Cardiomyopathies are an important and heterogeneous group of diseases. The European society of cardiology working group on myocardial and pericardial diseases has defined cardiomyopathy as ‘a myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality’1. It has grouped cardiomyopathies into five specific morphological and functional phenotypes – dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), arrhythmogenic right ventricular cardiomyopathy (ARVC) and unclassified cardiomyopathies1. In this article we will review the current role of beta blockers in these cardiomyopathies, mainly DCM and HCM.

Dilated Cardiomyopathy

Dilated cardiomyopathy is characterized by global decrease in myocardial contractility and left ventricular systolic function (LVSD). Myocardial systolic dysfunction is associated with neurohumoral activation which initially aims to preserve cardiac output. With time, elevated adrenergic tone and neurohormonal activity becomes counterproductive and leads to progressive structural remodeling marked by dilatation, hypertrophy, and declining left ventricular ejection fraction (LVEF).2,3 The level of neurohumoral activation correlates strongly with the risk of HF progression and death.4-6 Blockade of neurohormonal activation with beta blockers is especially important in retarding HF progression. However, β-blockers have been underused, possibly because of perceptions of adverse events, concerns of clinical worsening in patients with decompensated heart failure, or negative effects on short-term clinical outcomes.7 In this review, we discuss an evidence based approach, supporting the role of β-blockers in DCM.

Asymptomatic DCM Patients with Decreased LV systolic function

In asymptomatic DCM patients with LVSD, neurohumoral blockade with β-blockers may reverse ventricular remodeling, prevent progression to symptomatic HF, and improve clinical outcomes.8    Post hoc analysis of the Studies of Left Ventricular Dysfunction (SOLVD) - Prevention Trial which included 4223 asymptomatic patients with an LVEF ≤35% showed that 24%

of patients who were receiving both β-blockers and enalapril had significantly lower rates of mortality due to HF than those receiving only enalapril (p=0.003).9 Lower rates of arrhythmic and pump failure death and risk of death or hospitalization for heart failure were observed in patients receiving β-blockers in addition to enalapril. This trial had small number of patients with nonischemic LVSD.

In CARMEN (Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure Evaluation) trial, 572 mild heart failure patients were randomly assigned to carvedilol, enalapril or their combination.10 In the latter, carvedilol was up-titrated before enalapril.

LV end-systolic volume index (LVESVI) was reduced by 5.4 ml/m2 (p = 0.0015) in combination therapy compared to enalapril at 18 months. Carvedilol alone also significantly reduced LVESVI by 2.8 ml/m2 (p = 0.018) compared to baseline, whereas enalapril did not. In this trial, 33% of patients had non-ischemic LVSD. Thus CARMEN trial demonstrated that early combination of ACE-I and carvedilol reverses LV remodelling in patients with mild LVSD – both ischemic and non-ischemic.
REVERT (REversal of VEntricular Remodeling with Toprol-XL) Trial assessed the role of two different doses of extended-release metoprolol succinate  (200 mg or 50 mg) added to standard therapy for 1 year in reversing ventricular remodeling in 149 asymptomatic patients with LV EF < 40%.11 In this trial 54% of all patients had ischemic etiology. The higher dose metoprolol group had a significant decrease of 14.3 mL/m2 in LVSVI compared with placebo (p<0.05), whereas the lower dose group had no change compared with placebo.

Symptomatic DCM Patients

Several large, randomized, controlled clinical trials have documented the benefits of bisoprolol, carvedilol, and metoprolol succinate in the treatment of symptomatic patients with HF and LVSD (Table 1). These studies have included patients with both ischemic LVSD and DCM of other etiologies (33 to 52%). More than 90% of patients in these trials were on ACE inhibitors. The proven benefits of β-blockers for symptomatic patients with HF include decrease in all-cause mortality, cardiovascular mortality, mortality due to stoke and sudden deaths. β-blockers also decrease the risk of hospitalization, improve LVEF and clinical status, and decrease rate of disease progression

