test de efort

ISSN: 1583-2996

President: Gabriel Tatu-ChioiuPresident elect: Drago VinereanuFormer president: Ioan M. ComanVice-presidents: Dan Dobreanu

Bogdan A. PopescuSecretary: Antoniu PetriTreasurer: Daniel LighezanMembers: Eduard Apetrei Daniela Barto Mircea Cintez Radu Ciudin Ovidiu Chioncel Ruxandra Christodorescu Dan Deleanu Alexandru Deutsch Gabriela Doro Daniel Gherasim Carmen Ginghin Adriana Ilieiu Ruxandra Jurcu Adrian Mereu Florin Mitu tefan Mo Mircea I. Popescu Diana n

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erban Blnescu - Bucureti Luigi Paolo Badano - Italia Ion V. Bruckner - BucuretiAlexandru Cmpeanu - BucuretiGheorghe Cerin - ItaliaMircea Cintez - BucuretiRadu Ciudin - BucuretiD. V. Cokkinos - GreciaIoan Mircea Coman - BucuretiG. Andrei Dan - BucuretiDan Deleanu - BucuretiGenevieve Derumeaux - FranaDoina Dimulescu - BucuretiMaria Dorobanu - Bucuretitefan Iosif Drgulescu - TimioaraGuy Fontaine - FranaAlan Fraser - AngliaCtlina Arsenescu-Georgescu - Iai

Mihai Gheorghiade - USALeonida Gherasim - BucuretiAurel Grosu - Chiinu,R. MoldovaAssen R. Goudev - BulgariaAnthony Heagerty - MareaBritanieAlexandru Ioan - BucuretiDan Dominic Ionescu -CraiovaGabriel Kamensky - SlovaciaAndre Keren - IsraelMichel Komajda, FranaGiuseppe Mancia - ItaliaIoan Maniiu - SibiuAthanasios Manolis - GreciaMartin S. Martin - SUAGerald A. Maurer - Austriaerban Mihileanu - FranaTiberiu Nanea, Bucureti

Gian Luigi Nicolosi - ItaliaPeter Nilsson - SuediaNour Olinic - Cluj-NapocaFausto Pinto - PortugaliaClin Pop - Baia MareJosep Redon - SpaniaWillem J. Remme - OlandaMichal Tendera - PoloniaIon intoiu - BucuretiPanagiotis Vardas - GreciaMargus Viigimaa - EstoniaDrago Vinereanu - BucuretiMarius Vintil - BucuretiDumitru Zdrenghea -Cluj-Napoca

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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 Romn de Cardiologie Str. Avrig nr. 63, Sector 2, Bucureti Tel./Fax: +40.21.250 01 00, +40.21.250 50 86, +40.21.250 50 87; E-mail: offi [email protected]

Acute type A aortic dissection. A single center experience 251O. Stiru, L.F. Dorobantu, A. Pasare, S. Bubenek, D. Filipescu, H. Moldovan, V. A. Iliescu

Predictive value of exercise stress testing in a tertiary cardiological center 260D. Gherasim, M. Jalb, M. Lupu, D. Deleanu, C. Ginghin, E. Apetrei

Dillemas in the use of therapeutic hypothermia aft er cardiac arrest 268D. Zahger

Cardiac dysfunction of antineoplastic agents in breast cancer patients 271A. M. Popar-Voica, A. Clin, B. A. Popescu, A. M. Mitric, R. Anghel, R. Jurcu, C. Ginghin

Utility and prognostic value of exercise stress testing in postrevascularization patients 278D. Gherasim, B. Moise, E. Apetrei

Behcet disease: one of the etiologies of myocardial infarction in youngpatients 286B. Hanane, N. Malika, H. Rachida

Unexplained left ventricular hypertrophy, arrhythmias and conductiondisorders: take into account Anderson-Fabry Disease (AFD).A case report of a diagnosed and under treatment AFD in a heterozygous female, with severe left ventricular hypertrophy and conductiondisorders 289C. Vcrescu, D. Lighezan, M. Mangea, E. Goan, T. Ruhmann, D. Cozma

What could hide an oncologic patient with exertional dyspnea? 294R. Silite, M. Jidveian, R. Ianula, D. SptaruComplication of a diagnostic peripheral arteriography 297L. Predescu, M. Postu, P. Platon, M. Rugina, M. Gavanescu, M. Croitoru, A. Bucsa, L. Zarma, D. Deleanu

European Guidelines on cardiovascular disease prevention in clinicalpractice (version 2012) 299

National and international cardiology agenda 2015 391

Instructions for authors 395

Vol. 24, No. 4, 2014

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CASE PRESENTATION

IMAGES IN CARDIOLOGY

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INSTRUCTIONS FOR AUTHORS

ORIGINAL ARTICLES

Disecia acut de aort de tip A. Experiena unui singur centru 251O. Stiru, L.F. Dorobantu, A. Pasare, S. Bubenek, D. Filipescu, H. Moldovan, V. A. Iliescu

Valoarea predictiv a testului ECG de efort ntr-un centru teriarde cardiologie 260D. Gherasim, M. Jalb, M. Lupu, D. Deleanu, C. Ginghin, E. Apetrei

Dileme n utilizarea hipotermiei terapeutice dup stopul cardiac 268D. Zahger

Disfuncia cardiac indus de agenii antitumorali la pacientele cuneoplasm mamar 271A. M. Popar-Voica, A. Clin, B. A. Popescu, A. M. Mitric, R. Anghel, R. Jurcu, C. GinghinUtilitatea i valoarea prognostic a testului de efort postrevascularizare 278D. Gherasim, B. Moise, E. Apetrei

Boala Behcet: una dintre cauzele infarctului miocardic la pacienii tineri 286B. Hanane, N. Malika, H. Rachida

Hipertrofi e ventricular stng de cauz neexplicat asociat tulburrilorde ritm sau de conducere: suspiciune de boal Fabry-Anderson.O prezentare de caz a unei paciente heterozigot diagnosticate i ntratament pentru boala Fabry-Anderson, cu hipertrofi e stng sever i tulburri de conducere 289C. Vcrescu, D. Lighezan, M. Mangea, E. Goan, T. Ruhmann, D. Cozma

Ce poate ascunde un pacient oncologic cu dispnee de efort? 294R. Silite, M. Jidveian, R. Ianula, D. Sptaru

Complicaie a unei arteriografi i periferice diagnostice 297L. Predescu, M. Postu, P. Platon, M. Rugina, M. Gavanescu, M. Croitoru, A. Bucsa, L. Zarma, D. Deleanu

Ghidul Societii Europene de Cardiologie pentru prevenia bolilorcardiovasculare in practica clinic (versiunea 2012) 299

Calendarul manifestrilor tiinifi ce cardiologice 2015 391Manifestri tiinifi ce i cursurile Societii Romne de Cardiologie 2015Manifestri tiinifi ce internaionale 2015

Instruciuni pentru autori 395

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REFERATE GENERALE

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INSTRUCIUNI PENTRU AUTORI

IMAGINI N CARDIOLOGIE

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Vol. 24, No. 4, 2014

ARTICOLE ORIGINALE

Romanian Journal of Cardiology | Vol. 24, No. 4, 2014

ORIGINAL ARTICLES

Acute type A aortic dissection. A single center experienceOvidiu Stiru1, Lucian F. Dorobanu1, Alexandra Pasare1, erban Bubenek1, Daniela Filipescu1, Horaiu Moldovan1, Vlad. A. Iliescu1

Contact address:Ovidiu Stiru, MDEmergency Institute for Cadiovascular Diseases Prof. Dr. C. C. Iliescu Sos. Fundeni 258, sector 2, 022328 Bucharest, Romania Phone/Fax: +40213175227E-mail: [email protected]

1 Emergency Institute for Cadiovascular Diseases Prof. Dr. C. C. Iliescu Bucharest, Romania

Abstract: Objective Acute aortic dissection (AAD) is the most frequent and catastrophic manifestation of the so-called acute aortic syndrome (along with intramural hematoma, penetrating aortic ulcer, and ruptured thoracic aortic aneurysm)3. Th e objective of this study was evaluating the cases of acute type A aortic dissection treated in Prof. Dr. C.C. Iliescu Emer-gency Institute for Cardiovascular Diseases over the last nine years, creating a more comprehensive image of this pathology. Material and method 290 patients (174 male, 116 female, mean age: 55.8812.13 years) were admitted for acute type A aortic dissection (ATAAD) in our Institute between January 2005 and May 2013, in all cases transesophageal echocardiogra-phy being performed for diagnostic confi rmation. Th e main demographic, clinical and perioperative characteristics of these patients were followed and the identifi cation of several factors capable of increasing morbidity and mortality rates associated with acute type A aortic dissection was attempted. Results Th e distribution of cases was uniform over time, with a slight decrease of 30-day mortality (p=0.985) and intraoperative mortality rates (p=0.119). Mean age was 55.8812.13 years and men were more oft en aff ected than women (3:2 gender rate). Ascending aorta replacement was the operation performed with the highest frequency (29.71%) and the lowest mortality rate (16.05%) while the highest one associated with ascending, arch and descending aorta replacement (83.3%). 29.10% patients were extubated in the fi rst postoperative day. Th e most frequent complications were: acute renal failure (61.62%), low ejection fraction 30% (57.20%), multiple system organ failure (MSOF) (39.48%), neurologic dysfunction (23.62%). Prolonged cardiopulmonary bypass (CPB) time (over 400 minutes, p=0.001) as well as replacement of the descending aorta (p=0.023) or the aortic arch (p=0.009) associated mortality rates of 80% and 50%, respectively. Conclusion Type A acute aortic dissection is a frequent pathology in the cardiovascular surgical area. Moreo-ver, it can prove to be a surgical challenge, with increased morbidity and mortality, but in experienced centers the results are more than satisfying. In our experience prolonged CPB time (over 400 minutes) as well as aortic arch and descending aorta replacement signifi cantly increased the.Keywords: type A acute aortic dissection, surgical treatment, mortality rate.

