Abstract Background Exploring experimental models of heart failure with preserved ejection fraction (HFpEF) may help to understand the mechanisms leading to this challenging condition. Purpose In a translational model, we aimed to assess the relative contribution of hypertension and obesity in inducing structural, functional and hemodynamic changes associated to the HFpEF phenotype. Methods We investigated 3 groups of male 40 weeks old rats: control Wistar Kyoto (WKY, n=10), Spontaneous Hypertensive Rats (SHR, n=10) and SHR with obesity induced by consumption of cafeteria diet during 28 weeks (Ob-SHR, n=9). Animals were submitted to assessment of: body weight, systolic (SBP) and diastolic (DBP) blood pressure; in vivo structural and functional changes evaluated by high resolution Echocardiography including left atrial dimension (LA), left ventricle (LV) diastolic dimension (LVDD), LV posterior wall thickness (LVPW), LV wall relative thickness (LVWRT), LV ejection fraction (LVEF). Invasive hemodynamic evaluation assessed the intraventricular pressure curves obtaining LV end diastolic pressure (LVEDP) and calculation of LV diastolic time constant (Tau). After euthanasia, thoracic aorta was used for vascular function assessment by measuring the maximal cumulative concentration-effect curves of contraction to phenylephrine (PE), expressed as Emax (%). Protein expression of Intercellular Adhesion Molecule 1 (ICAM-1) was determined in myocardial tissue (% in relation to WKY). Results were expressed as mean ± SEM and effects of groups vs time were compared with mixed ANOVA. Results The results are shown in the table. We observed higher levels of SBP and DBP in SHR and Ob-SHR when compared to WKY, but with similar values between SHR and Ob-SHR groups. Regarding the structural LV changes, we observed LV remodeling and LA dilation in both SHR and Ob-SHR groups, but with no difference between both hypertensive groups. The Ob-SHR was the only group showing increased LVEDP in comparison to other groups. The Tau was also increased in the Ob-SHR animals. Concordantly, the Ob-SHR group showed increased expression of ICAM-1 (figure - A) that was concomitant to abnormal vascular response with increased contraction to PE (figure - B) as compared to SHR and WK groups. Conclusions In this translational model of HFpEF in rats, the structural changes related to LV remodeling were similar in SHR and Ob-SHR, probably reflecting comparable higher levels of blood pressure observed in both groups. In contrast, elevated EDP, a hallmark of HFpEF, was only seen in the Ob-SHR group and this was concomitant to diastolic dysfunction, endothelial inflammatory activation and altered vascular function. Our results indicate that obesity is a key factor inducing vascular and myocardial changes that triggers HFpEF phenotype in this model.
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