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

Dessì,Mariele; Piras,Alessandra; Madeddu,Clelia; Cadeddu,Christian; Deidda,Martino; Massa,Elena; Antoni,Giorgia; Mantovani,Giovanni; Mercuro,Giuseppe

doi:10.3892/etm.2011.305

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

Authors:
- Mariele Dessì
- Alessandra Piras
- Clelia Madeddu
- Christian Cadeddu
- Martino Deidda
- Elena Massa
- Giorgia Antoni
- Giovanni Mantovani
- Giuseppe Mercuro
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Affiliations: Department of Medical Oncology, University of Cagliari, 09042 Monserrato (CA), Italy, Department of Cardiovascular and Neurological Sciences, University of Cagliari, 09042 Monserrato (CA), Italy, Cattedra di Oncologia Medica, Università di Cagliari, Azienda Ospedaliero-Universitaria di Cagliari, 09042 Monserrato (CA), Italy
Published online on: June 30, 2011 https://doi.org/10.3892/etm.2011.305
Pages: 1003-1009

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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/m2 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 t2 (cumulative dose of 200 mg/m2 of EPI) in comparison to t0. Conversely, at t3 (300 mg/m2 EPI), t4 (400 mg/m2 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 t0 (baseline). The differences between SR changes in the PLA and TEL arms were significant from 300 mg/m2 EPI (t3) up to the 12-month FU. Serum levels of IL-6 increased significantly in the PLA arm at 200 mg/m2 EPI (t2) in comparison to baseline, but remained unchanged in the TEL arm. The same trend was demonstrated for ROS levels which significantly increased at t2 vs. baseline in the PLA arm, while remained unchanged in the TEL arm. The mean change in ROS and IL-6 at t2 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 t2 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.

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