Heart and Metabolism

Latest trends in the treatment of ischemic heart failure: new perspectives using a metabolic approach

P. Meurin
Centre de Réadaptation Cardiaque de la Brie, Villeneuve Saint Denis, France
Correspondence: Dr P. Meurin, Centre de Réadaptation Cardiaque de la Brie,
77174 Villeneuve Saint Denis, France Tel: +33 1 60 43 59 59, e-mail: philippemeurin@tfou.com

Heart failure: a cardiovascular disease with a poor prognosis
Congestive heart failure (CHF) is a growing epidemic worldwide that results in significant morbidity and mortality, especially in aging populations.[1] Coronary artery disease, hypertension, and diabetes are the major etiologic risk factors.[2,3] Continuing advances in the treatment of acute coronary syndromes that save many lives may result in a growing population of survivors with left ventricular dysfunction progressively leading to heart failure. Although preventive measures of cardiovascular risk factors have evolved in recent decades, including the management of hypertension, they have not reduced the incidence of CHF. Epidemiologic studies in Western Europe and the USA revealed that CHF is the leading indication for hospitalization in patients over 65 years of age.[4–6] CHF is therefore a primary user of health care resources.
Ironically, the significant decline in mortality from coronary artery disease and hypertension, along with increasingly elderly populations, have significantly raised the prevalence and incidence of coronary heart disease.
Despite progress in the treatment of CHF with the use of ACE inhibitors,[7,8] and more recently with the introduction of b-blockers,[9–11] the prognosis of this disease remains poor: in epidemiologic studies mortality has reached 40% at 1-year follow-up.[12–15]
Clinical examination, chest x-ray, ECG, and more recently, administration of brain natriuretic peptide, enable accurate diagnosis in most patients. Clinical practice guidelines for the management and treatment of CHF have been developed through careful evaluation of the international literature, generated from well-controlled randomized trials, large-scale epidemiologic studies, and expert opinions. All recommendations in the European and North American guidelines emphasize the importance of both nonpharmacological (counseling, education, lifestyle modification, cardiac rehabilitation, and multidisciplinary intervention) and pharmacological treatment (ACE inhibitors, b-blockers, diuretics, digitalis). Nevertheless, experts agree that many patients do not receive the recommended optimal treatment.[16,17] The main problem faced by physicians lies in its implementation. Indeed, the patients in unselected populations with CHF are older, include a higher percentage of women, have preserved systolic function, and have more concomitant disease than patients in clinical trials. Therefore, in applying the guidelines it is often difficult to obtain the target doses of ACE inhibitors and/or b-blockers. Adding other hemodynamic agents such as calcium channel blockers or angiotensin receptor blockers does not provide additional benefits in terms of mortality.[18]
Clinical research has therefore recently been oriented toward the development of new therapeutic agents to improve the status of patients with CHF.

Metabolic agents: a new therapeutic approach to myocardial ischemia
Recently introduced metabolic agents such as the new class of 3-KAT inhibitors represent a very promising and radically different approach to the treatment of coronary heart disease. Metabolic agents such as trimetazidine (Vastarel 20 mg) demonstrate interesting anti-ischemic and cardioprotective properties yet are free of any adverse hemodynamic effects. Trimetazidine, the first 3-KAT inhibitor available worldwide for clinical use in ischemic heart disease, was tested in patients with severe cardiomyopathy and left ventricular dysfunction in three randomized trials.
The first double-blind, placebo-controlled study was reported by Brottier et al[19] to examine the benefits of trimetazidine tid in addition to classic heart failure treatment in 20 patients. All patients had severe CHF (six patients in NYHA class IV, 14 in NYHA class III). At 6-month follow-up, dyspnea, left ventricular ejection fraction, and cardiac volume were significantly improved in the trimetazidine group in comparison with placebo (P < 0.001, P < 0.018, P < 0.034, respectively).
The initial promising results of Brottier et al were confirmed by more recent studies. Lu et al[20] administered oral trimetazidine tid vs placebo for 2 weeks in 15 patients with coronary artery disease and moderately reduced left ventricular ejection fraction with a positive response to dobutamine stress echocardiography. The end points of this double-blind, crossover study were improvement in the ischemic threshold, as measured by dobutamine dose and infusion time, and improvement in left ventricular function assessed by changes in wall motion score index (WMSI) at rest and at peak dobutamine. The total duration of the trial was 30 days. WMSI was significantly lower with trimetazidine tid than with placebo, both at rest and at peak dobutamine infusion (P = 0.013 and P = 0.018, respectively). Furthermore, trimetazidine significantly increased the dobutamine infusion time and provided an increase in the administered dobutamine dose (P = 0.019 and P = 0.003) (Figures 1 and 2).

Figure 1. Vastarel 20 significantly induced a longer dobutamine infusion time.
Figure 2. Vastarel 20 significantly induced a higher dobutamine infusion dose.

The results of this study indicate that trimetazidine may not only protect from dobutamine-induced ischemic dysfunction, but may also improve resting regional left ventricular function, without affecting hemodynamic parameters of myocardial oxygen consumption.
The above results are consistent with those of Belardinelli and Purcaro[21] who, in a randomized, placebo-controlled study, examined the effects of trimetazidine tid vs placebo on the contractile response of chronically dysfunctional myocardium to low-dose dobutamine in ischemic cardiomyopathy. Thirty-eight patients with postnecrotic left ventricular dysfunction and multivessel coronary artery disease were randomized to either trimetazidine tid or placebo in two matched groups. At baseline and at 2-month follow-up, all patients underwent low-dose dobutamine echocardiography (5–20 mg/kg per min) and a symptom-limited exercise test. Patients treated with trimetazidine had a significant improvement in rest and peak systolic WMSI (P < 0.001) and in ejection fraction (P < 0.001), without changes in heart rate and blood pressure at follow-up. Additional benefits were observed with a significant increase in peak VO2 in the trimetazidine group compared with placebo (P = 0.001).
These three randomized, double-blind, placebo-controlled studies have demonstrated consistent results achieved with trimetazidine in chronic heart failure. Trimetazidine improves resting ventricular function in patients with coronary artery disease and various degrees of contractile impairment. It also appears to prevent or delay regional myocardial dysfunction, and ameliorate functional capacity, as assessed by peak VO2. Trimetazidine, which acts through inhibition of fatty acid b-oxidation, may have prognostic and therapeutic implications for the management of patients with ischemic heart failure and coronary artery disease in the future.

REFERENCES

1: Eur Heart J 1997 Feb;18(2):208-25