Lack of Synergy between Major Risk Factors, Obesity and Hypertension, in Development of Heart Failure with Preserved Ejection Fraction
Authors: Brandt Maarten M. , Nguyen Isabel T.N. , Krebber Merle M. , den Ouden Krista , Verhaar Marianne C. , Duncker Dirk J. , Mokry Michal , Joles Jaap A. , Cheng Caroline 
Published: June 2021

BackgroundObesity and hypertension are highly associated with diastolic dysfunction. The current consensus is that metabolic‐ and hypertensive disease, like other comorbidities, contribute synergistically to a systemic state of inflammation, leading to coronary microvascular dysfunction, oxidative stress, cardiomyocyte stiffness and myocardial fibrosis. As unambiguous evidence for such a synergistic relation is currently lacking, we aimed to clarify if and how obesity and hypertension interact in development of diastolic dysfunction.MethodsMale lean and obese ZSF1 rats, of which the latter were previously shown to develop heart failure with preserved ejection fraction, were studied from 13 till 26 weeks of age. To assess the impact of severe hypertension, both lean and obese rats were treated with Deoxycorticosterone acetate implants plus 6% dietary salt (DS) or vehicle, from 19 to 26 weeks of age. In addition to echocardiographic, metabolic, and hemodynamic analyses, RNAseq and histochemistry were done on left ventricle tissue.ResultsBody weight, cholesterol, and triglycerides were elevated in obese rats (table 1). Systolic blood pressure (SBP) was increased by DS treatment. Ejection fraction (EF) was slightly reduced in both vehicle‐ and DS‐treated obese rats, though all animals remained within the spectrum of preserved EF (>50%). Illustrative for diastolic dysfunction, the ratio between peak velocity of early mitral inflow, and early diastolic mitral annulus velocity (E/e′), was increased in obese animals. Importantly, no synergistic effects were observed of obesity and hypertension (p=0.55). In the vehicle‐treated obese rats, diastolic dysfunction developed in absence of significant fibrosis. Computational pathway analysis of the RNAseq data using Ingenuity Pathway Analysis however, predicted a steep elevation in obesity‐induced mitochondrial fatty acid oxidation (p=1.99E‐09). Both DS‐treated lean and obese rats on the other hand, showed severe mitochondrial dysfunction, as evidenced by an overall downregulation of enzymes involved in oxidative phosphorylation, and elevated cardiac fibrosis, macrophage presence, and apoptosis.ConclusionIn this study, no synergistic effect was observed of obesity‐ and hypertension in development of diastolic dysfunction. Our findings indicate that the metabolic derangements had a more pronounced contribution to diastolic dysfunction, whereas DS‐induced hypertension mainly triggered loss of cardiomyocytes, macrophage influx, and fibrosis.Support or Funding InformationThis study was supported by a grant from the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation [CVON2014‐11 (RECONNECT)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.