Cellular and molecular aspects of contractile dysfunction in heart failure

A number of molecular and cellular alterations have been identified in the failing human heart that help to understand contraction and relaxation abnormalities. Cyclic AMP dependent pathways are desensitized due to quantitative changes in beta-adrenoceptors, beta-adrenoceptor kinase, and inhibitory G-proteins. Calcium homeostasis is impaired, characterized by a decreased calcium reuptake rate of the sarcoplasmic reticulum, an increased threshold of the calcium release channel, and an increased Na+/Ca2+ exchanger expression. Myofibrillar function may be affected by a decrease in Mg2(+)-ATPase activity and in troponin I phosphorylation, and by changes in TnT isoform expression. These alterations seem to occur independently of the underlying etiology of heart failure and are most likely consequences rather than primary causes of the disease. Most likely, chronic neurohumoral activation and abnormal mechanical load initiate the majority of the hitherto known changes in the myocardium and promote the further progression of cardiac failure as part of a vicious circle. Further extension of knowledge of pathophysiological mechanisms should improve therapeutical strategies which aim at slowing the progression of heart failure and at reversing secondary alterations by interrupting the deleterious influence of neurohumoral activation. Future progress will depend on answers to current gaps in our knowledge of heart failure, including the unknown primary cause of idiopathic dilated cardiomyopathy, factors underlying the greatly variable progression of pump failure, as well as the exact pathophysiological role of the molecular alterations as described in this review.