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Prognostic Value of a Restrictive Mitral Filling Pattern in Patients With Systolic Heart Failure and an Implantable Cardioverter-Defibrillator
Prognostic Value of a Restrictive Mitral Filling Pattern in Patients With Systolic Heart Failure and an Implantable Cardioverter-Defibrillator Christian Bruch, MD*, Michael Gotzmann, Jürgen Sindermann, MD, Günter Breithardt, MD, Thomas Wichter, MD, Dirk Böcker, MD, and Rainer Gradaus, MD In patients with chronic heart failure and reduced systolic function, an implantable cardioverter-defibrillator (ICD) improves the prognosis, but morbidity and mortality remain high. We attempted to identify the prognostic impact of Doppler echocardiography and QRS duration in such patients. We prospectively enrolled 84 patients with chronic heart failure, an ICD, and impaired systolic function (mean ejection fraction 29 ⴞ 10%). Echocardiographic measurements included left ventricular dimensions/volumes, ejection fraction, mitral E/A ratio, deceleration time, and tissue Doppler analysis of mitral annular velocities (S=, E=, A=). A cardiac event (death from pump failure or appropriate ICD therapy, i.e., antitachycardia pacing/shock due to sustained ventricular tachycardia or ventricular fibrillation) was defined as the study end point. During a follow-up of 373 ⴞ 254 days, 22 patients (26%) had an event (death from pump failure, n ⴝ 7; patients who received an appropriate ICD therapy, n ⴝ 16). In patients with an event, the QRS duration was longer (169 ⴞ 41 vs 146 ⴞ 37 ms, p ⴝ 0.023), the mitral E/E= ratio was higher (16.0 ⴞ 6.5 vs 12.8 ⴞ 5.9, p ⴝ 0.044), and a restrictive filling pattern was more frequent (44% vs 9%, p ⴝ 0.017). Stepwise multivariate Cox regression analysis identified a restrictive filling pattern as the only independent predictor of an event (hazard ratio 3.65, 95% confidence interval 1.54 to 8.64, p ⴝ 0.003). For patients with a restrictive filling pattern, the outcome was markedly poorer than that for patients with a nonrestrictive pattern (event-free survival rate 38% vs 72%, p ⴝ 0.005). In conclusion, in patients with chronic heart failure, an ICD, and systolic dysfunction, a restrictive filling pattern is an independent predictor of adverse cardiac events. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;97:676 – 680)
This prospective study was designed to assess the prognostic value of Doppler echocardiography and tissue Doppler imaging in patients with heart failure (HF) and an implantable cardioverter-defibrillator (ICD) and to compare it against traditional markers, such as New York Heart Association (NYHA) functional class, ejection fraction, and QRS duration.
Methods Study patients: The study population consisted of a consecutive series of 98 patients who were followed after receiving ICDs between 2000 and 2003 at our institution (Hospital of the University of Münster). Patients were prospectively included if they fulfilled the following criteria: a history of chronic HF according to the Framingham criteria,1 left ventricular ejection fraction ⬍45% as detected by echo-
Department of Cardiology and Angiology, Hospital of the University of Münster, Münster, Germany. Manuscript received August 6, 2005; revised manuscript received and accepted September 12, 2005. *Corresponding author: Tel: 49-251-83-47-684; fax: 49-251-83-47635. E-mail address: [email protected] (C. Bruch). 0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.09.114
cardiography, and clinical stability after ⱖ2 months on standard medical therapy. Patients with severe valvular disease (n ⫽ 5) or atrial fibrillation (n ⫽ 9) were excluded, so that 84 subjects formed the final study cohort. Of these patients, 62 (74%) received ICDs for secondary prevention and 22 (26%) for primary prevention of sudden cardiac death. All implanted devices were capable of storing intracardiac electrograms and had antitachycardia pacing capabilities in combination with cardioversion/defibrillation treatment features. All treated episodes were classified as inappropriate or appropriate by 1 experienced cardiologist (RG), who had no knowledge of the remaining clinical data. Electrocardiographic analysis: The QRS duration was measured on a 12-lead electrocardiogram using leads V3 to V6. A mean of ⱖ3 QRS complexes was used for further analysis. Left bundle branch block was diagnosed on the basis of a QRS duration ⬎120 ms, absent Q waves, and wide slurred R waves in V5 and V6, and monophasic QS or rS waves in leads V1 and V2. Echocardiography: Echocardiographic images were taken according to the guidelines of the American Society of Echocardiography.2 Peak velocities of early (E) and late www.AJConline.org
