Metabolic Remodeling in the Hypertrophic Heart

Abstract

When it comes to fuel for energy production, it is commonly accepted that the heart is an omnivore, capable of oxidizing a wide range of carbon substrates, and that this metabolic plasticity is necessary to maintain a high and variable workload in the midst of an ever-changing hormonal and nutritional state.1 It is also widely appreciated that shifts in substrate utilization in the heart occur in response to chronic metabolic and hemodynamic stresses.2–5 What is less clear, however, is whether such chronic metabolic shifts should be considered a cause or consequence in the pathogenesis of contractile dysfunction. In the case of diabetes mellitus, the heart exhibits an increased dependence on fatty acids for oxidative energy production, and this increase in lipid metabolism has been proposed to significantly contribute to the etiology of impaired cardiac function.6 Similarly, increased rates of fatty acid oxidation immediately after an ischemic event have been implicated in exacerbation of reperfusion injury.7 However, in both of these pathophysiological settings, compelling data to support a direct causal relationship between contractile abnormalities and metabolic dysregulation remain elusive. Article, see p 728 In response to pressure overload–induced cardiac hypertrophy, the heart reverts more toward a fetal-like metabolic profile, indicative of a decrease in fatty acid oxidation (concomitant with an increased reliance on carbohydrates for oxidative energy metabolism).3 It has been suggested that this substrate shift, which is associated with reactivation of other fetal-like hallmarks (eg, myosin heavy chain isoform switching), contributes to the progression to overt contractile failure.8 Dietary, pharmacological, and genetic strategies have been used in attempts to provide insight regarding the impact that substrate shifts have on pressure overload–induced remodeling; however, mixed results have been reported. …