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Left Ventricular Lead Position and Nonspecific Conduction Delay Are Predictors of Mortality in Patients During Cardiac Resynchronization Therapy
Canadian Journal of Cardiology 27 (2011) 363–368
Clinical Research
Left Ventricular Lead Position and Nonspecific Conduction Delay Are Predictors of Mortality in Patients During Cardiac Resynchronization Therapy Dirk Prochnau, MD, Helmut Kuehnert, MD, Matthias Heinke, PhD, Hans R. Figulla, MD, and Ralf Surber, MD Department of Internal Medicine I, Friedrich Schiller University, Jena, Germany
ABSTRACT
RÉSUMÉ
Background: Cardiac resynchronization therapy (CRT) is an established treatment of severe systolic heart failure with intraventricular conduction delay. The influence on mortality of the left ventricular (LV) pacing site and the type of bundle-branch block during CRT is unclear. Objectives: This study investigates the clinical significance of LV lead position, as well as nonspecific conduction delay, in CRT. Methods: 143 consecutive patients (mean age, 63.9 ⫾ 8.9 years; 121 men) underwent implantation of a CRT device according to established criteria. At the time of implantation, the LV lead position and the type of bundle-branch block were recorded. The etiology of the heart failure was ischemic in 49 patients (34.3%) and nonischemic in 94 patients (65.7%). Results: After a median follow-up of 19 months, 39 patients (27.3%) died, most of them (72%) of cardiovascular causes. The mortality was significantly higher in patients with an anterior or anterolateral LV lead position (P ⫽ 0.03). Multivariate analysis suggests that an anterior or anterolateral LV lead position, a nonspecific conduction delay, male sex, and a New York Heart Association functional class worse than III, are all independent predictors of mortality during the follow-up period. Conclusion: LV lead position and nonspecific conduction delay are predictors of mortality in patients during cardiac resynchronization therapy.
Introduction : La thérapie de resynchronisation cardiaque (TRC) est un traitement établi pour l’insuffisance cardiaque systolique sévère avec un délai de conduction intraventriculaire. L’influence sur la mortalité du site de stimulation ventriculaire gauche (VG) et le type de bloc de branche durant la TRC n’est pas claire. Objectifs : Cette étude examine autant la signification clinique de la position de la sonde VG que le délai de conduction non spécifique de la TRC. Méthodes : Cent quarante-trois patients consécutifs (âge moyen de 63,9 ⫾ 8,9 ans; 121 hommes) ont subi l’implantation d’un appareil de TRC selon le critère établi. Au moment de l’implantation, la position de la sonde VG et le type de bloc de branche ont été enregistrés. L’étiologie de l’insuffisance cardiaque était d’origine ischémique chez 49 patients (34,3 %) et d’origine non ischémique chez 94 patients (65,7 %). Résultats : Après un suivi moyen de 19 mois, 39 patients (27,3 %) sont morts, la plupart (72 %), de causes cardiovasculaires. La mortalité a été significativement plus élevée chez les patients avec une position antérieure et antérolatérale de la sonde VG, (P ⫽ 0,03). L’analyse multivariable suggère que la position antérieure ou antérolatérale de la sonde VG, le délai de conduction non spécifique, le sexe masculin et une classification fonctionnelle du New York Heart Association plus mauvaise que III sont tous des prédicteurs indépendants de mortalité durant la période de suivi. Conclusion : La position de la sonde VG et le délai de conduction non spécifique sont des prédicteurs de mortalité chez les patients durant la thérapie de resynchronisation cardiaque.
The prevalence of symptomatic heart failure in the general European population ranges from 0.4% to 2%.1 Despite the use of full conventional treatment, including angiotensin-converting enzyme inhibitors, -blockers, and spironolactone mortality and morbidity among patients with chronic heart
failure and reduced left ventricular (LV) ejection fraction remain high. In all, 40% of patients with a new diagnosis of heart failure die within 1 year.2 About 30% of patients with severe heart failure suffer from discoordinated ventricular contraction due to intraventricular conduction delay,3 usually resulting from a left bundle-branch block (LBBB). Prospective randomized controlled trials support the clinical efficacy and safety of cardiac resynchronization therapy (CRT) in patients with mild, moderate, or severe heart failure and ventricular dyssynchrony.4-9 Acute and short-term hemodynamic benefits of LV or biventricular pacing include decreases in filling pressures and
Received for publication October 19, 2009. Accepted June 7, 2010. Corresponding author: Dr Dirk Prochnau, Department of Internal Medicine I, Friedrich Schiller University, Erlanger Allee 101, 07747 Jena, Germany. E-mail: [email protected] See page 368 for disclosure information.
0828-282X/$ – see front matter © 2011 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.cjca.2010.12.066
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mitral regurgitation and improvements in diastolic filling and cardiac output.10 CRT makes heart failure patients feel better, improves cardiac structure and function, and reduces all-cause, as well as heart failure morbidity and mortality. Preliminary reports suggest that the LV stimulation site plays an important role in the outcome of CRT.11,12 The recommended LV lead position for CRT is at the lateral or posterolateral wall, given that these are the sites of greatest contractile delay.13,14 However, LV leads cannot always be implanted at this site. Until now only a small amount of data has been available related to clinical outcome and mortality after CRT in the case of failed implantation at the lateral or posterolateral wall. The aim of the current study was to compare the long-term outcomes in patients who had LV leads placed in different anatomic locations for biventricular pacing. Furthermore, we studied the influence of the type of preexisting bundle-branch block (BBB) on mortality rates after implantation. Methods Patients A total of 143 consecutive heart failure patients with an LV ejection fraction of 35% or less and a QRS duration ⬎ 120 milliseconds on electrocardiogram (ECG) or permanent right ventricular pacing were included in our study. Patients with a recent (⬍ 3 months previous) myocardial infarction or with revascularization-correctable coronary artery disease were ex-
Figure 2. (A) Typical left bundle-branch block. (B) QRS prolongation due to a nonspecific conduction delay.
