prof. Dr. Carmen Ginghina is elected as head of the Fundeni cardiology clinic and is currently running in this position. During this time the clinic continued to be involved in numerous activities. Th e clinic’s activity with 4th year students was continued, as well as courses for residents in the 3rd year. Residents from the CC Iliescu Cardiology clinic and from Car-diology clinics all around the country participate at these courses. Training course for trans-thoracic and trans-esophageal ultrasound, vascular Doppler and in-terventional cardiology are organized twice a year. A total of 14 courses are organized in the clinic each year, excepting the courses for students and residents. Prof. Dr. Carmen Ginghina is very active from a professional and scientifi c point of view and she stimulated her col-leagues and and residents to take an active interest in research and publishing quality papers. Th e residents, under the direct guidance of the head of the the clinic help publish a yearly volume entitled “Cardiac patients Imagistics”, continuing with a modern approach the se-ries “Commented and Illustrated cases in Cardiology”. Several books and monographies were published (see Annex). Th e level of scientifi c activity is very high, an important role in this aspect being held by the Cardiac Ultrasound Laboratory, with a European accreditation. Over 200 ISI credited publications were published in the last 10 years. Some of the members of the clinic are part of the boards of the national scientifi c organizati-ons such as the Romanian Society of Cardiology and the Society’s work Groups (see the volume Th e Roma-nian Society of Cardiology - short history - no. 56, An-nex I) and in the European Society of Cardiology and Echocardiography. Th e current leadership of the clinic has also kept in mind the future, supporting and pro-moting young doctors. Today, the members of the CC Iliescu Cardiology clinic are: Prof. Dr. Carmen Ginghi-na - head of clinic, Prof. Dr. C Macarie, Assoc. Prof. Dr. Ion Coman, Assoc. Prof. Bogdan Popescu, Dr. R. Ciu-din lecturer, Dr. Ioana Stoian lecturer, Adrian Mereuta lecturer, Dr. Ruxandra Jurcut lecturer, Dr. Andrei Carp

CE, research center in Cardiology. Th is title was gran-ted by the Ministry of Health. It is the fi rst clinic in the country meeting the criteria for such a title (aft er a ri-gorous evaluation of research and didactic activities). Th e clinic runs research programs with partners from abroad. Due to our active involvement in international cardiology, the members of this clinic were elected to international comities, received honorary distinctions and rewards and were visiting professors in univer-sities from the US (North Carolina) and England. In 1995 Prof. Apetrei is elected to the Medical Sciences Academy and since 2006 he is vice-president of this Academy and Dr. H C of the University of Medicine from Iasi (2007). In 2009 Prof. Dr. Carmen Ginghina is elected to the Medical Sciences Academy, fellow of the American College of cardiology and Prof. Dr. C. Maca-rie is also elected to the Medical Sciences Academy and fellow of the American College of Cardiology. Manny members of the clinic were presidents of the Romani-an Society of Cardiology: Prof. E. Apetrei (1994-1998), Prof. C. Macarie (1998-2002), Prof. Carmen Ginghina (2002-2005). Assoc. Prof. Dr. I. Coman is the elected president for 2011-2014 (see the book Short History of the Romanian Society of Cardiology).

In 1996 Dr. C. Macarie become an Asssociate Pro-fessor position and in 1997 second position of Associa-te Professor is occupied by Dr. Carmen Ginghina. Both positions were occupied aft er a open competition. In 1997 the clinic had the following confi guration: Prof. Dr. Eduard Apetrei - head of clinic, Assoc. Prof. Dr. Cezar Macarie, Assoc. Prof. Carmen Ginghina, Dr. Ion Coman lecturer, Dr. R. Ciudin lecturer, Dr. Ioana Sto-ian lecturer, Dr. Andrei Carp Assistant Professor, Dr.

Figure 3. 1991 - in the fi rst line, from right to left : Prof. C. Carp, Prof. Patri-cia Come (Harvard, SUA), Conf. E. Apetrei and a group of students. In the back line: Dr. Carmen Ginghina.



12. Cardiopatiile ischemice coronariene. Clinica ,dia-gnostic si tratament. L. Kleinerman (red.), Horten-sia Cionca, M.Ghita, M. Efraim Editura Medicala Bucuresti. 1966; 248 pagini

13. Cardiopatiile ischemice coronariene. Clinica, diag-nostic si tratament. Editia a II a Kleinerman (red.), Hortensia Cionca, M. Ghita, M. Efraim L. Editura Medicala Bucuresti. 1973; 381 pagini

14. Miocardiopatiile cornice. Vintila Mihailescu, Lilia-na Hagi Paraschiv-Dosius, Petronela Vintila.Editu-ra Medicala Bucuresti 1973

15. Actualitati in diagnosticul si tratamentul bolilor de inima. V. Cunescu, D. Draghici Editura Medicala Bucuresti 1974; 228 pagini

16. Actualitati in diagnosticul si tratamentul bolilor de inima. V. Cunescu, D. Draghici Editura Medicala Bucuresti 1976; 382 pagini

17. Mecanofonocardiografi a. Eduard Apetrei, E. Viciu Editura Medicala, Bucuresti, 1977; 164 pagini

18. Terapia intensive in cardiologie. 2 editii Sub redactia Petronela Vintila Editura Medicala Bucuresti 1979,1981; 336 pagini

19. Arteriopatii periferice. E. Viciu, Eduard Apetrei. Editura Medicala, Bucuresti, 1979; 455 pagini

20. Cardiopatia ischemica. L. Kleinerman (red.), Edu-ard Apetrei, Hortensia Cionca, Liliana Dosius, Mar-cel Efraim. Editura Medicala, Bucuresti, 1981; 431 pagini

21. Bolile cardiovasculare. Calauza practicianului. Vin-tila V. Mihailescu Editura Medicala 1981; 237 pa-gini

22. Insufi cienta cardiaca. Mecanisme. Evaluare. Trata-ment. Cezar Macarie, Dan-Dominic Ionescu. Edi-tura Militara. Bucuresti 1982; 310 pagini

23. Indreptar de diagnostic si tratament al bolilor cardi-ovasculare Cositin Carp (sub red.) Editura Medica-la Bucuresti 1985; 456 pagini

24. Ecocardiografi e. E. Apetrei. ISBN: 973-39 005-1, Editura Medicala, Bucuresti, 1990; 286 pagini

25. Actualitati in cardiologie. L. Gherasim. Eduard Apetrei. ISBN: 973-9397-007. Editura Amaltea Bu-curesti, 1998; 592 pagini

26. Clasifi cari si unele ghiduri practice in bolile cardio-vasculare. Eduard Apetrei, lleana Arsenescu. ISBN: 973-9394-19-1, Bucurestii - Editura Info-Medica. Bucuresti, 1999; 180 pagini

27. Boli congenitale, Carmen Ginghina, Eduard Ape-trei, C. Macarie. ISBN: 973-96286-9-4, Editura Amaltea, Bucuresti, 2001

28. Clasifi cari si unele ghiduri practice in bolile cardio-vasculare, Eduard Apetrei, lleana Arsenescu. Editia

- Assistant Professor, Monica Rotareasa - Assistant Pro-fessor, Matei Costel - Assistant Professor, Dr. Cosmin Calin - Assistant Professor, Carmen Beladan - Assis-tant Professor, Ioana Savu Ionita - Assistant Professor, Mona Musteata - Assistant Professor. Th ere also a re-sea r ch center with permanent employees - Dr. Andre-ea Calin, Dr. Monica Rosca. Prof. Dr. E. Apetrei is still responsible of doctoral students. Trainings abroad and in Romania of young cardiologists made possible the consolidation of a powerful clinic in terms of research, especially in echocardiography, but not limited to this fi eld. Together with the other Cardiology clinics in the country, the CC Iliescu clinic goes to great lengths to train students, residents in cardiology and specialists in the diff erent branches of cardiology. Medical research is also one of the strong points of the CC Iliescu Car-diology clinic.

ANNEXBook, treaties, monographies

Written by the members of the Cardiology Clinic

1. De vorba cu studentii. Notiuni de fi ziologie, fi ziopa-tologie, semiologie, patologie si terapeutica cardia ca editia I-a editii). CC Iliescu Editura Cartea de aur. Bucuresti 1939; 450 pagini

2. De vorba cu studentii. Notiuni de fi ziologie, patolo-gie si terapeutica cardia ca editia II-a. CC Iliescu Editura Cartea de aur. Bucuresti 1943; 489 pagini

3. Endocardita lenta. CC Iliescu. Sub red Editura de stat pentru literatura stiintifi ca. Bucuresti 1953

4. Electrocardiografi a. I. Lobel Editura Medicala Bu-curesti 1956; 575 pagini

5. Sindromul de ischemie periferica. C.C. Iliescu sub red Editura Medicala Bucuresti 1956; 457 pagini

6. Stenoza Mitrala. Clinica fi ziopatologica. Vintila V. Mihailescu, Elena Malitchi Editura Medicala. Bu-curesti 1956; 162 pagini

7. Cordul pulmonar cronic. Vintila V. Mihailescu Edi-tura Medicala Bucuresti 1958; 164 pagini

8. Sindroamele coronariene. C.C. Iliescu, Laurian Ro-man Editura Medicala Bucuresti 1960; 223 pagini

9. Probleme de patologie cardiovasculara. L. Kleiner-man; F M. Ghita; Olga Dumitrescu, Sabina Leca Mi nisterul Sanatatii, ASCAR. Bucuresti 1964); 460 pagini

10. Indreptar de diagnostic si tratament in bolile cardi-ovasculare. C.C. Iliescu, Elena Malitchi, Dinu Dra-ghici C.C. Editura Medicala, Bucuresti 1966.

11. Hipertensiunea arteriala. Vintila V. Mihailescu Edi-tura Medicla Bucuresti 1966; 245 pagini



44. Cardiologie, cazuri comentate si Ilustrate, vol.IV. Eduard Apetrei, Carmen Ginghina. Editura Pro Bucuresti, 2004; 275 pagini.

45. Insufi cienta cardiaca - de la studii clinice la ghiduri. Cezar Macarie, Ovidiu Chioncel. Editura Medicala, Bucuresti; 2005

46. Esenţialul în ecocardiografi e. Ginghină C, Popescu BA, Jurcuţ R. Editura Medicală Antaeus, București, 2005

47. Hipertensiunea pulmonara in practica de cardio-logie. Carmen Ginghina. Ed. Academiei Romane, 2006

48. Velocity Vector Imaging technology. A new tool for myocardial function evaluation - technique and cli-nical cases. Ruxandra Jurcut. Editura Medicala An-taeus, Bucuresti, 2007. ISBN: 978-973-88434-6-2

49. Insufi cienta cardiaca acuta-abordare practica. Ce-zar Macarie Ovidiu Chioncel. Editura ErcPress, Bucuresti, 2008

50. Imagistica la bolnavii cardiaci. Din pagina cartii la ecranul computerului. Vol III. Sub redactia Car-men Ginghina. Editura Medicala. Bucuresti, 2008. ISBN: 978-973-39-0681-0; 95 pagini.

51. Insufi cienta cardiaca acuta - Ghid pentru pacienti. Cezar Macarie, Ovidiu Chioncel. Editura Medicala. Bucuresti, 2008

52. Enciclopedia Medicala Romaneasca De la origini pana in prezent. Ursea N., (sub redactia), Angheles-cu N, Antonescu D. Apetrei E. Editura Universitara Carol Davila, Bucurest. ISBN: 978-973-708-331-9. 2009; 5 volume

53. Imagistica la bolnavii cardiaci. Din pagina cartii la ecranul computerului. Vol V. Sub redactia Carmen Ginghina. Editura Medicala. Bucuresti, 2009

54. Mic tratat de Cardiologie. Carmen Ginghina. Ed. Academiei Romane, 2010. ISBN: 978-973-27-1931-2; 894 pagini

55. Imagistica la bolnavii cardiaci. Din pagina cartii la ecranul computerului. Vol V. Sub redactia Car-men Ginghina. Editura Medicala. Bucuresti, 2010. ISBN: 978-973-39-0699-5; 124 pagini

56. Societatea Romana de Cardiologie. Scurta istorie. E. Apetrei. Media Med Publicis. Bucuresti, 2011.

57. Ecocardiografi a Doppler. (Tratat însoțit de DVD) . Popescu BA, Ginghină C. Editura Medicală, Bucu-rești, 2011

58. Imagistica la bolnavii cardiaci. Din pagina cartii la ecranul computerului. Vol V. Sub redactia CarmenGinghina. Editura Medicala. Bucuresti, 2011. ISBN:978-973-39-0717-6; 129 pagini. ISBN: 978-973-39-0717-6; 129 pagini

a II-a, Bucuresti. ISBN: 973-9394-63-9 Editura In-fo-Medica, Bucuresti, 2001; 210 pagini

29. Cordul diabetic. Carmen Ginghina, Gheorghe S. Ba-canu, Mirela Marinescu, Dinu Dragomir. Editura Info Medica Bucuresti 2001. ISBN: 973-9394-57-4 144 pagini

30. Insufi cienta cardiaca. Cezar Macarie, Eduard Ape-trei, Carmen Ginghina. Editura Amaltea, Bucures-ti, 2001; 211 pagini

31. 111 teste grila comentate pentru rezidentiat. Speci-alitati medicale si chirurgicale. Ruxandra Ciobanu, Ilinca Gussi, Ciprian Jurcut, Silviu Stanciu. Ed. Me-dicala, Bucuresti, 2001

32. Electrocardiografi a. Eduard Apetrei, loana Stoian. Editura Info-Medica, Bucuresti, 2002; 327 pg. Car-te premiata de Academia Romana (2003)

33. Ecocardiografi e in imagini. Eduard Apetrei, B.A. Popescu CD si volum, Ed. INSEI Print, Bucuresti, 2002

34. Cardiologie (Cazuri comentate si ilustrate), vol. I. Eduard Apetrei, Carmen Ginghina, C. Macarie. Editura Info-Medica, Bucuresti, 2002; 167 pagini

35. Indreptar de diagnostic si tratament in Infarctul mi-ocardic acut. Carmen Ginghina, Mirela Marinescu, Dinu Dragomir. Ed. Info medica 2002. ISBN: 973-9394-73-6; 363 pagini

36. Pericardiologia – de la diagnostic la tratament. Car-men Ginghina, Dinu Dragomir, Mirela Marinescu. Ed. InfoMedica 2002. ISBN: 973-9393-88-4; 283 pagini

37. Tratat de cardiologie. Volumul I. Costin Carp. Edi-tura Medicala Nationala Bucuresti. 2002. ISBN 9783-8194-65-2; 1161 pagini

38. Tratat de cardiologie. Volumul II. Costin Carp. Editura Medicala Nationala Bucuresti 2003. ISBN 973-8194-82-2, 1174 pagini

39. Cardiologie (Cazuri comentate si ilustrate), vol. II. Eduard Apetrei. Editura Stiintifi ca si Tehnica, Bu-curesti, 2003; 187 pagini

40. Diagnosticul modern al disectiei de aorta. Ioan Co-man. Ed. BIC All, 2003. ISBN: 973-571-471-x; 95 pagini

41. Aritmiile cardiace la copil si adultul tanar. Radu Ciudin, Carmen Ginghina, Ioana Ghiorghiu. Edi-tura Info medica Bucuresti 2003; ISBN: 973-7912-16-0; 419 pagini

42. Cardiologie (Cazuri comentate si ilustrate), vol. III. Eduard Apetrei. Editura Info-Medica, Bucuresti, 2004; 253 pagini

43. Evaluarea ultrasonografi ca vasculara. Compact disc. Eduard Apetrei, lleana Arsenescu. Editura IN-SEI, Bucuresti; 2004



62. Esenţialul în ecocardiografi e. Editia a doua, revi-zuita si adaugita. Ginghină C, Popescu BA, Jurcuţ R. Editura Medicală Antaeus, București, 2013; 383 pagini

63. Imagistica la bolnavii cardiaci. Din pagina cartii la ecranul computerului. Vol VII. Sub redactia Car-men Ginghina. Editura Medicala. Bucuresti, 2013. ISBN: 978-973-39-0749-7; 124 pagini

Th is list does not include chapters written in other books and monographies. Th e list of ISI articles will be published later.

59. Imagistica la bolnavii cardiaci. Din pagina cartii la ecranul computerului. Vol V. Sub redactia Car-men Ginghina. Editura Medicala. Bucuresti, 2011. ISBN: 978-973-39-07 17-6; 129 pagini

60. Imagistica la bolnavii cardiaci. Din pagina cartii la ecranul computerului. Vol V. Sub redactia Car-men Ginghina. Editura Medicala. Bucuresti, 2012. ISBN: 978-973-39-0735-0; 142 pagini

61. Cateterismul cardiac pentru clinician. Dan Delea-nu, Carmen Ginghina. Editura Medicala Antaeus, Bucuresti, 2012. ISBN: 978-6068470-01-6; 394 pa-gini. Carte premiata de Academia de Stiinte Medi-cale (2013)


ORIGINAL ARTICLE

Investigation of patients’ adherence to Angiotensin II Receptor Blockers drug treatment for hypertensive patients in primary medical care (I ADHERE)Daniel Gherasim1, Mircea Iurciuc2, Cristina Voiculet3, Alina Giuca4, Virgil Petrescu5, Florin Maghiar6,Alexandra Gherghina7, Adrian Tase8, Carmen Ginghina1,9

Contact address:Daniel Gherasim, Clinic of Cardiology, Emergency Institute for Cardio-vascular Diseases, 258 Fundeni Avenue, 2nd District, Bucharest, Zip code 022328. E-mail: [email protected]

1 “Prof.Dr.C.C.Iliescu” Emergency Institute for Cardiovascular Diseases, Bucharest2 “Victor Babes” University of Medicine Timisoara 3 Clinical Emergency Hospital Constanta4 Emergency County Clinical Hospital, Cardiology Center, Craiova5 Colentina Universitary Hospital, Bucharest6 University of Medicine Oradea7 Clinical Emergency Hospital Brasov8 University of Pitesti, Faculty of Nursing, Emergency County Hospital Pitesti9 “Carol Davila” University of Medicine and Pharmacy, Cardiology Depart-ment, Bucharest

Abstract: Th e aim of the study was to evaluate the compliance with angiotensin II receptor blockers (ARBs) treatment in hypertensive patients persistent on this medication for at least 6 month and to identify the factors asociated with it. Material and method – Open-label, non-randomized, national, retrospective disease registry, that collected data from 12,538 hyper-tensive patients in treatment with an ARB for the last 6 months, from 621 study centers of ambulatory clinical practice, ma-inly cardiological or primary medical care all over the country. Th e study evaluated the level of ARBs treatment compliance, assessed by applying the adapted Medication Adherence Self-Report Inventory questionnaire (MASRI) part I and estimated the medication possesion rate (MPR). Th e MASRI is a questionnaire fi lled in by patients addresseing the frequency and correct timing of medication intake. Results – Th e patients, 45.4% male and 54.3% female, with a mean age of 60.9 years old, were treated with combination therapy in >80% of cases and the drugs most frequently associated to sartans were diuretics (~57%).Th e mainly associated risk factors were hypercholesterolemia (73,7%) and obesity (59,6%) and the most part of the patients are coming from urban environment (73,7%). MPR was above 80% value, considered to be the inferior level of adherence to anti-hypertensive therapy, in 96.6% of the patients on ARB monotherapy and in 96.5% of those with ARB in combinations. None of the evaluated demographic or medical factors infl uenced signifi cantly the compliance with ARB treatment. In the subgroup of patients with ARBs in combinations, urban environment determined signifi cantly higher compliance than rural environment [relative risk (RR) = 1.093, confi dence interval (CI) = 1.018 – 1.173]. Conclusion – Our study showed a very good compliance with ARB treatment in hypertensive patients persistent on ARB treatment for 6 month, in ambulatory practice; MPR> 80% has been registered in 96.5% of the patients with ARBs treatment, in monotherapy or in combinations.Keywords: Hypertension, compliance, angiotensin II receptor blockers

Abstract: Obiectivele studiului – Evaluarea complianţei la tratamentul cu blocanţi ai receptorilor de angiotensină II (BRA) la pacienţii hipertensivi cu o persistenţă de cel puţin 6 luni pe această terapie și, de asemenea, identifi carea factorilor asociaţi. Material și metodă – Registru de boală naţional, retrospectiv, nerandomizat în care au fost colectate date de la 12,538 de paci-enţi hipertensivi care urmau tratament cu un BRA de 6 luni, din 621 de centre de consultaţie de specialitate în ambulatoriu, în principal de cardiologie sau de medicină primară, din toată ţara. Studiul a evaluat complianţa la tratamentul cu BRA, determi-nată prin aplicarea unui chestionar adaptat de auto-raportare a aderenţei la medicație (MASRI partea I) și estimarea ratei de posesie a medicaţiei (medication possesion rate, MPR). MASRI este un chestionar completat de către pacienţi care se referă la frecvenţa și la corectitudinea administrării medicaţiei. Rezultate – Pacienţii, 45,4% bărbaţi și 54,3% femei, cu o vârstă medie de 60,9 ani, primeau terapie combinată în mai mult de 80% din cazuri, iar medicamentele cel mai frecvent asociate sartanilor au fost diureticele (~57%). Principalii factori de risc asociaţi au fost hipercolesterolemia (73,7%) și obezitatea (59,6%) iar ma-joritatea pacienţilor provenea din mediul urban (73,7%). MPR a fost peste valoarea de 80%, considerată a fi limita inferioară pentru aderenţa la terapia antihipertensivă, pentru 96,6% dintre pacienţii cu BRA în monoterapie și pentru 96,5% pentru cei cu BRA în terapie combinată. Niciunul dintre factorii demografi ci sau medicali evaluaţi nu a infl uenţat semnifi cativ compli-anţa la tratamentul cu BRA. În subgrupul de pacienţi cu BRA în cadrul unei terapii combinate, provenienţa din mediul urban

Daniel Gherasim et al.Investigation of patients’ adherence to Angiotensin II Receptor Blockers


eff ective in reducing the risk of total cardiovascular eve nts and specifi c events such as stroke, myocardial in farction and heart failure10,11. Despite the availability of safe and eff ective antihypertensive agents, hyperten-sion and its concomitant risk factors remain uncontro-lled in most patients12.

One of the major factor of poor control of hyperten-sion is nonadherence of the patients to medical treat-ment. Studies have shown that around 50% of indivi-duals discontinue antihypertensive medications within 6 to 12 months of their initiation13.

Overall, one third of patients used antihypertensive therapy continuously during the 10 years of follow-up and one third permanently discontinued therapy14.

Nonadherence to medical treatments is an increasin-gly recognized cause of adverse outcomes and increa-sed health care costs. Drug compliance is defi ned as the extent to which patients follow medical instructions. Th is term was replaced by ‘adherence’ which includes also the responsibility of the caregivers. Adherence has been defi ned as ‘the active, voluntary, and collaborati-ve involvement of the patient in a mutually acceptable course of behaviour to produce a therapeutic result’15. Medication persistence refers to the act of continuing the treatment for the prescribed duration. It may be de-fi ned as “the duration of time from initiation to discon-tinuation of therapy”16.

Th ere are many diff erent methods of assessing adhe-rence to medications. Osterberg et al17 categorized the-se methods as either direct or indirect. Direct methods include directly observed therapy, measurement of the level of medicine or metabolite or the biological mar-ker in blood sample. Despite the fact that these direct me thods are considered to be more robust than indi-rect methods, they are not practical for routine clinical use. Indirect methods of adherence assessment include pa tient questionnaires, self-reports, pill counts, rate of pre scription refi lls, assessment of the patient’s clinical response, electronic medication monitors, measure-ment of physiological markers and patient diaries. Th e most commonly used indirect methods include patient self-report, pill counts and pharmacy refi lls18.

Th e objective of our study is to evaluate the compli-ance with ARBs medication of hypertensive patients

INTRODUCTIONTh e World health statistics – Geneva 2012 report, re-leased on 16 May 2012, puts the spotlight on the gro-wing problem of the noncommunicable diseases bur-den. One in three adults worldwide, according to the re port, has raised blood pressure – a condition that ca uses around half of all deaths from stroke and heart di sease1. Epidemiological data for Romania are coming from SEPHAR studies which took place in 2005 and 2011, being initiated with the purpose of estimating the hypertension’s prevalence, treatment and control in adult population for developing prevention strategies in hypertension management. In SEPHAR II study hy-per tension was recorded in 40.4% of cases (798 subjects from 1975 responders)2. Other studies conducted on selected populations showed a variable HT prevalen-ce3,4.

Th e raised levels of blood pressure represent the con-sequence of a complex interplay of environmental and genetic factors. Th e primary goal of treatment of the patient with high blood pressure is to achieve the maxi-mum reduction in the long-term total risk of cardiovas-cular morbidity and mortality. Th is requires treatment of all identifi ed risk factors and the appropriate ma-nagement of associated clinical conditions, as well as treatment of the raised blood pressure per se5. Th e use of antihypertensive drug therapy has been shown to re-duce the risk of stroke and coronary heart disease by an estimated 30-40% and 20%, respectively, in long-term randomized controlled trials (RCTs)6.

Th e underlying haemodynamic disorder in the ma-jority of cases is a rise in peripheral vascular resistance, so the vasodilatator eff ect was an important feature for the strategies developed over time for the treatment of hypertension7. Among the antihypertensive clases, a special interest is given to the renin-angiotensin system (RAS) blockers, related to the role of this sistem in the pathophysiology of hypertension and organ injury8.

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are widely used in patients with hypertension, heart failure and diabetes as well as in other clinical conditions sharing an increased cardiovascular risk9. Individual trials and meta-analyses showed that both ACEIs and ARBs are

a determinat o complianţă semnifi cativ mai mare comparativ cu cel rural [risc relativ (RR) = 1.093, interval de încredere (II) = 1.018 – 1.173]. Concluzie – Studiul nostru a arătat o complianţă foarte bună la tratamentul cu BRA la pacienţii hipertensivi persistenţi pe această terapie timp de 6 luni, trataţi in ambulator; indicele de posesie a medicaţiei MPR> 80% a fost înregistrat la 96,5% dintre pacienţii în tratament cu BRA, în monoterapie sau în terapie combinată.Cuvinte cheie: hipertensiune arterială, complianţă, blocanţi de receptor de angiotensină II



already treated for at least 6 month with these drugs. Another goal is to raise the awereness on the impor-tance of treatment adherence in chronic patients and to identify the factors asociated with it.

MATERIALS AND METHODSI ADHERE is an open-label, non-randomized, natio-nal (Romania), multicentric, retrospective disease re-gistry, sponsored by Sanofi , that collected data from 12,538 pa tients, in 621 study centers of ambulatory cli-nical pra ctice, cardiological or primary medical care all over the country. All patients signed an informed con-sent for participation and were informed on the study objec tives.

Th e purpose of I ADHERE was to establish the achie-vement of the prescribed regimen of ARBs (amount of medication actually taken), based on a questionnaire fi lled by patients, in a population persistent on ARBs treatment for at least 6 months. Th e study evaluated the level of ARBs treatment compliance, assessed by ap-plying the adapted Medication Adherence Self-Report Inventory questionnaire (MASRI) part I and estimated the medication possesion rate (MPR). Th e MASRI is a 12-item questionnaire originally developed for use in Human Immunodefi ciency Virus (HIV) populations. Th e MASRI addresses the frequency and correct ti m-ing of medication intake. Its reliability and specifi city were high using a set of measures such as test-retest co-n sistency and internal consistency19. In our study we used only the fi rst adapted section of the questionnaire re lated to the amount of medication actually taken. (Fi-gure 1).

Patients included in this study were adults hyperten-sive patients (according to ESC/ESH guidelines, 2007),

age >18 years, men and women, in treatment with an ARBs (in either monotherapy or in combination) for the last 6 months, who accepted to sign the informed consent. Exclusion criteria were: patient’s refusal to sign the informed consent; patient’s refusal or incapa-city to complete the MASRI questionnaire; ARB treat-ment for other indication than hypertension.

Primary objectives were the assessment of adheren-ce on ARB treatment in hypertensive patients who are persistent on ARBs treatment for at least 6 months, eva-luating the level of compliance, in ambulatory practice, by the use of a MASRI (Medication Adherence Self-Report Inventory) type auto-evaluation questionnaire and the estimation of MPR (medication possession rate) considering that MPR 0.80 is the inferior margin of adherence to antihypertensive therapy (according with Siegel D et al.).

We looked also (as secondary objectives) for: fi nd-ing factors associated with adherence (MPR >0.80) to ARBs given in monotherapy or given in combinations in a population persistent on this medication for 6 mo-nths; assessment of standard diagnostic procedures for hypertension in the ambulatory clinical practice and for assessment of standard therapy for hypertension in the ambulatory clinical practice. We collected demogra-phic data of the patients, and also we noted personal history of cardiovascular disease and organ damages, risk factors / comorbidities, standard of diagnostic pro-cedures for hypertension (type of laboratory exams / other exploratory investigations recommended) and pre viously antihypertensive treatment prescribed.

Statistical methodsTh e main statistical analysis was descriptive: for the con tinuous data the mean, median and mode values,

Figure 1. Adapted MASRI questionnaire used in I ADHERE study.

MASRI questionnaire (adapted) – fi rst section:

Did you miss the daily dose of ARB (INN……..) yesterday?Yes No Don’t know Did you miss the daily dose of ARB (INN………) the day before yesterday?Yes No Don’t know Did you miss the daily dose of ARB (INN………) 3 days ago?Yes No Don’t know How many daily doses of ARBs have you missed in the 2 weeks before that?0 1 2 or more* Don’t know * please approximate the number of missed doses_ _ _ _When was the last time you missed a daily dose of ARB?Today Yesterday Earlier this week Last week Less than a month ago More than a month ago Never Don’t know Please estimate the proportion of total daily dosage of ARBs (INN……..) you have taken during the last month?……………………….% from the total amount of dosesEX: 0% (means you have taken no medication); 50% (means you have taken half your medication); 100% (means you have taken every single dose of medication).



standard deviations and 95% two-tailed confi dence interval (CI) have been calculated and for categorical data the proportions and 95% CI (two-sample Z-test). Presuming that 50% of patients have a good treatment adherence, for estimating the adherence rate with a precision of 1.5% and assuming a level of alpha error of 0.05 and a power of 90%, we needed to include at least 4538 patients. If we also assume an attrition rate of 25%, then 5672 patients should have been included. Th is sample size has been amended one month aft er the fi rst patient was enrolled. For establishing positi-ve correlation between some factors and drug therapy adherence, the Odds Ratio (OR) had to be calculated, the cut-off value for positive correlation being fi xed at 1.5. For the secondary exploratory end-points, the sample-size estimation had to take into consideration the frequency of the factors involved as independent variables in the regression model. For some certain va-luable factors, these frequencies estimated are low (no more than 2%). Assuming a cut-off value for OR of 1.5 and also a p-value of 0.05 and a power of 90%, the sam-ple-size had to be at least of 10,555 patients.

RESULTS

Characteristics of the patientsData were collected for 12,538 patients out of whom only 12,483 were eligible according to the inclusion criteria and were included in the study analysis. 55 pa-tients have been excluded from the analysis because they didn’t meet the inclusion criteria – 13 were not hypertensive patients (according to ESC/ESH guideli-nes, 2007), and 42 were not treated with ARBs during the 6 months preceding the study visit. Th e 12,483 eli-gible patients were diagnosed with arterial hypertensi-

on (according to ESC/ESH guidelines, 2007) and were treated with sartans 6 months before the enrollment. 45.4% were male and 54.3% were female (for 0.4% data were missing) and the mean age was 60.9 years. 24.8% of them were living in rural areas, while 73.7% were co-ming from urban environment, for 1.5% this data were missing.

Th e mean duration of the arterial hypertension was 6.3 years. Th e mean values of blood pressure (BP) regi-s tered at the study visit were: 153.6 mmHg (sistolic BP), 89.3 mmHg (diastolic BP), (with a maximul value of 280 mmHg for sistolic BP and 160 mmHg for diastolic BP).

Associated risk factors: 34.4% of the patients were smokers (for 0.8% data were missing); 73.7% had hyper-cholesterolemia (HC) (for 2.9% cholesterol was not de-termined and for 0.6% data were missing), and 52.8% hypertriglyceridemia (HT) (for 3.7% triglycerides were not determined and for 0.9% data were missing). 59.6% of the patients had abdominal obesity, defi ned as: > 102 cm for male and > 88 cm for female patients (for 1.6% was not determined, for 1% data were missing); 32.6% had diabetes mellitus (DM) type 1 or type 2 (for 2.7% unknown, for 0.9% data were missing) (Figure 2).

Many of the patients had target organ damage: 49.8% had left ventricular hypertrophy (ECG diagnosed) with 4.1% not determined (for 1.1% data were missing); 38% had retinopathy (for 1.7% data were missing). Prote-inuria (>300 mg/24 hours) was determined for 15.4% of the patients and it was present in 8.9% of the cases. Mean value of serum creatinine was 1.07 mg/dl; 8.8% of patients had chronic renal failure (for 2.4% data were missing).

Another important aspect was the high frequence of cardiovascular diseases in hypertensive patients in-

Figure 2. Percentages (%) of patients with associated risk factors: HC – hypercholesterolemia; HT – hypertriglyceridemia; DM – diabetes mellitus.



cluded in this study. 40.3% of the patients had history of coronary disease (angina pectoris and/or myocardi-al infarction), for 0.8% data were missing; 16.8% had history of cerebrovascular disease (stroke/transient is-chemic attack), for 1.7 data were missing; 13.9% had peripheral artery disease (for 9.3% was undetermined and for 0.9% data were missing), 11% of the patients had atrial fi brillation with 1.9% not determined and 25% had heart failure (10.3% with reduced ejection fraction and 14.7% with preserved ejection fraction), for 1.5% data were missing (Figure 3). Th e data regar-ding previous history of cardiovascular diseases were based upon the patients’ medical documents.

Blood pressure measurement was based on specifi c recommendations of the European Society of Hyper-tension 6; the methods used for BP monitoring in pa-tients with hypertension are represented in Figure 4, with the measure of blood presure in the clinic offi ce beeing performed at almost half of the patients.

Th e laboratory investigations and the search for sub-clinical organ damage are presented in Table 1.

The antihypertensive treatmentIn the 6 months before the enrollment in the study the recommended antihypertensive treatment was ARBs in 12,483 patients (100% as per inclusion criteria), ACE-Is in 1271 patients (10.2%), calcium channel blockers (CCB) in 3484 patients (27.9%), beta-blockers in 7063 patients (56.6%) and diuretics in 7178 patients (57.5%). ARBs were recommended as monotherapy in 15.9% and in combinations in 84.1% of the patients. At the study visit the treatment recommended was represen-ted by the following: ARBs in 12,467 patients (99.9%), ACEIs in 1201 patients (9.6%), CCB in 3537 patients (28.3%), beta-blockers in 4690 patients (37.6%) and di-uretics in 7164 patients (57.4%) of the patients.

As a profi le, the enrolled patients were hypertensives mainly comming from urban environment, had abdo-minal obesity and dyslipidemia, many of them were on combination therapy and the drugs most frequently associated to sartans were diuretics.

Th e compliance on ARBs treatment was evaluated in patients treated with ARBs at least 6 months before the enrollment by using an adapted MASRI (Medication Adherence Self-Report Inventory) questionnaire secti-on I (Table 2).

Medication Possession Rate (MPR) was evaluated in relation with the answers given to the last questions of the adapted questionnaire: What is the approximate per centage of the total ARB daily doses that you have been taking during the last month?Ta

ble

1. AB

I – A

nkle

Bra

chia

l Ind

ex, F

BG –

Fas

ting

Blo

od G

luco

se, T

C –

Tota

l Cho

lest

erol

, HDL

-C –

HDL

Cho

lest

erol

, LDL

-C -

LDL C

hole

ster

ol, T

G –

Trig

lyce

ride

mia

.

EKG

Echo

card

iogr

aphy

Opt

ic fu

n-du

s exa

mC

hest

radi

-og

raph

yA

BIFB

GTC

HD

L C

LDL

CTG

Alb

umin

uria

Seru

m

crea

tinin

eN

atre

mia

Kal

emia

Yes n

(%)

1218

6 (9

7.6%

)98

22 (7

8.7%

)96

81(7

7.6%

)78

95(6

3.2%

)55

38

(44.

4%)

1218

1 (9

7.6%

)12

097

(96.

9%)

1089

4 (8

7.3%

)10

676

(85.

5%)

1189

4 (9

5.3%

)64

11 (5

1.4%

)11

708

(93.

8%)

7452

(5

9.7%

)77

57

(62.

1%)

No

n (%

)23

8 (1

.9%

)24

06 (1

9.3%

)25

77(2

0.6%

)41

28

(33.

1%)

6158

(4

9.3%

)22

2 (1

.8%

)30

5 (2

.4%

)13

89

(11.

1%)

1575

(1

2.6%

)58

9 (4

.7%

)53

83 (4

3.1%

)60

9 (4

.9%

)44

04

(35.

3%)

4111

(3

2.9%

)

Miss

ing

data

n

(%)

59 (0

.5%

)25

5 (2

%)

225

(1.8

%)

460

(3.7

%)

787

(6.3

%)

80 (0

.6%

)81

(0.6

%)

200

(1.6

%)

232

(1.9

%)

068

9 (5

.5%

)16

6 (1

.3%

)62

7 (5

%)

615

(4.9

%)



According to the answers to this question, in 1912 (96.6%) of the patients who have been recommended ARB in monotherapy and in 10,136 (96.5%) of those with ARB in combinations, it has been registered a MPR above 80%, value considered the inferior level of ad herence to anti HTN therapy.

DISCUSSIONHypertension, defi ned as a systolic blood pressure (SBP) ≥140 mmHg and/or a diastolic blood pressure (DBP) ≥90 mmHg, is one of the most important pre-ven table causes of premature death worldwide, contri-buting to approximately half of all global cardiovascu-lar disease5. In many countries, up to 30% of adults have hy pertension; cardiovascular disease incidence doubles for every 10 mmHg increase in DBP or every 20 mmHg in crease in SBP20.

Blood pressure can be reduced either by lifestyle in-terventions or by pharmacotherapy to obtain the best outcome for the patient21.

Adequate measurement of BP is the most-important requirement for the diagnosis and treatment of pati-ents with suspected hypertension. Th e use of metho-dologies such as ambulatory and home BP monitoring have become powerful tools for defi ning the ‘real’ BP of patients.

An important issue reff ers to following the physician’s therapy by the patient. Nonadherence to antihyperten-sive treatment is a common problem in cardiovascular pre vention and may infl uence prognosis.

Data published in 2009 by Mazzaglia et al., on newly diagnosed hypertensive patients initially free of cardio-vascular diseases, obtained from 400 Italian primary care physicians, showed that only high adherence to

Figure 3. Percentages (%) of patients with associated cardiovascular diseases: CAD – coronary diseases;CVD - cerebrovascular diseases; PAD – peripheral artery diseases; AF - atrial fi brillation; HF – heart failure.

Figure 4. Percentages (%) of patients with BP determined by the following methods: missing data-MD; not determined-ND; self-determination-SD; self-determination +consulting room–SD+CR; self-determination +consulting room+24h monitoring-SD+CR+M; self-determination+24h monitoring- SD+M; consulting room- CR; consulting room+24h monitoring- CR+M; 24h monitoring- M.



treatment (proportion of days covered, ≥80%), signi-fi cantly decreased risk of acute cardiovascular events22. Adherence to prescription, investigated based on a qu-estionnaire in a female population aged 35-65 years in Sweden, revealed that age, scheduled check-up, percei-ved importance of medication, concerns about medi-cation safety and taking medication for a respiratory or a cardiovascular disease were signifi cantly related to adherence. Adherence ranged from 15-98% being the lowest among young women who regarded their me-dication as unimportant and who had no scheduled check-up and the highest among elderly women who regarded their medication as important and who had a scheduled check-up23. Adherence is better when the pa tient accepts the severity of his/her illness, trusts the therapist and believes in the eff ectiveness of the re commended therapeutic measures. Non-adherence

is, among other factors, negatively associated with the level of education. Another important factors infl uen-cing adherence include the aff ordability of the therapy and the susceptibility to adverse eff ects of drugs in in-dividual patients15.

ARBs adherence was previously studied evaluating persistence in newly diagnosed hypertensive patients who were initiated on irbesartan. Patients on irbesartan had statistically signifi cant higher persistence (of 60.8% for monotherapy and of 76.8% for either monothera-py or in combinations), followed by patients who were initiated on all other ARBs with a persistence rate of 51.3% (74.9% either as monotherapy or in combinati-on). Diuretics scored lowest with a persistence rate of 34.4% (65.5% either as monotherapy or in combinati-ons) at 1 year24.

Did you miss your daily dose of ARB yesterday? ARB in combination (n=10504) ARB monotherapy (n=1979) TotalNo 10,234 97.4% (a) 1930 97.5% (a) 97.4%Yes 188 1.8% (a) 40 2.0% (a) 1.8%I don’t know 44 0.4% (a) 6 0.3% (a) 0.4%No answer 38 0.4% 3 0.2% 0.3% Did you miss to your daily dose of ARB the day before yesterday? ARB in combination ARB monotherapy TotalNo 10,261 97.7% (a) 1939 98% (a) 97.7%Yes 102 1.0% (a) 21 1.1% (a) 1.0%I don’t know 68 0.6% (a) 13 0.7% (a) 0.6%No answer 73 0.7% 6 0.3% 0.6% Did you miss your daily dose of ARB three days ago? ARB in combination ARB monotherapy TotalNo 10,081 96% (a) 1883 95.1% (b) 95.8%Yes 144 1.4% (a) 30 1.5% (a) 1.4%I don’t know 204 1.9% (a) 59 3.0% (b) 2.1%No answer 75 0.7% 7 0.4% 0.7% How many daily ARB doses have you missed during last 2 weeks? ARB in combination ARB monotherapy TotalNo dose 9446 89.9% (a) 1781 90% (a) 89.9%1 dose 616 5.9% (a) 96 4.9% (a) 5.7%2 or more doses 114 1.1% (a) 30 1.5% (a) 1.2%I don’t know 225 2.1% (a) 62 3.1% (b) 2.3%No answer 103 1% 10 0.5% 0.9% When was the last time when you missed a daily dose of ARB ? ARB in combination ARB monotherapy TotalToday 215 2% (a) 28 1.4% (a) 1.9%Yesterday 140 1.3% (a) 27 1.4% (a) 1.3%Th is week 265 2.5% (a) 47 2.4% (a) 2.5%Last week 617 5.9% (a) 92 4.6% (b) 5.7%Less than 1 month ago 334 3.2% (a) 54 2.7% (a) 3.1%More than 1 month ago 511 4.9% (a) 75 3.8% (b) 4.7%Never 7496 71.4% (a) 1515 76.6% (b) 72.2%I don’t know 832 7.9% (a) 130 6.6% (b) 7.7%No answer 94 0.9% 11 0.6% 0.8%

Table 2. Adapted MASRI type auto-evaluation questionnaire section I; (a) and (b) denotes a subset of categories which column proporti-ons differ (a/b) or do not differ (a/a) signifi cantly from each other at the 0.05 level.



