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European Journal of Heart Failure 2004 6(4):463-466; doi:10.1016/j.ejheart.2003.12.007
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© 2004 European Society of Cardiology

Beneficial effects of carvedilol on angiotensin-converting enzyme activity and renin plasma levels in patients with chronic heart failure

Alain Cohen Solala,*, Guillaume Jondeaub, Florence Beauvaisa and Alain Berdeauxc

a Service de Cardiologie, Centre Hospitalier Universitaire Beaujon, Assistance Publique – Hôpitaux de Paris, Faculté Xavier Bichat Hôpital Beaujon, 100 Boulevard du Général Leclerc, 92110 Clichy, France
b Service de Cardiologie, Centre Hospitalier Universitaire Ambroise Paré, Assistance Publique – Hôpitaux de Paris, Faculté Paris Ile de France Ouest, Université Versailles Saint Quentin Boulogne, France
c Service de Pharmacologie, Centre Hospitalier Universitaire Kremlin Bicêtre Faculté du Kremlin Bicêtre, Le Kremlin Bicêtre, France

* Corresponding author. Tel.: +33-1-40-87-57-85; fax: +33-1-40-87-08-38. E-mail address: alain.cohen-solal{at}bjn.ap-hop-paris.fr


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
Objective: To assess the effects of carvedilol treatment on the renin–angiotensin system in patients with chronic heart failure (CHF).

Background: Carvedilol improves survival of patients suffering from CHF but the effects of the drug on angiotensin-converting enzyme (ACE) activity, renin and aldosterone are not well characterized in patients receiving an ACE inhibitor.

Methods: A randomized, multicenter, double-blind, 6-month, placebo-controlled study of carvedilol vs. placebo was conducted in 64 CHF patients. Circulating levels of ACE activity, active renin and aldosterone as well as left ventricular diameters and ejection fraction by echography were assessed.

Results: During the study, left ventricular ejection fraction increased from 25±11% to 31±12% with carvedilol and from 27±12% to 28±12% with placebo (P=0.03). This beneficial effect was associated with marked blunting of active renin secretion (–53% in the carvedilol group vs.–13% in the placebo group, P=0.04). ACE activity was reduced by 30% in the carvedilol group (P=0.07 vs. placebo). Aldosterone was not changed.

Conclusion: Carvedilol markedly reduced the increase in active renin observed with time despite ACE-inhibitors and tended to decrease ACE activity. These findings may in part explain the beneficial actions of carvedilol and highlights the profound effect of betablockade on renin in patients already receiving ACE-inibitors.

Key Words: Carvedilol • Angiotensin-converting enzyme (ACE) • Renin

Received May 6, 2003; Revised October 7, 2003; Accepted December 11, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
Beta-blockers have beneficial effects in patients with chronic heart failure (CHF) [1,2] but their exact mechanisms of action, however, remain unclear. Their effects on the renin–angiotensin system, although long recognized in hypertension [3], have seldom been considered in CHF patients simultaneously treated with an angiotensin converting enzyme (ACE) inhibitor.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
This was a double-blind, parallel, placebo-controlled trial to investigate the effect of carvedilol on cardiac sympathetic drive and oxidative stress in patients with CHF. The results of the principal analysis have been reported [6]. A secondary end-point of the study was to assess the effect of treatment on neuro-hormonal variables, and these results are presented here.

Patients with CHF, in NYHA class II–III, with a left ventricular ejection fraction (LV EF) less than 40%, receiving at least diuretics and ACE-inhibitors were eligible for the study. The exclusion criteria were as follows: stenotic valvulopathy, hypertrophic or restrictive cardiomyopathy, symptomatic cardiac arrhythmias not controlled by treatment or by a cardiac defibrillator; unstable angina; recent myocardial infarction; myocarditis; sinus node dysfunction; pace-maker implanted; 2nd or 3rd degree atrioventricular block; bradycardia <60 min–1; sitting systolic arterial pressure <90 mmHg; asthma or COPD; non-equilibrated insulin-dependent diabetes mellitus; hepatic insufficiency; severe renal insufficiency (plasma creatinine >250 micromol/l); pregnancy. The protocol was approved by the local ethical committee and informed consent was obtained in all patients.

Patients were randomized 1/1 to receive either carvedilol (starting at 3.125 mg twice daily, uptitrated every 2 weeks to 25 mg BID) or a placebo. The study drug dosage was maintained constant throughout the trial. The final evaluation was made after 6 months of treatment, while the patients were still receiving the allocated study drug.

All evaluations, except maximal exercise testing, were made at baseline and repeated at the end of the study. Blood tests were done in the morning, with the patients in the supine position and at rest for 1 h. Active renin and aldosterone plasma levels were measured by immunoassay [4] and plasma ACE activity was measured by the method of Cushman and Cheung [5]. Plasma catecholamines were measured by high phase liquid chromatography. At echocardiography, left ventricular end diastolic and end systolic diameters were measured from a parasternal long axis view on a two-dimensional guided TM recording at 50 mm/s. All videotapes were analyzed blind by a core laboratory. Left ventricular ejection fraction was measured by radionuclide ventriculography by a central core laboratory. Functional status was evaluated by the NYHA classification. Baseline exercise capacity was assessed by a cardiopulmonary exercise test.