The US Heart Failure Program randomly assigned 1094 symptomatic heart failure patients with LVEF ≤ 35% to carvedilol or placebo.12 This study was prematurely stopped as it showed a remarkable 65% reduction in mortality in the carvedilol group compared to placebo over a mean follow-up of 6.7 months (p<0.001). In addition, carvedilol therapy was accompanied by a 27 percent reduction in the risk of hospitalization for cardiovascular causes (p=0.036), as well as a 38 percent reduction in the combined risk of hospitalization or death (24.6 percent vs.15.8 percent, p<0.001).
CIBIS II (Cardiac Insufficiency Bisoprolol Study II) trial compared bisoprolol, a β1 selective antagonist, with placebo in patients with LVEF ≤ 35%.13 This trial recruited patients with moderate to severe heart failure (NYHA III/IV) and 50 percent of patients had non-ischemic LVSD. During a mean follow-up of 1.3 years, bisoprolol group had significant reduction in all-cause mortality (34% reduction compared with placebo; p<0.0001), cardiac mortality (p=0.0049), hospitalization for any cause (p=0.0006), and hospitalization for worsening HF (32% reduction compared with placebo; p<0.0001).
MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure) trial evaluated the efficacy of controlled-release/extended-release metoprolol succinate in 3991 symptomatic HF patients (NYHA classes II to IV; LVEF ≤40%) stabilized with optimum standard treatment.14 After a mean follow-up of 1 year, metoprolol succinate reduced all-cause mortality by 34% (p=0.0062). There were significantly fewer sudden deaths in the metoprolol CR/XL group than in the placebo group (p=0·0002) and also fewer deaths from worsening heart failure (p=0·0023).
In BEST (β-Blocker Evaluation of Survival Trial) trial, bucindolol, a nonselective β-adrenergic antagonist, was compared with placebo in 2708 symptomatic patients (NYHA class III or IV; LVEF ≤35%) receiving optimal medical therapy including ACE inhibitors.15 After 2-year follow-up, there was a nonsignificant 10 percent reduction in all-cause mortality in the bucindolol arm (p=0.13). However, bucindolol significantly reduced cardiovascular mortality by 14% vs placebo (p=0.04) and also significantly decreased heart failure hospitalizations (p<0.001).
COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival Study) trial evaluated carvedilol in 2289 symptomatic HF patients with LVEF < 25%.16 There was 35% reduction in all cause mortality in the carvedilol group (p=0.001) and 27%

reduction in the combined risk of cardiovascular death or hospitalization (p=.00002).
COMET (Carvedilol or Metoprolol European Trial) trial compared carvedilol and metoprolol tartrate in patients with mild to moderate HF (LVEF < 35%).17 After a mean follow-up of 58 months, there was a significant reduction in all-cause mortality by 17% (p=0.0017) and cardiovascular mortality by 20% (p=0.0004) in the carvedilol arm compared to the metoprolol arm. Extrapolation from the survival curves suggested that carvedilol extended median survival by 1·4 years as compared with metoprolol tartarate.
A meta-analysis of 22 trials involving 10,135 stable patients with NYHA class II or III HF showed treatment with β-blockers results in 3.8 lives saved per 100 patients treated and 4.0 fewer hospitalizations per 100 patients treated.18
     In an uncontrolled and nonrandomized study, we studied the effect of propranolol in 56 symptomatic patients with DCM.19 There was a significant improvement in NYHA class, cardiothoracic ratio, and left ventricular end-diastolic dimension (p <0.01), while the LVEF increased from 23 to 35% (p < 0.001).

Decompensated DCM Patients

There is scarcity of data from large randomized trials for the use of β-blockers in decompensated HF. In a sub-analysis of COPERNICUS trial, involving high-risk subgroup of 624 patients (recent or recurrent cardiac decompensation [≥3 hospitalizations for HF within the previous year], need for intravenous inotropic or vasodilator therapy within 14 days before randomization, or baseline LVEF ≤15%), mortality risk was reduced by 39% in the carvedilol group compared to placebo (p=0.009).16 Predischarge initiation of β-Blockers in patients hospitalized for decompensated HF is well tolerated as demonstrated in IMPACT-HF trial.20 OPTIMIZE-HF trial evaluated the effect carvedilol use at the time of heart failure (HF) hospital discharge in 5791 patients in a web-based registry. Discharge use of carvedilol was associated with 54 percent reduction in mortality risk at 60 to 90 days (p = 0.0006) and 29 percent reduction in mortality or rehospitalization (p = 0.0175) compared to no predischarge β-blocker.21

 

Hypertrophic Cardiomyopathy

Propranolol was the first drug used in the medical management of HCM, and long-acting preparations of propranolol or agents such as atenolol, metoprolol, or nadolol have been employed more recently. Standard dosages of these drugs can mitigate disabling symptoms and limit the latent outflow gradient provoked during exercise when sympathetic tone is high and heart failure symptoms occur. However, there is little evidence that beta-blocking agents consistently reduce outflow obstruction under resting conditions.22 The beneficial effects of beta-blockers on symptoms of exertional dyspnea and exercise intolerance appear to be attributable largely to a decrease in the heart rate with a consequent prolongation of diastole and relaxation and an increase in passive ventricular filling. These agents lessen LV contractility and myocardial oxygen demand and possibly reduce microvascular myocardial ischemia. Large doses of propranolol (up to 1,000 mg per day) has been used and found to provide symptomatic benefit and improve long-term survival without major side effects in a small non-randomized trial.23

Conclusion

β-Blockers are a highly effective treatment for both asymptomatic and symptomatic patients with dilated cardiomyopathy. They reverse LV remodeling in both asymptomatic and symptomatic patients and improve survival and decrease hospitalization in symptomatic patients. Inspite of robust data from large randomized trials, β-blockers are significantly underutilized in this patient subset. Predischarge initiation of β-blockers in patients hospitalized with decompensated heart failure improves short term survival. β-blockers are effective first line therapy in symptomatic HCM patients with LV outflow track gradient at rest or on provocation.