In a more recent study adressing persistence with antihypertensive treatments for a period of 3 years, Hasford et al. concluded that persistence diff ers mar-kedly among the drug classes (p≤0.001) but even per-sistence of the best drug class is not suffi cient to provide an adequate blood pressure control in the population. Th e largest decline in persistence occurs in the fi rst 3 mo nths of treatment. In our study the patients were al-ready persistent on ARB treatment for 6 months, aspect which may explain the high level of compliance.

In Hasford at al. study, persistence with the initi-ally prescribed antihypertensive treatment was signifi -cantly diff erent (p<0.001) and longest for patients who-se initial prescription was for a free combination based on ACEIs, followed patients initially receiving a fi xed combination, including ARBs and ARBs monotherapy. Persistence was shortest with diuretics25.

Our study was addressing compliance and show high compliance rate to ARBs in a population persistent on this treatment for at least 6 months and also demons-trate that urban environment, possibly in relation with the level of education, and history of coronary disease are positively corelated with adherence to ARBs. None of the other factors including age, gender, hypertension duration, history of cerebrovascular diseases, diabetes mellitus or heart failure infl uenced signifi cantly the adherence to ARB treatment in our study.

Th e comparison between the answers to adapted MASRI questionnaire given by the group of patients with ARBs monotherapy vs. ARBs in combinations has been performed using Chi-Square Test. Diff erences statistically signifi cant between these subgroups have been identifi ed for the patients who didn’t miss (higher % in combination group) and those who didn’t know if they missed (higher % in monotherapy group) the daily dose of ARB 3 days before, for those who didn’t know how many daily ARB doses have missed during last 2 weeks (higher % in monotherapy group), and for those for whom the last day when they missed a daily ARB dose was last week or more than a month before (higher % in combination group), or never (higher % in monotherapy group) or who didn’t know the answer (higher % in combination group).

Our study was based on a questionnaire fi lled in by patients. An aspect that should be considered is that phy sicians generally overestimate the level of adheren-ce to therapy. Poor adherence should be suspected in those whose blood pressure appears resistant to treat-ment. Monitoring prescription refi lls and pill-counting are of value when nonadherence is suspected but can

be unreliable in patients who wish to avoid admitting their failure to adhere to prescribed regimens26.

A limitation of this retrospective registry is that the concept of adherence was separated in two parts – per-sistence being part of the inclusion criteria and compli-ance part of the primary objective and the purpose of the registry was to analyse the compliance with ARBs treatment in an already persistent population. Ano-ther limitation is that medication adherence appeared to be higher when measured using self-reported que s-tionnaires than when measured using electronic mo-n itoring devices. Th is questionnaires are subject to measurement bias such as social desirability, recall bias and response bias17. Th ere are mixed reports about the accuracy of self reported adherence, compared with the Medication Event Monitoring System –monitored adherence. MASRI questionnaire used in our study is one of the most commonly used and have shown good validity with Medication Event Monitoring System.

CONCLUSIONSOur study showed a very good compliance with ARB treatment in hypertensive patients persistent on ARB treatment for 6 month, in ambulatory practice. Th e le-vel of Medication Possession Rate (MPR) above 80%, has been registered in 96.5% of the patients with ARBs treatment, even in monotherapy or in combinations.

Th e following factors potentially associated with compliance with ARB therapy have been evaluated for those sub-groups of patients (ARB monotherapy and in combinations): age (with 50 years as threshold), gen-der, living environment (urban / rural), hypertension duration, history of coronary or cerebrovascular disea-ses, diabetes mellitus and heart failure. None of these individual factors infl uenced signifi cantly the compli-ance with ARB treatment.

In the subgroup of patients with ARBs monothera-py the potential factors evaluated did not signifi cantly infl uence patients compliance with the recommended treatment. In the subgroup of patients with ARBs in com binations urban environment determined signifi -cantly higher compliance than rural environment (RR = 1.093, CI = 1.018-1.173).

Th e logistic regression calculation (taking into acc-ount all these potential factors simultaneously) iden-tifi ed that patients living in urban area (p=0.017) and those with history of coronary disease (p=0.025) have a signifi cantly better treatment compliance with ARB treatment.



Th is research was funded by Sanofi .

Confl ict of interests:D.Gherasim: Speaker fees from Novartis and Les Labo-ratoires Servier for case presentationsM. Iurciuc: None declared.Cristina Voiculet: Speaker fees from Astra Zeneca for case presentationsAlina Giucă: Speaker fees from Novartis, Les Labora-toires Servier and Astra Zeneca LTD for case presen-tationV. Petrescu: Speaker fees from Astra Zeneca, Boehrin-ger-Ingelheim and KRKA for case presentationsF. Maghiar: None declared.Alexandra Gherghină: Speaker fees from Astra Zene-ca, Les Laboratoires Servier and Berlin Chemie for case presentationsA.Tase: Research fees from Les Laboratoires Servier, Sanofi and NovartisCarmen Ginghină: None declared.

References1. Th e World health statistics - Geneva 2012 report http://www.who.int/

mediacentre/news/releases/2012/world_health_statistics_20120516/en/index.html

2. Dorobanţu M, Darabont R, Ghiorghe S, Babes K, Pop D, Toma D, Vasilescu M, Dobreanu M, Tăutu O. Profi le of the Romanian Hyper-tensive Patient Data from SEPHAR II Study. Rom. J. Intern. Med., 2012, 50, 4, 285-296.

3. Ginghină C, Popescu B, Șerban M, et al.Th e Prevalence of hyperten-sion and left ventricular hypertrophy in a Romanian population. A clinical – echocardiographic study. J. Hypertension, vol.22, suppl 2, June 2004, S307.

4. Apetrei E, Kulcsar I, Stănescu Cioranu Rodica, Matei C, Cochino E, Ginghină C. Studiul Urziceni-Studiu populaţional retrospectiv de de-pistare a factorilor de risc pentru bolile cardiovasculare și intervenţie în populaţie, depistarea precoce a bolilor cardiovasculare. Revista Ro-mână de Cardiologie, vol.XXIII, Nr.2, 2008, p.136-145.

5. Kjeldsen S, Aksnes T, Fagard R, Mancia G. Hypertension in Th e ESC Textbook of Cardiovascular Medicine (2 ed.), edited by Camm AJ, Luscher T, Serruys P, Oxford University Press 2009.

6. 2007 Guidelines for the management of arterial hypertension Euro-pean Heart Journal 2007; 28: 1462-1536.

7. Sever PS, Messerli FH. Hypertension management 2011: optimal com bination therapy. European Heart Journal 2011p; 32: 2499-2506.

8. Kobori H, Nangaku M, Navar LG, Nishiyama A. Th e Intrarenal Re-nin-Angiotensin System: From Physiology to the Pathobiology of

Hypertension and Kidney Disease. Pharmacol Rev 2007; 59:251-287.9. Wong J, Patel RA, Kowey PR. Th e clinical use of angiotensin-conver-

ting enzyme inhibitors. Prog Cardiovasc Dis 2004; 47:116-130.10. Blood Pressure Lowering Treatment Trialists’ Collaboration. Eff ects

of diff erent blood-pressure-lowering regimens on major cardiovascu-lar events: results of prospectively-designed overviews of randomised trials. Lancet 2003; 362:1527-1535.

11. Staessen JA, Wang JG, Th ijs L. Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003. J Hypertens 2003; 21:1055-1076.

12. Messerli F, Williams B, Ritz E. Essential hypertension. Lancet 2007; 370:591-603.

13. Burnier M. Medication adherence and persistence as the cornerstone of eff ective antihypertensive therapy. Am J Hypertens. 2006;19:1190-1196.

14. Van Wijk BLG., Klungel OH, Heerdink ER, de Boer A. Rate and det e-r minants of 10-year persistence with antihypertensive drugs. J Hyper-tens 2005;23:2101-7.

15. Laufs U, Rettig-Ewen V, Böhm M. Strategies to improve drug adhere-nce. European Heart Journal 2011; 32: 264-268.

16. Cramer JA, Roy A, Burrell A, Fairchild CJ, Fuldeore MJ, Ollendorf DA, Wong P K. Medication Compliance and Persistence: Terminolo-gy and Defi nitions. Value in health 2008;11:44-47.

17. Oster berg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487-497.

18. Ho P. M., Bryson C. L., Rumsfeld J. S. Medication Adherence Its Im-portance in Cardiovascular Outcomes. Circulation. 2009;119:3028-3035.

19. Shi L, Liu J, Koleva Y, Fonseca V, Kalsekar A, Pawaskar M. Concor-dance of Adherence Measurement Using Self-Reported Adherence Questionnaires and Medication Monitoring Devices. Pharmacoeco-nomics 2010; 28 (12): 1097-1107.

20. Lewington S, Clarke R, Qizilbash N, et al. Age-specifi c relevance of usual blood pressure to vascular mortality: a meta-analysis of indi-vidual data for one million adults in 61 prospective studies. Lancet 2002; 360:1903-13.

21. Ruilope L. M. Current challenges in the clinical management of hy -pertension. Nat. Rev. Cardiol. 2012; 9:267-275.

22. Mazzaglia G, Ambrosioni E, Alacqua M, Filippi A, Sessa E, Immordi-no V, Borghi C, Brignoli O, Caputi AP, Cricelli C, Mantovani LG. Ad-herence to Antihypertensive Medications and Cardiovascular Mor-bidity Among Newly Diagnosed Hypertensive Patients. Circulation 2009;120:1598-1605.

23. Bardel A,Wallander MA, Svardsudd K. Factors associated with adhe-rence to drug therapy: a population-based study. Eur J Clin Pharma-col 2007;63:307-314.

24. Hasford J, Mimran A, Simons WR. A population-based European co-hort study of persistence in newly diagnosed hypertensive patients. Journal of Human Hypertension 2002; 16: 569-575.

25. Hasford J, Schröder-Bernhardi D, Rottenkolber M, Kostev K, Dietle-in G. Persistence with antihypertensive treatments:results of a 3-year follow-up cohort study. Eur J Clin Pharmacol 2007; 63:1055-1061.

26. Chobanian AV. Impact of Nonadherence to Antihypertensive Th era-py. Circulation 2009;120:1558-1560.


ORIGINAL ARTICLE

The study of vascular reactivity in the ascending aorta after aortic coarctation corrective surgeryIoana Adriana Ghiorghiu, Mădălina Elena Iancu*, Marinela Şerban, Carmen Ginghină

Contact address:Ioana Ghiorghiu, MD, “Prof Dr C.C. Iliescu” Institute of Emergency for Cardiovascular Diseases, Sos Fundeni No. 258, 022322, Bucharest.E-mail: [email protected]

”Prof. Dr. C.C. Iliescu” Emergency Institute for Cardiovascular Diseases, Bucharest* "Regina Maria" Private Healthcare Network

Abstract: Premises – Th e elastic structure of the aorta permits it to act as a conduct for the cardiovascular system1. Its elastic properties moderate the left ventricle’s performance and help regulate the coronary fl ow. Patients undergoing aortic coarctati-on (AoCo) surgery suff er from a change in elasticity of the ascending aorta, favoring early atherosclerotic change2. Th is change of the vascular elasticity can be assessed using the elasticity indices: aortic strain, distensibility and stiff ness. A change in the aortic elasticity parameters consequently determines hemodynamic changes, as well as alterations to the dimensions of the ascending aorta in patients who underwent AoCo corrective surgery. Materials and methods – 23 patients who underwent surgery for AoCo were included in the study, with a proper correction, supported by clinical and echocardiographic data. Th e control lot consisted of 20 healthy subjects. Th e two lots had a similar structure regarding age and sex. Th e vascular reactivity was assessed by aortic strain, distensibility and stiff ness measured with TTE according to classic formulas. Results – Patients who underwent AoCo surgery presented modifi cations of the vascular reactivity indexes of the ascending aorta, respectively decreased distensibility capacity (p<0,001), reduced aortic strain (p<0,001), increased aortic stiff ness (p<0,001) compared to the control lot. Th e dimensions of the ascending aorta are statistically signifi cant greater, compared to a control lot consisting of healthy subjects. Conclusions – Assessment of vascular reactivity in the ascending aorta in patients who achieved correc-tion of Ao Co shows a more rigid ascending aorta with diminished elasticity and distensibility, compared to a control group of healthy subjects. Th e elastic properties were highlighted by the assessment of classical vascular reactivity indices (stiff ness, aortic strain and distensibility). Th e ascending aorta shows higher dimensions that are likely due to altered vascular reactivity at this level.Keywords: Aortic coarctation, vascular reactivity, aortic strain, distensibility, stiff ness, ascending aorta size

Rezumat: Premize – Artera aortă are o structură elastică care îi conferă o funcţie de conduct la nivelul aparatului cardiovas-cular1. Datorită proprietăţilor elastice contribuie la reglarea performanţei VS și a fl uxului coronarian. Pacienţii cu coarctaţie de aortă (Co Ao) operată prezintă o modifi care a funcţiei elastice a aortei ascendente care predispune la modifi cări aterosclerotice precoce2. Această modifi care a elasticităţii vasculare poate fi evaluată cu indicii de elasticitate: strain aortic, distensibilitate, rigiditate. Modifi carea parametrilor de elasticitate aortici determină modifi cări ale hemodinamicii sanguine la acest nivel dar și ale dimensiunilor aortei ascendente la pacienţii post corecţia Co Ao. Material și metodă – Au fost luați în studiu un număr de 23 pacienți cu coarctație de aortă operați cu datele clinice și ecocardiografi ce ale unei corecţii bine realizate și un lot con-trol de 20 subiecţi sănătoși, cele două loturi având o structură asemănătoare ca vârsta și sex. Rezultate – Pacientii cu Co Ao operată au avut indici de reactivitate vasculară la nivelul aortei ascendente modifi caţi, respectiv distensibilitate aortică redusă (p<0,001), strain-ul aortic redus (p<0,001), rigiditate aortică crescută (p<0,001) comparativ cu lotul martor. Dimensiunile aortei ascendente post corecţia Co Ao sunt semnifi cativ statistic mai mari comparativ cu un lot martor de subiecți sănătoși. Concluzii – Evaluarea reactivităţii vasculare la nivelul aortei ascendente la pacienţii la care s-a realizat corecţia unei coarctaţii de aortă evidenţiază o aortă ascendentă mai rigidă, cu elasticitate și distensibilitate diminuate. Aceste proprietăţi elastice au fost evidenţiate prin determinarea indicilor clasici de reactivitate vasculară (strain aortic, rigiditate și distensibilitate). Aorta ascendentă prezintă dimensiuni crescute care sunt cu mare probabilitate determinate de reactivitatea vasculară modifi cată de la acest nivel.Cuvinte cheie: Coarctaţie de aortă, reactivitate vasculară, strain aortic, distensibilitate, rigiditate, dimensiuni aortă ascendentă


Ioana Ghiorghiu et al.Vascular reactivity after repair of coarctation of the aorta

INTRODUCTIONAoCo is a congenital heart disease benefi ting from sur-gical correction since 19443 and interventional angio-plasty since 19824. In this time frame, a large number of patients survived correction, representing a part of the “grown-up congenital heart disease” population. Stu-dies conducted on these patients have revealed a wide spectrum of cardiovascular comorbidities, even in ca-ses with a good anatomical result at the isthmic region.

Studies published in the literature have not succee-ded in positively identifying the factors leading to post-correction complications. If the age of correction and a bicuspid aorta were documented by several studies6, the data for the other parameters (correction method, the remaining gradient in the itshmic region, the an-kle-arm index) is contradictory. A new factor consi-dered of great importance in the development of post-correction complications is currently investigated - the ascending aorta’s vascular reactivity.

Previous studies have shown an early vascular re-modeling of the ascending aorta6 and of the vascular territory preceding the isthmic region. Vascular remo-deling includes a modifi ed vascular reactivity and an increase of intima media thickness at the level of the great arteries’8,9. Th e studies have revealed a more sti-ff er aorta, with a decreased elasticity, leading to aortic di latation as the patient ages6,10. Th is modifi ed vascular reactivity has been identifi ed even in newly born babies and infants and it is detectable before the intervention and remains partially stable, even when the correction is succesfull11. Th e change in vascular reactivity seems to be the determining cause of post corrective surgery complications8,9,11,12. It has been proven that the chan-ges of vascular reactivity leads to the increase of car-diovascular risk and early atherosclerosis. Identifying these problems at the level of the ascending aorta lead to a new vision of AoCo, which is no longer regarded as an isolated problem of the aortic isthm, but rather a ge neralized problem of the precoarctation vascular te-rri tory14.

MATERIALS AND METHODSTh e study of vascular reactivity in the ascending aorta has been conducted on a lot consisting of 23 patients treated for AoCo (21 patients with surgical correction and 2 patients who underwent balloon angioplasty) (Ta ble 1). Th ey were admitted between 2001 and 2007 in ”Prof. Dr. C.C. Iliescu” Emergency Institute for Car-diovascular Diseases. Th e study also had a control lot of 20 healthy subjects with a similar distribution regar-d ing sex and age to the ones present in the study lot.

Inclusion criteria: An interventional or surgical correction for AoCo Clinical criterion of a successful correction - nor-

mal pulse amplitude at the femoral arteries Echocardiographic criterion for a good correcti-

on - velocity in the ascending aorta <3 m/s and the absence of anterograde diastolic fl ux (diastolic tail)

Normal blood pressure values with/without anti-hypertensive drugs

Exclusion criteria: Signifi cant aortic insuffi ciency (>IIIrd degree ac-

cor ding to the echocardiographic classifi cation Aortic stenosis Aortic metallic prosthesis Arterial hypertension (patients without treatment

or with uncontrolled values under treatment) Signifi cant stenosis (post-corrective gradient >30

mmHg)Th e patients were excluded because we considered

that they present lesions accompanied by signifi cant he modynamic alterations, infl uencing the vascular ela-sti city parameters calculated for the ascending aorta.

Analyzing the male/female ratio we notice a slight pre ponderance of the male patients. Th e BP values were signifi cantly higher in patients who underwent co rrective surgery for AoCo, compared to healthy sub-jects (p<0.05 but were within normal limits for all the pa tients enrolled in the study).

Th e parameters parameters for vascular reactivity of the ascending aorta:

Th e following classic aortic elasticity indices were measured15: Aortic strain = 100 (Ao S - Ao D)/Ao D Aortic distensibility index = (2(Ao S – Ao D)/Ao

D(PP)) (10-6cm2dyne-1) Aortic stiff ness index (SI) = ln (SBP/DBP)/ ((Aos

– AoD)/AoD)Th e dimensions of the aorta were: AoS - systolic di-

ameter, AoD - diastolic diameter (as measured in 2D guided M mode, 3 cm above the aortic valve, Ao D measured at the peak of the R wave, with a simultaneo-us EKG, Ao S measured at the maximum anterior mo-vement of the aortic wall) (Figure 1). Th e values of the blood pressure are represented by SBP = Sistolic blood pressure, DBP = diastolic blood pressure - values mea-sured at the right arm.

Th ere are few papers in the literature studying the elastic function of the aorta post AoCo corrective sur-gery, using these parameters7,11,14.



Th e echocardiographic examination was performed with an Aloka Alpha 10 Prosound (Aloka Japan) devi-ce. Th e echocardiographic images were recorded si-mu l taneously with an EKG signal, with at least 3 sinus rhy thm cardiac cycles being recorded, using the medi-an value of the measurements. Th e patients were exa-mined in left lateral decubitus postion, with a 4MHz trans ducer.

Th e aortic elasticity parameters were determined by using an echocardiography transducer set for M mode examination guided by a 2D image (we considered it necessary to place the M mode perpendicularly on the long axis of the ascending aorta in order to measure the maximal diameters)14. Th e patient was placed in left la-teral decubitus and a long parasternal axis section was performed. Th e following parameters were measured in M mode section, placed 3 cm above the aortic ring, using the “edge to edge” technique: AoS – the systolic diameter of the ascending aor-

ta - it is measured at the point of the maximum anterior movement of the aortic wall

AoD – the diastolic diameter of the ascending aorta - it is measured at the end of the diastole, co rresponding to the Q wave on the EKG

Th e dimensions of the ascending aorta and of the aortic arch were measured from the suprasternal view, also from this view were measured the dimensions of the great vessels. Th e dimension of the abdominal aorta was measured from the subcostal view. Blood pressure was measured on the right arm, im mediately aft er the beginning of the echocardiographic examination. An aneroid capsule sphygmomanometer was used, with an adequately sized cuff for the arm’s width (the width of the cuff >2/3 of the diameter of the arm). Th e ausculta-tion method was employed.

Th e statistic analysis of the data was performed by using SPSS soft ware, v. 14.0 for Windows. Th e data was presented in percentiles and as median values ± stan-dard deviation (SD) for the continuous variables. Th e diff erences between the diff erent group’s median values were compared by using the t test for independent va-riables, the Mann – Whitney U, or Wilcoxon test. A p <0.05 was considered to be statistically signifi cant and a p<0.01 was considered highly signifi cant.

RESULTSDiff erent measurements of the aorta were performed at various levels, as well as measurements of the origins of the large vessels emerging from the ascending aorta: Th e aortic ring Th e aorta at the level of the Valsalva sinuses Th e ascending aorta 3 cm from the aortic ring, in

a parasternal long axis Th e aortic cross (before the origin of the left com-

mon carotid artery) Th e descending aorta, below the isthmic region Th e abdominal aorta Th e origin of the left common carotid artery Th e origin of the left subclavian arteryTh e values obtained through 2D measurements were

considered in relation to the corporeal surface. Th e me-dian values obtained were indexed with the corporeal surface and are presented in Table 2, compared to the values recorded for the control lot:

Th e dimensions of the aorta were signifi cantly hig-her at the level of the aortic ring (11+/-1,5 mm/m2

Table 1. The characteristics of the study lot

Patients (n=23) Control lot (n=20) pAge (years) 28,65±9,98 29,70±10,92 0,789Sex (M/F) 17/6 12/8 0,337Systolic BP (mmHg) 123,04±13,63 114,50±13,56 0,034Diastolic BP (mmHg) 75,22±11,63 73,00±10,81 0,300Corporeal surface (m²) 1,81±0,21 1,79±0,21 0,826

Figure 1. Measuring the aortic dimensions in 2D guided M mode, in order to calculate the elasticity parameters of the ascending aorta. Th e M mode section is perpendicular to the long axis of the ascending aorta. Th e AoS andthe AoD are measured.



versus 9,9 +/- 0,8 mm/m2), the ascending aorta (3 cm above the aortic ring), (17,3 +/- 5,6 mm/m2 versus 13,4 +/- 1,8 mm/m2) and abdominal aorta(9±1,99 mm/m2 versus 7,24±1,34 mm/m2) in patients suff ering from AoCo, compared to the healthy subjects. Th e dimensi-ons measured at the level of the Valsalva sinuses were also higher, but the p value was not statistically signi-fi cant.

Th e values obtained for the aortic cross in patients who underwent surgery were smaller than the ones ob-tai ned for the control lot, but without any statistic sig-nifi cance. Higher values (statistically signifi cant) were obtained at the origin of the great vessels (left subcla-vian artery, left common carotid artery), starting from the aortic cross in patients with surgically corrected AoCo, compared to the control lot.

Th e elasticity indices of the ascending aorta for pa-tients operated for AoCo were compared to elasticity indices obtained from the ascending aorta of healthy subjects. Th e results are presented in Table 3.

Th e distensibility and aortic strain indices are sta-tistically signifi cant lower in the ascending aorta and stiff ness indices are statistically signifi cant higher in patients, compared to the control lot, contouring the picture of a less elastic, less distenssible, but stiff er as-cending aorta.

Th e correlation between the dimensions of the ascen-ding aorta and aortic elasticity indices

A correlation between the dimensions of the aorta measured as previously mentioned and the vascular reactivity indices (calculated by using unanimously ac-

Table 2. The dimensions of the aorta and of the great vessels originating from the aorta

Aortic artery diameters indexed with the corporeal surface Patients operated for AoCo Control lot p

Aortic ring (mm/m²) 11±1,5 9,9±0,8 0,004Aorta - Valsalva sinuses (mm/m²) 18,5±5,8 15±1,8 0,01Ascending aorta (mm/m²) 17,3±5,6 13,4±1,8 0,003Aortic cross 10,73±2,19 11,38±1,94 0,400Left common carotid artery - origin (mm/m²) 3,46±0,67 2,94±0,35 0,003Left subclavian artery – origin (mm/m²) 5,27±1,35 4,78±1,02 0,005Descending aorta (mm/m²) 9,00±2,06 8,02±1,29 0,100Abdominal aorta (mm/m²) 9,00±1,99 7,24±1,34 0,002p <0.01 statistically significantp <0.005 highly statistically significant

Table 3. Vascular reactivity indices

Patients Control lot pAortic distensibility (10-6 cm²dyne-1)(Ao dis) 3,97±2,44 11,44±5,97 <0,001

Ao strain (%) 9,17±6,20 23,85±11,16 <0,001Aortic stiff ness (aortic stiff ness)(AoSI) 10,17±6,17 2,19±0,89 <0,001

Table 4. The correlation between the dimensions of the ascending aorta and aortic elasticity indices

Aortic distensibility Aortic strain Aortic stiff ness Aorta - ring -,492(**) -,477(**) ,630(**)Aorta - Valsalva sinuses -,607(**) -,585(**) ,704(**)Ascending aorta -,595(**) -,565(**) ,700(**)Aortic cross -0,14 -0,11 0,13Left common carotid artery – origin (mm/m²) -,402(**) -,427(**) ,408(**)Left subclavian artery – origin (mm/m²) -0,23 -0,2 0,21Descending aorta (mm/m²) -0,24 -0,24 0,24Abdominal aorta (mm/m²) -0,23 -0,21 0,29*p <0.05 – statistically significant**p <0.001 – highly statistically significant



cepted formulas - distensibility, aortic strain and aortic stiff ness) was done in order to obtain an objective view of the infl uence of the modifi ed aortic vascular reac-tivity on the dimensions of the ascending artery. Th e results are presented in Table 4.

Th e dimensions of the aorta at level of the aortic ring, Valsalva sinuses and ascending aorta negatively correlate with aortic distensibility and aortic strain (a less distensible aorta is larger at the level of the aortic ring), but is positively correlated to the aortic stiff ness (a more rigid aorta has greater dimensions measured at the aortic ring). All 3 correlations have p <0.001. A negative correlation is suggested between the dimensi-ons of the aorta at the aortic cross and distensibility and aortic strain. A positive correlation is suggested betwe-en the afore mentioned dimensions and the aortic sti-ff ness, both without statistically signifi cant indices. Th e aortic cross was the only segment of the aorta which had smaller dimensions in patients who underwent corrective surgery for AoCo, compared to the central lot, revealing once more a degree of hypoplasia of the aortic cross in these patients. Th e left common carotid artery negatively correlates with the distensibility and aortic strain indices and a positive correlation with the aortic stiff ness index, with p <0.001. We can conclude that the less distensible, more stiff er aortic pattern is maintained in the left common carotid artery. Th e same types of correlations are present in the descending and abdominal aorta, as well as in the left subclavian artery, without statistically signifi cant p values. Moreover, for these last results, it is important to mention and dis-cuss the fact that the thoracic descending aorta and the abdominal aorta represent the aortic territory situated below the coarctation, with a diff erent vascular reacti-vity. Th e left subclavian artery has its own particularity, as the main source for collateral circulation. Its dilata-tion is owed mostly to the increased preoperatory debit and less to the vascular reactivity changes.

DISCUSSIONSPrevious studies published in the literature have shown the presence of an early vascular remodeling in the ascending aorta7,11,14 and in the precoarctation vascu-lar territory. Vascular remodeling includes an altered vascular reactivity and the increase of the intima me-dia thickness of the endovascular layer of the large vessels8,9. Studies revealed a more stiff er aorta, with de creased elasticity, resulting in a tendency to dilate in time10,11. Th is modifi ed vascular reactivity was identi-fi ed beginning with infants7, it is present before the cor-

rection and remains partially unmodifi ed even when the corrective surgery was successful11. Th e changes in vascular reactivity seem to be the determining cause of most postsurgery complications8,9,11,12.

Vascular reactivity indices have presented the follow-ing particularities in patients who underwent correcti-ve surgery for AoCo: Distensibility (3,97±2,44 10-6cm2dyne-1 in patients

with AoCo versus 11,44 ± 5,72 10-6cm2dyne-1 in healthy subjects) and aortic strain (9,17±6,2% in patients with AoCo versus 23,85±11,16% in healthy subjects) registered lower values than normal, thus the capacity of the ascending aorta to expand itself and store kinetic energy at the moment of impact with the blood pumped by the heart during the systole is low.

Aortic stiff ness registered increased va lu es (10,17 ± 6,17 in patients with AoCo versus 2,19 ± 0,89 in healthy subjects), characterizing a more stiff er aorta, probably secondary to the particular anato-mical structure.

Th e results of this study show that the vascular re-activity indices characterizing the elastic nature of the ascending aorta are modifi ed even in cases with a good correction of the isthmic lesion. Th e modifi cations in the elastic properties of the ascending aorta change the hemodynamic behavior at this level and infl uences BP, velocity and the irrigation pattern of two very impor-tant arterial territories: the carotid and the coronary systems. Th e modifi ed elasticity parameters in the as-cending aorta determine an increase of the vascular resistance in the precoarctational territory. We can conclude that the aft er load of the LV, which is much higher before the correction, decreases - but does not return to normal values aft er corrective surgery. Th is might be one of the factors determining the persistence of increased BP values, despite a good anatomical result aft er the correction of an AoCo8.

Considering the vascular reactivity of the arterial system in patients with corrected AoCo it seems to be divided in two segments with particular reactivity: the more rigid, less elastic precoarctation segment and the post coarctational segment, with a normal vascular re-activity. Th e two segments react diff erently during an eff ort, determining a dynamic tightening of the isthmic region, even in cases with a good anatomical correcti-on11. Th is could partially explain the persistence of high BP values aft er corrective surgery, especially during an eff ort. On the other hand, constantly increased blood pressure values can determine the fragmentation of the



elastin fi bers from the media layer and changes in the intima layer, determining early atherosclerotic lesions. Hence, increased blood pressure values can be both ca-use and eff ect of the modifi ed vascular reactivity.

Th e modifi ed vascular reactivity has long term con-sequences on the function of the LV (both the systolic and diastolic components)13 and on the irrigation of the myocardium via the coronary arteries. Th ese con-sequences appear as a result of the modifi cation indu-ced in the blood velocity and in the behavior of the re-fl ected wave. Th e residual hypertrophy of the LV walls can be partially explained by the increased stiff ness and decreased distensibility12.

Histology studies conducted on aortic tissue samples obtained from the AoCo resection area have revealed a larger quantity of collagen and a smaller quantity of smooth muscle fi bers in the precoarctation area of the aorta, than in the area located below the coarctation16. Th ese histological modifi cations are the basis of the functional changes previously described and have led to the conclusion that this arterial malformation is a generalized arteriopathy of the precoarctational area and not just an anomaly located in the isthmic region. Th is global approach of the precoarctational arterial system could better explain the complications connec-ted to the arterial wall (aneurysms, early atherosclero-tic lesions, aortic dissection) and the early age of debut, compared to the general population.

Th e median age of the patients in the lot for which vascular reactivity was studied was 28.65±9.98 years. Th is is an age characterizing a young population, but with a series of complications connected to the arterial wall, associating increased intima median thickness of the carotid, a subclinic marker of atherosclerotic lesi-ons. Th e median age for the diagnosis of vascular re-activity changes raises the valid question of what is the age for the onset of these reactivity modifi cations. Th e-re are studies conducted on lots of newly-born babies and infants, suff ering from AoCo, pre and post opera-tory7, which have demonstrated that even infants have preoperatory changes of the vascular reactivity. Th ese modifi cations persist in the postoperative period. Th e described modifi cations are similar to those described by the present study, respectively reduced elasticity, re-duced distensibility and an increased stiff ness.

Considering the fact that these parameters can be measured with an echocardiograph which does not re quire supplementary programs and the validation through various studies of these indices obtained by transthoracic echocardiogram (non-invasive method)

we can ask ourselves as cardiologists whether or not these indices could be determined in series for these patients, in order to quantify the risk of complications connected to the arterial wall. Th e vascular reactivity indices (distensibility, strain and stiff ness) proved to be useful in long term care of patients suff ering from Marfan syndrome, with a greater capacity of prediction regarding the risk of dissection and aortic rupture than the dimensions of the aorta13. In patients suff ering from Marfan syndrome it has been demonstrated that aortic dissection can appear even in patients who do not pre-sent a signifi cant dilatation of the ascending aorta, but have altered vascular reactivity indices.

Th e dimensions of the ascending aortaAltered elasticity properties of the ascending aorta

modify not only the hemodynamic behavior at this le-vel, but also the dimensions of the ascending aorta11,14,17.

In patients suff ering from AoCo the aorta is more di-lated at the aortic ring (11±1.5 mm/m2 corporeal surfa-ce for patients versus 9.4±0.8 mm/m2 corporeal surface for healthy subjects), Valsalva sinuses (18,5±5,8 mm/m² corporeal surface for patients versus 15±1,8 mm/m2 corporeal surface for healthy subjects) and ascending aorta 17,3±5,6 mm/m2 corporeal surface for patients versus 13,4±1,8 mm/m2 corporeal surface for healthy subjects). Th ese increased dimensions can be the con-sequence of modifi cations in the media layer, which has a small number of smooth muscle fi bers and a lar-ger number of collagen fi bers which suff er a degradati-on process over time, leading to a progressive dilatation at this level11. Th is takes us to the conclusion that the aortic dilatation present at the aortic ring and ascen-ding aorta are secondary to the particular histological structure of the ascending aorta and not a consequence of the associated aortic valve lesions.

Th e histological basis of the anatomic modifi cations is represented by a particular structure of the ascend-ing aorta, especially in the aortic media layer, which contains elastic fi bers with a particular structure, with a reduced capacity of elastic recoil at the moment of impact with the blood, permitting a gradual plastic de-formation of the ascending aorta17. Th e same type of histological structures of the ascending aorta is descri-bed in several affl ictions: Marfan syndrome, bicuspid aortic valve, aortic coarctation). Th ere are no histologi-cal and genetic comparative studies for these diseases. Such studies could have revealed whether or not the microscopic anatomic structure is identical and if the determining genetic modifi cation is similar. However,



several studies have succeeded in creating an objective view of the functional behavior of the ascending aorta, which is similar in all of these patients7,11.

Th is study has identifi ed statistically signifi cant mo-difi cations in the size of the left common carotid ar-tery (3.46±0.67 mm/m2 corporeal surface for patients versus 2.94±0.35 mm/m2 corporeal surface for healthy subjects) and left subclavian artery (5.27±1.35 mm/m2 corporeal surface for patients versus 4.28±1.02 mm/m2 corporeal surface for healthy subjects). In the case of the left subclavian artery the dilatation at the point of origin can be explained by the fact that it is the so-urce of the collateral circulation and its dilatation is a characteristic of AoCo. However, the persistence of this dilatation aft er the correction of the lesion can only be partially explained in this manner. Th is dilatation is most likely owed to the particular anatomical structure of the precoarctational arteries. Th e origin of the left common carotid artery is more dilated in patients than in the control lot, further supporting the idea that the precoarctational arteries have a particular anatomical structure, favoring a progressive dilatation of the vessel at this level, despite a successful correction.

CONCLUSIONSTh e evaluation of the elastic properties of the ascen-ding aorta has shown a more stiff er (aortic stiff er in pa-tients 10.17±6.17 versus 2.19±0.89 in healthy subjects, p <0.001), less distensible (distensibility in patients 3.97±2.44 10-6 cm2dyne-1 versus 11.44±5.92 10-6 cm2dy-ne-1 in healthy subjects, p <0,001) aorta, with a dimi-nished elasticity (aortic strain in patients 9.17±6.20% versus 23.85±11.16% in healthy subjects, p <0.001) af-ter the correction of the AoCo.

An increase in the dimensions of the ascending aor-ta appears secondary to the changes in the vascular re-activity.

Th e evaluation of the ascending aorta’s elastic pro-perties by the determination of vascular reactivity re-presents the transition to the direct functional evaluati-on of the ascending aorta.

By determining both the dimensions of the ascend-ing aorta, as well as the vascular reactivity indices, this study represents a complex evaluation, both morpho-logical, as well as functional of the ascending aorta in patients who have previously underwent corrective sur gery for an isthmic AoCo.

Confl ict of interest: none declared.

Bibliography1. O´Rourke MF, Hashimoto J – Mechanical factors în arterial aging. A

clinical perspective, Journal of American College of Cardiology 2007; 50;1-13

2. Soon Yong Suh, Eung Ju Kim, Cheol Ung Choi et col– Aortic Upper Wall Tissue Doppler Image Velocity: Relation to Aortic Elasticity and Left Ventricular Diastolic Function, Echocardiography: A Journal of Cardiovascular Ultrasound@ Allied Tech,vol 26, issue 9, october2009, pg 1064-1074

3. Kaemmerer Harald în Gatzoulis MA, Webb DG, Daubeney Piers EF – Diagnosis and Management of Adult Congenital Heart Disease, Ed Churchill Livingstone, 2004, pg 253-265

4. Morriss Mary HJ, Mc Namara Dan G în Garson Arthu r Jr, Bricker Timothy J, Fisher David J, Neish Steven R- Th e Science and Practice of Pediatric Cardiology, second edition, Ed Williams and Wilkins, 1998, pg 1317-1346

5. Eric Rosenthal: Coarctation of the aorta from fetus to adult:curable condition or life long disease process?;Heart 2005;91:1495-1502

6. Yskert von Kodolitsch, Muhammet A Aydin, Dietmar H K oschyk et col– Predictors of Aneurysmal Formation Aft er Surgical Correction of Aortic Coarctation, Journal of the American College of Cardiolo-gy, 2002, 39,no4, 617-623

7. Vogt M, Kühn A, Baumgartner D et col– Impaired Elast ic Properties of teh Ascending Aorta în Newborns, Before and Early Aft er Success-ful Coarctation Repair – Proof of a Systemic Vascular Disease of the Prestenotic Arteries, Circulation, 2005;111;3269-3273

8. de Divitiis M, Pilla C, Kattenhorn M et col– Ambulator y Blood Pre-ssure, Left Ventricular Mass and Coduit Artery Function Late Aft er Successful Repair of Coarctation of the Aorta, Journal of the Ameri-can College of Cardiology, 2003, vol 41, 12, 2259-2265

9. Meyer AA., Joharchi MS, Kundt G, Schuff – Werner P, S teinhoff G, Kienast W – Predicting the risk of early atherosclerotic disease deve-lopment în children aft er repair of aortic coarctation, European Heart Journal, (2005), 26, 617-622

10. Iancu M E, Ghiorghiu I, Serban M, Craciunescu I, Hodo A , Popescu BA Ginghina C – Determinants and pattern of ascending aorta dila-tation in patients with repaired aortic coarctation, European Journal of Echocardiography(2010)11(suppl2/ii58-ii86 doi)

11. Vitarelli A, Conde Y, Cimino E et col– Assessment of As cending Aorta Distensibility Aft er Successful Coarctation Repair by Strain Doppler Journal of American Society of Echocardiography 2008 Jun; 21(6):729-36.

12. Yat Yin Lam, Mullen JM, Kaya M, Wei Li, Gatzoulis MA, H enein MY – Left ventricular long axis dysfunction în adults with corrected aortic coarctation is related to an older age at intervention and increased aortic stiff ness, Heart 2009 May;95(9):733-9

13. de Groot E, Hovingh GK, Wiegman A, et al Measurement o f arterial wall thickness as a surrogate marker for atherosclerosis. Circulation 2004;109;Suppll1;III 33-8

14. Nistri S, Grande Allen J, Noale M et col– Aortic elastic ity and size în bicuspid aortic valve syndrome, European Heart Journal, doi 10.1093; eurheartj/ehm 528, 20 dec 2007

15. Nichols W Wilmer – Clinical Measurement of Arterial Stiff ness Obtained From Non Invasive Pressure Wave Forms, American Jour-nal of Hypertension, 2004, 10.009 doi 10.1016

16. Sehested J, Baandrup U, Mikkelsen E, Diff erent reactivity and struc-ture of the prestenotic and post stenotic aorta în human coarctation: implication for baroreceptor function.Circulation, 1982;6;1060-1065

17. Nistri S, Sorbo MD, Marin M et al, Aortic root dilatation in young man with normally functioning bicuspid aortic valves Heart 1999;82; 19-22


REVIEWS

Almanac 2013: acute coronary syndromes*Pascal Meier1,2, Alexandra J Lansky1, Andreas Baumbach3

Received 12 July 2013. Accepted 24 July 2013

Contact address:Pascal Meier, MDYale—UCL Cardiovascular Research Programme, Th e Heart Hospital, University College London Hospitals UCLH, UCLH16-18 Westmoreland Street, London W1G 8PH, UK; [email protected]

Abstract: Unstable coronary artery plaque is the most common underlying cause of acute coronary syndromes (ACS) and can manifest as unstable angina, non-ST segment elevation infarction (NSTE-ACS), and ST elevation myocardial infarction (STEMI), but can also manifest as sudden cardiac arrest due to ischaemia induced tachyarrhythmias. ACS mortality has decre-ased significantly over the last few years, especially from the more extreme manifestations of ACS, STEMI, and cardiac arrest. Th is trend is likely to continue based on recent therapeutic progress which includes novel antiplatelet agents such as prasugrel, ticagrelor, and cangrelor.

