Left bundle-branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: A report from the Italian Network on Congestive Heart Failure Samuele Baldasseroni, MD,a,e Cristina Opasich, MD,b Marco Gorini, MS,a Donata Lucci, MS,a Niccolò Marchionni, MD,c Maurizio Marini, MD,a,c Carlo Campana, MD,a Giampaolo Perini, MD,a Antonella Deorsola, MD,a Giulio Masotti, MD,c Luigi Tavazzi, MD,d and Aldo P. Maggioni, MD,a on behalf of the Italian Network on Congestive Heart Failure Investigators Florence and Pavia, Italy

Background A deleterious effect of complete left bundle-branch block (LBBB) on left ventricular function has been established. Nevertheless, the independent effect of a widened QRS on mortality rate in congestive heart failure (CHF) is still controversial. Therefore, we carried out this analysis to determine whether LBBB is an independent predictor of mortality in CHF.

Methods and Results We analyzed the large Italian Network on CHF Registry of unselected outpatients with CHF of different causes. The registry was established by the Italian Association of Hospital Cardiologists in 1995. Complete 1-year follow-up data were available for 5517 patients. The main underlying cardiac diagnosis was ischemic heart disease in 2512 patients (45.6%), dilated cardiomyopathy in 1988 patients (36.0%), and hypertensive heart disease in 714 patients (12.9%). Other causes were recorded in the remaining 303 cases (5.5%). LBBB was present in 1391 patients (25.2%) and was associated with an increased 1-year mortality rate from any cause (hazard ratio, 1.70; 95% confidence interval, 1.41 to 2.05) and sudden death (hazard ratio, 1.58; 95% confidence interval, 1.21 to 2.06). Multivariate analysis showed that such an increased risk was still significant after adjusting for age, underlying cardiac disease, indicators of CHF severity, and prescription of angiotensin-converting enzyme inhibitors and β-blockers. Conclusion LBBB is an unfavorable prognostic marker in patients with CHF. The negative effect is independent of age, CHF severity, and drug prescriptions. These data may support the rationale of randomized trials to verify the effects on mortality rate of ventricular resynchronization with multisite cardiac pacing in patients with CHF and LBBB. (Am Heart J 2002;143:398-405.)

Although the mortality rate from heart disease is declining as a consequence of improved treatment and primary prevention in industrialized countries,1 the number of patients affected by congestive heart failure (CHF) is still increasing. This is a consequence of From the aItalian Association of Hospital Cardiologists Research Center, Florence, the bDepartment of Cardiology, Salvatore Maugeri Foundation, Pavia, the cDepartment of Critical Care Medicine and Surgery, Section of Gerontology and Geriatric Medicine, University of Florence, the dDepartment of Cardiology, San Matteo Hospital, Pavia, and the eDepartment of Internal Medicine and Cardiology, University of Florence, Italy. The Italian Network on Congestive Heart Failure Registry was supported in part by Merck Sharp & Dohme spa Italy. See the Appendix for a complete list of participating Centers and Investigators. Submitted May 16, 2001; accepted October 25, 2001. Reprint requests: Aldo P. Maggioni, MD, ANMCO Research Center — Via La Marmora 34, 50121 Florence, Italy. E-mail: [email protected] Copyright 2002, Mosby, Inc. All rights reserved. 0002-8703/2002/$35.00 + 0 4/1/121264 doi:10.1067/mhj.2002.121264

increased longevity and of the age-associated increase in the prevalence of heart diseases in general, and of CHF in particular.2 The number of patients with CHF has increased dramatically in all age groups and by almost 500% in the more than 85 year age group from 1950 to 1993.1 Projections suggest that by the year 2016 the absolute number of patients with CHF will further increase from 1996 by 55.9% and 52.5% in the 65 to 75 year and the more than 75 year age groups, respectively.1 Among the many clinical and pathophysiologic factors that have been proposed as prognostic indicators in CHF, reduced left ventricular ejection fraction,3,4 neurohormonal activation,3 and reduced exercise tolerance expressed as peak oxygen consumption,3,5,6 or performance in the 6-minute walk test,7 have been identified as independent predictors of mortality rate. Data concerning the prognostic significance of intraventricular conduction defects and, in particular, of complete left bun-

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dle-branch block (LBBB) in CHF are more conflicting. In fact, the deleterious effect of LBBB on left ventricular systolic and diastolic function has been established in subjects without overt heart disease8 and in patients with dilated cardiomyopathy,9 and whether mortality rate is increased independently with a widening of QRS is still controversial.10-18 Therefore, we carried out this analysis of a database of unselected outpatients with CHF of different causes, who were followed by a large number of cardiologic centers in Italy. The purpose was evaluation of the prevalence of complete LBBB and testing of whether complete LBBB is an independent predictor of all-cause mortality and of sudden death in patients with CHF.

