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Severe Left Ventricular Dyssynchrony Is Associated With Poor Prognosis in Patients With Moderate Systolic Heart Failure Undergoing Coronary Artery Bypass Grafting

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Severe Left Ventricular Dyssynchrony Is Associated With Poor Prognosis in Patients With Moderate Systolic Heart Failure Undergoing Coronary Artery Bypass Grafting
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  Heart Failure  Severe Left Ventricular Dyssynchrony Is Associated With Poor Prognosis inPatients With Moderate Systolic HeartFailure Undergoing Coronary Artery Bypass Grafting  Martin Penicka, MD, P H D,* Jozef Bartunek, MD, P H D,§ Otto Lang, MD, P H D,†Karel Medilek, MD,‡ Petr Tousek, MD,* Marc Vanderheyden, MD,§ Bernard De Bruyne, MD, P H D,§Michaela Maruskova, MD,* Petr Widimsky, MD, P H D* Prague and Hradec Kralove, Czech Republic; and Aalst, Belgium Objectives  The objective of the present study was to assess the relationship between the presence of left ventricular (LV)dyssynchrony and clinical outcome in patients with moderate systolic heart failure undergoing coronary arterybypass graft (CABG) surgery. Background  The presence of LV dyssynchrony is associated with poor prognosis in patients with LV dysfunction. Methods  The study consisted of 215 consecutive patients with ischemic cardiomyopathy and dyspnea (age 65  9 years,81% male) undergoing CABG. Dyssynchrony was calculated by tissue Doppler imaging from regional time inter-vals in basal LV segments before and 1 month after CABG. Myocardial viability was assessed using single-photon emission computed tomography (SPECT) before CABG. Results  Twenty-five patients (11.6%) died within 30 days (in-hospital mortality) of CABG. The presence of pre-CABG dys-synchrony  119 ms had the highest predictive accuracy for in-hospital mortality, with a sensitivity of 84% and aspecificity of 71%. During the median follow-up period of 359 days (interquartile range 219 to 561), an addi-tional 19 patients (10.3%) died and 34 patients (18.5%) were hospitalized for worsening heart failure. At Coxregression analysis, post-CABG dyssynchrony  72 ms and  5 viable segments were identified as independentpredictors of clinical events, with a hazard ratio (HR) of 5.02, 95% confidence interval (CI) 2.57 to 10.02 (p  0.001), and an HR of 0.63, 95% CI 0.55 to 0.75 (p  0.001), respectively. Patients without post-CABG dyssyn-chrony and with viable myocardium had excellent prognosis compared with patients with severe post-CABG dys-synchrony and nonviable myocardium (event rate 3% vs. 64%; p  0.001). Conclusions  The presence of severe LV dyssynchrony is associated with poor clinical outcomes despite revascularization.These results advocate a routine assessment of both LV dyssynchrony and viability to predict outcome in systolicheart failure patients undergoing CABG surgery. (J Am Coll Cardiol 2007;50:1315–23) © 2007 by theAmerican College of Cardiology Foundation Coronary artery bypass graft (CABG) surgery improvesprognosis in patients with ischemic cardiomyopathy andangina (1–2). In contrast, in patients with left ventricular(LV) dysfunction who have dyspnea as the main symptom,the role of surgical revascularization is poorly defined (3). These patients are scarce in clinical trials, and it is contro- versial whether they benefit from revascularization. Obser- vational studies (4) have emphasized the need for detectionof myocardial viability to identify patients with reversibledysfunction, in whom survival may improve after CABGsurgery. However, a significant number of patients with alarge area of viable myocardium do not experience func-tional and prognostic improvement despite CABG