INTRODUCTIONIn the USA every year nearly 1.2 million patients are hos pitalized for acute coronary syndrome (ACS)1. How ever, the proportion of ACS with ST elevation myo cardial infarction (STEMI) appears to be decli-ning2,3. We can only speculate upon the reasons: po-tential explanations include the reduction in smoking, the age structure of the population (STEMI is more common in middle age while non-ST segment eleva-tion (NSTE-ACS) occurs more in the elderly), and broa der use of statin therapy. Over the last few years there has been a significant improvement in outcomes aft er STEMI in regard to mortality, cardiogenic shock, and heart failure1. Similar trends have been seen for other manifestations of ACS, such as sudden cardiac arrest (SCA)4,5. Astonishingly, the clinical outcomes for NSTE-ACS now appear to be worse than for STEMI. However, such figures are misleading, and short term (in-hospital) outcome is still better for NSTE-ACS than for STEMI, while the longer term mortality rate is hi-gher for NSTE-ACS, but this is probably influenced by the diff erent age and risk structure of the STEMI and NSTE-ACS populations: NSTE-ACS patients are gene-rally older and oft en have multivessel (MV) coronary artery disease (CAD).

ST ELEVATION MYOCARDIAL INFARCTIONA major reason for the improved outcomes for STEMI over the last decades has been the increasing availabi-

lity of primary percutaneous coronary intervention (PCI) services, which all try to continuously improve their performance (‘door-to-balloon time’). Initiati-ves include telemetric transmission of ECGs from the ambulance services, and training of ambulance staff in ECG interpretation. More important than door-to-balloon time is of course the overall ‘symptom onset to balloon time’. Patients have become much better in-formed about symptoms of ‘heart attacks’, and many ambulance services transfer patients with a suspected STEMI directly to a primary PCI service rather than going to the nearest hospital.

PRIMARY PERCUTANEOUS CORONARY INTERVENTIONNot only has the rate of primary PCI increased over the years, but progress in device technologies and adjunc-tive pharmacology has also improved the procedural success rate – for example, the availability of stents and second generation drug eluting stents, thrombus aspi-ration devices, and safer and more eff ective periproce-dural anticoagulation/antiplatelet treatments. Th rom-bus aspiration has been shown to improve outcomes in smaller randomized trials and is currently recom-mended by European and American PCI guidelines. However, its eff ect should probably not be overrated. A recent large scale randomized trial in 452 patients, INFUSE-AMI (Intracoronary Abciximab and Aspirati-on Th rombectomy in Patients with Large Anterior Myo-cardial Infarction) did not demonstrate an eff ect of ma-

1 Division of Cardiology, Yale Medical School, New Haven, Connecticut, USA2 Yale—UCL Cardiovascular Research Programme, Th e Heart Hospital, University College London Hospitals UCLH, London, UK3 Division of Cardiology, Bristol Heart Institute, Bristol, UK* To cite: Meier P, Lansky AJ, Baumbach A. Heart Published Online First: doi:10.1136/heartjnl- 2013-304649

Pascal Meier et al.Almanac 2013: acute coronary syndromes


nual thrombus aspiration on infarct size when used in conjunction with bivalirudin (and intracoronary abci-ximab)6,7. Intravenous glycoprotein (Gp) IIb/IIIa inhi-bitors have an immediate and potent platelet inhibitory eff ect and certainly improve thrombus resolution; they may reduce infarct size6 while their eff ect on clinical out comes is somewhat more debatable. Bivalirudin, a direct thrombin inhibitor, which has anticoagulant and probably also antiplatelet eff ects (via suppression of thro mbin dependent platelet activation8), can be used as an alternative to heparin and Gp IIb/IIIa inhibi-tors, and has shown reduced bleeding and even redu-ced mortality in the HORIZON-AMI trial (Heparin plus a glycoprotein IIb/IIIa Inhibitor versus Bivalirudin Monotherapy and Paclitaxel-Eluting Stents versus Bare-Metal Stents in Acute Myocardial Infarction)6. Bleeding reduction has become a key aim in primary PCI beca-use of the well documented (but less well understood) association with increased mortality (Table 1).

Transradial versus transfemoral accessAnother rather elegant option used increasingly, which may reduce bleeding, involves the transradial approach instead of the traditional transfemoral access9. An in-creasing wealth of data indicate that this reduces blee-ding in general; some data even suggest that it reduces mortality when used for primary PCI, but the latter eff ect is debatable10,11. A recent meta-analysis of nine studies involving 2977 patients with STEMI demons-trated an impressive nearly 50% reduction in mortality for the transradial approach (OR 0.53, 95% CI 0.33 to 0.84; p=0.008)10. While the authors concluded that the transradial approach should be preferred in STEMI pa-tients, an accompanying editorial highlighted some limitations of these data11. Some data indicate a nega-

tive impact of transradial PCI. Baklanov et al12 showed a longer median door-to-balloon time with transra-dial PCI. Another retrospective comparison by Cafri et al13, however, showed similar door-to-balloon time irrespective of the access route. Even in elderly people, where there is more advanced atherosclerosis, the ra-dial access does not seem to delay reperfusion as it does not lead to any increase in the door-to-balloon time14. Th ere have also been concerns that transradial access may increase the risk of neurological complications com pared to transfemoral access. However, in a retros-pective analysis of the British Cardiovascular Interven-tion Society database conducted between January 2006 and December 2010, Ratib et al15 have shown that there is no significant association between the use of radial access and the occurrence of neurological complicati-ons.

Overall, transradial PCI is certainly a promising te-chnique when used by experienced operators. Howe-ver, despite its benefits, its use is highly variable across countries. In France and Japan it is the predominant access route11. In the UK, its use increased nearly four-fold from 17.2% in 2006 to 57% in 201116. Th e USA has the lowest rate of radial access adoption

for PCI worldwide (only one in six PCIs)17. Even here, there has been an increase in use of radial access. In the first quarter of 2007, 1.2% of PCIs were by the transradial approach; this increased to 16.1% in the third quarter of 2012. Th ere is little doubt that the in-creasing use of transradial PCI has led to a reduction in access site complications12,16,17,18.

While some data indicate that the transradial route may reduce mortality in STEMI patients, this has not been demonstrated in NSTE-ACS. In the RIVAL (Ra-

Table 1. Bleeding avoidance strategies9

Strategy CommentsRadial instead of femoral access

Reduces access site bleeding risk (and potentially also mortality in high risk groups)

Bivalirudin Bivalirudin superior to heparin and glycoprotein IIb/IIIa inhibitors, reduces bleeding (and reduces mortality in STEMI patients)

Fluoroscopy guided punctu-re for femoral access

High (or low) puncture to be avoided. Th e femoral head has a consistent relationship with the common femoral artery, and localization using fl uoroscopy is a useful landmark. However, randomized studies failed to show a clinical benefi t but were underpoweredFewer vascular complications with this approach in randomized trials

Ultrasound guided puncture for femoral access

1347

Vascular closure devices Controversial study results. Increasing evidence pointing towards a positive eff ect of vascular closure devices, especially if used with bivalirudin

Individualized bleeding risk assessment

Individualized risk assessment and adjustment of clinical practice using risk models, for example, NCDR CathPCI blee-ding risk model (bivalirudin, radial access, etc)

NCDR, National Cardiovascular Database Registry; PCI, percutaneous coronary interventions; STEMI, ST elevation myocardial infarction.



dial vs Femoral Access for Coronary Intervention) trial, currently the largest randomized trial on this topic, there was no diff erence in major clinical outcomes in NSTE-ACS patients19. In a cohort of high risk NSTE-ACS patients enrolled in the EARLY-ACS trial (Early Gly coprotein IIb/IIIa Inhibition in non-ST-Segment Ele-vation Acute Coronary Syndrome), there were no sig-n i ficant diff erences in either bleeding or ischaemic out comes whether radial or femoral access was used20.

A recent consensus statement by the European Soci-ety of Cardiology (ESC) states that a default radial ap-proach is feasible in routine practice in both stable and unstable patients21. Th e ESC recommends performing transradial PCI in STEMI patients only aft er the ope-rator has become familiar with this approach in stable patients and in diagnostic procedures.

Culprit lesion PCICulprit lesion only treatment versus a ‘complete revas-cu larization’ approach remains the subject of some debate. One could argue either way: a complete revas-cularization strategy may improve overall myocardial perfusion in the critical initial phase; but on the other hand, we know that major adverse complications are increased during acute PCI, and this also may have an impact on the outcome following treatment of non-acute, non- culprit lesions. A randomized study of 214 patients showed that angioplasty of the culprit vessel only was associated with higher rates of adverse events (50.0%) during a mean follow up of 2.5 years than MV PCI, regardless of simultaneous complete revasculari-zation (23.1%) or a staged complete revascularization (20.0%)22. A recent report of the Ibaraki Cardiovascular

Assessment Study registry of Japan showed significantly higher mortality with PCI of a non-culprit lesion in the same setting as the culprit lesion than with PCI of only the culprit lesion23. In contrast, results based of the American College of Cardiology National Cardio-vascular Database Registry (NCDR-CathPCI) showed similar morbidity and mortality rates with either single vessel or MV PCI24. While these data were conflicting, most studies were non-randomized and need to be in-terpreted with caution. A large meta-analysis of 18 ran-domized controlled trials (RCTs), including the above mentioned RCT, involved 40 280 patients and showed that staged PCI was associated with lower short and long term mortality compared to culprit vessel PCI and MV PCI25. Th erefore, current guidelines discourage the performance of multivessel PCI for STEMI and suggest that non-culprit lesions should be staged26,27. However, if STEMI patients present in cardiogenic shock or aft er an SCA, they should be considered for complete revas-cularization in one sitting.

The time effectTh e current ESC guidelines recommend that STEMI patients should be immediately transported within 2 h of onset of symptoms to a PCI-capable center without delay28. In clinical practice, it is extremely difficult to achieve this goal of symptom onset-to-balloon time29. System delays have been shown to be associated with mortality at a median follow-up of 3.4 years in STEMI patients treated with primary PCI30. In a more recent study, shorter symptom onset-to-balloon time predic-ted lower mortality in the long term31. A longer treat-ment delay was seen in females, patients living in a ru-

Figure 1. Change in short and intermediate term mortality aft er ST elevation myocardial infarction. Standardised 30 day and 31–365 day mortality aft er first hospitalization for myocardial infarction among men and women between 1984 and 2008 in Denmark33. Reprinted with permission from BMJ Publishing Group.



ral area >22 km from hospital, and when patients were admitted to the emergency department of the hospital instead of direct emergency medical services (EMS) transportation. Researchers suggest that a more gene-ralised use of ambulance/EMS would reduce treatment delays and associated mortality.

Optimal duration of monitoring/hospital stayTh e duration of hospital stay has decreased dramati-cally over the years, which has a major impact on health care expenditure and on patient quality of life. Current practice is widely variable across countries and centres, but it is unclear whether early hospital discharges are safe32. It is very reassuring that, despite the continuous reduction in hospital stay, outcomes have significantly improved (Figure 1).

Two new studies have demonstrated that dischar-ging low risk STEMI patients within 2 days following primary PCI is safe and feasible34,35. Over 40% of the STEMI patients in one of the studies met early dischar-ge criteria34. An early discharge could lower healthcare costs considerably.

Based on the literature, we propose the following cri-teria to define low risk patients for early discharge:

1. Age <70 years2. Short pain to reperfusion interval (<4 h)3. Uncomplicated primary PCI with good result

(TIMI (Th rombolysis in Myocardial Infarction) 3 flow and prompt complete ST elevation resoluti-on)

4. Left ventricular ejection fraction >45% without symptoms of heart failure

5. No significant arrhythmias during the first 24 h6. Socially supported, collaborative/compliant pati-

ent.

NON-ST ELEVATION ACS

Risk predictionTh ere is a great need for proper risk prediction in ACS patients for clinical decision making, especially with regard to coronary angiography. Th ere are several risk prediction models in use. Th e Global Registry of Acute Coronary Events (GRACE) is among the most com-monly used scores. Recently, a mini-GRACE (MG) risk score has been developed which excludes creatinine and Killip class from the original eight-factor GRACE risk model. Th e adjusted mini-GRACE (AMG) risk score includes ‘prescription of a loop diuretic during admission’ in place of Killip class and creatinine con-centration. Both risk scores showed good accuracy in

the Myocardial Ischemia National Audit Project (MI-NAP), with the AMG risk score performing somewhat better than the MG risk score36.

Laboratory markers may further help with this risk stratification. Th e maximal troponin value in patients presenting with NSTE-ACS has been shown to be an independent predictor of in-hospital morbidity and mortality37. Other predictive markers include interleu-kin 10, myeloperoxidase, and placental growth factor38.

Role and timing of PCI in NSTE-ACSFor intermediate to high risk patients, there is strong evidence supporting routine angiography rather than conservative management. However, the optimal time for coronary angiography is not clear. Th ough an early invasive approach seems favorable, studies testing the timing eff ect used varying time points for ‘early’ and ‘delayed’ angiography. In very high risk patients such as those with refractory angina, severe heart failure, life threatening ventricular arrhythmias or haemodynamic instability or an evolving myocardial infarction (MI), an urgent invasive approach is indicated. For patients not belonging to this high risk category, the optimal timing is not clear. Th ere is no clear benefit with re-gard to ‘hard’ clinical end points for an early invasive strategy within 24 h, but an increasing number of cen-ters undertake an early invasive strategy within 24 h for intermediate to high risk patients. Such an approach is probably reasonable, as an earlier approach certainly helps to reduce hospital stay. Factors such as diabe-tes, renal function, left ventricular function, recurrent symptoms, and previous revascularization should be considered along with the TIMI or GRACE score.

Intravascular imagingIntravascular imaging guided PCI is a concept that evolved when devices such as intravascular ultrasound (IVUS) and more recently optical coherence tomogra-phy (OCT) became available. Th ere are two diff erent modes of use, either for the pre-PCI assessment in or-der to better understand the coronary plaque (stable or unstable plaque, diameter and length, thrombus bur-den, etc), or for post-PCI assessment of stent expan-sion and apposition. Th e advantages are obvious; in contrast to angiography as an eyeballing tool, which allows measurement of luminal diameters in a few ort-hogonal views, coronary IVUS provides a tomographic view. Furthermore, the resolution is much better than for angiography.

Th e first concept, pre-PCI assessment of lesions has been tested in the multicenter PROSPECT (Providing Regional Observations to Study Predictors of Events



clopidogrel is the most commonly used agent for this purpose at the moment. However, the problems with this treatment are the rather long delay until maximal platelet inhibition is reached and the high rate of poor responders46. One approach that has been tested re-peatedly is triple antiplatelet therapy using cilostazol. Even though results of this approach have indicated some benefit, it is rarely used47,48. One reason for this is probably the development of newer generation P2Y12 receptor blockers such as prasugrel, ticagrelor, and can-grelor. Th ey block the binding of ADP to the platelet re-ceptor P2Y12, thereby inhibiting platelet aggregation.

Naturally, we would expect that stronger antiplatelet inhibition comes with an increased bleeding risk. Many patients therefore receive proton pump inhibitors (PPI). However, the data do not completely following this logic.

Prasugrel: Th e TRITON-TIMI 38 trial was a head-to-head comparison between aspirin and prasugrel versus aspirin plus clopidogrel in 13 608 moderate to high risk ACS patients under-going PCI. In most ca-ses, the study drug was given aft er coronary angiogra-phy. At 15 months follow-up, MACE (cardiovascular death, non-fatal MI, or non-fatal stroke) was reduced with pra sugrel (9.9% vs 12.1%; HR 0.81, 95% CI 0.73 to 0.90) Th is composite end point was mainly driven by a reduction in non-fatal MI. Major bleeding was some what increased with prasugrel (2.4% vs 1.8%; HR 1.32, 95% CI to 1.68). Bleeding was mainly increased in those with a history of stroke or transient ischemic attack, age ≥75 years or a bodyweight ≤60 kg. Th e TRI-LOGY ACS trial tested prasugrel versus clopidogrel with NSTE-ACS not undergoing PCI. Th ere was no statistically significant diff erence in MACE rate (13.9% vs 16.0%; HR 0.91, 95% CI 0.79 to 1.05).

Ticagrelor: In contrast to clopidogrel and prasugrel, ticagrelor binds reversibly to the P2Y12 platelet recep-tor. Th is agent was tested in the PLATO trial (18 624 patients) in patients with ACS, and also those who did not undergo PCI but had medical therapy. Treatment was started early, at a median of 5 h aft er hospital ad-mission. Th is study showed a reduced risk for MACE (defined as cardiovascular death, MI, or stroke) in the ticagrelor arm (9.8% vs 11.7%, HR 0.84, 95% CI 0.77 to 0.92), and there was also a reduced risk for car dio-vascular mortality as a single end point. Overall, the-re was no significant diff erence in the rates of major bleeding between the ticagrelor and clopidogrel groups (11.6% vs 11.2%, respectively). However, there was a

in the Coronary Tree) study39. Th is study showed that IVUS can be used to define characteristics of vulne-rable plaques. Th e highest risk phenotypes associated with non-culprit major adverse cardiac events (MACE) in cluded thin-cap fibroatheromas, plaque burden >70%, and minimal lumen area <4.0 mm. However, these data are not sufficient to advocate using IVUS de-rived plaque characteristics to decide whether a lesion needs to be treated40.

While IVUS is based on ultrasound, OCT is based on light, which has a much shorter wavelength, and therefore achieves 10-fold better spatial resolution com pared to IVUS41.Th is allows better definition of the thin fibrous caps and the circumferential extent of the necrotic cores. It helps detect other microstructural features such as cholesterol crystals, thrombus, calcium deposits, fibrous plaques, and lipid-rich plaques42. OCT can visualize features not seen by IVUS such as intimal flaps and defects in the intima, disruptions in the me-dia, and stent strut apposition.

A Japanese study that analyzed the culprit lesion in AMI patients found that the incidence of plaque ruptu-re observed by OCT was significantly higher than that observed by both angioscopy and IVUS43. OCT was also superior in detecting fibrous cap erosion and thin cap fibroatheroma, and OCT could also estimate the fibrous cap thickness.

However, the depth of imaging penetration is limi-ted to only a few millimeters with this new technique44. So, it is unable to image the adventitia and assess the plaque burden. Th erefore, Alfonso et al45 had the idea of a combined use of OCT and IVUS in patients with stent thrombosis. Since image length was shorter with OCT, they suggested overlapping OCT runs to cir- cumvent the problem. Th e challenge of OCT is that it requires a field clear of blood for imaging.

Because OCT has superior resolution to IVUS, it clearly recognizes stent struts on heavily calcified are-as which are difficult to identify with IVUS. Post-in-tervention OCT also produces a sharper image of the neointimal-thrombus boundary and provides a reliable diagnosis of in-stent restenosis or neoatherosclerosis. In current practice, OCT and IVUS seem to comple-ment each other with their respective advantages and disadvantages. However, we have to be aware that data on clinical outcomes are limited and that these tech-niques add to procedural costs.

Antiplatelet therapyAspirin is still the basis of every antiplatelet therapy. However, dual antiplatelet therapy of aspirin and a P2Y12 receptor blocker is clearly more eff ective and



(OHCA)). Survival for OHCA patients has been poor for several decades, averaging <10% to hospital dis-charge, and may be even lower, particularly in remote areas. However, in recent years survival has increased, especially in metropolitan areas. Th e London Ambu-lance Service observed an increase in survival rates from 12% to 32% between 2007 and 20125.

We can only speculate about the reasons for this im-provement since few single interventions have really proven to be eff ective54. It is therefore more likely that it is the combination of multiple eff ective treatments that is responsible for the observed improvements in sur-vival. Early chest compressions and early defibrillation are the undisputed game changers55. It is likely that the availability of public automatic defibrillators, defibrillators of the EMS and public awareness, and an increa-sing number of lay people trained in chest compressi-on, played major roles56.

However, other factors such as therapeutic hypother-mia and immediate angiography to define and potenti-ally treat the underlying cause are important as well57,58. An observational study of 9971 patients with OHCA of suspected cardiac cause were assessed regarding the hospital they were referred to. Th ose treated at hos-pitals with 24 h cardiac interventional services had a better survival (OR 1.40, 95% CI 1.12 to 1.74; p=0.003).

Current guidelines recommend immediate angio-graphy in patients aft er successful resuscitation for an OHCA (return of a spontaneous circulation) in case of ST elevations in the post-resuscitation ECG. However, the accuracy of post-resuscitation ECGs is unclear and there are grounds for recommending early angiogra-phy in all patients over 35-40 years, regardless of the ECG, if there is no obvious non-cardiac cause.

Cardiac rehabilitation after ACSWhile it seems intuitive that cardiac rehabilitation pro-grams are beneficial by providing careful follow-up, supervised physical activity and guidance on lifestyle modification, clinical data on its eff ect are controver-sial. Very recently, cardiac rehabilitation for ACS has been challenged again by the multicenter RCT of com-prehensive cardiac rehabilitation in patients following acute MI (RAMIT: Rehabilitation Aft er Myocardial Infarction Trial)59. In this study, cardiac rehabilitation in patients aft er an AMI had no eff ect on mortality or morbidity, cardiac medication, risk factors or lifestyle modification. However, we have to be aware that the RAMIT trial was small and if we look at the evidence more comprehensively, by pooling all available RCTs as done by a Cochrane review (combining 47 studies),

higher risk of non-coronary artery bypass surgery re-lated major bleeding (4.5% vs 3.8%).

Cangrelor: In contrast to these drugs, cangrelor is administered intravenously. It has been tested against placebo and against clopidogrel. Th e CHAMPION- PLATFORM trial (placebo control) was stopped ear-ly because an interim analysis showed disappointing re sults. Th e CHAMPION-PCI trial (clopidogrel as a comparator) failed to show a significant benefit as well. Th e most recent and largest study, the CHAMPION-PHOENIX trial, compared cangrelor against pre-loa-ding with 300-600 mg of clopidogrel. Th is study not only included ACS but also patients with stable CAD. It found a reduced risk for ischemic events (death, MI, ischemia-driven revascularization or stent thrombosis) over the first 48 h without any increase in major ble-eding risk49. Its role in clinical practice in the context of having ticagrelor and prasugrel available is not cle-ar yet, and it has never been compared against these agents.

With additional and more potent antiplatelet the-rapies now available, the challenge is to decide which agent to use and when. Currently, the decision is usu-ally based on clinical and risk factors; pharmacogene-tics may also play a role in guiding therapies in the fu-ture50.

Gastrointestinal (GI) bleeding is one of the more common risks of strong antiplatelet therapy. Th erefore, PPI are oft en prescribed as well. A recent study found, interestingly, that lower GI bleeding is more common than upper GI bleeding in patients on PPI51. Further-more, the impact of PPI on the clopidogrel eff ect has been a matter of controversy for some time. Laboratory studies have suggested a reduced antiplatelet eff ect if PPI are used. However, studies looking at clinical end points have shown conflicting results. A recent syste-matic review provides a very good overview, including 33 studies, and concludes that clinical data are highly conflicting but that even newer, better designed studies do not show evidence of a relevant adverse eff ect of PPI in patients on clopidogrel regarding clinical out-comes52.

SUDDEN CARDIAC ARRESTSCA is a less common but oft en fatal presentation of ACS53. While there are other reasons for SCA, especi-ally in younger patients, the most common cause for tachyarrhythmic cardiac arrests in patients over 40 is myocardial ischemia4,37. Most of these cardiac arrests occur out of hospital (out-of-hospital cardiac arrest



Competing interests: None.Provenance and peer review Commissioned; internally peer reviewed.

References1. Members WG, Roger VL, Go AS, et al. Heart disease and stroke sta-

tistics—2012 update: a report from the American Heart Association. Circulation 2012;125: e2–220.

2. Knight CJ, Timmis AD. Almanac 2011: acute coronary syndromes. Th e national society journals present selected research that has driven recent advances in clinical cardiology. Heart 2011;97:1820–7.

3. Yeh RW, Sidney S, Chandra M, et al. Population trends in the inciden-ce and outcomes of acute myocardial infarction. N Engl J Med 2010; 362:2155–65.

4. Nolan JP, Lyon RM, Sasson C, et al. Advances in the hospital mana-gement of patients following an out of hospital cardiac arrest. Heart 2012;98:1201–6.

5. Fothergill RT, Watson LR, Chamberlain D, et al. Increases in survival from out-of-hospital cardiac arrest: a five year study. Resuscitation 2013;84:1089–92.

6. Stone GW, Maehara A, Witzenbichler B, et al. Intracoronary abci-ximab and aspiration thrombectomy in patients with large anterior myocardial infarction: the INFUSE-AMI randomized trial. JAMA 2012;307:1817–26.

7. Stone GW, Witzenbichler B, Guagliumi G, et al. Heparin plus a glyco-protein IIb/IIIa inhibitor versus bivalirudin monotherapy and pacli-taxel-eluting stents versus bare-metal stents in acute myocardial in-farction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial. Lancet 2011;377:2193–204.

8. Kimmelstiel C, Zhang P, Kapur NK, et al. Bivalirudin is a dual inhibi-tor of thrombin and collagen-dependent platelet activation in patients undergoing percutaneous coronary intervention. Circ Cardiovasc In-terv 2011;4:171–9.

9. Meier P, Frohlich GM, Lansky AJ. Bleeding complications in percuta-neous coronary interventions. Cardiology 2013;125:213–16.

10. Mamas MA, Ratib K, Routledge H, et al. Influence of access site se-lection on PCI-related adverse events in patients with STEMI: meta-analysis of randomised controlled trials. Heart 2012;98:303–11.

11. Meier P, Windecker S, Lansky AJ. Radial versus femoral access for pri-mary percutaneous coronary intervention: is there a preferred route to the heart? Heart 2012;98:269–70.

12. Baklanov DV, Kaltenbach LA, Marso SP, et al. Th e prevalence and outcomes of transradial percutaneous coronary intervention for ST-segment elevation myocardial infarction: analysis from the National Cardiovascular Data Registry (2007 to 2011). J Am Coll Cardiol 2013; 61:420–6.

13. Cafri C, Zahger D, Merkin M, et al. Efficacy of the radial approach for the performance of primary PCI for STEMI. J Invasive Cardiol 2013; 25:150–3.

14. Secco GG, Marinucci L, Uguccioni L, et al. Transradial versus transfe-moral approach for primary percutaneous coronary interventions in elderly patients. J Invasive Cardiol 2013;25:254–6.

15. Ratib K, Mamas MA, Routledge HC, et al. Influence of access site choice on incidence of neurologic complications aft er percutaneous coronary intervention. Am Heart J 2013;165:317–24.

16. Ratib K, Routledge H, Mamas MA, et al. Trends in access site choice and PCI outcomes: insights from the UK national PCI dataset. Heart 2012;98:A28–A9.

17. Feldman DN, Swaminathan RV, Kaltenbach LA, et al. Adoption of radial access and comparison of outcomes to femoral access in per-cutaneous coronary intervention: an updated report from the Nati-onal Cardiovascular Data Registry (2007–2012). Circulation 2013; 127:2295–306.

18. De Luca G, Schaff er A, Wirianta J, et al. Comprehensive meta-analysis of radial vs femoral approach in primary angioplasty for STEMI. Int J Cardiol 2013 (Epub ahead of print).

19. Mehta SR, Jolly SS, Cairns J, et al. Eff ects of radial versus femoral ar-tery access in patients with acute coronary syndromes with or without ST-segment elevation. J Am Coll Cardiol 2012;60:2490–9.

there is a significant, albeit modest, eff ect on morta-lity60. Th is meta-analysis did not include the RAMIT findings which would have further reduced the estima-ted eff ect on all-cause mortality from 13% to 11%61. It is important to note that the Cochrane review focused on physical exercise based rehabilitation, the probability being that non-exercise based rehabilitation (patient education) has little eff ect on mortality aft er MI62.

Th e problem with combining results of multiple trials is, of course, that this does not account for the ‘evolution’ of such interventions63. Th e results of the re cent OMEGA study, which was a non-randomized cohort study, have shown that a short term compre-hensive cardiac rehabilitation program aft er acute MI significantly improved the 1-year prognosis64. Th ose who attended rehabilitation programs had lower all-ca-use mortality than those who did not, but without ran-domized treatment assignment, interpretation of such data is difficult. Th ere was a significant dose–response relationship; the more sessions attended the lower the all-cause mortality. However, low attenders were more likely to be smokers, and when adjustments were made for baseline diff erences in smoking status the dose–res-ponse association disappeared.

Th ough cardiac rehabilitation as currently provided in many countries may not be eff ective in reducing hard clinical end points, it still helps provide informa-tion, advice, and reassurance and helps in long term secondary prevention65.

CONCLUSIONSTh e treatment options for ACS have improved signi-ficantly over the past few years, contributing to notable improvements in outcomes. Th is is especially the case for STEMI, while long term mortality aft er an NSTE-ACS is still considerable. Th e very recent introduction of third generation antiplatelet therapies (prasugrel, ticagrelor) and the most recent intravenous form, can-grelor, are likely to continue to improve clinical outco-mes aft er ACS. Th ese more potent agents can increase bleeding risks, and considering the association betwe-en bleeding and outcomes, periprocedural bleeding avoidance strategies are important. Th ey may include radial access angiography; ultrasound guided femoral access, and the use of bivalirudin.

Contributors: PM draft ed the manuscript. AB, AJL and AB revised the manuscript critically for intellectual content. All three authors contributed significantly to this paper and have approved the final version.



Institute for Cardiovascular Outcomes Research (NICOR). Heart 2012;99:35–40.

37. Jolly SS, Shenkman H, Brieger D, et al. Quantitative troponin and death, cardiogenic shock, cardiac arrest and new heart failure in pa ti entswith non-ST-segment elevation acute coronary syndromes (NSTE ACS): insights from the Global Registry of Acute Coronary Events. Heart 2011;97:197–202.

38. Oemrawsingh RM, Lenderink T, Akkerhuis KM, et al. Multimarker risk model containing troponin-T, interleukin 10, myeloperoxidase and placental growth factor predicts long-term cardiovascular risk af-ter non-ST-segment elevation acute coronary syndrome. Heart 2011; 97:1061–6.

39. Stone GW, Maehara A, Lansky AJ, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011;364:226–35.

40. Lodi-Junqueira L, de Sousa MR, da Paixao LC, et al. Does intravas-cular ultrasound provide clinical benefits for percutaneous coronary intervention with bare-metal stent implantation? A meta-analysis of randomized controlled trials. Syst Rev 2012;1:42.

41. Maehara A, Mintz GS, Weissman NJ. Advances in intravascular ima-ging. Circ Cardiovasc Interv 2009;2:482–90.

42. Yabushita H, Bouma BE, Houser SL, et al. Characterization of human atherosclerosis by optical coherence tomography. Circulation 2002; 106:1640–5.

43. Kubo T, Imanishi T, Takarada S, et al. Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical cohe-rence tomography compared with intravascular ultrasound and coro-nary angioscopy. J Am Coll Cardiol 2007;50:933–9.

44. Lindsay AC, Viceconte N, Di Mario C. Optical coherence tomography:has its time come? Heart 2011;97:1361–2.

45. Alfonso F, Dutary J, Paulo M, et al. Combined use of optical coheren-ce tomography and intravascular ultrasound imaging in patients un-dergoing coronary interventions for stent thrombosis. Heart 2012;98: 1213–20.

46. Sambu N, Radhakrishnan A, Dent H, et al. Personalised antiplatelet therapy in stent thrombosis: observations from the Clopidogrel Resis-tance in Stent Th rombosis (CREST) registry. Heart 2012;98:706–11.

47. Park KW, Park JJ, Lee SP, et al. Cilostazol attenuates on-treatment platelet reactivity in patients with CYP2C19 loss of function alleles receiving dual antiplatelet therapy: a genetic substudy of the CILON-T randomised controlled trial. Heart 2012;97:641–7.

48. Tamhane U, Meier P, Chetcuti S, et al. Efficacy of cilostazol in redu-cing restenosis in patients undergoing contemporary stent based PCI: a meta-analysis of randomised controlled trials. EuroIntervention 2009;5:384–93.

49. Bhatt DL, Stone GW, Mahaff ey KW, et al. Eff ect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med 2013; 368:1303–13.

50. Verschuren JJ, Jukema JW. Pharmacogenetics of antiplatelet therapy: ready for clinical application? Heart 2011;97:1268–76.

51. Casado Arroyo R, Polo-Tomas M, Roncales MP, et al. Lower GI blee-ding is more common than upper among patients on dual antiplatelet therapy: long-term follow-up of a cohort of patients commonly using PPI co-therapy. Heart 2012;98:718–23.

52. Focks JJ, Brouwer MA, van Oijen MG, et al. Concomitant use of clo-pidogrel and proton pump inhibitors: impact on platelet function and clinical outcome- a systematic review. Heart 2013;99:520–7.

53. Perkins GD, Brace SJ, Smythe M, et al. Out-of-hospital cardiac ar-rest: recent advances in resuscitation and eff ects on outcome. Heart 2011;98:529–35.

54. Brooks SC, Bigham BL, Morrison LJ. Mechanical versus manual chest compressions for cardiac arrest. Cochrane Database Syst Rev 2011: CD007260, doi.10.1002/ 14651858.CD007260.pub2.

55. Meier P, Baker P, Jost D, et al. Chest compressions before defibrillation for out-of-hospital cardiac arrest: a meta-analysis of randomized con-trolled clinical trials. BMC Med 2010;8:52.

56. Adielsson A, Hollenberg J, Karlsson T, et al. Increase in survival and bystander CPR in out-of-hospital shockable arrhythmia: bystander CPR and female gender are predictors of improved outcome. Experi-ences from Sweden in an 18-year perspective. Heart 2011;97:1391–6.

20. Klutstein MW, Westerhout CM, Armstrong PW, et al. Radial versus femoral access, bleeding and ischemic events in patients with non-ST-segment elevation acute coronary syndrome managed with an invasi-ve strategy. Am Heart J 2013;165:583–90 e1.

21. Hamon M, Pristipino C, Di Mario C, et al. Consensus document on the radial approach in percutaneous cardiovascular interventions: po-sition paper by the European Association of Percutaneous Cardiovas-cular Interventions and Working Groups on Acute Cardiac Care and Th rombosis of the European Society of Cardiology. EuroIntervention 2013;8:1242–51.

22. Politi L, Sgura F, Rossi R, et al. A randomised trial of target-vessel versus multi-vessel revascularisation in ST-elevation myocardial in-farction: major adverse cardiac events during long-term follow-up. Heart 2010;96:662–7.

23. Abe D, Sato A, Hoshi T, et al. Initial culprit-only versus initial mul-tivessel percutaneous coronary intervention in patients with ST-seg-ment elevation myocardial infarction: results from the Ibaraki Cardi-ovascular Assessment Study registry. Heart Vessels 2013 March 26th (Epub ahead of print).

24. Brener SJ, Milford-Beland S, Roe MT, et al. Culprit-only or multi-vessel revascularization in patients with acute coronary syndromes: an American College of Cardiology National Cardiovascular Databa-se Registry report. Am Heart J 2008;155:140–6.

25. Vlaar PJ, Mahmoud KD, Holmes DR Jr, et al. Culprit vessel only ver-sus multivessel and staged percutaneous coronary intervention for multivessel disease in patients presenting with ST-segment elevation myocardial infarction: a pairwise and network meta-analysis. J Am Coll Cardiol 2011;58:692–703.

26. Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascu-larization. Eur Heart J 2010;31:2501–55.

27. Kushner FG, Hand M, Smith SC Jr, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/ Ameri-can Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009;54:2205–41.

28. Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revas-cularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Th oracic Surgery (EACTS). Eur Heart J 2010;31:2501–55.

29. Eagle KA, Nallamothu BK, Mehta RH, et al. Trends in acute reperfusi-on therapy for ST-segment elevation myocardial infarction from 1999 to 2006: we are getting better but we have got a long way to go. Eur Heart J 2008;29:609–17.

30. Terkelsen CJ, Sorensen JT, Maeng M, et al. System delay and mortality among patients with STEMI treated with primary percutaneous coro-nary intervention. JAMA 2010;304:763–71.

31. Rollando D, Puggioni E, Robotti S, et al. Symptom onset-to-balloon time and mortality in the first seven years aft er STEMI treated with primary percutaneous coronary intervention. Heart 2012;98:1738–42.

32. Khavandi A, Freeman P, Meier P. Discharge aft er primary angioplasty at 24 h: feasible and safe or a step too far? Cardiology 2013;125:176–9.

33. Schmidt M, Jacobsen JB, Lash TL, et al. 25 year trends in first time hospitalisation for acute myocardial infarction, subsequent short and long term mortality, and the prognostic impact of sex and comorbi-dity: a Danish nationwide cohort study. BMJ 2012;344:e356.

34. Jones DA, Rathod KS, Howard JP, et al. Safety and feasibility of hospi-tal discharge 2 days following primary percutaneous intervention for ST-segment elevation myocardial infarction. Heart 2012;98:1722–7.

35. Noman A, Zaman AG, Schechter C, et al. Early discharge aft er pri-mary percutaneous coronary intervention for ST-elevation myocardi-al infarction. Eur Heart J Acute Cardiovasc Care 2013 February 14th (epub ahead of print).

36. Simms AD, Reynolds S, Pieper K, et al. Evaluation of the NICE mini-GRACE risk scores for acute myocardial infarction using the Myocar-dial Ischaemia National Audit Project (MINAP) 2003–2009: National



57. Arrich J, Holzer M, Havel C, et al. Hypothermia for neuroprotection in adults aft er cardiopulmonary resuscitation. Cochrane Database SystRev 2012;(9): CD004128.

58. Stub D, Smith K, Bray JE, et al. Hospital characteristics are associated with patient outcomes following out-of-hospital cardiac arrest. Heart 2011;97:1489–94.

59. West RR, Jones DA, Henderson AH. Rehabilitation aft er myocardial infarction trial (RAMIT): multi-centre randomised controlled trial of comprehensive cardiac rehabilitation in patients following acute myo-cardial infarction. Heart 2012;98:637–44.

60. Heran BS, Chen JM, Ebrahim S, et al. Exercise-based cardiac rehabi-litation for coronary heart disease. Cochrane Database Syst Rev 2011: CD001800, doi.10.1002/ 14651858.CD001800.pub2.

61. Doherty P, Lewin R. Th e RAMIT trial, a pragmatic RCT of cardi-ac reha bilitation versus usual care: what does it tell us? Heart 2012; 98:605–6.

62. Brown JP, Clark AM, Dalal H, et al. Patient education in the mana-gement of coronary heart disease. Cochrane Database Syst Rev 2011: CD008895.

63. Wood D. Is cardiac rehabilitation fit for purpose in the NHS: maybe not. Heart 2012;98:607–8.

64. Rauch B, Riemer T, Schwaab B, et al. Short-term comprehensive car-diac rehabilitation aft er AMI is associated with reduced 1-year mor-tality: results from the OMEGA study. Eur J Prev Cardiol 2013 doi: 10.1002/14651858.CD008895. pub2.

65. West RR, Henderson AH. Cardiac rehabilitation and exercise trai-ning. Heart 2013;99:753–4.


REVIEWS

Almanac 2013: heart failure*Andrew L ClarkReceived 31 July 2013. Accepted 4 August 2013

Contact address:Professor Andrew L Clark, Academic Cardiology, Hull York Medical School, Castle Hill Hospital, Castle Road, Cottingham HU165JQ, UK; [email protected]

EPIDEMIOLOGY, THE NATIONAL AUDIT AND GUIDELINESTh e National Heart Failure Audit continues to be an invaluable resource for understanding how acute heart failure is managed in England and Wales. Th e most re-cent report1 describes just over 37 000 hospitalizations. As in previous publications, fewer than half the pati-ents were managed in cardiology wards, yet those who were had a better outcome; half were referred at dis-charge to cardiologists for follow-up and they, too, had a better outcome. An innovation in the audit this time was the publication of hospital level analysis. It would be invidious to pick out names, but it is very striking how variable are the rates of such basic items as the use of echocardiography, availability of a cardiologist to manage the patients and the rate of prescription of di ff erent drugs.

Studies show that, during long-term follow-up, pa-tients managed by heart failure specialists including ‘heart failure nurses’ are more likely to be treated with the appropriate medication in the appropriate dose, have lower (re-)admission rates to hospital and a better prog nosis2. Th ere is reasonable evidence that there are better outcomes if part of the multidisciplinary inter-vention is made in the home3. Th ere is strong eviden-ce that specialist clinics reduce the risk of readmission with heart failure immediately aft er an index admissi-on4.

Also available to the clinician are the heart failure guidelines from the National Institute for Health and Care Excellence (NICE)5,6 and the associated quality standards7. Th e NICE standards make it clear what NHS services across England and Wales should be stri-ving towards. Combined with the hospital level analysis from the audit, the quality standards should give clini-cal teams the ammunition they need when discussing their heart failure service with management teams in both primary and secondary care.

However, it is becoming ever clearer that the systems used for managing heart failure at present are unlikely to be adequate in future: a study from the USA8 predicts that the costs of managing heart failure will more than double by 2030, mainly due to the ageing of the popu-lation. Th e capacity of the health service to accommo-date the increasing numbers is not infinite. Part of the solution will surely have to be a change towards greater efficiency of use of limited resources, but reducing the risk of developing heart failure will also be a major con-tributor. Of some relief to many doctors, coff ee appears to off er some protection9!

Th e latest guidelines from the European Society of Cardiology were published in 2012, merging the man-agement of acute and chronic heart failure10. Th ey continue to emphasize the central role of natriuretic peptide testing for diagnosis – which is still not uni-versally available in the UK but a key part of the NICE recommendations. Th e guidelines emphasize that mi-neralocorticoid receptor antagonists should now be considered to be part of standard therapy for anyone with symptomatic heart failure and should be used in preference to angiotensin receptor blockers as add-on therapy ACE inhibitors and β blockers.

