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.

Mouse Genome-Wide Association Study of Preclinical Group II Pulmonary Hypertension Identifies Epidermal Growth Factor Receptor

“…The fold change in RV MaxP with high-fat feeding by background strain ( Figure 1A) is also reported in an article by Meng and colleagues (30) to identify an ideal strain for the development of a murine model of heart failure with preserved ejection fraction. Additional details on these methods are provided in the online supplement.…”

“…Interestingly, those mouse studies were conducted in C57BL/6J mice, and studies in AKR/J mice, which express higher levels of EGFR, may yield different results. In addition, EGFR-based interventions may depend on the specific type of PH-in contrast to chronic hypoxia-induced PH, our HFD-induced model appears to mimic PH secondary to left-sided heart disease (30). It is worth noting that, although the expression of Egfr was higher in the PH-susceptible AKR/J strain than in C57BL/6J, its expression in lung tissue was unchanged between RD and HFD groups.…”

“…As expected, fold change in RV MaxP was significantly positively correlated with that of RV ESP ( Figure E4A, Spearman's r = 0.9423, P , 0.0001). In addition, the fold change in both LV MaxP ( Figure E4B, r = 0.4208, P = 0.0106) and LV ESP ( Figure E4C, r = 0.3490, P = 0.0369) showed positive and significant association with the fold change in RV MaxP, suggesting that the two phenotypes may be related as seen in PH secondary to left-sided heart disease; this finding is explored in detail in an accompanying article by Meng and colleagues (30). Interestingly, although our model of PH relied on intervention through HFD, fold change in body weight was not significantly correlated with fold change in RV MaxP ( Figure E4D, r = 0.1320, P = 0.4427), suggesting that factors besides susceptibility to HFD-induced weight gain determine the extent of PH.…”

Assessment of Right Ventricular Function in the Research Setting: Knowledge Gaps and Pathways Forward. An Official American Thoracic Society Research Statement

“…A model of PH due to LV diastolic dysfunction using Su5416 administration in obese ZSF1 rats has recently been published; this model exhibits moderate PH, but no overt RVF (89). Similarly, AKR/J mice fed with a high-fat diet develop increased LV end-diastolic pressure and biventricular hypertrophy, but it is unknown if they develop RVF (90). As in patients, animal models may require substantial time to develop RVF; this feature may be overlooked because of cost and time constraints, as well as arbitrary requirements by animal care committees that animals be killed if they become ill. Clinically relevant surrogate endpoints of failure to thrive (e.g., weight loss or decreased oral intake) may occur before overt RVF develops in these models.…”

Do BRD(4)S of a Feather Flock Together?

“…While we traditionally consider PAH a disease that selectively affects the pre-capillary arterioles, coronary artery disease (CAD) is reported to be 4-times more prevalent in patients with PAH, suggesting possible common mechanisms of disease or risk factors. Indeed, PAH is associated with a higher prevalence of the metabolic syndrome, an observation that is particularly notable in patients who develop pulmonary vascular remodeling in the setting of heart failure with preserved ejection fraction 4 .…”