surgery (5). In contrast, several studies have reported a survivalbenefit of postsurgical revascularization, irrespective of thedegree of viability (6), or recovery of left ventricular ejectionfraction (LVEF) (7). This suggests that, in patients with From the *Cardiocenter, Department of Cardiology, and †Department of NuclearMedicine, Third Faculty of Medicine, Charles University, and University HospitalKralovske Vinohrady, Prague, Czech Republic; ‡Department of Cardiosurgery,Medical Faculty, Hradec Kralove, Czech Republic; and the §Cardiovascular Center,OLV Hospital, Aalst, Belgium. Supported by grant IGA NR: 8524-5 awarded by theCzech Ministry of Health and by the Charles University Prague Research ProjectMSM 0021620817 awarded by the Czech Ministry of Education. Drs. Penicka andBartunek are consultants to Boston Scientific, St. Paul, Minnesota.Manuscript received January 16, 2007; revised manuscript received March 19, 2007accepted March 19, 2007. Journal of the American College of Cardiology Vol. 50, No. 14, 2007© 2007 by the American College of Cardiology Foundation ISSN 0735-1097/07/$32.00Published by Elsevier Inc. doi:10.1016/j.jacc.2007.03.070  heart failure, the assessment of myocardial viability alone is notaccurate enough to predict out-come after revascularization andthat other variables may be im-portant. Cardiac dyssynchrony isassociated with functional deteri-oration and poor prognosis inadvanced systolic heart failure(8–11). Correction of dyssyn-chrony with biventricular pacingimproves symptoms, LVEF, andsurvival (12). The objective of the present study was to assessthe prevalence of pre- and post-CABG LV dyssynchrony and itsrelationship to clinical outcomein patients with stable ischemic cardiomyopathy and dys-pnea as the predominant symptom. Methods Patients.  This was a prospective multicenter study. Be-tween June 2002 and December 2005, 215 consecutivepatients (age 65    9 years, 81% male) with ischemiccardiomyopathy, undergoing CABG surgery, who fulfilledthe inclusion/exclusion criteria were recruited to the study.Inclusion criteria included: 1) effort dyspnea (New York Heart Association [NYHA] functional class I, II, or III) asthe main cardiovascular symptom for at least 3 months; and2) stable LV dysfunction with LVEF    40% for at least 3months. Patients with NYHA functional class IV symptomsduring the 30-day period before CABG surgery, acutecoronary syndrome in the previous 3 months, any valvularheart disease requiring surgery, malignancy, sustained ven-tricular tachycardia, or survivors of cardiac arrest wereexcluded from the study. All patients recruited to the study had CABG surgery as the sole procedure. No patientsunderwent concomitant LV remodeling, aneurysmectomy,mitral valve repair, or Maze procedure. The study wasapproved by the ethical committee of each institution. Allpatients gave written informed consent before recruitment. Study protocol.  In the week leading up to CABG surgery,each patient underwent echocardiography and tissue Dopp-ler imaging (TDI) to assess LV volumes, LVEF, andpre-CABG LV dyssynchrony. In addition, myocardial per-fusion and glucose uptake were assessed by single-photonemission computed tomography (SPECT) using technetium-99m tetrofosmin and F18-fluorodeoxyglucose, respectively. The TDI was repeated 1 month after surgery to recordpost-CABG dyssynchrony. At 6-month follow-up, echo-cardiography was repeated to assess LV volumes and LVEF. Echocardiography and TDI.  