ACUTE HEART FAILUREFor many years the focus of heart failure research has been on patients with chronic stable heart failure. Th e-re has been little new for acute heart failure for many years. Recruiting patients with acute heart failure is difficult: they present acutely, oft en in the middle of the night, and are oft en extremely unwell. However, clini-cal trials are now reporting which are starting to chal-lenge the ‘standard’ management of acute heart failure.

Common precipitants of an admission to hospital with heart failure include intercurrent illness, an ische-mic event or an arrhythmia. Lists of precipitants oft en quote ‘environment’ without specifying further what

* To cite: Clark AL. Heart. Published Online First: doi:10.1136/heartjnl-2013-304761


Andrew L ClarkAlmanac 2013: heart failure

that might mean; but now we have some hard eviden-ce. In a meta-analysis, Shah and colleagues11 found very strong relations between the risk of both hospitalizati-on for heart failure and death and many environmental pollutants including carbon monoxide, sulfur dioxide, nitrogen dioxide and particulate matter. Th ere is a clear public health interest in reducing environmental pollu-tion, and we can now see the economic consequences of pollution in terms of heart failure admissions.

Fluid managementData from the national audit suggest that around half of patients admitted to hospital with heart failure have moderate or severe fluid retention. Traditional mana-gement has been by fluid restriction (oft en with salt restriction), but there is remarkably little evidence to show that this treatment is eff ective. In a small but in-triguing study, Aliti et al12 randomized 75 patients to a radical fluid-restricted (800 mL/day) and sodium-re-stricted (800 mg/day) regime versus no such restricti-on. Th ere was no eff ect of the restricted diet on clinical outcomes (particularly weight loss and readmission rates at 30 days), but the fluid restriction led to greater thirst. While this is certainly not definitive evidence, it does challenge standard practice and should lead to larger trials.

Th e standard therapy for fluid retention is intra-ve-nous diuretic use, oft en using infusions over several days. It might be possible to use ultrafiltration to re-move fluid more rapidly, and an early trial of 200 pa-tients suggested that ultrafiltration might reduce the need for emergency attendances with heart failure up to 3 months aft er discharge compared with standard therapy13. In CARRESS-HF, however, the eff ects of ultrafiltration in 188 patients with the combination of fluid retention due to heart failure and worsening renal failure were studied. Th e primary endpoint was creati-nine and weight loss at 96 h. Perhaps surprisingly, renal function deteriorated more in the ultrafiltration group than with standard therapy. Th ere was no diff erence between the groups in either mortality or 90-day read-mission rate.

It is difficult to know how to interpret these data. Th e patients in CARESS-HF diff ered from those in UNLOAD, being at much higher risk because of their renal failure at baseline. Despite the patients at trial en-try having ‘persistent congestion’ and worsening renal function (mean creatinine at trial entry 180 μmol/L), those randomized to standard therapy lost over 4 kg in weight with no change in creatinine at 96 h. Th ose randomized to ultrafiltration had a similar weight loss. It

may simply be that the rise in creatinine of around 20 μmol/L with ultrafiltration represented hemoconcen-tration rather than reflecting any significant change in renal function. Ultrafiltration holds out the hope of more rapid removal of fluid for patients with heart fa-ilure (the median length of stay for fluid retention re-mains around 11 days), but its precise role has still not been defined.

RelaxinTh ere has been much excitement about serelaxin, hu-man recombinant relaxin-2. Relaxin is mainly known for its eff ect in pregnancy, but it causes arterial vaso-dilation with little eff ect on venodilation. A small dose-finding trial suggested that it might lead to more rapid relief of breathlessness in patients with acute heart fai-lure, with a suggestion that it might improve outcome14. In the RELAX-AHF trial15, 1161 patients with acute heart failure were randomised to receive 48 h infusions of placebo or serelaxin. Th e serelaxin-treated patients had a modest improvement in their breathlessness, but only in one of the two scales used. More interestingly, though, there was a reduction in mortality at 6 months in the serelaxin group compared with placebo.

How this will translate into clinical practice is not at all clear. Although the Food and Drug Administration in the USA has given serelaxin ‘Breakthrough Th era-py’ designation16, suggesting that they believe serelaxin re presents ‘a substantial improvement over currently available therapies’, the data from RELAX-AHF are not convincing. Th ere were only a small number of events, serelaxin appeared to have no eff ect on other events, and the comparator limb of the trial was placebo (and not another vasodilator such as a nitrate). Nevertheless, if the results are confirmed in further trials, serelaxin may represent the first major step forward in treating acute heart failure in many years.

Neprilysin inhibitionLCZ696 is the first in a new class of drugs termed ARNIs—that is, a combined angiotensin II receptor antagonist (valsartan) with a neprilysin inhibitor. Ne-prilysin is the enzyme responsible for the breakdown of natriuretic peptides, so its blockade increases the amount of natriuretic peptide in the circulation. In the PARAMOUNT trial17, 301 patients with heart failure and a normal ejection fraction were randomized to re-ceive the combined inhibitor or valsartan alone. Th ose receiving LCZ696 had a greater decline in N-terminal prohormone of brain natriuretic peptide at 12 weeks (an eff ect lost by 36 weeks), and there was greater im-



provement in symptoms. Th e positive results will pro-bably trigger a large outcome study, although there will be problems in knowing what the comparator to LCZ might be18.

LevosimendanTh e REVIVE studies testing the eff ects of levosimendan in patients with acute heart failure have finally been published, around 8 years aft er they were first presen-ted19. Levosimendan is a calcium sensitizing drug – it has inotropic and vasodilator eff ects. Th ere was much initial enthusiasm over its possible role in acute heart failure and, in REVIVE, there was a greater likelihood of clinical improvement with levosimendan. Howe-ver, there was an increased risk of death, albeit non-significant, in the levosimendan group.

Th e delay in publication highlights a very important issue in clinical trials – namely, that neutral or negati-ve trials might go unreported. Levosimendan has been widely available in Europe, but its potentially deleterio-us eff ects may not be recognized by those using it. Th o-se designing and running clinical trials have a moral obligation to publish their data: patients have, aft er all, agreed to take part in clinical trials on the basis that the results may benefit others20.

CHRONIC HEART FAILURE

IvabradineTh e SHIFT study21 suggested that the addition of iva-bradine, which slows the heart rate by inhibiting sinus node depolarisation, improves outcomes in patients with heart failure due to left ventricular systolic dys-function, in sinus rhythm and with a heart rate ≥70/min. Th e benefit seen was largely a reduction in hospi-talisation for heart failure, but a post hoc analysis suggested that there may be a survival benefit for patients with a resting heart rate ≥75/min22.

A single technology assessment of ivabradine by NICE23,24 recommends ivabradine as an adjunct for pa-tients with a resting heart rate ≥75/min who are already on standard therapy (including appropriate β blocker at the maximally tolerated dose), but goes on to suggest that ivabradine should only be started by a heart fai-lure specialist. Th e need for a specialist goes some way to addressing the major concern that ivabradine mi-ght come to be seen as an acceptable alternative to β blockers when the evidence that β blockers improve survival is overwhelming.

Th e ivabradine discussion highlights the potential importance of heart rate reduction as a therapeutic tar-get. A challenging reinterpretation of the data from the

DIG trial suggests that digoxin in patients with heart failure in sinus rhythm had a similar reduction in the endpoint used in the SHIFT study (namely, cardiovas-cular death or hospitalization for heart failure) as iva-bradine, with the eff ect being a reduction in hospitali-zation rather than an increase in survival25. Although digoxin is very variably used nowadays, it may be that we should be revisiting its use as heart rate-reducing agent.

AliskirenInhibition of the renin-angiotensin-aldosterone system (RAAS) has been the cornerstone of heart failure ma-nagement for decades but, although the outlines of the system are well known, the full ramifications of the RAAS are still being uncovered. For example, angio-tensin II (Ang II) can be broken down by ACE2 to yield Ang1–7, which itself has biological activity26. Th ere are many potential targets for treatment becoming available. One potential target has been the initial step in the cascade inhibition of the enzymatic activity of renin itself.

Aliskiren is a direct renin inhibitor. Early work su-ggested that it might have a more profound eff ect on su ppressing natriuretic peptide production than stan-dard therapy27, and its ability to avoid any escape from ACE inhibition makes it an attractive agent. However, two trials have cast doubt on its eff ectiveness. In the ALTITUDE trial28, 8561 patients with diabetes, chro-nic kidney disease, cardiovascular disease or both were randomized to receive aliskiren or placebo in addition to standard therapy. Th e trial was stopped early aft er an interim efficacy analysis, and there was a suggesti-on (although not statistically significant) that aliskiren might be harmful. In the ASTRONAUT study29,30, 1639 patients were randomized to aliskiren or placebo aro-und 5 days aft er an index heart failure admission, again in addition to standard therapy. Th ere was no eff ect on the main outcome measures of cardiovascular death or rehospitalization with heart failure at 6 and 12 months, but a definite signal that aliskiren might be deleterious in patients with diabetes.

Th e ATMOSPHERE study31 is rather diff erent. It is a study of patients with chronic heart failure due to left ventricular systolic dysfunction and a raised natriure-tic peptide level. Patients are randomized to aliskiren, enalapril or both. Fewer patients have diabetes (around a third), and renal function is considerably less im-paired in patients in the ATMOSPHERE trial than in those in the ALTITUDE study32. Th e results of the AT-MOSPHERE trial should give a much more profound



understanding of the possible role of aliskiren: it is su-rely possible that it might have a role as an alternative to conventional RAAS blockade rather than as an add-on.

Aldosterone antagonistsTh e problem of heart failure with a normal ejection fraction (HeFNEF) remains tricky. It has proved a di-fficult entity to define clinically despite its apparent freq uency in epidemiological studies, and no clinical trial has yet shown any convincing benefit from any treat ment strategy. Another disappointment is spiro-nolactone. In patients with heart failure due to left ven tricular systolic dysfunction, there is no doubt that mineralocorticoid antagonists help improve cardiac function, symptoms and survival33. Mineralocorticoid antagonists might be thought to be particularly likely to work in HeFNEF through their antifibrotic pro-perties. However, in the Aldo-DHF study conducted in 422 patients with HeFNEF, spironolactone had no eff ect on exercise capacity, symptoms or quality of life34. Th e mean N-terminal prohormone of brain natriuretic peptide level in the patients included in the study was only 158 ng/L, suggesting that yet again a trial of HeF-NEF has included patients who really do not have heart failure or, if they do, they are patients with an intrinsi-cally good prognosis.

DEVICE THERAPY AND MONITORING

Remote monitoringTh ere has been a great deal of enthusiasm for telemo-nitoring, particularly among commissioners who see it as a way of reducing admissions to hospital among pa-tients with chronic disease. Th e role of remote monito-ring for patients with heart failure has been much deba-ted. Although early studies suggested that there might be a major benefit, more recent trials have been much less positive, perhaps because the background standard of care against which telemonitoring is being compared has improved.

It might be that targeted intensive monitoring during periods of high risk, such as immediately aft er hospital discharge, makes the best use of remote monitoring. In a meta-analysis of trials involving over 6000 patients, Pandor et al35 found that remote monitoring following an admission with heart failure was associated with im-proved survival, particularly where usual care was less good.

DefibrillatorsIt is commonly thought that having discharges from an implantable cardioverter-defibrillator (ICD), whether

appropriate or inappropriate, is associated with an adverse prognosis in patients with heart failure36. Th e commonest reason for an inappropriate shock is atrial fibrillation with a rapid ventricular response; additio-nally, it is becoming increasingly apparent that antita-chycardia pacing may treat ventricular tachycardia wi-thout a shock being necessary. Th e MADIT-RIT trial37 reported that programming techniques that both in-crease antitachycardia pacing and delay ICD discharges reduce the risk of inappropriate discharge. Th ere was a reduction in all-cause mortality of around a half in the advanced programming group.

Intriguingly, in a cohort study of 1698 patients, Deyell et al38 found no association between inappropri-ate ICD shock and an adverse outcome. In contrast, an appropriate shock was associated with a HR of 3.11 for the combined endpoint of death and transplantati-on. Th e reasons for the discrepancy are not clear: it may be related to the fact that the patients in Deyell et al’s cohort were less severely symptomatic and were more likely to be on β blocker therapy. However, regardless of the prognostic implications, by reducing inappropri-ate shocks, advanced programming of ICDs improves patients’ quality of life by reducing the risk of a very unpleasant ICD discharge.

Cardiac resynchronisation therapyTh e other major device for heart failure is, of course, the cardiac synchronization therapy (CRT) pacema-ker. Although it has been proved to increase life expec-tancy in patients with heart failure due to left ventricu-lar systolic dysfunction, sinus rhythm and left bundle branch block, controversies remain. Many are convin-ced that patients in atrial fibrillation or other forms of conduction defect might benefit, although there is no evidence from randomized trials to support these be-liefs39,40. A particular recurring theme is the concept of ‘response’: around a third of patients are said not to res-pond to CRT based on either their symptom status or some echocardiographic index of left ventricular func-tion. Th e subtext is that there might be some patients with conventional indications for CRT who perhaps should be denied the treatment, and others with no in-dication who might benefit based on some measure of so-called dyssynchrony preoperatively.

As Witte points out41, deactivating a CRT device in a supposed ‘non-responder’ results in hemodynamic wor sening42. Defining ‘response’ in terms of symptoma-tic change, or worse, a surrogate measure such as left ven tri cular volume, is doomed to fail – we cannot know what would otherwise have happened to the pa-



waiting lists are at high risk of sudden death, and in a retrospective observational study of over 1000 patients listed for potential cardiac transplantation, Frölich et al found a marked survival benefit for patients recei-ving an ICD for primary prevention independent of the etio logy of heart failure – only around one-third of the patients had ischemic heart disease50. Th e eff ect was very much less marked for patients receiving an ICD for secondary prevention. Maybe ICDs should be considered more widely in patients on a transplant wai-ting list.

Some cells from myocardial biopsy samples cluster together to form cardiospheres which can potentially diff erentiate into many cell types. In a very small study to demonstrate safety, patients treated with intracoro-nary cardiosphere-derived cells (CDCs) following myo cardial infarction had smaller volumes of scar and lar ger volumes of viable heart mass than those receiving standard care51. CDCs join a long list of potential sou rces of stem cells, none of which has really borne fruit despite enormous enthusiasm.


References1. National Heart Failure Audit April 2011–March 2012. National

Centre for Cardiovascular Prevention and Outcomes, University Col-lege London, 2012. https:// www.ucl.ac.uk/nicor/audits/heartfailure/ad d itionalfiles/pdfs/annualreports/annual12. pdf

2. Takeda A, Taylor SJ, Taylor RS, et al. Clinical service organisation for heart failure. Cochrane Database Syst Rev 2012;9:CD002752.

3. Holland R, Battersby J, Harvey I, et al. Systematic review of multidis-ciplinary interventions in heart failure. Heart 2005;91:899–906.

4. Th omas R, Huntley A, Mann M, et al. Specialist clinics for reducing emergency admissions in patients with heart failure: a systematic re-view and meta-analysis of randomised controlled trials. Heart 2013; 99:233–9.

5. National Institute for Health and Care Excellence. Chronic heart fai-lure. Clinical guideline 108. London, 2010.

6. Al-Mohammad A, Mant J. Th e diagnosis and management of chronic heart failure: review following the publication of the NICE guidelines. Heart 2011;97:411–16.

7. National Institute for Health and Care Excellence. Chronic heart fai-lure quality standard: QS9. London, 2011.

8. Heidenreich PA, Albert NM, Allen LA, et al. Forecasting the impact of heart failure in the United States: a policy statement from the Ame-rican Heart Association. Circ Heart Fail 2013;6:606–19.

9. Mostofsky E, Rice MS, Levitan EB, et al. Habitual coff ee consumption and risk of heart failure: a dose-response meta-analysis. Circ Heart Fail 2012;5:401–5.

10. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: Th e Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787–847.

11. Shah AS, Langrish JP, Nair H, et al. Global association of air pollution and heart failure: a systematic review and meta-analysis. Lancet. Pu-blished Online First: 9 July 2013. doi:10.1016/S0140-6736(08)61345-8

tient without the device. One interesting new piece of information is that there appears to be an inverse re-lation between the duration of heart failure symptoms prior to CRT implantation and subsequent survival, particularly in those with abnormal renal function43. Th is finding is surely expected: the earlier in the natural history of illness we intervene, the greater is the likely eff ect. However, it does highlight the need to think abo-ut implanting CRT in patients with less severe symp-toms if they have left bundle branch block44, rather than waiting until patients are worse but may have less to gain.

Further encouragement for earlier CRT implantati-on comes from the BLOCK-HF study in which patients with impaired left ventricular systolic function and a conventional indication for pacing in the shape of atri-oventricular block were studied45. All the patients had a CRT device implanted, but they were randomised later to conventional dual chamber pacing or biventricu-lar pacing. Nearly 700 patients were included, and the average left ventricular ejection fraction was as high as 40%. None had a conventional indication for CRT. Th ose receiving active CRT pacing had a reduction in the primary endpoint of all-cause mortality, heart fai-lure-related urgent care or a >15% increase in left ven-tricular end-systolic volume.

Vagal stimulationA fascinating new device for patients with chronic heart failure is the vagal stimulator, which might poten-tially be combined with existing devices46. Patients with chronic heart failure commonly have an imbalance be-tween their enhanced sympathetic nervous system ac-tivity and a decline in parasympathetic activity. Th e vagal stimulator delivers electrical stimulation to the va gus nerve in the neck, timed to the cardiac cycle. Pre liminary work suggested that it might have some eff ect on exercise capacity and quality of life and left ventricular function47. A study of 650 patients is being mounted to assess its eff ects on all-cause mortality and hospitalization for heart failure48.

END-STAGE HEART FAILUREFor patients with end-stage heart failure, there has been some controversy as to whether implantable defi-brillators should be used. Th e UK guidelines on referral for heart transplantation49 address the issue of use of implantable defibrillators in terms of NICE guidance, and point out that we do not have much information to guide the management of those without ischemic heart disease. However, patients on cardiac transplant



33. Phelan D, Th avendiranathan P, Collier P, et al. Aldosterone antago-nists improve ejection fraction and functional capacity independently of functional class: a meta-analysis of randomised controlled trials. Heart 2012;98:1693–700.

34. Edelmann F, Wachter R, Schmidt AG, et al. Eff ect of spironolacto-ne on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA 2013;309:781–91.

35. Pandor A, Gomersall T, Stevens JW, et al. Remote monitoring aft er recent hospital discharge in patients with heart failure: a systema tic review and network meta- analysis. Heart.Published Online First: 16 May 2013. http://heart.bmj.com/content/early/2013/05/15/hear tjnl-2013-303811.full.pdf+html?sid=25776cbc-1e08-4e6f-abc1-6388 28de7d98

36. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008;359:1009–17.

37. Moss AJ, Schuger C, Beck CA, et al. Reduction in inappropriate thera-py and mortality through ICD programming. N Engl J Med 2012;367: 2275–83.

38. Deyell MW, Qi A, Chakrabarti S, et al. Prognostic impact of inappro-priate defibrillator shocks in a population cohort. Heart 2013;99: 1250–5.

39. Hawkins NM, Petrie MC, Burgess MI, et al. Selecting patients for cardiac resynchronization therapy: the fallacy of echocardiographic dyssynchrony. J Am Coll Cardiol 2009;53:1944–59.

40. Tang AS, Wells GA, Talajic M, et al. Cardiac-resynchronization thera-py for mild-to-moderate heart failure. N Engl J Med 2010;363:2385–95.

41. Witte KK. Cardiac resynchronisation therapy for chronic heart failu-re: predicting and measuring ‘response’. Heart 2013;99:293–4.

42. Mullens W, Verga T, Grimm RA, et al. Persistent hemodynamic bene-fits of cardiac resynchronization therapy with disease progression in advanced heart failure. J Am Coll Cardiol 2009;53:600–7.

43. Verbrugge FH, Dupont M, Vercammen J, et al. Time from emerging heart failure symptoms to cardiac resynchronisation therapy: impact on clinical response. Heart 2013;99:314–19.

44. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. Published Online First: 5 June 2013. http://circ.ahajournals.org/content/early/2013/06/03/CIR.0b01 3e31829e8776.long

45. Curtis AB, Worley SJ, Adamson PB, et al. Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK HF) Trial Investigators. Biventricular pacing for atri-oventricular block and systolic dysfunction. N Engl J Med 2013;368: 1585–93.

46. Schwartz PJ. Vagal stimulation for the treatment of heart failure: a translational success story. Heart 2012;98:1687–9.

47. Schwartz PJ, De Ferrari GM, Sanzo A, et al. Long term vagal stimula-tion in patients with advanced heart failure: first experience in man. Eur J Heart Fail 2008;10:884–91.

48. Hauptman PJ, Schwartz PJ, Gold MR, et al. Rationale and study de-sign of the increase of vagal tone in heart failure study: INOVATE-HF. Am Heart J 2012;163:954–62.

49. Banner NR, Bonser RS, Clark AL, et al. UK guidelines for referral and assessment of adults for heart transplantation. Heart 2011;97:1520–7.

50. Fröhlich GM, Holzmeister J, Hübler M, et al. Prophylactic implan-table cardioverter defibrillator treatment in patients with end-stage heart failure awaiting heart transplantation. Heart 2013;99:1158–65.

51. Makkar RR, Smith RR, Cheng K, et al. Intracoronary cardiosphere-derived cells for heart regeneration aft er myocardial infarction (CA-DUCEUS): a prospective, randomised phase 1 trial. Lancet 2012;379: 895–904.

12. Aliti GB, Rabelo ER, Clausell N, et al. Aggressive fluid and sodium re-striction in acute decompensated heart failure a randomized clinical trial. JAMA Intern Med 2013;173:1058–64.

13. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensa-ted heart failure. J Am Coll Cardiol 2007;49:675–83.

14. Teerlink JR, Metra M, Felker GM, et al. Relaxin for the treatment of patients with acute heart failure (Pre RELAX AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study. Lancet 2009;373:1429–39.

15. Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant hu-man relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 2013;381:29–39.

16. http://www.novartis.com/newsroom/media-releases/en/2013/171 1047.shtml (accessed 2 Jul 2013).

17. Solomon SD, Zile M, Pieske B, et al. Th e angiotensin receptor neprily-sin inhibitor LCZ696 in heart failure with preserved ejection frac tion: a phase 2 double-blind randomised controlled trial. Lancet 2012;380: 1387–95.

18. Cleland JG, Clark AL. Heart failure—does it matter whether LVEF is reduced? Lancet 2012;80:1363–5.

19. Packer M, Colucci W, Fisher L, et al. Eff ect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC Heart Fail 2013;1:103–11.

20. Goldacre B. Are clinical trial data shared sufficiently today? No. BMJ 2013;347:f1880.

21. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875–85.

22. Böhm M, Borer J, Ford I, et al. Heart rate at baseline influences the eff ect of ivabradine on cardiovascular outcomes in chronic heart fai-lure: analysis from the SHIFT study. Clin Res Cardiol 2013;102:11–22.

23. National Institute for Health and Care Excellence. Ivabradine in chro-nic heart failure. 2012. http://www.nice.org.uk/TA267

24. Hardman SM. Ivabradine in heart failure: NICE guidance. Heart. Pu blished Online First: 18 June 2013. http://heart.bmj.com/content/early/2013/06/17/heartjnl-2012-303490.full.pdf+html?sid=29e1ec6a-5827-4d48-95ac-87be0a60b7c6

25. Castagno D, Petrie MC, Claggett B, et al. Should we SHIFT our think-ing about digoxin? Observations on ivabradine and heart rate reduc-tion in heart failure. Eur Heart J 2012;33:1137–41.

26. Chemaly ER, Hajjar RJ, Lipskaia L. Molecular targets of current and pro spective heart failure therapies. Heart 2013;99:992–1003.

27. McMurray JJ, Pitt B, Latini R, et al. Eff ects of the oral direct renin inhi-bitor aliskiren in patients with symptomatic heart failure. Circ Heart Fail 2008;1:17–24.

28. Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367:2204–13.

29. Gheorghiade M, Albaghdadi M, Zannad F, et al. Rationale and design of the multicentre, randomized, double-blind, placebo-controlled Alis k iren Trial on Acute Heart Failure Outcomes (ASTRONAUT). Eur J Heart Fail 2011;13:100–6.

30. Gheorghiade M, Böhm M, Greene SJ, et al. Eff ect of aliskiren on post-discharge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial. JAMA 2013;309:1125–35.

31. Krum H, Massie B, Abraham WT, et al. Direct renin inhibition in addition to or as an alternative to angiotensin converting enzyme in-hibition in patients with chronic systolic heart failure: rationale and design of the Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE (ATMOSPHERE) study. Eur J Heart Fail 2011;13:107–14.

32. McMurray JJ, Abraham WT, Dickstein K, et al. ALTITUDE, and the implications for ATMOSPHERE. Eur J Heart Fail 2012;14:341–3.


REVIEWS

Almanac 2013: cardiac arrhythmias and pacing—an editorial overview of selected research that has driven recent advances in clinical cardiology*Reginald Liew1,2

Received 5 July 2013. Revised 16 July 2013. Accepted 18 July 2013

Contact address:Reginald Liew, MD,Gleneagles Hospital, 6A Napier Road, Singapore 258500, SingaporeE-mail: [email protected]

Abstract: Important advances have been made in the past few years in the fields of clinical cardiac electrophysiology and pa cing. Researchers and clinicians have a greater understanding of the pathophysiological mechanisms underlying atrial fibrillation (AF), which has transpired into improved methods of detection, risk stratification, and treatments. Th e introduc-tion of novel oral anticoagulants has provided clinicians with alternative options in managing patients with AF at moderate to high thromboembolic risk and further data has been emerging on the use of catheter ablation for the treatment of symp-tomatic AF. Another area of intense research in the field of cardiac arrhythmias and pacing is in the use of cardiac resynchro-nization therapy (CRT) for the treatment of patients with heart failure. Following the publication of major landmark rando-mized controlled trials reporting that CRT confers a survival advantage in patients with severe heart failure and improves symptoms, many subsequent studies have been performed to further refine the selection of patients for CRT and determine the clinical characteristics associated with a favorable response. Th e field of sudden cardiac death and implantable cardiover-ter defibrillators also continues to be actively researched, with important new epidemiological and clinical data emerging on improved methods for patient selection, risk stratification, and management. Th is review covers the major recent advances in these areas related to cardiac arrhythmias and pacing.

ATRIAL FIBRILLATION

Epidemiology of atrial fibrillationA number of large scale epidemiological studies using registry databases and prospective cohort data have reported novel associations between atrial fibrillation (AF) and other non-traditional risk factors for AF. Th e-se include an increased risk of incident AF in patients with high glycosylated hemoglobin (HbA1c) and poor glycemic control1, coeliac disease2, rheumatoid arthri-tis3 and psoriasis4, use of non-aspirin, non-steroidal anti-inflammatory drugs (NSAIDs)5, and increased height6. Another interesting association is the finding from a substudy of 260 patients with chronic AF from the SAFETY trial (Standard versus Atrial Fibrillation Specific Management Study) that mild cognitive impai-r ment is highly prevalent among older, high risk pa-tients hospitalized with AF7. In another substudy of the Cardiovascular Health Study, investigators found that higher base-line circulating concentrations of to-

tal long chain n-3 polyunsaturated fatty acids (PUFA) were associated with a lower risk of incident AF8.

Other interesting recent epidemiological studies on AF include the association of incident AF with an in-creased risk of developing end stage renal disease in pa-tients with chronic kidney disease9, and a community based study of 3220 patients which showed that new AF in patients with no history of AF before a myocardi-al infarction increased mortality in patients with myo-cardial infarction10. In a large Swedish registry study of 100 802 patients with AF, Friberg et al11 found that is-chemic strokes were more common in women than in men, supporting the notion that female gender should be taken into consideration when making decisions about anticoagulation treatment. Furthermore, among older patients admitted with recently diagnosed AF, the risk of stroke appears to be greater in women than in men, regardless of warfarin use12, and among healthy women new onset AF was found to be independently

1 Duke-NUS Graduate Medical School, Singapore, Singapore2 Gleneagles Hospital, Singapore, Singapore* To cite: Liew R. Heart. Published Online First: doi:10.1136/heartjnl-2013-304592


Reginald LiewAlmanac 2013: cardiac arrhythmias and pacing

associated with all cause cardiovascular and non-car-dio vascular mortality13.

Medical management of AFData from the RealiseAF study, an international, ob-servational, cross-sectional survey of patients with any history of AF in the previous year, suggested that pati-ents in which their AF was ‘controlled’ (defined as si-nus rhythm or AF with a resting heart rate ≤80 beats/min) had a better quality of life and fewer symptoms than those whose AF was uncontrolled14. Nonetheless, even patients with controlled AF experienced frequent symptoms, functional impairment, altered quality of life and cardiovascular events-hence the importance of ongoing eff orts to develop novel and better treatments for AF. Th e RECORDAF (Registry on Cardiac Rhythm Disorders Assessing the Control of Atrial Fibrillation) re-gistry was a worldwide, prospective observational sur-vey of AF management in an unselected, community based cohort over a 12 months period15. Th e investiga-tors found that in 5171 patients whose data were avai-lable, therapeutic success (driven by control of AF) was achieved in 54% overall (rhythm control 60% vs rate control 47%). Th e choice of rate or rhythm strategy did not aff ect clinical outcomes (which were driven mainly by hospitalizations for arrhythmia and other cardiovas-cular causes), although the choice of rhythm control re-duced the likelihood of AF progression.

Th e RACE (Rate Control Efficacy in Permanent Atri-al Fibrillation) II trial was the first formal assessment of alternative rate control goals in AF and demonstrated for the first time that a ‘lenient rate control’ strategy (target resting heart rate <110 beats/min) was non-inferior to a ‘strict rate control’ strategy (target resting heart rate <80 beats/ min and heart rate during mode-rate exercise <110 beats/min)16. Two subsequent sub-studies of the RACE II trial showed that the stringency of rate control had no significant eff ect on the quality of life in patients with permanent AF17 and that leni-ent rate control did not have an adverse eff ect on atrial and ventricular remodeling compared with strict rate control (although female gender was independently associated with significant adverse cardiac remode-ling)18. In another sub-study looking at cardiovascular outcomes in subjects from the original AFFIRM trial (Atrial Fibrillation Follow-Up Investigation of Rhythm Management), investigators found that the composite outcome of mortality or cardiovascular hospital stays was better in rate compared with rhythm control stra-tegies (using amiodarone or sotalol)19. Non-cardiovas-cular death and intensive care unit hospital stay were

more frequent in patients on amiodarone, and time to cardiovascular hospital stay was shorter. In a prospec-tive, randomized, open label trial of pharmacological cardioversion in patients with persistent AF, Yamase et al compared amiodarone with bepridil in 40 consecuti-ve subjects20. Th e investigators found that bepridil was superior to amiodarone in achieving sinus conversion (85% vs 35%; p<0.05) and maintaining sinus rhythm af-ter an average follow-up of 14.7 months (75% vs 50%).

Th e issue of whether PUFA have any beneficial eff ects on AF remains a topical one. A large meta-analysis of 10 randomized controlled trials involving 1955 patients found that PUFA supplementation had no significant eff ect on AF prevention21. In the FORWARD trial (Ran-domized Trial to Assess Efficacy of PUFA for the Mainte-nance of Sinus Rhythm in Persistent Atrial Fibrillation), 586 outpatient participants with confirmed symptoma-tic paroxysmal AF who required cardioversion or had at least two episodes of AF in the preceding 6 months were randomly assigned to receive placebo or PUFA (1 g/day) for 12 months22. Th e investigators found that PUFA supplementation did not reduce the recur-rence of AF or have any beneficial eff ects on the other prespecified end points (all cause mortality, non-fatal stroke, non-fatal acute myocardial infarction, systemic embolism or heart failure). In a large placebo contro-lled, randomized clinical trial involving 1516 patients in 28 centres, perioperative supplementation of PUFA, although well tolerated, was not shown to reduce the risk of postoperative AF23. In contrast, another rando-mized, double blind, placebo controlled trial involving 199 patients who received either PUFA (2 g/day) or placebo for 4 weeks before direct current (DC) cardi-oversion found that patients who received PUFA were more likely to be in sinus rhythm at 1 year follow-up compared with control patients24.

Monitoring and assessment of AFTh e detection of paroxysmal AF can be difficult with current methods and technology; hence ongoing eff orts are being made to improve methods for detection and diagnosis. Th e association between subclinical AF and cryptogenic stroke has gained increasing prominence with more careful monitoring of patients using invasive and non-invasive methods. In a nice study of 2580 pa-tients aged 65 years or older with a pacemaker or defibrillator recently implanted and no history of AF, in-vestigators detected subclinical atrial tachyarrhythmia in 261 patients (10.1%)25. Over a mean follow-up of 2.5 years, patients with subclinical atrial tachyarrhyth-mias were found to have an increased risk of clinical



AF and of ischaemic stroke or systemic embolism (HR 2.49, 95% CI 1.28 to 4.85; p=0.007). In patients who do not have pacemakers or defibrillators who present with cryptogenic stroke, longer term ambulatory ECG monitoring using external or implantable devices may be worth considering to help confirm a diagnosis of subclinical AF26,27. In a study of 100 patients being scre-ened for AF, investigators compared the eff ectiveness of using 7-day triggered ECG monitoring with 7-day con-tinuous Holter ECG monitoring for detection of AF28. An arrhythmia was recorded in 42 subjects (42%) with continuous ECG recordings versus 37 subjects (32%) with triggered monitoring (p=0.56). Th e sensitivity of triggered ECG monitoring was found to be lower than that of continuous ECG monitoring, mainly due to a shorter eff ective monitoring duration, although quali-tative triggered ECG analysis was less time consuming than continuous ECG analysis. In another larger study of 647 patients with implantable continuous moni-toring devices, intermittent rhythm monitoring was found to be significantly inferior to continuous moni-toring for the detection of AF and was not able to iden-tify AF recurrence in a great proportion of patients at risk29. In an interesting study investigating the use of N-terminal pro B-type natriuretic peptide (NT-proBNP) values to estimate the recency of AF onset and safety of cardioversion, investigators separated 86 patients pre-senting with presumed recent onset AF into two groups (43 in each group), based on NTproBNP concentrati-ons above and below a cut-off value, and subjected all subjects to transoesophageal echocardiography30. NT-proBNP concentrations below the cut-off value were found to be the most powerful predictor of the presen-ce of thrombus, suggesting that a short term increase in NT-proBNP aft er AF onset might be useful in assessing the recency of onset of the AF episode, if unknown, and might be potentially used to help determine the safety of cardioversion.

Catheter ablation of AFAlthough antiarrhythmic drugs (AADs) and catheter ablation are the main treatment options available to maintain sinus rhythm in symptomatic patients with AF, many clinicians and patients still opt for an initi-al conservative strategy and consider catheter ablati-on only aft er one or more AADs have been tried and found to be ineff ective. Th e question of whether ca-theter ablation of AF is an eff ective initial therapy for paroxysmal AF was addressed in a small randomized study in which 294 patients (with no history of AAD use) were randomly assigned to an initial strategy with

radiofrequency catheter ablation or therapy with a class 1c or III AAD31. Th e investigators found no significant diff erence between the ablation and drug therapy groups in the cumulative burden of AF (90th centile of arrhythmia burden 13% and 19%, respectively; p=0.10) in the initial 18 months. However, at 24 months, AF burden was significantly lower in the ablation group compared with the drug therapy group (9% vs 18%; p=0.007) and more patients in the ablation group were free from symptomatic AF (93% vs 84%; p=0.01). In the drug therapy group, 54 patients (36%) subsequently underwent ablation.

In another small randomized study of AF ablation in patients with persistent AF, advanced heart failure and severe left ventricular (LV) systolic dysfunction, Mac-Donald et al32 found that catheter ablation was success-ful at restoring sinus rhythm in 50% of patients, althou-gh the procedure was associated with a significant complication rate of 15%. In addition, catheter ablation did not improve LV ejection fraction (LVEF) (as measured using cardiovascular magnetic resonance) or other secondary outcomes, calling into question the risk/benefit ratio of performing AF ablation in patients with persistent AF and LV dysfunction. An internatio-nal multicentre registry study of 1273 patients under-going AF ablation suggested that maintenance of sinus rhythm through catheter ablation was associated with a lower risk of stroke and death compared with a control group consisting of medically treated patients with AF in the Euro Heart Survey33.

Several studies have recently been reported which increase our understanding of the factors associated with success or failure following AF ablation. Th e im-portance of pulmonary vein (PV) isolation was further reinforced by Miyazaki et al34 who reported long term clinic outcomes of 83.6% (480 out of 574 patients) with a mean follow-up of 27±14 months using an extensive PV isolation approach in patients with both paroxysmal and persistent AF34. Late recurrences (defined as 6–12 months following the initial AF ablation proce-dure) was associated with PV reconnection in all pa-tients, while very late recurrences (>12 months aft er the procedure) were associated with non-PV triggers in 85.7% of cases. Th e added benefit of performing additional linear ablation lines aft er PV isolation on improving outcomes following AF ablation has been further questioned in a prospective, randomized study of 156 patients with paroxysmal AF who were randomly assigned to undergo PV isolation only, PV isolation and a roof line, or PV isolation, roof line and



a posterior inferior line35. Th e investigators found no improvement in clinical outcome in the patients who received the additional lines while, unsurprisingly, the addition of the linear ablations significantly prolonged procedure times. A number of investigators have found that many factors are predictive of or adversely related to outcome following AF ablation in addition to well established factors, such as type of AF (paroxysmal or persistent), left atrial size, and presence of LV dysfunc-tion. Th ese novel factors include cardiac related factors, such as atrial electromechanical interval on pulse wave Doppler imaging36 and left atrial fibrosis as assessed by measuring echocardiograph derived calibrated integra-ted backscatter37, pericardial fat38, plasma biomarkers (such as plasma B-type natriuretic peptide values39), renal dysfunction40, and the metabolic syndrome41. Interestingly, the presence of dissociated PV potenti-als, oft en used as a marker of successful PV isolation, was not found to predict AF recurrence in a study of 89 consecutive patients over a mean follow-up of 21±8 months42. In a small randomized controlled study of 161 patients, a 3 month course of colchicine (0.5 mg twice daily) was found to decrease early AF recurren-ce aft er PV isolation, probably due to a reduction in inflammatory mediators, including interleukin 6 (IL-6) and C reactive protein (CRP)43. Colchicine (1.0 mg twi-ce daily initially followed by a maintenance dose of 0.5 mg twice daily for 1 month) was also found to reduce the incidence of post-operative AF and decrease in-ho-spital stay in a multicentre, double blind, randomized trial of 336 patients44. In an interesting small randomi-zed study of PV isolation with and without concomitant renal artery denervation in 27 patients with refractory symptomatic AF and resistant hypertension, Pokusha-lov et al showed that renal artery denervation reduced systolic and diastolic blood pressure and reduced the recurrence of AF during 1 year follow-up45.

Another area of research in the field of AF ablati-on has been on the factors associated with increased complications from the procedure. Using data from the California State Inpatient Database, Shah et al found that among 4156 patients who underwent an initial AF ablation procedure, 5% had periprocedural com-plications (most commonly vascular) and 9% were readmitted within 30 days46. Factors associated with a higher risk of complications and/or 30-day readmissi-on following an AF ablation were older age, female sex, prior AF hospitalizations, and recent hospital proce-dure experience. In another retrospective study of 565 patients, both the CHADS2 and CHA2DS2-VASc scores

were found to be useful predictors of adverse events following AF ablation47.

Th e first randomized clinical trial comparing the efficacy and safety of catheter ablation of AF with sur-gical ablation involved 124 patients with drug refrac-tory AF48. Th e investigators found that the primary end point (freedom from left atrial arrhythmia >30 s without AADs aft er 12 months) was 36.5% for the ca-theter ablation group and 65.6% for the surgical group (p=0.0022), but patients in the surgical group experien-ced significantly greater adverse eff ects (driven mainly by procedural complications) compared to the cathe-ter ablation group. Pison et al reported relatively high 1 year success rates (93% for paroxysmal AF and 90% for persistent AF) with a combined transvenous endo-cardial and thorascopic epicardial approach for a single AF ablation procedure in a small cohort of 26 patients with AF49.

Strategies to decrease thromboembolismTh e use of novel oral anticoagulants to decrease the risk of stroke and systemic thromboembolism in patients with AF has gained increasing use and acceptance over the past several years following the publication of a number of landmark multicentre, randomized clinical trials comparing their efficacy with conventional vita-min K antagonists50-53. A meta-analysis of 12 studies totaling 54 875 patients showed a significant reducti-on of intracranial hemorrhage with these novel anti-coagulants compared with vitamin K antagonists, and a trend toward reduced major bleeding54. Th ese novel oral anticoagulants may also have a role in patients undergoing DC cardioversion. A sub-study of patients with AF who underwent cardioversion in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Th erapy) trial showed that dabigatran (at two doses of 110 and 150 mg twice daily) is a reasonable alternative to warfarin, with low frequencies of stroke and major bleeding within 30 days of cardioversion55.

Th ese novel oral anticoagulants may also have a role to play in the periprocedural anticoagulation of patients undergoing radiofrequency ablation for AF. Several re-gistry and observational studies have suggested that dabigatran is as safe as periprocedural warfarin in pa-tients undergoing AF ablation56-58, although one study suggested an increased risk of bleeding and thrombo-embolic complications with dabigatran compared with warfarin59. A prospective randomized controlled trial is required to definitively address the issue as to whether these novel oral anticoagulants can be used in place of warfarin for periprocedural anticoagulation in patients



decreased the risk of heart failure events in relatively asymptomatic patients with a low ejection fraction and wide QRS complexes66, a number of subsequent analyses have provided further interesting information. Th is includes data on the benefits of CRT in reducing the risk of recurring heart failure events67 and atrial ar-rhythmias68, identification of additional factors that are associated with improved response to CRT69,70 and with a super-response (defined by patients in the top quar-tile of LVEF change)71, factors associated with greatest improvement in quality of life72, and information on optimal lead positioning of the LV lead73,74.

