Electrophysiologic consequences of KATP gain of function in the heart: Conduction abnormalities in Cantu syndrome

BACKGROUND Gain-of-function (GOF) mutations in the K-ATP channel subunits Kir6.1 and SUR2 cause Cantu syndrome (CS), a disease characterized by multiple cardiovascular abnormalities. OBJECTIVE The purpose of this study was to better determine the electrophysiologic consequences of such GOF mutations in the heart. METHODS We generated transgenic mice (Kir6.1-GOF) expressing ATP-insensitive Kir6.1[G343D] subunits under a-myosin heavy chain (alpha-MHC) promoter control, to target gene expression specifically in cardiomyocytes, and performed patch-clamp experiments on isolated ventricular myocytes and invasive electrophysiology on anesthetized mice. RESULTS In Kir6.1-GOF ventricular myocytes, K-ATP channels showed decreased ATP sensitivity but no significant change in current density. Ambulatory ECG recordings on Kir6.1-GOF mice revealed AV nodal conduction abnormalities and junctional rhythm. Invasive electrophysiologic analyses revealed slowing of conduction and conduction failure through the AV node but no increase in susceptibility to atrial or ventricular ectopic activity. Surface ECGs recorded from CS patients also demonstrated first-degree AV block and fascicular block. CONCLUSION The primary electrophysiologic consequence of cardiac K-ATP GOF is on the conduction system, particularly the AV node, resulting in conduction abnormalities in CS patients who carry K-ATP GOF mutations.