Kerkelä R et al. (2006) Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12: 908–916

Imatinib mesylate is a tyrosine kinase inhibitor used in the treatment of cancers including chronic myeloid leukemia. In their study, however, Kerkelä et al. report that this drug can be cardiotoxic, causing severe left ventricular dysfunction and heart failure in occasional patients.

The authors studied 10 individuals who, having had no previous history of left ventricular dysfunction, presented after a mean 7.2 ± 5.4 months of imatinib treatment with major volume overload, symptoms of NYHA class 3–4 heart failure, and low ejection fraction associated with mild left ventricular dilation, among other signs of heart dysfunction. Transmission electron micrographs of myocardial biopsies from two of these individuals and three imatinib-treated mice demonstrated membrane whorls in vacuoles and the sarcoplasmic reticulum, and mitochondrial abnormalities. Ex vivo investigations of mitochondrial function and studies of isolated cardiomyocytes suggested that mitochondria were a primary target of imatinib; mitochondrial dysfunction and the consequent reduction in cellular energetics are intrinsic to imatinib-induced cardiotoxicity. The authors showed that the cardiotoxicity is probably due to inhibition of one specific target of imatinib, the c-Abl protein kinase. Cardiomyocyte death was largely prevented by deactivation of the endoplasmic reticulum stress response induced by imatinib.

The authors recommend further investigations into imatinib-induced cardiotoxicity to define its frequency. In the meantime, patients on imatinib should be watched for heart problems. Other drugs currently being developed to target c-Abl as well as some other nonreceptor tyrosine kinases could also have some cardiotoxicity, and the authors suggest that the effect of some of these agents on left ventricular function might be assessed prospectively in clinical trials.