Abstract
Introduction: By performing basic and clinical researches, we investigated the clinical significance of reactive oxygen species (ROS) biomarker and the mechanism of ROS production in heart failure with preserved left ventricular ejection fraction (HFpEF). Methods and Results: (1) We measured derivatives of reactive oxidative metabolites (DROM), new biomarker of ROS, in 287 HFpEF patients, and followed them. DROM was significantly higher in HFpEF patients compared to risk factor matched non-HF patients (p<0.001), and was associated with the severity of HF (p<0.001). Kaplan-Meier analysis demonstrated higher probability of cardiovascular events in high-DROM than low-DROM group (p=0.01). Multivariate Cox hazard analysis identified ln-DROM as independent predictor for cardiovascular events (p=0.04). (2) We examined the association of ROS with galectin-3, a predictor of cardiovascular events in HFpEF, by using angiotensin II (AII) receptor blocker (ARB) and galectin-3-inhibitor (Gal3-i) administrated Dahl salt-sensitive rats (DS rats), useful model of HFpEF. Increased left ventricular (LV) galectin-3 protein expressions by Western blotting in HFpEF DS rats were inhibited by ARB, indicating AII-induced galectin-3 expression in HFpEF. Furthermore, Gal3-i significantly reversed LV hypertrophy in DS rats suffered HFpEF (p=0.02), accompanied by the tendency of reduction in collagen-related mRNA gene expression (collagen-I, -III and MMP-2) by real-time RT-PCR. Serum DROM and LV mRNA gene expressions of subunits of ROS generative NADPH oxidase (p22 phox and NOX-2) were increased in HFpEF rats, and Gal3-i tended to downregulate them. These indicated AII induced galectin-3 is involved in LV fibrosis via ROS. (3) Galectin-3 at coronary sinus was higher than at aortic root in HFpEF patients, but not different in non-HF, indicating galectin-3 production in coronary circulation in HFpEF. Moreover, Kaplan-Meier analysis demonstrated higher probability of cardiovascular events in plasma high galectin-3 than in low galectin-3 group in HFpEF patients (p<0.05), indicating clinical significance of galectin-3. Conclusions: These studies demonstrated clinical significance and novel mechanism of ROS in HFpEF.
Published Version
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