QTc Interval is Prolonged in Hypercholesterolemic Mice

Hypercholesterolemia has been associated with ventricular arrhythmias and sudden cardiac death (SCD). Elevated cholesterol levels alter membrane properties and can affect cardiac ion channel function leading to rhythm disturbances. QT prolongation which reflects ventricular repolarization is a known risk factor for ventricular arrhythmia. Thus, the objective of this study was to investigate the effects of hypercholesterolemia on QTc interval using mice overexpressing human ApoB-100 (hAPOB+/+) which exhibit high levels of cholesterol. Surface ECG were recorded from anaesthetized male and female hAPOB+/+ mice and their age-matched littermate controls at 2, 4, 6, 9 and 12 mo. The 4mo male hAPOB+/+ mice displayed longer QTc intervals (ms) than the controls (4mo, CTL: 63.4±1.0, n=38; hAPOB+/+: 70.4±1.5, n=36, p<0.05). This difference was further accentuated at 9 and 12 mo (9mo, CTL: 63.8±0.6, n=12; hAPOB+/+: 76.5±2.4, n=12; 12mo, CTL: 66.1±1.6, n=10; hAPOB+/+: 79.8±2.1, n=12, p<0.05 vs 4mo). The increased QTc interval was independent of body weight (g) (12mo, CTL: 66±2, n=10; hAPOB+/+: 80±2, n=12, p=NS). In addition, female hAPOB+/+ mice also had a significantly longer QTc interval compared to their respective controls but unlike the males this difference became significant only at 6mo (6mo, CTL: 63.1±1.2 n=30; hAPOB+/+: 70.9±1.6, n=24, p<0.05) and did not increase further with age. Western Blot and qPCR analyses of ventricular K+ channels (Kv1.5, Kv2.1, Kv4.2, Kv4.3 and Kir2.1) showed no differences in the protein and mRNA expression of control and hAPOB+/+ mice. Altogether, these findings indicate that hypercholesterolemia lengthens ventricular repolarization in both males and females with a more severe phenotype in males. K+ channel expression were unchanged in hAPOB+/+ mice suggesting that the cholesterol-induced QT prolongation would be due to changes in membrane properties affecting K+ channel functions.