A Preclinical Rat Model of Heart Failure With Preserved Ejection Fraction With Multiple Comorbidities

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a common complex clinical syndrome for which there are currently few evidence-based therapies. As patients with HFpEF very often present with comorbidities comprising the metabolic syndrome, we hypothesized, that metabolic syndrome could lead over time to the development of diastolic dysfunction and HFpEF. Obesity-prone rats were exposed to high-fat diet and compared to obesity-resistant rats fed with standard chow. Phenotyping of metabolic syndrome, associated with echocardiographic and cardiac hemodynamic measurements, was performed after 4 and 12 months. Blood and myocardial tissue sampling were performed for pathobiological evaluation. High-fat diet in obesity-prone rats elicited metabolic syndrome, characterized by increased body and abdominal fat weights, glucose intolerance and hyperlipidemia, as well as increased left ventricular (LV) systolic pressure (after 12 months). This was associated with LV diastolic dysfunction (assessed by increased LV end-diastolic pressure) and pulmonary hypertension (assessed by increased right ventricular systolic pressure). Echocardiography revealed significant concentric LV hypertrophy, while LV ejection fraction was preserved. LV remodeling was associated with cardiomyocyte hypertrophy, as well as myocardial and perivascular fibrosis. Circulating levels of soluble ST2 (the interleukin-1 receptor-like) markedly increased in rats with HFpEF, while plasma NT-proBNP levels decreased. RNA-sequencing analysis identified clusters of genes implicated in fatty acid metabolism and calcium-dependent contraction as upregulated pathways in the myocardium of rats with HFpEF. High-fat diet during 12 months in obesity-prone rats led to the development of a relevant preclinical model of HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions.

Unravelling the ageing-reversal potency of stem cell-derived extracellular vesicles in a rat model of premature cardiac senescence

“…Several limitations of our study need to be considered. As mentioned before, the rat model of D-GAL-induced premature ageing we used in the study did not recapitulate all the cardiac changes, especially those related with diastolic dysfunction, described previously (Chang et al, 2016; Hubesch et al, 2022; Kim et al, 2023; Werner et al, 2018). This might have affected mostly the potentially beneficial effects of the P-EVs.…”

Cardiac sympathetic overdrive, M2 macrophage activation and fibroblast heterogeneity are associated with cardiac remodeling in a chronic pressure overload rat model of HFpEF

“…More recently, some of the most compelling data indicated unchanged inflammatory cells infiltration in myocardium whereas the circulating inflammatory biomarker sST2 was largely increased in a metabolic syndrome associated HFpEF rat model. Therefore, it cannot be excluded that other circulating inflammatory markers, which were not tested here, could be strongly activated ( Hubesch et al, 2022 ).…”

Early Alteration of Right Ventricle–Pulmonary Artery Coupling in Experimental Heart Failure With Preserved Ejection Fraction

“…Animals used in the present study were diet‐induced obesity‐prone and obesity‐resistant Sprague Dawley rats raised using selected breeders obtained from Charles River Laboratories Inc. (Wilmington, MA). As previously reported, 13 experimental HFpEF associated with multiple comorbidities (ie, metabolic syndrome) was induced in 4‐week‐old obesity‐prone rats (n=13) fed with a high‐fat diet (473 kcal/100 g; 45% of energy from lipids and 17% from sucrose; D1245; Research Diets, New Brunswick, NJ) for 12 months. Nine 4‐week‐ old obesity‐resistant rats fed with a standard rat chow diet (339 kcal/100 g; 5% of energy from lipids and 2% from sucrose; A03 Safe Diets, Augy, France) for 12 months were used as controls.…”

“…In this context, we developed an experimental rat model of HFpEF associated with multiple comorbidities, as a robust preclinical model of HFpEF mimicking key features observed in patients including aging and comorbidities. 13 In the present study, we evaluated whether these rats developed PH and RV dysfunction as observed in patients with HFpEF and studied underlying pathophysiological mechanisms.…”