All studies were performed with a commercially available system equipped with TDI(Vivid 7, Vingmed-General Electric, Horten, Norway). TheLV volumes and LVEF were assessed in apical 4- and2-chamber views using the biplane Simpson method. The TDI was performed in pulsed wave mode. In 3 apical views(4-, 3-, and 2-chamber), longitudinal myocardial velocities were recorded in 6 basal segments of the LV. Moreover,peak mitral annular velocities during systole (Sm) and early diastole (Em) were assessed as the mean from 4 corners of the mitral annulus (septal, lateral, anterior, and inferior).Sample volume was placed in the middle of each basalsegment. Gain and filters were adjusted to obtain an optimaltissue signal. Myocardial velocities were recorded at end-expiration at a sweep speed of 100 mm/s. All studies werestored both in digital (raw data) format and on S-VHS videotape for off-line analysis. The mean from 3 consecutivebeats was taken for each measurement. Echocardiographers were blinded to clinical follow-up data.  Assessment of LV dyssynchrony by TDI.  To assess thepre- and post-CABG LV dyssynchrony, time delay betweenthe onset of QRS complex on the surface electrocardiogramand the onset of the systolic velocity wave on the TDIrecording was assessed in each basal LV segment. Dyssyn-chrony was calculated as the difference between the shortestand the longest time delay in the 6 basal segments. Thus,LV dyssynchrony represents a delay in the onset of contrac-tion between the segment with the earliest and the segments with the latest systolic wall motion (13). Intra- and inter-observer variability for the assessment of LV dyssynchrony  were 7.1% and 8.2%, respectively.  Assessment of viability by SPECT.  In brief (5),technetium-99m tetrofosmin (600 MBq) was injected in-travenously to evaluate resting perfusion. After a light mealand administration of acipimox, F18-fluorodeoxyglucose (185 MBq) was injected intravenously to assess myo-cardial glucose uptake. Dual-isotope simultaneousimage acquisition was performed 45 min after F18- fluorodeoxyglucose injection using high-energy 511-keV collimators. A symmetrical 15% energy window waspreset on each side of the 140-keV photon peak of technetium-99m tetrofosmin and 511-keV photon peak of F18-fluorodeoxyglucose. Data were acquired over 360°and stored in a 64  64 computer matrix. The images weredisplayed as polar maps, which were normalized to maxi-mum activity (set at 100%). To assess myocardial viability,polar maps were divided into 16 segments. Segmentsshowing normal perfusion of technetium-99m tetrofosminand segments with perfusion defect but preserved or in-creased F18-fluorodeoxyglucose (perfusion-metabolismmismatch) were considered to be viable. Segments with amatch (concordantly reduced perfusion and metabolism) were considered to be nonviable. Statistical analysis.  Data are presented as mean    SD ormedian and interquartile range (IQR). Two-sided pairedand unpaired Student  t   test or Pearson correlation coeffi-cient were used as appropriate. The Fisher exact test wasused to compare categoric variables in 2    2 contingency table. In cases where the contingency table had more than 2rows or 2 columns, the chi-square test was used. Receiver- Abbreviationsand Acronyms CABG  coronary arterybypass graftEm  peak early diastolicmitral annular velocityLV  left ventricularLVEF   left ventricularejection fractionSm  peak early systolicmitral annular velocitySPECT  single-photonemission computedtomographyTDI  tissue Dopplerimaging 1316 Penicka  et al.  JACC Vol. 50, No. 14, 2007 Heart Failure, Dyssynchrony, and Prognosis After CABG  October 2, 2007:1315–23  operating characteristic (ROC) curves were constructed toassess optimal cutoff values for LV dyssynchrony and thenumber of dysfunctional viable segments required to predictclinical events. Independent predictors of death from any cause and hospitalization for worsening heart failure wereidentified using the Cox proportional hazard model andexpressed as a hazard ratio (HR) and 95% confidenceinterval (CI). Cumulative survival curves for composite of death from any cause and hospitalization for worseningheart failure were derived according to the Kaplan-Meiermethod, and differences between curves were analyzed by log-rank statistics. For all tests, p  0.05 was considered tobe significant. All analyses were conducted using SPSSsoftware (version 13, SPSS Inc., Chicago, Illinois). Results  Thirty-day outcome.  