Methods Study design, collected data, and definitions Data for this analysis were originated from the database of the Italian Network CHF Registry,19 a survey designed in 1995 by an ad hoc committee of the Italian Association of Hospital Cardiologists (Florence, Italy). One-hundred fifty cardiologic centers accepted participation in the study. Centers were distributed across the national territory and were more frequently located in Northern (46%) than in Central (24%) or Southern (30%) Italy, well representing the whole country. Short training sessions were organized to prepare clinicians to collect and enter data with standardized methods. With an ad hoc designed software, patient data were recorded at each center by trained cardiologists and then were pooled into a single database at the Italian Association of Hospital Cardiologists Research Center. Entry into the database required that the patient had a diagnosis of New York Heart Association (NYHA) classification I to IV CHF on the basis of the guidelines of the European Society of Cardiology.20 Demographic, clinical, instrumental, and laboratory variables and information on drug therapy were collected for each patient. At baseline, a 12-lead electrocardiogram was recorded and coded by a single cardiologist at each participating center, with a standardized format outlined in the database. In particular, presence of LBBB was recorded and QRS duration was coded as less than 120 ms, 120 to 140 ms, or more than 140 ms. This information was used by the computer program to control for the acceptability of the diagnosis of LBBB and to distinguish between incomplete (QRS duration, 120 to 140 ms) and complete (QRS duration, >140 ms) block. Patients were followed according to the routine clinical practice of the participating centers. In this context, patients underwent standard chest xray, 24-hour Holter electrocardiogram monitoring, 2-dimensional echocardiography, and blood sampling for the most common laboratory tests (eg, creatinine level, electrolyte level, etc) when the attending cardiologists deemed them necessary. Cardiologists at the participating centers were responsible for defining the cause of CHF and the NYHA classification, noting whether a 3rd heart sound was audible and computing the cardiothoracic ratio. When an echocardiographic examination was performed, calculation of left ventricular ejection fraction from 4-chamber apical echocardiographic view was also done. Ventricular tachycardia was

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defined as an episode of tachycardia with widened QRS that lasted longer than 3 beats with a heart rate of more than 100 beats/min, as revealed with 24-hour Holter electrocardiogram monitoring. Renal dysfunction was diagnosed for serum creatinine level of more than 2.5 mg/dL. Previous hospitalizations for CHF in the last year were also recorded. After the baseline visit, the patients were followed. In the case of out-of-hospital death, the event was confirmed with telephone interview of patient’s relatives, with a standard questionnaire aimed at determining the mode of death (sudden versus non sudden).

Study population As of January 2000, 6593 patients had complete 1-year follow-up information. We excluded from this analysis 1076 patients for any of the following reasons: CHF as the result of primary valvular heart disease (n = 745), inadequate quality of electrocardiogram (n = 270), and cardiac transplantation within the 1st year of follow-up examination (n = 61). Thus, the study population for this analysis consisted of 5517 patients.

Statistical analysis The data were analyzed with the SAS statistical package and are presented as mean ± standard deviation. The univariate association of complete LBBB with several demographic and clinical characteristics and with 1-year mortality rate was analyzed with the χ2 test. Cox proportional hazards multivariate models with calculation of the adjusted hazard ratio and 95% confidence interval were used to identify the independent determinants of all-cause mortality rate and of mortality rate as the result of sudden death. A 2-tailed P value of less than .05 was considered statistically significant.

Results The study population of 5517 patients had a mean age of 63 ± 12 years (range, 14 to 96 years) and included 1295 women (23.5%) and 1544 cases (28.0%) that were classified in NYHA class III to IV. The 1076 patients with complete 1-year follow-up data who were excluded from this analysis had a similar age (65 ± 12 years; range, 17 to 91 years) but a larger prevalence of women (38.6%; P < .01) and of NYHA classification III to IV (38.8%; P < .01).

Complete left bundle-branch block: prevalence and associated clinical characteristics Complete LBBB was diagnosed in 1391 of 5517 patients (25.2%), complete right bundle-branch block was diagnosed in 336 of 5517 patients (6.1%), and other forms of intraventricular delay were diagnosed in 339 of 5517 patients (6.1%). Demographic and clinical characteristics of patients with LBBB are reported in Table I. The prevalence of patients older than 70 years was similar in the group with and without LBBB, and female patients were significantly more represented in the group with LBBB. Cause of CHF was different between the 2 groups, with dilated cardiomyopathy

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Figure 1

Table I. Main demographic and clinical characteristics of 5517 patients with congestive heart failure and presence or absence of associated complete left bundle-branch block Complete LBBB Variable

One-year mortality rate for all-cause death and sudden death in study population of 5517 patients with congestive heart failure (gray bars) and in subgroups with complete left bundlebranch block (black bars) or without complete left bundlebranch block (white bars). Unadjusted hazard ratio (HR) is also reported with 95% confidence interval.