Rezumat: Obiectiv Disecia acut aortic reprezint cea mai frecvent i catastrofi c entitate a aa-numitului sindrom aortic acut (alturi de hematomul intramural, ulceraia aortic penetrant i anevrismul toracic rupt). Obiectivul acestui studiu a fost evaluarea cazurilor de disecie acut aortic de tip A tratate n cadrul Institutului de Urgen pentru Boli Cardiovasculare Prof. Dr. C.C. Iliescu n cursul ultimilor nou ani, conturnd o imagine mai clar a acestei patologii. Material i metod 290 pacieni (174 brbai, 116 femei, vrsta medie: 55,88 12,13 ani) au fost internai cu suspiciunea de disecie acut aortic de tip A n cadrul Institutului n perioada ianuarie 2005 mai 2013, ecocardiografi a transesofagian (ETE) fi ind efectuat pentru confi rmarea diagnosticului n toate cazurile. Principalele caracteristici demografi ce, clinice i perioperatorii ale acestor pacieni au fost urmrite, realizndu-se un studiu descriptiv, cruia i s-a adugat o component analitic prin identifi carea principalilor factori responsabili pentru creterea ratelor morbiditii i mortalitii asociate. Rezultate Distribuia cazu-rilor a fost uniform de-a lungul timpului, cu o uoar scdere a ratelor mortalitii (p=0.985) i mortalitii intraoperatorii (p=0,119). Vrsta medie a lotului a fost de 55,8812,13 ani, brbaii fi ind mai des afectai dect femeile, cu un raport pe sexe de 3:2. nlocuirea de aort ascendent a fost intervenia cea mai frecvent (29,71%), care a asociat i cea mai mic rat a mor-talitii (16.05%), n timp ce la polul opus s-a situat nlocuirea de aort ascendent, cros aortic i aort descendent, cu o mortalitate asociat de 83,3%. 29,10% dintre pacieni au fost detubai n prima zi postoperator. Cele mai frecvente complicaii au fost, n ordine descresctoare: disfuncia cardiac (57,20%), insufi ciena renal acut (IRA) (61,62%), difuncia sistemic multipl de organ (DSMO) (39,48%), disfuncia neurologic (23,62%). Durata prelungit a bypass-ului cardiopulmonar (peste 400 minute, p=0,001) alturi de nlocuirea aortei descendente (p=0,023) sau a crosei aortice (p=0,009) au asociat mortaliti de 80%, respectiv 50%. Concluzii Disecia acut aortic de tip A reprezint o patologie frecvent n sfera chirurgical cardi-ovascular. Dei frecvent se dovedete a fi o provocare chirurgical, cu rate crescute de morbiditate i mortalitate, n centrele

Ovidiu Stiru et al.Acute type A aortic dissection. A single center experience

Romanian Journal of CardiologyVol. 24, No. 4, 2014

BACKGROUNDAcute aortic syndrome (AAS) is a collective term for several life-threatening acute aortic conditions1 with similar presentations2: aortic dissection, intramural hae matoma (IMH), penetrating atherosclerotic ulcer and traumatic transection1, of which acute aortic di-ssection is the most frequent and catastrophic manifes-tation, with a reported incidence of no less than 30 ca-ses per million individuals per year3. In its natural evo-lution ATAAD associates a mortality rate of about 1% per hour initially, 50% by the end of the third day and almost 80% by the end of the second week. Much lower, although still signifi cant are the mortality rates asso-ciated with acute type B aortic dissection (ATBAD): 10% at 30 days, reaching values higher than 70% in the highest-risk groups3. Diagnostic delay is frequent, increased by a wide spectrum of presentations that do not evoke clinical suspicion, and adversely aff ects out-come2. In these cases the gold standard investigation is transesophageal echocardiography (TEE), ideally performed with the cardiac surgical team standing by1. Aft er diagnosis establishment, decisions regarding the initial management, transfer, indication and timing of surgery, and intervention for malperfusion complicati-ons are mandatory. Th e surgical treatment of ATAAD has not been yet subjected to any randomized trials, but novel therapies particularly with regard to ex-tent of surgeryare being devised and implemented, especially in the treatment of ATBAD2, which is rather diff erent. It has been proven that in the absence of com-plications optimal medical therapy of ATBAD is repor-tedly yielding an impressively low 30-day mortality rate of 10% or less. On the other hand, patients presenting with complicated type B dissection are at substantial risk of death or major sequelae; in their case a surgi-cal or endovascular intervention must be considered3. Overall, except in highly specialized centers, surgical outcomes might be static, and there is abundant room for improvement2.

MATERIAL AND METHODS

PatientsProf. Dr. C.C. Iliescu Emergency Institute for Cardi-ovascular Diseases database was queried to identify all patients who underwent surgery for aortic dissection

repair between January 2005 and May 2013. A total of 290 patients who underwent repair for acute type A aortic dissections during this period of time were iden-tifi ed (116 female, 174 male, mean age 55.88 years). Patients who did not undergo surgery were excluded from the study. In all cases TEE was performed for diagnosis confi rmation in ICU department or on the operating table. All demographic and procedural data and perioperative features of the patients were collec-ted and introduced in an Excel database. 31 variables were defi ned, SPSS v 16.0 and univariate analysis were used for statistical analysis and a transverse retrospec-tive study was created.

Defi nitionsAcute type A aortic dissection was defi ned as any sur-gically confi rmed dissection process that involved the ascending aorta, presenting within 2 weeks from symp toms onset. Cerebrovascular accident was defi ned as any central neurological defi cit persisting for more than 24 h, with CT or MRI confi rmation. Chronic renal insu ffi ciency was defi ned according to estimated glo-merular fi ltration rate. Diabetes was defi ned as a his-tory of diabetes mellitus, regardless of the duration or treatment of the disease. Acute renal failure was defi -ned as one or both of the following: either a sudden in-crease in the serum creatinine levels over 2.0 mg/dl or a new requirement for dialysis, postoperatively. Ope-rative mortality included all deaths occurring in the admission period during which the operation had been performed, regardless of its duration, as well as those occurring aft er hospital discharge, but within 30 days of the procedure.

Operative techniqueTh e acces was performed through a standard median sternotomy. Total cardiopulmonary bypass (CBP) was established in most cases by arterial cannulation of the femoral or right axillary artery and venous cannulation of the right atrium. Myocardial protection was ensu-red through antegrade or retrograde cold blood car-dioplegia administration. A vent was placed in the left ventricle via the right superior pulmonary vein. Aft er a transverse aortotomy, the ascending aorta and the aortic valve were inspected and the segment including the proximal entry tear was resected, followed by re-pair or replacement of the aortic valve, when needed

experimentate rezultatele tratamentului sunt mai mult dect satisfctoare. n experiena noastr, durata crescut a bypass-ului cardiopulmonar (peste 400 minute) i nlocuirea de aort descendent sau cros s-au asociat semnifi cativ statistic cu creterea mortalitii.Cuvinte cheie: disecia acut aortic de tip A, tratament chirurgical, mortalitate.



and replacement of the ascending aorta. Aft er reaching a mean temperature of 25-28C, the aortic clamp was removed and the aortic arch examined and replaced whenever an arch tear would be identifi ed. Th e distal anastomosis with prosthetic collagen impregnated low porosity graft was then completed under circulatory ar-rest with antegrade selective cerebral perfusion. Biolo-gical glue and Tefl on strips were used in all patients for reinforcement of both proximal and distal suture lines.

RESULTS290 patients were operated in Prof. Dr. C. C. Iliescu Emergency Institute for Cardiovascular Diseases be -tween January 2005 and May 2013, the cases being ho mogenously distributed throughout the years. Pre-operative patient characteristics are summarized in Ta-ble 1. Th e mean age of the lot was 55.88 12.13 years (minimum 20, maximum 96 years), with a slight male predominance (1.5 - gender rate) which became grea-ter for the fi rst two age groups (out of three of 20 years interval defi ned): 3 in patients under 40 years of age and 1.84 in those between 40 and 60 years old, respecti-vely. Among associated comorbidities, primary arterial hypertension prevailed (75%). In all cases transesopha-geal ecocardiography was performed for diagnostic confi rmation in the ICU department or in the opera-ting room (OR).

Th e most used site for arterial cannulation, with a decreasing frequency over time, was the right axillary

artery (65.95%), immediately followed by right or left femoral artery (22.94%) (Figures 1, 2). In all cases the entry point was removed, thus performing the repla-cement of one or more aortic segments involved: an isolated aortic replacement was most oft en necessary (29.71%), accompanied by hemiarch (34.8%), arch (13.8%) and descending aorta replacement (4.8%). Th e aortic root was involved in 37.6% cases, repaired in al-most three quarters of them through sinotubular junc-tion recalibration, comissures resuspension, David or Yacoub techniques and in one quarter replaced, either isolated or as part of a Bentall operation. Operative pa-tient features are summarized in Tables 2 and 3. Circu-latory arrest with moderate or deep hypothermia was

Figure 1. Femoral artery cannulation trend over time.

Table 1. Preoperative patient characteristics

Table 2. Operative patient characteristics

Characteristic FrequencyAge Male FemaleMean (55.88 years)20-40 years 75% 25%41-60 years 65% 35%61-80 years 48.60% 51.40%Gender 60% 40%Associated comorbiditiesArterial hypertension 90.40%Bicuspid aortic valve 8.90%Marfan Syndrome 8.10%Diabetes mellitus 5.80%Annuloarctic ectasia 2.60%History of myocardial infarction 2.10%Previous surgery on the thoracic aorta 2.10%Imagistic investigationsTransesophageal echocardiography 100%Contrast CT 53.90%Coronary angiography 3.10%Aortography 2.60%MRI 1.05%

Variable Frequency (%)Arterial cannulation siteRight axillary artery 65.95%Femoral artery 22.94%Left axillary artery 2.87%Ascending aorta 2.51%Right subclavian artery 1.79%Right axillary artery, femoral artery 1.79%Aortic arch 0.72%Ascending aorta, femoral artery 0.36%Aortic valve procedureSinotubular junction recalibration 45%Bentall 29%Comissure resuspension 17%Yacoub 5%David 2%Replacement 2%



performed in all cases for tear inspection of the aortic arch. Th e average CPB time was signifi cantly longer in operations involving the aortic arch and the descen-ding aorta (452 min) compared to those with isolated replacement of the ascending aorta (172 min). Selective antegrade cerebral perfusion was used in all cases of arch or hemiarch replacement.