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Table 1 Clinical characteristics of study patients Total (n ⫽ 84)
Variable
Age (yrs) Men/women (%) Body surface area (m2) Ischemic/nonischemic cardiomyopathy NYHA functional class QRS duration (ms) Left bundle branch block Medication Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker Diuretics Digoxin  Blockers Class III antiarrhytmic agents
Event
p Value
Yes (n ⫽ 22)
No (n ⫽ 64)
60 ⫾ 12 80/20 1.9 ⫾ 0.2 74%/26% 2.7 ⫾ 0.5 153 ⫾ 39 31 (37%)
61 ⫾ 12 73/27 1.9 ⫾ 0.2 59%/41% 2.8 ⫾ 0.5 169 ⫾ 41 9 (41%)
60 ⫾ 12 82/18 1.9 ⫾ 0.2 68%/32% 2.7 ⫾ 0.5 146 ⫾ 31 22 (35%)
0.78 0.34 0.39 0.46 0.31 0.023 0.78
94% 91% 70% 90% 31%
91% 95% 71% 86% 30%
95% 90% 69% 92% 31%
0.48 0.44 0.83 0.46 0.93
Table 2 Echocardiographic characteristics of study patients Variable
Left atrial diameter (cm) LV diastolic diameter index (cm/m2) LV systolic diameter index (cm/m2) LV diastolic volume index (ml/m2) LV systolic volume index (ml/m2) LV ejection fraction (%) Fractional shortening (%) Puked Wave Doppler Mitral E/A ratio Deceleration time Restrictive filling pattern Tissue Doppler S= (cm/s) E= (cm/s) A= (cm/s) E/E= ratio
Total (n ⫽ 84)
Event
p Value
Yes (n ⫽ 22)
No (n ⫽ 64)
5.0 ⫾ 0.8 3.6 ⫾ 0.5 3.0 ⫾ 0.5 129 ⫾ 46 93 ⫾ 40 29 ⫾ 10 18 ⫾ 7
5.1 ⫾ 0.7 3.7 ⫾ 0.5 3.1 ⫾ 0.5 143 ⫾ 46 102 ⫾ 40 29 ⫾ 10 19 ⫾ 6
5.0 ⫾ 0.9 3.5 ⫾ 0.5 3.0 ⫾ 0.5 125 ⫾ 47 90 ⫾ 40 29 ⫾ 10 18 ⫾ 7
0.87 0.20 0.32 0.079 0.19 0.87 0.51
1.93 ⫾ 1.16 188 ⫾ 80 16 (22%)
2.25 ⫾ 1.18 173 ⫾ 68 12 (44%)
1.82 ⫾ 1.14 193 ⫾ 84 4 (9%)
0.105 0.26 0.017
4.64 ⫾ 1.12 5.85 ⫾ 1.75 6.30 ⫾ 2.35 13.6 ⫾ 6.2
4.25 ⫾ 0.93 5.43 ⫾ 1.41 6.41 ⫾ 2.99 15.9 ⫾ 6.5
4.77 ⫾ 1.16 6.00 ⫾ 1.84 6.27 ⫾ 2.13 12.8 ⫾ 5.9
0.069 0.30 0.607 0.045
LV ⫽ left ventricular.
(A) diastolic filling and deceleration time were derived from transmitral Doppler recordings. A restrictive filling pattern was defined by an E/A ratio ⬎2, a deceleration time of ⬍150 ms, and a mitral annular E= velocity of ⬍8 cm/s.3 Tissue Doppler-derived peak systolic (S=) and early (E=), and late (A=) diastolic velocities were derived from the septal and lateral mitral annulus, and averaged for each patient.4 The inter- and intraobserver correlation for conventional echocardiographic measurements and tissue Doppler variables reached 0.92 and 0.98, respectively. Outcome measurements and statistical analysis: To study the prognostic impact of Doppler echocardiography and tissue Doppler imaging in our study population, the follow-up period started at the time of the index echocardiogram. Patients were seen regularly on an outpatient basis at 3- to 6-month intervals, and the device was interrogated for treated episodes at each visit. Detailed follow-up infor-
mation was also obtained by telephone interview with the patients or their physicians. A cardiac event (death from pump failure or appropriate ICD therapy, i.e., antitachycardia pacing or shock due to sustained ventricular tachycardia or ventricular fibrillation) was defined as the combined study end point. The numerical values are expressed as means ⫾ SDs. Continuous variables were compared between groups using an unpaired t test (for normally distributed variables) or the Mann-Whitney U statistic test (for non-normally distributed variables). Chi-square analysis was used to compare categorical variables. Clinical, electrocardiographic, and echocardiographic variables were evaluated for the combined study end point in a Cox proportional hazard model. Receiver-operating characteristic curves were generated to define the cut-off values for the variables with a significant association (p ⬍0.05) with the end point. Multivariate re-
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Table 3 Univariate Cox regression analysis: predictors of cardiac events Variable Restrictive filling pattern QRS duration E/E= ratio
Chi-square
Hazard Ratio (95% confidence interval)
p Value
7.86
3.65 (1.54–8.64)
0.011
4.98 7.68
1.01 (1.001–1.023) 1.09 (1.026–1.167)
0.028 0.006
gression analysis was performed to identify independent predictors of outcome. Event-free survival was analyzed by the Kaplan-Meier method, and survival curves were compared by the log-rank test. A p value of ⬍0.05 was considered significant.
