Vascular endothelial growth factor inhibitor-induced cardiotoxicity: prospective multimodality assessment incorporating cardiovascular magnetic resonance imaging

Abstract

Background Vascular endothelial growth factor inhibitors (VEGFIs) are effective anticancer agents, but are associated with cancer therapy-related cardiac dysfunction (CTRCD) and hypertension. The timing, frequency and magnitude of these toxicities are poorly defined. The objective of this study is therefore to investigate the incidence, time course and mechanisms of VEGFI-associated CTRCD and hypertension. Methods Patients commencing VEGFI underwent blood pressure (BP) monitoring, echocardiography and cardiac biomarker measurement at baseline and prospectively over 24 weeks. Serial adenosine stress perfusion cardiovascular MRI (CMR) was performed in a substudy. CTRCD was defined as left ventricular ejection fraction (LVEF) decline by ≥10 percentage points from baseline to a value <50%. Results 78 patients participated (68% men; age 63±11 years). 15 patients (19%) developed CTRCD, and it was evident at 4 weeks in 93% of cases. Overall, LVEF was 4.2% (95% CI: -6.2% to -2.3%, p<0.001) lower than baseline at 4 weeks. At 4 weeks, N-terminal pro-brain natriuretic peptide, but not troponin, was higher in patients with CTRCD. 62 (77%) patients developed hypertension. Home systolic and diastolic BP increased by 7.2 mm Hg (4.7-9.8, p<0.001) and 4.8 mm Hg (3.1-6.5, p<0.001), respectively, at 1 week. There was no association between change in LVEF and BP. CMR-derived LVEF, T1 relaxation times and resting myocardial blood flow (n=46) were 5.2% (-7.3% to -3.1%, p<0.001), 27 ms (-40 to -14, p<0.001) and 14.7 mL/100mL/min (-24.2 to -5.1, p=0.004), respectively, lower at 4 weeks. Conclusion VEGFI-associated CTRCD is frequent and occurs early. This finding has implications for prioritising early cardiac imaging follow-up after commencing treatment. Underlying mechanisms include myocardial and microvascular effects that are at least partly independent of hypertension.