Figure 1. Characterization of left ventricular lead position. The thick black line indicates the interventricular septum. Left anterior oblique projection. Left ventricular lead position was related to the following sectors: (1) posterior; (2) posterolateral; (3) lateral; (4) anterolateral; (5) anterior/anteroseptal.
cluded. The etiology of heart failure in the included patients was considered to be ischemia in the presence of significant coronary artery disease (⬎ 75% stenosis in 1 or more of the major epicardial coronary arteries) and/or a history of myocardial infarction or prior revascularization.15 Prior to the implant procedure, patients underwent baseline evaluations that included a study of their history, standard blood tests, New York Heart Association (NYHA) class assessment, 2-dimensional Doppler flow echocardiography, and 12-lead ECG. Clinical evaluation and device interrogation were carried out throughout the follow-up period (every 3 months). Device implantation Patients underwent implantation of a cardiac resynchronization device, along with 3 pacing leads: a standard atrial lead,
Prochnau et al. Mortality During CRT
365 Table 2. Baseline ECG characteristics
Table 1. Baseline patient characteristics Mean ⫾ SD or %
Variable Age (years) Male Ischemic cardiomyopathy NYHA classification NYHA III NYHA III-IV NYHA IV Intravenous inotropes LVEF (%) LVED (mm) Peak oxygen consumption (mL/kg/min) Peak oxygen consumption ⬍ 14 mL/kg/min or NYHA IV ACE-I or ARB -blocker Loop diuretics Spironolactone or eplerenone Digitalis Amiodarone
63.9 ⫾ 8.9 84.6% 34.3% 64.7% 21.6% 13.7% 5.8% 23.6 ⫾ 6.8 71.1 ⫾ 9.7 13.5 ⫾ 3.2 58.2% 97.1% 91.4% 97.8% 68.3% 66.9% 12.2%
ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; LVED, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.
a standard right ventricular lead, and an LV lead. A coronary sinus venogram was obtained by means of a balloon catheter, followed by the insertion of the LV pacing lead. The LV pacing lead was inserted into either the lateral or posterolateral cardiac vein whenever possible. Anterior or anterolateral sites were used only when other sites were not accessible. In the case of an unsuccessful transvenous implantation, an epimyocardial LV lead was implanted. Final lead tip position was determined by biplanar fluoroscopy (usually from posterior-anterior and 60° left anterior oblique views). In the left anterior oblique view, the LV lead position was determined by where the lead tip was located in any of the 5 sectors, as shown in Figure 1. The right atrial and ventricular leads were positioned conventionally. At 1 day after implantation, the unchanged LV lead position was
Sinus rhythm Atrial fibrillation Right ventricular pacing Type of bundle-branch block LBBB Nonspecific conduction delay RBBB PQ (ms) Intrinsic QRS (ms)
n
Mean ⫾ SD or %
85 34 20
61.2% 24.5% 14.4%
103 13 3 85 119
86.6% 10.9% 2.5% 223 ⫾ 42 176 ⫾ 30
LBBB, left bundle-branch block; RBBB, right bundle-branch block.
assessed from a chest radiograph. The final lead positions were judged by 2 independent cardiologists blinded as to the outcome of the patients. Biventricular pacemakers (Insync, Insync III from Medtronic Inc, Minneapolis, MN, USA; Contak TR or Contak TR II from Guidant Inc, St. Paul, MN, USA) were implanted in 40 patients (according to the European Society of Cardiology and German guidelines before 2005), and biventricular defibrillators (Insync III Marquis from Medtronic Inc; Contak CD or Renewal 1, Renewal 2, Renewal 4, and Renewal 4 AVT from Guidant Inc; Atlas⫹HF from St Jude Medical) were implanted in 97 patients. Electrocardiogram QRS duration (milliseconds), PR interval (milliseconds), and QTc interval (milliseconds) were measured on a 12-lead surface ECG recorded at a speed of 50 mm/s immediately before (intrinsic conduction) and after (biventricular pacing) implantation. BBB before implantation was defined according to common diagnostic criteria. Nonspecific conduction delay was defined as QRS widening without a typical BBB pattern. Examples of LBBB and nonspecific conduction delay are shown in Figure 2.
Figure 3. Enrollment and follow-up of patients in the study. CRT, cardiac resynchronization therapy; LV, left ventricular.
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Statistical analysis
Mortality
Continuous variables are expressed as mean ⫾ standard deviation. Categorical data are summarized as frequencies and percentages. Differences in baseline characteristics among patients were analyzed with either an unpaired Student t test for continuous variables or a chi-square or Fisher exact test for discrete variables, as appropriate. Event and survival curves were determined according to the Kaplan-Meier method, with comparisons of cumulative event rates by the log-rank test. To adjust for potential confounding factors in LV lead position such as age, gender, etiology, NYHA functional class, QRS duration, BBB configuration, underlying rhythm, or LV diameter, a multivariate logistic regression model was estimated. In the multivariate model, continuous covariates were categorized according to age (in 10-year steps), LV ejection fraction (in 5% steps), and QRS duration (in steps of 10 milliseconds). The multivariate analyses were also repeated without categorizing covariates. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated as an estimate of all-cause mortality. All tests of statistical significance were 2-tailed, and a P value ⬍ 0.05 was considered statistically significant. The statistical analyses were computed with SPSS (SPSS Inc, Chicago, IL, USA) statistical software.
