Abstract
Background: Hypercholesterolemia is associated with alteration of the lipid composition of the sarcolemma which may cause augmentation of the L-type calcium current (ICaL) and appears to be protective against ventricular fibrillation in patients with myocardial infarction.Hypothesis: Hypercholesterolemia increases ICaL resulting in action potential (AP) prolongation which protects against ischemia induced arrhythmias.Methods: ECG was measured in LDL-receptor knockout (LDLr-/-) mice with elevated LDL cholesterol and wild type mice (WT). AP, ICaL and calcium handling were determined in left ventricular myocytes. In perfused hearts the left anterior descending artery was ligated. Arrhythmia inducibility was tested every 30s by three premature stimuli with a coupling interval of 10ms longer than the refractory period followed by a 500ms pause. Area at risk (AAR) was determined with Evans Blue.Results: Cholesterol concentration in left ventricular myocytes was higher in LDLr-/- mice than WT (34.4±2.8 vs 25.5±0.4 μmol/gr protein) resulting in AP and QTc prolongation (APD90 102±4 vs 84.4±3.1, QTc 50.9±1.3 vs 43.8±1.18ms and increased ICaL (12.1±1.1, and 9.4±0.7 pA/pF) and calcium transient amplitude (74±4 vs 35±3 nM). The incidence of induced premature beats was not significantly different. In 7/7 LDLr-/- and 8/9 WT hearts arrhythmias could be provoked. In LDLr-/- hearts, only 5/412 induction attempts resulted in VT/VF whereas in WT hearts 30/477 induction attempts resulted in VT/VF. (p<0.05) The AAR was not different between LDLr-/- and WT mice.Conclusion: Hypercholesterolemia protects against the occurrence of re-entrant arrhythmias during myocardial ischemia by QTc and AP prolongation due to increased ICaL.
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