Postoperative characteristics are depicted in Table 4. Th e average patient was intubated for 23.65 hours and spent 13.6 days in the ICU ward. 29.10% pati-ents were extubated in the fi rst postoperative day. Th e most frequent complications were: acute renal failu-re (61.62%), ejection fraction 40% (57.20%), MSOF (39.48%), neurologic dysfunction (23.62%). Surgical reexploration was necessary in 26.57% cases, the most common cause being postoperative bleeding. Th e ove-rall mortality rate was 31.37% (91 patients), with no

signifi cant diff erences in time, while a marked decre-ase of intraoperative deaths in the last years, although not statistically signifi cant, is visible in the chart below (2005 9.09%; 2013 1.92%, p=0.119). Greatest mor-tality rates associated with ascending, arch, descending aorta replacement (83.3%) and with replacement of des cending aorta (60%). Related to the replaced aortic segment, mortality rates signifi cantly grew at univari-ate analysis in descending aorta (p=0.023, OR=3.325, 95%CI: 1.118-9.891) and arch replacement (p=0.009, OR=2.422, 95% CI: 1.227-4.781). Also, while CPB ti-mes under 400 minutes associated an overall mortality rate of 24.57%, over this value the mortality rate tripled: 82.46% (p=0.001, OR=15.127, 95% CI: 1.789-127.899).

Operations performed Frequency (%) Mortality rate (%) Cerebral perfusion (%) CPB time (min)Cross-clamp time

(min)Ascending aorta 29.71% 16.05% 6.61% 172 99Ascending aorta and hemiarch 23.55% 27.27% 38% 258 125Aortic root and ascending aorta 22.46% 25.4% 4.13% 241 167Aortic root, ascending aorta and hemiarch

11.96% 39.39% 21.50% 294 175

Ascending aorta and arch 6.88% 45% 12.40% 350 198Aortic root, ascending aorta and arch 5.07% 33.33% 9% 398 273Descending aorta 0.12% 60% 3% 285 103Ascending aorta, arch, descending aorta

0.20% 83.3% 5% 452 283

Root, ascending aorta, arch, descen-ding aorta

0.04% 0% 1% 351 284

Table 3. Operative patient characteristics

Variable TimeMean ventilatory support period 23.65 hoursMean length of ICU stay 13.6 daysComplications Frequency (%)Ejection fraction 40% 57.20%Acute renal failure 61.62%MSOF 39.48%Hemodialysis 36.16%Sepsis 31%Cerebral stroke 23.62%Cardiac tamponade 26.57%Acute myocardial infarction 9.96%Peripheral ischaemia 6.27%Visceral ischaemia 3.69%Mediastinitis 3.32%ReinterventionsBleeding 36%Deep wound infection 5%Myocardial ischaemia 2%Tamponade 2%Peripheral ischaemia 3%Mortality rate 31.37%

Table 4. Postoperative characteristics

Figure 2. Axillary artery cannulation trend time.



DISCUSSIONAcute aortic syndromes (AAS) constitute a spectrum of conditions characterized by disruptions in the integrity of the aortic wall, with potentially catastrophic con-sequences, including classic aortic dissection, intramu-ral hematoma and penetrating aortic ulcer4, although recent evidences suggest that IMH may in fact be the classic aortic dissection with small intimal tears that are not evident with current aortic imaging techniques5. Of these, acute aortic dissection is the most frequent and catastrophic manifestation1. Traditional classifi cation systems, such as the Stanford and DeBakey, facilitate the decision-making process4; more recently though, a classifi cation based on the pathophysiological featu-res of the aortic lesion rather than its location has been proposed; currently it is recommended that AAD be classifi ed according to both lesion type and location. Still, while the primary goal of surgery is to obliterate the intimal tear in the ascending aorta, thereby pre-venting fl ow and encouraging thrombosis of the false lume1, neither of these classifi cation systems dictates the site of the originating entry tear2.

Diagnosis of ATAADTh e estimated total incidence of AAD (type A and B) reaches 30 to 43 cases per million of population per year and apparently continues to increase. ATAAD constitutes more than half of these, while DeBakey type I lesions predominate. It is not known whether the apparent increase in incidence represents improved rates of diagnosis or the dramatic consequence of an aging population2.

While immediate decisions with regard to initial management, transfer, appropriateness of surgery, ti-ming of operation and intervention for malperfusion complications are mandatory, the diverse presentations of ATAAD can delay the diagnosis, adversely aff ec-ting outcomes2,6,7. Approximately 75% of patients with

acute dissection have their initial diagnosis made in a nonspecialised hospital. In ATAAD, the period of time between presentation and defi nitive management rea-ches ~12 h in the majority of patients, but has been re-ported as long as ~24 h in 20% to 50% of cases in some series8. Symptoms, signs, electrocardiograms and chest X-rays lack sensitivity and specifi city, therefore the diagnosis may be overlooked in 40% of cases, some-times being established only at autopsy8. Th e primary presentation of AAD to the emergency room (ER) is most commonly an elderly male, with hypertension and sudden onset chest pain8, as it was in our study. On hospital admission, 50% of patients are hemodynami-cally unstable, ~25% have a neurological defi cit, over 20% have cardiac tamponade and 6% have already un-dergone cardiopulmonary resuscitation9. It has been reported that malperfusion syndromes may be associ-ated in as many as 20-30% of patients presenting with type A dissection; although oft en under-recognized at that time, they remain responsible for signifi cantly in-creased mortality rates10.

Without clinical suspicion, patients are not immedi-ately channeled into an appropriate imaging pathway2. Acute aortic syndromes have no reliable point-of-ca-re biomarkers2,8. D-dimer measurements might be for now the most useful tool: a negative assay is highly pre-dictive that a patient does not have dissection, whereas a high level makes the diff erential diagnosis of ATAAD or pulmonary embolism far more likely and once sus-pected, defi nitive imaging comprising CT, transtho-racic echocardiography (TTE), transesophageal echo-cardiography and MRI, is required for confi rmation2. TTE is a rapid and readily available investigation in the emergency department and it should be performed without delay in patients with suspected AAS. Owing to an inadequate window for imaging the ascending aorta9, TTE has a reported sensitivity of 59-83% in ATAAD and a much lower one in descending aortic dissection, but a specifi city of 63-93% for the diagnosis of aortic dissection1. Th e sensitivities of MRI, TEE and CT in detecting acute aortic dissection are similar at approximately 95%9. In a comprehensive meta-analysis of all three modalities, the most recent studies reported 100% sensitivity and 100% specifi city for TEE, helical CT and MRI, whereas conventional CT (probably the most widely used technique) was less accurate (sensi-tivity 83-94%, specifi city 87-100%). Th e intimal tear is usually located in the proximal ascending aorta or just distal to the left subclavian artery, measuring less than 5 mm in length - TEE identifi es it in about 78-100%

Figure 3. Mortality rates over time.



of the cases. In another 10-20% of cases, the intimal fl ap propagates retrogradely, involving the origin of one or both of the coronary arteries1. In this situation, the role of preoperative coronary angiography is still controversial. Th e low rate of concomitant coronary artery disease, the risk of catheter-induced lesions and management delay are substantial arguments against it. Angiography may be indicated during or aft er surgery (in the era of the hybrid procedures) in patients with visceral malperfusion and dilatation of the descending aorta for appropriate treatment guidance9.

Surgical indications and predictors of operative mortalityAs mentioned above, time-honored dictum is that type A aortic dissection requires urgent surgery. Th ere are, however, controversial situations where the patients treatment may stop with medical management: pati-ents with completed stroke, comorbid conditions (e.g., cancer, advanced multiple organ dysfunction, advan-ced age), prior aortic valve replacement (AVR), and hospital presentation 48 to 72 hours beyond symptoms onset11. Th e mortality of untreated ATAAD reportedly reaches values of 1% to 2%/h in the fi rst 24 hours, up to 90% of patients succumbing within 30 days. Surgical repair remains high-risk, with both mortality and ne-urological complication rates of 15% to 30%. No ran-domized studies of medical vs surgical management in ATAAD have ever been performed, but on the available evidence, surgery converts a 90% mortality rate to at least a 70% survival rate and no more than 2 patients need to be treated to gain survival benefi t2. Reported in-hospital mortality for surgically treated cases of ATAAD varies between 5% and 27.4%, reaching valu-es of 28% in the International Registry of Acute Aortic Dissection (IRAD) and 17%, respectively, in the Ger-man Registry of Acute Aortic Dissection (GERAADA)9. For patients who present with uncomplicated ATBAD, the survival rate approaches 90% with medical therapy alone, while IRAD reported a mortality rate in patients undergoing surgical repair of 29.3%12. Type II aortic dissection appears to associate a better prognosis than Type I, in terms of perioperative, long-term, and ane-urysm-free patient survival, related to the propensity for distal malperfusion phenomena and persistence of a distal false lumen. Arterial hypertension, althou-gh considered one of the most important predisposing factors of acute aortic dissection, does not seem to in-fl uence the prognosis of these patients13. Preoperative coma, as well as the state of shock secondary to either cardiac tamponade or coronary dissection and ische-

mia are consistent predictive factors for postoperative mortality2. In a 2012 study Perrault found cardiogenic shock, cerebral ischemia and massive hemorrhage to be responsible for almost 85% of perioperative deaths. According to Pacini et al., the presence of malperfu-sion tripled the overall mortality rates associated with ATAAD (43.7% in the group with malperfusion vs 15% in that with no malperfusion)10. Another major deter-minant of outcome in type-A dissection is advanced age. While ATAAD incidence increases with age, re-cent studies have highlighted the excessive risks asso-ciated in patients over 70 years old5. As with all car-diovascular surgery emergencies, advanced age proved an independent predictor of worse operative morta-lity and morbidity and reduced longer-term survival of ATAAD. However, in western societies one-fi ft h of the population are 65 years of age and this fraction is increasing2. Mehta and associates have shown that the mortality rate associated with surgery for ATAAD is 45% in patients 80 to 84 years of age and 50% for those 85 or older11. Data from the IRAD registry suggest that one-third of patients presenting with ATAAD are over 70 years of age, with only 47.6% of those older than 80 years of age undergoing surgery. Surgical mortality for this group reaches 40%, compared with 58% for the medically managed patients2. In a 2013 study, Piccardo reported an overall mortality rate in the group of surgi-cally treated octogenarians with ATAAD of 44.3% and identifi ed the presence of complications as the only risk factor for in-hospital mortality. His conclusion was that octogenarians with uncomplicated ATAAD may bene-fi t from emergency surgical repair14. Our study inclu-ded 11.72% of patients with ages between the range of 70 and 96 years old, without signifi cantly increased mortality rates. Still, the management of acute type A aortic dissection in these age groups remains contro-versial14.

