Arrhythmogenic gene remodelling in elderly patients with type 2 diabetes with aortic stenosis and normal left ventricular ejection fraction

Abstract

Type 2 diabetes is associated with higher rate of ventricular arrhythmias and this is hypothesised to be independent of coronary artery disease or hypertension. To investigate further we compared changes in left ventricular myocardial gene expression in Type 2 diabetes to patients in a control group with left ventricular hypertrophy. 9 control patients and 7 patients with type 2 diabetes with aortic stenosis undergoing aortic valve replacement had standard ECGs, signal averaged ECGs and echocardiograms prior to surgery. During surgery, a left ventricular biopsy was taken and mRNA expression for genes relevant to the cardiac action potential were estimated by RT-PCR. Mathematical modelling of the action potential and calcium transient was undertaken using the O'Hara-Rudy model using scaled changes in gene expression. Echocardiography revealed similar values for left ventricular size, filling pressures and ejection fraction between groups. No difference was seen in positive signal averaged electrocardiograms between groups but the standard ECG demonstrated a prolonged QT interval in the diabetes group. Gene expression of ERG and Kir 3.1 were lower in the diabetes group, whereas Kir 2.1, Kir3.4 and NCX1 expression were higher. Modelling suggested these changes would lead to prolongation of the action potential duration with generation of early after-depolarisations secondary to a reduction in density of the I_{K, r} current (rapid delayed rectifier K⁺ current) and increased I_Na/Ca current (Na⁺-Ca²⁺ calcium exchange current). This data suggest that diabetes leads to pro-arrythmogenic changes in myocardial gene expression independently of left ventricular hypertrophy or fibrosis in an elderly population.

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