Genetic Determinants of Heart Failure Susceptibility and Response in the Collaborative Cross Mouse Population

Genetic variation and lived experiences shape how our hearts respond to chronic stress and development of heart failure, manifested as compromised pumping function and abnormal hemodynamics. The hallmark of heart failure etiology is excessive stress signals followed by maladaptive structural, electrical, and functional changes to the heart muscle, also known as cardiac remodeling. The specific genetic mechanisms which underly such phenomenon, however, are still unclear, due in part to difficulties in accounting for environmental effects in human population studies. To overcome this challenge, we used the Collaborative Cross (CC) mouse population to investigate heritable susceptibility to cardiovascular stress by chronic β-adrenergic receptor stimulation with the β-agonist isoproterenol, which targets the common signaling gateway to heart failure, regardless of the particular upstream stressor. Across 8 founder and 63 CC lines, we measured non-failing and failing heart characteristics represented by cardiac structure and function, organ weights, and cell morphology. Genome-wide QTL mapping detected 49 genome-wide significant loci, collapsing to 20 unique intervals (nine significant for multiple traits and eleven trait-specific), averaging 12.83 Mb in size. To identify high-confidence candidate genes from these loci, we augmented our trait mapping with coding variants drawn from sequencing data, tractability in our in vitro rat cardiomyocyte model, and previously reported protein functions and mouse or human phenotypes. This approach recovered both known regulators, such as Hey2, and new candidates. Functional tests in in vitro models highlight three candidate genes that modulate hypertrophic growth: Abcb10, Mrps5 and Lmod3. Abcb10 knockdown increased cell size at baseline and further with isoproterenol, consistent with loss of a mitochondrial stress-buffering role. Mrps5 knockdown blunted stress-induced hypertrophy, possibly related to its previously known involvement in oxidative stress regulation. Lmod3 knockdown also attenuated hypertrophy, potentially via actin-assembly control under adrenergic stress. Together, these results reveal heritable pathways of β-adrenergic remodeling in mice and provide an interpretable, translational, and stepwise framework to prioritize candidate genes within broad loci for mechanistic studies of heart failure.