All these and other factors have been incorporated into predictive risk models on the basis of IRAD and individual center data, which might aid the decision making process. However, although each complication might engender additional risk, this does not preclude a superior outcome with surgery and rigid treatment exclusion criteria are inappropriate2.

*Th e aim of ATAAD surgery is prevention of intra-pe-ricardial rupture, of coronary ostial dissection or aor-tic valve deterioration, with correction of any of these when present, correction of distal malperfusion and permanent obliteration of the distal false lumen (FL).



Th is is usually accomplished by ascending aorta re-placement accompanied, where possible, by excision of the proximal entry tear, therefore restoring the do-minant true lumen (TL) fl ow in the distal aorta. Tech-niques used to achieve these aims have not been subject to randomized studies so they remain issues of debate2.

Arterial cannulation siteTh e optimal site of arterial cannulation also remains controversial. While femoral artery has been the pri-mary site for arterial cannulation in surgery for ATAAD for a long time2,15, it has lost popularity during recent years given the worse outcomes it appears to associate compared to other strategies in contemporary studies9. Apparently, retrograde perfusion through the femoral artery may further exacerbate dissected intimal fl aps and determine organ malperfusion, progressive arch vessel compromise, and neurologic injury and it has also been associated with a greater stroke risk in pati-ents with concurrent distal aortic aneurysmal or athe-rosclerotic disease2,15. Previous studies have reported an incidence of malperfusion syndrome with femoral cannulation of 2.5% to 13%15. In autopsy series, femo-ral artery cannulation associated a theoretical potential for brain malperfusion of 42%, whereas with perfusion via the axillary artery this potential was limited to only 16%. However, the clinical incidence of these events is low. Th erefore, in ATAAD, initial femoral artery can-nulation remains reasonable, if provided malperfusion monitoring is applied and potential distal aortic patho-logy is excluded2. Besides the decreased risk of stroke or malperfusion, the theoretical advantages of axillary artery cannulation in ascending aorta and arch surgery include the continuous provision of cerebral fl ow by means of selective antegrade cerebral perfusion. Th e complications of this technique, such as axillary ar-tery or brachial plexus injury, arm ischaemia and low CPB fl ow are becoming well-known, ranging betwe-en 0% and 5%15. It remains controversial whether the axillary artery should be cannulated directly, or using the sidegraft technique9. In our Institute the primary arterial cannulation site was chosen according to pre-operative imaging techniques and intraoperative fi n-dings, thus explaining the variable frequencies between the axillary and femoral arteries over the years. Central cannulation is another option, many surgeons prefer-ring to cannulate the dissected aorta itself either with TTE or TEE guidance or under direct vision aft er tran-secting the tourniquet controlled distal ascending aor-ta, therefore allowing very fast cannulation in an emer-gency. Left ventricular apex is another potential can-

nulation site7. In a 2013 meta-analysis, axillary artery cannulation seemed to give better short-term mortality and neurological dysfunction rates than femoral artery cannulation16. Because no study was a randomized trial these results are more than uncertain2,16; as the patho-anatomy diff ers among patients with ATAAD, so does the optimal cannulation strategy9.

Aortic valve involvementApproximately 30% of patients with ATAAD have an aortic diastolic murmur and one-half have aortic re-gurgitation on ETT, the surgical management of which is controversial too. Preservation of the native aortic valve has obvious advantages. In case of normal leafl et morphology, of fl ap interference with valve closure or central regurgitation due to prior dilation of the sino-tubular junction, valve competence can usually be re-stored by re-affi xing the commissures to the aortic wall. However, despite satisfactory early outcomes of this procedure, 20% to 25% of patients will develop late root enlargement or progression of aortic regurgitation, ne-cessitating aortic valve replacement or ARR; risk factors including an aortic annulus of 27 mm in diameter and above-moderate valve regurgitation at initial surgery. In patients with pre-existing root pathology VSRR may be an option, with the added disadvantages of longer operating times and superior technical requirements. Of the 2 types of valve sparing root replacement, the re-implantation technique might be superior in ATAAD2. Kallenbach et al. reported their data aft er operating on 295 patients for acute type A aortic dissection with use of the supracommissural technique, Bentall pro-cedure and valve-sparing reimplantation technique. In terms of survival and reoperation rates, the authors concluded that the reimplantation technique yields re-sults comparable to those of the established procedu-res17. Some centers prefer a more aggressive strategy, replacing the aortic valve and adding the well-known risks of prosthetic valves. An aortic root repair (ARR) procedure could also increase risk in inexpert hands. Th us, the role of aggressive ARR management of the aortic valve versus conservative valve re-suspension is incompletely defi ned2.

In our series aortic valve involvement reached 37.6% of cases. A conservative approach was adopted whene-ver possible and in only 25% of these cases was the aor-tic valve replaced either isolated or as part of a Bentall operation. When a competent non-calcifi ed bicuspid aortic valve (BAV) is detected, the decision to conserve will depend upon age, presence of annulo-aortic ect-asia and degree of aortic root destruction. If the valve



a higher incidence of complications during follow-up20. In the present study an isolated ascending aortic repla-cement was most oft en necessary, with an associated mortality rate of 16.05%, combined with a distally ex-tended aorta replacement in 41% of cases. Aortic arch and descending aorta replacement were performed with a frequency of 12.19% and 0.36%, respectively. Both of them signifi cantly increased mortality rates, reaching values of 60% and 83.3%, respectively, once more de-monstrating that open aortic arch reconstruction re-mains a formidable operative procedure, recommended only in highly experienced centers. Probably in associ-ation with these complex procedures prolonged CPB time also signifi cantly increased mortality rates: a CPB duration of 400 minutes or longer related to a mortality rate of 82.46%. Recently published results indicate that the dreaded complications of arch repair, namely death and stroke, can occur at rates under 5% in these experi-enced centers. Himanshu and Deeb reported in a 2013 study on 721 patients with open arch reconstruction a mortality rate of 21.6%21. Novel hybrid techniques have been developed in the treatment of ATAAD with arch involvement. A recent prospective study on the use of hybrid operating rooms for the management of acute dissection demonstrated that a hybrid OR enabled the identifi cation of downstream malperfusion sites, 23% of patients requiring primary endovascular interventi-on and 35% requiring descending aortic repair in addi-tion to ascending aortic replacement10. Th e elephant trunk is the classical extension of the aortic arch repla-cement into the descending aorta. During arch replace-ment, the distal end of the aortic graft is advanced into the descending aorta and connected to the distal aorta in a second procedure. Th is technique has been refi ned by the use of stent-graft -reinforced hybrid prostheses which are implanted into the descending aorta in an antegrade fashion during arch replacement (frozen elephant trunk), leading to high false-lumen occlusion rates5,9. However, thoracic endovascular aortic repair (TEVAR), subject of the INSTEAD trial, has become the standard treatment for several descending aorta pathologies. In malperfusion syndromes resulting from dynamic true-lumen compression through a dead-end false lumen, fenestration of the dissection membrane is regarded as a complementary treatment. Today, the method has mostly been replaced by TEVAR9. Operati-ve mortality for acute type A dissection is multifactori-al, but remains poorly elucidated10. Although on a des-cending trend over the last nine years, mortality rates in this study maintain at high levels. Overall, except in

is functionally abnormal, but without associated sinus disease, prophylactic simple aortic valve replacement is justifi ed. Alternatively, reparative bicuspid valve proce-dures are well-reported, but their application should be judicious2. According to Schfers et al., the presence of BAV does not infl uences the outcomes of valve-sparing root replacement (VSRR) procedures. In their series of 153 patients, freedom from reoperation and freedom from recurrent moderate or severe AR were 95% and 90% respectively aft er 10 years17. Th e type of disease (i.e. valve insuffi ciency vs stenosis) infl uences though the natural history of the aortopathy in BAV patients, as a history of AVR surgery does too18. Also these pati-ents have a distinctive dissection pattern with the entry tear frequently located in the aortic root and-despi-te their younger age-are at risk of substantial hospital mortality. It has been reported that composite root re-placement yields an excellent outcome in BAV patients suff ering from aortic dissection, equal to an age- and gender-matched normal population19. Th e routine use of intra-operative TEE is now regarded as an essential adjunct2.

Extension of aortic repair In ATAAD the primary intimal tear is usually present within the ascending aorta, sometimes accompanied by secondary, more distal tears. Sometimes, involve-ment of the ascending aorta can result from retrograde propagation of the dissection fl ap with the primary tear originating within the arch or descending aorta. Occa-sionally, no intimal tear is identifi ed2. Th e aortic arch is dissected in more than 70% of ATAADs. Aortic arch dilatation or obstruction of the supra-aortic vessels is common in ATAAD; luminal arch inspection under DHCA is thus required. Th e thoracic and abdominal portions of the descending aorta are involved in 40 and 30% of patients respectively, but are responsible for just a minority of acute complications. Th erefore, the des-cending aorta itself is not usually treated during emer-gency surgery for ATAAD. However, in over 70% of pa-tients the FL is chronically perfused, carrying the risk of further enlargement9. Suboptimal connection of the distal part of the graft implanted in the ascending aor-ta to the TL or presence of secondary entry tears may account for the postoperative persistence of residual fl ow into the distal FL. Th e long-term outcomes of aor-tic dissections with patent false lumen show a high risk of complications, sudden death and need for surgery, particularly from the third year of evolution. In addi-tion to Marfan syndrome, maximum aortic diameter and the presence of a large, proximal entry tear imply



5. Augoustides JGT., FASE, FAHA,* Andritsos M. Innovations in Aortic Disease: Th e Ascending Aorta and Aortic Arch, Journal of Cardiotho-racic and Vascular Anesthesia, 2010; 24: 198-207.

6. Iliescu VA, Dorobantu LF, Stiru O, Chioncel O, Moldovan H, Bube-nek-Turconi S, et al. Six years experience in acute aortic dissection type A retrospective single centre study, 62nd Congress of ESCVS, Regensburg. Th e Journal of Cardiovascular Surgery. 2013; 54: :3-3.

7. Iliescu VA, Dorobantu L, Stiru O, Bubenek S, Miclea I, Rugina M, et al. Combined cardiac neurosurgical treatment of acute aortic dissec-tion, stroke and coma, Tex Heart Inst J., 2008; 35: 200-202.

