Integration of pathways that signal cardiac growth with modulation of myofilament activity.

We review evidence for integrated effects of the signals that promote cardiac growth and remodeling and that modify the processes of excitation-contraction coupling. We have focused on integration of alterations in myofilament function with cell growth on the basis of genetic linkage analysis demonstrating that sarcomeric mutations are causal in hypertrophic cardiomyopathies. This evidence argues strongly for a path of communication between the intrinsic functional changes associated with a sarcomeric protein mutation and nuclear events. Our hypothesis is that this communication is also essential to the transduction of extrinsic signals leading to hypertrophy and failure. Understanding this network of signaling pathways is certain to lead to better diagnostic and treatment approaches to heart failure.