Limited synergy of obesity and hypertension, prevalent risk factors in onset and progression of heart failure with preserved ejection fraction
Brandt, Maarten M; Nguyen, Isabel T N; Krebber, Merle M; van de Wouw, Jens; Mokry, Michal; Cramer, Maarten J; Duncker, Dirk J; Verhaar, Marianne C; Joles, Jaap A; Cheng, Caroline
(2019) Journal of Cellular and Molecular Medicine, volume 23, issue 10, pp. 6666 - 6678
(Article)
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
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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.
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Keywords: deoxycorticosterone acetate, diastolic function, ejection fraction, heart failure, hypertension, obesity, diastolic function, Molecular Medicine, Cell Biology, Journal Article
ISSN: 1582-1838
Publisher: Wiley-Blackwell
Note: Funding Information: Funding information This work was supported by Netherlands Foundation for Cardiovascular Excellence [to CC], Netherlands Organization for Scientific Research Vidi grant [no. 91714302 to CC], the Erasmus MC fellowship grant [to CC], the Regenerative Medicine Fellowship grant of the University Medical Center Utrecht [to CC] and the Netherlands Cardiovascular Research Initiative: An initiative with support of the Dutch Heart Foundation [CVON2014-11 RECONNECT to CC, JAJ, DD, and MV]. The authors thank Krista Den Ouden and Adele Dijk for excellent technical assistance, prof. Victor van Hinsbergh for critically reading the manuscript, and Utrecht Sequencing Facility for providing the sequencing service and data. Utrecht Sequencing Facility is subsidized by the University Medical Center Utrecht, Hubrecht Institute and Utrecht University. Publisher Copyright: © 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
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