Variables are described by their mean and standard deviation (S.D.). Statistics were done with the SAS program. Student's t-test was used for continuous variables in case of normality of the distribution and equality of the variances. Otherwise, a Wilcoxon non-parametric test was used. A Chi2 test was used for categorical variables. The statistical significance level was set at P<0.05. Results are presented according to the intention-to-treat method.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
Sixty-four patients were selected. Seven patients were included but not randomized and seven others dropped out before the end of the study. Therefore, 50 patients were randomized and are included in the statistical analysis. The main results of the trial have been presented elsewhere [6].

There were 42 men and eight women, with a mean age of 59±10 years (Table 1). Etiology of heart failure was primary cardiomyopathy in 29 cases, ischemic heart disease in 20 cases and previous hypertension was present in 10 cases (some patients had more than one etiology for heart failure). Thirty-nine patients were in NYHA class II and 11 in class III; 96% (all but two) of the patients were in sinus rhythm. Both groups were comparable regarding demography, EF, functional class, exercise capacity and hormonal values, except for norepinephrine (Tables 1 and 2).


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  		Table 1 Baseline variables

 


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  		Table 2 Results at baseline and at the end of the study

 
There was one sudden death in each group. Four patients receiving placebo presented a decompensation during the study period compared with none of the patients receiving carvedilol (P<0.05).

Carvedilol significantly improved LVEF as compared to placebo (Table 2). End-diastolic and end-systolic left ventricular diameters significantly decreased with carvedilol but not with placebo. A beneficial effect of the active treatment on functional status was reported by patients (P=0.003): functional class improved in 85% of the patients receiving carvedilol compared to only 33% of the patients receiving placebo.

Carvedilol treatment reduced the plasma active renin by more than 50% (P=0.04 vs. placebo) and plasma ACE activity by 30% (P=0.07) (Fig. 1). There was no significant difference in aldosterone or norepinephrine in the two groups of patients at the end of the study.


Figure 1
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  		Fig. 1 Active renin (left), and ACE activity (right) in the placebo and the carvedilol groups at baseline and after 6-months treatment. P values are for changes from baseline to 6-months between placebo and carvedilol.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 Acknowledgments
 References
 
Beta-blockers exert beneficial actions in patients with CHF, mainly by reducing cardiac sympathetic drive, but depression of the renin–angiotensin system may also play a significant, but overlooked, role.

Six-months treatment with carvedilol in the present study clearly afforded a beneficial effect on symptoms, hospitalization rate and left ventricular remodeling, concommitent with a 50% reduction in active renin in the plasma, raising the possibility that a marked down-regulation of the renin–angiotensin system may participate in the beneficial effect of this drug. A decrease in renin activity with betablockers in CHF patients has also been reported in other open-label studies [7,8] and in the RESOLVD study [9].

In the placebo group, ACE activity tended to increase at 6 months. This illustrates the escape from ACE inhibition that may occur with time, despite continuous treatment with ACE-inhibitors [10]. Whether this results from a true pharmacological tolerance to these drugs or from a natural progression of the disease needs to be clarified. Conversely, ACE activity tended to be reduced by the addition of carvedilol (P=0.07) while the dosage of ACE-inhibitor remained constant throughout the study in both groups of patients. We are unaware of any study having previously assessed the effects of betablockers on ACE activity in CHF patients. In normal subjects, suppression of plasma ACE activity induced by ACE-inhibitors was unchanged when a betablocker was added [11,12]. The mechanism of this interaction is unknown. In rabbit endothelial cells, ACE activity is increased by isopreterenol via activation of the ACE promoter [13], suggesting a direct effect of adrenergic stimulation. Decreased ACE activity with carvedilol may also result from decreased angiotensin I formation secondary to decreased renin secretion. Overall these results suggest that carvedilol may prevent ACE-inhibitor tolerance and potentiates their inhibitory effects on the renin–angiotensin system. In fact, most of the studies reporting an increase in angiotensin II levels with time in patients with heart failure were performed before the widespread use of beta-blockade, so that escape to ACE-I has mainly been documented in patients in the absence of beta-blocker therapy.

Active renin level was strongly decreased by carvedilol, a finding in agreement with that of Holmer et al. in hypertension [14] and after myocardial infarction [15] with various beta-blockers. However, as it is now demonstrated with ACE-inhibitors, the parallel inhibition of aldosterone production was minor despite the marked reduction in renin. Although we did not measure plasma angiotensin II, it has been shown to be decreased by beta-blockers in hypertension [3] and in heart failure [16], a result in keeping with the inhibitory effect of beta-blockade on ACE activity reported in our study.

