Effects of Anti‐Cancer Therapy on Human Microvascular Function ‐ a Longitudinal Study

Abstract

RationalCardiovascular toxicities that result from anti‐cancer therapy (CT) significantly contribute to the morbidity and mortality of breast cancer survivors. While the negative impact of CTs such as trastuzumab or doxorubicin on cardiomyocytes is well‐established, significantly less is known about how the circulatory system is affected. Impaired microvascular (MV) function as measured by coronary flow reserve is a recognized predictor of future adverse cardiovascular events. Our goal is to understand how CT damages the microcirculation and how that damage contributes to acute and long‐term cardiovascular toxicities.MethodsTo study the direct effect of CT on the MV function, we are conducting a longitudinal study of neoadjuvant breast cancer patients. Patient adipose samples are collected before, during, and after CT treatment. Endothelial‐dependent dilation to flow (FMD) and acetylcholine (Ach) and smooth muscle‐dependent dilation to papaverine were evaluated in freshly isolated microvessels via video microscopy. NO and mitochondrial ROS were evaluated via florescence microscopy. Data are presented as a percentage of maximum diameter and are analyzed with ANOVA RM with statistical significance set at *p<0.05; data are expressed as mean ± standard error. Additionally, angiogenic potential was evaluated using a matrigel plug assay. Data are presented as a percentage of wells with capillary sprouts. Cardiac function was monitored via standard clinical echocardiogram.ResultsVessels from breast cancer patients showed normal FMD and Ach responses and a normal increase in NO production to flow stimulus before CT; however, CT resulted in impairment of FMD (pre‐CT 80.9±4.2%; during‐CT 21.8%±3.1%*; post‐CT 30.3±4.5%*) and dilation to Ach (pre‐CT 81.3±9.1%; during‐CT 23.1%±1.8%*; post‐CT 38.6±6.5%*). Smooth muscle‐dependent dilation (to papaverine) was not affected by CT treatments. Angiogenic potential was impaired in adipose samples collected during CT (6.5%±6.5%) compared to pre‐CT (47.3%±10.4%). Surprisingly, despite significantly decreased endothelial function, angiogenic potential completely recovered one month after final CT treatment (59.8%±16.4%). No clinical signs of reduced cardiac function were observed in any of our study participants.ConclusionOur study shows for the first time a longitudinal evaluation of human microvascular function in response to anti‐cancer therapy. We observed significant reductions in MV function during treatment with CT in the absence of a clinically relevant reduction in cardiac function. Our findings suggest that CT‐induced MV dysfunction precedes and may contribute to future adverse CV events.Support or Funding InformationThis work was supported by NIH R01 HL133029, We Care Foundation Grant; MCWCardiovascular Center Pre‐PPG grant, Advancing a Healthier Wisconsin – Redox Biology Grant.