8. Ranasinghe AM., Bonser RS. Biomarkers in Acute Aortic Dissection and Other Aortic Syndromes, J. Am. Coll. Cardiol., 2010; 56: 15351539.

9. Kruger AT, Conzelmann LO, Bonser RS, Borger MA, Czerny M, et al. Acute aortic dissection type A, British Journal of Surgery, 2012; 99: 13311344.

10. Appoo JJ, Pozeg Z. Strategies in the surgical treatment of type A aortic arch dissection, Ann Cardiothorac Surg., 2013; 2: 205-211.

11. Feldman M, Shah M, Eleft eriades JA. Medical Management of Acu-te Type A Aortic Dissection, Ann Th orac Cardiovasc Surg., 2009;15: 286-293.

12. Zheng J, Lu S, Sun X, Hong T, Yang S, et al. Surgical management for acute type A aortic dissection in patients over 70 years-old. Cardi-othorac Surg., 2013; 8:78.

13. Apetrei E, Cioranu R, Ginghina C, Coman I, Macarie C. Hyperten-sion does not infl uence prognosis in aortic dissection, XIIIth World Congress of Cardiology Free papers, Eds: Monduzzi, Bologna, 1998; 389-393.

14. Piccardo A, Le Guyader A, Regesta T, Gariboldi V, Zannis K, et al. Oc-togenarians with uncomplicated acute type a aortic dissection benefi t from emergency operation, Ann Th orac Surg., 2013; 9: 851-856.

15. Lee HK, Kim GJ, Cho JY, Lee JT, Park I, et al. Comparison of the Out-comes between Axillary and Femoral Artery Cannulation for Acute Type A Aortic Dissection, Korean J Th orac Cardiovasc Surg., 2012; 45: 85-90.

16. Ren Z, Wang Z, Hu R, Wu H, Deng H, et al. Which cannulation (axillary cannulation or femoral cannulation) is better for acute type A aortic dissection repair? A meta-analysis of nine clinical studies, Eur J Cardiothorac fi rst published online July 11, 2014; in press

17. Badiu C, Voss B, Dorfmeister M, Lange R. Valve-Sparing Root Repla-cement. Where Are the Limits?, Tex Heart Inst J., 2011; 38: 661662.

18. Etz CD, von Aspern K, Hoyer A, Girrbach FF, Leontyev S, et al. Acute type A aortic dissection: characteristics and outcomes comparing pa-tients with bicuspid versus tricuspid aortic valve, Eur J Cardiothorac Surg., fi rst published online October 15, 2014; ; in press

19. Girdauskas E, Disha K, Borger MA, Kuntze T. Risk of proximal aortic dissection in patients with bicuspid aortic valve: how to address this controversy?, Interact Cardiovasc Th orac Surg., 2014;18: 355-9.

20. Evangelista A, Salas A, Ribera A, Ferreira-Gonzlez I, Cuellar H, et al. Long-term outcome of aortic dissection with patent false lumen: predictive role of entry tear size and location, Circulation, 2012; 12: 3133-41.

21. Patel HJ, Deeb GM. Open aortic arch reconstruction, Ann Cardiotho-rac Surg., 2013; 2: 181-183.

highly specialized centers, surgical outcomes might be static, and there is abundant room for improvement2.

CONCLUSIONSAcute type A aortic dissection is a frequent pathology in the cardio-vascular surgical area. Moreover it can prove to be a surgical challenge, with increased morbi-dity and mortality rates, particularly in extended, com-plicated forms. Th e rapidity of diagnostic confi rmation and institution of treatment are essential in these cases. Surgical techniques have diversifi ed and improved, es-pecially in the fi eld of aortic valve and root reconstruc-tion and in the fi eld of cerebral protection enabling more extensive aortic arch surgery and lowering mor-bidity and mortality rates. Endovascular strategies are also emerging, apparently with favorable results. Surgi-cal treatment of ATAAD remains controversial, but in experienced centers the results appear to be more than satisfying.

Note: Th is work received fi nancial support through the project CERO - CAREER PROFILE: ROMANIAN RESEARCH, contract no. HRD / 159 / 1.5 / S / 135760, fi nanced from the European Social Fund through the Sectorial Operational Programme Human Resources Development 2007-2013Authors contributions: All authors have contributed to the manuscript and approved the fi nal version.

References 1. Meredith EL, Masani ND. Echocardiography in the emergency assess-

ment of acute aortic syndromes, European Journal of Echocardio-graphy, 2009; 10: 3139.

2. Bonser RS., Ranasinghe AM., Loubani M, Evans JD., Th alji NMA., et al. Evidence, Lack of Evidence, Controversy, and Debate in the Provi-sion and Performance of the Surgery of Acute Type A Aortic Dissec-tion, J. Am. Coll. Cardiol., 2011; 58: 24552474.

3. Criado FJ, Aortic dissection - a 250-year perspective, Tex Heart Inst J., 2011; 38: 694-700.

4. Bonaca MP, OGara PT. Diagnosis and management of acute aortic syndromes: dissection, intramural hematoma, and penetrating aortic ulcer, Curr Cardiol Rep., 2014; 10: 536.


ORIGINAL ARTICLES

Predictive value of exercise stress testing in a tertiary cardiological centerDaniel Gherasim1, Maria Jalb1, Marina Lupu2, Dan Deleanu1, Carmen Ginghin1,3, Eduard Apetrei1,3

Contact address:Dr. Daniel Gherasim, Clinical Cardiology, Prof. Dr. C. C. Iliescu Emer-gency Institute for Cardiovascular Disease, Bucharest, Sos.Fundeni 258, Sector 2, Bucharest, Zip code 022328E-mail: [email protected]

1 Prof.Dr. C.C. Iliescu Emergency Institute for Cardiovascular Disease, Bucharest2 Panduri Medical Center, Bucharest3 Carol Davila University of Medicine and Pharmacy, Cardiology Depart-ment, Bucharest

Abstract: Purpose Exercise stress testing (ET) is a valuable screening test for the detection of obstructive coronary artery disease (CAD). Previous studies from the literature show an overall sensitivity of 68% and specifi city of 77% with variable predictive values depending on pretest probability. Th e purpose of the current study was to evaluate the diagnostic value of ET in the modern era of cardiology. Aims Th is is a retrospective study on 404 patients with chest pain suggestive for angina and with no history of ischaemic heart disease, which have performed a treadmill exercise stress testing and than aft er and a selective coronary angiography, from October 2008 to January 2013. Th e coronary angiography was performed between 2 - 60 days aft er the test. A positive test was defi ned as horizontal or downsloping ST segment depression or elevation of 0.1 mV (1mm) or slowly upsloping of 1.5 mm (the slowly upsloping was defi ned as


Daniel Gherasim et al.Predictive value of exercise stress testing

INTRODUCTIONCardiovascular disease (CVD) remains the global main cause of death, accounting for 17.3 million deaths per year and continues to cause a much greater mortality burden among Europeans than any other disease: 51% of deaths among women and 42% among men in the last year of reported data1. Coronary heart disease only, accounts for almost 1.8 milion deaths, or 20% of all deaths in Europe annualy, but the patterns vary widely in individual countries2. In our country, age-standar-dized mortality is still high, despite a decrease of mor-tality rate in the last 10 years with 16% in men and 22% in women2.

Chest pain is the most common presenting compla-int indicating CAD and is seen frequently by primary care physicians or cardiologists.

Th e exercise treadmill test is used in the evaluation of symptomatic patients to predict the presence and ex-tent of coronary artery disease (CAD). A large number of noninvasive stress testing are currently available, but the exercise ECG is still used as a standard for compa-rison with other clinical and testing risk markers. It is also the least costly of all provocative noninvasive tests, do not always require a cardiologist, and are convenient for the patient because are oft en an offi ce-based investi-gation. Th e ECG exercise test (ET) for the diagnosis of obstructive CAD has a class I indication (class I: condi-tions for which there is evidence and/or general agree-ment that a given procedure or treatment is useful and efective) in the subgroup of adults with an intermediate pretest probability of CAD on the basis of gender, age, and symptoms3.

Th e studies evaluating the diagnostic accuracy of the ET have proved a mean sensitivity of 68% and a mean test specifi city of 77%, with sensitivities ranging from 23% to 100% and specifi cities ranging from 17% to 100%, but the large proportions of studies and meta-analysis was published about 20 or 30 years ago4. Th e prevalence of CAD was changing and also, over the past two decades the frecquency and severity of abnor-mal stress testing have progressively decreased5. In the

modern era of cardiology, to analyse the sensitivity and specifi city of ECG exercise testing could be a challenge.

In our knowledge, there are no available data regar-dind the sensitivity or specifi city of ET nowdays in our country.

STUDY GROUPTh is is a retrospective study of 404 patients, which were referred for exercise testing in our Institute between Oc-tober 2008 to January 2013, according to the following inclusion criteria: 1) chest pain suggestive for angina; 2) no history or electrocardiographic evidence of pre-vious myocardial infarction; 3) no left bundle branch block, WPW syndrome, ECG criteria for left ventricu-lar hypertrophy (LVH) or valvular disease which can infl uence the interpretation of ST segment deviation or left ventricular function; 4) absence of clinical indicati-on for urgent coronary revascularization.

