Integrative Pathophysiology of a Novel Rodent Model of Postmenopausal Heart Failure with Preserved Ejection Fraction

Abstract

PurposeApproximately 50% of heart failure patients have heart failure with preserved ejection fraction (HFpEF), and currently there are no proven therapies for this population. There is an urgent need to develop animal models of HFpEF to understand the mechanisms of this disease and discover treatments. Notably, 70–85% of HFpEF patients are postmenopausal women. We hypothesized that a novel animal model that recapitulated classical risk factors for HFpEF (i.e., female sex, aging/menopause, hypertension, obesity/high fat, high sugar diet) would display cardiac abnormalities, skeletal muscle dysfunction, and exercise intolerance consistent with disease features seen in humans.MethodsFemale, ovariectomized, spontaneously hypertensive rats (SHR) were fed a Western diet (high saturated fat, high sugar) for ~16 weeks to model HFpEF pathophysiology. Female, sham surgery, lean diet, Wistar‐Kyoto rats were used as controls. We evaluated glucose tolerance, tail‐cuff blood pressure, running time to exhaustion, echocardiography, in vitro skeletal muscle force, intact mitochondrial respiration and reactive oxygen species emission, and cardiac and skeletal muscle histology. All researchers were blinded to group assignment during terminal experiments and statistical analyses. Data were compared using Student's t‐tests and are shown as mean ± SD from n = 4–8 rats per group.ResultsHFpEF rats displayed a 20±6% increase in body weight, 20±22% greater area under the glucose response curve, 36±14% higher mean arterial pressure, 70±47% elevation in liver enzymes, and 42±12% decrease in high‐intensity running endurance (p<0.05). Left ventricle (LV) of HFpEF rats exhibited hypertrophy (in mg/mm: Control 17±0.5, HFpEF 21±0.7, p<0.05), fibrosis (in %: Control 2±1.0, HFpEF 4±1.9, p=0.10) and elevated E wave deceleration rate indicative of restrictive LV filling (in m/s2: Control 21±5, HFpEF 35±4, p<0.05). LV fractional shortening, a marker of systolic function, was preserved (in %: Control 47±7, HFpEF 44±7, p>0.05). In limb skeletal muscle, HFpEF caused weakness (force in N/g: Control 17±3, HFpEF 14±1, p<0.05), impaired maximal mitochondrial respiration (in pmol O2/s/mg: Control 71±27, HFpEF 39±11, p<0.05), and a trend toward elevated mitochondrial H2O2 emission (in pmol/min/mg: Control 0.8±0.4, HFpEF 1.7±0.9, p=0.10). In this early stage of HFpEF, there was no limb muscle atrophy in type I (in μm2: Control 1986±526, HFpEF 1752±364), type IIa (in μm2: Control 1595±339, HFpEF 2022±663), or type IIb/x (in μm2: Control 3605±536, HFpEF 4111±653) tibalis anterior fibers (p>0.05), but there was an increase in fibrosis (in %: Control 0.7±0.3, HFpEF 1.5±1, p<0.05).ConclusionOur preclinical model recapitulates key cardiovascular, metabolic, and skeletal muscle features of the disease with a pronounced decrease in high intensity running endurance. The model is clinically relevant for post‐menopausal women with HFpEF ‐ the patient group that represents the majority of the HFpEF population. This model will be valuable for future studies aiming to elucidate mechanisms of disease development and novel treatments.Support or Funding InformationBREATHE T32 HL134621This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.