Metabolic Modulation in Heart Failure: The Coming of Age

Abstract

Chronic heart failure (CHF) affects 5 million patients in the US alone and is the only major cardiovascular condition for which incidence, prevalence, morbidity and mortality are increasing. The resulting 1 million hospitalizations and 286 700 deaths annually translates into costs of $29.6 billion per annum [1]. Despite continuing advances in the treatment of CHF, with combined neurohormonal blockade, complex and expensive device therapies delivering cardiac resynchronisation and various surgical interventions including revascularisation and transplantation [2], there is an urgent need for new therapies with novel modes of action to treat this epidemic. It has been recognised for over half a century that the heart is a metabolically active organ [3] that generates ∼30 Kg (∼50 times its own weight) of ATP per day [4]. There is evidence to suggest that CHF represents a state of cardiac energy starvation [5]. There has been a correspondingly substantial literature focussing on relative changes in substrate utilisation (Free Fatty Acids (FFA) vs. carbohydrate) in CHF and in LVH. Recent data in CHF suggests that there is not just a reduction in FFA metabolism [6] but a more generalised down regulation of metabolic flux through all pathways [7]. Nevertheless agents which cause a preferential shift towards greater carbohydrate utilisation are emerging as promising therapies for the treatment of CHF [8]. The normal heart, subsists mainly (∼70%) on FFA but can increase its reliance on the remaining substrates (e.g. glucose and lactate) during periods of increased demand [8]. While theoretically FFA metabolism liberates significantly more energy than carbohydrates (300 vs 220 kcal/mole of C2 units), in practice excess FFA appear to be detrimental. This inefficiency appears to result from: FFA promoting the elaboration of energetically wasteful mitochondrial uncoupling proteins [9], FFA oxidation resulting in a lower [ATP] produced/O2 utilised which is detrimental in the mitochondrially impaired milieu of CHF [8] and the impairment of carbohydrate metabolism resulting in an increased lactate and proton production by the heart. In the early 1970’s, Mjos seminally recognised that these influences impaired myocardial function in vivo [10]. Importantly, animal and human models of moderate CHF suggest that FFA metabolism is maintained or increased (though not consistently so across all studies); a rationale therefore exists to suppress FFA oxidation in order to improve CHF [8]. To address this hypothesis, a number of agents including trimetazidine, perhexiline, etomoxir and oxfenicine, considered to be FFA oxidation inhibitors (FOXi) have been investigated in experimental and clinical CHF. While the latter two agents were successful in animal models of CHF [11], and in the case of etomoxir in a very small study in patients [12], a more systematic Phase II clinical trial testing etomoxir in CHF, termed ERGO-1, was terminated early due to an unacceptable rate of side effects. This may be attributable to the fact that agents such as etomoxir are irreversible and powerful FOXi; FFA metabolism may be necessary to some degree to fuel the heart. In contrast, partial FOXi (pFOXi) such as trimetazdine and perhexiline Cardiovasc Drugs Ther (2007) 21:5–7 DOI 10.1007/s10557-007-6000-z