After a median follow-up time of 19 months, 39 patients (28.4%) had died, 28 (72%) of cardiac-related causes (21 of them of pump failure, 7 of sudden cardiac death) and 11 (28%) of noncardiac causes. The Kaplan-Meier curves for all-cause mortality dependent on LV lead position and type of BBB are shown in Figure 4. The event rate was significantly lower in patients with a posterior, posterolateral, or lateral LV lead position (P ⫽ 0.036). A typical LBBB was associated with a better prognosis, compared with a nonspecific conduction delay (P ⫽ 0.033). Multivariate analysis demonstrated that the etiology of heart failure, sustained ventricular arrhythmias, and the LV ejection fraction before implantation were not predictors of mortality. In contrast, we found that an anterior or anterolateral LV lead posi-
Results Baseline characteristics Baseline characteristics of the 143 consecutive patients (mean age, 63.9 ⫾ 8.9 years; 121 men) are summarized in Table 1. Patients had severe depressed LV function, with a mean LV ejection fraction of 23.6% ⫾ 6.8%, and enlarged left ventricles, with a mean LV end diastolic diameter of 71.1 ⫾ 9.7 mm. The intrinsic QRS duration was 176 ⫾ 30 milliseconds. In those patients with intrinsic AV conduction, 86.6% had an LBBB, 2.5% a right bundle-branch block (RBBB), and 10.9% a nonspecific conduction delay. All baseline ECG parameters of patients are shown in Table 2; 90 patients were in NYHA class III, and 49 were in an NYHA class worse than III; 8 patients required catecholamines prior to implantation. The etiology of the heart failure was ischemic in 49 patients (34.3%) and nonischemic in 94 patients (65.7%). In 136 patients the LV lead was successfully implanted through the coronary sinus. Five patients received an epicardial LV pacing lead (3 acute, 2 because of phrenic nerve stimulation), and 4 patients were denied the epicardial approach and were thus excluded. A dislocation of the transvenous LV lead occurred in 4 patients. In 1 patient a dislocation occurred after 1 day, and in the 3 other patients, the dislocation occurred after 1, 3, and 8 months, respectively. In all these cases, a revision was performed successfully. In the analysis of mortality, 137 of the 143 patients were included for analysis (excluding the 4 patients who were denied epicardial implantation and 2 who were in NYHA class III at baseline and were lost to follow-up). The disposition of subjects is presented in Figure 3. In the analyzed patients, 115 (84%) had a LV lead implanted in a lateral, posterolateral, or posterior region, and 22 (16%) had the LV lead implanted in an anterior or anterolateral region.
Figure 4. Kaplan-Meier curves for all-cause mortality depending on (A) left ventricular lead position (solid line, posterior-to-lateral lead position; dotted line, anterolateral and anterior lead position) and (B) type of bundle-branch block (solid line, left bundle-branch block; dotted line, nonspecific conduction delay).
Prochnau et al. Mortality During CRT
Figure 5. Hazard ratios (multivariate model) for all-cause mortality during cardiac resynchronization therapy. An anterior or anterolateral LV lead position, male sex, a nonspecific conduction delay, and a functional class worse than NYHA class III were independent predictors of a higher mortality, whereas an ICD-backup was associated with a better prognosis. ICD, implantable cardioverter-defibrillator; LV, left ventricular; NYHA, New York Heart Association; VT/VF, ventricular tachycardia/ventricular fibrillation.
tion (OR 3.3; 95% CI, 1.1-10.2), male sex (OR 5.6; 95% CI, 1.1-29.5), a nonspecific conduction delay (OR 5.5; 95% CI, 1.323.9), and an NYHA functional class worse than III (OR 4.2; 95% CI, 1.6-10.6) were independent predictors of mortality (Fig. 5). However, a resynchronization device with an implantable cardioverter-defibrillator backup led to a lower mortality (OR 0.3; 95% CI, 0.1-0.9) during CRT. Discussion The results of our study support the importance of the LV lead position in CRT. We found that an anterior or anterolateral position of the LV lead was associated with higher mortality during long-term follow-up. Furthermore, a nonspecific conduction delay was associated with a worse prognosis. Intraventricular conduction defects occur in up to 50% of patients with heart failure, leading to ventricular dyssynchrony with hemodynamic embarrassment.16 Although dyssynchrony is not found in all patients with intraventricular delays, it tends to increase with the severity of the conduction defect. In fact, mortality rates increase with QRS width.17,18 CRT has been shown to improve functional status, especially in patients with intraventricular conduction defects of the left bundle-branch type and advanced heart failure.19,20 Until now clinical trials examining mortality after CRT did not distinguish among the different types of BBB (the Cardiac Resynchronization in Heart Failure trial used a QRS duration ⬎ 120 milliseconds as a marker of cardiac dyssynchrony)21,22 or distinguished only between LBBB and other conduction delays (The Comparison of Medical Therapy, Pacing,
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and Defibrillation in Heart Failure [COMPANION] trial).8 Subgroup analysis of mortality rates in patients with BBB other than LBBB (22% of all patients in the COMPANION trial) did not reveal any differences between CRT and the conventional therapy group.8 However, we found by multivariate analysis that a nonspecific conduction delay was associated with a 5.5-fold increase in mortality. The pathophysiological reason for the increased mortality could be that the nonspecific conduction delay is caused by severe damage of the cardiac tissue and fibrosis, leading to a globally slow conduction outside the specific conduction system, either in the scar tissue (in patients with previous myocardial infarction) or in the poorly conducting myocardium (in patients with nonischemic chronic heart failure). This condition might lead to CRT’s having a reduced effect. However, in our opinion it is not possible to conclude that CRT has no beneficial effect in such patients, since the prognosis in patients with a nonspecific conduction delay might be even worse without CRT. Biventricular pacing can produce acute improvements in symptoms, hemodynamic measures, and echocardiographic parameters.4 It was shown that CRT with LV free-wall stimulation is linked to significantly better LV systolic performance, compared with anterior stimulation. LV and biventricular stimulation of free-wall sites yielded a significantly larger change in LV pressure (dP/dt)max and pulse pressure compared with anterior sites.23 However, a few studies