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

Abstract

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 diseasefree 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. IntroductionAnthracyclines (ANTs) are among the most effective anticancer drugs used in the treatment of a wide spectrum of malignancies. Regrettably, their clinical use is limited by the occurrence of dose-related cardiotoxicity (4).Several studies have shown that chemotherapy-induced cardiotoxicity (CTX) produced by ANTs is at least partially mediated by chronic inflammation and oxidative stress, with proinflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α and reactive oxygen species (ROS) (2) playing a central role (5,6). It has also been shown that the use of a conventional cardioprotective agent, such as dexrazoxane,

Myocardial Protection During Cardiotoxic Chemotherapy

“…The evidence for cardioprotection from angiotensin receptor blocker administration is scarce because their effects have been assessed in only 2 small studies in low-risk patients, one of them during just 1 week of follow-up. [69][70][71] An ongoing study is testing the cardioprotective effects of candesartan during trastuzumab therapy (http://www.clinicaltrials. gov; NCT00459771).…”

“…76 Finally, a study has recently reported the preventive effects of spironolactone on anthracycline-induced myocardial toxicity in patients with breast cancer. 77 Important limitations of all of these studies [67][68][69][70][71][72][73][74][75][76][77][78] include the small number of patients treated, differences in study design, varying malignancies being studied and chemotherapy regimens used, and short follow-up times. In addition, in most studies, the mortality rate was lower than expected, and the reported beneficial effects on the incidence of HF and LVEF decline did not translate to lower mortality ( Table 2).…”

Nonpegylated Liposomal Doxorubicin as a Component of R-CHOP Is an Effective and Safe Alternative to Conventional Doxorubicin in the Treatment of Patients With Diffuse Large B-Cell Lymphoma and Preexisting Cardiac Diseases

“…This was caused by myocardial ischemia and severe pneumonia in 2 patients each, another patient was in a generally reduced condition. Two vascular events happened within 6 months after chemotherapy, a cerebral bleeding during [35][36][37] A Grade III/IV hematotoxicity was observed in 52%. However, febrile neutropenia was observed in only 1 case.…”

Survivorship - lebenslange Begleitung von Krebspatienten

“…Therapie-Responder hatten zudem weniger kardiale Ereignisse. In einer weiteren kontrollierten Studie wurde die Wirksamkeit von Telmisartan bei Epirubicin-induziertem frühem Myokardschaden untersucht [50]. Mit dem Sartan konnte im Vergleich zu Placebo die LVEF signifikant besser stabilisiert werden und erreichte nach einem Follow-up von 12 Monaten wieder den Normbereich.…”