Part of the beneficial effect of carvedilol could, therefore result from its inhibitory action on the renin angiotensin system, complementary to that of ACE-inhibitors. The beneficial effect of the combination of both drugs in congestive heart failure may result from the ability of betablockers to (1) further decrease renin angiotensin system upstream of the site of action of ACE-inhibitors; and (2) to avoid the escape of ACE inhibition observed during long term therapy with ACE inhibitors given alone.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
Acknowledgments
 References
 
Carvedilol decreased ACE activity and markedly blunted the progressive increase in active renin observed with time in the placebo group despite ongoing ACE-inhibitor treatment. These findings may partly explain the beneficial effects of carvedilol, especially on cardiac remodelling.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
References
 
This study was granted by Carveteam, thenProduits Roche groups. We thank Bernard Caviezel, Amin Kadi, Angela Moryussef, and Laurent Joubert for their help in the design of the protocol; Cecile Jourdan and François Montestruc for the statistical analysis of the data.


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

  1. Heidenreich P.A., Lee T.T., Massie B.M. Effect of beta-blockade on mortality in patients with heart failure: a meta-analysis of randomized clinical trials. J Am Coll Cardiol (1997) 30:27–34.[Abstract]
  2. Lechat P., Packer M., Chalon S., Cucherat M., Arab T., Boissel J.P. Clinical effects of beta-adrenergic blockade in chronic heart failure: a meta-analysis of double-blind, placebo-controlled, randomized trials. Circulation (1998) 98:1184–1191.[Abstract/Free Full Text]
  3. Blumenfeld J., Sealey J., Mann S., et al. adrenergic receptor blockade as a therapeutic approach for suppressing the renin–angiotensin–aldosterone system in normotensive and hypertensive subjects. Am J Hypertension (1999) 12:451–459.[CrossRef][Web of Science][Medline]
  4. Menard J., Guyenne T., Corvol P., Pau B., Simon D., Ronducci R. Direct immunometric assay of active renin in human plasma. J Hypertension (1985) 3(suppl_3):5275–5278.
  5. Cushman D., Cheung H. Spectrophotometric assay and properties of angiotensin-converting enzyme of rabbit lung. Biochem Pharmacol (1971) 20:1637–1648.[CrossRef][Web of Science][Medline]
  6. Cohen-Solal A., Merlet P., Delahaye N., et al. Effects of six months carvedilol treatment on cardiac sympathetic activity in patients with chronic heart failure: the SYMPOXYDEX trial (abstract). J Am Coll Cardiol (2001) 37(suppl A):420A.
  7. Eichhorn E.J., McGhie A.L., Bedotto J.B., et al. Effects of bucindolol on neurohormonal activation in congestive heart failure. Am J Cardiol (1991) 67:67–73.[CrossRef][Web of Science][Medline]
  8. Teisman A.C., van Veldhuisen D.J., Boomsma F., et al. Chronic beta-blocker treatment in patients with advanced heart failure. Int J Cardiol (2000) 73:7–12.[CrossRef][Web of Science][Medline]
  9. The RESOLVD Investigators. Effects of metoprolol XR in patients with ischemic or idiopathic cardiomyopathy. The randomized evaluation of strategies for left ventricular dysfunction pilot study. Circulation 2000; 101: 378–384.
  10. Struthers A.D. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in chronic heart failure. J Card Fail (1996) 2:47–54.[CrossRef][Medline]
  11. van Griensven J., Seibert Grafe M., Schoemaker H., Frolich M., Cohen A. The pharmacokinetic and pharmacodynamic interactions of ramipril with propranolol. Eur J Clin Pharmacol (1993) 4:255–260.
  12. Hansen E., Bendtesen F., Henriksen J. Effects of plasma angiotensin-converting enzyme activity and circulating renin of lisinopril and enalapril alone and in combination with propranolol in healthy volunteers. Pharmacol Toxicol (1999) 84:110–114.[Web of Science][Medline]
  13. Xavier-Neto J., Pereira C., Junquera M., Carmona R., Krieger J. Rat angiotensin-converting enzyme promoter regulation by beta-adrenergics and cAMP in endothelium. Hypertension (1999) 34:31–38.[Abstract/Free Full Text]
  14. Holmer S.R., Hense H.W., Danser A.H., Mayer B., Riegger G.A., Schunkert H. Beta adrenergic blockers lower renin in patients treated with ACE inhibitors and diuretics. Heart (1998) 80:45–48.[Abstract/Free Full Text]
  15. Holmer S.R., Hengstenberg C., Mayer B., et al. Marked suppression of renin levels by beta-receptor blocker in patients treated with standard heart failure therapy: a potential mechanism of benefit from beta-blockade. J Intern Med (2001) 249:167–172.[CrossRef][Web of Science][Medline]
  16. Campbell D.J., Aggarwal A., Esler M., Kaye D. Beta-blockers, angiotensin II, and ACE inhibitors in patients with heart failure. Lancet (2001) 358:1609–1610.[CrossRef][Web of Science][Medline]

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