Clinical informations and risk factors evaluation were obtained before testing. Exercise testing was per-formed in the morning and aft er withdrawal, where was the case, of antianginal therapy for at least 72 ho-urs, on the treadmill (Burdick, USA) using the classi-cal Bruce protocol under supervision of the in charge cardiologist; recording of the ECG was done with the Mason-Likar torso-mounted limb system, ankle and wrist electrodes being replaced by electrodes mounted on the torso at the base of the limbs. Th e patients were encouraged not to tighly grasp the front or side rails of the treadmill and to exercise to their maximum. Th e test was symptom limited and was terminated when any of the following occurred: severe angina, dyspnoea, fatigue, hypotension, complex ventricular arrhythmia and >1 mm ST segment depression. Sub-maximal pre-dicted heart rate was calculated as 75% of maximal pre-dicted heart rate (ie 220-age). Th e ECG was recorded with a Siemens Megacart electrocardiograph on each stage, prior peak exercise and in the recovery period, at each minute. A paper spead of 25 mm/s was used an 1 vertical mm equals 0,1 mV. Th e ECG was read by measuring the ST segment deviation from the PQ (PR)

sibilitatea testului a fost de 85,3%, iar specifi citatea de 46,8%. Valoarea predictiv pozitiv a fost de 65,3%, iar cea negativ de 73,1%. Amplitudinea modifi carilor ST s-a corelat cu gradul stenozei. Nu a putut fi stabilit o corelaie ntre teritoriul n care au aprut modifi crile pe ECG i artera coronar implicat, exceptnd supradenivelarea segmentului ST n aVR care reprezint un indicator pentru stenoza de trunchi comun. Timpul de efort (capacitatea de efort) este corelat cu vrsta. Concluzii n epoca cardiologiei moderne, cnd sunt disponibile alte investigaii noninvazive cu sensibilitate superioar (ecografi a de efort, perfuzia miocardic de stress), testul de efort continu s arate o bun sensibilitate i rmne, datorit costului redus i accesi-bilitii, prima opiune n algoritmul de diagnostic al bolii coronariene.Cuvinte cheie: test de efort, factori de risc, valoare predictiv, stenoz coronarian semnifi cativ, capacitate de efort.



segment at 0,08 sec. from the J point. A positive test was defi ned as horizontal or downsloping ST segment depression or elevation of 0,1 mV (1 mm) or slowly upsloping of 1.5 mm, slowly being defi ned as



negative predictive value was 73.1%. Both sensitivity and specifi city were similar in men and women (0.87 and 0.46 for men, respectively 0.78 and 0.47 for wo-men). Th e PPV was greater for the men (0.75 vs 0.44 in women), but NPV was greater for the women (0.8 vs 0.66 for men), which corresponding with the higher prevalence of CAD in men compared with women in the same aging group. Most patients (29%) had only one coronary artery with stenosis; the sensitivity of the ET for the one-vessel disease was 74.5%, and specifi city was 50%. If the equivocal test would be included in the positive tests, the sensitivity of the test would be 94.5%, with a decrease in specifi city (31.2%); PPV would be 61.7%, and NPV 82.9%. We found, also, a high sensiti-vity (91.5%) and a low specifi city (37%) when we made

the calculation without take into account the equivocal tests, comparing only positive with pure negative tests.

For a better comparison between the results of ET and coronary arteries involvement, we have divided the study population in four groups: 1) patients with positive ET and signifi cant coronary lesions - true po-sitive tests (186 patients); 2) patients with positive ET and without signifi cant coronary artery stenosis - false positive tests (99 patients); 3) patients with negative or equivocal ET and without coronary stenoses - true ne-gative tests (87 patients); 4) patients with negative ET and signifi cant coronary stenosis - false negative tests (32 pacients). Th e characteristics of the four groups are presented in Table 3.

A pure negative ET (equivocal test not included) was recorded in 65.5% (57 patients) with no coronary ar-tery stenoses and only in 13 patients (40%) in whom the CAD was present. In 32 patients with signifi cant stenosis the ET was not positive. In these patients, the majority (25 patients) had one vessel disease (any coro-nary artery), one patient had three vessels disease and one patient had signifi cant stenosis of left main artery, but also of LAD and Cx.

Th e ECG teritory with ST deviations (anterior, in-ferior, antero-septal, lateral) is not specifi c for one or other of the coronary artery, except the ST depression in V3-V5 or ST elevation in aVR, V1 where odds ratio (OD) for the LM is statistically signifi cant, as shown in Table 2.

Figure 1. Th e prevalence of signifi cant coronary artery stenoses.

Table 2. The distribution on ECG territories compared with the involved coronary artery

No (%) OR 95% Confi dence IntervalI, aVL,V4-V6 LAD 33 (66%) 3.556 1.905 6.640

Cx 27 (54%) 3.603 1.964 6.607RC 26 (52%) 2.676 1.468 4.880LM 7 (14%) 2.343 0.949 5.784

V3-V5 LAD 54 (39.7%) 1.038 .681 1.584Cx 38 (27.9%) 0.980 .619 1.550RC 42 (30.9%) 0.946 .606 1.476LM 12 (8,8% 1.344 .628 2.878

II, III, aVF LAD 98 (48.8%) 2.268 1.506 3.414Cx 79 (39.3%) 3.108 1.960 4.930RC 95 (47.3%) 4.617 2.902 7.346LM 21 (10.4%) 2.515 1.122 5.635

aVR, V1 LAD 41 (63.1%) 3.241 1.868 5.625Cx 36 (55.4%) 4.154 2.395 7.204RC 34 (52.3%) 2.859 1.663 4.914LM 18 (27.7%) 10.436 4.728 23.037

V4-V6 LAD 89 (48.1%) 2.015 1.344 3.023Cx 74 (40%) 2.983 1.899 4.687RC 83 (44.9%) 3.146 2.032 4.873LM 16 (8.6%) 1.386 .658 2.922

No=number of cases with coronary arteries stenoses; OR = odds ratio



Th e most signifi cant stenoses were found in patients in whom the ST segment alteration in lateral leads V4-V6 or aVR and V1 have been revealed. In Figure 2 we have presented the exercise electrocardiogram of a pa-tient with severe stenosis located at the ostium of LAD, with ST depression in multiple leads, but also with ST elevation in aVR.

When we analysed the correlation between the num-ber of risk factors for CAD and the number of involved coronary arteries, an correlation Spearman coeffi cient of 0.210 was positive, indicating a positive relation, but

the power of this indicator is weak. More risk factors we have, more coronary artery with stenosis will be found (p



infl uence the exercise capacity.Th e amplitude of ST modifi cation was correlated

with the severity of coronary artery stenosis.Hypertension was the risk factor we have found in

325 patients. In this subgroup of patients, the ST seg-ment alterations was recorded predominantely in the lateral precordial leads V4-V6. Th e exercise time was almost one minut better (52 sec) in hypertensive pati-ents with a stenosis



Despite the fact known from old studies that ST de-pression is less likely to be associated with CAD in wo-men10,11, we found a high sensitivity for ET in women too (0.78%). Th e PPV was 0.44% (compared with 0.75 in men), but the NPV is superior in women (0.8 vs 0.66 in men). Th e diff erence could be explained by the dife-rences in the prevalence of CAD in women vs men12.

As we expected, we didnt fi nd a correlation between the ECG leads with ST changes and the coronary ar-tery involved. When LAD disease was found, in 66% of cases the ST depression had occurred in anterior leads I, aVl, V4-V6, but for the same disease we found ECG changes also in V3-V5 in 40% of cases, only in V4-V6 in 48%, and the same prevalence in inferior leads (48% of cases). In many cases we had concomitant ST chan-ges in more then one territory. Th e ecg changes was occurred in one territory in 23% of cases. But the am-plitude of ST depression was correlated with the degree of stenosis: more tight stenosis we had, more depth ST modifi cation.

A challenging issue in the literature was the predic-tive value of ST elevation in lead aVR in the setting of exercise testing. Prior studies have demonstrated the value of ST changing in aVR in acute coronary syndro-mes where the ST elevation may indicate severe steno-sis or occlusion of the left main coronary artery13-15. In the setting of ET only few studies16-18 raised the impor-tance of ST elevation in aVR as an important indicator for signifi cant LM stenosis or ostial LAD stenosis. In our study, the ST changes in aVR and V1 were statisti-cally signifi cant marker for the LM stenosis.

We found hypertension in 80.7% of cases, which is the double of the prevalence found in the SEPHAR II study, where the prevalence of hypertension was 40.1%19. Exercise responses regarding exercise BP, exer-cise capacity, ST changes in hypertensive patients are correlated with the risk of CV disease and CV death20,21.

In our study, the hypertensive patients developed ST segment depression predominantely in the lateral pre-cordial leads V4-V6, a fact which was revealed also in other ET studies22, and had a lower exercise capacity (they didnt reach the stage III of the Bruce protocol) if a signifi cant coronary artery stenosis occurred.

We note also that the exercise testing is a safe proce-dure. Th ere were no serious complications in this study, even in the patients with severe CAD.

Conclusions. In the modern era with dynamic chan-ges in the prevalence, impact and treatment of cardio-vascular risk factors and changes in the prevalence of CAD and CVD mortality, the predictive value of ECG

stress testing is not very well established. We have de-monstrated that in a specialised cardiological center, with a high expertise in ET, the sensitivity of the exer-cise testing for CAD is also high, both in men and wo-men, comparable or even superior with other imaging exercise techniques; exercise testing continue to be fi rst option in the diagnostic algorithm of coronary artery disease and with a good price/quality ratio.

Confl ic of interest: Th e authors declare that they dont have any confl ict of interest.Authors contributions: All authors have contributed to the manuscript and approved the fi nal version.

References1. Smith SC, Collins A, Ferrari R, Holmes DR, Logstrup S, Vaca D, Ral-

ston J, Sacco R, Stam H, Taubert K, Wood D, Zoghbi W.Our time:a call to save preventable death from cardiovascular disease. J Am Coll Cardiol.2012;60:2343-2348.

2. Nichols M, Townsend N, Scarborough P, Rayner M. Cardiovascular disease in Europe 2014:epidemiological update. Eur Heart J. 2014;35: 2950-2959

3. Gibbons RJ, Balady G, Bricker JT, Chaitman BR, Fletcher GF, Froeli-cher VF, Mark DB, McCallister BD, Mooss AN, OReilly MG, Winters WL. ACC/AHA 2002 Guideline Update for Exercise Testing.A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). 2002. American College of Cardiology Web site. Available at :www.acc.org/clinical/guidelines/exercise/dirIndex.htm

4. Fletcher G, Ades P, Kligfi eld P, Arena R, Balady GJ, Bittner VA, Coke LA, Jerome FL, Forman DE, Gerber TC, Gulati M, Madan K, Rhodes J, Th ompson PD, Williams MA. Exercise standards for testing and training:a scientifi c statement from the American Heart Association. Circulation. 2013;128:873-934

5. Rozanski A, Gransar H, Hayes S, Min J, Friedman JD, Th omson LEJ, Berman DS. Temporal trends in the frequency of inducible myocar-dial ischemia during cardiac stress testing.1991 to 2009. J Am Coll Cardiol. 2013;61:1054-65

6. Kligfi eld P, Lauer M. Exercise electrocardiogram testing.Beyond the ST segment. Circulation 2006; 114:2070-2082.

7. Ellestad, M.H.Predictive implications. In Stress testing. Principles and Practice. Fift h Edition. Eds: Ellestad MH. Oxford University Press, 2003, p271-309.

