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European Journal of Heart Failure 2004 6(1):17-21; doi:10.1016/j.ejheart.2003.09.006
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© 2004 European Society of Cardiology

Beta-adrenergic receptor blockade and the angiotensin-converting enzyme deletion polymorphism in patients with chronic heart failure

Pascal de Grootea, Nicole Helbecqueb, Nicolas Lamblina,b, Xavier Hermantb, Philippe Amouyelb, Christophe Bautersa,b,* and Jean Dallongevilleb

a Service de Cardiologie C, Hôpital Cardiologique Centre Hospitalier Universitaire de Lille, Boul Prof J Leclercq, 59037 Lille Cedex, France
b INSERM U508, Institut Pasteur de Lille 1 rue Calmette, 59010 Lille Cedex, France

* Corresponding author. Tel.: +33-3-20-44-50-45; fax: +33-3-20-44-48-81. E-mail address: cbauters{at}chru-lille.fr


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Beta-adrenergic receptor blockade is an established treatment of chronic heart failure (HF). Previous studies have suggested a potential pharmacogenetic interaction between beta-blocker therapy and the angiotensin-converting enzyme (ACE) I/D polymorphism in patients with HF.

Aims: We designed this study to analyze changes in myocardial function of HF patients in response to beta-blocker therapy as a function of the ACE I/D polymorphism.

Methods and results: We studied 199 consecutive patients with chronic HF not treated with beta-blockers. Before initiation of beta-blockers and 3 months after the maximal tolerated dose was reached, patients underwent echocardiography, radionuclide angiography, and a cardiopulmonary exercise test. We extracted genomic DNA from white blood cells and determined the ACE I/D polymorphism. Thirty-five (18%) patients had the II genotype, 86 (43%) the ID genotype and 78 (39%) the DD genotype. A significant and similar improvement in left ventricular ejection fraction (LVEF) was observed in II (from 0.30±0.10 to 0.41±0.13; P<0.0001), ID (from 0.29±0.11 to 0.39±0.13; P<0.0001) and DD patients (from 0.31±0.11 to 0.40±0.13; P<0.0001). Peak Vo2 before and after beta-blockade was similar among the three groups. The proportion of responders to beta-blockers (patients without cardiac events during titration who had an increase in LVEF >5% after beta-blockers) was similar among the three groups (II: 65.9%%, ID: 60.6%%, DD: 65.9%; P=NS). During a median follow-up of 933 days, there was no evidence for any effect of ACE I/D polymorphism on cardiac survival.

Conclusions: We observed no evidence of pharmacogenetic interaction between the ACE I/D polymorphism and the effects of beta-blockade on LVEF and other prognostic parameters in patients with chronic HF. Our results support the initiation of beta-blockers in HF patients with the II or the ID genotype as well as in those with the DD genotype.

Key Words: Congestive heart failure • Beta-blockers • Angiotensin converting enzyme • Polymorphism

Received May 7, 2003; Revised July 14, 2003; Accepted September 15, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Beta-adrenergic receptor blockade is an established treatment of chronic heart failure (HF). Mortality trials have clearly shown the beneficial effects of beta-blockers in patients with HF [1–3]. Although beta-blockers exert favourable effects in most patients, there is an inter-individual variability in the response, with some patients who are non-responders.

Previous studies have demonstrated important interactions between the renin–angiotensin and sympathetic nervous systems in patients with HF [4,5]. Recently, McNamara et al. [6] suggested a potential pharmacogenetic interaction between beta-blocker therapy and the angiotensin-converting enzyme (ACE) deletion polymorphism in patients with HF. In this study, beta-blocker therapy was associated with an improved transplant-free survival in DD patients but not in ID or II patients. Although this was a non-randomized observation, the demonstration of a genetically-defined subgroup of HF patients, who are non-responders to beta-blockers would have important clinical implications.

The exact mechanisms by which beta-blockers improve survival in HF patients are currently unknown, but various studies have documented a consistent long-term improvement in myocardial function [7–9]. In the Cardiac Insufficiency Bisoprolol Study (CIBIS), preservation of left ventricular function was found to play a key role in the beneficial effects of bisoprolol [10].

We thus designed a prospective study to analyze changes in myocardial function of HF patients in response to beta-blocker therapy, as a function of genetic polymorphisms. We report in this paper the impact of the ACE I/D polymorphism in 199 HF patients who had evaluation of left and right ventricular function and a cardiopulmonary exercise test both prior to initiation of beta-blockers and 3 months after the maximal dose was reached. We postulated that, with respect to pharmacogenetic modulation of beta-blocker therapy in HF, the effects of these drugs on intermediate parameters, such as left ventricular ejection fraction (LVEF), would be associated with the ACE gene polymorphism.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study population
All the patients referred to our department for a non-invasive prognostic evaluation of left ventricular systolic dysfunction before initiation of beta-blocker therapy were prospectively asked to enter this study. Patients were included if they were ambulatory, stable for at least 2 months and had a LVEF ≤45%. Patients were excluded if they had a recent (<3 months) myocardial infarction, unstable angina, or coronary revascularization. All patients underwent echocardiography, radionuclide angiography, and a cardiopulmonary exercise test as previously described [11]. Beta-blockers were started immediately after this first evaluation and the dose was progressively increased up to the maximal tolerated dose. Repeat evaluation was performed 3 months after the maximal tolerated dose was reached.

