Die Rolle des späten Natriumstroms (late INa) bei Druck-induzierter Hypertrophie und bei Herzinsuffizienz

Abstract

Heart failure, is associated with high mortality as a result of contractile dysfunction (pump failure) or sudden death caused by ventricular arrhythmias. There usually is an imbalance of cellular calcium (Ca2+) and sodium (Na+) homeostasis caused by abnormalities in intracellular Ca2+ handling and structural remodeling. These electrical remodeling in heart failure include prolongation of the cardiac action potential (AP) and an increased sarcoplasmic reticulum (SR) Ca2+-leak occurring as spontaneous SR Ca2+-release event which underlies the occurrence of delayed afterdepolarizations (DADs). A persistent Na current, also known as late Na current has been discussed to be a potent contributor to the progression and complications of heart failure. The present study shows the characteristics of the lateINa and its arrhythmogenic potential in the progression of pressure-induced heart disease. Transverse aortic constriction (TAC) was used to induce pressure overload in mice. After one week the slightly hypertrophied hearts with preserved systolic left ventricular function showed that both, lateINa and the action potential duration (APD) were unchanged. Most importantly five weeks after TAC we observed prolonged APDs and slowed lateINa decay time. Both could be normalized by sodium channel inhibitors ranolazine (Ran) or tetrodotoxin (TTX) at low concentration (both specific inhibitors of late INa) or by the Ca/calmodulin-dependent protein kinase II (CaMKII) inhibitor AIP. Isoproterenol increased the number of delayed afterdepolarizations (DAD) and the incidence of triggered activity in cardiomyocytes from failing but not sham hearts. Application of either Ran or AIP prevented the occurrence of DADs and the incidence of triggered activity. These results confirmed to the survival curves where the animals one week after TAC showed no increased mortality while animals with heart failure have an increased mortality. Western blot analyses indicate that increased CaMKII activity and a hyperphosphorylation of the Nav1.5 at the CaMKII phosphorylation site (Ser571) paralleled our functional observations five weeks after TAC surgery. In pressure overload-induced heart failure a CaMKII-dependent augmentation of lateINa plays a crucial role in the AP prolongation and generation of cellular arrhythmogenic triggers, which cannot be found in early and still compensated hypertrophy. Inhibition of lateINa and CaMKII exerts potent antiarrhythmic effects and might therefore be of potential therapeutic interest.