UNC45A contributes to profibrotic processes in the myocardium of sudden cardiac death victims

Myocardial fibrosis is a common pathological finding in sudden cardiac death (SCD) victims, observed in over 90% of cases. This study aimed to 1) identify novel candidate genes and genetic variants associated with myocardial fibrosis in SCD victims and 2) investigate the functional impact of selected candidate genes on cardiac cell biology.

Whole exome sequencing was performed on SCD victims with nonischemic cardiomyopathy: 127 individuals with primary myocardial fibrosis (PMF) as the only pathological finding. Associations with cardiac disease endpoints were evaluated using the Finnish national genetic study (FinnGen) dataset. RNA sequencing was conducted on myocardial samples from 12 PMF cases carrying selected variants. Candidate genes were further investigated through in vitro experiments assessing their role in myocardial fibrosis, including collagen production and proliferation of human cardiac fibroblasts, as well as calcium transients and hypertrophic responses in neonatal/adult rat cardiomyocytes.

We identified four rare variants in SCD cases with PMF and three variants in cases with myocardial fibrosis and LVH. Variants found in PMF cases were more frequently linked to cardiomyopathies in population level, whereas those identified in LVH cases showed associations with comorbid conditions such as hypertension.

Transcriptomic analysis of myocardial tissue from SCD victims revealed significant changes in gene expression, including upregulation of UNC45A. Expression of UNC45A was also observed to be higher in hearts of patients with dilated or ischemic cardiomyopathy compared to control hearts. Functional in vitro studies demonstrated that knockdown of UNC45A impairs both cardiomyocyte and fibroblast function. In cardiomyocytes, UNC45A deficiency led to reduced contractile activity and disrupted calcium handling. In cardiac fibroblasts, UNC45A knockdown altered proliferation rates and increased collagen production, suggesting a direct role in promoting myocardial fibrosis.

Our findings demonstrate that the genetic and transcriptional landscape of PMF shares molecular features with established cardiomyopathies. Through genomic and functional analyses, we identified UNC45A as a novel candidate gene implicated in the profibrotic remodeling of the myocardium. UNC45A appears to influence both cardiomyocyte and fibroblast function, contributing to altered calcium handling, reduced contractile activity, and enhanced collagen production. These results suggest that UNC45A may play a role in the pathogenesis of myocardial fibrosis and could represent a potential target for future therapeutic strategies.

Graphical Abstract