Results During a follow-up of 373 ⫾ 254 days, 7 patients died because of pump failure and 18 patients received appropriate ICD therapy (antitachycardia pacing, n ⫽ 9; ICD shock, n ⫽ 9). The total number of antitachycardia treated episodes was 444, and the total number of shocks was 20. Two patients underwent antitachycardia pacing with subsequent shock due to accelerated ventricular tachycardia. One patient, who underwent appropriate ICD shock, died of pump failure 10 months later. Thus, 22 patients (26%) had a cardiac event during follow-up. The baseline characteristics of the study population are listed in Table 1. Patients with or without an event did not differ significantly with respect to age, gender, etiology of chronic HF, NYHA functional class, or drug therapy. In patients with an event, the QRS duration was significantly prolonged compared with patients without an event.
Figure 1. Event-free survival in subgroups of patients according to presence or absence of restrictive filling pattern (RFP). Time-to-first event analysis by Kaplan-Meier method.
Echocardiographic measurements: Patients with or without event did not differ with respect to left ventricular systolic/diastolic diameters and volumes, ejection fraction, fractional shortening, deceleration time, mitral E/A ratio, or/and mitral annular velocities derived from tissue Doppler imaging (Table 2). In patients with an event, a restrictive filling pattern was more frequent and the mitral E/E= ratio was significantly elevated compared with event-free patients. Predictors of prognosis and survival analysis: On univariate Cox analysis, QRS duration, a restrictive mitral filling pattern, and the mitral E/E= ratio were significantly related to the study end point (Table 3). Stepwise multivariate Cox regression analysis identified a restrictive filling pattern as the only independent predictor of an event (hazard ratio 3.65, chi-square 7.86, 95% confidence interval 1.54 to 8.64, p ⫽ 0.011). For patients with a restrictive filling pattern, the outcome was markedly poorer than that for patients without a restrictive filling pattern (Figure 1). For patients with a QRS duration ⬎145 ms (cut-off value derived from receiver-operating characteristic analysis), a
Figure 2. Outcome in subgroups of patients according to QRS duration. Event-free survival in patients with QRS duration ⬎145 ms did not differ significantly from that of those with QRS duration ⱕ145 ms.
trend was noted toward a less-favorable outcome than for those with a QRS duration ⱕ145 ms. However, log-rank analysis yielded no statistically significant difference (Figure 2). Discussion This is the first study to compare the prognostic impact of conventional Doppler echocardiography and tissue Doppler
Heart Failure/Prognosis in Heart Failure Patients
imaging against established prognostic markers, namely NYHA functional class, ejection fraction, and QRS duration in patients with an ICD and underlying chronic HF. The main and new finding is that a restrictive mitral filling pattern is a stronger predictor of cardiac death and appropriate ICD therapy than established parameters in this subpopulation. Thus, assessment of diastolic function may be a useful addition in the risk stratification and follow-up of such patients. In patients with left ventricular dysfunction, ICD treatment significantly reduces mortality, as well as the risk of sudden death, whether patients have ischemic or nonischemic cardiomyopathy.5–9 However, despite this proved benefit, the prognosis for patients with chronic HF with an ICD remains severe, with a mortality rate of nearly 15% during an average follow-up of 20 months in a recent large multicenter trial.8 In addition, rehospitalization because of worsening chronic HF and ICD discharges are frequent, contributing to significant morbidity.10 Finally, ICD therapy is expensive and carries certain risks, so that an appropriate risk stratification is of tremendous importance. Several investigators have reported on the factors predicting mortality and/or the risk of device discharges in patients with chronic HF and an ICD, including the clinical status (i.e., NYHA functional class), ejection fraction, and QRS duration derived from the 12-lead electrocardiogram.10 –13 In the recently published Triggers Of Ventricular Arrhythmias (TOVA) study, NYHA class III chronic HF and an ejection fraction of ⬍20% independently predicted appropriate shocks for ventricular tachycardia/ventricular fibrillation in a prospective cohort of 1,140 patients.11 However, in patients with chronic HF, diastolic dysfunction is frequently observed, and a restrictive mitral filling pattern is an accepted prognosticator of adverse outcome.14 Recently, the mitral annular E= velocity, derived from tissue Doppler imaging, provided incremental prognostic information in patients after recent myocardial infarction.15,16 Our study has elucidated the prognostic impact of Doppler echocardiography and tissue Doppler imaging in patients with an ICD and underlying chronic HF, and is the first to confirm the role of a restrictive filling pattern in predicting cardiac death and appropriate ICD discharges. However, our findings are in line with previous clinical and experimental data. In various animal models, the importance of ventricular wall stretch caused by increased pressure and volume load (so-called mechanoelectric feedback) in the genesis of ventricular arrhythmias has been demonstrated.17,18 In the clinical setting, a significant relation between ventricular arrhythmias and elevated filling pressures was reported by Mortara and coworkers.19 In their study, 142 patients with chronic HF underwent 24-hour electrocardiographic monitoring, right-side cardiac catheterization, and evaluation of heart rate variability and baroreflex sensitivity. When patients were grouped according to the absence (n ⫽ 87) or presence (n ⫽ 55) of nonsustained ventricular tachycardia, patients with nonsus-
