Socking It to Cardiac Hypertrophy

In the heart, increases in contractile load provoked by hypertension or valvular disease promote increases in cardiac mass through the hypertrophy of cardiomyocytes. Injury or death to cardiomyocytes in a portion of the heart places a greater load on cells within uninjured areas and stimulates cellular hypertrophy. Similarly, in familial forms of hypertrophic cardiomyopathy, defects in genes encoding proteins of the sarcomere promote growth in the absence of a stimulus. Hypertrophic hearts are susceptible to abnormalities of cardiac rhythm and have impaired relaxation (diastolic dysfunction), although contractile performance can be preserved. However, when hypertrophic stimuli are unrelieved, the remodeling phenomenon progresses and increasing numbers of cardiomyocytes are replaced with fibrotic scar, which leads to decreased systolic function and circulatory failure.Article see p 796Neurotransmitters or hormones that bind to cell surface receptors modulate the rate and force of contraction by regulating the flux of calcium across the cell membrane or released from the sarcoplasmic/endoplasmic reticulum (SR/ER). In addition, Ca2+ signaling in the cardiomyocyte regulates the long-term remodeling responses of the heart to changing workloads by altering Ca2+-dependent gene expression and metabolism.1 In this way, Ca2+ can sense and respond to changes in muscle contraction through a link with hypertrophic gene expression.2 It is not intuitively obvious, however, how these Ca2+ signals could serve simultaneously as the proximate signal to control cardiac mass, specialized programs of gene expression, and the contractile and metabolic capacities of cardiomyocytes. Ca2+-dependent signaling events activated by increased contractile load somehow must be insensitive to the large fluctuations in cytosolic calcium that occur as a function of ambient contractile activity. This consideration may explain why although Ca2+-dependent signal transduction pathways that modulate gene expression have been well defined in other cell types for many years, …