Racial Disparities in Cardio-Oncology: Contributions of Anti-Cancer Therapy Induced Endothelial Dysfunction

Abstract

Background: Major adverse cardiovascular (CV) events (MACE) related to anti-cancer therapy (CTx) represent the leading cause of non-cancer related mortality among breast cancer (BC) survivors. Most preclinical studies have focused on the heart, but increasing evidence suggests decreased endothelial function is predictive of CTx induced cardiac events. To date, the role of microvascular endothelial (dys)function, a well-established predictor of MACE, has been mostly ignored and few mechanistic studies exist in human subjects. CV disease in general, and CTx induced adverse events specifically, are significantly more prevalent in Black (B) relative to non-Hispanic White (NHW) patients. Despite the overwhelming clinical evidence supporting these health disparities, the underlying causes are poorly understood. Our lab and others have demonstrated that isolated vessels from human tissue samples can be used to understand the mechanisms contributing to CV disease. The overall goal of this study is to determine the effect of anti-cancer therapy on microvascular function and identify possible racial disparities. Hypothesis: Ex vivo treatment with CTx leads to impaired endothelial function, which is augmented in healthy donor vessels from B compared to NHW patients. Methods: Human adipose arterioles obtained from de-identified surgical discarded specimens of healthy B and NWH patients were used for video-microscopy. Vessels were incubated ex vivo 16–20 h with CTx (trastuzumab-TZM, doxorubicin-Dox, or paclitaxel-PTX). Response to endothelial dependent flow mediated dilation (FMD 5-100 cmH2O pressure gradient), acetylcholine (ACh; 10−9 to 10−5 M), and the endothelial independent dilator papaverine (Pap 10-4 M) were evaluated. Data are presented as %Max diameter ± SEM, N. Statistical significance was established with 2-way ANOVA RM *p<0.05. Results: Exposure to Dox decreased FMD equally in vessels from B (19±3, n=8) vs. NHW patients (29±5 n=8). The TZM induced endothelial dysfunction in vessels from B patients (37±8*, n=11) was augmented compared to NHW patients (57±15, n=6). PTX did not impair FMD in NHW patients (93±0.9, n=7) but showed a significant reduction in vessels from B patients (49±10*, n=10). Similar results were observed with ACh dilation, but Max dilator capacity to papaverine was unchanged in either group (not shown). Conclusion: Our findings suggest that racial disparities may contribute to differences in microvascular function and clinical outcomes of BC patients. Since dysfunction of the microcirculation is a common predecessor to heart failure and other MACE, novel strategies designed to predict, manage, and treat these adverse effects are needed and should be tailored to individual patient populations. To date, we cannot differentiate between biological/genetic vs. social/environmental contributors to the observed microvascular responses to CTx; that will be the focus of future studies. This work was supported by the American Heart Association Scientific Focused Research Network grant (SFRN.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.