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tained ventricular tachycardias had significantly higher pulmonary artery and capillary pressures than patients without ventricular tachycardia.19 In our study, patients with a cardiac event had a higher prevalence of a restrictive filling pattern and a higher mitral E/E= ratio than patients without an event (Table 2). Because these 2 parameters are wellknown indicators of elevated filling pressures, our results confirm the important role of filling pressures in the genesis of ventricular arrhythmias and consecutive ICD discharges in patients with chronic HF. Recent evidence has shown that the QRS duration implies relevant prognostic information in patients with chronic HF and an ICD, particularly in those with more advanced HF and severely impaired left ventricular function.20 In a recent study from our institution, cardiac mortality was significantly higher for patients with chronic HF who had a QRS duration of ⱖ150 ms than for those with a QRS duration ⬍150 ms (2-year mortality rate 46.6% vs 18.2%, p ⫽ 0.04).13 In agreement with those findings, a prolonged QRS duration (⬎120 ms) was the only significant predictor of ventricular arrhythmia in 61 patients with an ICD and underlying coronary artery disease, who were followed for 3.0 ⫾ 1.8 years.21 However, in none of these previous studies was the prognostic impact of QRS duration compared with Doppler echocardiographically-derived parameters. In our study population, patients with a cardiac event had a significantly prolonged QRS duration, and the QRS duration was significantly associated with the study end point on univariate Cox proportional hazard analysis. When entered into a multivariate Cox model, the relation between QRS duration and the study end point was no longer significant, and a restrictive mitral filling pattern emerged as the only independent prognostic factor. However, these observations may have been attributable to our small study sample. Because patients with severe valvular disease or atrial fibrillation or under permanent pacemaker stimulation were excluded, the results of our study should not be extrapolated to such populations. Also, we have reported only a singlecenter experience, so our results should be confirmed in a multicenter approach, using larger sample sizes and longer follow-up periods. 1. Ho KK, Anderson KM, Kannel WB, Grossman W, Levy D. Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation 1993;88:107–115. 2. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I, et al, for the American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. Recommendations for quantitation of the left ventricular by two-dimensional echocardiography. J Am Soc Echocardiogr 1989;2:358 –367. 3. Garcia MJ, Thomas JD, Klein AL. New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32:865– 875. 4. Rivas-Gotz C, Manolios M, Thohan V, Nagueh SF. Impact of left ventricular ejection fraction on estimation of left ventricular filling
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The American Journal of Cardiology (www.AJConline.org) pressures using tissue Doppler and flow propagation velocity. Am J Cardiol 2003;91:780 –784. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. N Engl J Med 1999;341:882– 1890. Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H, Levine JH, Saksena S, Waldo AL, Wilber D, Brown MW, Heo M. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 1996;335:1933–1940. The Antiarrhythmic Versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 1997;337:1576 –1583. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML, for the Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877– 883. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, et al, for the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–237. Buxton AE, Sweeney MO, Wathen MS, Josephson ME, Otterness MF, Hogan-Miller E, Stark AJ, Degroot PJ, for the PainFREE Rx II Investigators. QRS duration does not predict occurrence of ventricular tachyarrhythmias in patients with implanted cardioverter-defibrillators. J Am Coll Cardiol 2005;46:310 –316. Whang W, Mittleman MA, Rich DQ, Wang PJ, Ruskin JN, Tofler GH, Muller JE, Albert CM, for the TOVA Investigators. Heart failure and the risk of shocks in patients with implantable cardioverter defibrillators: results from the Triggers Of Ventricular Arrhythmias (TOVA) study. Circulation 2004;109:1386 –1391.