and ischemic heart disease being the most common diagnosis in patients with and without LBBB, respectively. Although previous hospitalizations for CHF during the last year had a similar prevalence in both groups, there were several indicators of greater severity of clinical status in patients with LBBB as compared with those without LBBB. In particular, LBBB was associated with higher prevalence of NYHA classification III to IV CHF, reduced systolic blood pressure, 3rd heart sound, and abnormally increased cardiothoracic ratio (>0.55), while the prevalence of a heart rate higher than 100 beats/min was similar in the 2 groups. Echocardiographic results were available and of adequate quality to permit a reliable measurement of left ventricular ejection fraction in 3392 of 5517 patients (61.5%), a proportion that was similar in patients with and without LBBB (2523 of 4126 [61.1%] versus 869 of 1391 [62.5%]; P = not significant). Echocardiographic results also indicated a greater disease severity in patients with LBBB, who had a higher prevalence rate of severely reduced left ventricular ejection fraction ( 70 years Female gender CHF cause Dilated cardiomyopathy Ischemic heart disease Hypertensive heart disease Other causes Previous hospitalization for CHF NYHA classification III to IV Heart rate ≥ 100 beats/min Systolic blood pressure 130 mm Hg 3rd heart sound CT ratio > 0.55 LVEF 0.40 Chronic AF Ventricular tachycardia Renal failure Drug prescriptions Diuretics ACE inhibitors Digoxin Nitrates Antiplatelet agents Amiodarone β-blockers Ca-antagonists Other antiarrhythmic agents

Present Absent P (n = 1391) (n = 4126) value 30.0% 29.3%

31.7% 21.5%

NS .001

49.3% 33.7% 12.7% 4.2% 56.4% 32.8% 10.9%

31.6% 49.5% 13.0% 5.9% 54.3% 26.4% 10.7%

3.9% 61.2% 34.9% 34.2% 63.2%

2.7% 54.2% 43.1% 22.2% 55.0%

49.2% 40.3% 10.5% 13.3% 28.5% 2.1%

30.4% 44.5% 25.1% 19.3% 28.8% 2.5%

.001 NS NS

88.6% 87.4% 71.8% 38.7% 31.4% 24.7% 16.2% 9.7% 1.8%

82.0% 82.8% 62.8% 43.2% 38.5% 20.0% 19.0% 14.3% 2.2%

.001 .001 .001 .003 .001 .001 .017 .001 NS

.001 NS .001 NS .001 .001 .040 .001

LBBB, Left bundle-branch block; CHF, congestive heart failure; NYHA, New York Heart Association; CT, cardiothoracic; LVEF, left ventricular ejection fraction; AF, atrial fibrillation; ACE, angiotensin-converting enzyme; NS, not significant.

antiplatelet agents, β-blockers, and Ca-antagonists were prescribed more frequently to patients without LBBB.

Left bundle-branch block and prognosis Overall, 659 of 5517 patients (11.9%) died during the 1-year follow-up period, with 46.4% (n = 306) of deaths being classified as sudden. The 1-year all-cause mortality rate for patients with LBBB was 16.1% (224 of 1391), for patients with right bundle-branch block was 11.9% (40 of 336), and for patients with other intraventricular abnormalities was 8.8% (30 of 339). All-cause mortality and mortality rates as the result of sudden death were significantly greater among patients with LBBB (Fig 1). Adjusted analysis was performed to predict the adjusted hazard ratio for all-cause death and

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Table II. Independent predictors of 1-year risk of all-cause death in 5517 patients with congestive heart failure Variable Age (years)* Ischemic heart disease (yes vs no) Previous hospitalization for CHF (yes vs no) NYHA (III to IV vs I to II) Heart rate (beats/min)* Systolic blood pressure (mm Hg)* 3rd heart sound (yes vs no) Chronic AF (yes vs no) Ventricular tachycardia (yes vs no) Renal failure (yes vs no) ACE inhibitors (yes vs no) β-blockers (yes vs no) LBBB (yes vs no)

HR

95% CI

P value

1.023 1.015-1.031 1.247 1.054-1.474 1.749 1.463-2.092

.0001 .0100 .0001

1.931 1.008 0.986 1.421 1.316 1.758 1.664 0.821 0.747 1.360

.0001 .0019 .0001 .0001 .0046 .0005 .0260 .0464 .0244 .0004

1.639-2.276 1.003-1.013 0.982-0.990 1.203-1.678 1.088-1.590 1.278-2.419 1.063-2.604 0.676-0.997 0.579-0.963 1.148-1.610

*Introduced as continuous variables. Variables that were not significant (P > .10): sex, cardiothoracic ratio, left ventricular ejection fraction, and prescription of antiplatelet agents. HR, Hazard ratio; CI, confidence interval; CHF, congestive heart failure; NYHA, New York Heart Association; AF, atrial fibrillation; ACE, angiotensin-converting enzyme; LBBB, left bundle-branch block.

