Abstract 17003: Development of a Mouse Model of Metabolic Syndrome, Pulmonary Hypertension, and Heart Failure With Preserved Ejection Fraction (PH-HFpEF)
Introduction: Pulmonary hypertension associated with heart failure and preserved ejection fraction (PH-HFpEF; WHO Group II) secondary to left ventricular diastolic dysfunction is the most frequent cause of pulmonary hypertension. 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.
Methods and Results: 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 and left ventricular pressure-volume analysis. The high-fat diet induces obesity, glucose intolerance, insulin resistance, hyperlipidemia, as well as pulmonary hypertension, 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 RVSP compared to mice fed with regular diet, along with increased LVEDP, both RV and LV hypertrophy, glucose intolerance and elevated HbA1c levels. Time course assessments showed that HFD significantly increased body weight, RVSP, LVEDP, 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.
Conclusions: These studies validate a HFD/AKR/J mouse model of PH-HFpEF, which may offer a new avenue for testing potential mechanisms and treatments for this disease.
Author Disclosures: Y. Lai: None. Q. Meng: None. N. Kelly: None. M. Bueno: None. J. Baust: None. T. Bachman: None. R. Vanderpool: None. J. Radder: None. J. Hu: None. A. Morris: None. A. Mora: None. M. Gladwin: Consultant/Advisory Board; Modest; Bayer.
- © 2016 by American Heart Association, Inc.