Abstract 19680: Cardiovascular Hypercontractility in Cantu Syndrome Results From Neurohumorally-induced Increase in Cardiomyocyte L-type Ca2+ Current
Cantu Syndrome (CS) is a rare multi-system disease characterized by hypertrichosis, skeletal abnormalities, and cardiovascular disease. Disease-causing gain of function (GOF) mutations have been identified in the genes encoding both the pore forming subunit (KIR 6.1, KCNJ8) and the accessory subunit (SUR2, ABCC9) of the KATP channel, but mechanisms by which KATP GOF mutations confer disease remain unclear. The purpose of this study was to characterize CS cardiovascular disease in a patient cohort and use engineered mouse models to explore how the cardiovascular features arise. Cardiovascular phenotyping demonstrated that CS patients have significantly diminished blood pressure, dilated LV, increased LV mass, and increased contractility (LV global strain (longitudinal)) as assessed by echo. Ambulatory ECG analysis demonstrated diminished heart rate variability, circadian abnormalities, and low vagal function. KATP currents recorded from cardiac [[Unable to Display Character: –]]specific KIR 6.1 gain of function ((cGOF), G343D) ventricular cardiomyocytes (VM) demonstrated diminished sensitivity to ATP inhibition. Smooth muscle cells (SMC) from vascular-specific KIR 6.1 GOF (vGOF) similarly showed diminished sensitivity to ATP inhibition. cGOF mice showed increased cardiac ejection fraction compared to control mice, while vGOF mice showed increased cardiac strain rate (SR rad-d) by echocardiogram. Neither cGOF, nor vGOF mice showed thickened LV wall dimensions when compared with control mice. Whole cell calcium current recordings from cGOF mouse vm showed markedly increased L-type Ca2+ current (LTCCC) density that was comparable to that seen in WT vm treated with isoproterenol (iso). To increase KATP in both VM and SMC, slow release minoxidil (Min, a KATP channel opener) pellets, or placebo were implanted in WT mice for three weeks. Subsequent LTCCC recordings showed increased calcium current in MIN treated mice comparable to iso treated WT vm. Long-standing intracellular calcium excess is a well-described precipitant of cardiomyopathy and heart failure. Therefore, increased L-type calcium current found in KATP GOF models suggests a mechanistic link between increased KATP current and Cantu cardiac pathology.
Author Disclosures: M.D. Levin: Research Grant; Modest; NIH. G.K. Singh: None. A. Kovacs: None. P.K. Stein: None. H. Zhang: None. M.S. Remedi: None. B.A. Kozel: None. D.K. Grange: None. C.G. Nichols: Research Grant; Modest; NIH.
- © 2014 by American Heart Association, Inc.