12. Grimm W, Flores BT, Marchlinski FE. Shock occurrence and survival in 241 patients with implantable cardioverter-defibrillator therapy. Circulation 1993;87:1880 –1888. 13. Bode-Schnurbus L, Bocker D, Block M, Gradaus R, Heinecke A, Breithardt G, Borggrefe M. QRS duration: a simple marker for predicting cardiac mortality in ICD patients with heart failure. Heart 2003;89:1157–1162. 14. Xie GY, Berk MR, Smith MD, Gurley JC, DeMaria AN. Prognostic value of Doppler transmitral flow patterns in patients with congestive heart failure. J Am Coll Cardiol 1994;24:132–139. 15. Wang M, Yip GW, Wang AY, Zhang Y, Ho PY, Tse MK, Lam PK, Sanderson JE. Peak early diastolic mitral annulus velocity by tissue Doppler imaging adds independent and incremental prognostic value. J Am Coll Cardiol 2003;41:820 – 826. 16. Hillis GS, Moller JE, Pellikka PA, Gersh BJ, Wright RS, Ommen SR, Reeder GS, Oh JK. Noninvasive estimation of left ventricular filling pressure by E/e= is a powerful predictor of survival after acute myocardial infarction. J Am Coll Cardiol 2004;43:360 –367. 17. Lab MJ. Contraction-excitation feedback in myocardium: physiological basis and clinical relevance. Circ Res 1982;50:757–766. 18. Dean JW, Lab MJ. Contraction-excitation feedback in myocardium: physiological basis and clinical relevance. Circ Res 1982;50:757–766. 19. Mortara A, La Rovere MT, Pinna GD, Parziale P, Maestri R, Capomolla S, Opasich C, Cobelli F, Tavazzi L. Depressed arterial baroreflex sensitivity and not reduced heart rate variability identifies patients with chronic heart failure and nonsustained ventricular tachycardia: the effect of high ventricular filling pressure. Am Heart J 1997;134:879 – 888. 20. Olshansky B. Wide QRS, narrow QRS: what’s the difference? J Am Coll Cardiol 2005;46:317–319. 21. Guttigoli AB, Wilner BF, Stein KM, Markowitz SM, Iwai S, Shah BK, Yarlagadda RK, Lerman BB, Mittal S. Usefulness of prolonged QRS duration to identify high-risk ischemic cardiomyopathy patients with syncope and inducible ventricular tachycardia. Am J Cardiol 2005;95: 391–394.
This prospective study was designed to assess the prognostic value of Doppler echocardiography and tissue Doppler imaging in patients with heart failure (HF) and an implantable cardioverter-defibrillator (ICD) and to compare it against traditional markers, such as New York Heart Association (NYHA) functional class, ejection fraction, and QRS duration.
