The Lack of Cardiomyocyte Complex and Hybrid N‐glycans Result in Arrhythmic Dilated Cardiomyopathy, Heart Failure, and Premature Death
Authors: Ednie Andrew R. , Darville Lancia N. , Deng Wei , Bennett Eric S. 
Published: June 2021

The cardiac glycome, which is the complete set of glycan structures in the heart, is regulated through developmental and cell‐type specific mechanisms. We have shown that this regulation as well as an altered glycome can significantly impact cardiac electrical signaling. To determine more directly the impact of reduced N‐glycosylation on cardiac function, in vivo, we created a mouse strain in which the glycosyltransferase responsible for initiating the formation of complex and hybrid N‐glycans, Mgat1, was deleted in cardiomyocytes only (Mgat1KO). Mgat1KO mice have a significantly higher mortality rate, with all male Mgat1KO mice dying by 44 weeks of age (median age at death was 38 weeks, n=8). Mgat1KO mice present with significantly reduced ejection volumes by six weeks of age that deteriorates rapidly into heart failure between 16 and 30 weeks of age. Further, at an early age, dramatic cardiac arrhythmias present that are consistent with the observed significant effects on voltage‐gated ion channel glycosylation, gating, and functional expression. Our preliminary glycoproteomic and biochemical data show that specific voltage‐gated ion channel isoforms expressed in the Mgat1KO do not have complex and hybrid N‐glycans attached as demonstrated by lectin precipitation/mass spectrometry and protein purification followed by glycan detection through hydrophilic interaction liquid chromatography, respectively. These data support the functional changes in ion channel activity observed, providing evidence of a direct effect of Mgat1 gene deletion on the N‐glycan structures of specific ion channel proteins. The arrhythmias worsen with age, likely caused by the later onset of dilated cardiomyopathy that rapidly declines into arrhythmic heart failure and premature death. The observed altered activity of the less N‐glycosylated ion channels and arrhythmias are consistent with congenital forms of arrhythmic dilated cardiomyopathy and heart failure. Together, our data indicate that complete complex and hybrid N‐glycosylation are necessary for normal cardiac function. Further, the data suggest a link between aberrant glycosylation, chronic arrhythmia, and idiopathic dilated cardiomyopathy. That is, a reduction in N‐glycosylation of specific ion channel subunits causes a significant increase in cardiac arrhythmias and aberrant cytosolic Ca2+ handling that may contribute to the later onset of a thinner, enlarged left ventricle and reduced systolic function diagnosed as idiopathic arrhythmic dilated cardiomyopathy that leads to heart failure and increased mortality.Support or Funding InformationThis work was supported, in part by two grants from the National Science Foundation [IOS‐1146882 and CMMI‐1266331]; an American Heart Association, Greater Southeast Affiliate Grant‐In‐Aid [14GRNT20450148]; an American Heart Association, Greater Southeast Affiliate Postdoctoral Fellowship [15POST25710010]; and a grant from the National Heart, Lung, Blood Institute [1R01HL102171].