Abstract P390: Gender And Strain Background Affect Cardiopulmonary Function In Col4a3 -/- Alport Mice

Abstract

Background: Alport syndrome (AS) is a hereditary form of chronic kidney inflammation that results in renal failure (RF). Our group previously reported that Col4a3 -/- mice, a model of AS and RF, on 129J background exemplified multiple features of heart failure with preserved ejection fraction (HFpEF). This study investigates the effect of 3 different genetic backgrounds on cardiopulmonary function in Col4a3 -/- mice. Methods: Male and female Col4a3 -/- (Alport) and WT mice on 3 different genetic backgrounds, 129x1/SvJ, C57Bl/6 and BALBC, were examined using echocardiography, whole body plethysmography (WBP) and pressure-volume (PV) loop analysis. Ttest was used for statistical analysis. Four groups per strain were used (n= 4 to 15 per group). Results: Compared with their respective age-matched WT controls, both male and female 8-week-old Col4a3 -/- 129x1/SvJ mice demonstrated impaired systolic function (EF of 56% to 43.7%, p=0.0018 for females and 50.9% to 42% for males, p=0.044; SV, CO, p<0.05) and diastolic dysfunction (increased IVRT from 15.32ms to 21.72ms, p=0.0009 for females; 16.57ms to 26.21ms, p<0.0001 for males; increased MPI, P<0.05). Additionally, PV loop analysis showed an increased EDPVR and end diastolic pressure, prolonged time constant of LV relaxation, and decreased CO and SV (p<0.05). However for Col4a3 -/- BalbC (8-week-old) and Col4a3 -/- C57Bl/6 (20-week-old) strains, only females exhibited systolic (BalbC: EF% 51% to 45.66%, p=0.106 for females and 43.5% to 40.8% for males, p=0.508; B6: EF% 51.30% to 40.80% p=0.024 for females and 48.43% to 40.91%, p=0.3098 for males; SV, CO, p<0.05) and diastolic dysfunction (IVRT from 15.96ms to 24.91ms for Balb/C and 18.20ms to 25.63ms for B6, p<0.05). Male Col4a3 -/- BalbC had an increase in minimum pressure and end-systolic pressure, and an increased pressure at dV/dt-max. Male Col4a3 -/- C57Bl/6 mice had an increased ESPVR slope (p<0.05). All strains except BalbC males demonstrated alterations (p<0.05) in pulmonary function including decreased ventilation rate (MV, mL/min) and respiratory frequency (BPM), decreased peak expiratory flow, EF50, increased expiratory time, relaxation time, inspiratory time, and time of pause at end-of-expiration. Conclusion: Both male and female Col4a3 -/- 129x1/SvJ mice demonstrated impaired cardiopulmonary viability. However, Col4a3 -/- mice on BalbC or C57Bl/6 strains had cardiopulmonary deficits only in females.