Methods Study patients: The study population consisted of a consecutive series of 98 patients who were followed after receiving ICDs between 2000 and 2003 at our institution (Hospital of the University of Münster). Patients were prospectively included if they fulfilled the following criteria: a history of chronic HF according to the Framingham criteria,1 left ventricular ejection fraction ⬍45% as detected by echo-
Department of Cardiology and Angiology, Hospital of the University of Münster, Münster, Germany. Manuscript received August 6, 2005; revised manuscript received and accepted September 12, 2005. *Corresponding author: Tel: 49-251-83-47-684; fax: 49-251-83-47635. E-mail address: [email protected] (C. Bruch). 0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.09.114
cardiography, and clinical stability after ⱖ2 months on standard medical therapy. Patients with severe valvular disease (n ⫽ 5) or atrial fibrillation (n ⫽ 9) were excluded, so that 84 subjects formed the final study cohort. Of these patients, 62 (74%) received ICDs for secondary prevention and 22 (26%) for primary prevention of sudden cardiac death. All implanted devices were capable of storing intracardiac electrograms and had antitachycardia pacing capabilities in combination with cardioversion/defibrillation treatment features. All treated episodes were classified as inappropriate or appropriate by 1 experienced cardiologist (RG), who had no knowledge of the remaining clinical data. Electrocardiographic analysis: The QRS duration was measured on a 12-lead electrocardiogram using leads V3 to V6. A mean of ⱖ3 QRS complexes was used for further analysis. Left bundle branch block was diagnosed on the basis of a QRS duration ⬎120 ms, absent Q waves, and wide slurred R waves in V5 and V6, and monophasic QS or rS waves in leads V1 and V2. Echocardiography: Echocardiographic images were taken according to the guidelines of the American Society of Echocardiography.2 Peak velocities of early (E) and late www.AJConline.org
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Table 1 Clinical characteristics of study patients Total (n ⫽ 84)
Variable
Age (yrs) Men/women (%) Body surface area (m2) Ischemic/nonischemic cardiomyopathy NYHA functional class QRS duration (ms) Left bundle branch block Medication Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker Diuretics Digoxin  Blockers Class III antiarrhytmic agents
Event
p Value
Yes (n ⫽ 22)
No (n ⫽ 64)
60 ⫾ 12 80/20 1.9 ⫾ 0.2 74%/26% 2.7 ⫾ 0.5 153 ⫾ 39 31 (37%)
61 ⫾ 12 73/27 1.9 ⫾ 0.2 59%/41% 2.8 ⫾ 0.5 169 ⫾ 41 9 (41%)
60 ⫾ 12 82/18 1.9 ⫾ 0.2 68%/32% 2.7 ⫾ 0.5 146 ⫾ 31 22 (35%)
0.78 0.34 0.39 0.46 0.31 0.023 0.78
94% 91% 70% 90% 31%
91% 95% 71% 86% 30%
95% 90% 69% 92% 31%
0.48 0.44 0.83 0.46 0.93
Table 2 Echocardiographic characteristics of study patients Variable
Left atrial diameter (cm) LV diastolic diameter index (cm/m2) LV systolic diameter index (cm/m2) LV diastolic volume index (ml/m2) LV systolic volume index (ml/m2) LV ejection fraction (%) Fractional shortening (%) Puked Wave Doppler Mitral E/A ratio Deceleration time Restrictive filling pattern Tissue Doppler S= (cm/s) E= (cm/s) A= (cm/s) E/E= ratio
Total (n ⫽ 84)
Event
p Value
Yes (n ⫽ 22)
No (n ⫽ 64)
5.0 ⫾ 0.8 3.6 ⫾ 0.5 3.0 ⫾ 0.5 129 ⫾ 46 93 ⫾ 40 29 ⫾ 10 18 ⫾ 7
5.1 ⫾ 0.7 3.7 ⫾ 0.5 3.1 ⫾ 0.5 143 ⫾ 46 102 ⫾ 40 29 ⫾ 10 19 ⫾ 6
5.0 ⫾ 0.9 3.5 ⫾ 0.5 3.0 ⫾ 0.5 125 ⫾ 47 90 ⫾ 40 29 ⫾ 10 18 ⫾ 7
0.87 0.20 0.32 0.079 0.19 0.87 0.51
1.93 ⫾ 1.16 188 ⫾ 80 16 (22%)
2.25 ⫾ 1.18 173 ⫾ 68 12 (44%)
1.82 ⫾ 1.14 193 ⫾ 84 4 (9%)
0.105 0.26 0.017
4.64 ⫾ 1.12 5.85 ⫾ 1.75 6.30 ⫾ 2.35 13.6 ⫾ 6.2
4.25 ⫾ 0.93 5.43 ⫾ 1.41 6.41 ⫾ 2.99 15.9 ⫾ 6.5
4.77 ⫾ 1.16 6.00 ⫾ 1.84 6.27 ⫾ 2.13 12.8 ⫾ 5.9
0.069 0.30 0.607 0.045
LV ⫽ left ventricular.
