Stratification by Race Reveals Disparate Vascular Toxicity in Response to Anti‐Cancer Therapies

Abstract

IntroductionCardiovascular toxicity is the primary reason for halting anti‐cancer therapy (CTx) or limiting the dose, and cardiovascular side effects of CTx represent a major clinical problem with implications for survival and quality of life. Ongoing work in our laboratory suggests that CTx induces microvascular endothelial dysfunction, which is a well‐established predictor of future CV events. CV disease in general and CTx‐induced adverse events are significantly more prevalent in Black patients (B) relative to non‐Hispanic White patients (NHW). Despite clinical evidence of these health disparities, little to no data exist to explain the underlying causes. Therefore, we tested the novel hypothesis that CTx‐induced microvascular dysfunction is augmented in B, which may explain the increase in cardiotoxic events in this population compared to NHW.MethodsFresh human tissues were obtained as de‐identified surgical discard specimens. Peripheral adipose arterioles (100–200 µm) from healthy B and NHW were incubated ex vivowith the CTx agents, doxorubicin (Dox), trastuzumab (TZM), or paclitaxel (PTX) for 16–20 h and used for isolated arteriole preparations. Endothelium‐dependent vasodilation in response to flow (Flow‐Mediated Dilation, FMD; 5–100 cmH2O pressure gradient) or acetylcholine (ACh; 10−9 to 10−5 M) and smooth muscle‐dependent dilation to papaverine (100 µM) were evaluated. Data are presented as % max. diameter ± SEM, N. Statistical significance was established with two‐way ANOVA RM.ResultsUnder control conditions, there was no difference in microvascular FMD in healthy B (ACh: 89.8±4.0%, n=5; 85.8±1.8%, n=6) vs. NHW (ACh: 86.2±3.2%, n=6; 78.7±5.9%, n=8). Ex vivo exposure to Dox impaired endothelial function in arterioles from both B and NHW (ACh: 45.0±10.5%, n=4 and 34.2±9.8%, n=7; FMD: Figure 1A). TZM impaired endothelial function to a greater extent in arterioles from B (ACh: 36.1±7.1%, n=3; FMD: Figure 1B) compared to NHW (ACh: 44.4±8.6%, n=8; FMD: Figure 1B). Interestingly, PTX did not affect endothelial function in NHW (ACh: 91.5±1.6%, n=4; FMD: Figure 1C), but impaired endothelial function in arterioles from B (ACh: 54.7±12.9%, n=3; FMD: Figure 1C). Max dilator capacity to the endothelium‐independent dilator papaverine was not changed in either group (not shown).ConclusionOur findings reveal disparate effects of CTx agents on microvascular endothelial function from B and NHW patients. This raises the possibility that microvascular dysfunction may contribute to the known disparities in adverse CV clinical outcomes of cancer patients and potentially other CV pathologies (e.g., disparities in adverse events associated with PTX‐eluting stents.) Future work should differentiate between biological/genetic vs. social/environmental contribution to observed microvascular responses to CTx.