Impaired microvascular reactivity in patients treated with 5-fluorouracil chemotherapy regimens: Potential role of endothelial dysfunction

Stephen T Hammond; Dryden R Baumfalk; Shannon K Parr; Alec L E Butenas; Britton C Scheuermann; Vanessa-Rose G Turpin; Bradley J Behnke; Mehmood H Hashmi; Carl J Ade

doi:10.1016/j.ijcha.2023.101300

Impaired microvascular reactivity in patients treated with 5-fluorouracil chemotherapy regimens: Potential role of endothelial dysfunction

Int J Cardiol Heart Vasc. 2023 Nov 17:49:101300. doi: 10.1016/j.ijcha.2023.101300. eCollection 2023 Dec.

Authors

Stephen T Hammond^{1

2

3}, Dryden R Baumfalk¹, Shannon K Parr¹, Alec L E Butenas¹, Britton C Scheuermann¹, Vanessa-Rose G Turpin¹, Bradley J Behnke^{1

4}, Mehmood H Hashmi⁵, Carl J Ade^{1

4

6}

Affiliations

¹ Department of Kinesiology, Kansas State University, Manhattan, KS, USA.
² Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
³ Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA.
⁴ Johnson Cancer Research Center, Kansas State University, Manhattan, KS, USA.
⁵ Cotton O'Neil Cancer Center, Stormont Vail Health, Topeka, KS, USA.
⁶ Physicians Associates Studies, Kansas State University, Manhattan, KS, USA.

Abstract

Background: 5-fluorouracil (5-FU) is the second most common cancer chemotherapy associated with short- and long-term cardiotoxicity. Although the mechanisms mediating these toxicities are not well understood, patients often present with symptoms suggestive of microvascular dysfunction. We tested the hypotheses that patients undergoing cancer treatment with 5-FU based chemotherapy regimens would present with impaired microvascular reactivity and that these findings would be substantiated by decrements in endothelial nitric oxide synthase (eNOS) gene expression in 5-FU treated human coronary artery endothelial cells (HCAEC).

Methods: We first performed a cross-sectional analysis of 30 patients undergoing 5-FU based chemotherapy treatment for cancer (5-FU) and 32 controls (CON) matched for age, sex, body mass index, and prior health history (excluding cancer). Cutaneous microvascular reactivity was evaluated by laser Doppler flowmetry in response to endothelium-dependent (local skin heating; acetylcholine iontophoresis, ACh) and -independent (sodium nitroprusside iontophoresis, SNP) stimuli. In vitro experiments in HCAEC were completed to assess the effects of 5-FU on eNOS gene expression.

Results: 5-FU presented with diminished microvascular reactivity following eNOS-dependent local heating compared to CON (P = 0.001). Iontophoresis of the eNOS inhibitor L-NAME failed to alter the heating response in 5-FU (P = 0.95), despite significant reductions in CON (P = 0.03). These findings were corroborated by lower eNOS gene expression in 5-FU treated HCAEC (P < 0.01) compared to control. Peak vasodilation to ACh (P = 0.58) nor SNP (P = 0.39) were different between groups.

Conclusions: The present findings suggest diminished microvascular function along the eNOS-NO vasodilatory pathway in patients with cancer undergoing treatment with 5-FU-based chemotherapy regimens and thus, may provide insight into the underlying mechanisms of 5-FU cardiotoxicity.

Keywords: 5-fluorouracil; Cardio-oncology; Cardiotoxicity; Endothelium; Microcirculation.

Grants and funding

T32 HL134643/HL/NHLBI NIH HHS/United States