A total of 25 patients (11.6%) died within 30 days after CABG surgery. The causes of deaths were refractory heart failure in 23 patients and sepsis in 2patients. Table 1 shows baseline characteristics in the30-day survivors and nonsurvivors. Patients had on average2.5  0.8 significantly stenosed coronary arteries. Completerevascularization of all stenosed lesions was obtained in 189(88%) of patients.Patients who died within 30 days after surgery hadsignificantly greater pre-CABG LV dyssynchrony and asmaller area of viable myocardium than survivors (p   0.001) (Fig. 1). Other baseline clinical and echocardio-graphic variables, including the EuroSCORE, were similarin both groups. At ROC analysis, the presence of pre-CABG surgery dyssynchrony of   119 ms (sensitivity 84%,specificity 71%) and   5 dysfunctional viable segments(sensitivity 72%, specificity 61%), showed the highest pre-dictive accuracy for in-hospital mortality (Fig. 2). Theprevalence of severe (  119 ms) pre-CABG dyssynchrony inthe entire cohort was 36%. Twenty-one (27%) of 77 patients with severe pre-CABG dyssynchrony died compared withonly 4 (3%) of 138 patients without significant dyssyn-chrony (p  0.001, Fisher exact test). Outcome from day 31 to the end of the follow-upperiod.  Six patients (3.2%) who had an acute coronary syndrome during this follow-up period were excluded. Thus, a total of 184 patients (age 66  9 years, 84% male) who survived the first 30 days after CABG surgery enteredthe analysis. During median follow-up of 359 days (IQR 219 to 561 days), an additional 19 patients (10.3%) died and34 patients (18.5%) were hospitalized for worsening heartfailure. All of the observed deaths were cardiovascular (9 Baseline Characteristics According to 30-Day OutcomeTable 1 Baseline Characteristics According to 30-Day Outcome Nonsurvivors (n  25) Survivors (n  190) p Value Age, yrs 66  8 65  9 NSMale gender, n (%) 19 (76) 156 (82) NSDiabetes mellitus, n (%) 9 (36) 76 (40) NSPrior myocardial infarction, n (%) 15 (60) 137 (72) NSStenosed coronary arteries, n 2.4  0.8 2.5  0.8 NSACE inhibitors, n (%) 18 (72) 129 (68) NSBeta-blockers, n (%) 20 (80) 162 (85) NSLoop diuretics, n (%) 20 (80) 136 (72) NSAmiodarone, n (%) 2 (8) 10 (5) NSAngina pectoris, n (%) 13 (52) 94 (50) NSNYHA functional class 2.5  1.0 2.3  1.1 NSDuration of heart failure, yrs 1.2 (IQR 0.7–1.5) 1.0 (IQR 0.6–1.5) NSLogistic EuroSCORE (%) 9.1  13.3 8.0  16.1 NSAtrial fibrillation, n (%) 4 (16) 29 (15) NSQRS duration, ms 110  31 106  23 NSLeft bundle branch block, n (%) 3 (12) 20 (11) NSLV end-diastolic volume, ml 155  29 153  41 NSLV end-systolic volume, ml 112  35 107  36 NSLVEF, % 28  6 30  6 NSPre-CABG mitral regurgitation, n (%)None or mild 21 (84) 158 (83) NSModerate (grades 2/4 and 2   /4) 4 (16) 32 (17)Sm, cm/s 2.3  1.2 2.4  1.3 NSEm, cm/s 2.4  1.4 2.5  1.5 NSPre-CABG LV dyssynchrony, ms 186  63 79  55   0.001Severe (  119 ms) pre-CABG dyssynchrony, n (%) 21 (84) 56 (29)   0.001Dysfunctional viable segments, n (%) 3.7  1.8 5.9  3.6   0.001 ACE    angiotensin-converting enzyme; CABG    coronary artery bypass grafting; Em    peak early diastolic mitral annular velocity; IQR   interquartile range; LV  left ventricular; LVEF  left ventricular ejection fraction; NYHA  New York Heart Association; Sm  peak early systolicmitral annular velocity. 