Abstract Body: Introduction - HFpEF accounts for more than half of the 6.7 million Americans living with heart failure, with women having a higher lifetime risk of HFpEF than men. To investigate the underlying mechanisms, we developed a diet-induced HFpEF model which recapitulates diastolic dysfunction, hypertension, coronary flow reserve, and obesity.
Methods – Male, female, or ovariectomized (Ovx) female Ldlr^-/- mice were placed on either chow or a high fat sucrose-containing (HFSC) diet for 12- or 24-weeks. Regression diet groups were switched back from the HFSC to chow diet. Echocardiography was used to assess cardiac function and other hemodynamic parameters. Histology and immunofluorescence techniques were used to quantify fibrosis, arteriolar diameters, and other metrics.
Results – Left ventricular end diastolic pressure (LVEDP) increased significantly between chow and HFSC groups for males (p<0.0001), females (p = 0.0019) and Ovx mice (p = 0.0001). Global longitudinal strain (GLS) was also reduced in the HFSC group (p<0.0001 for M, F and Ovx). Similarly, coronary flow reserve (CFR) was lower in the HFSC group in females (p<0.0001) and Ovx (p = 0.0427), but not in males. Pulse wave velocity (PWV) was significantly increased in females (p = 0.0021) and Ovx mice (p = 0.0022), but not in males. Aortic pressure was significantly increased in the HFSC group for males (p = 0.0004), females (p = 0.017) and Ovx mice (p = 0.0257). Arteriolar diameter was reduced in HFSC females compared to chow (p<0.0001) and increased in the regression group (p = 0.0277). In contrast, arteriolar diameters increased in Ovx mice in the HFSC group (p<0.0001) and regression group (p = 0.0004). Perivascular fibrosis (PVF) increased in males (p = 0.0352) and females (p = 0.0743) on a HFSC diet compared to their chow controls. Arterioles in the Ovx group had abundant PVF compared to males (p<0.0001) or females (p = 0.0082) even in the chow group.
Conclusion – HFSC diet leads to HFpEF in male, female and Ovx Ldlr^-/- mice and leads to dramatic changes in hemodynamics, vessel diameter, and PVF in a sex-dependent manner, indicating that the common HFpEF phenotype is achieved by distinct molecular mechanisms unique to each sex. These findings establish a one-hit model with translational potential for HFpEF research.