Efficiency of atorvastatin in the protection of anthracycline-induced cardiomyopathy.

m g o d 0 m v s To the Editor: Antineoplastic agents of the anthracycline (ANT) group are commonly and effectively used in various forms of malignancies. Anthracyclines might lead to irreversible cardiomyopathy (CMP), despite their beneficial effects. A number of mechanisms, such as elevation in free superoxide anion radicals, apoptosis, and mitochondrial dysfunction have been implicated in ANT-induced CMP. However, oxidative stress has been widely considered as the major pathogenetic mechanism (1). Statins have been shown to possess antioxidative, pleiotropic effects (2) besides their anti-inflammatory and lipid-lowering effects, which led us to conduct the present study to test the potential role of statin in ANT-induced CMP prophylaxis. In the present study, a total of 40 patients (17 men) with a mean age of 53 15 years who were undergoing ANT chemotherapy were enrolled. The patients were randomized into statin group or control group (n 20 in each group). The patients who had a history of chemotherapy or radiotherapy, with symptoms of heart failure or left ventricular (LV) dysfunction at baseline echocardiography, who had a history of CAD, or with moderate-to-severe valve disease were excluded. None of the patients were under medication that could affect cardiac functions. The statin group received administration of 40 mg/day atorvastatin before chemotherapy, regardless of their baseline lipid values, and the therapy continued for 6 months. All patients received chemotherapy 1/month with either adriamycin or idarubicin for a period of 6 months. The primary endpoint was the establishment of impairment in LV systolic functions defined as an ejection fraction (EF) of 50%. All patients were evaluated by echocardiography before and 6 months after chemotherapy by 2 independent, blinded cardiologists. Continuous variables were described as mean SD and analyzed with t test and Mann-Whitney U test when appropriate. Fisher exact test was used for categoric variables. Twosample t test was used to compare mean changes after chemotherapy between 2 groups. The statin and control groups were similar in age (53.7 14.2 years and 52.6 17.6 years, respectively), sex (male 40% and 45%, respectively), diagnosis (non-Hodgkin’s lymphoma 60% and 55%; multiple myeloma 10% and 20%; leukemia 30% and 25%, respectively), and in treatment with other chemotherapeutic agents (vincristine 90% and 95%; cyclophosphamide 80% and 85%; methotrexate 25% and 25%; and prednisolone 60% and 55% or dexamethasone 10% and 15%, respectively). The doses of adriamycin (261.4 61.1 mg vs. 251.1 77.2 mg) or idarubicin (262.5 55.6 mg vs. 330.0 14.1 mg) were similar in statin and control groups. No differences were observed between the groups in terms of baseline glucose, lipid, high-sensitivity-C-reactive protein levels, or renal and liver function tests. In the statin group, a significant decrease was observed with respect to lipid parameters, as expected. No elevation was observed in serum high-sensitivity C-reactive protein levels after chemotherapy in the statin group, whereas there was a significant increase in the control group (3.84 0.89 mg/dl vs. 5.43 1.78 mg/dl, p 0.0001). Compared with baseline value (Table 1), on control echocardiography, no difference was observed in the mean EF of the statin group (61.3 7.9% vs. 62.6 9.3%, p 0.144). However, the decrease in the control group was significant (62.9 7.0% vs. 55.0 9.5%, p 0.0001). Although 1 patient in the statin group was observed with an EF below 50%, 5 patients in the control group were observed with values below 50% (p 0.18). In the statin group, no significant difference was observed between baseline and follow-up values in terms of systolic (30.9 7.2 mm vs. 29.6 6.1 mm, p 0.148) and diastolic diameters (46.5 7.2 m vs. 46.3 6.8 mm, p 0.868). However, in the control roup, significant increases were observed in the follow-up values f systolic (30.3 5.4 mm vs. 32.3 5.4 mm, p 0.0001) and iastolic diameters (47.2 5.2 mm and 49.2 6.2 mm, p .013). Mean reduction in left ventricular ejection fraction and ean increase in left ventricular end-diastolic diameter and left entricular end-systolic diameter were significantly lower in the tatin arm as compared with the control group (p 0.0001; p 0.021; p 0.001, respectively). The clinical use of doxorubicin and other quinonehydroquinone antitumor ANTs is limited by dose-related cardiotoxicity. One-electron redox cycling of the quinone moiety has long been known to form reactive oxygen species in excess of the limited antioxidant defenses of cardiomyocytes, which render cardiomyocytes to oxidant stress and death (1). Strategies have been proposed to reduce ANT-induced cardiotoxicity, including continuous instead of bolus infusion, liposomal ANT administraComparison of Echocardiographic Parameters in the Study Group Between Baseline and Follow-Up Valu s Table 1 Comparison of Ec ocardiographic Parameters in the Study Group Between Baseline and Follow-Up Values