Analysis of electrocardiography parameters in BXD strains and quantitative trait loci for arrhythmia disorders in the mouse BXD family

Introduction: Heart rhythm disorders or cardiac arrhythmias can cause sudden death and heart failure. Risk factors for cardiac arrhythmias vary including genetics, age, and other environmental and lifestyle factors. To sought how genetic background affects an expression of cardiac rhythm phenotypes, we assessed electrocardiography (ECG) traits in BXD family of mice derived from crosses between DBA/2J (D2) and C57BL/6J (B6) strains and explored the quantitative genetic architecture of those traits. Methods: ECG tracings were recorded in 44 BXD male (M) and female (F) strains (N >5 mice/sex) at 4-5 months of age anesthetized with 2% isoflurane. Heart rate (HR), ECG parameters, and frequency of arrhythmias in percentile (‰) were associated with blood pressure, echocardiography, and heart transcriptome values followed by quantitative trait loci (QTLs) mapping. Results: Parental D2 strains had the lowest HR and significantly prolonged QT intervals (62.82 ± 9.42 ms in D2F and 53.42 ± 1.73 ms in D2M) compared to sex matched B6 parental strains. Significantly widened QRS complexes were seen in BXD65F (14.27±2.97 ms) compared to 11.67±1.03 ms in B6F controls. In males, BXD83M had the widest QRS (13.48±1.74 ms) vs 10.89±0.41 ms seen in B6M controls. We found a significant association between QRS duration and increased left ventricular internal diameter (LVID) and reduced ejection fraction and fractional shortening. Further, varied cardiac arrhythmias including bradycardia, atrioventricular block (AVB), premature atrial or ventricular complexes (PAC and PVC, respectively), ventricular tachycardia (VT) and sick sinus syndrome (SSS) were seen among BXD strains. PACs were recorded in BXD73F (14.57 ‰), 40M, 101F, 51M, and 101M strains. Strains, BXD79M (14.97 ‰), 83M, 78M, 69F, and 171F, had frequent PVCs compared to B6 controls. AVB II was recorded in BXD48M and BXD66M had SSS. Both PAC and PVC were positively associated with cardiac phenotype burden. Specifically, PVCs were significantly correlated with echocardiographic pulmonary vein peak pressure, LVID and volumes at end-diastole (P = 0.04) among male BXDs. In females, right ventricular internal diameters (RVID) and cardiac output were significantly correlated with PVC and PAC frequencies. Moreover, PVCs were significantly correlated with systolic blood pressure in both male and female mice. QTL mapping identified a significant locus on Chromosome 3 associated with QTC and JT durations, while the same locus was suggestive for association with QT interval, suggesting that Chromosome 3 loci may be associated with repolarization abnormalities such as long QT syndromes. Conclusions: ECG parameters, heart rate, type and frequency of arrhythmias significantly varied between mouse strains of the BXD family suggesting an influence of genetic background on expression of those traits. Abnormal heart rhythms detected in BXD strains mimic cardiac rhythm and conduction disorders in humans. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.