Alterations in mitochondrial function are likely cause of imatinib-induced cardiotoxicity

The tyrosine kinase inhibitor imatinib is cardiotoxic and can lead to severe left ventricular dysfunction and heart failure in humans, according to research involving humans, mice and cultured cardiomyocytes.

Based on their findings, published in Nature Medicine, researchers encouraged further study and stressed that individuals taking imatinib should be monitored closely for symptoms and/or signs of left ventricular dysfunction.

"Our findings also raise concerns that agents currently in development that target Abl and other nonreceptor tyrosine kinases might be cardiotoxic," the researchers stated. In addition, phase 1 and 2 studies and/or phase 3 studies that involve new agents should be assessed for their effect on left ventricular function, they said.

The 10 CML patients treated with imatinib developed severe congestive heart failure (CHF) despite having normal left ventricular ejection function prior to taking the agent (ejection fraction 56% ±7%). However, between 1 and 14 months after starting the treatment, they displayed symptoms corresponding to New York Heart Association (NYHA) class 3 or 4 heart failure (mean NYHA class 3.5±0.5; P<.001 vs pretreatment).

In addition, imatinib-treated mice developed left ventricular contractile dysfunction.

The triggering mechanism, the researchers stated, seems to be activation of the endoplasmic reticulum (ER) stress response that protects cells by shutting down general protein translation while upregulating the expression of specific protective stress response genes. If ER stress is prolonged, however, prodeath pathways including Jun N-terminal kinases (JNKs) activate.

"We show that these pathways are activated in cardiomyocytes exposed to imatinib, leading to profound alterations of mitochondrial function and to cardiomyocyte death," the authors stated.

The cardiotoxicity of imatinib was "an unanticipated side effect," the researchers stated. They noted that previous findings had identified mitochondria as a chief target of imatinib and implicated mitochondrial dysfunction and the consequent energy rundown as a crucial factor in the cardiotoxicity.

The study's authors specified no rate of failure, although they stated that the effects of the drug on cellular energetics were "profound." ATP concentration dropped by approximately 65% in the cardiomyocytes. By comparison, another cardiotoxic chemotherapeutic agent, trastuzumab, produces a 35% decline in ATP.

While a 65% reduction in ATP concentration within an individual cell probably would not compromise many cellular processes, an overall reduction of 65% seems to reflect a situation in which there are cells with severe depletion of ATP and others with normal or near-normal levels, the authors said.

SOURCE Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12:908–916.