8. Gianrossi R, Detrano R, Mulyhill D, LehmannK, Dubach P, Colom-bo A, McArthur D, Froelicher V. Exercise-induced ST depression in the diagnosis of coronary artery disease. A meta-analysis.Circulati-on.1989;80:87-98

9. Montalescot G, Sechtem U, Achenbach S, Andreotti F,Arden C, Budaj A, Bugiardini R, Crea F, Cuisset T, Di Mario C, Ferreira JR, Gersh BJ, Gitt AK, Hulot JS, Marx N, Opie LH, Pfi sterer M, Prescott E, Rus-chitzka F, Sabat M, Senior R, Taggart DP, Van der Wall EE, Vrints CJM. 2013 ESC guidelines on the management of stable coronary ar-tery disease. Th e Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;83:660-666.

10. Kwok Y,Kim C, Grady D, Segal M, Redberg R.Meta-analysis of exerci-se testing to detect coronary artery disease in women. Am J Cardiol. 1999;36:169-173

11. Wong YK, Dawkins S, Grimes R, Smith F, Dawkins KD, Simpson IA. Improving the positive predictive value of exercise testing in women. Heart 2003; 89: 1416-1421.

12. Go AS, Mozaff arian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Hei JA, Howard VJ, Huff man MD, S Judd SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid DJ,



18. Rugin M, Molfea V, Deleanu D, Iliescu VA, Bubenek-Turconi S, Gherasim D, Predescu L, Dorobanu L, tiru O, Foi D, Coman IM. Chronic proximal coronary occlusion in an oligosymptomatic diabe-tic patient-medical and surgical therapy. Rom J Cardiol. 2011;21(3): 261-265

19. Dorobanu M, Barto D, Apetrei E, Arsenescu-Georgescu C, Pop D, Ghiorghe S, Tnsescu R, Craiu E, maniiu I, Tutu O. Hypertensi-on in Romania: where we are and what can be done ? Results from SEPHAR II study. Rom J Cardiol. 2012;22(4):177-184)

20. Mundal R, Kjeldsen SE, Sandvik L, Erikssen G, Th aulow E, Erikssen J. Exercise blood pressure predicts cardiovascular mortality in middle-aged men.Hypertension1994:24:56-62

21. Kokkinos P, Manolis A, Pittaras A, Doumas M, Giannelou A, Pana-giotakos DB, Faselis C, NarayanP, Singh S, Myers J. Exercise capacity and mortality in hypertensive men with and without additional risk factors. Hypertension 2009; 53:494-499.

22. Michaelides AP, Liakos CI, Raft opoulos LG, Antoniades C, Vyssoulis G, Andrikopoulos G, Ioakeimides N, Tsioufi s C, Soulis D, Stefanadis C. Electrocardiographic criteria for detecting coronary artery disease in hypertensive patients with ST-segment changes during exercise tes-ting. J Electrocardiol. 2009;42:405-409.

Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler III ER, Moy CS, Mussolino ME, Neumar RW, Nichol G, Pandey DK, Payn-ter NP, Reeves MJ, Sorlie PD, Stein J, Towfi ghi A, Turan TN, Virani SS,. Wong ND, Woo D, Turner MB. Heart disease and stroke statis-tics-2014 update: a report from American Heart Association. Circu-lation 2014; 129: e28-e292

13. Barrabes JA, Figueras J, Moure C, Cortadellas J, Soler-Soler J. Pro-gnostic value of lead aVR in patients with a fi rst non-ST-segment ele-vation acute myocardial infarction. Circulation. 2003; 108:814-819.

14. Chioncel O, Carp A, elaru A, Deleanu D, Zarma L, Macarie C. Va-loarea predictiv pozitiv a modifi crilor ECG pentru anatomia coro-narian: corelaie factori de risc, clinic, ECG, leziuni coronariene (in Romanian). Revista Romn de Cardiologie 1999;2:56-63

15. Szymanski FM, Grabowski M, Filipiak KJ, Karpinski G, Opolski G. Admission ST-segment elevation in lead aVR as the factor improving complex risk stratifi cation in acute coronary syndromes. Am J Emerg Med. 2008;26:408-412

16. Uthamalingam S, Zheng H, Leavitt BA, Pomerantsev E,Ahmado I, Gurm G, Gewirtz H. Exercise-induced ST-segment elevation in Ecg lead aVR is a usefull indicator of signifi cant left main or ostial LAD coronary artery stenosis. J Am Coll Cardiol Img. 2011; 4:176-86)

17. Egher L, GherasimD, C.Cosmin, Ginghin C. ECG stress test in... left main stenosis. Rom J Cardiol. 2012: 22(4):324-325.


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Dillemas in the use of therapeutic hypothermia after cardiac arrestDoron Zahger

Contact address:Doron Zahger, MDDepartment of Cardiology, Soroka University Medical CenterFaculty of Health Sciences, Ben Gurion University of the NegevBeer Sheva, Israel. Email: [email protected]

BACKGROUNDSudden cardiac death is a leading cause for mortality and severe disability worldwide. Survival following out of hospital cardiac arrest remains very low, in the range of 5-10%1 and many survivors are left with signifi cant neurological impairment. Most patient who die aft er out of hospital cardiac arrest die as a direct consequen-ce of the neurological insult.

Hypothermia has long been known to be associated with better outcome following drowning and was used to protect the brain during cardiac and brain surgery. In 2002 two pivotal trials were published which de-monstrated the ability of mild therapeutic hypothermia (MTH) to improve survival and neurological outcome following out of hospital cardiac arrest2,3. Since then, MTH was recommended by the resuscitation guideli-nes and adopted in many centers. However, important questions remain concerning the use of this modality in real practice. Th is brief review highlights the main current dilemmas in the fi eld.

THE PIVOTAL TRIALSTh e European HACA investigators randomized 275 patients with out of hospital cardiac arrest due to ven-tricular fi brillation (VF) to either MTH or standard treatment. Cooling was achieved in hospital by means of ice packs and cooling blankets and treatment was given for 24 hours. Bernard and co workers from Aus-tralia randomized 77 survivors of out of hospital VF to MTH or standard treatment. Cooling was started pre hospital and achieved by ice packs. In both trials the experimental arm involved cooling to 32-34 degre-es. Th e HACA trial showed a signifi cant reduction in mortality and neurological disability in the MTH arm. Th e smaller Australian trial could only show improved neurological outcome. A meta analysis of the rando-

mized trials showed a signifi cant 68% increase in the rate of survival with favorable neurological outcome at hospital discharge4.

QUESTION 1: Should MTH be applied regardless of initial rhythm?

Both seminal trials which examined the role of MTH following cardiac arrest included only patients whose initial rhythm was VF. It is well documented that pati-ents with non shockable rhythms on presentation have a much worse prognosis than patients presenting in VF, probably refl ecting a longer time to initiation of resus-citation and/or more profound myocardial damage5. A number of registries examined the role of this treat-ment among patient initially presenting with non shoc-kable rhythms (asystole or pulseless electrical activity). In a large French registry Dumas et al. compared the eff ects of MTH among patients who presented with VF or with a non shockable rhythm6. Among 1145 patients admitted aft er out of hospital cardiac arrest 457 recei-ved MTH aft er an initial shockable rhythm. Of those, 44% had a favorable neurological outcome compared to just 15% of patients who received MTH aft er pre-senting with a non shockable rhythm. In a multivariate analysis MTH predicted better outcome only among patients presenting with a shockable rhythm but see-med ineff ective among others. Sandroni al performed a meta analysis of all studies which examined the eff ect of MTH aft er non VT/VF cardiac arrest7. Th eir results showed a very small, but signifi cant benefi t of treatment in this population. However, the quality of the data was very poor and was based mostly on observational data.

In summary: MTH does not seem harmful in pa-tients who initially presented with a non shockable rhythm. Th e prognosis of these patients is very poor

1 Soroka University Medical Center Faculty of Health Sciences, Ben Gurion University of the Negev


Doron ZahgerDillemas in the use of therapeutic hypothermia after cardiac arrest

and might be improved very slightly with MTH. Until larger randomized trials are available the decision re-garding MTH should be individualized based on all re-levant factors such as the patients age, time to initiation of CPR, time to return of spontaneous circulation and neurological status on admission. Current guidelines provide similar recommendations.

QUESTION 2: Should MTH be started pre hospital?

As mentioned above, the Australian study used pre hospital cooling while in the European trial cooling was initiated in the Emergency Department. Pre hos-pital cooling is logistically challenging but animal data suggest earlier cooling may improve outcome. Wolff et al.8 examined the relation between time to achieve-ment of target temperature and outcome and showed that neurological outcomes were better among those patients in whom target temperatures were achieved faster. Bernard and co-workers randomized 234 pati-ents aft er cardiac arrest to pre hospital or in hospital cooling9. Neurological outcomes did not diff er signi-fi cantly between groups. Similarly, a meta analysis of all studies available until 2013 failed to show an eff ect of pre hospital cooling on survival aft er cardiac arrest as compared to in hospital cooling10. Finally, Kim et al randomized 1364 survivors of out of hospital cardiac arrest to pre hospital or in hospital cooling and could not demonstrate any benefi cial eff ect of the earlier in-tervention, even though core temperature was reduced earlier in the intervention group11.

In summary: there is no justifi cation to routinely ini-tiate MTH in the pre hospital cooling, especially con-sidering the substantial logistical diffi culties involved. Whether such intervention might be justifi ed when evacuation times are very prolonged remains to be de-termined.

QUESTION 3: What should the target temperature be?

Th e initial trials of MTH compared cooling to 32-34 degrees Celsius to no cooling. More recently, the Tar-geted Temperature Management trial randomized 939 patient aft er out of hospital cardiac arrest to receive ei-ther cooling to 32-34 degrees or to a milder form of temperature control of 36 degrees12. To the surprise of many, despite the achieved diff erence in body tempera-ture according to the protocol no signifi cant diff erences were found in survival or neurological outcome betwe-en groups. Th e reasons for this surprising fi nding are incompletely understood. First, it is important to realize

that the experimental arm in this study included a mild form of temperature control and is not the equivalent of no cooling. Conceivably, it might be more important to prevent hyperthermia, which is common aft er car-diac arrest, than to induce hypothermia. Another im-portant might be the fact that in this study the median time to initiation of bystander CPR was only 1 minute. Th is very fast response might have resulted in a gene-rally better neurological outcome and it might therefo-re have been harder to show an eff ect of hypothermia. However, the time to return of spontaneous circulation in this trial was about 25 minutes, similar to the initial studies of MTH. Furthermore, this study of 939 patients is much larger than all previous studies combined and its results appear robust. Following this study ILCOR has issued a statement that until more thorough review of the data is performed clinicians should adhere to the previous recommendation (i.e. cooling to 32-34 degre-es) but the committee recognized that some clinicians may choose to follow the milder form of temperature controlled suggested by this trial.

