Basic Pathophysiology of Congestive Heart Failure

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Abstract
Three popular but still untested hypotheses explaining contractile dysfunction in congestive heart failure are a) a mismatch between energy supply and demand, b) abnormalities in excitation-contraction coupling because of Ca2+ availability and/or mobilizations, of a change in monofilament calcium responsiveness. In this article, we will review current findings as well as areas of controversy regarding the contributions of altered calcium homeostasis, myofilament contractile activation, and energy metabolism to cardiac dysfunction in congestive heart failure. We propose that all three factors contribute to the contractile dysfunction seen in congestive heart failure. With the development of calcium indicators and nuclear resonance techniques investigators now have the tools needed to quantitate intracellular calcium concentrations and to study energy parameters in intact heart preparations. Recent experiments also have assessed sarcoplasmic reticulum calcium mobilization. The combinations of biochemistry and physiology have provided some expected as well as unexpected experimental results. In this review, we will attempt to define the relationship among [Ca2+]i Ca2+ moblization, myofilament Ca2+ activation, and contractile dysfunction in heart failure. Using these data, we will discuss the popular hypothesis that changes in Ca2+, mobilization alters contractility. In addition, we will describe the relationship between energy reserve and contractile reserve in human heat failure. Prolonged inhibition of energy reserve caused by either decreasing creatine kinase activity or decreasing the tissue content of its guanidine substrate creatine can result in or exacerbate consecutive heart failure, because there is a mechanistic relationship between energy reserve and cardiac dysfunction. Furthermore, there is a mechanistic relationship between myocardial energetic and calcium mobilization. To maintain intracellular calcium concentrations within a fixed range (ie, 100–2000 nM), energy is required to fuel calcium pumps. The by-products of adenosine triphosphate (ATP) hydrolysis inhibit calcium pump activity. If energy supply is reduced and/or intracellular calcium levels are elevated, by-products of ATP hydrolysis (and thereby, energy use in the heart) can actually accumulate at least transiently. In this way, a vicious cycle coupling ATP hydrolysis and calcium movements may ensue. The scenario has practical clinical consequences for patients with end-stage heart failure. Failing hearts have a slowed restoration of diastolic calcium levels and are energy compromised. When these hearts attempt to increase work, further ATP hydrolysis is required, resulting in a mismatch between energy supply and demand and leading to cardiac decompositions. When stressed by increased work and/or further decreases in energy supply, even patients with compensated heart disease often demonstrate decomposition and contractile failure in part as a result of a mismatch between energy supply and demand.

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