Exercise Improves Diastolic Function In HFpEF By Reducing Intrinsic Cardiomyocyte Stiffness And Fibrosis

Abstract

INTRODUCTION In heart failure with preserved ejection fraction (HFpEF), the underlying systemic inflammatory state is related to myocardial stiffening. However, optimal treatment remains largely undefined. PURPOSE: To investigate the effect of exercise training (ExT) on left ventricle (LV) stiffness in a rat model of HFpEF. METHODS: The study was performed with nine-week old ZSF1 obese rats (Ob n=20). At the 16th week, they were randomly divided in sedentary (ObSED, n=10) and exercised (ObEX, n=10; treadmill ExT during 4 weeks, 5 days/week, 60 min/day, at a speed of 20m/min). In the 18th week, all animals underwent echocardiographic evaluation. In the 20th week, animals were sacrificed and samples from heart and LV were collated for: i) histological analysis (cross-sectional area (CSA), collagen content; ii) passive tension analysis in skinned cardiomyocytes); iii) assessment of expression on matrix metaloproteinases (MMP-2,-9) and its tissue inhibitors (TIMP-1 and 2) by western blot analysis and iv) zimography assessment of proteolytic activity. RESULTS: Both groups presented preserved ejection fraction (>70%). ExT improved diastolic function evidenced by E/E´ ratio (14,81±2,27 vs 16,53±1,47 p<0,05). Moreover, in skinned cardiomyocytes, the ObEx showed decreased passive tension, which suggests a reduction in myocardial stiffness (p<0.05). No significant differences were observed between the groups in body mass, heart and LV weight, CSA, and MMPs and TIMPs expression and activity (p>0.05). However, the ratio collagen/muscle was significantly reduced in ObEX, compared to ObSED (0.08 vs. 0.12 p<0.05). CONCLUSION: ExT improves diastolic function mainly due to the decrease on collagen deposition and diminished cardiomyocyte stiffness. FUNDING: Grant from the European Commission FP7-Health-2010; MEDIA-261,409. CIAFEL is funded by European Regional Development Fund through the Operational Competitiveness Programme, and by FCT (UID/DTP/00617/2013). Schmidt, C.: CAPES (BEX 0554/14-6). Moreira-Gonçalves, D.: FCT (SFRH/BPD/90010/2012).