Pathogenesis of cardiotoxicity induced by anthracyclines.
ABSTRACT Anthracyclines are potent anti-neoplastic drugs used in the treatment of solid and hematologic cancers. However, their use is limited by cumulative dose-related cardiotoxic adverse effects, which are progressive and irreversible from the first dose. Clinical trial data have shown that anthracycline cardiotoxicity is associated with slowly progressive deterioration of cardiac function, which continues for years after treatment cessation. Cardiac damage has been shown at cumulative doses as low as 200 mg/m2, well below levels currently assumed to induce injury. The widespread use of anthracyclines in childhood leukemia has resulted in an improved long-term prognosis; however, these patients are subsequently at high risk of developing long-term cardiac damage, with studies suggesting as many as 65% of survivors of childhood leukemia will develop cardiac abnormalities. Middle aged and elderly patients who are prone to cardiac disease may be more vulnerable to the cardiotoxic effects of anthracyclines. Therapies or strategies to prevent anthracycline-induced cardiotoxicity are essential; ideally, these should be initiated at the beginning of anthracycline therapy to reduce the possibility of cardiac damage and to ensure the optimal use of chemotherapy.
SourceAvailable from: Nakarin Sansanayudh[Show abstract] [Hide abstract]
ABSTRACT: Background: Anthracycline-induced cardiotoxicity can result in acute, sub-acute and chronic complications, which can lead to cardiomyopathy and heart failure. The mortality and morbidity are increased in patients who have anthracycline-induced cardiotoxicity. A few previous studies have demonstrated the efficacy of some agents in preventing cardiotoxicity from anthracycline. Objectives: To assess the efficacy of an angiotensin II receptor blocker (candesartan), in preventing anthracycline-induced cardiotoxicity, and to evaluate the side effects of candesartan in cancer-patients who received doxorubicin. Methods: Consecutive patients who were scheduled for treatment with doxorubicin from March 1, 2009 to January 31, 2010 were recruited. Breast cancer or lymphoma patients, who had definite coronary artery disease (CAD), left ventricular (LV) dysfunction; chronic kidney disease (CKD) and hyperkalemia were excluded. Patients were randomized into two groups; the first group received candesartan 4-32 mg daily while the second group did not (controls group) until the end of the anthracycline regimen. Baseline echocardiographic parameters were measured and followed up after 3 courses of anthracycline administration. The changing of echocardiographic parameters, serum potassium levels and serum creatinine levels were recorded and analyzed. Results: There were 21 patients enrolled. The mean age of the candesartan group was 51.1 ± 11.31years, and 54.20 ± 10.21 years for the control group (p=0.528). No significant changes were observed in blood pressure and heart rate between the two groups. There were significant increases in potassium and creatinine levels in the candesartan group (p= 0.001 and 0.001, respectively). There was a significant difference in left ventricular ejection fraction (LVEF) at the end of the study between the candesartan and control group (67.10 ± 6.12% and 62.60 ± 7.75% respectively, p= 0.023). There was a significant decrease in LVEF (69.00 ± 8.82% and 62.60 ± 7.75%, p=0.03) from the baseline to the half course of chemotherapy in the control group. There was no significant change in LVEF observed in the candesartan group. Conclusion: These results indicate that candesartan may have a potential in preventing the anthracycline-induced cardiotoxicity in cancer patients. It increases serum potassium levels and creatinine levels but does not induce hyperkalemia or acute kidney injury. Future long-term and larger population studies are necessary.
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ABSTRACT: Although doxorubicin (DOX) is a highly effective anti-tumor agent used to treat a variety of cancers, DOX administration is associated with significant side effects including myopathy of both cardiac and skeletal muscles. The mechanisms responsible for DOX-mediated myopathy remain a topic of debate. We tested the hypothesis that both increased mitochondrial reactive oxygen species (ROS) emission and activation of the cysteine protease calpain are required for DOX-induced myopathy in rat cardiac and skeletal muscle. Cause and effect was determined by administering a novel mitochondrial-targeted antioxidant to prevent DOX-induced increases in mitochondrial ROS emission whereas a highly-selective pharmacological inhibitor was exploited to inhibit calpain activity. Our findings reveal that mitochondria are a major site of DOX-mediated ROS production in both cardiac and skeletal muscle fibers and prevention of DOX-induced increases in mitochondrial ROS emission protects against fiber atrophy and contractile dysfunction in both cardiac and skeletal muscles. Further, our results indicate that DOX-induced increases in mitochondrial ROS emission are required to activate calpain in heart and skeletal muscles and importantly, calpain activation is a major contributor to DOX-induced myopathy. Together, these findings disclose that increased mitochondrial ROS production and calpain activation are significant contributors to the development of DOX-induced myopathy in both cardiac and skeletal muscle fibers.This article is protected by copyright. All rights reservedThe Journal of Physiology 01/2015; DOI:10.1113/jphysiol.2014.286518 · 4.54 Impact Factor
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ABSTRACT: BackgroundAnthracyclines are important components of many chemotherapeutic protocols. The present study aimed to evaluate the repolarization changes in electrocardiography (ECG) which may predict drug induced arrhythmia.Materials and MethodsIn this cross-sectional study, the recorded ECGs were assessed for QT dispersion (QTd), QT corrected dispersion (QTcd), T peak to Tend dispersion (TPed), and P dispersion (Pd) in 12 ECG leads. The demographic information, including sex, age, and duration of drug consumption, were recorded, as well. ResultsIn this study, 112 patients, including 58 females (52%) and 54 males (48%) with the mean age of 8.7±4.5 years, as the case group were compared with 43 children, including 17 males (40%) and 26 females (60%), in the control group. Most of our patients (88%) had received usual doses of anthracyclines; i.e., 330 mg/m2. QT dispersion of the patients and the controls was 0.054±0.02 and 0.05± 0.02 seconds, respectively. No significant difference was found between the patients and the controls regarding corrected QT dispersion (P> 0.05). However, P dispersion time had increased in the patients' group. Our study showed that the duration of anthracyclines therapy did not cause any significant increase in ventricular re-polarization parameters. ConclusionAnthracyclines may show their cardiac toxicity through increasing P dispersion.07/2014; 4(3):103-8.