sudden death at 1 year. In these models, we entered age, heart rate, and systolic blood pressure as continuous variables and all the other variables presented in Table I, as dichotomous variables, with inclusion of LBBB as a covariate. Of the variables pertaining to drug prescription, we included only those referring to agents with proven effects on mortality rate in randomized clinical trials. Thus, only prescriptions of ACE inhibitors,21,22 antiplatelet agents,23 and β-blockers24,25 were entered as further dichotomous covariates in these models, whose results are summarized in Tables II and III. The risk of all-cause death at 1 year was significantly increased with increasing age and in the presence of ischemic heart disease, previous hospitalization for CHF, and several indicators of greater disease severity or comorbidity, such as NYHA classification III to IV, increased heart rate or reduced systolic blood pressure, 3rd heart sound, chronic atrial fibrillation, sustained ventricular tachycardia, and renal failure (Table II). Prescription of ACE inhibitors and β-blockers had significantly independent protective effects against the risk of all-cause death, and sex, the cardiothoracic ratio, left ventricular ejection fraction, and prescription of antiplatelet agents were not confirmed to be significant predictors of that risk (Table II). After adjustment for all these covariates, complete LBBB still maintained its unfavorable prognostic effect and, on average, it was estimated to increase the risk of all-cause death at 1 year by 36% (Table II). The same variables, with the further exclusion of heart rate, renal failure, and prescription of ACE inhibitors, were significantly associated

Table III. Independent predictors of 1-year risk of sudden death in 5517 patients with congestive heart failure Variable Age (years)* Ischemic heart disease (yes vs no) Previous hospitalization for CHF (yes vs no) NYHA (III to IV vs I to II) Systolic blood pressure (mm Hg)* 3rd heart sound (yes vs no) Chronic AF (yes vs no) Ventricular tachycardia (yes vs no) β-blockers (yes vs no) LBBB (yes vs no)

HR

95% CI

P value

1.015 1.004-1.027 .0106 1.319 1.030-1.691 .0285 1.879 1.445-2.445 .0001 1.520 0.990 1.714 1.375 1.961 0.665 1.348

1.193-1.936 0.984-0.996 1.346-2.181 1.038-1.823 1.250-3.078 0.455-0.972 1.051-1.729

.0007 .0007 .0001 .0266 .0034 .0352 .0188

*Introduced as continuous variables. Variables that were not significant (P > .10): sex, cardiothoracic ratio, left ventricular ejection fraction, heart rate, renal failure, and prescription of angiotensin-converting enzyme inhibitors and antiplatelet agents. HR, Hazard ratio; CI, confidence interval; CHF, congestive heart failure; NYHA, New York Heart Association; AF, atrial fibrillation; LBBB, left bundle-branch block.

with the risk of sudden death at 1 year (Table III). Also in this multivariate model, LBBB was independently associated with the risk of sudden death, which was increased by almost 35% in the presence of this intraventricular conduction defect.

Discussion The association of a wide QRS with increased mortality rate in CHF has been repeatedly investigated, but results have been conflicting. Although some studies showed that a wide QRS has an independent, unfavorable prognostic significance and increases the mortality rate of patients with CHF during periods of follow-up examination extended to 5 years,11,12,14 other studies adopting similar multivariate approaches did not confirm this finding.10,13,16 Such discrepancies may arise from the variable cutoffs adopted to define the conduction defect, ranging from a mild widening of the QRS complex above 120 ms12 to complete LBBB10,11,13,14,16 and from large differences in the covariates included in multivariate analyses. A further cause of conflicting results may be represented by the variable cause of CHF in the different studies that, in most cases, included only patients with dilated cardiomyopathy,12-14,16 with only 2 studies including a few patients with ischemic heart disease.10,11 However, all these studies included limited numbers of patients, ranging from 6216 to 441,13 and only recently a preliminary report of a large survey of 3654 patients confirmed a direct association of QRS duration with 1-year mortality rate in CHF from dilated cardiomyopathy.18 Thus, we decided to limit our analysis only to the prognostic significance of complete LBBB, with a data-

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base that was produced by an Italian epidemiologic survey of outpatients referred to cardiology centers for evaluation and treatment of CHF. The registry was large enough to warrant adequate numbers for analysis.19 Our results from 5517 patients showed that complete LBBB develops in as many as 25% of patients with CHF of any origin and is associated with a 70% increase in the univariate risk of all-cause mortality rate at 1 year. At univariate analysis, complete LBBB was also associated with a series of CHF-specific indicators of disease severity, and the relevance of these findings was further supported by the observation that drugs that are commonly used in the routine control of CHF symptoms were prescribed more frequently to patients with LBBB than to those without LBBB. Conversely, patients without LBBB more frequently underwent treatment with antiischemic or antithrombotic agents, a finding consistent with the observation that ischemic heart disease was the most frequent cause of CHF in this subgroup. Such complex relationships needed to be accounted for in multivariate models that included several clinical variables together with drug prescriptions. In fact, ACE inhibitors, which were more frequently prescribed to patients with LBBB, are well shown to be able to reduce mortality rate in CHF,21,22 and a similar result also can be obtained with antiplatelet agents23 and βblockers,24,25 which were used more frequently in patients without LBBB. In this perspective, the strength of our results is increased by the observation that, even after adjusting for a large number of covariates that included the most relevant variables that describe CHF severity and prescriptions of these pharmacologic agents, LBBB retained its unfavorable, independent prognostic value, consisting of a 36% adjusted increase in all-cause mortality rate at 1 year. In the multivariate model predicting the risk of sudden death, the presence of LBBB maintained a quantitatively similar effect, with an increase in the risk of almost 35%. Consistent with previous findings from large randomized, controlled trials, our observational data showed a protective effect of ACE inhibitors21,22 and β-blockers24,25 against all-cause death. Prescription of antiplatelet agents was not associated with such a significant protective effect that, however, had been previously proven only in a subanalysis of the Studies of Left Ventricular Dysfunction trial.23 In the largest of the previous studies that showed the unfavorable prognostic significance of intraventricular conduction defects in CHF, age, creatinine level, heart rate, and left ventricular ejection fraction were the other independent predictors of 1-year total mortality rate,18 and in our study, left ventricular ejection fraction was not confirmed to be an independent predictor of death after multivariate analysis. This difference might derive from several other variables that we took into account which might have overridden the variance

