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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 through chronic \u03b2-adrenergic receptor stimulation with the \u03b2-agonist isoproterenol (ISO), which targets the common signaling gateway to heart failure, regardless of the particular upstream stressor. Across 8 founder and 63 CC lines, we measured nonfailing 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 (9 significant for multiple traits and 11 trait-specific), averaging 12.83\u2005Mb 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 an in vitro rat cardiomyocyte model, and previously reported protein functions and\/or mouse or human phenotypes. This approach recovered both known regulators, such as Hey2, and new candidates. Functional tests in in vitro models highlight 3 candidate genes that modulate hypertrophic growth: Abcb10, Mrps5, and Lmod3. Abcb10 knockdown increased cell size at baseline and further with ISO, 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 \u03b2-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.<\/jats:p>","DOI":"10.1093\/genetics\/iyag028","type":"journal-article","created":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T02:00:47Z","timestamp":1769824847000},"source":"Crossref","is-referenced-by-count":2,"title":["Genetic determinants of heart failure susceptibility and response in the collaborative cross mouse population"],"prefix":"10.1093","volume":"233","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4032-3141","authenticated-orcid":false,"given":"Todd H","family":"Kimball","sequence":"first","affiliation":[{"name":"Department of Genetics and Computational Medicine Program, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599 ,","place":["United 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