L'étirement des myocytes cardiaques : un facteur adaptatif de la fonction myocardique.

Abstract

La loi de Starling, enoncee il y a plus d' un siecle, etablit l' augmentation de la performance cardiaque lors de l' etirement de ses fibres. Elle a trois composantes: (1) une immediate, liee aux ponts etablis entre l' actine et la myosine dont le recouvrement depend de la longueur initiale du sarcomere ; (2) une progressive en quelques minutes, qui repose sur l' activation du muscle. Le mecanisme suggere serait l' augmentation de l' affinite de la troponine C pour le calcium lors de l' allongement des fibres; (3) une, enfin, dont la constante de temps se compte en heures et jours : la modification de l' expression des genes cellulaires et de la synthese proteique sous l' effet du signal declenche par l' etirement. La transmission de ce signal impliquerait l' activation de la proteine-kinase C, de la voie de Ras et des MAP-kinases. L' induction genique permet l' adaptation du coeur a la surcharge par l' hypertrophie ventriculaire, mais conduit aussi a la diminution de la contractilite et a l' induction de fibrose.

The Starling law of the heart which was described more than a century ago is still the subject of intense investigations. It consists of the increase in myocardial function induced by stretching myocardial fibers. Fiber shortening is increased by increased sarcomere length which improves actin-myosin cross bridge interaction and by an increased fiber activation ("length-dependent activation"). Cellular mechanisms leading to length-dependent activation are mainly an increase in troponin C affinity for calcium and an activation of phospholipase C producing inositol triphosphate and diacylglycerol which activates protein kinase C (PKC). PKC phosphorylates a number of substrates which increase contractility. Phospholipase C activation is produced by the activation of stretch activated ion channels and by an autocrine-paracrine release of angiotensin II by stretched cardiomyocytes. Stretch also modulates myocardial function by inducing and modifying cardiac gene expression. The first genes to be induced are "early" genes such as c-Fos and c-Myc. Later, genes of the fetal phenotype are induced. In the whole heart, stretch is associated with other mechanical stimuli (mainly cyclic increase in pressure). PKC plays a key role in gene induction with a cascade of enzyme activation starting with Ras activation followed by the mitogen activated protein kinase cascade. The induction of genes leads to an adaptation of the heart to a sustained overload with a ventricular hypertorphy. Most aspects of the hypertorphy are beneficial but they are associated with detrimental effects such as decreased contractility and induction of fibrosis.