Effects of Rosuvastatin and Candesartan on the Electrical Remodeling in Cardiac Hypertrophy and Failure in vivo

Ventricular hypertrophy is a remodeling response and is observed in most cases of CHF in humans and in animal models. Cardiac remodeling is initially adaptive, but later becomes maladaptive, leading to progressive decompensation. Cardiac hypertrophy is associated with a significantly increased risk of cardiovascular morbidity and mortality, much of which stems from electrical modeling and arrhythmogenesis. One of the best documented changes in hypertrophy and heart failure is the prolongation of the ventricular action potential, which underlies the propensity to arrhythmia, syncope, and sudden death. The most consistent change in ionic currents is a reduction in the density of transient outward current Ito. A prominent feature of the myocyte of the hypertrophic/failing heart is an alteration of Ca2+ handling and an enhanced activity of the Na+- Ca2+ exchanger, which may give rise to arrhythmias. Statins are HMG-CoA reductase inhibitors that are widely used in lipid-lowering therapy. Statins have potential therapeutic benefit to patients with heart failure, irrespective of lipidlowering effect. Rosuvastatin is a new highly effective synthetic hydrophilic statin. However, the influence of rosuvastatrin on the electrical remodeling in heart failure or hypertrophy is still unknown. Candesartan is a highly effective AT1 receptor blocker that is widely used in the treatment of hypertension and heart failure. This drug induces prevention or regression of in vivo LV pressure-overload hypertrophy. However, the functional studies of candesartan on the ionic channel remodeling have never been evaluated. The heart weight, hemodynamic, ECG, conduction system, action potential, and ionic channel parameters are considered to be predictive of cardiac remodeling changes induced by cardiac hypertrophy/failure models. In our preliminary study, we have established the MCT (60 mg/kg)- and aortic banding-induced cardiac hypertrophy/ failure model. In this project, therefore, we intend to examine the chronic treatment with either rosuvastatin or candesartan on the ion channel remodeling in these models. The influences of treatment on the hemodynamic parameters will be evaluated with catheter system in anaesthetized animals. The effects on electrophysiological properties of conduction system will be determined in Langendorff-perfused isolated hearts. The effects on action potential will be determined both in the isolated ventricular tissues and myocytes. Besides, the action potential and conduction waveform in isolated hearts will be evaluated by the optical mapping technique. The ionic currents and intracellular Ca2+ transient will be measured by patch-clamping and fluorescent imaging techniques, respectively. We hope that this project can provide the important informations about the preventive effects of rosuvastatin and candesartan treatment on the electrophysiological and ion channel remodeling of cardiac hypertrophy or failure.

Project ID:PC9706-0789
External Project ID:NSC96-2320-B182-026-MY3