Energy deficiency in the failing heart: Linking increased reactive oxygen species and disruption of oxidative phosphorylation rate

Heart failure is a complex syndrome of numerous dysfunctional components which converge to cause chronic progressive failure of ventricular contractile function and maintenance of cardiac output demand. The aim of this brief review is to highlight some of the mounting evidence indicating that augmented superoxide, related reactive oxygen species and other free radicals contribute to the oxidative stress evident during the progression of heart failure. While much of the source of increased reactive oxygen species is mitochondrial, there are other intracellular sources, which together are highly reactive with functional and structural cellular lipids and proteins. Bioenergetic defects limiting ATP synthesis in the failing myocardium relate not only to post-translational modification of electron transport respiratory chain proteins but also to perturbation of Krebs Cycle enzyme-dependent synthesis of NADH. Accumulation of pathological levels of lipid peroxides relate to dysfunction in the intrinsic capacity to clear and renew dysfunctional proteins. This review also features key limitations of human heart failure studies and potential clinical therapies that target the elevated oxidative stress that is a hallmark of human heart failure.