Development and Characterization of a Novel Small Animal Model of Heart Failure with Preserved Ejection Fraction

Abstract

Heart Failure with Preserved Ejection Fraction (HFpEF) is a complex heterogeneous disease that currently affects approximately 3 million in the US and accounts for 60% of all heart failure hospitalizations. HFpEF is associated with significant morbidity, mortality and healthcare expenditures. At present, there are no FDA approved therapies for reducing mortality and hospitalization in HFpEF patients. The lack of approved therapies is due in part to a lack of preclinical models that faithfully mimic the clinical presentation of HFpEF.The obese ZSF‐1 rat is genetically predisposed to the development of hypertension, obesity, dyslipidemia, and diabetes, all of which contribute to the pathogenesis of HFpEF. We investigated the suitability of the obese ZSF‐1 rat as a model of HFpEF. Both obese and lean control ZSF‐1 rats (n = 4–6 per group) were utilized for these studies. The rats were studied from 16 weeks to 24 weeks of age. We measured several clinical parameters including cardiac structure and function (2‐D echocardiography), left ventricular (LV) pressures (LV Millar catheter), cardiac fibrosis, conscious blood pressure and heart rate (DSI radiotelemeters), vascular function, exercise capacity (rodent treadmill), and serum lipid and triglyceride levels (standard blood ELISA assays).Obese ZSF‐1 rats exhibited a significant increase in body weight and systemic blood pressure combined with hyperglycemia and insulin insensitivity. Echocardiographic evaluation of the left ventricle (LV) revealed highly significant increases in both the E/A and E/E′ ratios. LV end‐diastolic pressure (LVEDP) and LV relaxation (Tau) were decreased in the obese ZSF‐1 rats. Histological evaluation of the hearts revealed significant increases in cardiac fibrosis and cardiac myocyte injury in the obese vs. lean ZSF‐1. Furthermore, vascular reactivity and circulating nitric oxide levels were reduced in the obese ZSF‐1 rats. Exercise capacity testing revealed that exercise capacity was very significantly reduced in the ZSF‐1 obese rat throughout the 8 week experimental protocol. All these findings are consistent with the HFpEF phenotype observed in human HFpEF patients.This preclinical model of HFpEF, will provide novel insights into the pathobiology of HFpEF and provide a critically important platform for testing HFpEF therapeutics. Our future studies will be aimed at the identification of novel therapeutic interventions to treat HFpEF.Support or Funding InformationNational Institutes of General Medical Sciences (NIGMS) COBRE grant no. P30GM106392 to Dr. KapustaFigure 1