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attributable to left ventricular ejection fraction. Among these we included NYHA classification, which, even though in gross terms, may well reflect exercise capacity, which has been proven as an important prognostic factor in CHF.3,5-7 Asynchrony of left ventricular contraction26 and impairment in the systolic and diastolic left ventricular function8,9 induced by complete LBBB have been clearly proven. In 1990, Hochleitner et al27 showed that optimizing the atrioventricular delay with dualchamber cardiac pacing can improve the hemodynamic profile of patients with CHF. These results were not confirmed by other authors,28 and, even more importantly, because only right ventricular pacing is involved, this proposed strategy cannot be relevant to treatment of LBBB, for which prognosis is actually worse. Multisite stimulation with the purpose of restoring ventricular relaxation and contraction sequences to as homogeneous as possible appears to be more promising, particularly for patients with LBBB. Indeed, in patients with CHF, multisite cardiac pacing can increase the abnormally shortened left ventricular filling time while simultaneously decreasing the interventricular septal dyskinesia—thereby improving left ventricular contractility (dP/dt)—and mitral valve regurgitation.29 Several studies have recently shown that left29,30 and biventricular cardiac pacing31-33 of patients with CHF and complete bundle-branch block can improve exercise tolerance, clinical status, healthrelated quality of life, and neurohormonal profile and can reduce the hospitalization rate. Uncertainties remain regarding the role of QRS duration or QRS shortening as predictors of the response34 and the population of patients more likely to receive a benefit from resynchronization therapy.35 A recent review of the available literature suggests that patients with QRS duration of more than 150 ms associated with significant mitral regurgitation and P-R prolongation possibly could receive the most relevant benefit from resynchronization strategies.30,35,36 However, it has not yet been shown that this therapeutic approach can also improve the survival rate of patients with CHF. Our results provide a support to warrant controlled studies, adequately powered to specifically investigate this unsolved issue. There are some limitations in our study that must be acknowledged. Because of the original purpose of the database that we used for this analysis, examination of electrocardiogram and measurement of QRS duration were not carried out in a single, core laboratory with standardized, blinded methods and quality control techniques. For this reason, we decided to limit the analysis only to the effect of a definite diagnosis of complete LBBB that, beyond morphologic criteria, was further confirmed with a QRS duration of more than 140 ms and, most importantly, was made in any case by quali-

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fied cardiologists. Another limitation is represented by the fact that patients with complete 1-year follow-up data who were excluded from the analysis were more frequently women and presented a higher prevalence rate of NYHA classification III to IV CHF. However, this difference reflects predominantly the higher frequency of valvular heart disease among women,19 a cause of CHF that was not included in this analysis because its natural history and management are completely different from that of CHF as the result of ischemic heart disease or dilated cardiomyopathy. Another limitation, common to all observational and randomized control trials for CHF, was represented by the fact that cause of CHF was diagnosed without requiring a systematic use of coronary angiographic data determining a possible underestimation of the rate of ischemic cause.37 However, the relative prevalence of dilated cardiomyopathy and ischemic heart disease that we found in such a large population was consistent with data from other studies of patients with CHF in which coronary angiographic data were not systematically obtained.38 We also did not make any attempt at simultaneous adjustment for significant comorbidities other than renal failure, a limitation that becomes particularly important if we consider that CHF is becoming a sort of geriatric epidemic1,2 and that older patients commonly have an increased burden of concomitant diseases that may affect their overall prognoses.35 In this sense, our registry of outpatients followed by cardiologists included a CHF population with a mean age lower than that generally observed in surveys conducted by internal medicine physicians, general practitioners, or geriatricians. Finally, the definition of sudden death was not standardized but, rather, was on the basis of the individual judgment expressed by the responsible cardiologist at each center. However, it must be pointed out that the almost 50% prevalence rate of sudden death that we observed in our study is in keeping with results from previous studies of patients with CHF.39,40 In spite of these limitations, we believe that our analysis provides important information to support the view that complete LBBB is unequivocally associated with greater disease severity and mortality in patients with CHF. The cause-and-effect relationship of this association, and whether correction of left ventricular asynchrony caused by the intraventricular conduction defect may reduce such an increased risk of mortality, should be investigated with adequately powered and properly designed studies.

