title: 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.
authors.affiliation: 1 Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.|2 School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Meng
authors.affiliation: 1 Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.|3 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Yen-Chun
authors.initials: YC
authors.lastname: Lai
authors.affiliation: 3 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Kelly
authors.affiliation: 1 Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.|3 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Marta
authors.initials: M
authors.lastname: Bueno
authors.affiliation: 1 Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Baust
authors.affiliation: 1 Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Timothy N
authors.initials: TN
authors.lastname: Bachman
authors.affiliation: 1 Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Goncharov
authors.affiliation: 1 Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Vanderpool
authors.affiliation: 3 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Josiah E
authors.initials: JE
authors.lastname: Radder
authors.affiliation: 1 Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Jian
authors.initials: J
authors.lastname: Hu
authors.affiliation: 1 Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.|3 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Elena
authors.initials: E
authors.lastname: Goncharova
authors.affiliation: 3 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Morris
authors.affiliation: 1 Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.|3 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Mora
authors.affiliation: 3 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
authors.affiliation: 1 Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.|3 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
mesh_terms: D000818:Animals; D001794:Blood Pressure; D003971:Diastole; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D006333:Heart Failure / Q000150:complications* / Q000473:pathology / Q000503:physiopathology*; D006976:Hypertension, Pulmonary / Q000150:complications* / Q000473:pathology / Q000503:physiopathology*; D024821:Metabolic Syndrome / Q000150:complications* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008806:Mice, Inbred AKR; D015203:Reproducibility of Results; D013318:Stroke Volume; D013599:Systole
keywords: AKR/J; group 2 pulmonary hypertension; metabolic syndrome; pulmonary hypertension; pulmonary hypertension–heart failure with preserved ejection fraction