Genetic mapping of electrocardiographic values in a genetic reference population of BXD mice uncovers distinct loci regulating cardiac repolarization in males and females

Introduction: Heart rhythm disorders or cardiac arrhythmias can cause sudden death and heart failure. Risk factors for cardiac arrhythmias include genetics, sex, age, environment, diet, and other factors. Objectives: To determine the underlying sex and genetic background relations in expression of cardiac rhythm phenotypes, we assessed electrocardiography (ECG) traits in the BXD family of recombinant inbred (RI) mice and explored a quantitative genetic architecture of those traits. Methods: The results of five-minute surface ECG recording in 44 BXD strains (N>5 mice/sex/strain/4-5-month-old) were associated with blood pressure (BP), echocardiography (ECHO), genome and heart transcriptome values followed by quantitative trait loci (QTLs) mapping. Results: Significant variabilities in heart rate (HR), ECG, BP and ECHO parameters were recorded among male and female BXD strains. Correlation analysis identified a significantassociation between QRS duration and increased left ventricular internal diameter (LVID), reduced ejection fraction (EF%) and fractional shortening (FS%). Varied arrhythmias [bradycardia, atrioventricular block, premature atrial/ventricular complexes (PAC/PVC), ventricular tachycardia and sick sinus syndrome] were recorded among BXDs. Both PACs and PVCs were significantly associated with cardiac function and BP burden. While systolic BP values were significantly correlated with the frequency of PVCs in both male and female mice, the correlation was opposite with a negative association in female mice, while male mice showed positive association. Frequent PVCs and PACs were significantly correlated with right ventricular internal diameter (RVID) and cardiac output in female mice. Among male BXDs, frequency of PVCs was significantly (p<0.05) correlated with LVID, LV volumes, pulmonary vein peak pressure, and prolonged QT, QTc and JT intervals. A high variability in QTc and JT intervals were genetically regulated (P≤0.03) among male and female mice, while no underlying sex basis was determined. Further genetic mapping identified a significant QTL on murine Chromosome (Chr) 3 associated with QTc and JT durations in male BXDs, while the Chr 9 locus was suggestive for association with QTc and QT durations in females. A candidate gene, Gon4l, was predicted to be associated with repolarization abnormalities such as long or short QT syndromes in males. Conclusions: The study identified varied associations of ECG, BP, and ECHO traits between BXD strains and sexes. Significant differences in arrhythmia-induced phenotype burden between female and male mice from the same BXD strain indicates the sex-dependent outcomes of rhythm disturbances on expression of BP, cardiac morphology (LVID, RVID, and volumes) and function (EF% and FS%) phenotypes. We conclude that the BXD family of RI mice can serve as an invaluable preclinical tool for comparative prediction and systems genetics studies for cardiac rhythm and repolarization disorders in humans. R01 HL128350 (LL) R01 HL151438 (JAT, LL, EP) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.