Abstract
Background:
Alport syndrome (AS) is a hereditary form of chronic kidney inflammation that results in renal failure (RF). We previously reported that
Col4a3
-/-
129J mice, a model of AS and RF, 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 from 129x1/SvJ, C57Bl/6 and BALBC strain 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= 4-15/group).
Results:
Compared with their respective age-matched WT controls, male and female 8-week-old
Col4a3
-/-
129x1/SvJ mice demonstrated impaired systolic function (EF of 56 to 43.7%, p=.002 for females and 50.9 to 42% for males, p=.044; SV, CO, p<.05) and diastolic dysfunction (increased IVRT from 15.3 to 21.7ms, p=.0009 for females; 16.6 to 26.2ms, p<.0001 for males; increased MPI, P<.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). For
Col4a3
-/-
BalbC and
Col4a3
-/-
C57Bl/6 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=.51; B6: EF% 51.3 to 40.8% p=.02 for females and 48.4 to 40.9%, p=.31 for males; SV, CO, p<.05) and diastolic dysfunction (IVRT from 16 to 24.1ms for BalbC and 18.20 to 25.63ms for B6, p<0.05). Male
Col4a3
-/-
BalbC had an increase in minimum and end-systolic pressures, and an increased pressure at dV/dt-max. Male
Col4a3
-/-
C57Bl/6 mice had an increased ESPVR slope (p<.05). All strains except BalbC males demonstrated alterations (p<.05) in pulmonary function including decreased ventilation rate (MV) and respiratory frequency, 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.