The study was approved by the ethics committee of our institution and written informed consent was obtained from all patients before inclusion.

Between April 1998 and December 2001, 233 consecutive patients were started on beta-blockers after an initial evaluation. Out of these 233 patients, 14 (6%) died and two had planned cardiac transplantation during titration of beta-blocker therapy; eight (3%) patients had side-effects requiring cessation of beta-blockers and three patients had non-cardiovascular complications. Among the 206 remaining patients who were eligible for a second prognostic evaluation 3 months after the maximal tolerated dose of beta-blockers was reached, seven (3%) patients refused the follow-up visit; thus, 199 patients had a non-invasive evaluation of HF, both before and after beta-blockers were added to their treatments and are the subject of this report.

2.2. Genetic analysis
Venous blood sampling was performed at the time of initial evaluation. Genomic DNA was extracted from white blood cells by a ‘salting out’ procedure as previously described [12]. The ACE fragment containing the I/D sequence was amplified by polymerase chain reaction (PCR). The ACE polymorphism was detected as previously described [13].

2.3. Follow-up
A clinical follow-up was performed by contact with the patients, the general practitioner or the cardiologist. Cardiac mortality was defined as cardiac death or urgent cardiac transplantation (United Network for Organ Sharing status 1).

2.4. Statistical analysis
Results are presented as mean±S.D. Comparisons between groups for continuous data were made with paired or unpaired Student t-tests, or ANOVA. Discrete variables were compared using a {chi}2-analysis. The Kaplan–Meier method was performed to estimate the cumulative survival with a comparative log-Rank test to compare survival rates of subgroups according to ACE polymorphism. Statistical analysis was performed with SPSS software (version 9, Chicago, IL). A value of P<0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
The baseline characteristics of the study population are shown in Table 1. The characteristics of the 199 patients who had the two consecutive evaluations did not differ from those of the overall population. Most of the patients were male (83%) with a mean age of 56±12 years, 37% of the patients had ischemic cardiomyopathy. Thirteen patients were not treated with ACE inhibitors, of whom 11 received angiotensin receptor blockers. One hundred and thirty patients were treated with bisoprolol (mean dose=8.7±2.5 mg/day) and 69 with carvedilol (55±27 mg/day).


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  		Table 1 Baseline characteristics of the study population at initial evaluation (before initiation of beta-blocker therapy)

 
Beta-blockers significantly improved radionuclide LVEF from 0.30±0.10 to 0.40±0.13 (P<0.0001). Similar results were obtained when using echocardiography for the evaluation of LVEF. The left ventricular end diastolic diameter was reduced by beta-blockers (from 65±9 to 63±9 mm, P=0.001). Beta-blockers significantly reduced heart rate, without affecting peak Vo2.

Thirty-five (18%) patients had the II genotype, 86 (43%) the ID genotype and 78 (39%) the DD genotype; the distribution was compatible with that expected from the Hardy–Weinberg equilibrium. As shown in Table 2, the baseline characteristics were similar among the three genotypes. We analyzed the response to beta-blockade as a function of the ACE genotype: a similar response was observed among the three groups. A significant and similar improvement in LVEF was observed in II (from 0.30±0.10 to 0.41±0.13; P<0.0001), ID (from 0.29±0.11 to 0.39±0.13; P<0.0001) and DD patients (from 0.31±0.11 to 0.40±0.13; P<0.0001). Peak Vo2 before and after beta-blockade was similar among the three groups. The improvement in LVEF did not differ among genotypes either in the bisoprolol or in the carvedilol subgroups (data not shown).


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  		Table 2 Clinical characteristics and response to beta-blockade of the 199 patients with two prognostic evaluations according to the ACE I/D polymorphism

 
Taking into account in the analysis, the patients who died during titration of beta-blockers or who did not undergo the repeat evaluation due to heart decompensation after initiation of beta-blockers, we defined responders and non-responders to beta-blockers in the 233 patients who had a first evaluation. Non-responders were patients who died or had cardiac complications related to beta-blockers, or had an increase in LVEF <5% after beta-blockade; responders were patients without cardiac events during titration who had an increase in LVEF >5% after beta-blockade [14]. There was no association between the ACE I/D polymorphism and the response to beta-blockers. The proportion of responders was similar among the three groups (II: 65.9%, ID: 60.6%, DD: 65.9%; P=NS).

Clinical follow-up was obtained for 233 patients; no patient was lost to follow-up. During a median follow-up period of 933 days, there were 46 cardiac-related deaths, six transplantations, of which one was urgent and two deaths from non-cardiac causes. There was no evidence of any effect of ACE I/D polymorphism on cardiac survival; cardiac-related death or urgent transplantation occurred in 10, 16, and 21 patients in the II, ID, and DD groups, respectively. The survival rates were similar in II, ID, and DD patients (Fig. 1).


