Abstract 13902: Aberrant Sialylation Modulates Cardiac Excitability and Conduction
We recently showed that regulated changes in the cardiac glycome result in voltage-gated Na+ channels that are less sialylated as well as in altered cardiomyocyte INa and action potential (AP) waveforms. Here we sought to question whether cardiac excitability and conduction are modulated by basal sialylation and through aberrant changes in sialylation similar to that common among Congenital Disorders of Glycosylation (CDG), a set of > 40 inherited diseases with variable, but relatively modest reductions in glycoprotein glycosylation. Reduced glycoprotein sialylation is common to nearly all forms of CDG. Many of the neuromuscular and cardiac symptoms associated with CDG suggest reduced excitability, but the mechanism responsible is not yet understood. A knockout mouse strain of a cardiac-expressed sialyltransferase, ST3Gal4, was used to question how cardiac electrical signaling is modulated by small changes in sialylation. Cardiac excitability and conduction were markedly altered in ST3Gal4 knockout (ST3Gal4(-/-)) mice compared to control; ECGs indicated conduction anomalies with increased susceptibility to arrhythmias. Using optical mapping techniques, nine of ten isolated ST3Gal4(-/-) hearts but only one of nine control hearts showed aberrant conduction. Multiple conduction anomalies presented in 70% of the ST3Gal4(-/-) hearts, with ventricular fibrillation observed in 20% of the hearts. In an effort to understand the molecular/cellular mechanism by which modest changes in sialylation modulate excitability, ST3Gal4(-/-) myocytes isolated from the left ventricular apex (n=5) demonstrated a 30 % (p<0.05) increase in APD90 compared to controls (n=8). The current densities of the peak and slowly inactivating sustained (IKslow) repolarizing voltage-sensitive K+ currents were attenuated (n<0.05) at all depolarizing potentials in the ST3Gal4(-/-) mice (n=6) compared to controls (n=13). This reduction in K+ current should act to extend the AP, as observed. Thus, a reduction in glycoprotein sialylation consistent with that observed in nearly all forms of CDG accounts for significant changes in cardiac excitability and conduction that can be described, at least in part, through aberrant voltage-gated K+ channel activity.
- © 2011 by American Heart Association, Inc.