(A) diastolic filling and deceleration time were derived from transmitral Doppler recordings. A restrictive filling pattern was defined by an E/A ratio ⬎2, a deceleration time of ⬍150 ms, and a mitral annular E= velocity of ⬍8 cm/s.3 Tissue Doppler-derived peak systolic (S=) and early (E=), and late (A=) diastolic velocities were derived from the septal and lateral mitral annulus, and averaged for each patient.4 The inter- and intraobserver correlation for conventional echocardiographic measurements and tissue Doppler variables reached 0.92 and 0.98, respectively. Outcome measurements and statistical analysis: To study the prognostic impact of Doppler echocardiography and tissue Doppler imaging in our study population, the follow-up period started at the time of the index echocardiogram. Patients were seen regularly on an outpatient basis at 3- to 6-month intervals, and the device was interrogated for treated episodes at each visit. Detailed follow-up infor-
mation was also obtained by telephone interview with the patients or their physicians. A cardiac event (death from pump failure or appropriate ICD therapy, i.e., antitachycardia pacing or shock due to sustained ventricular tachycardia or ventricular fibrillation) was defined as the combined study end point. The numerical values are expressed as means ⫾ SDs. Continuous variables were compared between groups using an unpaired t test (for normally distributed variables) or the Mann-Whitney U statistic test (for non-normally distributed variables). Chi-square analysis was used to compare categorical variables. Clinical, electrocardiographic, and echocardiographic variables were evaluated for the combined study end point in a Cox proportional hazard model. Receiver-operating characteristic curves were generated to define the cut-off values for the variables with a significant association (p ⬍0.05) with the end point. Multivariate re-
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Table 3 Univariate Cox regression analysis: predictors of cardiac events Variable Restrictive filling pattern QRS duration E/E= ratio
Chi-square
Hazard Ratio (95% confidence interval)
p Value
7.86
3.65 (1.54–8.64)
0.011
4.98 7.68
1.01 (1.001–1.023) 1.09 (1.026–1.167)
0.028 0.006
gression analysis was performed to identify independent predictors of outcome. Event-free survival was analyzed by the Kaplan-Meier method, and survival curves were compared by the log-rank test. A p value of ⬍0.05 was considered significant.
Results During a follow-up of 373 ⫾ 254 days, 7 patients died because of pump failure and 18 patients received appropriate ICD therapy (antitachycardia pacing, n ⫽ 9; ICD shock, n ⫽ 9). The total number of antitachycardia treated episodes was 444, and the total number of shocks was 20. Two patients underwent antitachycardia pacing with subsequent shock due to accelerated ventricular tachycardia. One patient, who underwent appropriate ICD shock, died of pump failure 10 months later. Thus, 22 patients (26%) had a cardiac event during follow-up. The baseline characteristics of the study population are listed in Table 1. Patients with or without an event did not differ significantly with respect to age, gender, etiology of chronic HF, NYHA functional class, or drug therapy. In patients with an event, the QRS duration was significantly prolonged compared with patients without an event.
Figure 1. Event-free survival in subgroups of patients according to presence or absence of restrictive filling pattern (RFP). Time-to-first event analysis by Kaplan-Meier method.
Echocardiographic measurements: Patients with or without event did not differ with respect to left ventricular systolic/diastolic diameters and volumes, ejection fraction, fractional shortening, deceleration time, mitral E/A ratio, or/and mitral annular velocities derived from tissue Doppler imaging (Table 2). In patients with an event, a restrictive filling pattern was more frequent and the mitral E/E= ratio was significantly elevated compared with event-free patients. Predictors of prognosis and survival analysis: On univariate Cox analysis, QRS duration, a restrictive mitral filling pattern, and the mitral E/E= ratio were significantly related to the study end point (Table 3). Stepwise multivariate Cox regression analysis identified a restrictive filling pattern as the only independent predictor of an event (hazard ratio 3.65, chi-square 7.86, 95% confidence interval 1.54 to 8.64, p ⫽ 0.011). For patients with a restrictive filling pattern, the outcome was markedly poorer than that for patients without a restrictive filling pattern (Figure 1). For patients with a QRS duration ⬎145 ms (cut-off value derived from receiver-operating characteristic analysis), a
Figure 2. Outcome in subgroups of patients according to QRS duration. Event-free survival in patients with QRS duration ⬎145 ms did not differ significantly from that of those with QRS duration ⱕ145 ms.
