In a diabetic rabbit model, rapid delayed rectifier K+ current (I(Kr)) was reduced by approximately 70%, representing the major ionic mechanism for a 20% prolongation in action potential duration.
What are the ionic mechanisms underlying abnormal QT prolongation and associated arrhythmias in a diabetic rabbit model?
This study provides the first documentation that I(Kr) channelopathy is the major ionic mechanism underlying diabetic QT prolongation and associated arrhythmias.
Abnormal QT prolongation with the associated arrhythmias is considered the major cardiac electrical disorder and a significant predictor of mortality in diabetic patients. The precise ionic mechanisms for diabetic QT prolongation remained unclear. We performed whole-cell patch-clamp studies in a rabbit model of alloxan-induced insulin-dependent diabetes mellitus. We demonstrated that heart rate-corrected QT interval and action potential duration (APD) were prolonged by approximately 20% with frequent occurrence of ventricular tachyarrhythmias. Several K(+) currents were found decreased in diabetic rabbits including transient outward K(+)current (I(to)) that was reduced by approximately 60%, rapid delayed rectifier K(+) current (I(Kr)) reduced by approximately 70% and slow delayed rectifier K(+) current (I(Ks)) reduced by approximately 40%. The time-dependent kinetics of these currents remained unaltered. The peak amplitude of L-type Ca% current (I(CaL)) was reduced by approximately 22% and the inactivation kinetics was slowed; the integration of these two effects yielded approximately 15% reduction of I(CaL). The inward rectifier K(+) current (I(K1)) and fast sodium current (I(Na)) were unaffected. Simulation with LabHEART, a computer model of rabbit ventricular action potentials, revealed that inhibition of I(to) or I(Ks) alone fails to alter APD whereas inhibition of I(Kr) alone results in 30% APD prolongation and inhibition of I(CaL) alone causes 10% APD shortening. Integration of changes of all these currents leads to approximately 20% APD lengthening. Protein levels of the pore-forming subunits for these ion channels were decreased to varying extents, as revealed by immunoblotting analysis. Our study represents the first documentation of I(Kr) channelopathy as the major ionic mechanism for diabetic QT prolongation.
Zhang et al. (Mon,) conducted a other in Diabetic QT prolongation and associated arrhythmias. Alloxan-induced insulin-dependent diabetes mellitus vs. Non-diabetic controls (implied) was evaluated on QT interval, action potential duration (APD), and ionic currents. In a diabetic rabbit model, rapid delayed rectifier K+ current (I(Kr)) was reduced by approximately 70%, representing the major ionic mechanism for a 20% prolongation in action potential duration.