Abstract
Obesity and hypertension are prevalent comorbidities in heart failure with preserved ejection fraction. To clarify if and how interaction between these comorbidities contributes to development of diastolic dysfunction, lean and obese ZSF1 rats were treated with deoxycorticosterone acetate implants and a high‐salt diet (DS) to induce severe hypertension, or with placebo. In addition to echocardiographic, metabolic and hemodynamic analyses, immunohistochemistry and RNAseq were performed on left ventricular tissue. Obesity negatively affected cardiac output, led to an elevated E/e’ ratio and mildly reduced ejection fraction. DS‐induced hypertension did not affect cardiac output and minimally elevated E/e’ ratio. Diastolic derangements in placebo‐treated obese rats developed in absence of inflammation and fibrosis, yet in presence of oxidative stress and hypertrophic remodelling. In contrast, hypertension triggered apoptosis, inflammation and fibrosis, with limited synergy of the comorbidities observed for inflammation and fibrosis. Transcriptional data suggested that these comorbidities exerted opposite effects on mitochondrial function. In placebo‐treated obese rats, genes involved in fatty acid metabolism were up‐regulated, whereas DS‐induced a down‐regulation of genes involved in oxidative phosphorylation. Overall, limited interaction was observed between these comorbidities in development of diastolic dysfunction. Importantly, differences in obesity‐ and hypertension‐induced cardiac remodelling emphasize the necessity for comorbidity‐specific phenotypical characterization.
Highlights
The chronic and progressive condition, in which the heart is unable to maintain cardiac output commensurate with the body's requirements, is referred to as heart failure (HF)
HF can be divided into HF with reduced ejection fraction (HFrEF), marked by the inability to adequately contract during systole, and HF with preserved ejection fraction (HFpEF)
cLean + DS vs lean (DS) treatment triggered severe hypertension in both lean and obese ZSF1 rats, and the combination of these factors enabled us to study if and how obesity and hypertension contribute to the development of diastolic dysfunction at a functional, histological and transcriptional level
Summary
The chronic and progressive condition, in which the heart is unable to maintain cardiac output commensurate with the body's requirements, is referred to as heart failure (HF). HFpEF is associated with impaired cardiac relaxation and increased passive cardiac stiffness, resulting in elevated end‐diastolic pressure and impaired left ventricular (LV) filling.[1] HFpEF accounts for over 50% of all HF cases in Europe and the United States of America, yet currently no effective treatment is available for this specific form of HF.[1]. We tested the hypothesis that metabolic and hypertensive disease act synergistically in development and/or progression of HFpEF For this purpose, male lean and obese ZSF1 rats, of which the latter were previously shown to develop diastolic dysfunction between week 10 and 20 of natural ageing,[12,13] were studied from 12 weeks of age. Metabolic and hemodynamic analyses, immunohistochemistry and RNAseq on LV apex tissue was performed, which enabled us to dissect which pathophysiological and transcriptional adaptations were associated with obesity and its associated biochemical aberrations, and which adaptations with DS‐induced hypertension
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