References

1. Perry Elliott, Bert Andersson, Eloisa Arbustini, et al. Classification of the cardiomyopathies: a position statement from the european society of cardiology working group on myocardial and pericardial diseases. Eur Heart J. 2008;29:270–276
2. Cohn JN, Ferrari R, Sharpe N; International Forum on Cardiac Remodeling. Cardiac remodeling—concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J Am Coll Cardiol. 2000;35(3):569-582.
3. Packer M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure [editorial]. J Am Coll Cardiol. 1992;20(1):248-254.
4. Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311(13):819-823.
5. Francis GS, Cohn JN, Johnson G, Rector TS, Goldman S, Simon A; V-HeFT VA Cooperative Studies Group. Plasma norepinephrine, plasma rennin activity, and congestive heart failure: relations to survival and the effects of therapy in V-HeFT II. Circulation. 1993;87(6)(suppl):V140-V148.
6. Kaye DM, Lefkovits J, Jennings GL, Bergin P, Broughton A, Esler MD. Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol. 1995;26(5):1257-1263.
7. Ventura HO. Benefits of inpatient initiation of β-blockers. Am Heart J. 2004;148(6):944-950.
8. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline update for the diagnosis and management of chronic heart failure in the adult: Task Force on Practice Guidelines (Writing Committee to update the 2001 guidelines for the evaluation and management of heart failure). Circulation. 2005;112(12):e154-e235.
9. Exner DV, Dries DL, Waclawiw MA, Shelton B, Domanski MJ. Betaadrenergic blocking agent use and mortality in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a post hoc analysis of the studies of left ventricular dysfunction. J Am Coll Cardiol. 1999;33(4):916-923.
10. Remme WJ, Riegger G, Hildebrandt P, et al; CARMEN investigators and co-ordinators. The benefits of early combination treatment of carvedilol and an ACE-inhibitor in mild heart failure and left ventricular systolic dysfunction: the carvedilol and ACE-inhibitor remodelling mild heart failure evaluation trial (CARMEN). Cardiovasc Drugs Ther. 2004;18(1):57-66.
11. Colucci WS, Kolias TJ, Adams KF, et al; REVERT Study Group. Metoprolol reverses left ventricular remodeling in patients with asymptomatic systolic dysfunction: the REversal of VEntricular Remodeling with Toprol-XL (REVERT) trial. Circulation. 2007 Jul 3;116(1):49-56

12. Packer M, Bristow MR, Cohn JN, et al; US Carvedilol Heart Failure Study Group. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure N Engl J Med. 1996;334(21):1349-1355.
13. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353(9146):9-13.
14. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353(9169):2001-2007.
15. Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001;344(22):1659-1667.
16. Packer M, Fowler MB, Roecker EB, et al; Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106(17):2194-2199.
17. Poole-Wilson PA, Swedberg K, Cleland JG, et al; COMET Investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003;362(9377):7-13.
18. Brophy JM, Joseph L, Rouleau JL. β-blockers in congestive heart failure: A bayesian meta-analysis. Ann Intern Med. 2001;134:550-560.
19. Talwar KK, Bhargava B, Upasani PT, et al; Hemodynamic predictors of early intolerance and long-term effects of propranolol in dilated cardiomyopathy. J Card Fail. 1996;2(4):273-7.
20. Gattis WA, O’Connor CM, Gallup DS, et al ; Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: results of the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial. J Am Coll Cardiol 2004; 43(9):1534-41.
21. Fonarow GC, Abraham WT, Albert NM, et al; Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure. A report from the OPTIMIZE-HF registry. J Am Coll Cardiol 2007; 50:768-777.
22. Maron BJ, McKenna WJ, Danielson GK, et al; American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol 2003; 42(9): 1687-1713.
23. Ostman-Smith I, Wettrell G, Riesenfeld T. A cohort study of childhood hypertrophic cardiomyopathy: improved survival following high-dose beta-adrenoceptor antagonist treatment. J Am Coll Cardiol 1999;34:1813–22.