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3. Cohn JN, Rector TS. Prognosis of congestive heart failure and predictors of mortality. Am J Cardiol 1988;62:25A-30. 4. Carson P, Johnson G, Fletcher R, et al. Mild systolic dysfunction in heart failure (left ventricular ejection fraction > 35%): baseline characteristics, prognosis and response to therapy in the Vasodilator in Heart Failure Trials (V-HeFT). J Am Coll Cardiol 1996;27:642-9. 5. Opasich C, Pinna GD, Bobbio M, et al. Peak exercise oxygen consumption in chronic heart failure: toward efficient use in the individual patient. J Am Coll Cardiol 1998;15:776-5. 6. Myers J, Gullestad L, Vagelos R, et al. Cardiopulmonary exercise testing and prognosis in severe heart failure: 14 mL/kg/min revisited. Am Heart J 2000;139:78-84. 7. Willenheimer R, Erhardt LR. Value of 6-min-walk test for assessment of severity and prognosis of heart failure. Lancet 2000;355:515-6. 8. Grines CL, Bashore TM, Boudoulas H, et al. Functional abnormalities in isolated left bundle-branch block. The effect of interventricular asynchrony. Circulation 1989;79:845-53. 9. Xiao HB, Lee CH, Gibson DG. Effect of left bundle-branch block on diastolic function in dilated cardiomyopathy. Br Heart J 1991;66: 443-7. 10. Kelly TL, Cremo R, Nielsen C, et al. Prediction of outcome in latestage cardiomyopathy. Am Heart J 1990;119:1111-21. 11. Fappani A, Caprini L, Benedini G, et al. The prognosis of the patient with heart failure: an analysis of the most significant clinical and instrumental parameters. Cardiologia 1991;36:431-8. 12. Koga Y, Wada T, Toshima H, et al. Prognostic significance of electrocardiographic findings in patients with dilated cardiomyopathy. Heart Vessels 1993;8:37-41. 13. Gavazzi A, De Maria R, Porcu M, et al. Dilated cardiomyopathy: a new natural history? The experience of the Italian Multicenter Cardiomyopathy Study (SPIC). G Ital Cardiol 1995;25:1109-25. 14. Huang X, Shen W, Gong L. Clinical significance of complete left bundle-branch block in dilated cardiomyopathy. Chin Med Sci J 1995;10:158-60. 15. Xiao HB, Roy C, Fujimoto S, et al. Natural history of abnormal conduction and its relation to prognosis in patients with dilated cardiomyopathy. Int J Cardiol 1996;53:163-70. 16. Juilliere Y, Barbier G, Feldmann L, et al. Additional predictive value of both left and right ventricular ejection fractions on long-term survival in idiopathic dilated cardiomyopathy. Eur Heart J 1997;18:276-80. 17. Shamim W, Francis D, Yousufuddin M, et al. Intraventricular conduction delay. A predictor of mortality in chronic heart failure? Eur Heart J 1998;19(Suppl P):P926. 18. Gottipaty V, Krelis S, Lu F, et al. The resting electrocardiogram provides a sensitive and inexpensive marker of prognosis in patients with chronic congestive heart failure. J Am Coll Cardiol 1999; 33(suppl A):145A. 19. Opasich C, Tavazzi L, Lucci D, et al. Comparison of one-year outcome in women versus men with chronic congestive heart failure. Am J Cardiol 2000;86:26-30. 20. The Task Force on Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis of heart failure. Eur Heart J 1995;16:741-51. 21. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-35. 22. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302. 23. Al-Khadra AS, Salem DN, Rand WM, et al. Antiplatelet agents and

