Administration of Sunitinib, an Oral Angiogenesis Inhibitor, Is Associated With Hypertension, but Not With Structural Cardiac Changes or Cardiomyocyte Mitochondrial Dysfunction: Pp.22.363

Objectives: Inhibition of angiogenesis by blocking vascular endothelial growth factor (VEGF)-mediated signaling is an established treatment for various forms of cancer. This therapy is frequently associated with hypertension, but may also cause cardiac toxicity, mainly a decreased left ventricular ejection fraction (LVEF). Cardiomyocyte hypertrophy and changes in cardiac mitochondrial structure (swelling) have been reported in mice, suggesting that impaired adenosine triphosphate (ATP) generation secondary to mitochondrial dysfunction underlies the decrease in LVEF. We aimed to assess the effects of sunitinib on blood pressure (BP), cardiac structure and mitochondrial function in an ex-vivo rodent model. Methods: Normotensive male Wistar-Kyoto rats were administered sunitinib (n = 10) or vehicle (n = 6) by oral gavage and BP and heart rate (HR) were monitored telemetrically until a plateau in BP occurred at which time animals were euthanized. Blood and hearts were collected for determination of brain natriuretic peptide (BNP)-45 levels, heart weight, cardiomyocyte size and isolation of cardiomyocyte mitochondria for measurement of complex I- and II-dependent ATP production. Results: A plateau in BP rise was found after 6 days of treatment. At that time, mean arterial BP had increased from 98.3 ± 0.3mmHg to 126 ± 1.5mmHg and HR had decreased from 319.3 ± 1.4bpm to 271.6 ± 3.0bpm (both p < 0.001), while BP and HR did not change in the control group. Circulating BNP-45 levels were almost 2-fold (163.9 ± 33.9ng/ml vs 92.7 ± 15.0ng/ml; p = 0.03) and serum creatinine levels (28.8 ± 6.4 vs 8.0 ± 2.7 μmol/l; p = 0.03) almost threefold higher in the sunitinib compared to the control group. Heart weight-to-body weight ratio and cardiomyocyte area were not different between groups. Complex I-dependent ATP production between the sunitinib and control group (659.7 ± 88.1; vs 1028 ± 278 nmol/mg mitochondrial protein/30 min; p = 0.26) and complex II-dependent ATP-production (955.6 ± 93.3 vs 1409 ± 255 nmol/mg mitochondrial protein/30 min; p = 0.15) did not differ. Conclusions: Although circulating BNP-45 levels were increased in sunitinib-administered rats, no evidence for structural cardiac abnormalities or impaired cardiomyocyte mitochondrial ATP production was found. The rise in BNP-45 might be a consequence of the BP-rise and the decrease in renal function.