1317 JACC Vol. 50, No. 14, 2007  Penicka  et al. October 2, 2007:1315–23  Heart Failure, Dyssynchrony, and Prognosis After CABG  sudden cardiac and 10 pump failure deaths). No patient waslost to follow-up, and survival status was established in allindividuals. Table 2 shows baseline and 1-month post-CABG surgery clinical and echocardiographic characteris-tics in patients with and without clinical events. Patients with a clinical event were older than patients without anevent. In addition, patients with clinical events had smallerpost-CABG Sm and Em (p    0.05), greater pre- andpost-CABG dyssynchrony (p    0.001), and less viablemyocardium (p    0.001) than patients without clinicalevents. Other clinical variables and degree of LV remodel-ing were similar between groups. Independent predictors of death from any cause andhospitalization for worsening heart failure between day 31 to the end of the follow-up period.  The ROC curves were constructed to analyze the accuracy of the 3 baseline variables with the greatest difference between the groups topredict clinical events (Fig. 3). Post-CABG dyssynchrony, with a cut-off value of    72 ms (n    77 patients), showedthe highest accuracy to predict clinical events. The accuracy of the number of dysfunctional but viable segments (cut-off  value   5 segments [n    88 patients]) and pre-CABGdyssynchrony (cut-off value  72 ms [n  94 patients]) werelower than post-CABG dyssynchrony. In Cox regressionanalysis ( Table 3), post-CABG LV dyssynchrony    72 msand  5 dysfunctional but viable segments were identified asthe independent predictors of all-cause death and heartfailure hospitalization. Table 4 and Figure 4 show clinical outcome in 4 groups of patients divided according to thedegree of post-CABG dyssynchrony (  72 vs.  72 ms) andextent of viable myocardium (  5 viable segments vs.   5 viable segments). Patients with significant post-CABGdyssynchrony and a small extent of viable myocardium hadthe highest event rate (64%) and significantly shorterevent-free survival (p    0.001) compared with the 3 othergroups. In contrast, patients without post-CABG dyssyn-chrony and with a large extent of viable myocardium hadexcellent outcome, with an event rate of 3%, and signifi-cantly longer event-free survival (p    0.001) than theother groups. Intermediate event rates were observed inpatients without post-CABG dyssynchrony but with smallextent of viable myocardium and in patients with significantpost-CABG dyssynchrony but large extent of viablemyocardium. Figure 1 Pre-CABG Dyssynchrony and Myocardial Viability in 30-Day Survivors and Nonsurvivors Degree of the pre-CABG left ventricular dyssynchrony   (left)  and degree of viable myocardium  (right) in patients who died versus survived during the first 30 days after CABG. CABG   coronary artery bypass grafting. Figure 2 Pre-CABG Dyssynchrony,Myocardial Viability, and 30-Day Mortality Agreement between the presence (  DYS) or absence (  DYS) of severe pre-CABG left ventricular dyssynchrony (  119 ms)  (top) , the absence (  viable) orpresence (  viable) of viable myocardium (  5 viable segments)  (bottom)  andthe 30-day mortality. AUC  area under curve; CABG  coronary artery bypassgraft; DYS  dyssynchrony. 1318 Penicka  et al.  JACC Vol. 50, No. 14, 2007 Heart Failure, Dyssynchrony, and Prognosis After CABG  October 2, 2007:1315–23  Impact of surgery on LV dyssynchrony.  