Cardiomyocytes and non-muscle cells in cardiac hypertrophy: a molecular perspective

Abstract

Myocardial hypertrophy may occur as an inherited cardiac abnormality (primary) or in response to increased cardiac work (secondary). While familial hypertrophic cardiomyopathy is inherited as an autosomal dominant trait and is genetically considered a heterogeneous disorder, acquired hypertrophy develops as a compensatory mechanism to chronic increase in cardiac work. Although the latter is an adaptive process, it represents an early phase in a continuum leading to heart failure and may contribute to subsequent morbidity and mortality. Cardiac hypertrophy involves not only growth of individual myocytes but also hyperplasia of the non-myocyte elements that actually comprise two-thirds of the cardiac cells. These include fibroblasts, vascular smooth muscle cells and endothelial cells. Studies suggest that a delicate interaction between cardiac myocytes and non-myocyte cells, or an interaction between cardiac cells and extracellular matrix, exists during the development of hypertrophy. At the molecular level, the myocardial process is characterized by immediate activation of protein kinase cascade and transient expression of proto-oncogenes, such as c-fos, c-jun, c-myc and Egr-1, followed by transcriptional changes in genes coding for contractile proteins and membrane ion transport proteins. In the pressure overloaded heart, collagen fibres accumulate in the interstitium and lead to increased chamber stiffness and diastolic dysfunction. The signal for hypertrophy is a combination of mechanical stretch, neurohumoral factors and endogenous growth factors, such as endothelin, angiotensin II or TGFβ. Unraveling the pathways by which these signals orchestrate into defined response, with activation of specific subsets of cardiac muscle genes leading to altered phenotypes, is a major future challenge. This information holds the key to understanding the pathogenesis and mechanisms of compensatory hypertrophy progressing to heart failure. Such knowledge could lead to identification of new therapeutic targets and new innovations in management.