Identification and Progression of Aortic Valve Regurgitation in the db/db Mouse Model of Type 2 Diabetes Mellitus
Authors: McDermott Michael , Trask Aaron J 
Published: June 2021

Cardiovascular complications, including heart failure, coronary microvascular disease and valvular disease, are leading causes of mortality in patients with type 2 diabetes mellitus (T2DM). Importantly, there is a strong correlation between patients with T2DM and aortic valve disease (AVD), such as calcified aortic valve, valvular stenosis, or regurgitation. Therefore, the goal of this study was to evaluate the hypothesis that db/db mice with T2DM exhibited some manifestations of valve disease. To investigate this, we examined cardiac structure and function of db/db mice at two time points to determine the presence and extent of AVD. Heterozygous Db/db (control) and homozygous db/db (T2DM) mice were subjected to echocardiography at 16 and 24 weeks of age. At 16 weeks of age 30% of db/db mice (3 of 10) presented with aortic regurgitation compared to 0% of the controls (0 of 9). By 24 weeks of age, 48% of db/db mice (15 of 31) developed aortic regurgitation compared to 15% of controls (4 of 26). At this same time‐point, 32% of db/db mice (10 of 31) showed peak aortic velocities above 1600 mm/s, suggesting a stenotic phenotype, while the incidence was only 15% for controls (4 of 26). Left ventricular end‐diastolic volumes (LVEDVs) were decreased in db/db mice at both 16‐ and 24 weeks compared to controls (16 wks: control 75.1 μl ± 1.9 vs db/db 61.1 μl ± 1.9: p<0.0001; 24 wks: control 82.1 μl ± 2.2 vs db/db 69.1 μl ± 1.6; p=0.0008). However, db/db mice with regurgitant valves had an increased LVEDV and stroke volume (SV) compared with those that did not (24 wks: LVEDV 74.7 μl ± 1.9 vs 63.4 μl ± 1.9 respectively; p=0.06. SV: 49.9 ml ± 1.3 vs 40.9 ml ± 1.5 respectively; P=0.01). Furthermore, there were significant increases in LVEDV (61.1 μl ± 1.8 to 69.1 μl ± 1.6; p=0.03) and stroke volume (SV: 38.8 ml ± 1.1 to 45.3 ml ± 1.2; p=0.004) of db/db mice from 16 weeks to 24 weeks. Interestingly, as the db/db mice age, there was a significant decrease in body weight from 16 weeks to 24 weeks (51.1 g ± 0.5 to 44.7 g ± 1.3 respectively; P<0.0001). However, further analysis shows that this difference is driven by db/db mice exhibiting a regurgitant phenotype, which weighed significantly less than the db/db mice with normal flow (40.6 g ± 1.56to 48.6 g ± 1.7 respectively; P=0.0002). T2DM mice with normal flow exhibited no difference in body weight with age (16 vs 24 weeks; p>0.99). Finally, E/A ratio was significantly higher for db/db mice at both 16 weeks (1.77 ± 0.04 vs 1.53 ± 0.03; p<0.0001) and 24 weeks (1.84 ± 0.05 vs 1.59 ± 0.04; p=0.009). These data show the presence of aortic valve regurgitation in a small subset of db/db mice that, interestingly, correlated with a reduction in body weight over time. The db/db mouse T2DM model exhibits features of diastolic dysfunction as evidenced by reduced LVEDV compare to control; however, db/db mice that had regurgitation showed an expected elevation in LVEDV and SV. Taken together, our data suggest that db/db mice can develop AVD that coincides with diastolic dysfunction. Further studies are needed to investigate the underlying mechanism that leads to the development of the AVD phenotype in db/db mice.Support or Funding InformationSupport: NIH R00 HL116769, NIH R21 EB026518, and NCH to AJTThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.