The prevalence of significant (  72 ms) pre- and post-CABG dyssynchrony  was 51% and 42%, respectively. The pre-CABG dyssyn-chrony correlated significantly with the post-CABG dys-synchrony (r  0.73; r 2  0.53; p  0.001). Twenty-seven(29%) of 94 patients with significant pre-CABG surgery dyssynchrony (  72 ms) showed minor dyssynchrony (  72ms) after CABG, and none of these patients experiencedany clinical events during the follow-up period. Ten (11%)of 90 patients without pre-CABG dyssynchrony developedsignificant dyssynchrony after CABG. Of note, all of thesepatients had nonviable myocardium. Relationship of post-CABG LV dyssynchrony with func-tional and clinical outcome.  Table 5 shows baseline and6-month follow-up characteristics of patients with (n  77)and without (n    107) significant (  72 ms) post-CABGdyssynchrony. The baseline clinical variables and degree of LV remodeling were similar in both groups. Patients withsignificant post-CABG dyssynchrony had a smaller extentof viable myocardium and greater pre-CABG dyssynchrony than patients without post-CABG dyssynchrony. At the6-month follow-up, patients without post-CABG dyssyn-chrony had superior functional and clinical outcome com-pared with patients with significant post-CABG dyssyn-chrony. Both groups showed a significant reduction inangina and NYHA functional class. However, greater im-provement (p    0.01) was observed in patients withoutpost-CABG dyssynchrony. The LVEF also increased inboth groups, but significantly more (p  0.001) in patients without post-CABG dyssynchrony. The LV volumes de-creased only in patients without post-CABG dyssynchrony.Post-CABG dyssynchrony showed a significant correlation with the change in both LV end-systolic volume (r  0.30;p    0.001) and LVEF (r    0.51; p    0.001) betweenbaseline and 6-month follow-up. Furthermore, a higherpercentage of patients without post-CABG dyssynchrony felt improved by surgery compared with patients withresidual post-CABG dyssynchrony (p  0.01, Fisher exact Figure 3 Accuracy of LV Dyssynchrony and MyocardialViability to Predict Long-Term Clinical Events Receiver-operating characteristic curves to predict clinical events occurring fromday 31 after CABG to the end of the follow-up period for pre- and post-CABGleft ventricular dyssynchrony and the number of dysfunctional but viable seg-ments. Sp  specificity; Ss  sensitivity; other abbreviations as in Figure 2. Baseline and 1-Month Post-CABG Characteristics in Patients With andWithout Clinical Events Between Day 31 After CABG and End of Follow-Up PeriodTable 2 Baseline and 1-Month Post-CABG Characteristics in Patients With andWithout Clinical Events Between Day 31 After CABG and End of Follow-Up Period  Clinical Event (n  53)   Clinical Event (n  131) p Value Age, yrs 69  9 62  9 0.01Male gender, n (%) 43 (81) 112 (85) NSDiabetes mellitus, n (%) 23 (43) 47 (36) NSPrior myocardial infarction, n (%) 42 (79) 95 (73) NSAngina pectoris, n (%) 28 (53) 64 (49) NSNYHA functional class 2.4  1.0 2.3  1.1 NSDuration of heart failure, yrs (IQR) 1.1 (0.7–1.4) 1.0 (0.7–1.5) NSAtrial fibrillation, n (%) 8 (15) 21 (16) NSQRS duration, ms 114  29 105  23 NSLeft bundle branch block, n (%) 10 (19) 10 (8) 0.04LV end-diastolic volume, ml 154  35 152  35 NSLV end-systolic volume, ml 110  32 108  34 NSLVEF, % 30  6 30  6 NSPost-CABG mitral regurgitation, n (%)None or mild 45 (85) 105 (80) NSModerate (grades 2/4 and 2   /4) 7 (13) 21 (16)More than moderate (grade  2   /4) 1 (2) 5 (4)Post-CABG Sm, cm/s 2.4  1.2 2.7  1.4 0.03Post-CABG Em, cm/s 2.6  1.4 3.0  1.5 0.01Pre-CABG LV dyssynchrony, ms 106  62 70  58   0.001Post-CABG LV dyssynchrony, ms 105  70 46  37*   0.001Dysfunctional viable segments, n (%) 4.1  3.3 6.6  3.4   0.001 Post-CABG indicates 1 month after CABG. *p  0.001 pre-CABG versus post-CABG dyssynchrony in patients without a clinical event.Abbreviations as in Table 1. 1319 JACC Vol. 50, No. 14, 2007  Penicka  et al. October 2, 2007:1315–23  Heart Failure, Dyssynchrony, and Prognosis After CABG

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