In a prospective, randomized controlled study to address whether ventricular dysynchrony on echocar-diography predicted response to CRT, Diab et al found that the presence of echocardiographic dysynchrony identified patients who derived the most improvement from CRT, although patients without dysynchrony also showed more benefit and less deterioration with CRT than without. Th e authors concluded that the latter group of patients should not be denied CRT75. CRT ap-peared to produce some benefits in patients with heart failure and a normal QRS duration, with patients expe-riencing an improvement in symptoms, exercise capa-city and quality of life, although there was no diff eren-ce in total or cardiovascular mortality in patients who received CRT compared with those receiving optimal pharmacological management76. Among patients with heart failure and prolonged QRS duration who recei-ved a CRT device, those with a left bundle branch block (LBBB) morphology derived greater benefit (lower risk of ventricular arrhythmias and death and improved echocardiographic parameters) compared with pati-ents who had a non-LBBB QRS pattern (right bundle branch block (RBBB) or intraventricular conduction disturbances)77.

Th e issue of whether CRT in patients undergoing atrioventricular (AV) junction ablation for permanent AF was superior to conventional RV pacing in reducing heart failure events was addressed in a prospective, ran-domized, multicentre study involving 186 patients78. Over a median follow-up of 20 months (IQR 11-24 months) fewer patients in the CRT group (11%) expe-rienced primary end point events (death from heart fa-ilure, hospitalization due to heart failure or worsening heart failure) compared with patients in the RV group (26%; CRT vs RV group: sub-hazard ratio (SHR) 0.37, 95% CI 0.18 to 0.73; p=0.005). Total mortality was si-milar in both groups. In a follow-up analysis looking at the predictors of clinical improvement aft er the ‘ablate

undergoing AF ablation. Economic evaluation of these novel oral anticoagulants suggest that they may be cost eff ective as a first line treatment for the prevention of stroke and systemic embolism60, especially in patients at high risk of hemorrhage or stroke, unless interna-tional normalized ratio (INR) control with warfarin is already excellent61.

Another strategy to decrease thromboembolic e vents in patients with AF that is gaining favor invol-ves the use of mechanical left atrial appendage (LAA) occ lu sion devices. In a systematic review of 14 studies, im p la n tation of LAA occlusion devices in patients with AF was successful in 93% of cases, with periprocedural mor tality and stroke rates of 1.1% and 0.6%, respecti-vely; the overall incidence of stroke among all studies was 1.4% per annum62. A substudy of the PROTECT AF (Percutaneous Closure of the LAA versus Warfarin Th e-rapy for Prevention of Stroke in Patients with AF) study repo rted that 32% of implanted patients had some de-gree of peridevice flow at 12 months on transoesopha-geal echo cardiography, although this did not appear to be associated with an increased risk of thromboembo-lism com pared to patients with no peridevice flow who disco n tinued warfarin63. A systematic review aimed at determining which subgroups of patients would benefit most from LAA closure devices looked at the location of atrial thrombi in patients with AF in a total of 34 stu-dies64. Th e investigators concluded that patients with non-valvular AF may derive greater benefit from LAA closure devices – 56% of patients with valvular AF had atrial thrombi located outside the LAA, 22% in mixed cohorts and 11% in non-valvular AF patients.

CARDIAC RESYNCHRONISATION THERAPY AND PACING

Cardiac resynchronization therapyRecent research in the area of cardiac resynchronizati-on therapy (CRT) has looked at the long term eff ects of CRT pacing on LV and right ventricular (RV) function and further into which sub-groups of patients may de-rive greatest benefit from CRT pacing. A favorable RV functional response to CRT appears to be associated with improved survival in patients with CRT devices, and RV function was found to be an independent pre-dictor of long term outcome aft er CRT insertion in a study of 848 CRT recipients65. Following the landmark MADIT-CRT (Multicenter Automatic Defibrillator Im-plantation Trial-Cardiac Resynchronization Th erapy) study, which demonstrated that CRT combined with implantable cardioverter defibrillator (ICD, CRT-D)



ents have a long history of recurrent syncope and may benefit from cardiac pacing, although in a small series of 18 patients (followed up for up to 14 years), no pa-tient had permanent AV block86. Th e prognosis among healthy individuals admitted with their first episode of syncope was studied in a Danish nationwide registry involving 37 017 patients with syncope and 185 085 age and sex matched controls87. Patients who were ad-mitted with syncope had significantly increased all ca-use mortality, cardiovascular hospitalization, recurrent syncope and stroke event rates and were more likely to have a pacemaker or ICD inserted later.

CIED related infectionCIED infection is recognized as a significant cause of morbidity, mortality, and increased healthcare costs. Th e clinical characteristics, outcome, and health care implications of CIED related infections and endocar-ditis was analyzed in a prospective cohort study using data from the International Collaboration on Endocar-ditis-Prospective Cohort Study (ICE-PCE) involving 61 centres in 28 countries88. CIED infection was dia-gnosed in 177 out of 2760 patients (6.4%). In-hospital and 1 year mortality rates were 14.7% (95% CI 9.8% to 20.8%) and 23.2% (95% CI 17.2% to 30.1%), respecti-vely. Th e rate of concomitant valve infection was high (found in 66 patients, 37.3%, 95% CI 30.2% to 44.9%) and early device removal was associated with impro-ved survival at 1 year. In an attempt to assess the long term outcomes and predictors of mortality in patients treated according to current recommendations for CIED infection, Deharo et al conducted a two-group matched cohort study of 197 cases of CIED infection89. Long term mortality rates were similar between cases and matched controls (14.3% vs 11.0% at 1 year and 35.4% vs 27.0% at 5 years, respectively; both p=NS). In-dependent predictors of long term mortality were older age, CRT, thrombocytopenia, and renal insufficiency. In another study examining whether the timing of the most recent CIED procedure influenced the clinical presentation and outcome of lead associated endocar-ditis (LAE), investigators found that early LAE presen-ted with signs and symptoms of local pocket infection, whereas a remote source of bacteremia was present in 38% of late LAE but only 8% of early LAE90. In-hospital mortality was low (early 7%; late 6%).

and pace’ strategy, more patients in the CRT group res-ponded to treatment (83% vs 63% in the RV group)79. CRT mode and echo-optimized CRT were found to be the only independent protective factors against non-response (HR=0.24, 95% CI 0.10 to 0.58, p=0.001 and HR=0.22, 95% CI 0.07 to 0.77, p=0.018, respectively). In the PACE (Pacing to Avoid Cardiac Enlargement) tri-al, RV pacing in patients with bradycardia and preser-ved LVEF was associated with adverse LV remodelling and deterioration of systolic function at the second year, which was prevented by biventricular pacing80.

Heart block and pacemakersTh e long term survival of older patients (average age 75 ±9 years) with Mobitz I second degree AV blo-ck was examined in a retrospective cohort study of 299 pa tients81. Th e investigators found that 141 pa-tients (47%) had a cardiac implantable electronic de-vice (CIED) inserted during the follow-up period, of which 17 were ICDs. Patients with a CIED had grea-ter cardiac co morbidity than those without a CIED, although CIED implantation was associated with a 46% reduc tion in mortality (HR 0.54, 95% CI 0.35 to 0.82; p=0.004). In another observational study of the impact of the ventricular pacing site on LV function in chil-dren with AV block, van Geldrop et al found that LV fractional shortening was significantly higher with LV pacing than with RV pacing82.

Further research on the topic of whether cardiac pacing is beneficial in patients with neurally mediated syncope suggests that dual chamber pacing may be use-ful in patients with severe asystolic forms. In the ran-domized multicentre ISSUE-3 trial (Th ird International Study on Syncope of Uncertain Etiology) patients with syncope due to documented asystole on an implantable loop recorder were randomly assigned to dual cham-ber pacing with rate drop response or to sensing only83. Th ose assigned to dual chamber pacing had fewer syncopal episodes during follow-up (32% absolute and 57% relative reduction in syncope). A positive test with intravenous adenosine 50-triphosphate (ATP) has been shown to correlate with a subset of patients with neurally mediated syncope84. A randomized, multicen-tre trial of the potential benefit of the ATP test in el-derly patients (mean age 75.9±7.7 years) with syncope of unknown origin reported that active dual chamber pacing in those with a positive ATP test reduced synco-pe recurrence risk by 75% (95% CI 44% to 88%)85. Long term outcome data on a distinct form of AV block, paroxysmal AV block, which cannot be explained by currently known mechanisms, suggest that these pati-



city (African Americans having a higher risk) as well as traditional risk factors96.

More intense research has been conducted in a va-riety of settings on the early repolarization syndrome (ERS) since landmark studies showed a link with idi-opathic ventricular fibrillation and sudden death97,98. Th ese include studies on ERS on cardiac arrest survi-vors with preserved ejection fraction99, in families with sudden arrhythmic death syndrome100 and other fami-lies with an early repolarization pattern on the ECG101, and in Asian populations102. However, there is still some controversy over the exact clinical significance of these ECG findings and what the implications are103,104.

Th e genetics of inherited cardiac conditions and how specific genotypes can lead to clinical manifesta-tions of disease, aff ect SCD risk or guide management continues to attract intense interest105-108. Results from the DARE (Drug-induced Arrhythmia Risk Evaluation) study, in which 167 single nucleotide polymorphisms spanning the NOS1AP gene, were evaluated in 58 Cau-casian patients who had experienced drug induced QT prolongation and 87 Caucasian controls, demonstra-ted that common variations in the NOS1AP gene were associated with a significant increase in drug induced long QT syndrome109. Th is may have clinical implicati-ons for future pharmacogenomics testing in patients at risk of drug induced long QT syndrome and safer pre-scribing. In another study assessing whether non-car-diovascular hERG (human Ether à go-go-Related Gene) channel blockers are associated with an increased risk of SCD in the general population, investigators com-pared 1424 cases of SCD with 14 443 controls110. Use of hERG channel blockers was found to be associated with an increased risk of SCD and drugs with a high hERG channel inhibiting capacity had a higher risk of SCD than those with a low hERG channel inhibiting capacity.

Implantable cardioverter defibrillatorsTh e clinical parameters associated with death befo-re appropriate ICD therapy in patients with ischemic heart disease who had an ICD inserted for primary prevention were assessed in a retrospective cohort study of 900 patients111. Th e investigators found that New York Heart Association (NYHA) functional class ≥ III, advanced age, diabetes mellitus, LVEF ≤25%, and a history of smoking were significant independent pre-dictors of death without appropriate ICD therapy, and suggested that this information may facilitate a more patient tailored risk estimation. Another risk score for predicting acute procedural complications or death af-

VENTRICULAR ARRHYTHMIAS AND SUDDEN CARDIAC DEATH

Epidemiology of sudden cardiac deathSudden death is a frequent and well recognized risk in patients following myocardial infarction. In a study analyzing data from 1067 patients from VALIANT (Valsartan in Acute Myocardial Infarction Trial) who had sudden death, investigators found that a high pro-portion of the deaths occurred at home, although in-hospital events were more common early on91. Patients who were asleep were more likely to have unwitnessed events. Although sudden cardiac death (SCD) and co-ronary artery disease (CAD) have many risk factors in common, certain clinical and electrocardiographic parameters may be useful to help separate out the two risks. For example, in a study of 18 497 participants from the ARIC (Atherosclerosis Risk in Communities) study and the Cardiovascular Health Study, Soliman et al found that aft er adjusting for common CAD risk factors, hypertension, increased heart rate, QTc prolon-gation, and abnormally inverted T waves were found to be stronger predictors of high SCD risk92. In com-parison, elevated ST segment height (measured at both the J point and 60 ms aft er the J point) was found to be more predictive of high incident CAD risk.

More research has also been performed on SCD in other sub-groups. In a prospective, national survey of sports related sudden death performed in France from 2005 to 2010, involving subjects 10-75 years of age, investigators found that the overall burden of sudden death was 4.6 per million population per year, with 6% of cases occurring in young competitive athletes and more than 90% of cases occurring in the context of re-creational sports93. Bystander cardiopulmonary resus-citation (CPR) and initial use of cardiac defibrillation were the strongest independent predictors for survival to hospital discharge, although bystander CPR was only initiated in one third of cases. In a retrospective autopsy study of 902 young adults (mean age 38±11 years) who had suff ered non-traumatic sudden death, the cause of sudden death was attributed to a cardi-ac condition in 715 (79.3%) and unexplained in 187 (20.7%)94. In another nationwide study on the inciden-ce of SCD in persons aged 1-35 years, 7% of all deaths were attributed to SCD95. Th e incidence of SCD in the young, estimated to be 2.8% per 100 000 person-years, was higher than previously reported. Risk factors for SCD in post-menopausal women may include more novel parameters, such as higher pulse, higher waist-to-hip ratio, elevated white blood cell count, and ethni-



ventricle) with LVEF >30% had a similar risk to those with LVEF ≤30%, while in patients with LVEF ≤30%, minimal or no scarring was associated with low risk, similar to those with LVEF >30%.

Th e use of intracardiac ICD parameters to assess risk has also received further attention. In a prospective, multicentre study of 63 ICD patients, T wave alternans and non-alternans variability (TWA/V) was found to be significantly greater before ventricular tachycardia/ventricular fibrillation (VT/VF) episodes than during baseline rhythm117. Th e investigators suggested that continuous measurements of TWA/V from the intra-cardiac ICD electrograms may be a useful parameter to detect impending VT/VF and allow the device to initi-ate pacing therapies to prevent the ventricular arrhyth-mias from occurring. In contrast, an early analysis of a prospective, single centre study on the use of ICD based ischemia monitoring on clinical care and pati-ent management reported that this parameter was not clinically useful and actually increased the number of unscheduled outpatient visits in patients with this fea-ture on their ICD compared with patients with ICDs without this capability118.

Reports on the complications and negative aspects of ICDs include problems associated with the Sprint Fidelis ICD leads119-121 and potential psychological im-pact and phobic anxiety among ICD recipients122. In a study of 3253 patients from 117 Italian centres who un-derwent de novo implantation of a CRT-D device, in-vestigators found that device related events were more frequent in patients who received CRT-D devices com-pared with those who received ICDs only (single or dual chamber), although these events were not associ-ated with a worse clinical outcome123. In a multicentre, longitudinal cohort study of 104 049 patients receiving single and dual chamber ICDs, dual chamber devi-ce implantation was more common, but was associa-ted with increased peri-procedural complications and in-hospital mortality compared with single chamber ICDs124. A retrospective, single centre cohort study of 334 hypertrophic cardiomyopathy patients with ICDs reported that this group of patients had significant car-diovascular mortality and were exposed to frequent in-appropriate shocks and implant complications125. Ad-verse ICD related events (inappropriate shocks and/or implant complications) were seen in 101 patients (30%; 8.6% per year), and patients with CRT-D were more li-kely to develop implant complications than those with single chamber ICDs and had a higher 5-year cardio-vascular mortality rate.

ter ICD implantation using 10 readily available variables from 268 701 ICD implants was developed to provide useful information in guiding physicians on patient se-lection and determining the intensity of post-implant care required112. A risk score aimed at predicting the long term (8 years) benefit of primary prevention ICD implantation was applied to 11 981 patients from the MADIT-II trial113. Th e investigators found that patients with low and intermediate risk (0 or 1-2 risk factors, respectively) benefitted more from ICD implantation, compared with patients with high risk (≥3 risk factors) who had multiple comorbidities, in which there was no significant diff erence in 8 years survival between ICD and non-ICD recipients.

Another risk score for the prediction of mortality in Medicare beneficiaries receiving ICD implantation for primary prevention was developed from a cohort of 17 991 patients and validated in a cohort of 27 893 patients114. Over a median follow-up of 4 years, 6741 (37.5%) patients in the development cohort and 8595 (30.8%) patients in the validation cohort died. Seven cli-nically relevant predictors of mortality were identified and used to develop a model for determining those pa-tients at highest risk for death aft er ICD implantation. Future selection of ICD recipients for primary preven-tion ICDs may therefore be refined and more perso-nalized to the individual patient’s risk/ benefit profile with the use of such models, rather than being based predominantly on LVEF, as is recommended by current guidelines.

Other investigations, such as cardiac magnetic re-sonance (CMR) imaging to identify and characterize myocardial scar, may be a useful addition to future risk stratification of patients for primary prevention ICD implantation. Th e ability of scar characteristics assessed on CMR to predict ventricular arrhythmias was evalua-ted in a study of 55 patients with ischemic cardiomyo-pathy who received an ICD for primary prevention and in whom CMR with late gadolinium enhancement had been performed before ICD implantation115. All CMR derived scar tissue characteristics were found to be pre-dictive for the occurrence of ventricular arrhythmias, supporting the potential use of this imaging modality to help refine risk stratification of patients and improve selection for ICD implantation. Th is finding was furt-her supported by a prospective study of 137 patients evaluated with CMR before ICD implantation for pri-mary prevention116. Myocardial scarring on CMR was found to be an independent predictor of adverse outco-mes. Patients with significant scarring (>5% of the left



those that occurred at home (34% vs 12%, respectively; adjusted OR 2.49, 95% CI 1.03 to 5.99; p=0.04)136. Ho-spital characteristics associated with improved pati-ent outcomes following OHCA were analyzed from the Victorian Ambulance Cardiac Arrest Registry of 9971 patients over an 8 year period137. Outcome following OHCA was found to be significantly improved in ho-spitals with 24 h cardiac interventional services (OR 1.40, 95% CI 1.12 to 1.74; p=0.003) and patient recep-tion between 08.00 and 17.00 h (OR 1.34, 95% CI 1.10 to 1.64; p=0.004). OHCA in children was assessed in a prospective, population based study of victims yo-unger than 21 years of age138. Th e incidence of pedia-tric OHCA was 9.0 per 100 000 pediatric person-years (95% CI 7.8 to 10.3), whereas the incidence of pedia-tric OHCA from cardiac causes was 3.2 (95% CI 2.5 to 3.9). Th e authors concluded that OHCA accounts for a significant proportion of pediatric mortality, although the vast majority of OHCA survivors have a neurologi-cally intact outcome.

Studies on the optimal sequence of CPR measures to use in OHCA patients have reported varying results. In a meta-analysis of four randomized controlled clinical trials enrolling 1503 subjects with OHCA, no significant diff erence was found between chest compression first versus defibrillation first in the rate of return of spon-taneous circulation, survival to hospital discharge or favorable neurologic outcomes, although subgroup analyses suggested that chest compression first may be beneficial for cardiac arrests with a prolonged response time139. In a more recent, nationwide, population ba-sed observational study involving OHCA patients in Japan who had a witnessed arrest and received shocks with public access AED, compression only CPR was found to be associated with a significantly higher rate of survival at 1 month and more favorable neurological outcomes compared with conventional CPR measures (chest compression and rescue breathing)140. However, for children and younger people who have OHCA from non-cardiac causes, and in people in whom there was a delay in starting CPR, other studies have suggested that conventional CPR is associated with better outcomes than chest compression only CPR141,142.

CONCLUSIONSImportant progress has been made over the past few years in our understanding of basic and clinical cardiac electrophysiology which have advanced and improved the management of patients with heart rhythm disor-ders. Multiple studies have demonstrated an associa-

Strategies to reduce ICD complications and inappro-priate shocks include using special diagnostic ICD al-gorithms to identify potential lead problems early126, and changes in ICD programming with a prolonged delay in therapy for tachyarrhythmias of ≥200 beats/min or higher, as demonstrated in the MADIT-RIT (MADIT-Reduction in Inappropriate Th erapy) trial127. Increasing clinical experience is also being gained in the use of subcutaneous ICDs128,129, which holds great potential in reducing some types of ICD related com-plications, although an initial learning curve needs to be overcome first. Real world data of ICD implantation and use show that patients treated by very low volume operators (physicians who implanted ≤1 ICDs per year) were more likely to die or experience cardiac compli-cations compared with operators who frequently performed ICD implantation130. Another strategy to reduce ICD complications is to improve the selecti-on process of those patients who would truly benefit from these devices. In an observational outcome study of consecutive subjects referred to a regional inherited cardiac conditions clinic because of a relative who had sudden unexpected death, the number of ICDs inser-ted as a result of specialist assessment was found to be very small (2%)131.

Out-of-hospital cardiac arrestSurvival from out-of-hospital cardiac arrest (OHCA) appears to have increased over the past several years, probably as a result of better pre-hospital care (early recognition, more eff ective CPR, faster emergency ser-vices response) and advances in the hospital manage-ment of patients following OHCA132,133. Data from the London Ambulance Service’s cardiac arrest registry from 2007 to 2012 showed an improvement in OHCA survival over the 5 year study period134. In an obser-vational Swedish registry study of 7187 patients with OHCA over an 18 year period, bystander CPR was found to increase from 46% to 73% (95% CI for OR 1.060 to 10.081 per year), early survival increase from 28% to 45% (95% CI 1.044 to 1.065), and survival to 1 month increase from 12% to 23% (95% CI 1.058 to 1.086)135. Strong predictors of early and late survival were a short interval from collapse to defibrillation, bystander CPR, female gender, and place of collapse. A large prospective cohort study of OHCA in North American adults involving 12 930 subjects (2042 occur-ring in a public place and 9564 at home) also found that the rate of survival to hospital discharge was better for arrests in public settings with automated external defibrillators (AEDs) applied by bystanders compared to



9. Bansal N, Fan D, Hsu Cy, et al. Incident atrial fibrillation and risk of end-stage renal disease in adults with chronic kidney disease. Circu-lation 2013;127:569–74.

10. Jabre P, Jouven X, Adnet Fdr, et al. Atrial fibrillation and death af-ter myocardial infarction: a community study. Circulation 2011; 123: 2094–100.

11. Friberg L, Benson L, Rosenqvist M, et al. Assessment of female sex as a risk factor in atrial fibrillation in Sweden: nationwide retrospective cohort study. BMJ 2012;344:e3522.

12. Avgil TM, Jackevicius CA, Rahme E, et al. Sex diff erences in stroke risk among older patients with recently diagnosed atrial fibrillation. JAMA 2012;307:1952–8.

13. Conen D, Chae CU, Glynn RJ, et al. Risk of death and cardiovascular events in initially healthy women with new-onset atrial fibrillation. JAMA 2011;305:2080–7.

14. Steg PG, Alam S, Chiang CE, et al. Symptoms, functional status and quality of life in patients with controlled and uncontrolled atrial fibrillation: data from the RealiseAF cross-sectional international re-gistry. Heart 2012;98:195–201.

15. Camm AJ, Breithardt G+, Crijns H, et al. Real-life observations of clinical outcomes with rhythm- and rate-control therapies for atri-al fibrillation: RECORDAF (Registry on Cardiac Rhythm Disorders Assessing the Control of Atrial Fibrillation). J Am Coll Cardiol 2011; 58:493–501.

16. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010; 362:1363–73.

17. Groenveld HF, Crijns HJGM, Van den Berg MP, et al. Th e eff ect of rate control on quality of life in patients with permanent atrial fibrillation: data from the RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) study. J Am Coll Cardiol 2011;58:1795–803.

18. Smit MD, Crijns HJGM, Tijssen JGP, et al. Eff ect of lenient ver-sus strict rate control on cardiac remodeling in patients with atrial fibrillation: data of the RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) study. J Am Coll Cardiol 2011;58:942–9.

19. Saksena S, Slee A, Waldo AL, et al. Cardiovascular outcomes in the AFFIRM trial (Atrial Fibrillation Follow-Up Investigation of Rhythm Management): an assessment of individual antiarrhythmic drug the-rapies compared with rate control with propensity score-matched analyses. J Am Coll Cardiol 2011;58:1975–85.

20. Yamase M, Nakazato Y, Daida H. Eff ectiveness of amiodarone versus bepridil in achieving conversion to sinus rhythm in patients with per-sistent atrial fibrillation: a randomised trial. Heart 2012;98:1067–71.

21. Liu T, Korantzopoulos P, Shehata M, et al. Prevention of atrial fibrillation with omega-3 fatty acids: a meta-analysis of randomised clinical trials. Heart 2011;97:1034–40.

22. Macchia A, Grancelli H, Varini S, et al. Omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: results of the FORWARD (Randomized Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation) trial. J Am Coll Cardiol 2013;61:463–8.

23. Mozaff arian D, Marchioli R, Macchia A, et al. Fish oil and postope-rative atrial fibrillation: the Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) randomized trial. JAMA 2012;308:2001–11.

24. Nodari S, Triggiani M, Campia U, et al. n-3 Polyunsaturated fatty acids in the prevention of atrial fibrillation recurrences aft er electri-cal cardioversion: a prospective, randomized study. Circulation 2011; 124:1100–6.

25. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012;366:120–9.

26. Ritter MA, Kochhauser S, Duning T, et al. Occult atrial fibrillation in cryptogenic stroke: detection by 7-day electrocardiogram versus implantable cardiac monitors. Stroke 2013;44:1449–52.

27. Mittal S, Movsowitz C, Steinberg JS. Ambulatory external electrocar-diographic monitoring: focus on atrial fibrillation. J Am Coll Cardiol 2011;58:1741–9.

28. Roten L, Schilling M, Haberlin A, et al. Is 7-day event triggered ECG recording equivalent to 7-day Holter ECG recording for atrial fibri-llation screening? Heart 2012;98:645–9.

tion between AF and various systemic conditions and novel risk factors. Th ese studies highlight the impor-tance and complexity of this complex arrhythmia and further support the notion that AF is a systemic con-dition. Although many of these associations have not been shown to play a causal role, they may nonetheless prove useful clinically in future risk stratification scores for the diagnosis or treatment of AF. More research is still needed to increase our understanding of the un-derlying mechanisms responsible for the development and progression of AF and which patient subgroups will benefit most from specific treatments or the diff e-rent options for anticoagulation.

Th e field of CRT and pacing has also progressed ra-pidly over the past few years with a lot of interest in the optimal clinical parameters for selection of patients, prediction of response, and adverse remodeling . Simi-larly, as our understanding of the substrate responsi-ble for ventricular arrhythmias and SCD improves, the selection of suitable candidates for ICD therapy is be-coming more refined. Research into the complications associated with implantable cardiac devices, such as device infection and inappropriate shocks from ICDs, remains important as indications for device implanta-tion continue to expand and more and more patients with existing devices undergo device replacement procedures.


References1. Huxley RR, Alonso A, Lopez FL, et al. Type 2 diabetes, glucose ho-

meostasis and incident atrial fibrillation: the Atherosclerosis Risk in Communities study. Heart 2012;98:133–8.

2. Emilsson L, Smith JG, West J, et al. Increased risk of atrial fibrillation in patients with coeliac disease: a nationwide cohort study. Eur Heart J 2011;32:2430–7.

3. Lindhardsen J, Ahlehoff O, Gislason GH, et al. Risk of atrial fibrillation and stroke in rheumatoid arthritis: Danish nationwide cohort study. BMJ 2012;344:e1257.

4. Ahlehoff O, Gislason GH, Jorgensen CH, et al. Psoriasis and risk of atrial fibrillation and ischaemic stroke: a Danish Nationwide Cohort Study. Eur Heart J 2012;33:2054–64.

5. Schmidt M, Christiansen CF, Mehnert F, et al. Non-steroidal anti-inflammatory drug use and risk of atrial fibrillation or flutter: popula-tion based case-control study. BMJ 2011;343:d3450.

6. Rosenberg MA, Patton KK, Sotoodehnia N, et al. Th e impact of height on the risk of atrial fibrillation: the Cardiovascular Health Study. Eur Heart J 2012;33:2709–17.

7. Ball J, Carrington MJ, Stewart S. Mild cognitive impairment in high-risk patients with chronic atrial fibrillation: a forgotten component of clinical management? Heart 2013;99:542–7.

8. Wu JHY, Lemaitre RN, King IB, et al. Association of plasma phospho-lipid long-chain omega-3 fatty acids with incident atrial fibrillation in older adults: the Cardiovascular Health Study. Circulation 2012;125: 1084–93.



49. Pison L, La Meir M, van Opstal J, et al. Hybrid thoracoscopic surgical and transvenous catheter ablation of atrial fibrillation. J Am Coll Car-diol 2012;60:54–61.

50. Lopes RD, Al-Khatib SM, Wallentin L, et al. Efficacy and safety of api-xaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial. Lancet 2012;380:1749–58.

51. Patel MR, Mahaff ey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91.

52. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus war-farin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92.

53. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51.

54. Dentali F, Riva N, Crowther M, et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation 2012;126:2381–91.

55. Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients un-dergoing cardioversion. Circulation 2011;123:131–6.

56. Maddox W, Kay GN, Yamada T, et al. Dabigatran versus warfarin the-rapy for uninterrupted oral anticoagulation during atrial fibrillation ablation. J Cardiovasc Electrophysiol 2013;24:861–5.

57. Bassiouny M, Saliba W, Rickard J, et al. Use of dabigatran for peripro-cedural anticoagulation in patients undergoing catheter ablation for atrial fibrillation. Circ Arrhythm Electrophysiol 2013;6:460–6.

58. Kim JS, She F, Jongnarangsin K, et al. Dabigatran vs warfarin for radi-ofrequency catheter ablation of atrial fibrillation. Heart Rhythm 2013; 10:483–9.

59. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of dabigatran versus warfarin for periprocedural anticoagulation in pati-ents undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2012; 59: 1168–74.

60. Kansal AR, Sorensen SV, Gani R, et al. Cost-eff ectiveness of dabiga-tran etexilate for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation. Heart 2012;98:573–8.

61. Shah SV, Gage BF. Cost-eff ectiveness of dabigatran for stroke pro-phylaxis in atrial fibrillation. Circulation 2011;123:2562–70.

62. Munkholm-Larsen S, Cao C, Yan TD, et al. Percutaneous atrial ap-pendage occlusion for stroke prevention in patients with atrial fibri-llation: a systematic review. Heart 2012;98:900–7.

63. Viles-Gonzalez JF, Kar S, Douglas P, et al. Th e clinical impact of in-complete left atrial appendage closure with the watchman device in patients with atrial fibrillation: a PROTECT AF (Percutaneous Closu-re of the Left Atrial Appendage Versus Warfarin Th erapy for Preventi-on of Stroke in Patients With Atrial Fibrillation) substudy. J Am Coll Cardiol 2012;59:923–9.

64. Mahajan R, Brooks AG, Sullivan T, et al. Importance of the underlying substrate in determining thrombus location in atrial fibrillation: im-plications for left atrial appendage closure. Heart 2012;98:1120–6.

65. Leong DP, Hoke U, Delgado V, et al. Right ventricular function and survival following cardiac resynchronisation therapy. Heart 2013;99: 722–8.

66. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization the-rapy for the prevention of heart-failure events. N Engl J Med 2009; 361:1329–38.

67. Goldenberg I, Hall WJ, Beck CA, et al. Reduction of the risk of re-curring heart failure events with cardiac resynchronization therapy: MADIT-CRT (Multicenter Automatic Defibrillator Implantation Tri-al with Cardiac Resynchronization Th erapy). J Am Coll Cardiol 2011; 58:729–37.

68. Brenyo A, Link MS, Barsheshet A, et al. Cardiac resynchronization therapy reduces left atrial volume and the risk of atrial tachyarrhyth-mias in MADIT-CRT (Multicenter Automatic Defibrillator Implanta-tion Trial with Cardiac Resynchronization Th erapy). J Am Coll Car-diol 2011;58:1682–9.

69. Goldenberg I, Moss AJ, Hall WJ, et al. Predictors of response to car-diac resynchronization therapy in the Multicenter Automatic Defi-

29. Charitos EI, Stierle U, Ziegler PD, et al. A comprehensive evaluation of rhythm monitoring strategies for the detection of atrial fibrillation recurrence: insights from 647 continuously monitored patients and implications for monitoring aft er therapeutic interventions. Circula-tion 2012;126:806–14.

30. Deft ereos S, Giannopoulos G, Kossyvakis C, et al. Estimation of atrial fibrillation recency of onset and safety of cardioversion using NTproBNP levels in patients with unknown time of onset. Heart 2011;97:914–17.

31. Cosedis Nielsen J, Johannessen A, Raatikainen P, et al. Radiofrequen-cy ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med 2012;367:1587–95.

32. MacDonald MR, Connelly DT, Hawkins NM, et al. Radiofrequency ablation for persistent atrial fibrillation in patients with advanced heart failure and severe left ventricular systolic dysfunction: a rando-mised controlled trial. Heart 2011;97:740–7.

33. Hunter RJ, McCready J, Diab I, et al. Maintenance of sinus rhythm with an ablation strategy in patients with atrial fibrillation is associa-ted with a lower risk of stroke and death. Heart 2012;98:48–53.

34. Miyazaki S, Kuwahara T, Kobori A, et al. Long-term clinical outcome of extensive pulmonary vein isolation-based catheter ablation thera-py in patients with paroxysmal and persistent atrial fibrillation. Heart 2011;97:668–73.

35. Mun HS, Joung B, Shim J, et al. Does additional linear ablation aft er circumferential pulmonary vein isolation improve clinical outcome in patients with paroxysmal atrial fibrillation? Prospective randomised study. Heart 2012;98:480–4.

36. Chao TF, Sung SH, Wang KL, et al. Associations between the atrial electromechanical interval, atrial remodelling and outcome of cathe-ter ablation in paroxysmal atrial fibrillation. Heart 2011;97:225–30.

37. den Uijl DW, Delgado V, Bertini M, et al. Impact of left atrial fibrosis and left atrial size on the outcome of catheter ablation for atrial fibrillation. Heart 2011;97:1847–51.

38. Wong CX, Abed HS, Molaee P, et al. Pericardial fat is associated with atrial fibrillation severity and ablation outcome. J Am Coll Cardiol 2011;57:1745–51.

39. Hussein AA, Saliba WI, Martin DO, et al. Plasma B-type natriuretic peptide levels and recurrent arrhythmia aft er successful ablation of lone atrial fibrillation. Circulation 2011;123:2077–82.

40. Tokuda M, Yamane T, Matsuo S, et al. Relationship between renal function and the risk of recurrent atrial fibrillation following catheter ablation. Heart 2011;97:137–42.

41. Mohanty S, Mohanty P, Di Biase L, et al. Impact of metabolic syndro-me on procedural outcomes in patients with atrial fibrillation under-going catheter ablation. J Am Coll Cardiol 2012;59:1295–301.

42. Lee G, Kalman JM, Vohra JK, et al. Dissociated pulmonary vein poten-tials following antral pulmonary vein isolation for atrial fibrillation: impact on long-term outcome. Heart 2011;97:579–84.

43. Deft ereos S, Giannopoulos G, Kossyvakis C, et al. Colchicine for pre-vention of early atrial fibrillation recurrence aft er pulmonary vein isolation: a randomized controlled study. J Am Coll Cardiol 2012;60: 1790–6.

44. Imazio M, Brucato A, Ferrazzi P, et al. Colchicine reduces postopera-tive atrial fibrillation: results of the Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) atrial fibrillation subs-tudy. Circulation 2011;124:2290–5.

45. Pokushalov E, Romanov A, Corbucci G, et al. A randomized compa-rison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atri-al fibrillation and resistant hypertension. J Am Coll Cardiol 2012;60: 1163–70.

46. Shah RU, Freeman JV, Shilane D, et al. Procedural complications, rehospitalizations, and repeat procedures aft er catheter ablation for atrial fibrillation. J Am Coll Cardiol 2012;59:143–9.

47. Chao TF, LIN YJ, TSAO HM, et al. CHADS2 and CHA2DS2-VASc scores in the prediction of clinical outcomes in patients with atrial fibrillation aft er catheter ablation. J Am Coll Cardiol 2011;58:2380–5.

48. Boersma LVA, Castella M, van Boven W, et al. Atrial Fibrillation Ca-theter Ablation Versus Surgical Ablation Treatment (FAST): a 2-cen-ter randomized clinical trial. Circulation 2012;125:23–30.



90. Greenspon AJ, Prutkin JM, Sohail MR, et al. Timing of the most re-cent device procedure influences the clinical outcome of lead-associa-ted endocarditis: results of the MEDIC (Multicenter Electrophysiolo-gic Device Infection Cohort). J Am Coll Cardiol 2012;59:681–7.

91. Ye S, Grunnert M, Th une JJ, et al. Circumstances and outcomes of sudden unexpected death in patients with high-risk myocardial in-farction: implications for prevention. Circulation 2011;123:2674–80.

92. Soliman EZ, Prineas RJ, Case LD, et al. Electrocardiographic and cli-nical predictors separating atherosclerotic sudden cardiac death from incident coronary heart disease. Heart 2011;97:1597–601.

93. Marijon E, Tafflet M, Celermajer DS, et al. Sports-related sudden death in the general population. Circulation 2011;124:672–81.

94. Eckart RE, Shry EA, Burke AP, et al. Sudden death in young adults: an autopsy-based series of a population undergoing active surveillance. J Am Coll Cardiol 2011;58:1254–61.

95. Winkel BG, Holst AG, Th eilade J, et al. Nationwide study of sudden cardiac death in persons aged 1–35 years. Eur Heart J 2011;32:983–90.

96. Bertoia ML, Allison MA, Manson JE, et al. Risk factors for sudden cardiac death in post-menopausal women. J Am Coll Cardiol 2012;60: 2674–82.

97. Haissaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest asso-ciated with early repolarization. N Engl J Med 2008;358:2016–23.

98. Tikkanen JT, Anttonen O, Junttila MJ, et al. Long-term outcome asso-ciated with early repolarization on electrocardiography. N Engl J Med 2009;361:2529–37.

99. Derval N, Simpson CS, Birnie DH, et al. Prevalence and characte-ristics of early repolarization in the CASPER registry: cardiac arrest survivors with preserved ejection fraction registry. J Am Coll Cardiol 2011;58:722–8.

100. Nunn LM, Bhar-Amato J, Lowe MD, et al. Prevalence of J-point eleva-tion in sudden arrhythmic death syndrome families. J Am Coll Car-diol 2011;58:286–90.

101. Gourraud JB, Le Scouarnec S, Sacher F, et al. Identification of lar-ge families in early repolarization syndrome. J Am Coll Cardiol 2013;61:164–72.

102. Haruta D, Matsuo K, Tsuneto A, et al. Incidence and prognostic value of early repolarization pattern in the 12-lead electrocardiogram. Cir-culation 2011;123:2931–7.

103. Bastiaenen R, Behr ER. Early repolarisation: controversies and clini-cal implications. Heart 2012;98:841–7.

104. Junttila MJ, Sager SJ, Tikkanen JT, et al. Clinical significance of vari-ants of J-points and J-waves: early repolarization patterns and risk. Eur Heart J 2012;33:2639–43.

105. Bastiaenen R, Behr ER. Sudden death and ion channel disease: patho-physiology and implications for management. Heart 2011;97: 1365–72.

106. Nunn LM, Lambiase PD. Genetics and cardiovascular disease—cau-ses and prevention of unexpected sudden adult death: the role of the SADS clinic. Heart 2011;97:1122–7.

107. Corrado D, Basso C, Pilichou K, et al. Molecular biology and clinical management of arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart 2011;97:530–9.

108. Napolitano C, Bloise R, Monteforte N, et al. Sudden cardiac death and genetic ion channelopathies: long QT, Brugada, short QT, cate-cholaminergic polymorphic ventricular tachycardia, and idiopathic ventricular fibrillation. Circulation 2012;125:2027–34.

109. Jamshidi Y, Nolte IM, Dalageorgou C, et al. Common variation in the NOS1AP gene is associated with drug-induced QT prolongation and ventricular arrhythmia. J Am Coll Cardiol 2012;60:841–50.

110. van Noord C, Sturkenboom MCJM, Straus SMJM, et al. Non-cardi-ovascular drugs that inhibit hERG-encoded potassium channels and risk of sudden cardiac death. Heart 2011;97:215–20.

111. van Rees JB, Borleff s CJW, van Welsenes GH, et al. Clinical prediction model for death prior to appropriate therapy in primary prevention implantable cardioverter defibrillator patients with ischaemic heart disease: the FADES risk score. Heart 2012;98:872–7.

112. Haines DE, Wang Y, Curtis J. Implantable cardioverter-defibrillator registry risk score models for acute procedural complications or death aft er implantable cardioverter-defibrillator implantation. Circulation 2011;123:2069–76.

brillator Implantation Trial with Cardiac Resynchronization Th erapy (MADIT-CRT). Circulation 2011;124:1527–36.

70. Pouleur AC, Knappe D, Shah AM, et al. Relationship between impro-vement in left ventricular dyssynchrony and contractile function and clinical outcome with cardiac resynchronization therapy: the MA-DIT-CRT trial. Eur Heart J 2011;32:1720–9.

71. Hsu JC, Solomon SD, Bourgoun M, et al. Predictors of super-res-ponse to cardiac resynchronization therapy and associated improve-ment in clinical outcome: the MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization thera-py) study. J Am Coll Cardiol 2012;59:2366–73.

72. Veazie PJ, Noyes K, Li Q, et al. Cardiac resynchronization and quality of life in patients with minimally symptomatic heart failure. J Am Coll Cardiol 2012;60:1940–4.

73. Singh JP, Klein HU, Huang DT, et al. Left ventricular lead position and clinical outcome in the Multicenter Automatic Defibrillator Implan-tation Trial-Cardiac Resynchronization Th erapy (MADIT-CRT) trial. Circulation 2011;123:1159–66.

74. Kutyifa V, Zareba W, McNitt S, et al. Left ventricular lead location and the risk of ventricular arrhythmias in the MADIT-CRT trial. Eur Heart J 2013;34:184–90.

75. Diab IG, Hunter RJ, Kamdar R, et al. Does ventricular dyssynchrony on echocardiography predict response to cardiac resynchronisation therapy? A randomised controlled study. Heart 2011;97:1410–16.

76. Foley PWX, Patel K, Irwin N, et al. Cardiac resynchronisation therapy in patients with heart failure and a normal QRS duration: the RES-POND study. Heart 2011;97:1041–7.

77. Zareba W, Klein H, Cygankiewicz I, et al. Eff ectiveness of cardiac re-synchronization therapy by QRS morphology in the Multicenter Au-tomatic Defibrillator Implantation Trial–Cardiac Resynchronization Th erapy (MADIT-CRT). Circulation 2011;123:1061–72.

78. Brignole M, Botto G, Mont L, et al. Cardiac resynchronization therapy in patients undergoing atrioventricular junction ablation for perma-nent atrial fibrillation: a randomized trial. Eur Heart J 2011;32:2420–9.

79. Brignole M, Botto GL, Mont L, et al. Predictors of clinical efficacy of ablate and pace therapy in patients with permanent atrial fibrillation. Heart 2012;98:297–302.

