title: The utility of cardiac biomarkers and echocardiography for the early detection of bevacizumab- and sunitinib-mediated cardiotoxicity.
abstract: The recent introduction of novel anticancer therapies, including bevacizumab (BVZ) and sunitinib (SNT), is associated with an increased risk of cardiotoxicity. However, early identification of left ventricular (LV) systolic dysfunction may facilitate dose modification and avoid the development of advanced heart failure. Using a murine model of BVZ- and SNT-mediated cardiotoxicity, we investigated whether cardiac biomarkers and/or tissue velocity imaging (TVI) using echocardiography can detect early changes in cardiac function, before a decrease in LV ejection fraction is identified. A total of 75 wild-type C57Bl/6 male mice were treated with either 0.9% saline, BVZ, or SNT. Serial monitoring of blood pressure, high-sensitivity troponin I, and echocardiographic indexes were performed over a 14-day study period, after which the mice were euthanized for histological and biochemical analyses. Mice treated with either BVZ or SNT developed systemic hypertension as early as day 7, which increased by day 14. Cardiac biomarkers, specifically high-sensitivity troponin I, were not predictive of early LV systolic dysfunction. Although conventional LV ejection fraction values decreased at day 13 in mice treated with either BVZ or SNT, TVI confirmed early LV systolic dysfunction at day 8. Histological and biochemical analysis demonstrated loss of cellular integrity, increased oxidative stress, and increased cardiac apoptosis in mice treated with BVZ or SNT therapy at day 14. In a murine model of BVZ- or SNT-mediated cardiomyopathy, noninvasive assessment by TVI detected early LV systolic dysfunction before alterations in conventional echocardiographic indexes.
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Kimberly-Ann
authors.initials: KA
authors.lastname: Bordun
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Sheena
authors.initials: S
authors.lastname: Premecz
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Megan
authors.initials: M
authors.lastname: daSilva
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Soma
authors.initials: S
authors.lastname: Mandal
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Vineet
authors.initials: V
authors.lastname: Goyal
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Tamara
authors.initials: T
authors.lastname: Glavinovic
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Matthew
authors.initials: M
authors.lastname: Cheung
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: David
authors.initials: D
authors.lastname: Cheung
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Christopher W
authors.initials: CW
authors.lastname: White
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Rakesh
authors.initials: R
authors.lastname: Chaudhary
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Darren H
authors.initials: DH
authors.lastname: Freed
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota;
authors.forename: Hector R
authors.initials: HR
authors.lastname: Villarraga
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota;
authors.forename: Joerg
authors.initials: J
authors.lastname: Herrmann
authors.affiliation: Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Manish
authors.initials: M
authors.lastname: Kohli
authors.affiliation: Section of Cardiology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Amir
authors.initials: A
authors.lastname: Ravandi
authors.affiliation: Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: James
authors.initials: J
authors.lastname: Thliveris
authors.affiliation: Section of Oncology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; and.
authors.forename: Marshall
authors.initials: M
authors.lastname: Pitz
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Pawan K
authors.initials: PK
authors.lastname: Singal
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota;
authors.forename: Sharon
authors.initials: S
authors.lastname: Mulvagh
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Section of Cardiology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Section of Oncology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; and Department of Radiology, University of Manitoba, Winnipeg, Manitoba, Canada djassal@sbgh.mb.ca.
authors.forename: Davinder S
authors.initials: DS
authors.lastname: Jassal
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000068258:Bevacizumab; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure; D066126:Cardiotoxicity / Q000175:diagnosis / Q000209:etiology; D004452:Echocardiography; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007211:Indoles / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D011758:Pyrroles / Q000009:adverse effects*; D000077210:Sunitinib; D019210:Troponin I / Q000097:blood*; D016277:Ventricular Function, Left
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015415:Biomarkers; D007211:Indoles; D011758:Pyrroles; D019210:Troponin I; D000068258:Bevacizumab; D000077210:Sunitinib
keywords: apoptosis; bevacizumab; cardiac biomarkers; cardio-oncology; cardiotoxicity; echocardiography; heart failure; hypertension; sunitinib