Hypercholesterolemia Protects Against Ischemia-Induced Ventricular Tachycardia and Ventricular Fibrillation

Abstract

Background:Membrane cholesterol regulates ion channels. Hypercholesterolemia protect against ventricular fibrillation in patients with myocardial infarction. Hypothesis: Hypercholesterolemia increases action potential duration due to altered ion channels function and protects against ischemia induced re-entrant arrhythmias.Methods:QTc intervals were measured in 10 week old LDL-receptor (LDLr-/-) and APO1 (APO1-/-) knockout mice, and wild type mice (WT). Action potentials, calcium handling and ion currents were recorded in ventricular myocytes. In perfused hearts regional ischemia was induced by ligating the left anterior descending artery . Arrhythmias inducibility was tested every 30 s by applying premature stimuli followed by a 500 ms pause. The area at risk (AAR) was determined by perfusion with Evans Blue.Results:Serum LDL cholesterol was higher in LDLr-/- and serum HDL cholesterol was lower in APO1-/- mice than in WT. Resulting in an increased cholesterol content in ventricular myocytes. The L-type calcium current was increased in LDLr-/- and APO1-/- (12.1±0.7 and 12.8±0.8) compared to WT (9.4±1.1 pA/pF) resulting in altered calcium handling in LDLr-/- and APO1-/- vs WT mice (increased calcium transient and fractional SR calcium release) and prolongation of AP and QTc duration (APD90 102±4 and 106±3 vs 84.4±3.1 and QTc 50.9±1.3 and 52.3 vs 43.8±1.18 ms, respectively.In LDLr-/- and APO1-/- hearts 1.7 and 1.3% of the attempts to induce arrhythmias resulted in VT/VF compared to 6.9% in WT. There was no significant difference in the induction of premature beats although (12.8% in WT vs 15.5 and 15.8 in LDL-/- and APO-/-). The AAR was not significantly different in LDLr -/-, APO1-/- and WT mice.Conclusion:Hypercholesterolemia protects against the occurrence of re-entrant arrhythmias during myocardial ischemia due to AP prolongation caused by an increase of the L-type calcium current.