trend was noted toward a less-favorable outcome than for those with a QRS duration ⱕ145 ms. However, log-rank analysis yielded no statistically significant difference (Figure 2). Discussion This is the first study to compare the prognostic impact of conventional Doppler echocardiography and tissue Doppler
Heart Failure/Prognosis in Heart Failure Patients
imaging against established prognostic markers, namely NYHA functional class, ejection fraction, and QRS duration in patients with an ICD and underlying chronic HF. The main and new finding is that a restrictive mitral filling pattern is a stronger predictor of cardiac death and appropriate ICD therapy than established parameters in this subpopulation. Thus, assessment of diastolic function may be a useful addition in the risk stratification and follow-up of such patients. In patients with left ventricular dysfunction, ICD treatment significantly reduces mortality, as well as the risk of sudden death, whether patients have ischemic or nonischemic cardiomyopathy.5–9 However, despite this proved benefit, the prognosis for patients with chronic HF with an ICD remains severe, with a mortality rate of nearly 15% during an average follow-up of 20 months in a recent large multicenter trial.8 In addition, rehospitalization because of worsening chronic HF and ICD discharges are frequent, contributing to significant morbidity.10 Finally, ICD therapy is expensive and carries certain risks, so that an appropriate risk stratification is of tremendous importance. Several investigators have reported on the factors predicting mortality and/or the risk of device discharges in patients with chronic HF and an ICD, including the clinical status (i.e., NYHA functional class), ejection fraction, and QRS duration derived from the 12-lead electrocardiogram.10 –13 In the recently published Triggers Of Ventricular Arrhythmias (TOVA) study, NYHA class III chronic HF and an ejection fraction of ⬍20% independently predicted appropriate shocks for ventricular tachycardia/ventricular fibrillation in a prospective cohort of 1,140 patients.11 However, in patients with chronic HF, diastolic dysfunction is frequently observed, and a restrictive mitral filling pattern is an accepted prognosticator of adverse outcome.14 Recently, the mitral annular E= velocity, derived from tissue Doppler imaging, provided incremental prognostic information in patients after recent myocardial infarction.15,16 Our study has elucidated the prognostic impact of Doppler echocardiography and tissue Doppler imaging in patients with an ICD and underlying chronic HF, and is the first to confirm the role of a restrictive filling pattern in predicting cardiac death and appropriate ICD discharges. However, our findings are in line with previous clinical and experimental data. In various animal models, the importance of ventricular wall stretch caused by increased pressure and volume load (so-called mechanoelectric feedback) in the genesis of ventricular arrhythmias has been demonstrated.17,18 In the clinical setting, a significant relation between ventricular arrhythmias and elevated filling pressures was reported by Mortara and coworkers.19 In their study, 142 patients with chronic HF underwent 24-hour electrocardiographic monitoring, right-side cardiac catheterization, and evaluation of heart rate variability and baroreflex sensitivity. When patients were grouped according to the absence (n ⫽ 87) or presence (n ⫽ 55) of nonsustained ventricular tachycardia, patients with nonsus-
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tained ventricular tachycardias had significantly higher pulmonary artery and capillary pressures than patients without ventricular tachycardia.19 In our study, patients with a cardiac event had a higher prevalence of a restrictive filling pattern and a higher mitral E/E= ratio than patients without an event (Table 2). Because these 2 parameters are wellknown indicators of elevated filling pressures, our results confirm the important role of filling pressures in the genesis of ventricular arrhythmias and consecutive ICD discharges in patients with chronic HF. Recent evidence has shown that the QRS duration implies relevant prognostic information in patients with chronic HF and an ICD, particularly in those with more advanced HF and severely impaired left ventricular function.20 In a recent study from our institution, cardiac mortality was significantly higher for patients with chronic HF who had a QRS duration of ⱖ150 ms than for those with a QRS duration ⬍150 ms (2-year mortality rate 46.6% vs 18.2%, p ⫽ 0.04).13 In agreement with those findings, a prolonged QRS duration (⬎120 ms) was the only significant predictor of ventricular arrhythmia in 61 patients with an ICD and underlying coronary artery disease, who were followed for 3.0 ⫾ 1.8 years.21 However, in none of these previous studies was the prognostic impact of QRS duration compared with Doppler echocardiographically-derived parameters. In our study population, patients with a cardiac event had a significantly prolonged QRS duration, and the QRS duration was significantly associated with the study end point on univariate Cox proportional hazard analysis. When entered into a multivariate Cox model, the relation between QRS duration and the study end point was no longer significant, and a restrictive mitral filling pattern emerged as the only independent prognostic factor. However, these observations may have been attributable to our small study sample. Because patients with severe valvular disease or atrial fibrillation or under permanent pacemaker stimulation were excluded, the results of our study should not be extrapolated to such populations. Also, we have reported only a singlecenter experience, so our results should be confirmed in a multicenter approach, using larger sample sizes and longer follow-up periods. 1. Ho KK, Anderson KM, Kannel WB, Grossman W, Levy D. Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation 1993;88:107–115. 2. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I, et al, for the American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. Recommendations for quantitation of the left ventricular by two-dimensional echocardiography. J Am Soc Echocardiogr 1989;2:358 –367. 3. Garcia MJ, Thomas JD, Klein AL. New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32:865– 875. 4. Rivas-Gotz C, Manolios M, Thohan V, Nagueh SF. Impact of left ventricular ejection fraction on estimation of left ventricular filling
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