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survival: a cohort analysis from the Studies of Left Ventricular Dysfunction (SOLVD) trial. J Am Coll Cardiol 1998;31:419-25. Packer M, Colucci WS, Sackner-Bernstein JD, et al. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise. Circulation 1996;94:2793-9. Australia/New Zealand Heart Failure Research Collaborative Group. Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet 1997;349:375-80. Rosenbush SW, Ruggie N, Turner DA, et al. Sequence and timing of ventricular wall motion in patients with bundle-branch block. Assessment by radionuclide cineangiography. Circulation 1982;66:1113-9. Hochleitner M, Hortnagl H, Ng CK, et al. Usefulness of physiologic dual-chamber pacing in drug-resistant idiopathic dilated cardiomyopathy. Am J Cardiol 1990;66:198-202. Innes D, Leicth JW, Fletcher PJ. VDD pacing at short atrioventricular intervals does not improve cardiac output in patients with dilated heart failure. Pace 1994;17:959-65. Blanc JJ, Etienne Y, Gilard M, et al. Evaluation of different ventricular pacing sites in patients with severe heart failure: results of an acute hemodynamic study. Circulation 1997;96:3273-7. Kass Da, Chen CH, Curry C, et al. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 1999;99:1567-73. Saxon LA, Boehmer JP, Hummel J, et al. Biventricular pacing in patients with congestive heart failure: two prospective randomized trials. The VIGOR CHF and VENTAK CHF Investigators. Am J Cardiol 1999;83:120D-3. Auricchio A, Stellbrink C, Sack S, et al. The Pacing Therapies for Congestive Heart Failure (PATH-CHF) study: rationale, design, and endpoints of a prospective randomized multicenter study. Am J Cardiol 1999;83:130D-5. 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. Alonso C, Leclerq C, Victor F, et al. Electrocardiographic predictive factors of long term clinical improvement with multisite biventricular pacing in advanced heart failure. Am J Cardiol 1999;84:1417-21. Tavazzi L. Ventricular pacing: a promising new therapeutic strategy in heart failure. Eur Heart J 2000;21:1211-4. Cazeau S, Gras D, Lazarus A, et al. Multisite stimulation for correction of cardiac asynchrony [editorial]. Heart 2000;84:579-81. Fox KF, Cowie MR, Wood DA, et al. Coronary artery disease as the cause of incident failure in the population. Eur Heart J 2001; 22:228-36. Follath F, Cleland JG, Klein W, et al. Etiology and response to drug treatment in heart failure. J Am Coll Cardiol 1998;32:1167-72. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Interventional Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-7. Teerlink JR, Jalaluddin M, Anderson S, et al, on behalf of the PROMISE (Prospective Randomized Milrinone Survival Evaluation) Investigators. Ambulatory ventricular arrhythmias in patients with heart failure do not specifically predict an increased risk of sudden death. Circulation 2000;101:40-6.

Appendix Participating centers and investigators Piemonte Borgomanero (A. Mezzani, M. Bielli); Cuneo (U. Milanese, G. Ugliengo); Orbassano (R. Pozzi, F. Rabajoli);

American Heart Journal March 2002

Veruno (E. Bosimini); Valle d’Aosta Aosta (G. Begliuomini); Lombardia Belgioioso (A. Ferrari, F. Barzizza); Bergamo (M.G. Valsecchi, F. Dadda); Brescia (P. Faggiano); Cassano D’Adda (G. Castiglioni, G. Gibelli); Chiari (A.L. Turelli); Como (R. Belluschi); Cremona (C. Bianchi, C. Emanuelli); Desio (S. Gramenzi, G. Foti); Erba Medicina (D. Agnelli); Esine (G. Mascioli); Garbagnate Milanese (E. Cazzani); Gussago (E. Zanelli, D. Domenighini); Legnano (C. Castelli); Mariano Comense (E. Moroni); Milano Fondazione Don Gnocchi (E. Gara); Milano Osp Sacco Medicina (S. Guzzetti, S. Muzzupappa, M. Turiel, E. Cappiello, G. Sandrone); Milano Osp Niguarda II Cardiologia (F. Recalcati); Milano Pio Albergo Trivulzio (D. Valenti); Monza (F. Achilli, A. Vincenzi); Passirana (F. Rusconi, M. Palvarini); Pavia Policlinico San Matteo (S. Ghio, A. Fontana, A. Giusti, L. Scelsi, R. Sebastiani, M. Ceresa); Pavia I.I.A.A.R.R. S. Margherita (A. Ferrari); Saronno (D. Nassiacos, S. Meloni); Seriate (T. Nicoli); Sondalo (P. Bandini); Tradate Fondazione Maugeri (R. Pedretti, M. Paolucci); Tradate Osp Di Circolo Galmarini (L. Amati, M. Ravetta); Varese Osp Di Circolo (F. Morandi, S. Provasoli); Varese Osp Di Circolo Medicina (A. Bertolini, D. Imperiale, W. Agen); Vizzolo Predabissi (E. Planca, P. Quorso); P. A. di Trento Rovereto (A. Ferro); Rovereto Medicina (C. Pedrolli); Veneto Belluno (P. Russo, L. Tarantini); Castelfranco Veneto (G. Candelpergher); Conegliano Veneto (P.P. Cannarozzo); Feltre (F. De Cian, A. Agnoli); Montebelluna (M.G. Stefanini); Padova (L. Cacciavillani, G.M. Boffa); Pieve Di Cadore (L. Mario); Treviso (G. Renosto, P. Stritoni); Vicenza (L. Varotto, M. Penzo); Villafranca (G. Perini); Friuli Venezia Giulia Gorizia (G. Giuliano); Monfalcone (E. Barducci); San Vito al Tagliamento (R. Piazza); Udine Osp S. M. della Misericordia (M.C. Albanese, C. Fresco); Udine Casa di Cura (F. Picco, P. Venturini); Liguria Arenzano (A. Camerini, R. Griffo); Genova Osp Galliera (G. Derchi, L. Delfino); Genova-Sestri Ponente (L. Pizzorno); Genova Osp S. Martino (S. Mazzantini, F. Torre); Rapallo (S. Orlandi); Sarzana (D. Bertoli); Sestri Levante (A. Gentile); Emilia Romagna Bologna Poliambulatorio Tiarini (F. Naccarella, M. Gatti, M. Coluccini); Forlì (G. Morgagni); Modena Osp Sant’Agostino (G. Alfano); Modena Policlinico (L. Reggianini, S. Sansoni); Parma (W. Serra); Piacenza (F. Passerini); Riccione (P. Del Corso, L. Rusconi); Rimini (M. Marzaloni, M. Mezzetti), Scandiano (G.P. Gambarati); Toscana Castelnuovo Garfagnana (P.R. Mariani, C. Volterrani); Empoli (F. Venturi); Firenze Osp S. M. Nuova (G. Zambaldi); Firenze Osp Nuovo S. Giovanni di Dio (G. Casolo); Firenze Azienda Osp Careggi (G. Moschi); Fucecchio (A. Geri Brandinelli); Grosseto (G. Miracapillo); Lucca (A. Boni); Pescia (G. Italiani, W. Vergoni); Pisa Osp Santa Chiara (A.M. Paci); Pontedera (F. Lattanzi, B. Reisenhofer); San Giovanni Valdarno (D. Severini, T. Taddei); Viareggio (A. Dalle Luche, A. Comella); Umbria Foligno (U. Gasperini); Gubbio (M. Cocchieri); Perugia Monteluce (G. Alunni, E. Bosi, R. Panciarola); Spoleto (G. Maragoni, G. Bardelli); Marche Ancona Osp Sestilli (P. Testarmata); Ancona Osp Lancisi Centro Medicina Sociale (L. Pasetti, A. Budini); Ancona Osp Lancisi II Cardiologia (D. Gabrilelli); Camerino (B. Coderoni); Lazio Albano Laziale (P. Midi); Grottaferrata (C. Romaniello); Roma INRCA (D. Del Sindaco, F. Leggio); Roma Osp Forlanini (A. Terranova); Roma Osp San Camillo II Cardiologia (G. Pulignano); Roma Osp San Camillo Servizio (F. Pozzar); Roma Osp S. F. Neri (G. Ansalone, B. Magris, P. Giannantoni); Roma Osp S. Giovanni (G. Cacciatore, G. Bottero, G. Scaffidi); Roma Osp Sandro Pertini (C. Valtorta, A. Salustri); Roma Osp Sant’Euge-

