A growth factor, called PDGFR, which is a common target of cancer drugs, has been found to play an negative role in the heart's response to stress, according to researchers at The University of Texas M. D. Anderson Cancer Center.
In many cancers, the body makes too much platelet-derived growth factor receptor (PDGFR), a type of protein that controls cell growth, allowing cancer cells to increase uncontrollably.
AdvertisementSeveral chemotherapy agents, including Sutent(r) (sunitinib), Nexavar(r) (sorafenib) and Gleevec(r) (imatinib), work by targeting and inhibiting PDGFR.
This slows the growth of cancer - as well as angiogenesis, which is the growth of new blood vessels.
"Recently, some of these targeted anti-cancer drugs have been associated with heart failure. But the role of PDGFR signaling in the heart has been largely unexplored until now," said Dr. Aarif Khakoo.
In the study, the researchers showed that, while PDGFR-inhibiting agents may slow the growth of cancer cells, they also may impair the heart's ability to respond to stress.
Since these agents also often cause elevated blood pressure, this causes a double bind of added stress to the heart and lessened capacity to deal with this stress.
Using special laboratory mice with limited cardiac PDGFR and mice with normal PDGFR signaling, researchers performed transverse aortic constriction (TAC)- a procedure widely used to study heart disease in which a band is placed at the aortic arch, resulting in acute pressure overload.
And they found that the mice with limited PDGFR had heart failure.
"We showed that cardiomyocyte PDGFR expression and activation in heart muscle cells rises dramatically in response to pressure overload stress. 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," said Khakoo.
They also demonstrated that PDGFR signalling is crucial in the creation of new blood vessels that help the heart respond to stress.
The study opens the door to studying additional effects of PDGFR-inhibiting drugs on the heart, as well as ways to prevent damage to the heart.
"Patients with pre-existing heart disease may be at increased risk for cardiomyopathy and heart failure associated with these drugs. 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," said Khakoo.
The study has been published in the Journal of Clinical Investigation.