Abstract
Multiple tyrosine kinase inhibitors, such as sunitinib, have been clinically reported to induce various cardiovascular adverse events, including the heart failure, hypertension and QT-interval prolongation. In order to analyze its underlying pathophysiology, we intravenously administered sunitinib to the halothane-anesthetized dogs in a dose of 0.01 mg/kg/10 min followed by 0.1 mg/kg/10 min with a pause of 20 min between the doses (n=5). Cardiohemodynamic analysis showed that sunitinib significantly decreased the amplitude of maximum downstroke velocity of left ventricular pressure but increased the left ventricular end-diastolic pressure, suggesting the impairment of both ventricular active and passive relaxation phases, respectively. Echocardiographic examination also revealed the sunitinib–induced ventricular diastolic dysfunction observed by the cardiohemodynamic analysis. Left ventricular systolic function including ejection fraction and factional shortening tended to be increased by sunitinib. In addition, sunitinib significantly increased the plasma troponin I concentration in a dose-related manner, indicating the occurrence of myocardial cell damage. On the other hand, no significant change was detected in the heart rate, mean blood pressure, cardiac output, maximum upstroke velocity of left ventricular pressure or electrocardiographic variables. Thus, assessment of the left ventricular diastolic function and plasma troponin I can become sensitive markers for predicting sunitinib-induced acute cardiovascular adverse events.