In summary: Th e results of the TTM trial justify using a milder protocol of hypothermia, as done in this trial. Whether patients with longer delays to initiation of bystander CPR might benefi t from more profound cooling remains to be seen.

SUMMARYTh e key to improve survival aft er out of hospital car-diac arrest is rapid CPR and defi brillation. MTH has an important role in minimizing neurological outco-mes and improving survival. Cooling should be star-ted in comatose patients initially presenting with VF or pulseless VT while the benefi t among patients with an initially non shockable rhythm is questionable. MTH should generally be instituted in hospital. Good evi-dence supports a target temperature of 36 degrees as done in the TTM trial. Ongoing trials are expected to clarify further these critical questions in the application of MTH aft er cardiac arrest.

Confl ict of interest: none declaredReferences1. Berdowski J, Berg RA, Tijssen JG, Koster RW. Global incidences of

out-of-hospital cardiac arrest and survival rates: Systematic review of 67 prospective studies. Resuscitation. 2010 Nov;81(11):1479-87

2. Th e Hypothermia aft er Cardiac Arrest Study Group. Mild Th erapeu-tic Hypothermia to Improve the Neurologic Outcome aft er Cardiac Arrest. N Engl J Med 2002; 346:549-556.

3. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia. N Engl J Med 2002; 346: 557-563.

Doron ZahgerDillemas in the use of therapeutic hypothermia after cardiac arrest


4. Holzer M, Bernard SA, Hachimi-Idrissi S, Roine RO, Sterz F, Mllner M; Collaborative Group on Induced Hypothermia for Neuroprotec-tion Aft er Cardiac Arrest. Hypothermia for neuroprotection aft er cardiac arrest: systematic review and individual patient data meta-analysis. Crit Care Med. 2005 ;33(2):414-8.

5. Holmgren C1, Bergfeldt L, Edvardsson N, Karlsson T, Lindqvist J, Silfverstolpe J, Svensson L, Herlitz J. Analysis of initial rhythm, wit-nessed status and delay to treatment among survivors of out-of-hos-pital cardiac arrest in Sweden. Heart. 2010 Nov;96(22):1826-30.

6. Dumas F, Grimaldi D, Zuber B, Fichet J, Charpentier J, Pne F, Vivien B, Varenne O, Carli P, Jouven X, Empana JP, Cariou A. Is hypother-mia aft er cardiac arrest eff ective in both shockable and nonshockable patients?: insights from a large registry. Circulation. 2011 Mar 1;123 (8):877-86.

7. Sandroni C, Cavallaro F, Antonelli M. Th erapeutic hypothermia: is it eff ective for non-VF/VT cardiac arrest? Crit Care. 2013 Mar 19;17(2): 215.

8. Wolff B, Machill K, Schumacher D, Schulzki I, Werner D. Early achie-vement of mild therapeutic hypothermia and the neurologic outcome aft er cardiac arrest. Int J Cardiol. 2009 Apr 3;133(2):223-8

9. Bernard SA, Smith K, Cameron P, Masci K, Taylor DM, Cooper DJ, Kelly AM, Silvester W; Rapid Infusion of Cold Hartmanns (RICH)

Investigators. Induction of therapeutic hypothermia by paramedics aft er resuscitation from out-of-hospital ventricular fi brillation car-diac arrest: a randomized controlled trial. Circulation. 2010 Aug 17; 122(7):737-42.

10. Diao M, Huang F, Guan J, Zhang Z, Xiao Y, Shan Y, Lin Z, Ding L. Prehospital therapeutic hypothermia aft er cardiac arrest: a systematic review and meta-analysis of randomized controlled trials. Resuscita-tion. 2013 Aug;84(8):1021-8

11. Kim F, Nichol G, Maynard C, Hallstrom A, Kudenchuk PJ, Rea T, Co-pass MK, Carlbom D, Deem S, Longstreth WT Jr, Olsufk a M, Cobb LA. Eff ect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomi-zed clinical trial. JAMA. 2014 Jan 1;311(1):45-52.

12. Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, Pellis T, Stammet P, Wanscher M, Wise MP, neman A, Al-Subaie N, Boesgaard S, Bro-Jeppesen J, Brunetti I, Bugge JF, Hingston CD, Juff ermans NP, Ko-opmans M, Kber L, Langrgen J, Lilja G, Mller JE, Rundgren M, Rylander C, Smid O, Werer C, Winkel P, Friberg H; TTM Trial Inves-tigators. Targeted temperature management at 33C versus 36C aft er cardiac arrest. N Engl J Med. 2013 Dec 5;369(23):2197-206.


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Cardiac dysfunction of antineoplastic agents in breast cancer patients Anca-Maria Popar-Voica1,2, Andreea Clin1,2, Bogdan Alexandru Popescu1,2, Ana Maria Mitric3,Rodica Anghel1,3, Ruxandra Jurcu1,2, Carmen Ginghin1,2

Abstract: Cancer Th erapeuticsRelated Cardiac Dysfunction (CTRCD) has become one of the main causes of morbidity and mortality in cancer survivors. If CTRCD is detected early, prompt administration of cardioprotective treatment may slow the progression of left ventricular (LV) dysfunction and improve the prognosis. Th us, the management of patients with CTRCD should focus on early detection and prompt treatment. LV ejection fraction (EF) assessment by 2D TTE has a low sensitivity in detecting CTRCD at an early stage. Th ere is much interest in the use of myocardial deformation parameters measured by tissue Doppler imaging or speckle tracking echocardiography to identify early myocardial injury and to anticipate ventricular dysfunction in patients receiving chemotherapy. Peak systolic global longitudinal strain (GLS) could be the most consistent parameter that correlates with the subsequent development of CTRCD. Serial monitoring of GLS seems the ideal strategy for the detection of subclinical LV dysfunction. A relative percentage reduction in GLS of >15% is very likely to be abnormal, whereas a change of 15% este foarte probabil s fi e anormal, n timp ce o reducere

Anca-Maria Popara-Voica et al.Cardiac dysfunction of antineoplastic agents in breast cancer patients


lity in breast cancer survivors6. In patients with symp-tomatic heart failure (HF) from cancer treatment, the mortality rate has been reported to be as high as 60% at two years7,8. Th erefore, cardiotoxicity induced by can-cer therapy has become a matter of great concern and the subject of many research eff orts.

Cardiac toxicity induced by chemotherapy includes a broad spectrum of manifestations that range from car-diac dysfunction and HF to arterial hypertension, myo-cardial ischemia, thromboembolic events, arrhythmia and QT interval prolongation. Th is is why the National Cancer Institute refers to cardiotoxicity caused by anti-neoplastic agents in a general manner, as toxicity that aff ects the heart9. However, the term cardiotoxicity is usually used in reference to cardiac dysfunction and symptomatic HF, which are the most severe and best studied cardiac side eff ects of chemotherapy. An Expert Consensus Statement, endorsed by the American Soci-ety of Echocardiography and the European Association of Cardiovascular Imaging, was recently published and a more precise term, Cancer Th erapeutics-Related Car-diac Dysfunction (CTRCD) was introduced10, cardio-toxicity remaining a broader term.

Defi nition of CTRCDSince the early 60s, when cardiac dysfunction induced by anthracyclines was fi rst reported, several defi nitions have been proposed, but a consensus defi nition lacked for many years11. Back then, the diagnosis was based on the presence of signs and symptoms of HF or the evidence of ultrastructural abnormalities on endomyo-cardial biopsies. Later, left ventricular ejection fraction (LVEF) became the most used parameter for the dia-gnosis of cardiac dysfunction but with no clear cutoff values, which generated many diffi culties with respect to diagnosis, monitoring and treatment-related decisi-ons. Th e recently published Expert Consensus Stateme-nt fi nally provides a standardised defi nition of cardiac dysfunction induced by chemotherapy10. Cancer thera-peutics-related cardiac dysfunction (CTRCD) is defi -ned as a decrease in the left ventricular ejection frac-tion of >10%, to a value 5% below the baseline value10

Irreversible: improvement in LVEF by 5% below the ba-seline value10

Indeterminate: re-evaluation of patient not possi-ble10.

Types of CTRCDAmongst the various antineoplastic agents with poten-tial cardiac toxicity, anthracyclines (including doxoru-bicin, epirubicin and idarubicin) and trastuzumab, have been most commonly implicated and best studied in breast cancer patients. Th e combined therapy, using agents from both these classes, generally increases the incidence of CTRCD12-14.

Based on their potential to cause irreversible versus reversible damage to the cardiovascular system, Ewer et al. have proposed a classifi cation of anticancer agents, with anthracyclines being classifi ed as type I and tras-tuzumab as type II15. Th is classifi cation has extended into distinguishing two diff erent types of cardiotoxi-city16 in the larger acception of the term, and, by defa-ult, two types of CTRCD10.

Type I cardiotoxicity is related to the classic che-motherapy agents (anthracyclines, mitoxantrone, al-ky lating agents, antimicrotubule agents, antimetabo li-tes) and has as prototype the toxicity induced by an th-racyclines16-18. Type I chemotherapy agents are, usually, cytotoxic, inducing cell loss (necrosis/apoptosis) which leads to progressive and largely irreversible cardiovas-cular damage associated with increased rates of cardi-ovascular mortality16-18. It was shown that these agents induce ultrastructural damage (vacuoles, myofi brillar di sarray and dropout, necrosis) on endomyocardial biopsies and also release of myocardial injury markers (troponins), as consequence of myocyte damage and loss8,10,16,19. Moreover, there is a defi nite relation betwe-en the cumulative dose of anthracyclines and the inci-dence of cardiac dysfunction, as described fi rst by Von Hoff et al.8 and later, providing more accurate data, by Swain

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