The study investigates the cardiotoxic effects of imatinib mesylate (Gleevec), a small-molecule inhibitor of the Bcr-Abl fusion protein, which is used to treat chronic myelogenous leukemia. The researchers report on ten individuals who developed severe congestive heart failure while on imatinib treatment and show that imatinib-treated mice also exhibit left ventricular contractile dysfunction. Transmission electron microscopy reveals mitochondrial abnormalities and membrane whorls in both human and mouse hearts treated with imatinib, suggesting a toxic myopathy. In cultured cardiomyocytes, imatinib induces activation of the endoplasmic reticulum (ER) stress response, collapse of mitochondrial membrane potential, cytochrome c release, ATP depletion, and cell death. Retroviral gene transfer of an imatinib-resistant mutant of c-Abl, alleviation of ER stress, or inhibition of Jun N-terminal kinases largely rescues cardiomyocytes from imatinib-induced death. These findings indicate that cardiotoxicity is an unexpected side effect of c-Abl inhibition by imatinib.The study investigates the cardiotoxic effects of imatinib mesylate (Gleevec), a small-molecule inhibitor of the Bcr-Abl fusion protein, which is used to treat chronic myelogenous leukemia. The researchers report on ten individuals who developed severe congestive heart failure while on imatinib treatment and show that imatinib-treated mice also exhibit left ventricular contractile dysfunction. Transmission electron microscopy reveals mitochondrial abnormalities and membrane whorls in both human and mouse hearts treated with imatinib, suggesting a toxic myopathy. In cultured cardiomyocytes, imatinib induces activation of the endoplasmic reticulum (ER) stress response, collapse of mitochondrial membrane potential, cytochrome c release, ATP depletion, and cell death. Retroviral gene transfer of an imatinib-resistant mutant of c-Abl, alleviation of ER stress, or inhibition of Jun N-terminal kinases largely rescues cardiomyocytes from imatinib-induced death. These findings indicate that cardiotoxicity is an unexpected side effect of c-Abl inhibition by imatinib.