Long-term protective effects of the angiotensin receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress, and myocardial dysfunction.

Abstract

9006 Background: Chronic inflammation, oxidative stress and renin-angiotensin system (RAS) play a significant role in chemotherapy-induced cardiotoxicity (CTX). Telmisartan (TEL), an antagonist of the angiotensin II type-1 receptor, reduces anthracycline (ANT)-induced CTX. Methods: A phase II placebo (PLA)-controlled randomized trial was carried out to assess the role of TEL in the prevention of cardiac subclinical damage induced by epirubicin (EPI). Forty-nine patients (mean age ± SD, 53.0±8 years), cardiovascular disease-free with cancer at different sites and eligible for EPI-based treatment, were randomized to one of two arms: TEL n=25; PLA n=24. A conventional echocardiography equipped with Tissue Doppler imaging, strain and strain rate (SR) was performed, and serum levels of proinflammatory cytokines, IL-6 and TNF-α, and oxidative stress parameters, reactive oxygen species (ROS) and glutathione peroxidase were assessed. All assessments were carried out at baseline, after every 100 mg/m2 EPI dose and at 6, 12 and 18-month follow-up (FU). Results: A significant reduction in the SR peak in both arms was observed at t2 (cumulative dose of 200 mg/m2 EPI) in comparison to t0. Conversely, at t3, t4 (300, 400 mg/m2 EPI), 6, 12 and 18-month FU, the SR increased reaching the normal range only in TEL arm, while in PLA arm SR remained significantly lower as compared to t0. The differences between SR changes in PLA and TEL arms were significant from 300 mg/m2 EPI (t3) up to 18 month-FU. IL-6 increased significantly in PLA arm at t2 compared to t0, but remained unchanged in the TEL arm. ROS levels also increased significantly at t2 vs. baseline in PLA arm, while remained unchanged in TEL arm. The mean change in ROS and IL-6 at t2 was significantly different between the two arms. At 3, 6, 12 and 18 month-FU, ROS and IL-6 decreased in comparison to t2 in PLA arm, while remained low in TEL arm. Conclusions: Our results suggest that TEL is able to reverse acute EPI-induced myocardial dysfunction and maintain a normal systolic function up to 18 month-FU. These effects are likely due to two different mechanisms, RAS blockade and prevention of chronic inflammation/oxidative stress.