Obesity-prone rats fed with high-fat diet as a model of HFpEF

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a common and complex syndrome with high mortality and morbidity rates for which there are currently no evidence-based therapies. As patients with HFpEF very often harbor comorbidities of metabolic syndrome, we hypothesized, that metabolic syndrome in aging animals could be a major mechanism underlying the development of diastolic dysfunction and HFpEF. Therfeore, obesity-prone (OP) and -resistant (OR) rats were respectively fed with a high-fat diet (HFD) or a standard rat chow (Std) for 4 months or for 12 months ( n = 10 rats in each group; 4 groups). At the end of the protocol, abdominal obesity, complete phenotyping of metabolic syndrome, associated to echocardiographic and left and right ventricular catheterization measurements, were performed. Blood was sampled before euthanasia of the animals. After 4- and 12-month HFD, OP rats presented increased total body and abdominal fat weights, altered glucose tolerance test and dyslipidemia. In OP rats, left ventricular systolic (164 ± 6 versus 120 ± 5 mmHg, P < 0.001) and end-diastolic pressures (1.9 ± 0.3 versus 9.2 ± 1.9 mmHg, P < 0.05) increased after 12-month HFD, while there were unchanged after 4 months. Echocardiography showed increased left ventricular mass and relative surface area in 12-month HFD-fed OP rats, together with preserved ejection fraction (around 65%). Right ventricular systolic pressure was increased in 12-month HFD-fed OP rats (31.1 ± 0.8 versus 26.7 ± 0.4 mmHg, P < 0.01). In addition, circulating NT-proBNP levels were decreased compared to OR rats, while ST2 levels increased. Metabolic syndrome induced by 12-month HFD in OP rats leads to the development of HFpEF. In these rats, circulating NT-proBNP levels were decreased, while circulating ST2 levels were largely increased.