Author + information
- Received November 8, 2017
- Revision received December 22, 2017
- Accepted December 22, 2017
- Published online April 30, 2018.
- Rachel Truitt, PhDa,b,
- Anbin Mub,
- Elise A. Corbin, PhDb,c,
- Alexia Vite, PhDb,
- Jeffrey Brandimarto, PhDb,
- Bonnie Ky, MD, MSCEb,d and
- Kenneth B. Margulies, MDb,∗ ()
- aDepartment of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania
- bCardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- cDepartment of Mechanical Engineering and Applied Mechanics, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania
- dCenter for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- ↵∗Address for correspondence:
Dr. Kenneth B. Margulies, Perelman School of Medicine, University of Pennsylvania, Smilow Center for Translational Research, 3400 Civic Center Boulevard, 11-101, Philadelphia, Pennsylvania 19104.
• Sunitinib, an oral tyrosine kinase inhibitor used widely to treat solid organ tumors, frequently induces hypertension and causes LV dysfunction in up to 19% of treated individuals.
• Sunitinib-induced cardiotoxicity can be modeled using engineered CMT.
• In CMT, sunitinib induces dose- and duration-dependent activation of apoptosis pathways and decreases in CMT force generation, spontaneous beating, and mitochondrial membrane potential.
• Exposure of CMT to increased in vitro afterload intensifies the cardiotoxicity of clinically relevant sunitinib concentrations.
• These findings suggest that intensive antihypertensive therapy may be an appropriate strategy to mitigate LV dysfunction observed in patients treated with sunitinib.
Sunitinib, a multitargeted oral tyrosine kinase inhibitor, used widely to treat solid tumors, results in hypertension in up to 47% and left ventricular dysfunction in up to 19% of treated individuals. The relative contribution of afterload toward inducing cardiac dysfunction with sunitinib treatment remains unknown. We created a preclinical model of sunitinib cardiotoxicity using engineered microtissues that exhibited cardiomyocyte death, decreases in force generation, and spontaneous beating at clinically relevant doses. Simulated increases in afterload augmented sunitinib cardiotoxicity in both rat and human microtissues, which suggest that antihypertensive therapy may be a strategy to prevent left ventricular dysfunction in patients treated with sunitinib.
Supported by the National Center for Research Resources, grant UL1RR024134; the National Center for Advancing Translational Sciences, grant UL1TR000003; and in part by the University of Pennsylvania’s Institute for Translational Medicine and Therapeutics (ITMAT) Transdisciplinary Program in Translational Medicine and Therapeutics. Dr. Truitt received support from the American Heart Association Predoctoral Fellowship (11PRE7610168) and National Science Foundation Graduate Research Fellowship (2011125128) programs. Dr. Ky has received Pfizer’s Investigator Initiated Award. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received November 8, 2017.
- Revision received December 22, 2017.
- Accepted December 22, 2017.
- 2018 The Authors