CARDIAC PHENOTYPES IN THE COLLABORATIVE CROSS: DERIVATION AND UTILITY OF CARDIAC REFERENCE RANGES FOR MUS MUSCULUS

Abstract

Contemporary approaches for developing new interventions and for pre-clinical risk evaluation include assessments for cardiovascular structure and function, frequently performed in a variety of animal and in vitro models, but generally lack details on normal species-specific reference ranges similar to what exists for humans. The genetically diverse Collaborative Cross (CC) mouse reference population allows for modeling genetic variability equivalent to that present in the human population. The CC population was used to develop cardiac reference values for Mus musculus, identify candidate genes that are associated with those phenotypes, and demonstrate interindividual susceptibility to two known cardiotoxicants. Heart function was analyzed in males and females from 58 CC strains and C57BL/6J using high frequency ultrasound under both conscious and anesthetized conditions, as well as conscious electrocardiography to develop two standard deviation-based reference ranges for Mus musculus similar to what exists for humans. Additionally, genetic analysis was performed on the cardiac phenotyping data to determine candidate genes for genetic control of clinically relevant phenotypes. A subset of the 58 CC strains was also used to demonstrate interindividual susceptibility and response to isoproterenol and chloroquine. Strain was a significant source of variability with all data sets, and associated genes not previously linked to cardiac phenotypes in mice, but those linked in humans were found. These reference ranges and genetic analysis in the CC are a novel approach to cardiovascular research, ultimately allowing more accurate diagnoses and informative safety assessments in humans.