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

Abstract

Chronic inflammation, oxidative stress and the renin-angiotensin system (RAS) play a significant role in chemotherapy-induced cardiotoxicity (CTX). Telmisartan (TEL), an antagonist of the angiotensin II type-1 receptor, was found to reduce anthracycline (ANT)-induced CTX. We carried out a phase II placebo (PLA)-controlled randomized trial to assess the possible 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 determined. All assessments were carried out at baseline, after every 100 mg/m(2) of EPI dose and at the 12-month follow-up (FU). A significant reduction in the SR peak both in the TEL and PLA arms was observed at t(2) (cumulative dose of 200 mg/m(2) of EPI) in comparison to t(0). Conversely, at t(3) (300 mg/m(2) EPI), t(4) (400 mg/m(2) EPI) and the 12-month FU, the SR increased reaching the normal range only in the TEL arm, while in the PLA arm the SR remained significantly lower as compared to t(0) (baseline). The differences between SR changes in the PLA and TEL arms were significant from 300 mg/m(2) EPI (t(3)) up to the 12-month FU. Serum levels of IL-6 increased significantly in the PLA arm at 200 mg/m(2) EPI (t(2)) in comparison to baseline, but remained unchanged in the TEL arm. The same trend was demonstrated for ROS levels which significantly increased at t(2) vs. baseline in the PLA arm, while remained unchanged in the TEL arm. The mean change in ROS and IL-6 at t(2) was significantly different between the two arms. In the present study, we confirmed at the 3-month FU a trend toward a decrease in ROS and IL-6 from t(2) in the PLA arm. Our results suggest that TEL is able to reverse acute (early) EPI-induced myocardial dysfunction and to maintain later a normal systolic function up to the 12-month FU. These effects are likely to be due to different mechanisms, RAS blockade and prevention of chronic inflammation/oxidative stress.

Figure 1.

Consort diagram.

Figure 2.

SR analysis with TDI in the two arms. ^*p<0,05 vs. baseline; ^§p<0.05 between arms.

Figure 3.

Serum levels of IL-6 (pg/ml) during the EPI treatment and FU in the TEL and PLA arms. ^*p<0.05 between arms.

Figure 4.

Blood levels of ROS (FORT U) during the EPI treatment and FU in the TEL and PLA arms. ^*p<0.05 between arms.