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

ABSTRACT: Gain-of-function (GOF) mutations in the KATP channel subunits Kir6.1 and SUR2 cause Cantu syndrome (CS), a disease characterized by multiple cardiovascular abnormalities.The purpose of this study was to better determine the electrophysiologic consequences of such GOF mutations in the heart.We generated transgenic mice (Kir6.1-GOF) expressing ATP-insensitive Kir6.1[G343D] subunits under ?-myosin heavy chain (?-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.In Kir6.1-GOF ventricular myocytes, KATP 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.The primary electrophysiologic consequence of cardiac KATP GOF is on the conduction system, particularly the AV node, resulting in conduction abnormalities in CS patients who carry KATP GOF mutations.

SUBMITTER: Levin MD

PROVIDER: S-EPMC4624040 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Levin Mark D MD Zhang Haixia H Uchida Keita K Grange Dorothy K DK Singh Gautam K GK Nichols Colin G CG

Heart rhythm 20150630 11

<h4>Background</h4>Gain-of-function (GOF) mutations in the KATP channel subunits Kir6.1 and SUR2 cause Cantu syndrome (CS), a disease characterized by multiple cardiovascular abnormalities.<h4>Objective</h4>The purpose of this study was to better determine the electrophysiologic consequences of such GOF mutations in the heart.<h4>Methods</h4>We generated transgenic mice (Kir6.1-GOF) expressing ATP-insensitive Kir6.1[G343D] subunits under α-myosin heavy chain (α-MHC) promoter control, to target g ...[more]

PMID: 26142302

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Project description:Cantu syndrome (CS) is characterized by multiple vascular and cardiac abnormalities including vascular dilation and tortuosity, systemic hypotension, and cardiomegaly. The disorder is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunits. However, there is little understanding of the link between molecular dysfunction and the complex pathophysiology observed, and there is no known treatment, in large part due to the lack of appropriate preclinical disease models in which to test therapies. Notably, expression of Kir6.1 and SUR2 does not fully overlap, and the relative contribution of KATP GOF in various cardiovascular tissues remains to be elucidated. To investigate pathophysiologic mechanisms in CS we have used CRISPR/Cas9 engineering to introduce CS-associated SUR2[A478V] and Kir6.1[V65M] mutations to the equivalent endogenous loci in mice. Mirroring human CS, both of these animals exhibit low systemic blood pressure and dilated, compliant blood vessels, as well dramatic cardiac enlargement, the effects being more severe in V65M animals than in A478V animals. In both animals, whole-cell patch-clamp recordings reveal enhanced basal KATP conductance in vascular smooth muscle, explaining vasodilation and lower blood pressure, and demonstrating a cardinal role for smooth muscle KATP dysfunction in CS etiology. Echocardiography confirms in situ cardiac enlargement and increased cardiac output in both animals. Patch-clamp recordings reveal reduced ATP sensitivity of ventricular myocyte KATP channels in A478V, but normal ATP sensitivity in V65M, suggesting that cardiac remodeling occurs secondary to KATP overactivity outside of the heart. These SUR2[A478V] and Kir6.1[V65M] animals thus reiterate the key cardiovascular features seen in human CS. They establish the molecular basis of the pathophysiological consequences of reduced smooth muscle excitability resulting from SUR2/Kir6.1-dependent KATP GOF, and provide a validated animal model in which to examine potential therapeutic approaches to treating CS.

Dataset Information

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

Publications

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

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