showed no differences in long-term follow-up between patients with an LV lead in the anterior vs a posterolateral position.24-26 Rossillo and coworkers27 reported that placement of the LV lead in the lateral and posterolateral branches was associated with a significant improvement in functional capacity and a greater improvement in LV function, compared with the anterior LV lead location. This effect was not combined with a reduction in mortality. A recently published retrospective study analyzing the event-driven outcomes of mortality and hospitalization in patients enrolled in the COMPANION study found that LV lead position did not influence all-cause mortality, all-cause hospitalization, or heart failure hospitalization.28 In contrast, we found that an anterior or anterolateral position of the LV lead was associated with higher mortality, compared with a posterior or posterolateral position of the LV lead. Our results were significant in both univariate and multivariate analysis. The differences in mortality rates might be caused by the different study populations. In our study the etiology of chronic heart failure was ischemic in only 35% of cases, vs 61% in the study by Rossillo and coworkers27 and 59% in the COMPANION study.8 It has been shown that an ischemic etiology of heart failure is an independent predictor of cardiovascular mortality and hospitalization after CRT.29 Pacing the left ventricle in nonviable or scarred myocardium can result in less effective or even ineffective LV pacing. The consequence might be a failure of LV resynchronization with no response to CRT, even if extensive LV dyssynchrony exists.30 In patients with idiopathic dilated cardiomyopathy, localized scar tissue may be a lesser issue. However, it is important to realize that LV lead positioning may be limited by anatomic and technical factors, including the presence, accessibility, and lead stability within the appropriate region of the appropriate vein. The precise incidence of suitable veins for CRT is not known and may differ between patients with ischemic and nonischemic cardiomyopathy.31 When the suitable veins are not in the lateral or posterolateral region, surgical LV lead positioning may be considered, with the use of limited left lateral thoracotomy with
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direct epicardial LV lead placement32 to overcome the disadvantages of an anterior or anterolateral lead position.
15. Felker GM, Shaw LK, O’Connor CM. A standardized definition of ischemic cardiomyopathy for use in clinical research. J Am Coll Cardiol 2002; 39:210-8.
Acknowledgement We would like to thank Dr Charles Cranfield (University of Jena) for his careful reading of the manuscript.
16. Grines CL, Bashore TM, Boudoulas H, Olson S, Shafer P, Wooley CF. Functional abnormalities in isolated left bundle branch block: the effect of interventricular asynchrony. Circulation 1989;79:845-53.
Disclosures Dr Prochnau received lecture fees from Boston Scientific Corporation. Dr Surber received lecture fees from Boston Scientific Corporation and St. Jude Medical. Drs Kuehnert, Heinke, and Figulla have no conflicts of interest to disclose. References 1. Cowie MR, Struthers AD, Wood DA, et al. Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet 1997;350:1349-53. 2. Cowie MR, Wood DA, Coats AJ, et al. Survival of patients with a new diagnosis of heart failure: a population based study. Heart 2000;83:505-10. 3. Cazeau S, Ritter P, Lazarus A, et al. Multisite pacing for end-stage heart failure: early experience. Pacing Clin Electrophysiol 1996;19:1748-57. 4. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845-53. 5. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361:1329-38. 6. Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344:873-80. 7. Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA 2003;289:2685-94. 8. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140-50. 9. Auricchio A, Stellbrink C, Butter C, et al. Clinical efficacy of cardiac resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of ventricular conduction delay. J Am Coll Cardiol 2003;42:2109-16. 10. Auricchio A, Stellbrink C, Block M, et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. The Pacing Therapies for Congestive Heart Failure Study Group. The Guidant Congestive Heart Failure Research Group. Circulation 1999;99:2993-3001.
17. Aaronson KD, Schwartz JS, Chen TM, Wong KL, Goin JE, Mancini DM. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997;95:2660-7. 18. Shamim W, Francis DP, Yousufuddin M, et al. Intraventricular conduction delay: a prognostic marker in chronic heart failure. Int J Cardiol 1999;70:171-8. 19. Nelson GS, Berger RD, Fetics BJ, et al. Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block. Circulation 2000;102:3053-9. 20. Bradley DJ, Bradley EA, Baughman KL, et al. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials. JAMA 2003;289:730-40. 21. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539-49. 22. Cleland JG, Daubert JC, Erdmann E, et al. Baseline characteristics of patients recruited into the CARE-HF study. Eur J Heart Fail 2005;7: 205-14. 23. Butter C, Auricchio A, Stellbrink C, et al. Effect of resynchronization therapy stimulation site on the systolic function of heart failure patients. Circulation 2001;104:3026-9. 24. Gasparini M, Mantica M, Galimberti P, et al. Is the left ventricular lateral wall the best lead implantation site for cardiac resynchronization therapy? Pacing Clin Electrophysiol 2003;26:162-8. 25. Gold MR, Auricchio A, Hummel JD, et al. Comparison of stimulation sites within left ventricular veins on the acute hemodynamic effects of cardiac resynchronization therapy. Heart Rhythm 2005;2:376-81. 26. Lane RE, Chow AW, Mayet J, et al. The interaction of interventricular pacing intervals and left ventricular lead position during temporary biventricular pacing evaluated by tissue Doppler imaging. Heart 2007;93:1426-32. 27. Rossillo A, Verma A, Saad EB, et al. Impact of coronary sinus lead position on biventricular pacing: mortality and echocardiographic evaluation during long-term follow-up. J Cardiovasc Electrophysiol 2004;15:1120-5. 28. Saxon LA, Olshansky B, Volosin K, et al. Influence of left ventricular lead location on outcomes in the COMPANION study. J Cardiovasc Electrophysiol 2009;20:764-8.
11. Auricchio A, Klein H, Tockman B, et al. Transvenous biventricular pacing for heart failure: can the obstacles be overcome? Am J Cardiol 1999; 83:136D-42D.
29. Zhang Q, Fung JW, Chan JY, et al. Difference in long-term clinical outcome after cardiac resynchronisation therapy between ischaemic and non-ischaemic aetiologies of heart failure. Heart 2009;95:113-8.
