Abstract P125: Sunitinib-Induced Cardiomyopathy Is Due to PDGFR-á Inhibition and Can Be Prevented by Cotreatment with Thalidomide
Introduction: Suntinib malate (SM) is a small molecule tyrosine kinase inhibitor used for the treatment of metastatic renal cell carcinoma. However, nearly 20% of SM treated patients develop cardiomyopathy. We recently reported that the cardiomyocyte PDGFR-β regulates both cardiac and coronary microvascular function. In this study, we sought to define the mechanisms of SM-induced cardiomyopathy.
Methods: C57BL/6 mice were divided into 4 groups: vehicle control (Ctrl), SM, Ctrl+transverse aortic constriction (Ctrl-TAC) and SM-TAC. SM was given at 40 mg/kg/d. An additional group was treated with either SM (40mg/kg/d) plus vehicle control or SM plus thalidomide (75mg/kg/d) for 14 days and allowed to recover until day 28. Left ventricular ejection fraction (LVEF) and coronary flow reserve (CFR, a measurement of coronary microvascular function) were assessed by cardiac MRI and ultrasound, respectively. Pericyte coverage was assessed by immunofluorescent co-staining of CD31 (vessel) and NG2 (pericyte).
Results: SM induced cardiac and coronary microvascular dysfunction and impaired cardiac response to stress in a similar manner to that seen in PDGFR-β knockout mice. These functional impairments were accompanied by structural vascular defects and significant loss of microvascular pericyte coverage. This was recapitulated in aged (1 year) PDGFR-β knockout mice as well as with the drug CP673,541, which is a potent, more specific PDGFR inhibitor . Thalidomide is known to enhance vascular stability through enhancement of vascular pericyte coverage. Co-treatment with Thal prevented sunitinib-induced reduction in LVEF (SM-LVEF-41%; SM+thalidomide-49%, p<0.01) and preserved CFR (SM-CFR-2.14; SM+thalidomide 2.95). Thalidomide also significantly increased microvascular pericyte coverage.
Conclusion: SM-induced cardiac and microvascular dysfunction is most likely due to PDGFR-β inhibition and can be prevented by co-treatment with thalidomide. Our findings not only suggest a novel cardioprotective strategy for cancer patients at high-risk for sunitinib-induced cardiomyopathy but also suggest a critical role for pericytes in coronary microvascular and cardiac function.
- © 2011 by American Heart Association, Inc.