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nio (F. Amaddeo, G. Barbato); Roma Osp Santo Spirito (N. Aspromonte); Roma Osp Cristo Re (V. Baldo, E. Baldo); Abruzzo Popoli (C. Frattaroli, A. Mariani); Vasto (G. Di Marco, G. Levantesi); Molise Larino (A.P. Potena), Termoli (N. Colonna, A. Montano); Campania Napoli Osp Monaldi Medicina (P. Sensale, V. Rullo); Napoli Osp S. Gennaro (A. Somelli); Nola (F. Napolitano, P. Provvisiero); Oliveto Citra (P. Bottiglieri); Puglia Bari Policlinico (N. Ciriello); Brindisi (E. Angelini, C. Andriulo); Casarano (F. De Santis); Francavilla Fontana (F. Cocco); Galatina Medicina (A. Zecca); Gallipoli (A. Pennetta, F. Mariello); Lecce Osp Fazzi (F. Magliari, A. De Giorgi, M. Callerame); Mesagne (V. Santoro); San Pietro Vernotico (S. Pede, A. Renna); Scorrano (O. De Donno, E. De Lorenzi); Taranto Osp SS. Annunziata (G. Polimeni, V.A. Russo); Tricase (R. Mangia); Basilicata Policoro (L. Truncellito); Calabria Belvedere Marittimo (F.P. Cariello); Catanzaro Policlinico Servizio (M. Affinita); Catanzaro Policlinico Divi-

sione (F. Perticone, C. Cloro, D. Borelli); Cetraro (M. Matta, D. Lopresti); Cosenza Osp Dell’Annunziata (G. Misuraca, R. Caporale); Cosenza Osp Dell’Annunziata Medicina (P. Chiappetta); Reggio Calabria Osp Morelli (E. Tripodi, F. Tassone); Rossano (S. Salituri); Siderno (C. Errigo); Trebisacce (G. Meringolo, L. Donnangelo); Sicilia Avola (G. Canonico); Catania Osp Cannizzaro (R. Coco, M. Franco); Messina Osp Papardo (A. Coglitore, A. Donato); Messina Osp Piemonte (G. Di Tano); Messina Policlinico (D. Cento, C. De Gregorio); Palermo Casa Del Sole (M. Mongiovì); Palermo Osp Buccheri La Ferla FBF (A.M. Schillaci); Palermo Osp Civico (U. Mirto); Palermo Osp Ingrassia (F. Clemenza); Palermo Villa Sofia (F. Ingrillì); Piazza Armerina (A Cavallaro, B. Aloisi); Trapani (G. Ledda, C. Rizzo); Sardegna Cagliari Brotzu (M. Porcu, S. Salis, L. Pistis); Cagliari Osp SS. Trinità (G. Pili, S. Piras); Nuoro (I. Maoddi); Sassari (F. Uras).

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