Development of a Mouse Model of Metabolic Syndrome, Pulmonary Hypertension, and Heart Failure with Preserved Ejection Fraction

Abstract

Pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (PH-HFpEF; World Health Organization Group II) secondary to left ventricular (LV) diastolic dysfunction is the most frequent cause of PH. It is an increasingly recognized clinical complication of the metabolic syndrome. To date, no effective treatment has been identified, and no genetically modifiable mouse model is available for advancing our understanding for PH-HFpEF. To develop a mouse model of PH-HFpEF, we exposed 36 mouse strains to 20 weeks of high-fat diet (HFD), followed by systematic evaluation of right ventricular (RV) and LV pressure-volume analysis. The HFD induces obesity, glucose intolerance, insulin resistance, hyperlipidemia, as well as PH, in susceptible strains. We observed that certain mouse strains, such as AKR/J, NON/shiLtJ, and WSB/EiJ, developed hemodynamic signs of PH-HFpEF. Of the strains that develop PH-HFpEF, we selected AKR/J for further model validation, as it is known to be prone to HFD-induced metabolic syndrome and had low variability in hemodynamics. HFD-treated AKR/J mice demonstrate reproducibly higher RV systolic pressure compared with mice fed with regular diet, along with increased LV end-diastolic pressure, both RV and LV hypertrophy, glucose intolerance, and elevated HbA1c levels. Time course assessments showed that HFD significantly increased body weight, RV systolic pressure, LV end-diastolic pressure, biventricular hypertrophy, and HbA1c throughout the treatment period. Moreover, we also identified and validated 129S1/SvlmJ as a resistant mouse strain to HFD-induced PH-HFpEF. These studies validate an HFD/AKR/J mouse model of PH-HFpEF, which may offer a new avenue for testing potential mechanisms and treatments for this disease.

Keywords: AKR/J; group 2 pulmonary hypertension; metabolic syndrome; pulmonary hypertension; pulmonary hypertension–heart failure with preserved ejection fraction.

Figure 1.

Response to high-fat diet (HFD)–induced pulmonary hypertension (PH) in 36 strains of mice; 36 inbred and wild-derived mouse strains were subjected to regular diet (RD; 15% lipids/kcal) or HFD (60% lipids/kcal) for 20 weeks. Percentage changes in right ventricular systolic pressure (RVSP) were calculated as the HFD value divided by the average RD value in each mouse strain. Data are mean (±SEM; n = 3–8 mice/diet per strain).

Figure 2.

Validation of HFD-induced heart failure and preserved ejection fraction (PH-HFpEF) in AKR/J mouse. Male AKR/J mice (8 wk old) were exposed to RD and HFD for 16–20 weeks. (A) RVSP measured by right heart catheterization. (B) Representative RV pressure wave forms. (C and D) Left ventricular end-diastolic pressure (LVEDP) and LV ejection fraction (LVEF) measured by left heart catheterization. (E and F) RV and LV hypertrophy assessed by RV or LV weight over tibial length. (G) Pulmonary vascular resistance (PVR) measured in AKR/J mice fed with RD and HFD. (H) Representative images of lung sections stained with α-smooth muscle actin and quantification of medial index from the mean of 5–10 vessels per lung section from eight mice per group. Scale bar, 50 μm. (I and J) Body weights and HbA1c levels measured at the end of study. (K) Glucose tolerance test performed at Week 19. Data are mean (±SEM; n = 14 mice/group for glucose tolerance test; *P < 0.05 and **P < 0.01). S, septum.

Figure 3.

Dependence of RVSP, LVEDP, and biventricular hypertrophy on body weight and HbA1c in AKR/J mice. Correlation of body weight and RVSP (A), LVEDP (C), RV hypertrophy (RVH) (E), and LV hypertrophy (LVH) (G) in AKR/J mice. Correlation of HbA1c levels and RVSP (B), LVEDP (D), RVH (F), and LVH (H) in mice. Spearman r is shown.

Figure 4.

Progression of PH-HFpEF throughout the treatment of HFD in AKR/J mouse. Male AKR/J mice (8 wk old) were subjected to RD or HFD for the indicated time periods. (A) Body weights measured during a 20-week period. (B) HbA1c levels measured in whole-blood samples collected at Weeks 8, 12, and 20. (C and D) RVSP and LVEDP measured at Weeks 8, 12, and 20. Data are mean (±SEM). *P < 0.05 and ****P < 0.0001. (E and F) RV and LV hypertrophy assessed by RV or LV weight over tibial length at Weeks 8, 12, and 20. n = 4, 7, and 21 mice per group, respectively.

Figure 5.

129S1/SvlmJ is resistant to HFD-induced PH-HFpEF. Male 129S1/SvlmJ mice (8-wk-old) were exposed to RD or HFD. (A and B) Body weights and HbA1c levels measured at Week 20. (C) Glucose tolerance test performed with an intraperitoneal injection of dextrose (1.8 mg/g) at Week 19. (D, E, and F) RVSP, LVEDP, and LVEF measured at Week 20. (G and H) RV and LV hypertrophy determined by RV or LV weight over tibial length at Week 20. (I) RVSP measured after 20, 40, and 60 weeks of exposure to RD or HFD. Data are mean (±SEM; n = 3–6 mice per group; *P < 0.05).