80. Chan JY-S, Fang F, Zhang Q, et al. Biventricular pacing is superior to right ventricular pacing in bradycardia patients with preserved systolic function: 2-year results of the PACE trial. Eur Heart J 2011; 32:2533–40.

81. Coumbe AG, Naksuk N, Newell MC, et al. Long-term follow-up of ol-der patients with Mobitz type I second degree atrioventricular block. Heart 2013;99:334–8.

82. van Geldorp IE, Delhaas T, Gebauer RA, et al. Impact of the perma-nent ventricular pacing site on left ventricular function in children: a retrospective multicentre survey. Heart 2011;97:2051–5.

83. Brignole M, Menozzi C, Moya A, et al. Pacemaker therapy in pati-ents with neurally mediated syncope and documented asystole: third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial. Circulation 2012;125:2566–71.

84. Deharo JC, Mechulan A, Giorgi R, et al. Adenosine plasma level and A2A adenosine receptor expression: correlation with laboratory tests in patients with neurally mediated syncope. Heart 2012;98:855–9.

85. Flammang D, Church TR, De Roy L, et al. Treatment of unexplained syncope: a multicenter, randomized trial of cardiac pacing guided by adenosine 50 -triphosphate testing. Circulation 2012;125:31–6.

86. Brignole M, Deharo JC, De Roy L, et al. Syncope due to idiopathic paroxysmal atrioventricular block: long-term follow-up of a distinct form of atrioventricular block. J Am Coll Cardiol 2011;58:167–73.

87. Ruwald MH, Hansen ML, Lamberts M, et al. Prognosis among healthy individuals discharged with a primary diagnosis of syncope. J Am Coll Cardiol 2013;61:325–32.

88. Athan E, Chu VH, Tattevin P, et al. Clinical characteristics and out-come of infective endocarditis involving implantable cardiac devices. JAMA 2012;307:1727–35.

89. Deharo JC, Quatre A, Mancini J, et al. Long-term outcomes following infection of cardiac implantable electronic devices: a prospective mat-ched cohort study. Heart 2012;98:724–31.



128. Olde Nordkamp LRA, Dabiri Abkenari L, Boersma LVA, et al. Th e entirely subcutaneous implantable cardioverter-defibrillator: ini-tial clinical experience in a large Dutch cohort. J Am Coll Cardiol 2012;60:1933–9.

129. Jarman JWE, Lascelles K, Wong T, et al. Clinical experience of entirely subcutaneous implantable cardioverter defibrillators in children and adults: cause for caution. Eur Heart J 2012;33:1351–9.

130. Lyman S, Sedrakyan A, Do H, et al. Infrequent physician use of im-plantable cardioverter-defibrillators risks patient safety. Heart 2011; 97:1655–60.

131. Caldwell J, Moreton N, Khan N, et al. Th e clinical management of relatives of young sudden unexplained death victims; implantable defibrillators are rarely indicated. Heart 2012;98:631–6.

132. Perkins GD, Brace SJ, Smythe M, et al. Out-of-hospital cardiac arrest: recent advances in resuscitation and eff ects on outcome. Heart 2012; 98:529–35.

133. Nolan JP, Lyon RM, Sasson C, et al. Advances in the hospital mana-gement of patients following an out of hospital cardiac arrest. Heart 2012;98:1201–6.

134. Fothergill RT, Watson LR, Chamberlain D, et al. Increases in survival from out-of-hospital cardiac arrest: a five year study. Resuscitation 2013;84:1089–92.

135. Adielsson A, Hollenberg J, Karlsson T, et al. Increase in survival and bystander CPR in out-of-hospital shockable arrhythmia: bystander CPR and female gender are predictors of improved outcome. Experi-ences from Sweden in an 18-year perspective. Heart 2011;97:1391–6.

136. Weisfeldt ML, Everson-Stewart S, Sitlani C, et al. Ventricular tachyar-rhythmias aft er cardiac arrest in public versus at home. N Engl J Med 2011;364:313–21.

137. Stub D, Smith K, Bray JE, et al. Hospital characteristics are associated with patient outcomes following out-of-hospital cardiac arrest. Heart 2011;97:1489–94.

138. Bardai A, Berdowski J, van der Werf C, et al. Incidence, causes, and outcomes of out-of-hospital cardiac arrest in children: a comprehen-sive, prospective, population-based study in the Netherlands. J Am Coll Cardiol 2011; 57:1822–8.

139. Meier P, Baker P, Jost D, et al. Chest compressions before defibrillation for out-of-hospital cardiac arrest: a meta-analysis of randomized con-trolled clinical trials. BMC Med 2010;8:52.

140. Iwami T, Kitamura T, Kawamura T, et al. Chest compression-only cardiopulmonary resuscitation for out-of-hospital cardiac arrest with public-access defibrillation: a nationwide cohort study. Circulation 2012;126:2844–51.

141. Kitamura T, Iwami T, Kawamura T, et al. Conventional and chest-compression-only cardiopulmonary resuscitation by bystanders for children who have out-of-hospital cardiac arrests: a prospective, nati-onwide, population-based cohort study. Lancet 2010;375:1347–54.

142. Ogawa T, Akahane M, Koike S, et al. Outcomes of chest compressi-on only CPR versus conventional CPR conducted by lay people in patients with out of hospital cardiopulmonary arrest witnessed by bystanders: nationwide population based observational study. BMJ 2011;342:c7106.

113. Barsheshet A, Moss AJ, Huang DT, et al. Applicability of a risk sco-re for prediction of the long-term (8-year) benefit of the implantable cardioverter-defibrillator. J Am Coll Cardiol 2012;59:2075–9.

114. Bilchick KC, Stukenborg GJ, Kamath S, et al. Prediction of mortality in clinical practice for Medicare patients undergoing defibrillator im-plantation for primary prevention of sudden cardiac death. J Am Coll Cardiol 2012;60:1647–55.

115. de Haan S, Meijers TA, Knaapen P, et al. Scar size and characteris-tics assessed by CMR predict ventricular arrhythmias in ischaemic cardiomyopathy: comparison of previously validated models. Heart 2011;97:1951–6.

116. Klem I, Weinsaft JW, Bahnson TD, et al. Assessment of myocardial scarring improves risk stratification in patients evaluated for cardiac defibrillator implantation. J Am Coll Cardiol 2012;60:408–20.

117. Swerdlow C, Chow T, Das M, et al. Intracardiac electrogram T-wa-ve alternans/variability increases before spontaneous ventricular ta-chyarrhythmias in implantable cardioverter-defibrillator patients: a prospective, multi-center study. Circulation 2011;123:1052–60.

118. Forleo GB, Tesauro M, Panattoni G, et al. Impact of continuous intra-cardiac ST-segment monitoring on mid-term outcomes of ICD-im-planted patients with coronary artery disease. Early results of a pro-spective comparison with conventional ICD outcomes. Heart 2012; 98:402–7.

119. Hauser RG, Maisel WH, Friedman PA, et al. Longevity of Sprint Fide-lis implantable cardioverter-defibrillator leads and risk factors for fai-lure: implications for patient management. Circulation 2011;123:358–63.

120. Birnie DH, Parkash R, Exner DV, et al. Clinical predictors of Fidelis lead failure: report from the Canadian Heart Rhythm Society Device Committee. Circulation 2012;125:1217–25.

121. Parkash R, Th ibault B, Sterns L, et al. Sprint Fidelis lead fractures in patients with cardiac resynchronization therapy devices: insight from the Resynchronization/ Defibrillation for Ambulatory Heart Failure (RAFT) study. Circulation 2012;126:2928–34.

122. Cho EYN, von Känel R, Marten-Mittag B, et al. Determinants and trajectory of phobic anxiety in patients living with an implantable car-dioverter defibrillator. Heart 2012;98:806–12.

123. Landolina M, Gasparini M, Lunati M, et al. Long-term complicati-ons related to biventricular defibrillator implantation: rate of surgical revisions and impact on survival: insights from the Italian Clinical Service Database. Circulation 2011;123:2526–35.

124. Dewland TA, Pellegrini CN, Wang Y, et al. Dual-chamber implantable cardioverter-defibrillator selection is associated with increased com-plication rates and mortality among patients enrolled in the NCDR implantable cardioverter-defibrillator registry. J Am Coll Cardiol 2011;58:1007–13.

125. O’Mahony C, Lambiase PD, Quarta G, et al. Th e long-term survival and the risks and benefits of implantable cardioverter defibrillators in patients with hypertrophic cardiomyopathy. Heart 2012;98:116–25.

126. Swerdlow CD, Sachanandani H, Gunderson BD, et al. Preventing overdiagnosis of implantable cardioverter-defibrillator lead fractures using device diagnostics. J Am Coll Cardiol 2011;57:2330–9.

127. Moss AJ, Schuger C, Beck CA, et al. Reduction in inappropriate thera-py and mortality through ICD programming. N Engl J Med 2012;367: 2275–83.


REVIEWS

Fostering Diffusion of Scientific Contents of National Societies Cardiovascular Journals: The New ESC Search EngineFernando Alfonso1,2, Lino Gonçalves3, Fausto Pinto1, Adam Timmis1, Hugo Ector1,Giuseppe Ambrosio1,Panos Vardas1, On behalf of the Editors' Network European Society of Cardiology Task ForceAuthor Affiliations

Editors´ Network Members (Editors-in-Chiefs of National Society Cardiovascular Journals):

BYLINE NOT YET FINALISED Eduard Apetrei (Editor-in-Chief, Romanian Journal of Cardiology), Michael Aschermann (Editor-in-Chief, Cor et Vasa), Leonardo Bolognese (Editor-in-Chief, Giornale Italiano Di Cardiologia), Mirza Dilic (Editor-in-Chief, Medical Journal), Istvan Edes (Editor-in-Chief, Cardiologia Hungarica), Krzysztof J. Filipiak (Editor-in-Chief, Kardiologia Polska), Faig Guliyev (Editor-in-Chief, Azerbaijan Cardiology Journal), Habib Haouala (Editor-in-Chief, Cardiologie Tunisienne), Magda Heras (Editor-in-Chief, Revista Española de Cardiología). Mahmoud Mohamed Hassanein (Editor-in-Chief, Egyptian Heart Journal), Kurt Huber (Editor-in-Chief, Journal für Kardiologie), Mario Ivanusa (Editor-in-Chief, Cardiologia Croatica), Germanas Marinskis (Editor-in-Chief, Seminars in Cardiovascular Medicine), Izet Masic (Editor-in-Chief, Medical Archives), Miodrag Ostojic (Editor-in-Chief, Heart and Blood Vessels), Dimitar Raev (Editor-in-Chief, Bulgarian Cardiology), Mamanti Rogava (Editor-in-Chief, Cardiology and Internal Medicine XXI), Olaf Rødevand (Editor-in-Chief, Hjerteforum), Vedat Sansoy (Editor-in-Chief, Archives of the Turkish Society of Cardiology), Valentin A. Shumakov (Editor-in-Chief, Ukrainian Journal of Cardiology), and Th omas F. Lüscher (Editor-in-Chief, Kardiovaskuläre Medizin)

Contact address:Fernando Alfonso MD ESC Editors´ Network Task Force Chair. Interven-tional Cardiology. Cardiovascular Institute. Clínico San Carlos University Hospital. IdISSC. Plaza Cristo Rey. Madrid. 28040. Spain.E-mail: [email protected]

Abstract: European Society of Cardiology (ESC) National Society Cardiovascular Journals (NSCJ) are high-quality biome-dical journals focused on cardiovascular diseases. Th e Editors´ Network of the ESC devises editorial initiatives aimed at im-proving the scientifi c quality and diff usion of NSCJ. In this article we will discuss on the importance of the Internet, electronic editions and open access strategies on scientifi c publishing. Finally, we will propose a new editorial initiative based on a novel electronic tool on the ESC web-page that may further help to increase the dissemination of contents and visibility of NSCJ.Keywords: biomedical journal, editors network, open access, Internet, electronic editions

1 Nucleus Members Editors’ Network of the European Society of Cardio-logy2 ESC Editors’ Network Task Force Chair3 ESC Search Engine Task Force Chair

Fernando Alfonso et al.The New ESC Search Engine


European Society of Cardiology (ESC) National Society Cardiovascular Journals (NSCJ) are high-quality bio-medical journals devoted to publish original research and also educative material on cardiovascular disea-ses1-3. Th ese journals offi cially belong to the correspon-ding ESC national societies. However, many of them have achieved major international recognition, are in-cluded in most important bibliometric databases and have gained major scientifi c impact1-5. Some NSCJ off er full-text English content and are freely available from ele ctronic editions. NSCJ, however, are largely hetero-geneous and some of them are only published in local languages with a limited visibility1-3.

Th e main goal of biomedical journals is to publi-sh high quality scientifi c information. To achieve this goal, journals should compete for the best research ge-nerated in their fi eld being the “prestige” of the journal the main driver to attract original contributions1-3. In turn, journals prestige is based upon credibility, diff u-sion and scientifi c impact6. To ensure that the scientifi c process is fully respected journals relay in the “peer re-view” system. Th is process not only allows the Editors to select the best possible material for publication but also ensure the readers that the quality of the informa-tion follows the highest scientifi c standards. Actually, the process signifi cantly improves the fi nal quality of manuscripts eventually published. Once the article is defi nitively accepted for publication the Journal should guarantee its expedited publication and widespread di-ff usion among the scientifi c community1-3.

Th e Editors´ Network of the ESC provides a unique platform to devise editorial initiatives aimed to impro-ve the scientifi c quality and to facilitate diff usion of con tents from NSCJ1-5. Herein we will discuss on the importance of the Internet and electronic editions on scientifi c publishing. We will also review the growing relevance of open access strategies. Last but not least, we will propose a new initiative based on a novel elec-tronic tool that may further help to increase the diff u-sion, dissemination and overall visibility of NSCJ. Th is tool, located at the ESC web site, should foster colla-boration among the diff erent NSCJ and also broaden exposure from diverse scientifi c sites and ESC offi cial journals. Hopefully, this will help to further expand the scientifi c impact of European cardiovascular research.

Electronic Editions and the Internet: A paradigm shift in Scientifi c Publishing:Sharing the results of late breaking research through peer-reviewed journals remains the mainstay of the sci entifi c process and the progress in science1-3. Th e

success of research requires articles to be read, spre-ad, discussed and cited among interested investigators. Th erefore, in the fast moving and globalized world of science, journals should ensure the maximal accessibi-lity and diff usion of their articles1-3. Indeed, most pu-blications have already moved into a new “online era” where the emphasis is placed on the Internet and in electronic editions1-3. Just a few years ago scholars did all their reading from paper journal issues obtained as personal copies circulating inside their organizations, or by retrieving the issues from library archives7. Today the predominating reading mode is to download a di-gital copy and either read it directly off the screen or as a printout7. Currently, readers and investigators readily retrieve articles with just a click on their home or offi ce computers7.

Interestingly, the Internet not only impacts resear-ch but also clinical practice. Nowadays, physicians are freq uently approached and challenged by patients who had downloaded medical information from the inter-net. Oft en they face either unnecessarily worried pati-ents or patients with unrealistic expectations. Although some patients are confused others are over-informed and demand in-depth explanations regarding their diag nosis, management and prognosis. Patient-orien-ted information should be provided from the scienti-fi c societies to address these demands. Th erefore, even everyday clinical practice should accommodate the so-cio-cultural change induced by the Internet.

Access to medical information has been revolutio-ni zed by electronic editions. Likewise, bibliometric data bases are also evolving. MEDLINE, the ISI Web of Sci ence and more recently Scopus off er compre-hensive online information on medical literature8-11. In addition, Google Scholar is increasingly used by many investigators8-11. Scopus and specially Google Scholar obtain data from a larger data sources including widely diverse scientifi c items (not only ISI publications) and therefore off er a slightly diff erent perspective of the fi -eld. Interestingly, Google scholar is free and diff erent studies suggest that it provides accurate search and data analyses that diff er little from those obtained from clas-sical bibliometric sources8-11.

Traditionally, the most commonly used source of bi-bliometric data is the Th omson ISI Web of Knowledge, in particular the Science Citation Index and the Jour-nal Citation Reports, which provide the yearly Jour-nal Impact Factors. Recently, other indicators such as SCImago SJR or the Eigenfactor are emerging as alter-native indices of a journal’s quality8-11. Th ese consider not only the number but also the “quality” or relevance



of the citations received by a given paper. Quantitati-ve publication metrics (research output) and citations analyses (scientifi c infl uence) are key determinants of the scientifi c success of individual investigators and in-stitutions because the “publish or perish” dictum still prevails in most academic settings8-11. In this scenario, the electronic editions and accessibility on the Internet certainly play a critical role. Nowadays, once a paper is electronically published on a journal website, the information can propagate rapidly in the community and extremely high downloads could be the results of mechanisms such as the “Matthew eff ect” (richer get richer)12. Indeed, the relationship between the number of citations acquired by an article has been explored in relation to the number of downloads13. Hit counts on a journal website for an article during the week aft er the online publication predict the number of citations of that article in subsequent years14. Of note, Uniform Resource Locators (URLs), are being increasingly used in scientifi c publications15. Citation of URLs provide the possibility of calculating an objective electronic im-pact factor (eIF) to measure their impact on scientifi c research15. However, the stability of URLs remains a matter of concern and this should be guaranteed by the responsible organization because URLs are vulnerable to technical problems and may become inaccessible in a time-dependant manner15.

Notably, the Internet off ers a new window to scien-ce and provides new insights on access and use of re-search16. Currently web-usage-data may be analyzed in depth to outline a “map of knowledge”. According to Butler et al16 when readers click from one page to another while looking through online scientifi c jour-nals, they generate a chain of connections between links they think belong together. Th ese ‚clickstream eve nts’ may be analyzed to map such connections and to provide a snapshot of interconnections between dis-ci plines.

Usage maps reveal how oft en users looking at an article in journal A moved on to an article in journal B during a browser session. By aggregating all these complex relationships using network-visualization al-gorithms, maps can be generated based on the ‚distan-ces’ between journals and disciplines16. Th e structure of these maps is quite similar to those created using citation data: a network of clusters in diff erent fi elds within which journals have strong connections with one another but fewer links to other clusters. Interes-tingly, journals in the humanities and social sciences fi gure much more prominently in these maps than in

citation-based maps16. Another key diff erence between citation- and usage-based maps is that the former only refl ect citations by researchers who publish, but ignore the impact of papers on the medical community who read and apply the literature in medical practice but who rarely publish. Citation data may undervalue pa-pers written in practitioner-based fi elds that are widely read but not cited proportionally16. Moreover, usage maps are more up-to-date than citation ones because of the inherent delay in publication therefore providing a diff erent time-slice of the scientifi c process. Accor-dingly, both usage and citation data each provide com-plementary information on the impact of papers and journals on the scientifi c community16.

Electronic editions provide unique publishing pos-sibilities and open new venues in scientifi c communi-cation1-3. For instance, they off er a fl exible layout and structure for articles, new formats and the possibility of including additional documentation attached to the paper as media enhancements (videos, etc). Important sections as methods and additional data can be now presented as supplementary material without additio-nal costs. Electronic managing systems facilitate both the processes of peer-review and publishing1-3. Open peer-review and even post-publication readers´ com-ments may be uploaded on the journal website facilita-ting interactivity and a more transparent and dynamic scientifi c process. Finally, statistics on electronic papers (downloads and citation metrics) are off ered to the in-terest of readers and researchers17.

Publicly available data is advocated as a means to further promote transparency in research and a more open science18-20. Online editions allow the publicati-on of longer papers free from the economic burden of print charges. Posting the complete anonymized “raw data set” has been advocated

in this regard18-20. Th e raw data can be used to con-fi rm original results by independent analyses but also to explore related or new hypotheses, particularly when combined with other publicly available data sets. From an ethical perspective it appears unacceptable that whi-le patients are willing to share data about themselves with investigators and sponsors these may be unwilling to share the trial data with others. Data sharing has been already successful among genomic investigators. However, this strategy may cause concerns including inappropriate analyses, “data dredging” and drawing inappropriate conclusions18-20. Th e International Com-mittee of Medical Journals Editors has developed guide-lines for the preparation of raw clinical data for Publi-



cation18. Interestingly, this practice has been associated with a 69% increase in citations, independently of jour-nal impact factor, date of publication, and author coun-try of origin20. Th e correlation between publicly avai-lable data and increased literature impact may further motivate investigators to share their detailed research data.

On the other hand, the Web 2.0 is also been increa-singly used in the medical fi eld21-25. RSS feeds, podcasts, personal publishing platforms (blogs), social networks (like Twitter and Facebook), and social media are pro-posed as innovative tools for the education and update of clinicians. Th ey allow physicians to distribute, share and comment medical information21-25. However, the scientifi c community is less than eager to regard them as equivalent to the traditional models of information dissemination on peer-reviewed medical journals. In this regard, some have proposed that platforms of post-publication peer-review may provide the required safe guard in this new setting22. In addition, intuitive brow-sing of Journals´ content on smartphones and the iPad, is being provided by a growing number of publications (including the European Heart Journal)24 to enhance diff usion of contents21. Furthermore, some Web 2.0 technologies facilitate collaborative data collection for clinical trials23. Google Docs, for instance, is freely available and allows multiple users to enter patient data into electronic case report forms of multicenter trials through mobile devices23.

Finally, we should keep in mind that English repre-sents the “lingua franca” of science. Th is is important and eff orts should be made within the ESC to pre-vent tower-of-Babel phenomena in the digital era1-3. However, this may create major problems and unique challenges for non-English-speaking investigators and countries26. Actually, some NSCJ only publish in their mother tongue and therefore they are not readily acces-sible to the international scientifi c community. Some NSCJ have decided to publish their articles in both nati-ve language and English, to address healthcare professi-onals and international scholars, respectively. Diffi cult concepts are easier to remember in the mother tongue. Interestingly, Public Library of Science journals encou-rage non-English-speaking authors to provide a versi-on of their article in its original language as supporting material27. Science should not be considered an “ivory tower” separated from the rest of society but rather im-bedded on it to facilitate its cultural assimilation27.

Some Editorial Perspectives on “Open Access” Initiatives:Th e Internet and the electronic editions set the bases for Open Access (OA) initiatives28,29. Th e two main cha racteristics of OA publications are: 1) all published con tents are freely accessible through the Internet, and 2) readers are given copyright permission as long as authors and publishers receive the adequate attributi-on28. In turn, this model requires two major changes from the traditional –subscription based- model. First, OA shift s the fi nancing of publication from readers (subscriptions fees by individuals or universities) to authors and investigators (through the corresponding funding organization or academic institutions) by mean of articles processing fees28. Second, the copyri-ght is not longer used to prevent but rather to stimula-te re-publication. Subscription-based journals usually require authors to transfer the copyright to the journal to be empowered to restrict access to paying customers and threat with infringement lawsuits to competing publications. Major subscription-based journals are fi -nanced by individuals or medical societies but mainly by bundled e-license agreements between publishers and universities or librarians28,29. Electronic individual articles can also be accessed on a pay-per-view basis. Readers are charged one way or the other in the tra-ditional way whereas authors and investigators are charged in the OA model28,29. Some commercial publi-shers charge authors a publication fee to substitute for subscription revenue while signifi cantly limiting reuse. Th is initiatives, however, should not be considered real OA. Some traditional publishers have recently open to “hybrid” initiatives where authors are allowed (aft er paying a fee) to make individual articles OA28,29.

In the early 90´s, pioneer OA journals were founded by individual investigators based on voluntary work and usually were hosted in individual or university ser-vers29. Th ereaft er, many established journals made their articles OA when they implemented their digital editi-ons in parallel with print editions. Th is was especially the case for offi cial journals from medical societies and in non-English speaking countries in an attempt to in-crease their readership and impact30. In the last decade, new, formal, OA journals fl ourished using article pro-cessing charges to fi nance publications29. Interestingly, some major publishers (BioMed Central, Public Library of Science) became specialized in OA29. OA has to ma-jor pathways: 1) “Gold” OA (via direct publishing) and 2) “Green” OA (traditional publication in subscription-based journals with parallel openly posting on the Web



nifi cantly more downloads and reached a broader au-dience within the fi rst year. However, in this particular study, OA were cited no more frequently, nor earlier, than subscription-access articles within 3 years. It was suggested that the process of “social stratifi cation”, acc-ounting for a concentration of scientifi c authors at as mall number of elite research universities with excel-lent access to the scientifi c literature, might help to ex-plain this apparent paradox39. Moreover, this controlled study suggests that real benefi ciaries of OA publishing may notbe the research community but rather commu-nities of medical practice that consume, but rarely con-tribute to, the corpus of literature39.

As discussed, currently, embargoes are imposed by publishers for economic reasons. Th is may be a signifi -cant barrier to access in biomedical sciences. As previ-ously emphasized, it has been suggested that users fa-vor electronic access and oft en eschew articles that are not available electronically40. In a shy attempt to tackle these problems many journals off er now free access to all articles 6 months aft er publication and welcome the publication of articles as OA aft er a fee is paid by the authors.

However, research funding bodies are becoming in-creasingly sensible to this ethical issue. Many would ar-gue that it is unethical to use the research grants from government (people’s money) and not allow the sci-entifi c community to have free access to the results of the study. To address such issues, the Berlin declara tion suggested the establishment of OA repositories. Every investigator who has received public grants should sub-mit the full text of the paper published from his study to PubMed Central and also ensure self archiving at the corresponding university or research institution. Obvi-ously, OA journals provide an attractive solution to the problem of restricted access to results of publicly fun-ded research41.

Most countries and founding bodies are currently taking further actions to ensure OA for publicly fun-ded research41-43. Researches are compelled to make their work publicly available in repositories (green road) within 12 month of publication. Others bodies even suggest that authors should make their work free by the publisher upfront (gold road). Clearly, research budgets should be re-allocated with this aim although the logistics required and the implications of this chan-ge remain a matter of ongoing debate. On July 2012, a new OA policy was announced from the European Union that recommended OA policies for all the mem-ber states31,41-43. Hopefully, this will represent a para-

the fi nal manuscript). Green open access is delivered by repositories whereas gold open access is delivered by journals (31). Licences range from any kind of reuse providing proper attribution is made (CC-BY) to those that limit commercial use (CC-BY-NC)31.

Th e health of the free-access author-pay model may be demonstrated by data showing the steady growing of papers published in OA journals (20% per year) and also in the number of OA journals (15% per year), ei-ther as new journals or traditional journals switching to this model32. Currently 30% of all peer-review jour-nals in the world are open access31.

OA benefi ts science by accelerating dissemination and uptake of research fi ndings. A major advantage of OA is that readers can use any Web-based research tool to access and review the literature28. Th ese articles are quickly recognized and their results are readily picked up and discussed by peers33. As already mentioned, there are two main modalities of open access: open access journals and self-archiving. Interestingly, some studies suggest33 that articles immediately published as OA on the journal site (gold route) have higher impact than self-archived or otherwise openly accessible OA articles (green route).

Overall OA initiatives increase diff usion of contents, citations and eventually the impact factor of the corres-ponding journals33-35. Early studies 10 on MEDLINE as “full text on the net” also boosts their impact factor37. Th is bias is explained by the tendency to peruse what is more readily available37. OA initiatives also appear to increase the impact factor33-35. However, some argue that this eff ect may confound between open and elec-tronic access. Nevertheless, recent reports, suggest that in most developed countries journals articles receive an increase in citations when they come online freely but experience an additional jump when they fi rst come online through commercial sources35. Th is eff ect ap-pears to be reversed in poor countries where freeaccess articles are much more likely to be cited35. All together these fi ndings suggest that free Internet access widens the circle of those who read and make use of scientifi c research. In addition, this “OA impact advantage” does not appear to be a “quality bias” from authors self-se-lecting what to make OA, because some studies suggest that this advance persists aft er adjusting for many other potential confounders related to the editorial and re-search quality38.

Interestingly, a randomized trial on OA publishing analyzed the eff ects of free access on article downloads and citations39. Articles placed in the OA received sig-



is also presented (guideline, abstract, slide presentati-on, scientifi c report, news, clinical case, or a web docu-ment). Th e document origin can also be easily identi-fi ed at a glance through a small institutional logo which can also be found inside the results page, just below the icon showing the type of document. Also important to know is the document availability. A padlock symbol is displayed when a document is behind a login so that you can still see that the resource exists, meaning that its access is for members only. Th is tool also allows to refi ne the search by using fi lters located on the toolbar located on the left . With this toolbar you can fi lter the type of document you are looking for (only slides for example). It is also possible to fi lter only results from a given time period. During a congress, when a lot of content is published daily, you may fi lter for what’s new since yesterday, or you can fi lter only the results where a person is cited. Related terms are proposed by the en-gine from the keywords entered in your request to pro-pose other related topics which could be of interest. If you search the same term on a regular basis, you could be interested in using the RSS feed functionality. We may show any search result page as an RSS feed whi-ch you may subscribe to, and get regular updates about what’s new in this fi eld.

Time has come to involve the National Societies’ Journals!Th is project is already in its adulthood and time has come now to enter into a second phase of development and involve also the NSCJ. Th e ESC Board chaired by Michel Komajda decided to support the development of this project. Th e ESC Editor’s club gave also an enthusi-astic response and decided to contact those NSCJ that are already published in an electronic format and that are published in English. Some of them have already a signifi cant Impact Factor. Th e goal of this second phase of the project is to increase the visibility of the NSCJ and as a consequence to increase their reading and their level of reference in other international journals. Moreover, the excellent research that is performed at the National level in many countries in Europe will be-come more visible worldwide.

Th is new tool is already available and you will be able to get, aft er typing the keywords you can get two re-sults: one from the ESC documents, and a second one from the NSCJ. It will be possible for the user to see both in parallel and easily move from one result to the other with a simple click.

Th e fi rst NSCJ have been added to the search re-sults and can now be easily identifi ed and selected. Th e

digm shift in scientifi c publishing and will herald a new era of academic discovery.

The ESC Search Engine:In the last decade the amount of documents and edu-cational materials available inside the ESC websites family increased exponentially. Th is situation was na-turally associated with increasing diffi culties for the user to fi nd the information they need. It became qui-te obvious that a more comprehensive search solution was necessary. Th is is the reason why the ESC decided to provide a better search experience for the ESC site visitors44. Th e ESC search engine uses semantic analysis to provide the best results from the typed keywords45. Th is search engine project has four goals. First, to pro-vide a single entry point to multiple data sources. In fact, from a single entry point, the user will be able to explore ESC rich database of slides, scientifi c reports, guidelines, abstracts, clinical cases, news, and articles from the ESC Journals. Second, to propose a tool whi-ch can treat requests expressed in natural language, in a very user-friendly way. Th ird, to locate content that would be diffi cult to fi nd or access otherwise, therefore saving a lot of precious time. Finally, to allow visitors to fi nd contents by topic or person in an intuitive way.

In 2008, the ESC Board chaired by Roberto Ferrari, decided to support the development of a semantic sear-ch engine that would be able to search for information inside the ESC Central website and all the six Asso-ciations websites, as well (EHRA, EAE, EAPCI, HFA, EACPR, ACCA). Th is idea was based on the previously reported need of providing to the user a quick and easy way of getting the information needed from hundreds of thousands of documents available in all these websi-tes. Moreover, this engine is also looking into the ESC journals’ family were it is possible to get results from more than 30 000 papers! Not surprisingly, this tool was a major success, being already the second most vi-sited page of the ESC website, with 49,853 page views, in October and November of 201246. With the help of this search engine it is now extremely easy to get the information you need by just typing the key words on the top right hand side of the screen, inside the www.escardio.org landing page (Figure 1). Th e result is a list of documents addressing that specifi c topic, and it is up to the user to select the ones they want (Figure 2).

Inside this results page you can get a lot of informa-tion and functionalities. Within the document preview you can see how the document looks like (Figure 2). Th e relevance score assigned to this document is also displayed by the search engine. Th e type of document



Figure 1. ESC website landing page. Th e search engine box is located on the top right hand side of the screen (arrow).

Figure 2. Results page with relevant information about the documents found. On the right, there is a toolbar with a fi ltering system to refi ne the search.



8. Van Aalst, J. Using Google Scholar to estimate the impact of journal articles in education. Educational Researcher 2010;39:387-400.

9. Falagas ME, Pitsouni EI, Malietzis GA, Pappas G. Comparison of Pu-bMed, Scopus, Web of Science, and Google Scholar: Strengths and weaknesses. FASEB J 2008;22:338-42.

10. Kulkarni AV, Aziz B, Shams I, Busse JW. Comparisons of citations in Web of Science, Scopus, and Google Scholar for articles published in general medical journals. JAMA 2009;302:1092-6.

11. Alfonso F. Th e long pilgrimage of Spanish biomedical journals toward excellence. Who helps? Quality, impact and research merit. Endocri-nol Nutr. 2010 Mar;57(3):110-20.

12. Merton RK. Th e Matthew eff ect in science. Th e reward and commu-nication systems of science are considered. Science 1968;159:56–63.

13. Brody T, Harnad S, Carr L. Earlier Web usage statistics as predictors of later citation impact. Journal of the American Society for Informa-tion Science and Technology 2006;57:1060–1072.

14. Perneger TV. Relation between online “hit counts” and subsequent citations: prospective study of research papers in the BMJ. BMJ 2004;329:546-7.

15. Wren JD. URL decay in MEDLINE: a 4-year follow-up study. Bioin-formatics. 2008 Jun 1;24(11):1381-5.

16. Butler D. Web usage data outline map of knowledge. Nature. 2009; 458(7235):135.

17. Citrome L, Moss SV, Graf C. How to search and harvest the medical literature: let the citations come to you, and how to proceed when they do. Int J Clin Pract. 2009 Nov;63(11):1565-70.

18. Hrynaszkiewicz I, Norton ML, Vickers AJ, Altman DB. Preparing raw clinical data for publication: Guidance for journal editors, authors and peer reviwers. BMJ;2010:340:c181.

19. Ross JS, Lehman R, Gross CP. Th e importance of clinical trial data sharing. Towards more open science. Circ Cardiovasc Qual Outcomes 2012;5:238-40.

20. Piwowar HA, Day RS, Fridsma DB. Sharing Detailed Research Data Is Associated with Increased Citation Rate. PLoS ONE 2007;2(3):e308.

21. Santoro E, Caldarola P, Villella A. Using Web 2.0 technologies and so-cial media for the cardiologist’s education and update. G Ital Cardiol (Rome). 2011;12:174-81.

22. Chatterjee P, Biswas T. S Afr Med J. Blogs and Twitter in medical pu-blications: too unreliable to quote, or a change waiting to happen? 2011 Sep 27;101(10):712, 714.

23. Chan XH, Wynn-Jones W. Time for open access secure online data collection tool. BMJ 2012;11:49.

24. Masic I, Sivic S, Pandza H. Social Networks in medical education in Bosnia and Herzegovina. Nat Soc Med 2012;24(3):162-164.

25. Nallamothu BK, Lüscher TF. Moving from impact to infl uence: mea-surement and the changing role of medical journals. Eur Heart J. 2012 Dec;33(23):2892-6.

26. Heras M, Avanzas P, Bayes-Genis A, Pérez de Isla L, Sanchis J. 2011 Annual summary. Another meeting with our readers. Rev Esp Cardi-ol. 2011 Dec;64(12):1207-14.

27. Meneghini R, Packer AL. Is there science beyond English? Initiatives to increase the quality and visibility of non-English publications mi-ght help to break down language barriers in scientifi c communicati-on. EMBO Rep. 2007 Feb;8(2):112-6.

28. Carroll MW. Why full open access matters. PLoS Biol 2011;9:e101210. 29. Bjork BC. A study of innovative features in scholarly open access jo-

urnals. J Med internet Res 2011;13:e115. 30. Alfonso F, Almonte K, Arai K, Bacal F, Drago Silva JM, Galeano Fi-

gueredo J, Guarda E, Gutiérrez Sotelo O, Guzmán L, León Galindo J, Mario Lombana B, Márquez MF, Moreno Martínez FL, Navarro Robles J, Pinto F, Romero C, Tajer CD, Villarroel H, Wyss Quintana FS. Ibero-American cardiovascular journals. Proposals for a much-needed cooperation. Rev Esp Cardiol. 2009 Sep;62(9):1060-7.

31. Suber P. Ensuring open access for publicly funded research. BMJ 2012;345:e5184.

32. Whitfi eld J. Open access comes of age. Nature. 2011 Jun 21;474(7352): 428

33. Eysenbach G. Citation advantage of open access articles. PLoS Biol 2006;4(5): e157.

fi rst fi ve journals are: Revista Española de Cardiología, Heart and Blood Vessels, Journal of the Cardiology So-ciety of Serbia, Hellenic Journal of Cardiology, Egypti-an Heart Journal, and Romanian Journal of Cardiology. An arrangement has been made with the Brazilian So-ciety of Cardiology and its website should soon include our Search Engine. Th is is an interesting way to raise awareness about this very useful tool and allow the Bra-zilian cardiologists to have better access to our scienti-fi c resources.

Th ere is no doubt in our mind that by providing this tool the bonds between the ESC central and the Nati-onal Societies will be strengthen even further and that European Cardiovascular Science will become more vi-sible and easily accessible from any place in the world.

Acknowledgements: We are grateful for the support and assistance of Iris Chapuis, Isabelle Collin and Mu-riel Mioulet from the ESC National Cardiac Societies Relations Department at the Heart House.

Confl ict of Interest: No confl icts of interest in relation to this work were disclosed

References:1. Alfonso F, Ambrosio G, Pinto FJ, Van der Wall EE; Task Force of the

European Society of Cardiology, Kondili A, Nibouche D, Adamyan K, Huber K, Ector H, Masic I, Tarnovska R, Ivanusa M, Stanek V, Vide-baek J, Hamed M, Laucevicius A, Mustonen P, Cohen JY, Rogava M, Böhm M, Fleck E, Heusch G, Klawki R, Vardas P, Stefanadis C, Tenc-zer J, Chiariello M, Elias J, Benjelloun H, Rødevand O, Kułakowski P, Apetrei E, Lusov VA, Oganov RG, Obradovic V, Kamensky G, Kenda MF, Höglund C, Lüscher TF, Lerch R, Jokhadar M, Haouala H, Sansoy V, Shumakov V, Timmis A. European National Society cardiovascular journals. Background, rationale and mission statement of the „Edi-tors’ Club” (Task Force of the European Society of Cardiology). Heart. 2008 Jun;94(6):e19.

2. Alfonso F, Ambrosio G, Pinto FJ, Ector H, Vardas P, Kulakowski P, Timmis A; Editors’ Network ESC Task Force. European Society of Cardiology national cardiovascular journals: the ‚editors’ network’. Eur Heart J. 2010 Jan;31(1):26-8.

3. Alfonso F, Timmis A, Pinto FJ, Ambrosio G, Ector H, Kulakowski P, Vardas P; Editors’ Network European Society of Cardiology Task For-ce. Confl ict of interest policies and disclosure requirements among European Society of Cardiology National Cardiovascular Journals. Eur Heart J. 2012 Mar;33(5):587-94

4. Mills P, Timmis A, Huber K, Ector H, Lancellotti P, Masic I, Ivanusa M, Antoniades L, Aschermann M, Laucevicius A, Mustonen P, Arti-gou JY, Vardas P, Stefanadis C, Chiarello M, Bolognese L, Ambrosio G, van der Wall EE, Kułakowski P, Pinto FJ, Apetrei E, Oganov RG, Kamensky G, Lüscher TF, Lerch R, Haouala H, Sansoy V, Shumakov V, Tajer CD, Lau CP, Márquez M, Krittayaphong R, Arai K, Alfonso F. Th e role of European national journals in education. Heart J. 2009 Dec;95(24):e3.

5. Timmis AD, Alfonso F, Ambrosio G, Ector H, Kulakowski P, Pinto FJ, Vardas P; Editors’ Network. National society cardiovascular journals of Europe: Almanac 2011. Heart. 2011 Nov;97(22):1819

6. Alfonso F, Bermejo J, Segovia J. Impactology, impactitis, impactothe-rapy. Rev Esp Cardiol. 2005 Oct;58(10):1239-45.

7. Bjork B-C, Welling P, Laakso M, Majlender P, Hedlund T, et al. Open Access to the Scientifi c Journal Literature: Situation 2009. PLoS ONE 2010;5(6):e11273.



40. Crum JA. An availability study of electronic articles in an academic health sciences library. J Med Libr Assoc. 2011 Oct;99(4):290-6.

41. Manikandan S, Vani NI. Restricting access to publications from fun-ded research: ethical issues and solutions. J Postgrad Med. 2010 Apr-Jun;56(2):154-6.

42. Hawkes N. UK government comes down in favor of making all publi-cly funded research “open access”. BMJ 2012;345:e4878.

43. Noorden RV. Europe joins UK open-access bid. Britain plans to dip in to research funding to pay for results to be freely available. Nature 2012;487:285.

44. http://www.escardio.org/about/corporate-news/Pages/Search-the-ESC.aspx

45. http://www.escardio.org/about/welcome/Pages/Search-the-ESC.aspx 46. ESC Web activity report Oct 2012 to Nov 2012.

34. Norris M, Oppenheim C, Rowland F. Th e Citation Advantage of Open-Access Articles. Journal of the American Society for Informati-on Science and Technology 2008;59: 1963–1972.

35. Evans JE, Reimer J. Open access and global participation in science. Science 2009 Feb 20;323(5917):1025.

36. Mueller PS, Murali NS, Cha SS, Erwin PJ, Ghosh AK. Th e eff ect of on-line status on the impact factors of general internal medicine journals. Neth J Med. 2006 Feb;64(2):39-44.

37. Murali NS, Murali HR, Auethavekiat P, Erwin PJ, Mandrekar JN, Ma-nek NJ, Ghosh AKImpact of FUTON and NAA bias on Mayo Clin Proc. 2004 Aug;79(8):1001-6.visibilityof research.

38. Gargouri Y, Hajjem C, Larivière V, Gingras Y, Carr L, et al. Self-Selec-ted or Mandated, Open Access Increases Citation Impact for Higher Quality Research. PLoS ONE (2010);5(10): e13636.

39. Davis PM. Open access, readership, citations: a randomized control-led trial of scientifi c journal publishing. FASEB J. 2011 Jul;25(7):2129-34.


