P452Chronic exercise training modulates inflammation and reduces left ventricle stiffness in heart failure with preserved ejection fraction

Abstract

Introduction: Systemic inflammation and endothelial dysfunction have an important role for myocardial dysfunction and remodeling in heart failure with preserved ejection fraction (HFpEF). Microvascular endothelial inflammation leads to increased cardiomyocyte stiffness and interstitial fibrosis which induce diastolic LV dysfunction. Nonetheless, optimal treatment remains widely undefined. Purpose: To examine whether exercise training would be able to improve exercise capacity, diastolic function, left ventricle (LV) stiffness and exert an antiinflammatory effect in an animal model of HFpEF. Methods: Nine-week old ZSF1 obese rats (Ob n=20) were divided into two groups: sedentary (ObSED, n=10) and exercised (ObEX, n=20). At the 16th week of life, the ObEX group was submitted to treadmill exercise training during 4 weeks, 5 days per week, 60 min per day, at a speed of 20m/min. At the 19th week, all animals underwent echocardiographic evaluation. At the end of the protocol (20th week), all animals performed a maximal oxygen consumption (VO2max) test, hemodynamic evaluation, and blood and heart samples were collected for analysis. Plasma proteins were analyzed by ELISA [interleukin-6 (IL- 6), C-reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha), intercellular adhesion molecule (ICAM), protein carbonyl content (PCC), tissue inhibitors of metalloproteinases-1 (TIMP1), matrix metalloproteinases-9 (MMP9) and Nterminal pro-brain natriuretic peptide (NT-proBNP)]. Samples from heart and LV were collated for: i) histological analysis (cross-sectional area (CSA), collagen content and ii) passive tension analysis in skinned cardiomyocytes). Results: Exercise training improved VO2max (21.1±2.5 vs 17.2±1.8 mL kg-1 min-1) and attenuated diastolic dysfunction (E/E' ratio 13.8±1.8 vs 16.5±1.9) (p<0.05). The end-diastolic pressure volume relationship had a trend to decrease in ObEX that, together with the decreased passive tension presented in skinned cardiomyocytes, suggests a reduction in myocardial stiffness (p<0.05). No significant differences were observed between the groups in body mass, heart and LV weight and CSA (p>0.05). However, the ratio collagen/muscle was significantly reduced in ObEX when compared to ObSED (0.08 vs. 0.12 p<0.05). Exercised animals showed reduced levels of circulating IL-6, CRP, TNF-α, ICAM-1, PCC, NTproBNP and MMP9/TIMP1 (p<0.05). In addition, we found that the ratio E/E' was positively correlated with circulating IL-6 (r=0,63; p=0,02), NT-proBNP (r=0,64; p=0,02) and MMP9/TIMP1 (r=0,69; p=0,01). Conclusion: Chronic exercise training ameliorates exercise capacity, LV diastolic function and stiffness in rats WITH HFpEF. These improvements were associated with reduced circulating levels of inflammatory cytokines and markers of endothelial dysfunction, oxidative stress, neurohumoral activation and extracellular matrix remodeling.