12. Pappone C, Rosanio S, Oreto G, et al. Cardiac pacing in heart failure patients with left bundle branch block: impact of pacing site for optimizing left ventricular resynchronization. Ital Heart J 2000;1:464-9.
30. Bleeker GB, Kaandorp TA, Lamb HJ, et al. Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy. Circulation 2006;113:969-76.
13. Aranda JM Jr, Schofield RS, Leach D, Conti JB, Hill JA, Curtis AB. Ventricular dyssynchrony in dilated cardiomyopathy: the role of biventricular pacing in the treatment of congestive heart failure. Clin Cardiol 2002;25:357-62.
31. Van de Veire NR, Schuijf JD, De Sutter J, et al. Non-invasive visualization of the cardiac venous system in coronary artery disease patients using 64-slice computed tomography. J Am Coll Cardiol 2006;48:1832-8.
14. Ypenburg C, van Bommel RJ, Delgado V, et al. Optimal left ventricular lead position predicts reverse remodeling and survival after cardiac resynchronization therapy. J Am Coll Cardiol 2008;52:1402-9.
32. KoosR,SinhaAM,MarkusK,etal.Comparisonofleftventricularleadplacement via the coronary venous approach versus lateral thoracotomy in patients receiving cardiac resynchronization therapy. Am J Cardiol 2004;94:59-63.
Clinical Research
Left Ventricular Lead Position and Nonspecific Conduction Delay Are Predictors of Mortality in Patients During Cardiac Resynchronization Therapy Dirk Prochnau, MD, Helmut Kuehnert, MD, Matthias Heinke, PhD, Hans R. Figulla, MD, and Ralf Surber, MD Department of Internal Medicine I, Friedrich Schiller University, Jena, Germany
ABSTRACT
RÉSUMÉ
Background: Cardiac resynchronization therapy (CRT) is an established treatment of severe systolic heart failure with intraventricular conduction delay. The influence on mortality of the left ventricular (LV) pacing site and the type of bundle-branch block during CRT is unclear. Objectives: This study investigates the clinical significance of LV lead position, as well as nonspecific conduction delay, in CRT. Methods: 143 consecutive patients (mean age, 63.9 ⫾ 8.9 years; 121 men) underwent implantation of a CRT device according to established criteria. At the time of implantation, the LV lead position and the type of bundle-branch block were recorded. The etiology of the heart failure was ischemic in 49 patients (34.3%) and nonischemic in 94 patients (65.7%). Results: After a median follow-up of 19 months, 39 patients (27.3%) died, most of them (72%) of cardiovascular causes. The mortality was significantly higher in patients with an anterior or anterolateral LV lead position (P ⫽ 0.03). Multivariate analysis suggests that an anterior or anterolateral LV lead position, a nonspecific conduction delay, male sex, and a New York Heart Association functional class worse than III, are all independent predictors of mortality during the follow-up period. Conclusion: LV lead position and nonspecific conduction delay are predictors of mortality in patients during cardiac resynchronization therapy.
Introduction : La thérapie de resynchronisation cardiaque (TRC) est un traitement établi pour l’insuffisance cardiaque systolique sévère avec un délai de conduction intraventriculaire. L’influence sur la mortalité du site de stimulation ventriculaire gauche (VG) et le type de bloc de branche durant la TRC n’est pas claire. Objectifs : Cette étude examine autant la signification clinique de la position de la sonde VG que le délai de conduction non spécifique de la TRC. Méthodes : Cent quarante-trois patients consécutifs (âge moyen de 63,9 ⫾ 8,9 ans; 121 hommes) ont subi l’implantation d’un appareil de TRC selon le critère établi. Au moment de l’implantation, la position de la sonde VG et le type de bloc de branche ont été enregistrés. L’étiologie de l’insuffisance cardiaque était d’origine ischémique chez 49 patients (34,3 %) et d’origine non ischémique chez 94 patients (65,7 %). Résultats : Après un suivi moyen de 19 mois, 39 patients (27,3 %) sont morts, la plupart (72 %), de causes cardiovasculaires. La mortalité a été significativement plus élevée chez les patients avec une position antérieure et antérolatérale de la sonde VG, (P ⫽ 0,03). L’analyse multivariable suggère que la position antérieure ou antérolatérale de la sonde VG, le délai de conduction non spécifique, le sexe masculin et une classification fonctionnelle du New York Heart Association plus mauvaise que III sont tous des prédicteurs indépendants de mortalité durant la période de suivi. Conclusion : La position de la sonde VG et le délai de conduction non spécifique sont des prédicteurs de mortalité chez les patients durant la thérapie de resynchronisation cardiaque.
The prevalence of symptomatic heart failure in the general European population ranges from 0.4% to 2%.1 Despite the use of full conventional treatment, including angiotensin-converting enzyme inhibitors, -blockers, and spironolactone mortality and morbidity among patients with chronic heart
failure and reduced left ventricular (LV) ejection fraction remain high. In all, 40% of patients with a new diagnosis of heart failure die within 1 year.2 About 30% of patients with severe heart failure suffer from discoordinated ventricular contraction due to intraventricular conduction delay,3 usually resulting from a left bundle-branch block (LBBB). Prospective randomized controlled trials support the clinical efficacy and safety of cardiac resynchronization therapy (CRT) in patients with mild, moderate, or severe heart failure and ventricular dyssynchrony.4-9 Acute and short-term hemodynamic benefits of LV or biventricular pacing include decreases in filling pressures and
Received for publication October 19, 2009. Accepted June 7, 2010. Corresponding author: Dr Dirk Prochnau, Department of Internal Medicine I, Friedrich Schiller University, Erlanger Allee 101, 07747 Jena, Germany. E-mail: [email protected] See page 368 for disclosure information.