CASE PRESENTATION

Surprising awakening of a sleeping heartAlina Scridon1,2, Răzvan Constantin Șerban2, Ayman Elkahlout3, Mihaela Opriș2, Dan Dobreanu1,2

Contact address:Mihaela Opriș, MD, PhDDepartment of Cardiology, Emergency Institute for Cardiovascular Dis-eases and Transplantation Tîrgu Mureș, 50, Gheorghe Marinescu Street, 540136, Tîrgu Mureș, RomaniaE-mail: [email protected]

Abstract: Coronary artery disease is the most frequent cause of heart failure. Accumulating evidence indicate that patients with ischemic cardiomyopathy may benefi t from successful coronary revascularization in addition to optimal medical treat-ment. We report a notable case of very early, highly successful response to percutaneous coronary revascularization in a pati-ent with long history of coronary artery disease and severe myocardial hibernation. In patients with left ventricular dysfunc-tion due to chronic coronary artery disease and high probability of viable myocardium, prompt coronary revascularization should be considered.Keywords: hibernating myocardium, coronary artery disease, revascularization

Rezumat: Boala coronariană reprezintă cea mai frecventă cauză de insufi ciență cardiacă. Rezultatele studiilor clinice indică faptul că revascularizarea coronariană efi cientă la pacienții cu cardiomiopatie ischemică poate aduce benefi cii suplimentare tratamentului medical optimal. Lucrarea de față prezintă un caz particular de răspuns extrem de favorabil și foarte precoce la terapia de revascularizare coronariană percutană la un pacient cu istoric îndelungat de boală coronariană și hibernare miocar-dică severă. La pacienții cu disfuncție ventriculară stângă secundară afectării coronariene cronice și la care există o probabili-tate mare de miocard viabil, revascularizarea coronariană promptă ar trebui luată în considerare.Cuvinte cheie: hibernare miocardică, boală coronariană, revascularizare

INTRODUCTIONIn more than two thirds of cases, heart failure emana-tes from cardiac damage due to chronic coronary ar-tery disease1. Left ventricular (LV) dysfunction due to chronic myocardial ischemia has long been considered an irreversible process. Th e identifi cation of two new en tities, myocardial stunning and myocardial hiberna-tion, suggests however that this is not necessarily true2. Myo cardial stunning develops in relation with acute transient ischemia, whilst myocardial hibernation ari-ses from chronically reduced coronary blood fl ow3. More importantly, both settings imply the presence of viable myocardium. Accumulating evidence indicate that patients with ischemic cardiomyopathy may be-nefi t from successful coronary revascularization, dis-pla ying improved myocardial function, symptoms, and prognosis, due to functional improvement of the hy-po perfused, but viable myocardium2,4,5. However, the time-course and the extent of functional recovery aft er co ro nary revascularization seem to be highly depen-dent on the duration of myocardial hibernation6.

We report a notable case of very early, highly succe-ssful response to percutaneous coronary revasculariza-tion in a patient with a long history of coronary artery disease and severe myocardial hibernation.

CASE REPORTA 56-year-old Caucasian male presented for evaluati-on of New York Heart Association (NYHA) class III heart failure symptoms. At age 45 years, in the absen-ce of any prior symptoms or known cardiac pathology, he was admitted to hospital for a large anterior myo-cardial infarction. His risk factors included grade II arterial hypertension, dyslipidemia, and grade II obe-sity. Emergency coronary angiography performed 5 hours aft er the onset of symptoms revealed proximal subocclusion of the left anterior descending (LAD) ar-tery with TIMI I fl ow. No other signifi cant coronary lesions were observed at that time. He underwent pri-mary percutaneous coronary intervention with bare metal stent implantation of the LAD, with favorable post-procedural evolution. At discharge, the patient

1 Department of Physiology, University of Medicine and Pharmacy of Tîrgu Mureș, Romania2 Department of Cardiology, Emergency Institute for Cardiovascular Dis-eases and Transplantation Tîrgu Mureș, Romania3 Laboratory of Cardiac Catheterization, Emergency Institute for Cardio-vascular Diseases and Transplantation Tîrgu Mureș, Romania


Alina Scridon et al.Coronary revascularization in myocardial hibernation

was completely asymptomatic. Th e ECG revealed per-sistent ST-segment elevation in leads V2-5, pathologi-cal Q waves in V1-3 leads, and negative T waves in lead V6. Echocardiographic assessment showed normal LV function (LV ejection fraction of 60%), with moderate hypokinesia of the apical third of the interventricular septum, and of the anterior and lateral LV walls. He was discharged on double antiplatelet therapy, beta-blocker, angiotensin converting enzyme inhibitor and statin.

Th e patient did well for 8 years, when he was read-mitted for chest pain and heart failure symptoms at moderate exertion. He admitted having abandoned his treatment 6 years earlier. Th e ECG displayed a per-sistent pattern (Figure 1). Echocardiography revealed 50% LV ejection fraction, hypertrophied and slightly dilated LV (LV end-diastolic diameter 57 mm), akine-sia of the apex and of the apical third of the interven-tricular septum, hypokinesia of the apical third of the

anterior and lateral walls and of the middle third of the interventricular septum, and mild aortic and mitral valve regurgitation. Coronary angiography was per-formed, revealing no restenosis in the proximal LAD stent, a 30% stenosis followed by severe stenosis of the mid segment of the circumfl ex artery (ACx), and 30% stenosis in the proximal segment of the right coronary artery (RCA) (Figure 2A, B). Successful coronary an-gioplasty of the ACx with bare metal stent implantation was performed (Figure 2C). Th e patient was dischar-ged free from angina, on double antiplatelet therapy, beta-blocker, angiotensin conversion enzyme inhibitor, statin, and calcium channel blocker.

Th ree years later, the patient was readmitted with one month history of dyspnea and fatigue at mild exer-tion. Again, the patient admitted having abandoned his treatment one year earlier. Physical examination revea-led rales on pulmonary auscultation, and mild systolic

Figure 1. ECG tracing depicting ST-segment elevation in leads V2-5, pathological Q waves in V1-3 leads, and negative T waves in lead V6.

Figure 2. Coronary angiograms. (A) Right-anterior-oblique caudal view showing severe stenosis of the mid segment of the circumfl ex artery (ACx) (arrow). (B) Left -anterior-oblique cranial view showing 30% stenosis in the proximal segment of the right coronary artery (arrow). (C) Right-anterior-oblique caudal view showing the fi nal angiographic outcome of coronary angioplasty of the ACx with bare metal stent implantation (arrow).



and diastolic murmurs on the mitral and aortic points, respectively. ECG fi ndings were similar to the previous tracings. Compared to the prior examination, echo-

cardiography revealed severely impaired LV systolic function (LV ejection fraction 27%) with preserved LV walls thickness (Figure 3A), and the presence of an api-

Figure 3. Echocardiographic images. (A) M-mode of the left ventricle (LV) in left parasternal short axis view demonstrating hypertrophied and slightly dilated LV, and severely impaired LV systolic function (LV ejection fraction 27%). (B) B-mode in apical view showing the presence of an apical LV thrombus (arrow).

Figure 4. Coronary angiograms. (A) Right-anterior-oblique cranial view showing severe stenosis of the fi rst diagonal artery (arrow). (B) Right-anterior-oblique caudal view showing severe stenosis of the circumfl ex artery (ACx) proximal to the stent (arrow). (C) Left -anterior-oblique cranial view showing severe steno-sis of the fi rst segment of the right coronary artery (RCA) (arrow). (D) Right-anterior-oblique caudal view showing the fi nal angiographic outcome of coronary angioplasty of the ACx with bare metal stent implantation (arrow). (E) Left -anterior-oblique cranial view showing the fi nal angiographic outcome of coronary angioplasty of the RCA with bare metal stent implantation (arrow).



cal LV thrombus (Figure 3B), for which the patient was started on anticoagulation. Coronarographic examina-tion revealed 90% stenoses of the fi rst diagonal (Figure 4A), of the ACx proximal to the stent (Figure 4B), and of the fi rst segment of the RCA (Figure 4C). Percuta-neous transluminal angioplasty and primary stenting of the 90% stenoses of the ACx (Figure 4D) and RCA (Figure 4E) with bare metal stents was performed, with successful procedural outcome. Th ree days aft er the procedure, echocardiographic examination revealed sig ni fi cant recovery of LV systolic function, with >60% ba sal (Figure 5) and 45% global ejection fraction. Th e pa tient’s symptoms were relieved, and he was dischar-ged on oral anticoagulation with vitamin K antagonists, dual antiplatelet therapy, beta-blocker, angiotensin con verting enzyme inhibitor, calcium channel blocker, low-dose loop diuretic, statin, and gastric protection.

At 6-months follow-up, the patient continued to do well, with no further chest pain or dyspnea on exertion. Echocardiographic fi ndings were similar to pre-discha-r ge results, showing 45% LV ejection fraction and no intra-ventricular thrombosis.

DISCUSSIONHeart failure aff ects 1% to 3% of the general popula-tion, associating 5-year mortality rates as high as 75% following a fi rst hospital admission7. Although optimal pharmacological therapy signifi cantly reduces morta-lity among heart failure patients, this population conti-nues to display high mortality rates8.

More than two thirds of heart failure cases are rela-ted to chronic coronary artery disease1. Until recently,

LV dysfunction in these patients has been considered an irreversible process. However, in the past decades, myocardial hibernation, which can be demonstrated in up to one third of patients with chronic coronary arte ry disease and impaired LV function9, has been re-cog nized as an aggravating factor for LV dysfunction in this population2. Unlike tissue necrosis, myocardial hi bernation implies the presence of hypoperfused but viable myocardium10, and, more importantly, appears to be partially or even completely reversible upon sur-gical or percutaneous coronary revascularization3. Th is observation could explain the signifi cantly higher sur-vival rates associated with the use of revascularization strategies in addition to optimal pharmacological stra-tegies11. Indeed, accumulating evidence indicate that patients with heart failure due to chronically reduced coronary blood fl ow may benefi t from coronary revas-cularization through improved myocardial function, symptoms, and prognosis2,4,5. Furthermore, benefi t from revascularization may also be attributable to de-creased propensity to ventricular arrhythmias and re-duction of subsequent ischemic events due to restored coronary blood fl ow12,13.

Diff erentiation between LV dysfunction caused by myo cardial necrosis and scar tissue formation versus myocardial hibernation may thus have important clini-cal consequences14. In our patient, preserved thickness of LV walls despite severely impaired ejection fraction, indicating preserved myocardial viability15, prompted us to perform coronary angiography and stent angio-plasty of signifi cant coronary lesions. Given that the time-course and the extent of functional recovery af-

Figure 5. M-mode echocardiographic image of the left ventricle (LV) in left parasternal long axis view demonstrating signifi cant recovery of LV systolic func-tion post-coronary angioplasty, with >60% basal LV ejection fraction.



4. Beller GA. More evidence for the survival benefi t of coronary revas-cularization versus medical therapy in patients with ischemic cardi-omyopathy and hibernating myocardium. Circ Cardiovasc Imaging, 2013; 6(3): 355-7.

5. Henderson RA, Timmis AD. Almanac 2011: stable coronary artery disease. An editorial overview of selected research that has driven re-cent advances in clinical cardiology. Romanian Journal of Cardiology, 2012; 22(1): 15-25.

6. Rahimtoola SH, La Canna G, Ferrari R. Hibernating myocardium: another piece of the puzzle falls into place. J Am Coll Cardiol, 2006; 47: 978-80.

7. McMurray JJV, Stewart S. Th e burden of heart failure. Eur Heart J Suppl, 2002; 4: D50-8.

8. Khand A, Gemmel I, Clark AL et al. Is the prognosis of heart failure improving? J Am Coll Cardiol, 2000; 36: 2284-6.

9. Elsässer A, Schlepper M, Klövekorn WP et al. Hibernating myocar-dium: an incomplete adaptation to ischemia. Circulation, 1997; 96: 2920-31.

10. Lupașcu L, Popescu BA, Ginghină C. Viabilitatea miocardică – di-agnostic și implicaţii terapeutice. Revista Română de Cardiologie, 2010; 25(4): 248-53.

11. Di Carli MF, Hachamovitch R. New technology for noninvasive eva-luation of coronary artery disease. Circulation, 2007; 115: 1464-80.

12. Canty JM Jr, Suzuki G, Banas MD et al. Hibernating myocardium: chronically adapted to ischemia but vulnerable to sudden death. Circ Res, 2004; 94: 1142-9.

13. Wissner E, Mookadam F. Th irty-four years of hibernating myocar-dium: a case report. J Nucl Cardiol, 2007; 14(5): 745-9.

14. Buckley O, Di Carli M. Predicting benefi t from revascularization in patients with ischemic heart failure: imaging of myocardial ischemia and viability. Circulation, 2011; 123(4): 444-50.

15. Cwajg J, Cwajg E, Nagueh SF et al. End-diastolic wall thickness as predictor of recovery of function in myocardial hibernation. Relati-on to rest-redistribution Tl-201 tomography and dobutamine stress echocardiography. J Am Coll Cardiol, 2000; 35: 1152-61.

16. Sharafi A, Kassaian SE, Sharif AY et al. Signifi cant improvement in severely stunned left ventricle aft er percutaneous coronary interven-tion. J Teh Univ Heart Ctr 3, 2008; 173-5.

17. Bax JJ, Visser FC, Poldermans D et al. Time course of functional reco-very of stunned and hibernating segments aft er surgical revasculari-zation. Circulation, 2001; 104(12 Suppl 1): I314-8.

18. Schinkel AF, Poldermans D, Vanoverschelde JL et al. Incidence of re-covery of contractile function following revascularization in patients with ischemic left ventricular dysfunction. Am J Cardiol, 2004; 93(1): 14-7.

ter coronary revascularization seem to be highly de-pendent on the duration of the hibernating status6, the short history of heart failure symptoms in our patient could explain the very early signifi cant recovery of myo cardial function aft er successful coronary revascu-la rization.

Cases of signifi cant early recovery following percuta-neous coronary revascularization have already been re-ported. However, this usually happens in patients with stunned myocardium and LV dysfunction following acute coronary events16, whilst in patients with hiber-nating myocardium recovery usually takes longer17. Furthermore, early recovery of myocardial function upon percutaneous coronary revascularization in pati-ents with hibernating myocardium is usually less im-portant and occurs in patients with less severe LV im-pairment18.

CONCLUSIONSTh is case report illustrates a very early, highly success-ful response to revascularization in a patient with a long history of coronary artery disease and severe myocar-dial hibernation. In patients with LV dysfunction due to chronic coronary artery disease and high probability of viable myocardium, prompt coronary revasculariza-tion should be considered.

Confl icts of interests: none declared.

References1. Gheorghiade M, Sopko G, De Luca L et al. Navigating the crossroads

of coronary artery disease and heart failure. Circulation, 2006; 114: 1202-13.

2. Camici PG, Rimoldi OE. Th e contribution of hibernation to heart fa-ilure. Ann Med, 2004; 36: 440-447.

3. Rahimtoola SH. Th e hibernating myocardium. Am Heart J, 1989; 117: 211-21.


CASE PRESENTATION

Endovascular treatment in a case of transplantrenal artery stenosisAdrian Bucșa1, Cristina Bucșa2, Costel Matei1, Cristina Chirion2, Marian Croitoru1

Contact address:Adrian Bucsa, MD, „Prof. Dr. C. C. Iliescu” Emergency Institute forCardiovascular Diseases, BucharestE-mail: [email protected]

CASE PRESENTATIONWe present the case of a 45-year-old female patient ad-mitted for increases in the values of the blood pressure and of the serum creatinine during the last four weeks. Th e patient underwent a renal transplantation fourteen weeks ago. She was diagnosed with chronic renal failu-re when she was 33-year-old and aft er several years of conservative treatment she entered in the hemodialysis program. Aft er four months she received a kidney from her brother. Th e post-transplantation outcome was favourable and she was discharged 3 weeks aft er the surgery with a serum creatinine of 1.6 mg/dl and with normal blood pressure with only minimal medication (metoprolol 50 mg bid). At 10 weeks post-transplant there was a progressive increase in the blood pressure values to about 170/100 mm Hg and a gradual increase in the serum creatinine to 2.2 mg /dl and subsequently to 3.7 mg/dl. Th e investigations conducted by the ne-phrologist included among other tests, a Doppler ultra-sonography of the renal graft . Th is examination show-ed turbulent fl ow proximal to the arterial anastomosis with a maximum velocity of 180 cm/s; the blood fl ow at the level of the interlobar arteries had a slow ascending slope and the resistance index (RI) at this level was 0.5. Th ese parameters are strong indicators for a high-grade stenosis in the transplant renal artery1. Th e patient was sent to the department of interventional cardiology for confi rmation of the diagnosis and invasive treatment with angioplasty and stenting.

Th e physical exmination was not remarkable and the routine electrocardiogram and echocardiogram show-ed no abnormalities. Th e lab data indicated mild ane-mia (Hb=11.2 g/dl) and thrombocytopenia (131.000/mm3) and a serum creatinine of 3.4 mg/dl. Th e trans-planted kidney was, in this case, placed in the right iliac

fossa, the renal artery was connected end-to-end to the internal iliac artery of the recipient and the renal vein was connected end-to-side to the external iliac vein; the ureter was anastomosed with the bladder. Th e pa-tient was premedicated with 250 mg aspirin and 300 mg clopidogrel the day before the intervention. Th e ar-terial approach was made by inserting a 6F sheath in the left femoral artery. Aft er that, a diagnostic catheter JR 4.0 was advanced in cross-over into the right com-mon iliac artery and subsequently in the right inter-nal iliac artery. Manual injection of contrast medium confi rmed the presence of 90% stenosis at the presu-med site of surgical anastomosis with the graft artery (Figure 1). Angioplasty of the lesion was decided and performed by the direct implantation of a Herculink Elite renal stent, 5.5/18 mm, expanded at 11 atm. Th e angiographic result was very good (Figure 2). Th e post-procedural outcome was complicated by the formation of a pseudo-aneurysm at the puncture site, which was resolved by manual compression. Th e blood pressure normalised whithin 48 hours and a Doppler ultraso-nography performed in fi ft h day aft er the procedure showed a normal fl ow in the interlobar arteries with an RI of 0.63. Th e serum creatinine values dropped in the fi rst 48 hours at 2.2 mg/dl but aft er that rose aga-in to 3.8 mg/dl in the seventh day, decreasing again at 2.1 mg/dl at 14 days and 1.6 mg/dl at one month aft er the stent implantation. Th is evolution, with initial de-crease followed by gradual increase and return to nor-mal was interpreted as an episode of contrast induced nephropathy. It is known that the renal graft s may be particularly sensitive to ischemia and this can amplify the eff ects of other injuries, like the contrast media ad-ministration2. Also, the calcineurin inhibitor that the patient took as an immunosuppresive agent can have a deleterious eff ect on the allograft function.

1 „Prof. Dr. C. C. Iliescu” Emergency Institute for Cardiovascular Diseases, Bucharest2 Fundeni Clinical Institute, Bucharest

A. Bucsa et al.Endovascular treatment in a case of transplant renal artery stenosis


Th e patient was discharged with double antiplatelet me dication (aspirin 100 mg and clopidogrel 75 mg), statin, beta-blocker and, of course, the post-transplant me dication. Th e follow-up was made at 1, 3, 6 and 12 months. Th e values of the serum creatinine and the blood pressure were stable and a Doppler examination performed at six months showed an RI of 0.7 and a ma-ximum velocity of 103 cm/s. At six months the as pirin was discontinued due to the fear of gastric bleeding that may have occur. At 12 months there was a discussi-on between the cardiologist and the nephrologist about the oportunity of continuing colpidogrel administrati-on and the decision was to continue this medication for the next 12 months.We don’t expect to have any further problems with the stent because, as in all bare metal stent cases, the restenosis can occur only in the fi rst 6 months aft er implantation.

DISCUSSIONTh ere are several causes of impaired blood fl ow to the renal allograft . Th e lesions situated in the iliac artery, proximal to the anastomosis, are oft en of atherosclero-tic origin while those found in the allograft ’s artery are oft en due to progressive stenosis at the surgical anasto-mosis site. Transplant renal artery stenosis is more of-ten found in the recipients of living donor kidneys (as is the case of our patient) than in those of deceased donor graft s3. Th e explanation is the diff erence in the surgical technique for the arterial anastomosis. In living donor transplants the end of the donor renal artery is connec-ted directly to the side of the recipient’s internal iliac

artery, while in deceased donor transplants, a patch of donor aorta connected to graft ’s artery is sewn to the recipient’s iliac artery. Th is latter surgical technique (which, obviously can not be used in living donor transplants) is less likely to cause stenosis at the origin of the transplant renal artery4.

Table 14 summarizes the clinical presentations of the transplant artery stenosis. Of note, the presence of the bruits or murmurs in the area of the transplanted kid-ney can be misleading and is not necessarily an indi-cator for a vascular stenosis. Th e Doppler examination for the diagnosis must be performed by experienced operators because of unusual anatomic features and ul-trasound angles found in the pelvic area in this kind of situations. Magnetic resonance arteriography can also be used as a diagnostic tool but it is reported to have a high rate of false positive results5. Th e treatment of choice is the angioplasty with stenting but surgical cor-rection might be needed in case of repeated restenosis.

Th e experience of our department of invasive car-dio logy in this fi eld consists in three case of angioplas-

Figure 1. 90% stenosis of the renal transplant artery (arrow). Figure 2. Result aft er stent implantation.

Table 1. Common clinical features of transplant recipients with renal artery stenosis

Symptoms/signsDe novo hypertension any time posttransplantUnexplained worsening of blood pressure controlVolume retentionWorsening renal graft functionWorsening renal graft function aft er angiotensin II inhibitionBruits over the allograft


A. Bucsa et al.Endovascular treatment in a case of transplant renal artery stenosis

ty and stenting and one with balloon angioplasty only. Th e case we presented here is the most recent of all four. In all cases the angiographic results were good and the clinical improvement was evident and stable in time.

SUMMARYTh e increase in number of renal transplants in the re-cent years led to the appearance of a less known patho-logy until now: the transplant renal artery stenosis. Th e clinical features that are usually worsening hyper-tension and deterioration of the graft ’s function with rise in the serum creatinine’s values. Th e cause is oft en a progressive stenosis at the site of the arterial anasto-mosis and the diagnosis is generally made by Doppler ultrasound examination. Th e endovascular treatment consisting in angioplasty with stenting leads to good results both immediately and in long-term, and can

save the transplanted kidney. Th e renal graft ’s function can be transiently impaired due to the combined eff ect of ischemia, iodinated contrast media administration and other drugs that may interfere.


References1. Baxter GM. Ultrasound of renal transplantation. Clin Radiol 2001; 56:

802-818.2. Napoli V, Pinto S, Bargellini I, et al. Duplex doppler sonography of

trans plant renal artery stenosis before and aft er renal stenting. Eur Radiol 2002; 12:796-803.

3. Curtis JJ. Hypertension and kidney transplantation. Am J Kidney Dis 1986; 7:181-196.

4. FG Cosio, SC Textor. Hypertension aft er transplantation. In Weir RM, Medical management of kidney transplantation,Ed. Lippincott Willi-ams& Wilkins, 2005.

5. Loubeyre P, Cahen R, Grozel F, et al. Transplant renal artery stenosis. Transplantation 1996; 62:446-450.



Complex cardiac malformation in a young pregnant womanOana Năstase1, Roxana Enache2, Bogdan A. Popescu1,2, Carmen Ginghină1,2, Ruxandra Jurcuţ1,2

Contact address:Ruxandra Jurcuț, University of Medicine and Pharmacy “Carol Davila”, “Prof Dr C.C. Iliescu” Institute of Emergency for Cardiovascular Diseases, Sos Fundeni No. 258, 022322 Bucharest. E-mail [email protected]

This is the case of a 29 years-old, pregnant woman who presented in our center for cardiologic evalu-

ation at 28 weeks of pregnancy, being known since in-fancy with a complex cardiac malformation. Th e pati-ent was asymptomatic until two weeks before presenta-tion, when she started to describe dyspnea at important eff orts, coincidental with progression of pregnancy.

At transthoracic echocardiography signifi cant left ventricular hypertrophy (concentric wall thickness of 16 mm) was found, which appeared secondary to severe aortic stenosis. Th e continuous wave Doppler analysis of transaortic fl ow (Figure 1), showed a peak velocity of 4.7 m/s and a mean gradient of 56 mm Hg. Th ere was subvalvular obstruction realized by an incomplete dia phragm (Figure 2). Th e orifi ce area at the level of the diaphragm was estimated by 3D transthoracic echocar-diography planimetry at 1.8 cm2 (Figure 3). Th e patient had associated valvular stenosis probably secondary to jet-lesion, estimated by planimetry as moderate (aortic valve area of 1.4 cm2) (Figure 4) and mild aortic re-gurgitation. An interventricular basal septal aneurysm with a small left to right shunt was also seen (Figure 5).

Th ere was persistent ductus arteriosus with left -right shunt seen both from the parasternal short axis view and from the suprasternal view (Figure 6 and Figure 7). Th e suprasternal view revealed the coexistence of aortic coarctation with a peak Doppler gradient of 31 mmHg, indicating mild obstruction (Figure 8).

Patients with subvalvular aortic stenosis may tolerate pregnancy well as long as they remain relatively asy m-ptomatic and have a normal BP response during exer-cise1. Obstetric complications may be increased in pa-tients with severe AS (hypertension-related disorders, pre mature labour)1. Regular follow-up during preg-nancy is required by an experienced team. In severe AS, monthly or bimonthly cardiac evaluations including echo cardiography are advised to determine symptom status, progression of stenosis, or other complications. In severe aortic stenosis, particularly with symptoms during the second half of pregnancy, caesarean deli-very should be preferred with endotracheal intubation and general anesthesia. Th e patient had an uneventful preg nancy evolution and gave birth to a healthy baby at 38-weeks of pregnancy by caesarean section.

1 “Prof. Dr. C.C. Iliescu” Institute of Emergency for Cardiovascular Dis-eases2 University of Medicine and Pharmacy “Carol Davila”, Bucharest

Figure 1. Transthoracic echocardiography, apical fi ve chamber view, con-tinuous wave Doppler examination of transaortic fl ow: peak fl ow velocity of 4.7 m/s.

Figure 2. Th ree-dimensional transthoracic echocardiography parasternal long axis view focus on left ventricular outfl ow tract: the subaortic valve dia phragm (white arrow). LV = left ventricle, LA = left atrium, RV = right ventricle, Ao = aorta

RV

LV

LA

Ao


Oana Nastase et al.Complex cardiac malformation in a young pregnant woman

Figure 3. Th ree-dimensional transthoracic echocardiography apical fi ve-chamber view, reconstruction of the left ventricular outfl ow tract, view from the left ventricle. A circular diaphragm (white arrow) can be seen in left ven-tricular outfl ow tract, creating a stenosis with ananatomical aria at 1.8 cm2.

Figure 4. Th ree-dimensional transthoracic echocardiography – focus on the aortic valve: moderate valvular aortic stenosis – planimetric anatomic area of 1.4 cm2.

Figure 5. Transthoracic echocardiography, apical fi ve chamber view, focus on aortic valve: interventricular septum basal aneurysm with a small left -right shunt (white arrow) at this level seen at color Doppler.

Figure 6. Transthoracic echocardiography, short axis view at great vessels (A) and suprasternal view (B), color Doppler examination: patent ductus arteriosus with a diameter of 5 mm (white arrow).

A B

Oana Nastase et al.Complex cardiac malformation in a young pregnant woman



References1. Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C et al. ESC Co-

m mittee for Practice Guidelines. ESC Guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the Eu-ropean Society of Cardiology. Eur Heart J. 2011; 32(24):3147-97

Figure 7. Transthoracic echocardiography, parasternal short axis view, continuous wave Doppler examination of the patent ductus arteriosus shows continu-ous fl ow with maximal aorto-pulmonary gradient of 100 mmHg.

Figure 8. Transthoracic echocardiography, suprasternal view: aortic coarctation seen in 2D (A),with a peak systolic gradientof 31 mmHg at continuous wave Doppler examination (B).

A B

Aortic arch

Descending aorta

Aorticcoarctation



Ultrasound imaging of a bilateral carotid body paragangliomaRoxana Oana Darabont

Contact address:Roxana Oana Darabont, MD, PhD, Cardiology Department of University Emergency Hospital Bucharest, Splaiul Independentei Street, no. 169, 050098 Bucharest, Romania; fax: +40 21 3180576; phone: + 40 723 441 315. e-mail: [email protected];

Paragangliomas are rare tumors that grow from cells of the peripheral nervous system, which derive

from the embryonic neural crest cel1,2. Th e head and neck represent the most common topography of these tumors. At this level they originate mainly from carotid body (carotid bi fur cation), with other possible locati-ons on vagal body, in the middle ear, and larynx. Th e carotid body paragangliomas (CBPs) are highly vascu-larized lesions, therefore one formerly name used for them was “glomus tu mors”. Another ancient denomi-nation – “chemodectoma” – was indicating their possi-ble chemoreceptor function3.

CBPs are usually benign, non-secreting, slow grow-ing tumors4,5. About 60% of them did not exhibit grow-th in follow-up. Some reports are indicating that 4.2 years is the average double time for this tumors6. CBPs can be found at any age, but the usual age for onset is between the third and six de ca de of life (mean age 55 years)7,8 and is slightly more fre q u ent in women8. As a whole, carotid body tumors are b ilateral in 10% of cases9.

Th e true incidence of CBPs is still unknown as long as many cases remain undiagnosed and the disease is very rare, but it is estimated to 0.012%10.

Keywords: carotid body paraganglioma, ultrasound, color Doppler ultrasound

We are presenting the case of 30 years old male with asymptomatic bilateral swelling of the neck which is the usual presentation in 60-70% of CBP11. During the clinical exam we found a palpable mass on each side of the neck, in front of the sternocleidomastoidian mus-cle, being more easier moved horizontally rather than vertically (the Fontaine’s sign)12.

In other cases a pulsating mass can be detected at palpation. Very rarely a carotid bruit can be heard, due to an important compression induced by the tumor on the carotid arteries. Large CBP may be associated with

dysfunction of the vagal nerve or cranial nerves IX, XI, and XII, with Horner’s syndrome or defi cits of the fa-cial nerve13.

Th e usual diagnostic methods for this pathology are: B-mode and Doppler ultrasound, angio-CT, angio-MRI, 111 In-OctreoScan and digital subtraction angio-graphy. Depending on carotid arteries involvement CBPs can be of three categories, according to Shamblin clas sifi cation: class I – splaying of the carotid bifurca-tion with little attachment to the carotid vessels, class II – partial surrounding of the internal and external ca-ro tid arteries, Class III – complete surrounding of the carotid vessels14.

A relatively recent evaluation proved a sensitivity of 92% and a specifi city of 100% for the B-mode combi-ned with color Doppler ultrasound in the detection of carotid paragangliomas compared with CT/MRI. However, the diff erence in maximum diameter of the lesions measured at ultrasound versus CT/MRI was signifi cant (p=0.008), ranging between – 5 mm and + 16 mm (mean diff erence 2.2±6.0)15.

1 University of Medicine and Pharmacy “Carol Davila” – Cardiology De-partment of University Emergency Hospital Bucharest

Figure 1. B-mode ultrasound imaging of the right-sided carotid paragangli-oma. Th e tumor is oval, well-defi ned, inhomogeneous, hypoechoic. Cranio-caudal diameter has 21.5 mm and tranversal diameter has 28.3 mm.

Roxana Oana DarabontUltrasound imaging of carotid paraganglioma


In our case the diagnostic of carotid body tumor was fi rstly established at ultrasound exam. An oval, well-defi ned, inomogenous, hypoechoic and hypervascula-rized structure was observed at carotid bifurcation on the right side of the neck (Figure 1 and 2) and on the left side as well (Figure 3 and 4). Figure 4 is indicating a CBP of Shamblin class III, with complete surrounding of the carotid arteries. In Figure 5 it is illustrated the attachement of CBP on the entire proximal wall of the left internal carotid artery in longitudinal view. Figu-re 6 is emphasizing that the fl ow is still normal in left internal carotid artery despite the adjacent invasion of the tumor.

Aft er three years of follow-up the patient did not pro ceed to surgical correction of the bilateral CBP ta-king into account that the tumors are asymptomatic,

Figure 2. Color Doppler ultrasound of the vascularized right-sided carotid para ganglioma.

Figure 3. B-mode ultrasound imaging of the left -sided carotid paragangli o-ma with Shamblin class III characteristics – splaying of the carotid bifurca-tion and complete surroundings of the carotid arteries. Cranio-caudal dia-meter has 21.9 mm and transversal diameter has 34.8 mm. L-ECA = left external carotid artery; L-ICA = left internal carotid artery.

Figure 4. Color Doppler ultrasound of the hypervascularised left -sided caro-tid paraganglioma.

Figure 5. B-mode ultrasound imaging of the left sided paraganglioma atta-ched to the proximal wall of the left internal carotid artery in longitudinal view. L-ICA=left internal carotid artery.

Figure 6. Color and spectral Doppler ultrasound of the left internal carotid artery indicating normal fl ow at this level; L-ICA = left internal carotid ar-tery.


Roxana Oana DarabontUltrasound imaging of carotid paraganglioma

with very slow grow and the risk of intervention is sig-ni fi cantly high.


References 1. Najibi S, Terramani TT, Brinkman W et al. Carotid body tumors., J.

Am. Coll. Surg., 2002; 194: 538-539.2. Paal E, Chung EM, Head and neck pathology – Radiology classics:

vagal paraganglioma, Head and Neck Pathol., 2007; 1: 35-37.3. Martin TP. What we call them: the nomenclature of head and neck

paragangliomas, Clin. Otolaryngol., 2006; 31: 185-186.4. Myssiorek D, Ferlito A, Silver CE et al. Screening for familial paragan-

gliomas. Oral Oncol., 2008; 44: 532-537.5. Șanh A, Őz K, Ayduran E et al. Carotid body tumors and our surgical

approaches, Indian J. Otolaryngol. Haed Neck Surg. 2012; 64:158-161.6. Jansen JC, van den Berg R, Kuiper A. et al. Estimation of growth rate

in patients with head and neck paragangliomas infl uences the treat-ment proposal, Cancer, 2000; 88: 2811-2816.

7. Sajid MS, Hamilton G, Baker DM. A multicenter review of carotid body tumour management. Joint vascular research group. Eur. J. Vasc. Endovasc. Surg., 2007; 34: 127-130.

8. Luo T, Zhang C, Ning YC et al. Surgical treatment of carotid body tumor: case report and literature review, Journal of Geriatric Cardio-logy, 2013; 10: 116-118.

9. Pacheco-Ojeda L. Malignant carotid body tumors: report of three ca-ses. Ann. Otol. Rhinol. Laryngol., 2001; 110: 36-40.

10. Grotemeyer D, Loghmanieh SM, Pourhassan S et al. Dignity of ca-rotid body tumors. Review of the literature and clinical experiences. Chirurg, 2009; 80: 854-863.

11. Patetsios B, Gable DR, Garrett WV et al. Management of carotid body paragangliomas and review of a 30-year experience, Ann. Vasc. Surg., 2002; 16: 331-338.

12. Boedeker CC, Ridder GJ, Schipper J. Paragangliomas of the head and neck: diagnosis and treatment, Fam. Cancer, 2005; 4: 55-59

13. Off ergeld C, Brase C, Yaremchuk S. et al. Head and neck paragan-gliomas: clinical and molecular genetic classifi cation, Clinics, 2012; 67(S1): 19-28.

14. Shamblin WR, ReMine WH, Sheps SG et al. Carotid body tumor (chemodectoma). Clinico-pathologic analysis of ninety cases, Am. J. Surg., 1971; 122: 732-739.

15. Demattè S, Di Sarra D, Schiavi F et al. Role of ultrasound and color Doppler imaging in the detection of carotid paragangliomas, J. Ultra-sound, 2012; 15: 158-163.


UPDATES IN CARDIOLOGY

O comparație directă a rezultatelor precoce și tardive după trei tipuri diferite de revascularizare carotidi ană și chirurgie cardiacăPrevalența leziunilor carotidiene severe la pacienții cu indicație de chirurgie cardiacă este între 6-12%, dar mana gementul optim al acestor pacienți este controver-sat în lipsa unor trialuri clinice randomizate. Există în practica curentă trei abordări: endarterectomie caroti-diană urmată de chirurgie cardiacă (staged CEA-OHS), endarterectomie carotidiană concomitentă cu chirur-gia cardiacă (combined CEA-OHS) și angioplastie ca-rotidiană cu implantare de stent urmată de chirurgie cardiacă (staged CAS-OHS).

Autorii își propun să compare rezultatele celor trei procedee. Studiul s-a desfășurat în perioada 1997-2009 și au fost înrolați 350 de pacienți supuși unei intervenții de revascularizare carotidiană înaintea sau concomi-tent cu o intervenție chirurgicală cardiacă (într-un in-terval de maxim 90 de zile), urmăriți o perioadă medie de 3-7 ani. În funcție de procedura aleasă, pacienții au fost împărțiți în trei grupuri: staged CEA-OHS (45), combined CEA-OHS (195), staged CAS-OHS (110). Endpointul primar a fost unul compozit incluzând mortalitatea de orice cauză, accidentul vascular cere-bral (AVC) și infarctul miocardic (IM).

Rezultatele au arătat că la înrolare, prevalența bolii carotidiene simptomatice și a stenozei/ocluziei caroti-diene contralaterale a fost similară în cele trei grupuri, dar în grupul supus staged CAS-OHS a fost o pre-valență mai mare a antecedentelor de AVC (p=0,03), de re vascularizare carotidiană și a intervențiilor chirur-gi cale cardiace mai complexe. Pentru intervențiile în două etape, analiza complexă a arătat importanța inter-valului interprocedural. Astfel, în acest interval, staged CEA-OHS a fost asociată cu un risc semnifi cativ mai mare de IM. Rezultatele arată că nu a existat o diferență semnifi cativă în endpointul compozit pe termen scurt între staged CAS-OHS și combined CEA-OHS, dar sta-ged CAS-OHS a avut un risc mai mare de IM în inter-valul interprocedural, iar combined CEA-OHS a avut un risc mai mare de AVC perioperator. Pe termen lung (>12 luni) staged CAS-OHS a avut un risc semnifi cativ mai mic de evenimente compozite comparativ atât cu staged CEA-OHS (adjusted hazard ratio: 0,33; 95% CI: 0,15- 0,77; p=0,01) cât și cu combined CEA-OHS (ad-justed hazard ratio:0,35; 95% CI: 0,18-0,70; p=0,003). Staged CEA-OHS a avut riscul cel mai mare atât preco-ce cât și tardiv.

În concluzie, autorii subliniază că staged CAS-OHS și combined CEA-OHS prezintă riscuri similare de de-ces, AVC și IM pe termen scurt, ambele fi ind mai bune decât staged CEA-OHS. Cu toate acestea, după un an, re zultatele sunt semnifi cativ mai favorabile pentru sta-ged CAS-OHS. Un argument în favoarea combined CEA-OHS ar putea fi urgența necesității revasculariză-rii coronariene, având în vedere intervalul de 3-4 săptă-mâni necesar de dublă antiagregare după CAS, înain-tea OHS. Astfel, autorii consideră staged CAS-OHS de primă intenție dacă este acceptabilă ideea temporizării OHS cu 3-4 săptămâni.

Mehdi H. Shishehbor et al. A Direct Comparison of Early and Late Outcomes With Th ree Approaches to Ca-rotid Revascularizaton and Open Heart Surgery. J Am Coll Cardiol 2013; 62:1948-56. (ACM).

Rezerva contractilă a ventriculului drept la pacienții cu HTP severă – evaluare și semnifi cație prognosticăComparativ cu numărul mare de studii privind eva-luarea rezervei contractile a ventriculului stâng, pen-tru ventriculul drept nu există metode recunoscute de evaluare. Plecând de la prezumția intuitivă că există o relație între creșterea la efort a presiunii sistolice din artera pulmonară (PAPS) și funcția VD, autorii își pro-pun să analizeze creșterea PAPS la efort ca un indicator de rezervă contractilă a VD la pacienții cu HTP severă și insufi ciență cardiacă dreaptă.

Studiul citat a fost prospectiv și a inclus 124 de pa-cienți diagnosticați invaziv cu HTP arterială sau HTP cronică tromboembolică și cu disfuncție sistolică de VD în ciuda tratamentului optim, ce au fost urmăriți pe o perioadă medie de 3±1,8 ani. Pacienții au efectuat ecocardiografi e de stres și testul cardiopulmonar și, în funcție de creșterea PAPS la efort peste valoarea de 30 mmHg au fost împărțiți în două grupuri: cu/fără creș-terea PAPS cu peste 30 mmHg, aproximativ egale (58, respectiv 66 de pacienți). Din cei 124 de pacienți, 104 aveau HTP arterială și 20 HTP cronică tromboembo-lică inoperabilă. Rezultatele au arătat că la înrolare nu au existat diferențe semnifi cative între cele două gru-puri privind medicația, parametrii hemodinamici de repaus măsurați prin cateterism (PAP medie crescu-tă, rezistența vasculară pulmonară mare, indicele car-diac scăzut) sau parametrii ecocardiografi ci (aria VD crescută, TAPSE scăzut, etc.). La efort, creșterea PAPS cu mai puțin de 30 mmHg s-a asociat cu valori sem-nifi cativ mai mici pentru distanța parcursă la testul de


Updates in cardiology

internați în 26 de spitale din China în perioada august 2009 și mai 2013 pentru AVC ischemic acut, netrom-bolizat, debutat în primele 48 de ore, și cu valori mari ale TA. Au fost aleși în mod aleatoriu 2038 de pacienți care au primit tratament hipotensor, cu obiectivul de a reduce TA cu 10% până la 25% în primele 24 de ore după randomizare, obținerea unei TA <140/90 mm Hg în primele 7 zile și menținerea acestor valori pe par-cursul spitalizării. Ceilalți 2033 de pacienți cărora li s-a oprit medicația antihipertensivă au reprezentat lotul de control. End-pointurile primare stabilite au fost: rata mortalității și dizabilitatea majoră (defi nită ca scorul Scalei Rankin modifi cate ≥3) la 14 zile sau la externare.

