Metabolic reserve of the heart: the forgotten link between contraction and coronary flow.

Myocardial energy substrate metabolism entails a complex system of enzyme catalyzed reactions, in which the heart efficiently converts chemical to mechanical energy. The system is highly regulated and responsive to changes in workload as well as in substrate and hormone supply to the heart. Akin to the terms "contractile reserve" and "coronary flow reserve" we propose the term "metabolic reserve" to reflect the heart's capacity to respond to increases in workload. The heart's metabolic response to inotropic stimulation involves the ability to increase oxidative metabolism over a wide range, by activating the oxidation of glycogen and carbohydrate substrates. Here we review the known biochemical mechanisms responsible for those changes. Specifically, we explore the notion that disturbances in the metabolic reserve result in contractile dysfunction of the stressed heart.

Return to the fetal gene program protects the stressed heart: a strong hypothesis.

A common feature of the hemodynamically or metabolically stressed heart is the return to a pattern of fetal metabolism. A hallmark of fetal metabolism is the predominance of carbohydrates as substrates for energy provision in a relatively hypoxic environment. When the normal heart is exposed to an oxygen rich environment after birth, energy substrate metabolism is rapidly switched to oxidation of fatty acids. This switch goes along with the expression of "adult" isoforms of metabolic enzymes and other proteins. However, the heart retains the ability to return to the "fetal" gene program. Specifically, the fetal gene program is predominant in a variety of pathophysiologic conditions including hypoxia, ischemia, hypertrophy, and atrophy. A common feature of all of these conditions is extensive remodeling, a decrease in the rate of aerobic metabolism in the cardiomyocyte, and an increase in cardiac efficiency. The adaptation is associated with a whole program of cell survival under stress. The adaptive mechanisms are prominently developed in hibernating myocardium, but they are also a feature of the failing heart muscle. We propose that in failing heart muscle at a certain point the fetal gene program is no longer sufficient to support cardiac structure and function. The exact mechanisms underlying the transition from adaptation to cardiomyocyte dysfunction are still not completely understood.