Kerkelä R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006; [Epub ahead of print].Imatinib mesylate (Gleevec) is a small-molecule kinase inhibitor and inhibits the constitutively active fusion protein Bcr-Abl. Currently, imatinib is widely used in the treatment of Philadephia-chromosome positive leukemias. The drug is generally well tolerated. Anecdotal observations in clinical practice had indicated that some individuals might develop left ventricular dysfunction and even congestive heart failure (CHF), but this complication has received relatively little attention as yet. The authors of this paper report important new insights into the nature and mechanism of cardiotoxicity caused by imatinib. They describe 10 individuals presenting with severe CHF with considerable volume overload while receiving imatinib. In these patients, left ventricular function (LVF) prior to imatinib had been normal (ventricular ejection fractions estimated by radionuclide imaging: 56 ± 7 percent), but LVF declined sharply within one to 14 months of treatment towards an average value of 25 ± 8 percent. Mild left ventricular dilatation was apparent on echocardiography. Myocardial biopsies in two of these individuals showed extensive abnormalities on transmission electron micrographs typical of toxin-induced cardiomyopathies. The authors were able to reproduce the cardiotoxicity in experimental mice treated with imatinib within three to six months only at the highest (200 mg/kg/day) dose of various dose levels. Ultrastructural abnormalities in mouse heart muscle and deterioration of contractile function and left ventricular dilatation resembled the clinical changes. Thus, the administration of imatinib was sufficient by itself to induce cardiotoxicity in the murine model. Fibrosis, which usually accompanies cardiomyopathy, was not reported. Isolated cardiomyocytes were then exposed to imatinib in cell culture to explore the mechanism of cardiotoxicity at the cellular level. Drug exposure of the cells resulted in diverse alterations including progressive and severe ATP depletion and activation of the endoplasmatic reticulum stress response. These alterations culminated in classical apoptosis and necrotic cell death. Imitanib is not a selective Abl inhibitor; instead it may target various cellular kinases. However, some of the cardiotoxic effects were Abl-dependent. Gene transfer of an imatinib-resistant c-Abl into cardiomyocytes largely prevented imatinib-induced cellular changes and prevented cardiomyocyte cell death. On the other hand, the investigators did not show that Abl is also critical in maintenance of left ventricular function.
The results of these studies establish Abl as an important factor in the physiology of cardiomyocyte survival. However, it should be kept in mind that functional cardiac failure was reproduced only at an excessively high-dose level of imatinib in mice. In addition, it is of note that there have been recent studies that used lower dosages of imatinib and demonstrated favorable cardio-protective effects1 .
From a clinical standpoint, the results of this study are especially relevant as they make physicians well aware of the unanticipated cardiotoxic side effects of imatinib. Currently, the clinical significance of cardiotoxicity arising during/after imatinib treatment remains to be assessed. Clinical cases of cardiac failure have rarely been reported. Future studies will need to sort out if and how frequently cardiotoxicity develops in patients on imatinib, and how it depends on dose level and cumulative dose of imatinib. Furthermore, it is unclear whether the cardiotoxicity might precipitate at greater frequencies in patients who receive additional cardiotoxic therapies (e.g., anthracyclines), or in those with preexisting heart disease. In spite of these open questions, physicians for the time being will need to closely monitor their patients on imatinib for symptoms of left ventricular dysfunction and intervene at the earliest signs of clinical cardiotoxicity.
