Molecular biology of myocardial hypertrophy and failure: gene expression and trophic signaling

Pressure-overload cardiac hypertrophy is associated with the re-expression of an ensemble of genes representative of embryonic myocardium, whose protein products modulate myocardial function. Regulation of cardiac-specific gene expression in end-stage myocardial disease in humans implies a pathophysiologic role for altered gene expression in the progression from compensatory hypertrophy to decompensated heart failure. The molecular signals that transduce load into a hypertrophic cardiac myocyte phenotype involve mechanical deformation and the local myocardial production of trophic factors, including angiotensin II, and transforming and fibroblast growth factors. Growth factors provoke a pattern of gene expression in cultured cardiac myocytes resembling that seen in pressure overload in vivo, in keeping with an autocrine or paracrine model of hypertrophy. Moreover, growth factor stimulation and pressure-overload hypertrophy share intracellular signaling pathways, including the activation of nuclear proteins encoded by cellular oncogenes. Elucidation of these signaling pathways may provide new therapeutic targets for the treatment of cardiac muscle disease that overcomes the limitations of currently available strategies.