0828-282X/$ – see front matter © 2011 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.cjca.2010.12.066
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mitral regurgitation and improvements in diastolic filling and cardiac output.10 CRT makes heart failure patients feel better, improves cardiac structure and function, and reduces all-cause, as well as heart failure morbidity and mortality. Preliminary reports suggest that the LV stimulation site plays an important role in the outcome of CRT.11,12 The recommended LV lead position for CRT is at the lateral or posterolateral wall, given that these are the sites of greatest contractile delay.13,14 However, LV leads cannot always be implanted at this site. Until now only a small amount of data has been available related to clinical outcome and mortality after CRT in the case of failed implantation at the lateral or posterolateral wall. The aim of the current study was to compare the long-term outcomes in patients who had LV leads placed in different anatomic locations for biventricular pacing. Furthermore, we studied the influence of the type of preexisting bundle-branch block (BBB) on mortality rates after implantation. Methods Patients A total of 143 consecutive heart failure patients with an LV ejection fraction of 35% or less and a QRS duration ⬎ 120 milliseconds on electrocardiogram (ECG) or permanent right ventricular pacing were included in our study. Patients with a recent (⬍ 3 months previous) myocardial infarction or with revascularization-correctable coronary artery disease were ex-
Figure 2. (A) Typical left bundle-branch block. (B) QRS prolongation due to a nonspecific conduction delay.
Figure 1. Characterization of left ventricular lead position. The thick black line indicates the interventricular septum. Left anterior oblique projection. Left ventricular lead position was related to the following sectors: (1) posterior; (2) posterolateral; (3) lateral; (4) anterolateral; (5) anterior/anteroseptal.
cluded. The etiology of heart failure in the included patients was considered to be ischemia in the presence of significant coronary artery disease (⬎ 75% stenosis in 1 or more of the major epicardial coronary arteries) and/or a history of myocardial infarction or prior revascularization.15 Prior to the implant procedure, patients underwent baseline evaluations that included a study of their history, standard blood tests, New York Heart Association (NYHA) class assessment, 2-dimensional Doppler flow echocardiography, and 12-lead ECG. Clinical evaluation and device interrogation were carried out throughout the follow-up period (every 3 months). Device implantation Patients underwent implantation of a cardiac resynchronization device, along with 3 pacing leads: a standard atrial lead,
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365 Table 2. Baseline ECG characteristics
Table 1. Baseline patient characteristics Mean ⫾ SD or %
Variable Age (years) Male Ischemic cardiomyopathy NYHA classification NYHA III NYHA III-IV NYHA IV Intravenous inotropes LVEF (%) LVED (mm) Peak oxygen consumption (mL/kg/min) Peak oxygen consumption ⬍ 14 mL/kg/min or NYHA IV ACE-I or ARB -blocker Loop diuretics Spironolactone or eplerenone Digitalis Amiodarone
63.9 ⫾ 8.9 84.6% 34.3% 64.7% 21.6% 13.7% 5.8% 23.6 ⫾ 6.8 71.1 ⫾ 9.7 13.5 ⫾ 3.2 58.2% 97.1% 91.4% 97.8% 68.3% 66.9% 12.2%
ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; LVED, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.
a standard right ventricular lead, and an LV lead. A coronary sinus venogram was obtained by means of a balloon catheter, followed by the insertion of the LV pacing lead. The LV pacing lead was inserted into either the lateral or posterolateral cardiac vein whenever possible. Anterior or anterolateral sites were used only when other sites were not accessible. In the case of an unsuccessful transvenous implantation, an epimyocardial LV lead was implanted. Final lead tip position was determined by biplanar fluoroscopy (usually from posterior-anterior and 60° left anterior oblique views). In the left anterior oblique view, the LV lead position was determined by where the lead tip was located in any of the 5 sectors, as shown in Figure 1. The right atrial and ventricular leads were positioned conventionally. At 1 day after implantation, the unchanged LV lead position was
Sinus rhythm Atrial fibrillation Right ventricular pacing Type of bundle-branch block LBBB Nonspecific conduction delay RBBB PQ (ms) Intrinsic QRS (ms)
n
Mean ⫾ SD or %
85 34 20
61.2% 24.5% 14.4%
103 13 3 85 119
86.6% 10.9% 2.5% 223 ⫾ 42 176 ⫾ 30
LBBB, left bundle-branch block; RBBB, right bundle-branch block.
assessed from a chest radiograph. The final lead positions were judged by 2 independent cardiologists blinded as to the outcome of the patients. Biventricular pacemakers (Insync, Insync III from Medtronic Inc, Minneapolis, MN, USA; Contak TR or Contak TR II from Guidant Inc, St. Paul, MN, USA) were implanted in 40 patients (according to the European Society of Cardiology and German guidelines before 2005), and biventricular defibrillators (Insync III Marquis from Medtronic Inc; Contak CD or Renewal 1, Renewal 2, Renewal 4, and Renewal 4 AVT from Guidant Inc; Atlas⫹HF from St Jude Medical) were implanted in 97 patients. Electrocardiogram QRS duration (milliseconds), PR interval (milliseconds), and QTc interval (milliseconds) were measured on a 12-lead surface ECG recorded at a speed of 50 mm/s immediately before (intrinsic conduction) and after (biventricular pacing) implantation. BBB before implantation was defined according to common diagnostic criteria. Nonspecific conduction delay was defined as QRS widening without a typical BBB pattern. Examples of LBBB and nonspecific conduction delay are shown in Figure 2.
Figure 3. Enrollment and follow-up of patients in the study. CRT, cardiac resynchronization therapy; LV, left ventricular.
