Cardiac myocyte stretch: an adaptative factor of myocardial function

The Starling law of the heart which was described more than a century ago i s still the subject of intense investigations. It consists of the increase in myocardial function induced by stretching myocardial fibers. Fiber short ening is increased. by increased sarcomere length which improves actin-myos in cross bridge interaction and by an increased fiber activation (<<length- dependent activation). Cellular mechanisms leading to length-dependent acti vation are mainly an increase in troponin C affinity for calcium and an act ivation of phospholipase C producing inositol triphosphate and diacylglycer ol which activates protein kinase C (PKC). PKC phosphorylates a number of s ubstrates which increase contractility. Phospholipase C activation is produ ced by the activation of stretch activated ion channels and by an autocrine -paracrine release of angiotensin II by stretched cardiomyocytes. Stretch a lso modulates myocardial function by inducing and modifying cardiac gene ex pression. The first genes to be induced are <<early>> genes such as c-Fos a nd c-Myc. Later, genes of the fetal phenotype are induced. In the whole hea rt, stretch is associated with other mechanical stimuli (mainly cyclic incr ease in pressure). PKC plays a key role in gene induction with a cascade of enzyme activation starting with Ras activation followed the mitogen activa ted protein kinase cascade, The induction of genes leads to an adaptation o f the heart to a sustained overload with a ventricular hypertrophy. Most as pects of the hypertrophy are beneficial but they are associated with detrim ental effects such as decreased contractility and induction of fibrosis.