The molecular and cellular landscape of hypertrophic cardiomyopathy phenotypes: transition from obstructive to end-stage heart failure

Abstract

Hypertrophic cardiomyopathy (HCM) is a myocardial disorder which commonly presents as an obstructive or end-stage disease. This study aims to investigate the transcriptomic changes related to cardiac cell-specific expression profiles that underpin the molecular transition between the HCM phenotypes. This study utilizes bioinformatics meta-analysis to integrate independent datasets to generate a comprehensive gene expression profile of obstructive HCM and end-stage HCM phenotypes compared to donor hearts. Gene set enrichment and cellular deconvolution were applied to identify ontologies and pathways related to each phenotype and to enumerate cell abundances. The intersection between cell lineage genes and meta-genes was identified to explore the cellular contribution to the phenotypic molecular signatures. Meta-analysis revealed, enhanced muscle function and myocardial remodeling, alongside impaired immune and inflammatory processes in obstructive HCM. In contrast, enriched tissue matrix remodeling pathways and altered metabolic and signaling cascades were identified in end-stage HCM, indicating a shift towards cellular dysfunction and loss of homeostasis. These molecular profiles were associated with an altered cellular landscape, with increased cardiomyocytes and lower immune cell populations in obstructive samples but increased fibroblasts and smooth muscle cells in end-stage HCM, implicating extensive tissue remodeling. This study provides novel insights into the cellular contributions of contractile, immune, homeostatic, and vascular alterations underpinning each of the HCM phenotypes. KEY MESSAGES: HCM phenotypes are characterized by distinct molecular and cellular profiles. Obstructive HCM has an enriched contractile profile underpinned by an expanded cardiomyocyte population. End-stage HCM shifts the cellular profile towards extracellular and vascular remodeling.

Keywords: Cellular gene expression; End-stage heart failure; Hypertrophic cardiomyopathy; Meta-analysis; Obstructive disease; Phenotypic molecular signature.