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Alport syndrome (AS) is a hereditary renal disorder with no etiological therapy. In the preclinical Col4a3-/- model of AS, disease progression and severity vary depending on mouse strain. The sodium-glucose cotransporter 2 (SGLT2) is emerging as an attractive therapeutic target in cardiac/renal pathologies, but its application to AS remains untested. This study investigates cardiorespiratory function and SGLT2 renal expression in Col4a3-/- mice from three different genetic backgrounds, 129x1/SvJ, C57Bl/6 and Balb/C. male Col4a3-/- 129x1/SvJ mice displayed alterations consistent with heart failure with preserved ejection fraction (HFpEF). Female, but not male, C57Bl/6 and Balb/C Col4a3-/- mice exhibited mild changes in systolic and diastolic function of the heart by echocardiography. Male C57Bl/6 Col4a3-/- mice presented systolic dysfunction by invasive hemodynamic analysis. All strains except Balb/C males demonstrated alterations in respiratory function. SGLT2 expression was significantly increased in AS compared to WT mice from all strains. However, cardiorespiratory abnormalities and SGLT2 over-expression were significantly less in AS Balb/C mice compared to the other two strains. Systolic blood pressure was significantly elevated only in mutant 129x1/SvJ mice. The results provide further evidence for strain-dependent cardiorespiratory and hypertensive phenotype variations in mouse AS models, corroborated by renal SGLT2 expression, and support ongoing initiatives to develop SGLT2 inhibitors for the treatment of AS.

Background: Complete heart block is a known complication after transcatheter aortic valve replacement (TAVR), often requiring pacemaker implantation within 24 hours of the procedure.However, clinical markers for delayed progression to complete heart block after TAVR remain unclear. Objectives:We examined electrocardiographic data that may correlate with delayed progression to complete heart block and need for pacemaker.Methods: This is a single-center retrospective study of 608 patients who underwent TAVR between April 2008 and June 2017. We excluded 164 (27.0%) patients due to having a pacemaker before the procedure or expiring within 24 hours of the procedure (8, 1.3%). We excluded an additional 50 (8.2%) patients who received a pacemaker within 24 hours of the procedure. Electrocardiograms (EKGs) obtained after the procedure were compared to the preprocedural EKG to detect new changes.Results: Left bundle branch block, intraventricular conduction delay, left anterior fascicular block, and right bundle branch block were the most commonly seen conduction abnormalities after TAVR (25.1%, 10.9%, 7.5%, and 3.6%, respectively). Both left bundle branch block (odds ratio [OR] = 2.77 [95% confidence interval (CI): 1.24-6.22]) and right bundle branch block (OR = 13.2 [95% CI: 4.18-41.70]) carried an increased risk of pacemaker implantation after TAVR. Additionally, ΔPR greater than 40 ms from baseline also carried an increased risk of pacemaker implantation (OR = 3.53 [95% CI: 1.49-8.37]). Conclusion:Left bundle branch block, right bundle branch block, and ΔPR greater than 40 ms were all associated with delayed progression to complete heart block and need for pacemaker implantation after TAVR. K E Y W O R D SEKG, pacemaker implantation, transcatheter aortic valve replacement 846

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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.

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.

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