BIOCHEMICAL-ALTERATIONS AND DISTURBANCES OF THE EXCITATION-CONTRACTION COUPLING IN CONGESTIVE-HEART-FAILURE

In the chronically failing heart, subtle biochemical alterations occur at the level of a number of subcellular systems. The cellular elements that control activation and inactivation of the contractile proteins are the plasma membrane and the sarcoplasmic reticulum (SR). During the plateau phase of the action potential the slow calcium channel is activated so that calcium ions enter into the interior of the cell and initiate- as a trigger signal in loco-the calcium release from the SR-calcium-stores. In the absence of catecholamines the measured calcium ion currents are similar when normal human myocardium is compared to end-stage failing human myocardium. However, the increase in the calcium ion currents induced by maximum concentrations of catecholamines is significantly smaller in failing myocardium compared to normal myocardium. This observation can easily be explained by the down-regulation of the beta-1-adrenoceptors and the increase in the inhibitory G(i)-proteins. In the failing myocardium, therefore, a beta-1-adrenoceptor stimulation leads to an insufficient increase in cyclic adenosine monophosphate so that the opening probability of the calcium channels is not appropriately enhanced. This results in a decreased contractile reserve. As far as is known today, the inactivation mechanisms of the plasma membrane (sodium-calcium-exchanger, sodium-potassium ATPase, calcium ATPase) are not disturbed in the failing human myocardium. The calcium release from the SR can be quantified using either calcium indicators (aequorin, fura 2) or highly sensitive thermopiles. Both sophisticated heat measurements and fura-2 measurements indicated a decreased systolic calcium ion concentration. Because the calcium release channels of the SR seem to be unaltered in heart failure, it must be concluded that the calcium stores of the SR are not properly filled in the failing myocardium. This suggestion is supported by findings indicating lowered calcium ATPase activity of the SR and diminished gene expression of the calcium ATPase. As a consequence of such a disturbed SR function, the systolic calcium concentration is diminished and activation of the contractile proteins is inadequate. Accordingly, the systolic force development of isolated human ventricular preparations is greatly diminished in end-stage failing myocardium when compared to normal and measured at physiological conditions (37-degrees-C, 60 beats per min). Therefore, the decreased contractility of the failing myocardium, which is heart-rate dependent, can be explained by a primary disturbance of the SR function. Additionally, alterations of the plasma membrane prevent adequate functional responses of the failing myocardium to catecholamines.