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Statistical analysis
Mortality
Continuous variables are expressed as mean ⫾ standard deviation. Categorical data are summarized as frequencies and percentages. Differences in baseline characteristics among patients were analyzed with either an unpaired Student t test for continuous variables or a chi-square or Fisher exact test for discrete variables, as appropriate. Event and survival curves were determined according to the Kaplan-Meier method, with comparisons of cumulative event rates by the log-rank test. To adjust for potential confounding factors in LV lead position such as age, gender, etiology, NYHA functional class, QRS duration, BBB configuration, underlying rhythm, or LV diameter, a multivariate logistic regression model was estimated. In the multivariate model, continuous covariates were categorized according to age (in 10-year steps), LV ejection fraction (in 5% steps), and QRS duration (in steps of 10 milliseconds). The multivariate analyses were also repeated without categorizing covariates. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated as an estimate of all-cause mortality. All tests of statistical significance were 2-tailed, and a P value ⬍ 0.05 was considered statistically significant. The statistical analyses were computed with SPSS (SPSS Inc, Chicago, IL, USA) statistical software.
After a median follow-up time of 19 months, 39 patients (28.4%) had died, 28 (72%) of cardiac-related causes (21 of them of pump failure, 7 of sudden cardiac death) and 11 (28%) of noncardiac causes. The Kaplan-Meier curves for all-cause mortality dependent on LV lead position and type of BBB are shown in Figure 4. The event rate was significantly lower in patients with a posterior, posterolateral, or lateral LV lead position (P ⫽ 0.036). A typical LBBB was associated with a better prognosis, compared with a nonspecific conduction delay (P ⫽ 0.033). Multivariate analysis demonstrated that the etiology of heart failure, sustained ventricular arrhythmias, and the LV ejection fraction before implantation were not predictors of mortality. In contrast, we found that an anterior or anterolateral LV lead posi-
Results Baseline characteristics Baseline characteristics of the 143 consecutive patients (mean age, 63.9 ⫾ 8.9 years; 121 men) are summarized in Table 1. Patients had severe depressed LV function, with a mean LV ejection fraction of 23.6% ⫾ 6.8%, and enlarged left ventricles, with a mean LV end diastolic diameter of 71.1 ⫾ 9.7 mm. The intrinsic QRS duration was 176 ⫾ 30 milliseconds. In those patients with intrinsic AV conduction, 86.6% had an LBBB, 2.5% a right bundle-branch block (RBBB), and 10.9% a nonspecific conduction delay. All baseline ECG parameters of patients are shown in Table 2; 90 patients were in NYHA class III, and 49 were in an NYHA class worse than III; 8 patients required catecholamines prior to implantation. The etiology of the heart failure was ischemic in 49 patients (34.3%) and nonischemic in 94 patients (65.7%). In 136 patients the LV lead was successfully implanted through the coronary sinus. Five patients received an epicardial LV pacing lead (3 acute, 2 because of phrenic nerve stimulation), and 4 patients were denied the epicardial approach and were thus excluded. A dislocation of the transvenous LV lead occurred in 4 patients. In 1 patient a dislocation occurred after 1 day, and in the 3 other patients, the dislocation occurred after 1, 3, and 8 months, respectively. In all these cases, a revision was performed successfully. In the analysis of mortality, 137 of the 143 patients were included for analysis (excluding the 4 patients who were denied epicardial implantation and 2 who were in NYHA class III at baseline and were lost to follow-up). The disposition of subjects is presented in Figure 3. In the analyzed patients, 115 (84%) had a LV lead implanted in a lateral, posterolateral, or posterior region, and 22 (16%) had the LV lead implanted in an anterior or anterolateral region.
Figure 4. Kaplan-Meier curves for all-cause mortality depending on (A) left ventricular lead position (solid line, posterior-to-lateral lead position; dotted line, anterolateral and anterior lead position) and (B) type of bundle-branch block (solid line, left bundle-branch block; dotted line, nonspecific conduction delay).
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Figure 5. Hazard ratios (multivariate model) for all-cause mortality during cardiac resynchronization therapy. An anterior or anterolateral LV lead position, male sex, a nonspecific conduction delay, and a functional class worse than NYHA class III were independent predictors of a higher mortality, whereas an ICD-backup was associated with a better prognosis. ICD, implantable cardioverter-defibrillator; LV, left ventricular; NYHA, New York Heart Association; VT/VF, ventricular tachycardia/ventricular fibrillation.
