Abstract 17471: The Obese Zsf1 Rat as a New Model of Heart Failure with Preserved Ejection Fraction Accompanying the Metabolic Syndrome
Diastolic dysfunction, characterized by relaxation abnormalities and increased myocardial stiffness, and heart failure with preserved ejection fraction (HFpEF) are increasingly prevalent in Western societies accompanying well-known risk factors, such as hypertension, obesity and diabetes mellitus (DM). Nevertheless, pathophysiology and therapeutics of HFpEF remain poorly explored partly due to the lack of a satisfactory animal model. To establish and characterize an animal model of HFpEF, obese (ZSF1-Ob, n=11) and lean ZSF1 (ZSF1-Ln, n=11) rats and their respective Wistar-Kyoto controls (WKY, n=11) serially underwent insulin resistance and oral glucose tolerance testing, metabolic cage assessment and blood and urine sample collection, and echocardiography, at 10, 14 and 18 weeks of age, followed by invasive hemodynamic recordings and aortic ring preparations at 20 weeks. ZSF1-Ln presented hypertension and left ventricular hypertrophy, which were further aggravated in ZSF1-Ob, compared to WKY. Only ZSF1-Ob developed obesity, oral glucose intolerance, insulin resistance, hyperglycemia and glycosuria, consistent with type-2 DM and metabolic syndrome, but its creatinine clearance, however, was still unaltered. Though systolic function was preserved, as assessed by cardiac index, ejection fraction and the slope of the end-systolic pressure-volume relationship, ZSF-1 Ob alone showed increased E/E' on echocardiography, prolonged time constant of isovolumetric relaxation, elevated end-diastolic pressure and upward shifted end-diastolic pressure-volume relationship on invasive hemodynamic evaluation, and increased lung to body weight ratio, denoting HF with lung congestion. Additionally, only ZSF1-Ob showed increased vascular stiffness and reduced dilator responses to acetylcholine and nitroprusside, signaling endothelial dysfunction and hyporeactivity to nitric oxide, respectively. We conclude that cardiovascular risk factors in this experimental model of metabolic syndrome portend HF, preserved systolic function and diastolic dysfunction without renal dysfunction by the 20th week of age which makes obese ZSF1 rats ideal for future studies on the pathophysiology and therapeutics of HFpEF.
- © 2012 by American Heart Association, Inc.