Takeshi Wada1,2, Kentaro Ando1,3, Atsuhiko T Naito1,3, Yuji Nakamura1, Ai Goto3, Koki Chiba3, Nur Jaharat Lubna3, Xin Cao4, Mihoko Hagiwara-Nagasawa1, Hiroko Izumi-Nakaseko1, Yuji Nakazato2, Atsushi Sugiyama5,6. 1. Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan. 2. Department of Cardiology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu, Chiba, 279-0021, Japan. 3. Department of Pharmacology, Toho University Graduate School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan. 4. Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba, 274-8510, Japan. 5. Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan. atsushi.sugiyama@med.toho-u.ac.jp. 6. Department of Pharmacology, Toho University Graduate School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan. atsushi.sugiyama@med.toho-u.ac.jp.
Abstract
PURPOSE: Cancer chemotherapies have improved the prognosis of cancer patients in recent years; however, their side effects on the cardiovascular systems have emerged as a major concern in the field of both cardiology and oncology. In particular, multi-targeted tyrosine kinase inhibitors are known to induce various types of cardiovascular adverse events including hypertension, QT-interval prolongation and heart failure, but their underlying mechanisms remain elusive. To explore how to better predict such drug-induced cardiovascular adverse events, we assessed the electropharmacological effects of sunitinib using the halothane-anesthetized dogs (n = 5), while plasma concentrations of cardiac enzymes including aspartate aminotransferase, lactate dehydrogenase, creatinine kinase and cardiac troponin I were measured. METHODS: Sunitinib was intravenously administered at 0.01 and 0.1 mg/kg for 10 min with 20 min interval. RESULTS: Sunitinib decreased the amplitude of maximum downstroke velocity of the left ventricular pressure, prolonged the isovolumic relaxation time and increased the left ventricular end-diastolic pressure in a dose-related manner without affecting the other cardiohemodynamic and electrophysiological variables. More importantly, sunitinib significantly elevated cardiac troponin I level for 30-60 min after the high dose without altering the other biomarkers. CONCLUSIONS: Monitoring of the cardiac diastolic function together with cardiac troponin I after the start of sunitinib administration may become a reliable measure to predict the onset of sunitinib-induced cardiovascular adverse events.
PURPOSE:Cancer chemotherapies have improved the prognosis of cancerpatients in recent years; however, their side effects on the cardiovascular systems have emerged as a major concern in the field of both cardiology and oncology. In particular, multi-targeted tyrosine kinase inhibitors are known to induce various types of cardiovascular adverse events including hypertension, QT-interval prolongation and heart failure, but their underlying mechanisms remain elusive. To explore how to better predict such drug-induced cardiovascular adverse events, we assessed the electropharmacological effects of sunitinib using the halothane-anesthetized dogs (n = 5), while plasma concentrations of cardiac enzymes including aspartate aminotransferase, lactate dehydrogenase, creatinine kinase and cardiac troponin I were measured. METHODS:Sunitinib was intravenously administered at 0.01 and 0.1 mg/kg for 10 min with 20 min interval. RESULTS:Sunitinib decreased the amplitude of maximum downstroke velocity of the left ventricular pressure, prolonged the isovolumic relaxation time and increased the left ventricular end-diastolic pressure in a dose-related manner without affecting the other cardiohemodynamic and electrophysiological variables. More importantly, sunitinib significantly elevated cardiac troponin I level for 30-60 min after the high dose without altering the other biomarkers. CONCLUSIONS: Monitoring of the cardiac diastolic function together with cardiac troponin I after the start of sunitinib administration may become a reliable measure to predict the onset of sunitinib-induced cardiovascular adverse events.