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Jan 12, 2010

Scientists May Have Discovered Why Some Anticancer Agents Cause Heart Failure

  • Anticancer agents targeting platelet-derived growth factor receptor-beta (PDGFR-β) may also impair the heart's ability to respond to stress, according to researchers at The University of Texas M. D. Anderson Cancer Center. They found that inhibiting PDGFR-β in mice slows angiogenesis, which usually helps the heart respond to stress. This could explain why some targeted anticancer drugs have recently been associated with heart failure. 

    The study is called “Cardiomyocyte PDGFR-β signaling is an essential component of the mouse cardiac response to load-induced stress” and was published online January 11 in The Journal of Clinical Investigation.  

    Using special laboratory mice with limited cardiac PDGFR-β and mice with normal PDGFR-β signaling, the researchers performed transverse aortic constriction (TAC). During TAC a band is placed at the aortic arch, resulting in acute pressure overload.

    The mice with limited PDGFR-β had heart failure. Thus, the scientists believe that cardiomyocyte PDGFR-β is an essential upstream regulator of the stress-induced paracrine angiogenic potential of cardiomyocytes. These results suggest that PDGFR-β is a regulator of the compensatory cardiac response to pressure overload-induced stress.  

    “We showed that cardiomyocyte PDGFR expression and activation in heart muscle cells rises dramatically in response to pressure-overload stress,” says Aarif Khakoo, M.D., assistant professor in M. D. Anderson's department of cardiology and corresponding author on the study. “Furthermore, we showed that knockout of PDGFR in heart muscle results in cardiac dysfunction, heart failure, and a marked defect in stress-induced cardiac angiogenesis.”  

    High blood pressure may put patients who receive drugs like Sutent, Nexavar, and Gleevec, which all work by targeting and inhibiting PDGFR, at an even greater risk. Anticancer drugs targeting PDGFR often cause elevated blood pressure, resulting in both added stress to the heart and lessened capacity to deal with this stress.

    “Since these drugs also cause vascular stress in the form of severe high blood pressure in a significant number of patients, our findings suggest the double hit of high blood pressure and the blockade of PDGFR signaling may play a key role in heart problems when patients are treated with anticancer agents whose targets include PDGFR,” Dr. Khakoo says.  

    “Patients with pre-existing heart disease may be at increased risk for cardiomyopathy and heart failure associated with these drugs,” Dr. Khakoo explains. “If we can confirm this, it might help develop a tool to determine the individual risk for cancer patients being considered for treatment with PDGFR inhibitors and to develop strategies to prevent heart damage.”

     



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