În primele 24 de ore de la randomizare, TA sistolică medie a fost redusă de la 166.7 mm Hg la 144.7 mm Hg (-12.7%) în grupul pacienților care au primit tra-tament hipotensor și de la 165.6 mm Hg la 152.9 mm Hg (-7.2%) în grupul control (diferența −5.5% [95%CI, −4.9 la −6.1%]; diferența absolută, −9.1 mm Hg [95% CI, −10.2 la −8.1]; p <0.001). La 7 zile de la randomi-zare, TA sistolică medie în grupul celor cu tratament hipotensor a fost 137.3 mm Hg, iar în grupul control 146.5 mm Hg (diferența, −9.3 mm Hg [95%CI, −10.1 la −8.4]; p <0.001).

Endpointul primar nu a fost diferit semnifi cativ sta-tistic între cele două grupuri la 14 zile sau la externare (683 de evenimente adverse în grupul cu tratamentul hipotensor vs. 681 în grupul control; OR 1.00 [95%CI, 0.88 - 1.14]; p=98). Nici după 3 luni de urmărire a pacienților rata mortalității și dizabilitatea majoră nu au fost semnifi cativ diferite în cele două grupuri (500 de evenimente adverse în grupul cu tratamentul hipo-tensor vs. 502 în grupul control; OR 0.99 [95%CI, 0.86 - 1.15]; p=93).

În concluzie, acesta este primul studiu clinic rando-mizat cu sufi cientă putere statistică pentru a testa efec-tul scăderii imediate a valorilor TA asupra ratei mor-talității și dizabilității majore la pacienții cu AVC ische-mic acut. Rezultatele studiului au demonstrat că admi-nistrarea imediată a medicamentelor hipotensoare la această categorie de pacienți nu ameliorează semnifi -cativ prognosticul acestora la 14 zile sau la externare.

He J, Zhang Y, Xu T, Zhao Q, Wang D, Chen CS, Tong W, Liu C, Xu T, Ju Z, Peng Y, Peng H, Li Q, Geng D, Zhang J, Li D, Zhang F, Guo L, Sun Y, Wang X, Cui Y, Li y, Ma D, Yang G, Gao Y, Yuan X, Bazzano LA, Chen J. Eff ects of Immediate Blood Pressure Reduction on Death and Major Disability in Patients With Acute Ischemic Stroke. Th e CATIS Randomized Clinical Trial. JAMA. Published online on November 17, 2013. doi:10.1001/jama.2013.282543. (AM)

mers de 6 minute, pentru consumul maxim de O2/kg și pentru ratele de supraviețuire la 1-, 3-, și 4 ani. La tes-tul cardiopulmonar, valoarea cutoff pentru consumul maxim de VO2 care a subîmpărțit pacienții a fost de 11,4 ml/min/kg, pacienții cu consum VO2 peste această valoare au avut rate de supraviețuire semnifi cativ mai bune decât cei sub această valoare. La analiza univari-ată, parametrii predictivi pentru supraviețuire au fost: testul de mers de 6 minute, consumul maxim VO2 per se și indexat la greutate, PAPS maximă și creșterea PAPS. La analiza multivariată, creșterea PAPS la efort și consumul maxim VO2/kg s-au dovedit a fi predic-tori independenți de prognostic (HR, 2,56 pentru con-sumul maxim O2/kg și 2,84 pentru creșterea PAPS la efort).

Concluzia studiului a fost că creșterea PAPS la efort are o mare relevanță clinică și prognostică la pacienții cu HTP și poate sugera prezența rezervei contracti-le a VD subliniind rolul potențial al ecocardiografi ei Doppler de stres în evaluarea prognostică a pacienților cu HTP. Corelând aceste rezultate cu confi rmarea re-centă a faptului că funcția sistolică a VD este un pre-dictor prognostic mai puternic decât rezistența vascu-lară pulmonară, se conturează rolul posibil superior al evaluării rezervei contractile a VD față de parametrii hemodinamici de repaus (măsurați ecocardiografi c) în urmărirea și managementul terapeutic al pacienților cu HTP.

Ekkehard Grunig et al. Assessment and Prognostic Relevance of Right Ventricular Contractile Reserve in Pa-tients With Severe Pulmonary Hypertension. Circulation 2013;128:2005-2015. (ACM).

Efectele reducerii imediate ale tensiunii arteriale asupra decesului și dizabilității majore la pacienții cu accident vascular cerebral ischemic acutStudiul clinic randomizat CATISAccidentul vascular cerebral (AVC) este a doua cauză de deces și prima cauză de dizabilitate importantă pe termen lung din lume. Studiile clinice au demonstrat că reducerea tensiunii arteriale (TA) scade riscul de AVC la pacienții hipertensivi și normotensivi cu istoric de AVC sau accident ischemic tranzitor. Deși benefi ciile tratamentului hipotensor pentru prevenția primară și secundară a AVC-ului sunt cunoscute, efectele reduce-rii imediate a valorilor TA la pacienții cu AVC ischemic acut nu sunt încă bine stabilite.

Astfel, autorii acestui studiu clinic randomizat au avut ca obiectiv evaluarea efectului scăderii imediate a valorilor TA la pacienții cu AVC ischemic acut, ur-mărind rata mortalității și dizabilitatea majoră la 14 zile sau la externare. Au fost incluși 4071 de pacienți

Updates in cardiologyRomanian Journal of Cardiology

Vol. 23, No. 4, 2013

Repararea valvulară mitrală versus înlocuirea valvulară în regurgitarea mitrală ischemică severăRegurgitarea mitrală ischemică, consecință a remode-lării ventriculare stângi (VS) post infarct miocardic, se aso ciază cu un risc substanțial de deces. Tratamentul chi rurgical al acesteia diferă considerabil de cel al re-gur gitării mitrale degenerative, organice. Ghidurile ac-tuale recomandă intervenție chirurgicală pacienților cu re gurgitare mitrală ischemică severă care sunt simpto-matici în ciuda tratamentului maximal medicamentos, însă evidențele în ceea ce privește repararea versus în-locuirea valvulară sunt limitate.

În acest studiu au fost incluși 251 de pacienți diag-nos ticați cu regurgitare mitrală ischemică severă. Aceș-tia au fost supuși intervenției chirurgicale, fi ind ran-do mizați fi e pentru efectuarea reparării valvulare, fi e pentru înlocuirea acesteia cu prezervarea cordajelor, sco pul fi ind evaluarea efi cacității și siguranței acestor două tehnici. End-pointul primar a fost reprezentat de gradul de reversibilitate a remodelării VS, evaluată prin volumul telesistolic ventricular stâng indexat (VTSVSI) la 12 luni. End-pointurile secundare au fost reprezenta-te de rata mortalității și evenimentelor adverse cardia-ce sau cerebrovasculare. Din punct de vedere statistic, pen tru a evalua VTSVSI s-a utilizat testul „Wilcoxon rank-sum”.

La 12 luni, VTSVSI mediu în cadrul supraviețuitorilor a fost de 54.6±25.0 ml/m2 în grupul pacienților cu repa-rare valvulară (G1) și 60.7±31.5 ml/m2 în grupul celor cu înlocuire valvulară (G2) (modifi carea medie față de momentul inițial, −6.6 ml/m2 și −6.8 ml/m2, respectiv). Rata deceselor a fost de 14.3% în grupul G1 și 17.6% în G2 (reparare valvulară - HR 0.79; 95% intervalul de confi dență, 0.42-1.47; p = 0.45). Nu a fost o diferență semnifi cativă între cele 2 grupuri în ceea ce privește VTSVSI după ajustare pentru deces (scor z 1.33; p = 0.18). Rata recurenței regurgitării mitrale moderate sau severe la 12 luni a fost semnifi cativ statistic mai mare în grupul G1 față de G2 (32.6% vs. 2.3%, p <0.001). Nu s-a constat o diferență semnifi cativă între cele 2 grupuri în ceea ce privește rata evenimentelor adverse cardiace sau cerebrovasculare, statusul funcțional sau calitatea vieții la 12 luni.

În concluzie, nu a fost observată o diferență semni-fi cativă statistic în ceea ce privește remodelarea VS sau supraviețuirea la 12 luni la pacienții la care s-a efectuat înlocuire valvulară, comparativ cu repararea valvulară. Înlocuirea valvei mitrale a conferit o corecție mai du-rabilă a regurgitării mitrale ischemice, însă nu au fost observate diferențe în ceea ce privește prognosticul cli-

nic al pacienților din cele două grupuri studiate. Re-zu l tatele acestui studiu contrazic multe dintre datele pu blicate în literatură anterior pe acest subiect, și anu -me că repararea valvulară mitrală conferă avantaje in-clu zând o rată mai mică a mortalității perioperatorii, o ame liorare a funcției ventriculare stângi și o mai mare rată a supraviețuirii pe termen lung. Continuarea ur-mării pe termen lung a acestor pacienți este necesa ră pentru con fi rmarea rezultatelor acestui studiu, putând de aseme nea ajuta la identifi carea predictorilor de recu-rență a regurgitării mitrale și permițând astfel o selecție mai adecvată a pacienților.

Acker MA, Parides MK, Perrault L, Moskowitz A, Gelijns A, Voisine P, Smith P, Hung J, Blackstone E, Puskas J, Argenziano M, Gammie J, Mack M, Asche-im D, Bagiella E, Moquete E, Ferguson B, Horvath K, Geller N, Miller M, Woo J, D’Alessandro D, Ailawadi G, Dagenais F, Gardner T, O’Gara P, Michler R, Kron I. Mitral-Valve Repair versus Replacement for Severe Ische-mic Mitral Regurgitation. N Engl J Med November 18,2013; at NEJM.org; DOI: 10.1056/NEJMoa1312808 (AM)

Studiul CORAL: Angioplastia și terapia medicamentoasă în stenoza aterosclerotică de arteră renalăRezultatele studiilor de screening indică o prevalenţă a stenozelor aterosclerotice de arteră renală de până la 7% în rândul persoanelor cu vârsta peste 65 de ani. Ste nozele aterosclerotice de la nivelul arterelor rena-le pot conduce la hipertensiune arterială, nefropatie ischemică și la complicaţii multiple pe termen lung. Benefi ciile angioplastiei de arteră renală în prevenţia evenimentelor adverse majore renale și cardiovasculare sunt incerte. Există până în prezent trei trialuri clinice randomizate în care angioplastia de arteră renală nu a prezentat benefi cii în ceea ce privește valorile tensiunii arteriale și alte două trialuri clinice randomizate care nu au demonstrat un benefi ciu al stentării în ceea ce privește ameliorarea funcţiei renale.

Trialul CORAL (Th e Cardiovascular Outcomes in Re-nal Atherosclerotic Lesions) a avut ca scop evaluarea in-fl uenţei angioplastiei de arteră renală asupra incidenţei evenimentelor clinice adverse cardiovasculare și renale. S-a efectuat un studiu multicentric, randomizat, con-trolat, pe un număr de 947 de pacienţi care prezentau stenoze aterosclerotice la nivelul arterelor renale și care asociau hipertensiune arterială sistolică în ciuda tera-piei cu două sau mai multe medicamente antihiper-tensive (valori de 155 mmHg sau peste), boală renală cronică (RFG prin MDRD sub 60 ml/min/1.73 m2) sau ambele. Stenoza severă de arteră renală a fost defi nită



stentare 0.94; IC 95%, 0.76 la 1.17; p = 0.58). Nu s-au înregistrat diferenţe semnifi cative între cele două gru-puri nici în ceea ce privește ratele componentelor indi-viduale ale end point-ului compozit sau ale mortalităţii de orice cauză. Valoarea tensiunii arteriale sistolice a înregistrat o reducere în ambele grupuri (cu 15.6±25.8 mm Hg în grupul cu tratament medical și cu 16.6±21.2 mm Hg în grupul cu angioplastie și tratament medi-cal). S-a observat o reducere ușor mai mare, semnifi -cativă statistic, a tensiunii arteriale sistolice în favoarea grupului la care s-a efectuat stentarea (−2.3 mm Hg; IC 95%, −4.4 la −0.2; p = 0.03), dar aceasta nu s-a asociat cu o reducere a evenimentelor clinice.

Concluzia acestui studiu a fost aceea că stentarea arterelor renale, asociată terapiei medicale complexe și multifactoriale, nu a prezentat un benefi ciu semnifi ca-tiv în ceea ce privește prevenţia evenimentelor clinice faţă de terapia medicală izolată.

Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and Medical Th erapy for Atherosclerotic Renal-Artery Steno-sis. N Engl J Med 2013. DOI: 10.1056/NEJMoa1310753 (AP)

Trialul TTM (Targeted Temperature Management): temperatura țintă după stop cardiac, 33 grade versus 36 grade CelsiusPacienţii care nu și-au recăpătat starea de conștienţă, după un stop cardiac resuscitat în afara spitalului, se afl ă la risc crescut de deces, iar deteriorarea neurologi-că ulterioară este frecventă la cei care supravieţuiesc. Exis tă două trialuri clinice, efectuate la supravieţuitorii afl aţi în stare de inconștienţă după un stop cardiac re-suscitat (presupus a fi de cauză cardiacă și cu apariţia unei tulburări de ritm ce a necesitat defi brilare), care au comparat efectele hipotermiei terapeutice (între 32 și 34 grade Celsius timp de 12-24 de ore) cu efectele terapiei standard. Aceste trialuri au demonstrat că hipotermia terapeutică se asociază cu o îmbunătăţire semnifi cati-vă a funcţiei neurologice și a supravieţuirii. În prezent, in ducerea hipotermiei terapeutice este recomandată de ghidurile internaţionale, însă dovezile în acest sens sunt limitate iar valoarea temperaturii ţintă asociată cu cel mai bun prognostic este încă necunoscută.

Trialului TTM (Targeted Temperature Management) este un studiu randomizat desfășurat pe 939 de pacienţi selectaţi din 36 de unităţi de terapie intensivă din Euro-pa și Australia, în care s-au comparat rezultatele hipo-termiei terapeutice induse la o valoare de 33 versus 36 grade Celsius. Au fost selectaţi pacienţi cu vârsta peste 18 ani, afl aţi în stare de inconștienţă (scor Glasgow mai mic de 8) după moarte subită, presupusă a fi de cauză

angiografi c ca stenoză de cel puţin 80% dar mai mică de 100% din diametrul arterei, sau ca stenoză de cel puţin 60% dar mai mică de 80% din diametrul arterei și cu un gradient presional de cel puţin 20 mmHg.

Pacienţii au fost randomizaţi pentru management prin terapie medicală plus stentare la nivelul arterei re-nale (467 de pacienţi, ulterior doar 459 incluși în anali-za statistică) sau doar management prin terapie medi-cală (480 pacienţi, ulterior doar 472 incluși în analiza statistică).

În ceea ce privește medicaţia administrată, toţi parti-cipanţii au primit terapie antiagregantă plachetară, me-dicaţie pentru controlul valorilor tensionale, glicemiei și pentru tratarea dislipidemiei. În absenţa contraindi-caţiilor, s-au administrat candesartan cu sau fără hi-droclorotiazidă și agentul care conţine combinaţia fi xă de amlodipină cu atorvastatină, dozele fi ind ajustate în funcţie de valorile tensionale și de profi lul lipidic. Pen-tru valorile tensionale, ţinta a fost o valoare sub 140/ 90 mmHg la pacienţii fără afecţiuni coexistente și de sub 130/80 mmHg la pacienţii cu diabet sau cu boală renală cronică, medicaţia fi ind ajustată până la atinge-rea ţintelor.

În ceea ce privește angioplastia, s-au folosit stenturi Palmaz Genesis stent, iar la unii pacienţi, la aprecie-rea medicului, s-a efectuat predilatare. Au fost stentate toate stenozele mai mari sau egale de 60%. La pacienţii cu stenoze multiple, s-a efectuat stentarea multiplă în cadrul aceleiași proceduri sau la intervale de 2-4 săp-tamâni. A fost plasat și un dispozitiv de protecţie pen-tru embolie distală de tip Angioguard, iniţial la toţi pacienţii, ulterior folosirea acestuia a fost lăsată la apre-cierea medicului.

Participanţii au fost urmăriţi pe o perioadă medie de 43 de luni pentru producerea de evenimente adver se cardiovasculare și renale. Endpoint-ul primar a fost un compozit al decesului de cauză cardiovasculară sau re-nală, infarctului de miocard, accidentului vascular ce-rebral, spitalizărilor pentru insufi cienţă cardiacă con-gestivă, insufi cienţei renale progresive sau al nevoii de terapie de substituţie a funcţiei renale. End point-urile secundare au fost reprezentate de componentele indi-viduale ale end point-ului primar și de mortalitatea de orice cauză.

La fi nalul studiului s-a constatat că rata end point-ului compozit nu a prezentat diferenţe semnifi cative între grupul pacienţilor la care s-a efectuat stentarea de arteră renală plus administrare de terapie medicală și grupul pacienţilor care au primit doar terapie medi-cală (35.1% și respectiv 35.8%; rata hazardului pentru

Updates in cardiologyRomanian Journal of Cardiology

Vol. 23, No. 4, 2013

Algoritm de diagnostic în cardiomiopatii - o punte de legătură între fenotipul clinic și diagnosticul fi nal.Cardiomiopatiile, sunt un subiect deocamdata greu de stăpânit, atât din cauza varietății și variabilității, cât și a limitelor tehnice. Clasifi carea cardiomiopatii-lor din 2008 (conform ESC), împarte cardiomiopatii-le în funcție de fenotipul morfologic și funcțional în: cardiomiopatia hipertrofi că, cardiomiopatia dilatativă, cardiomiopatia aritmogenă de ventricul drept, cardio-miopatia restrictivă si cardiomiopatii neclasifi cate, care la rândul lor sunt împărțite în funcție de modalitatea de transmitere în familiale/genetice și non-familiale/non-genetice.

Acest articol ne propune o abordare de ansamblu a pacientului cu această patologie. Clinicianul încercând să obțina informații pe baza tuturor instumentelor care îi sunt la îndemână. Astfel că încă de la intrarea în cabi-net o anamneză amănunțită ne poate aduce informații prețioase, începând cu sexul, vârsta, istoricul personal și familial. Pe baza istoricului familial se poate contura modalitatea de transmitere a bolii (ex: boala Fabry are transmitere de la mama la fi u- X lincata).

O examinare fi zică atentă ne poate aduce o sumede-nie de “indicii" (stegulețe roșii – cum le place autorilor să spună) – ex: lentigo în sindromul LEOPARD, sin-drom de canal carpian în amiloidoză. Când examinăm un pacient cu cardiomiopatie trebuie să avem mereu în minte faptul că, de obicei, acestea apar în contextul unor boli multisitemice; prin urmare clinicianul ar tre-bui să aibă un index crescut de suspiciune și astfel să identifi ce expresiile fenotipice în alte organe ale acestor boli pentru a avea un diagnostic fi nal cât mai fi del și cât mai precoce; cunoscându-se faptul că de regulă acestea preced manifestările fenotipice cardiace (ex: distrofi ile musculare- asociere frecvent întâlnită – acești pacienți necesitând o abordare multidisciplinară, incluzând un specialist neurolog).

În următoarele etape de diagnostic, indiciile se adună și astfel se conturează încet-încet diagnosticul. Electro-cardiograma ne poate da de exemplu informații legate de afectarea membrilor din familie, la care unica ma-ni festare poate fi vizibilă doar electric (ex: unde T gi-gante, negative în cardiomiopatia hipertrofi că) sau des-pre o afectare subclinică a pacientului (ex: microvol taj în amiloidoză, pattern de pseudoinfarct în cardiomio-patia dilatativă).

Urmează examenele de laborator pe care autorii le-au împărțit în două categorii, de prim nivel (care se fac tuturor pacienților – ex: CK, proteinuria, funcția hepa-tică și renală sau analize care sunt destinate pacienților

cardiacă, resuscitată în afara spitalului, indiferent de rit mul cardiac prezent la debut. Durata de inducere a hipo termiei terapeutice a fost de 36 de ore, s-au folo-sit metode de suprafaţă sau intravasculare de inducere a hipotermiei, pacienţii au fost sedaţi pe toată această perioadă. Pacienţii au fost urmăriţi apoi pe o perioadă de 180 de zile după inducerea hipotermiei. S-a evaluat mor talitatea globală, ca rezultat fi nal al studiului, iar ca re zultate secundare defi citul neurologic si mortalitatea de cauză neurologică la 180 zile, evaluate prin scala CPS (Cerebral Performance Category) și scala Rankin modifi cată.

La fi nalul studiului, din grupul celor la care s-a in-dus hipotermia la 33 grade, 50% din pacienţi (235 din 473 de pacienţi) au decedat, în comparaţie cu 48% din grupul pacienţilor cu hipotermie la 36 grade (225 din 466 de pacienţi) (rata hazardului de 1.06 pentru tem-peratura de 33 grade, 95% IC, 0.89 la 1.28; p 0.51). La 180 de zile, 54% din pacienţii cu hipotermie la 33 grade au decedat sau au prezentat defi cit neurologic conform scalei CPC, în comparaţie cu 52% din pacienţii cu hi-potermie la 36 grade (rata de risc 1.02; IC 95%, 0.88 la 1.16; p 0.78). Defi citul neurologic la 180 de zile evaluat prin scala Rankin modifi cată a fost similar, rata fi ind de 52% pentru ambele grupuri (rata de risc 1.01; IC 95%; 0.89 la 1.14; p 0.87). Efecte adverse majore ale hipoter-miei s-au înregistrat la 93% din pacienţii afl aţi în gru-pul de 33 grade și la 90% din cei afl aţi în grupul de 36 grade (rata riscului 1.03; IC 95% CI, 1.00 la 1.08; p = 0.09). Hipopotasemia a fost mai frecventă în grupul de 33 grade Celsius (19%, vs. 13%; p 0.02).

Prin urmare, nu s-au înregistrat diferenţe semnifi ca-tive între cele două grupuri în ceea ce privește mortali-tatea globală și nici în ceea ce privește mortalitatea de cauză neurologică la 180 zile sau defi citul neurologic la 180 de zile. Hipotermia terapeutică indusă la 33 grade Celsius nu s-a dovedit a se asocia semnifi cativ cu efecte adverse majore mai importante sau mai frecvente faţă de hipotermia la 36 grade Celsius, dar nu a prezentat nici benefi cii semnifi cative statistic.

Concluzia acestui studiu a fost aceea că la supravie-ţuitorii inconștienţi după un stop cardiac resuscitat în afara spitalului inducerea hipotermiei terapeutice la va-loarea de 33 grade Celsius nu aduce benefi cii suplimen-tare faţă de hipotermia la 36 grade.

Nielsen N, Wetterslev J, Cronberg T, et al. et al. Tar-geted Temperature Management at 33°C versus 36°C af-ter Cardiac Arrest. N Engl J Med 2013. DOI: 10.1056/NEJMoa1310519 (AP).



ară are un rol limitat în diagnosticul cardiomiopatiilor, se folosesc radiotrasori specifi ci în funcție de tipul de cardiomiopatie suspicionat.

În privința investigațiilor invazive, deși biopsia mi-ocardică este standardul de aur pentru unele tipuri de cardiomiopatie (ex: sarcoidoză, amiloidoză, miocar-dită) biopsia extracardiacă este mai frecvent folosită, având în vedere impactul mai puțin marcat asupra pa-cientului (ex: biopsie țesut gras și rectal în amiloidoză).

Concluzii: autorii ne propun un algoritm de diag-nostic al cardiomiopatiilor, în care medicul este încura-jat să se folosească de toate instrumentele pe care le de-ține, începând cu simțul vizual până la investigații in-vazive cum este biopsia endomiocardică, pentru obți-nerea de “indicii” diagnostice care să il ajute la contu-rarea unui diagnostic cât mai corect și astfel pacientul să benefi cieze de un tratament țintit. De asemenea se accentuează importanța abordării multidisciplinare a acestor pacienți, știindu-se că de obicei cardiomiopatii-le apar în contextul unor boli multisistemice.

(Diagnostic work-up in cardiomyopathies: bridging the gap between clinical phenotypes and fi nal diagnosis. A position statement from the ESC Working Group on Myocardial and Pericardial Diseases. European Heart Journal (2013) 34, 1448–1458 doi:10.1093/eurheartj/ehs397) (SP)

Rubrică realizată de Alina Crăciun Mirescu, Anca Mateescu, Anca Popară, Polixenia Stanciu sub coordo-narea lui Bogdan. A. Popescu.

care ne sugerează o anumită patologie – ex: sideremia și feritina în hemocromatoză) și de nivel doi (care se fac doar atunci când suspicionăm un tip specifi c de car-diomiopatie- ex: alfa galactozidaza când suspicionăm boala Fabry; enzima de conversie a angiotensinei când suspicionăm sarcoidoza).

Testarea genetică a acestor pacienți este unul dintre benefi ciile inovațiilor din ultimii ani, în acest articol fi -ind mai puțin amănunțită, având în vedere publicarea în 2010 a unui articol de către aceeași autori, care dez-bate pe larg consilierea și testarea genetică a pacienților cu cardiomiopatii.

Ecocardiografi a este o investigație extrem de im-portantă și plină de “indicii”. Un bun cunoscător poa-te ușor să integreze informațiile oferite de aceasta și să contureze deja diagnosticul (ex: dacă la un pacient cu cardiomiopatie hipertrofi că se evidențiază îngroșarea valvelor atrioventriculare și a septului interatrial iar aspectul miocardului este “strălucitor” se poate suspi-ciona amiloidoza; sau la un pacient cu cardiomiopatie dilatativă și tulburare de cinetică parietala care nu res-pectă distribuția coronariană putem suspiciona mio-cardita).

Dintre investigațiile imagistice, Rezonanța Magneti-că Cardiacă are un rol aparte, deoarece caracterizează structura țesutului miocardic pe baza timpilor de rela-xare (ex: T2 scurt în hemocromatoză) și a modalității de captare a contrastului (ex: captare subendocardică în amiloidoză; captare la nivelul septului interventricu-lar și mușchii papilari în sarcoidoză). Imagistica nucle-


NATIONAL AND INTERNATIONAL CARDIOLOGY AGENDA 2014

EVENIMENTE SRC 2014

LUNA DENUMIREA MANIFESTĂRII DATA LOCAŢIA

Februarie

CAZURI CLINICE DIFICILE ÎN INSUFICIENȚA CARDIACĂDirectori de curs: Prof. Dr. C. Macarie, Prof. Dr. D. Vinereanu, Dr. O. Chioncel 21 februarie Timișoara

CARDIOCOAGDirectori de curs: Prof. Dr. D. Vinereanu, Prof. Dr. D. Lighezan 22 februarie Timișoara

DIAGNOSTICUL ȘI TRATAMENTUL ACTUAL AL SINDROAMELOR CORONARIENE ACUTEDirectori de curs: Prof. Dr. D. Dimulescu, Conf. Dr. S. Bălănescu

28 februarie București

Martie

CARDIOEFORT (efortul fi zic și bolile cardiovasculare)Directori de curs: Conf. Dr. F. Mitu, Dr. D. Gherasim 7 martie Iași

LIPID SCHOOL – GHIDUL DISLIPIDEMII 2012 (LIPS PLUS Sindroame Coronariene ACUTE)Directori de curs: Prof.Dr. D. Gaiţă, Prof. Dr. D. Vinereanu

14 martie Tg. Mureș

HIPERTENSIUNEA ARTERIALĂ – SĂ ANALIZĂM GHIDURILEDirectori de curs: Prof. Dr. M. Cinteză, Prof. Dr. C. Arsenescu Georgescu 14 martie Iași

SOLUŢII TERAPEUTICE ÎN INFARCTUL MIOCARDIC ACUT DE LA TEORIE LA PRACTICĂ - CAZURI CLINICE ÎN DIRECTDirectori de curs: Dr. D. Deleanu, Dr. A. Iancu, Dr. M. Croitoru

15 martie București

ELOGIUDirector de curs: Prof. Dr. Eduard Apetrei 21 martie Constanța

PARTICULARITĂŢI ALE BOLILOR CARDIOVASCULARE LA VÂRSTNIC (CARDIOSEN)Directori de curs: Conf. Dr. F. Mitu, Conf. Dr. D. Pop, Dr. D. Gherasim

21 martie Cluj-Napoca

CAZURI CLINICE DIFICILE ÎN CARDIOLOGIA DE URGENŢĂDirectori de curs: Conf. Dr. C. Pop, Dr. G. Tatu Chiţoiu, Conf. Dr. A. Petriș 21 martie Oradea

IMAGISTICA ÎN VALVULOPATIIDirectori de curs: Conf. Dr. B. A. Popescu, Conf. Dr. A. Ilieșiu 21 martie Craiova

REDRISC (REDucerea RISCului Rezidual)Directori de curs: Prof. Dr. C. Arsenescu Georgescu, Prof. Dr. G. A. Dan,Prof. Dr. D. Vinereanu

21 martie Timișoara

Aprilie

ACTUALITĂŢI ÎN ARITMOLOGIE (ARCA 3)Directori de curs: Dr. R. Vătășescu, Prof. Dr. D. Dobreanu, Prof. Dr. G. A. Dan 11 aprilie Iași

CARDIOEFORT (Efortul fi zic și bolile cardiovasculare)Directori de curs: Conf. Dr. F. Mitu, Dr. D. Gherasim 11 aprilie Sibiu

REDRISC (REDucerea RISCului Rezidual)Directori de curs: Prof. Dr.Cătălina Arsenescu Georgescu, Prof. Dr.G.A.Dan, Prof. Dr.D.Vinereanu

11 aprilie Constanța

CONFERINŢA NAŢIONALĂ DE ATEROTROMBOZĂModeratori: Prof. Dr. E. Apetrei, Prof. Dr. C. Popa 11 aprilie București

Mai

CONFERINŢA NAŢIONALĂ A GRUPURILOR DE LUCRU 8-9 mai Sibiu THE XIX WORLD CONGRESS OF ECHOCARDIOGRAPHY AND ALLIED TECHNIQUES 10-11 mai Sibiu


23 mai Tg. Mureș

HIPERTENSIUNEA ARTERIALĂ – SĂ ANALIZĂM GHIDURILEDirectorde curs: Prof. Dr. M. Cinteză 30 mai Tg. Jiu

Iunie

CAZURI CLINICE DIFICILE ÎN INSUFICIENȚA CARDIACĂDirectori de curs: Prof. Dr. C. Macarie, Prof. Dr. D. Vinereanu, Dr. O. Chioncel 13 iunie Constanța

ELOGIUDirectori de curs: Prof. Dr. E. Apetrei 20 iunie Piatra Neamț

EXPERT MEETING CARDIODIAB 26-28 iunie Poiana Brasov


Agenda

Septembrie

LIPID SCHOOL – GHIDUL DISLIPIDEMII 2012 (LIPS PLUS Sindroame Coronariene Acute)Directori de curs: Prof. Dr. D. Gaiţă, Prof. Dr. D. Vinereanu

12 sepembrie Suceava

ACTUALITĂŢI ÎN ARITMOLOGIE (ARCA 3)Directori de curs: Dr. R. Vătășescu, Prof. Dr. D. Dobreanu, Prof. Dr. G. A. Dan 12 septembrie Tg. Mures

Octombrie

CONGRESUL NAŢIONAL DE CARDIOLOGIE 2-4 octombrie SinaiaTHE 9TH EUROPEAN ECHOCARDIOGRAPHY COURSE ON CONGENITAL HEART DISEASE

15-18 octombrie Timișoara


17 octombrie Covasna

CAZURI CLINICE DIFICILE ÎN CARDIOLOGIA DE URGENŢĂDirectori de curs: Conf. Dr. C. Pop, Dr. G. Tatu Chiţoiu, Conf. Dr. A. Petriș 24 octombrie Brașov

SOLUŢII TERAPEUTICE ÎN INFARCTUL MIOCARDIC ACUT DE LA TEORIE LA PRACTICĂ - CAZURI CLINICE ÎN DIRECTDirectori de curs: Dr. D. Deleanu, Dr. A. Iancu, Dr. M. Croitoru

24 octombrie Cluj-Napoca

DIAGNOSTICUL ȘI TRATAMENTUL ACTUAL AL SINDROAMELOR CORONARIENE ACUTEDirectori de curs: Prof. Dr. D. Dimulescu, Conf. Dr. S. Bălănescu

31 octombrie Sibiu

Noiembrie

IMAGISTICA ÎN VALVULOPATIIDirectori de curs: Conf. Dr. A. Ilieșiu, Conf. Dr. B. A. Popescu 14 noiembrie Galați

CARDIOCOAGDirectori de curs: Prof. Dr. D. Vinereanu, Prof. Dr. D. Lighezan 22 noiembrie Sibiu

CARDIOLOGY EVENTS IN THE WORLD

MONTH NAME OF THE EVENT DATE PLACE

January

ACCA webinar on Acute Heart Failure 09 January - 09 January 2014 Online

XXIV European Days, Annual Meeting of the French Society of Cardiology

15 January - 18 January 2014 Paris, France

33rd Annual Scientifi c Meeting of the Belgian Society of Cardiology 30 January - 31 January 2014

Brussels, Belgium

ESC Webinar on Catheter Ablation for Atrial Fibrillation: Ready for prime time?

30 January - 30 January 2014 Online

February

Advanced Invasive Cardiac Electrophysiology (Course)13 February

- 15 February 2014

Sophia Antipolis,

France

2nd Edition of the Resistant Hypertension Course20 February

- 22 February 2014

Berlin,Germany

17th International Congress in Advances in Cardiac Ultrasound24 February

- 27 February 2014

Davos,Switzerland

Stent for Life Forum 2014 27 February - 01 March 2014

Prague,Czech Republic

March EHRA Cardiac Pacing, ICD and Cardiac Resynchronisation Course 17 March - 19 March 2014

Vienna,Austria

AprilEuroHeartCare 2014 04 April - 05

April 2014Stavanger,Norway

Fift h European Course on Adult Congenital Disease 10 April - 11 April 2014

Amsterdam,Netherlands

Agenda


AprilFift h European meeting on Adult Congenital Heart Disease 10 April - 11

April 2014Amsterdam,Netherlands

EuroHeartCare 2014 04 Apr 2014 - 05 Apr 2014

Stavanger, Norway

May

EuroPRevent 2014 08 May - 10 May 2014

Amsterdam, Netherlands

EuroCMR (Cardiovascular Magnetic Resonance) 2014 15 May - 17 May 2014

Vienna, Austria

Heart Failure 2014 17 May - 20 May 2014 Athens, Greece

World Congress on Acute Heart Failure 17 May - 20 May 2014

Athens,Greece

EuroPCR 2014 20 May - 23 May 2014

Paris,France

June

2nd Annual meeting on New Trends in Cardiovascular Drug Th erapy 30 May - 01 June 2014

Rome,Italy

Joint Meeting of the European Society of Hypertension (ESH) and International Society of Hypertension (ISH)

June 13 - 16, 2014 Athens, Greece

CARDIOSTIM-EHRA EUROPACE 2014 18 June - 21 June 2014 Nice, France

July Frontiers in CardioVascular Biology 2014 04 July - 06 July 2014

Barcelona, Spain

September

ESC Congress 2014 30 Aug 2014 - 03 Sep 2014

Barcelona, Spain

EuroTh rombosis Summit 201428 September

- 30 September 2014

Paris, France

October

Acute Cardiovascular Care 201418 October

- 20 October 2014

Geneva, Switzerland

Th e 11th Meeting of the ESC Working Group on Myocardial and Pericardial Disease

22 October - 24 October

2014Tel Aviv, Israel


REVIEWERS 2013

Thanks to our reviewers for 2013

Eduard Apetrei (5)Ion Bruckner (1)Ș erban Bă lă nescu (1)Radu Că pâlneanu (1)Carmen Ginghină (5)Gabriel Tatu-Ghiț oiu (1)

Andre Keren (1)Florin Mihă lț an (1)Tiberiu Nanea (1)Ion Țintoiu (1)Dumitru Zdenghea (1)


INSTRUCŢIUNI PENTRU AUTORI

Informații generaleRomanian Journal of Cardiology publică articole originale din domeniul fi ziologiei și patologiei cardiovasculare

sub forma studiilor clinice, de laborator, experimentale, epidemiologice etc. Autorii vor respecta principiile eticii și adevărului știinţifi c în realizarea studiului, obţinerea datelor și prezentarea rezultatelor.

Pentru publicare, articolele vor fi trimise într-un exemplar, împreună cu toate fi șierele pentru text (în format MS Word) și imaginile pe CD. Formatul manuscrisului este de tip A4, scris la două rânduri, cu caractere Times New Roman 12.

Articolele vor fi redactate în limba engleză. Cele trimise în limba română vor fi traduse de redacție în limba engleză (contra cost).

Fiecare manuscris trebuie să fi e însoţit de o scrisoare de intenţie a autorilor, semnată în original, care să afi rme că articolul nu a mai fost trimis simultan niciunei alte publicaţii și nu a mai fost publicat în altă revistă într-o formă substanţial similară. Responsabilitatea asupra conţinutului articolului aparţine în întregime autorilor.

Articolele vor fi semnate de toţi autorii. Toți autorii vor semna o declaraţie privind confl ictul de interese și contribuția avută la elaborarea lucrării. Primul autor are obligaţia de a colecta declaraţiile de la toți co-autorii.

Pregătirea manuscrisului Titlu: Pe pagina de titlu se va scrie titlul articolului în limba engleză și română, numele complet al autorilor,

gradul academic, afi lierea acestora, adresa de corespondenţă, precum și un titlu scurt în limba engleză (între 3-6 cuvinte) pentru paginile următoare ale articolului, și cuvintele cheie ale articolului. Vor fi precizate sursele de fi -nanţare ale lucrării (acolo unde este cazul).

Rezumatul: Rezumatul, în limba engleză și română, va cuprinde cel mult 200 de cuvinte. Va fi alcătuit din ur-mătoarele subtitluri: obiectivele studiului, metodologia folosită, rezultate și concluziile studiului.

Textul manuscrisului: Textul manuscrisului nu va depăși 12 pagini pentru studiile originale sau referatele gene-rale și 5 pagini pentru prezentările de caz. Prescurtările vor fi defi nite la prima lor folosire. Pentru denumirile me-dicamentelor sau ale altor substanţe folosite în studiile prezentate vor fi utilizate denumirile comune internaţionale. Aparatele utilizate în studii vor fi prezentate cu denumirea comercială, cu indicarea producătorului. Eventualele mulţumiri pentru colaborare vor fi inserate la sfârșitul textului.

Bibliografi a: Bibliografi a se va nota cu cifre arabe în ordinea crescătoare a apariţiei în text, unde vor fi notate superscript. Referinţele bibliografi ce vor cuprinde numele autorilor, titlul complet al articolului, revista, anul apa-riţiei, volumul, paginile. Prescurtarea numelui revistei se va face după cea folosită în Index Medicus.

Recomandăm introducerea referinţelor bibliografi ce actuale. Se recomandă citarea referinţelor bibliografi ce românești, iar în cazul în care autorii au mai publicat în Romanian Journal of Cardiology, citarea acestor publicaţii.

Ex: Ridker PM, Rifai N, Pfeff er M et al. Elevation of TNF-a and increased risk of recurrent coronary events aft er myocardial infarction. Circulation, 2000; 101: 2149-53 [pentru articole din reviste] Madahi J. Myocardial perfusion imaging for the detection and evaluation of coronary artery disease.In Cardiac Imaging: A Companion to Braunwald’s Heart Disease, Second edition. Eds: DJ Skorton, HR Schelbert, GL Wolf et al. WB Saunders, London, 1996, 193-203 [capitole în cărţi]

Figurile: Calitatea fi gurilor trebuie să fi e excelentă pentru a permite reproducerea corectă. Ele nu vor fi inserate în interiorul textului manuscrisului, ci vor fi prezentate separat. În format electronic vor fi trimise separat ca fi șiere imagine (JPG, TIFF etc.). Fiecare fi gură va fi însoţită de o legendă în care vor fi explicate, în mod concis, principale-le date referitoare la respectiva fi gură si eventualele prescurtari. Figurile vor fi numerotate cu cifre arabe în ordinea apariţiei lor în text. În text va fi precizat între paranteze rotunde numărul fi gurii la care se face referire (Ex: Fig. 3). Dacă este cazul, în paranteză va fi precizată sursa bibliografi că a fi gurii și, în acest caz, utilizarea fi gurii trebuie făcută cu avizul de copyright. Prezentarea sursei bibliografi ce va fi urmată de cifra corespunzătoare din bibliografi e. Figurile color vor fi publicate contra cost.

Tabelele: Tabelele vor fi numerotate cu cifre arabe în ordinea apariţiei în text și vor fi însoţite de titlul concis al tabelului și eventualele explicaţii. Vor fi precizate prescurtările utilizate în tabel. Dacă este cazul, în paranteză va fi precizată sursa bibliografi că a tabelului și avizul de copyright.


Instructions for authors

Textele trimise pentru a fi publicate vor fi referate de către 2 referenţi fără cunoașterea autorilor. Recomandările referenților sunt comunicate autorilor pentru refacerea articolului. Dacă articolul este aprobat pentru publicare, va fi transmisă data publicării. Refuzul publicării va fi motivat și comunicat în scris autorilor. Manuscrisele nepublicate nu se returnează autorilor.

Manuscrisele și suportul lor electronic (CD) vor fi trimise prin poștă sau e-mail la următoarea adresă:Romanian Journal of CardiologyÎn atenţia dlui Prof. Dr. Eduard Apetrei, redactor-șef Institutul de Urgență pentru Boli Cardiovasculare „Prof. Dr. C. C. Iliescu“, șos. Fundeni, nr. 258, 022328,

București, România.Tel./Fax: +40-21-318.35.92E-mail: [email protected], [email protected]

Publishing House: Media Med PublicisAdvertising: offi [email protected]: Th e Romanian Journal of Cardiology is distributed to the members of the Romanian Society of CardiologySubscription: offi [email protected]

www.mediamed.ro

Premiu


ROMANIAN JOURNAL OF CARDIOLOGY

acordă, în acest an,un premiu pentru cel mai bun articol original din anul 2013

(prim-autori sub 40 de ani).

2013_rrc4

Documents