myocardial hypertrophy

Pathogenesis

 The mechanisms of cardiac muscle hypertrophy involve many signal transduction pathways, leading to the induction of a number of genes, which in turn stimulate synthesis of numerous cellular proteins. The genes that are induced during hypertrophy include those encoding transcription factors (such as c-fos, c-jun); growth factors (TGF-β, insulin-like growth factor-1 [IGF-1], fibroblast growth factor); and vasoactive agents (α-adrenergic agonists, endothelin-1, and angiotensin II).

 There may also be a switch of contractile proteins from adult to fetal or neonatal forms. For example, during muscle hypertrophy, the α-myosin heavy chain is replaced by the β form of the myosin heavy chain, which leads to decreased myosin adenosine triphosphatase (ATPase) activity and a slower, more energetically economical contraction.

 In addition, some genes that are expressed only during early development are re-expressed in hypertrophic cells, and the products of these genes participate in the cellular response to stress.

 For example, in the embryonic heart, the gene for atrial natriuretic factor (ANF) is expressed in both the atrium and the ventricle. After birth, ventricular expression of the gene is down-regulated. Cardiac hypertrophy, however, is associated with reinduction of ANF gene expression. ANF is a peptide hormone that causes salt secretion by the kidney, decreases blood volume and pressure, and therefore serves to reduce hemodynamic load.

 What are the triggers for hypertrophy and for these changes in gene expression? In the heart, there are at least two groups of signals: mechanical triggers, such as stretch, and trophic triggers, such as polypeptide growth factors (IGF-1) and vasoactive agents (angiotensin II, α-adrenergic agonists).

 Current models suggest that growth factors or vasoactive agents produced by cardiac nonmuscle cells or by myocytes themselves in response to hemodynamic stress stimulate the expression of various genes, leading to myocyte hypertrophy. The size of cells is regulated by nutrients and environmental cues and involves several signal transduction pathways that are being unraveled.

 Whatever the exact mechanism of cardiac hypertrophy, it eventually reaches a limit beyond which enlargement of muscle mass is no longer able to compensate for the increased burden, and cardiac failure ensues. At this stage, a number of degenerative changes occur in the myocardial fibers, of which the most important are lysis and loss of myofibrillar contractile elements. Myocyte death can occur by either apoptosis or necrosis.

 The limiting factors for continued hypertrophy and the causes of the cardiac dysfunction are poorly understood; they may be due to limitation of the vascular supply to the enlarged fibers, diminished oxidative capabilities of mitochondria, alterations in protein synthesis and degradation, or cytoskeletal alterations.

Types

 dilated cardiac hypertrophy
 concentric cardiac hypertrophy

References

 Robbins

 Tarone G, Lembo G. Molecular interplay between mechanical and humoral signalling in cardiac hypertrophy. Trends Mol Med. 2003 Sep;9(9):376-82. PMID: 13129703

 Ritter O, Neyses L. The molecular basis of myocardial hypertrophy and heart failure. Trends Mol Med. 2003 Jul;9(7):313-21. PMID: 12900219

 Molkentin JD, Dorn GW: Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Annu Rev Physiol 63:391, 2001.

 MacLellan WR, Schneider MD: Genetic dissection of cardiac growth control pathways. Annu Rev Physiol 62:289, 2000.