tion (OR 3.3; 95% CI, 1.1-10.2), male sex (OR 5.6; 95% CI, 1.1-29.5), a nonspecific conduction delay (OR 5.5; 95% CI, 1.323.9), and an NYHA functional class worse than III (OR 4.2; 95% CI, 1.6-10.6) were independent predictors of mortality (Fig. 5). However, a resynchronization device with an implantable cardioverter-defibrillator backup led to a lower mortality (OR 0.3; 95% CI, 0.1-0.9) during CRT. Discussion The results of our study support the importance of the LV lead position in CRT. We found that an anterior or anterolateral position of the LV lead was associated with higher mortality during long-term follow-up. Furthermore, a nonspecific conduction delay was associated with a worse prognosis. Intraventricular conduction defects occur in up to 50% of patients with heart failure, leading to ventricular dyssynchrony with hemodynamic embarrassment.16 Although dyssynchrony is not found in all patients with intraventricular delays, it tends to increase with the severity of the conduction defect. In fact, mortality rates increase with QRS width.17,18 CRT has been shown to improve functional status, especially in patients with intraventricular conduction defects of the left bundle-branch type and advanced heart failure.19,20 Until now clinical trials examining mortality after CRT did not distinguish among the different types of BBB (the Cardiac Resynchronization in Heart Failure trial used a QRS duration ⬎ 120 milliseconds as a marker of cardiac dyssynchrony)21,22 or distinguished only between LBBB and other conduction delays (The Comparison of Medical Therapy, Pacing,
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and Defibrillation in Heart Failure [COMPANION] trial).8 Subgroup analysis of mortality rates in patients with BBB other than LBBB (22% of all patients in the COMPANION trial) did not reveal any differences between CRT and the conventional therapy group.8 However, we found by multivariate analysis that a nonspecific conduction delay was associated with a 5.5-fold increase in mortality. The pathophysiological reason for the increased mortality could be that the nonspecific conduction delay is caused by severe damage of the cardiac tissue and fibrosis, leading to a globally slow conduction outside the specific conduction system, either in the scar tissue (in patients with previous myocardial infarction) or in the poorly conducting myocardium (in patients with nonischemic chronic heart failure). This condition might lead to CRT’s having a reduced effect. However, in our opinion it is not possible to conclude that CRT has no beneficial effect in such patients, since the prognosis in patients with a nonspecific conduction delay might be even worse without CRT. Biventricular pacing can produce acute improvements in symptoms, hemodynamic measures, and echocardiographic parameters.4 It was shown that CRT with LV free-wall stimulation is linked to significantly better LV systolic performance, compared with anterior stimulation. LV and biventricular stimulation of free-wall sites yielded a significantly larger change in LV pressure (dP/dt)max and pulse pressure compared with anterior sites.23 However, a few studies showed no differences in long-term follow-up between patients with an LV lead in the anterior vs a posterolateral position.24-26 Rossillo and coworkers27 reported that placement of the LV lead in the lateral and posterolateral branches was associated with a significant improvement in functional capacity and a greater improvement in LV function, compared with the anterior LV lead location. This effect was not combined with a reduction in mortality. A recently published retrospective study analyzing the event-driven outcomes of mortality and hospitalization in patients enrolled in the COMPANION study found that LV lead position did not influence all-cause mortality, all-cause hospitalization, or heart failure hospitalization.28 In contrast, we found that an anterior or anterolateral position of the LV lead was associated with higher mortality, compared with a posterior or posterolateral position of the LV lead. Our results were significant in both univariate and multivariate analysis. The differences in mortality rates might be caused by the different study populations. In our study the etiology of chronic heart failure was ischemic in only 35% of cases, vs 61% in the study by Rossillo and coworkers27 and 59% in the COMPANION study.8 It has been shown that an ischemic etiology of heart failure is an independent predictor of cardiovascular mortality and hospitalization after CRT.29 Pacing the left ventricle in nonviable or scarred myocardium can result in less effective or even ineffective LV pacing. The consequence might be a failure of LV resynchronization with no response to CRT, even if extensive LV dyssynchrony exists.30 In patients with idiopathic dilated cardiomyopathy, localized scar tissue may be a lesser issue. However, it is important to realize that LV lead positioning may be limited by anatomic and technical factors, including the presence, accessibility, and lead stability within the appropriate region of the appropriate vein. The precise incidence of suitable veins for CRT is not known and may differ between patients with ischemic and nonischemic cardiomyopathy.31 When the suitable veins are not in the lateral or posterolateral region, surgical LV lead positioning may be considered, with the use of limited left lateral thoracotomy with
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direct epicardial LV lead placement32 to overcome the disadvantages of an anterior or anterolateral lead position.
15. Felker GM, Shaw LK, O’Connor CM. A standardized definition of ischemic cardiomyopathy for use in clinical research. J Am Coll Cardiol 2002; 39:210-8.
Acknowledgement We would like to thank Dr Charles Cranfield (University of Jena) for his careful reading of the manuscript.
16. Grines CL, Bashore TM, Boudoulas H, Olson S, Shafer P, Wooley CF. Functional abnormalities in isolated left bundle branch block: the effect of interventricular asynchrony. Circulation 1989;79:845-53.
Disclosures Dr Prochnau received lecture fees from Boston Scientific Corporation. Dr Surber received lecture fees from Boston Scientific Corporation and St. Jude Medical. Drs Kuehnert, Heinke, and Figulla have no conflicts of interest to disclose. References 1. Cowie MR, Struthers AD, Wood DA, et al. Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet 1997;350:1349-53. 2. Cowie MR, Wood DA, Coats AJ, et al. Survival of patients with a new diagnosis of heart failure: a population based study. Heart 2000;83:505-10. 3. Cazeau S, Ritter P, Lazarus A, et al. Multisite pacing for end-stage heart failure: early experience. Pacing Clin Electrophysiol 1996;19:1748-57. 4. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845-53. 5. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361:1329-38. 6. Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344:873-80. 7. Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA 2003;289:2685-94. 8. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140-50. 9. Auricchio A, Stellbrink C, Butter C, et al. Clinical efficacy of cardiac resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of ventricular conduction delay. J Am Coll Cardiol 2003;42:2109-16. 10. Auricchio A, Stellbrink C, Block M, et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. The Pacing Therapies for Congestive Heart Failure Study Group. The Guidant Congestive Heart Failure Research Group. Circulation 1999;99:2993-3001.
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29. Zhang Q, Fung JW, Chan JY, et al. Difference in long-term clinical outcome after cardiac resynchronisation therapy between ischaemic and non-ischaemic aetiologies of heart failure. Heart 2009;95:113-8.
12. Pappone C, Rosanio S, Oreto G, et al. Cardiac pacing in heart failure patients with left bundle branch block: impact of pacing site for optimizing left ventricular resynchronization. Ital Heart J 2000;1:464-9.
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13. Aranda JM Jr, Schofield RS, Leach D, Conti JB, Hill JA, Curtis AB. Ventricular dyssynchrony in dilated cardiomyopathy: the role of biventricular pacing in the treatment of congestive heart failure. Clin Cardiol 2002;25:357-62.
31. Van de Veire NR, Schuijf JD, De Sutter J, et al. Non-invasive visualization of the cardiac venous system in coronary artery disease patients using 64-slice computed tomography. J Am Coll Cardiol 2006;48:1832-8.
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32. KoosR,SinhaAM,MarkusK,etal.Comparisonofleftventricularleadplacement via the coronary venous approach versus lateral thoracotomy in patients receiving cardiac resynchronization therapy. Am J Cardiol 2004;94:59-63.