Pathological cardiac remodeling due to genetic defects in various cardiomyopathies or secondary to various cardiovascular diseases (e.g. hypertension) is a key process preceding heart failure. It is resulted from intricate interactions between genetic and environmental factors. Although significant progress has been made in genomic research, substantial knowledge gaps remain regarding: (1) the mechanisms by which non-coding and rare genetic variants disrupt molecular pathways associated with hypertrophy, fibrosis, and metabolic dysregulation; (2) tissue-specific transcriptional and splicing programs that contribute to maladaptive remodeling in primary cardiomyopathies (e.g., hypertrophic cardiomyopathy, HCM) compared to secondary injury caused by hypertension; (3) shared regulatory networks underlying the progression to heart failure across diverse etiologies. Our research consortium has assembled one of the largest multi-omics datasets, including HCM patients with whole-genome sequencing (WGS), whole-exome sequencing (WES), and myocardial transcriptome profiles; hypertensive patients with WGS, serving as a comparative cohort to identify secondary remodeling triggers. This study aim to reveal the genetic driving mechanism and myocardial remodeling characteristics! by combining data from the UK Biobank (UKBB), including omics information, cardiac imaging, and longitudinal clinical phenotypes to identification of coding/non-coding variants, abnormal splicing events, and regulatory elements specific to primary cardiomyopathies or hypertensia-associated myocardial remodeling, and ultimately to construct a stratified etiological model based on rare variant load, co-expression module, and epidemiological data to provide translational basis for targeted intervention of pathological cardiac remodeling.
