Interplay of Defective Excitation-Contraction Coupling, Energy Starvation, and Oxidative Stress in Heart Failure

In chronic heart failure, maladaptive remodeling of the left ventricle (LV) with systolic and diastolic dysfunction underlies the inability of the heart to pump sufficient blood to supply the body with blood and oxygen. Three integral aspects of this maladaptive LV remodeling are (1) defects in excitation-contraction (EC) coupling, particularly of cellular Ca2+ and Na+ homeostasis; (2) an energetic deficit; and (3) oxidative stress. Although these three aspects are often investigated separately from each other, their close and dynamic interplay are increasingly recognized. Central to this novel approach are mitochondria, which are the main source for cellular ATP, but also for reactive oxygen species, and their function is critically regulated by Ca2+ and Na+. Here, we review recent advances in our understanding of how maladaptive changes of EC coupling can contribute to the energetic deficit and oxidative stress, which may initiate a vicious cycle leading to progressive cardiac dysfunction.