ASB1 differential methylation in ischaemic cardiomyopathy. Relationship with left ventricular performance in end stage heart failure patients

TL;DR

This study identifies specific methylation changes in the ASB1 gene associated with left ventricular dysfunction in end-stage ischemic cardiomyopathy, revealing potential epigenetic targets for therapy.

Contribution

It is the first to link ASB1 methylation patterns with cardiac function in ICM patients, expanding understanding of epigenetic influences in heart failure.

Findings

Hypermethylation of ASB1 gene in ICM patients

Strong correlation between ASB1 methylation and LV function measures

Downregulation of ASB1 mRNA in ICM myocardium

Abstract

Aims: Ischaemic cardiomyopathy (ICM) leads to impaired contraction and ventricular dysfunction causing high rates of morbidity and mortality. Epigenomics allows the identification of epigenetic signatures in human diseases. We analyse the differential epigenetic patterns of ASB gene family in ICM patients and relate these alterations to their haemodynamic and functional status. Methods and Results: Epigenomic analysis was carried out using 16 left ventricular (LV) tissue samples, 8 from ICM patients undergoing heart transplantation and 8 from control (CNT) subjects without cardiac disease. We increased the sample size up to 13 ICM and 10 CNT for RNA-sequencing and to 14 ICM for pyrosequencing analyses. We found a hypermethylated profile (cg11189868) in the ASB1 gene that showed a differential methylation of 0.26 beta difference, P < 0.05. This result was validated by pyrosequencing technique (0.23 beta difference, P < 0.05). Notably, the methylation pattern was strongly related to LV ejection fraction (r = -0.849, P = 0.008) stroke volume (r = -0.929, P = 0.001) and end-systolic and diastolic LV diameters (r = -0.743, P = 0.035 for both). ASB1 showed a down regulation in mRNA levels (-1.2 fold, P < 0.05). Conclusion: Our findings link a specific ASB1 methylation pattern to LV structure and performance in end-stage ICM, opening new therapeutic opportunities and providing new insights regarding which is the functionally relevant genome in the ischemic failing myocardium. Keywords: ischaemic cardiomyopathy; epigenomics; heart failure; left ventricular dysfunction; stroke volume; ASB1.