Imatinib and other tyrosine kinase inhibitors can directly cause left ventricular dysfunction and even heart failure through inhibition of a key cardioprotective enzyme, according to an article published online July 23 by Nature Medicine.

American scientists led by Thomas Force, MD, demonstrated in studies in mice and in myocardial cells in culture that imatinib can cause heart failure. The study was prompted by 10 patients with chronic myelogenous leukemia who developed severe congestive heart failure while taking imatinib.

“We found that the molecular target of the drug, the Abelson tyrosine kinase protein, serves a maintenance function in cardiac muscle cells and is necessary for their health,”. Force explained. “While the cancer is treated effectively, there will be some percentage of patients who could experience significant left ventricular dysfunction and even heart failure from this.”

“Imatinib is a wonderful drug and patients with these diseases need to be on it,” he said. “We’re trying to call attention to the fact that imatinib and other similar drugs coming along could have significant side effects on the heart and clinicians need to be aware of this. It’s a potential problem because the number of targeted agents is growing rapidly.”

In chronic myelogenous leukemia, the gene for the enzyme Abelson tyrosine kinase (ABL) fuses with the gene BCR to produce a hybrid BCR-ABL enzyme that is always active. The overactive BCR-ABL enzyme, in turn, drives the excessive proliferation of white blood cells that is the hallmark of the leukemia.

According to Force, 10 patients taking imatinib at the University of Texas’ M.D. Anderson Cancer Center in Houston developed fairly severe heart failure with no prior symptoms. Because physicians there took baseline measures of the patients’ left ventricular heart function, the team was able to determine that heart failure developed in these patients between two and 14 months after beginning imatinib.

The team proved that ABL was the target by using viruses that coded for normal enzyme and an imatinib-resistant mutant. Imatinib inhibited the normal enzyme but not the mutant, and the mutant enzyme rescued heart cells from the toxic effects of imatinib, proving that ABL is the relevant target. As a result, second-generation drugs of the same class might also have similar toxicities in the heart.

“This finding is a big surprise and there may be a lot more of these,” Force noted. “It’s not a class effect like COX-2 inhibitors. The drugs are all tyrosine kinase inhibitors, but each tyrosine kinase is different. It’s difficult to predict what tyrosine kinases will have protective roles in the heart and inhibition of them will be toxic.”

With imatinib, for example, blocking a particular growth factor receptor is crucial to its effect against gastrointestinal stromal tumors. Designing a drug to inhibit the receptor but not the ABL enzyme could produce an effective drug that is not cardiotoxic.

“We’ve learned something about the biology of the heart,” Force said. “ABL is important for cardiomyocyte health. We also can learn something about how to stay away from these targets that are important and optimize the drugs.”

Several international academic centers are planning to begin a registry for new tyrosine kinase inhibitors. “As these drugs come out, we can more easily collect data on larger numbers of patients as they take the drugs to get an idea of the incidence of heart problems,” Force explained.