Figure 1
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  		Fig. 1 Kaplan–Meier survival curves according to the ACE I/D polymorphism.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Our study demonstrates the lack of a relationship between the ACE gene polymorphism and the effect of beta-blockers on LVEF and other well-known prognostic parameters in patients with chronic HF.

The long-term effects of beta-blockers in HF have been well characterized. Placebo-controlled studies have consistently demonstrated favorable effects of beta-blockers on ventricular function and remodeling, which are believed to play an important role in the clinical benefits of these drugs. The significant improvement in LVEF observed in the 199 patients who were evaluated both before and 3 months after beta-blockade is concordant with previous studies [7–9]; the lack of improvement in peak Vo2 is also concordant with previous studies [8,15]

Beta-blockers are beneficial in HF populations but at the individual level the response may be highly variable. In the present study, 6% of the patients had a >5% decrease in LVEF while 17% had a >20% increase in LVEF. Although some predictive factors have been identified [16], the response to beta-blockade remains difficult to anticipate. This inter-individual variability may be at least in part the result of genetic heterogeneity. In humans, levels of ACE are partly under genetic control [17] and are correlated with an Insertion (I)/Deletion (D) polymorphism: DD genotypes have higher levels of ACE than either ID or II genotypes [18]. Recently, McNamara et al. reported that treatment with beta-blockers was associated with a significant improvement in transplant-free survival only in DD patients [6]; II and ID patients were not improved by beta-blocker therapy. These results were attributed to the important interactions that exist between the renin–angiotensin and sympathetic nervous systems in patients with HF. ACE inhibitor treatment leads to a reduction in circulating catecholamines [4] and to an increase in myocardial beta-receptor density [5]; thus, the genetic dependence of beta-blocker activity in HF patients could reflect modulation of the effect of beta-blockers in the setting of genetically determined variable renin-angiotensin activation. However, as acknowledged by the authors, this was a non-randomized observation which should thus be taken as hypothesis-generating rather than conclusive; indeed, the demonstration that the beneficial effects of beta-blockers in HF are restricted to the DD subgroup (32% of all HF patients in the study of McNamara, 39% in our study) would be of major importance in clinical practice.

Our results do not support the conclusion that beta-blockers are solely useful in DD patients; II and ID patients had highly significant improvements in ventricular function that were similar to those observed in DD patients. With a statistical power of 0.80 and a significance value of 0.05, the sample size of this study allowed us to detect a 6% difference in LVEF after beta-blockers in DD patients vs. ID+II patients. Other prognostic parameters such as peak Vo2 were also similar among the three genotype groups after initiation of beta-blocker therapy. Although our study was focused on intermediate endpoints and as such should be confirmed by large studies with clinical endpoints, it supports the initiation of beta-blockers in HF patients with the II or the ID genotype as well as those with the DD genotype. Our clinical results showing no impact of the ACE I/D polymorphism on cardiac survival in patients with beta-blockers do not exclude a possible impact in patients without beta-blockers. Finally, although the ACE I/D polymorphism does not appear as an important modulator of the response of HF patients to beta-blockade, other variations in important candidate genes will have to be tested to determine whether genetic heterogeneity accounts for the variability of the response.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet (1999) 353:9–13.[CrossRef][Web of Science][Medline]
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  4. Cody R.J., Franklin K.W., Kluger J., Laragh J.H. Sympathetic responsiveness and plasma norepinephrine during therapy of chronic congestive heart failure with captopril. Am J Med (1982) 72:791–797.[CrossRef][Web of Science][Medline]
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  7. Hall S.A., Cigarroa C.G., Marcoux L., Risser R.C., Grayburn P.A., Eichhorn E.J. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade. J Am Coll Cardiol (1995) 25:1154–1161.[Abstract]
  8. Olsen S.L., Gilbert E.M., Renlund D.G., Taylor D.O., Yanowitz F.D., Bristow M.R. Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomized study. J Am Coll Cardiol (1995) 25:1225–1231.[Abstract]
  9. Bristow M.R., Gilbert E.M., Abraham W.T., et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation (1996) 94:2807–2816.[Abstract/Free Full Text]
  10. Lechat P., Escolano S., Golmard J.L., et al. Prognostic value of bisoprolol-induced hemodynamic effects in heart failure during the Cardiac Insufficiency BIsoprolol Study (CIBIS). Circulation (1997) 96:2197–2205.[Abstract/Free Full Text]
  11. de Groote P., Millaire A., Foucher-Hossein C., et al. Right ventricular ejection fraction is an independent predictor of survival in patients with moderate heart failure. J Am Coll Cardiol (1998) 32:948–954.[Abstract/Free Full Text]
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  16. Lechat P., Hulot J.S., Escolano S., et al. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial. Circulation (2001) 103:1428–1433.[Abstract/Free Full Text]
  17. Cambien F., Alhenc-Gelas F., Herbeth B., et al. Familial resemblance of plasma angiotensin-converting enzyme level: the Nancy Study. Am J Hum Genet (1988) 43:774–780.[Web of Science][Medline]
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