Effect of the Vascular Endothelial Growth Factor Inhibitor Toceranib on Cardiac Function and Endothelial Dysfunction Biomarkers in Dogs With Cancer

Abstract

Background: Hypertension is documented in dogs with cancer receiving toceranib, but no studies have evaluated left ventricular (LV) systolic function and biomarkers of endothelial function.

Objectives: To characterize changes in echocardiographic variables and biomarkers of endothelial function in dogs treated with toceranib.

Animals: Twenty-six client-owned dogs with no evidence of pre-existing cardiac disease or systemic hypertension are receiving a single agent toceranib for cancer treatment.

Methods: Dogs were enrolled in this prospective observational study with study visits at baseline, 1, 3, and 5 months after starting toceranib for echocardiographic exams, blood and urine collection, and blood pressure measurements, with an additional blood pressure obtained 2 weeks after starting toceranib. Serum markers of vascular endothelial function (VEGF, endothelin-1, platelet derived growth factor [PDGF], prostacyclin, cyclic guanosine monophosphate [cGMP]) and urinary nitrate were evaluated with ELISA.

Results: Dogs were enrolled between 2019 and 2023. Systolic blood pressure increased 2 weeks after initiating toceranib treatment (p = 0.009). Serum prostacyclin concentration was lower after 1 month of treatment (mean 98.8 pg/mL vs. 140.0 pg/mL at baseline, p = 0.03), and serum VEGF concentration was higher after 3 months of treatment (mean of 247.8 pg/mL vs. 135.4 pg/mL at baseline, p = 0.01). Global longitudinal strain (GLS) decreased at the five-month time point (mean -14.5% vs. -15.7% at baseline, p = 0.048) with no significant change in LV fractional shortening by M-mode or ejection fraction by Simpson's method of discs.

Conclusions: Dogs treated with toceranib might have higher systemic blood pressure associated with changes in VEGF and prostacyclin and decreased systolic function.

Keywords: cardiotoxicity; global longitudinal strain; tyrosine kinase inhibitor; vasculotoxicity.

FIGURE 1

Increased blood pressure and circulating serum VEGF with decreased circulating serum prostacyclin are associated with toceranib treatment. Both systemic blood pressure (BP) [n = 25 (2‐week), 24 (1‐month), 16 (3‐month) one‐sample t‐test] (A) and serum vascular endothelial growth factor (VEGF) [n = 13 (2‐week), 12 (1‐month), 11 (3‐month) one‐sample Wilcoxon] (B) increased with toceranib treatment. These changes are positively correlated (Spearman r = 0.33, p = 0.013). Solid line shows the linear regression, and the dotted lines are the 95% confidence bands (C). At the same time, serum prostacyclin, a vasodilator, decreased [n = 21 (2‐week), 15 (1‐month),11 (3‐month) one‐sample t‐test] with treatment. (D) *P < 0.05.

FIGURE 2

Increased left ventricular wall thickness and decreased global longitudinal strain are associated with toceranib treatment. After starting toceranib treatment, systolic function as measured by either left ventricular ejection fraction (LVEF) measured by the Simpson's method [n = 14 (1‐month), 10 (3‐month), 8 (5‐month)] (A) or fractional shortening by M‐mode [n = 12 (1‐month), 8 (3‐month), 7 (5‐month)] (B) did not change. However, an increase in interventricular septal thickness in end diastole (IVSd) was noted 3 months later but not after 5 months. [n = 15 (1‐month), 11 (3‐month), 8 (5‐month)] (C), and systolic function as measured by Global Longitudinal Strain (GLS) indicated a decrease in left ventricular contractile function [n = 12 (1‐month), 10 (3‐month), 7 (5‐month)] (D). Mixed effect analysis with Dunnett's multiple comparisons test. *P < 0.05, ***P < 0.001.