Adverse Effects of Chemotherapy on Human Microvascular Function

Abstract

RationalOne of the most devastating side effects of cancer treatment is chemotherapy (CT)‐induced heart failure, which results in significant morbidity for patients. Cardiovascular (CV)‐related side effects of CT are known to involve excess reactive oxygen species. However, the underlying mechanisms are disputed. To date little to no evidence exists that describe the direct effect of CT on the microcirculation, and none of these studies were performed in humans. Microvascular (MV) dysfunction is a known early indicator of numerous CV disease phenotypes. The goal of this study was to evaluate whether CT treatment affects human MV function.MethodsTo study the effect of CT on the MV system, flow mediated dilation (FMD) was evaluated in freshly isolated human microvessels from healthy patients that were ex vivo treated with various CT drugs (trastuzumab ‐ TZ, doxorubicin ‐ Dox, lapatinib ‐ Lb, or imatinib ‐ Ib). Mitochondrial DNA (mtDNA) damage was assessed using semi‐quantitative PCR comparing amplification of a small fragment to a large fragment in the mitochondrial genome.ResultsEx vivo treatment of microvessels with any of the four CT drugs reduced nitric oxide (NO)‐mediated dilation compared to untreated controls. TZ decreased FMD, and Dox treatment eliminated endothelial dilator capacity. TZ, Lb, and Ib treatments maintained MV dilation via a compensatory increase in mitochondrial H2O2‐mediated dilation. Smooth muscle dependent dilation to papaverine was not affected by any of the treatments. Analysis of mtDNA damage from HUVEC cells treated with Dox showed an increase in mtDNA damage, and mitochondria‐targeted Endo III treatment prevented Dox‐mediated loss of dilation. These studies suggest a role for mtDNA damage in the Dox phenotype.ConclusionsOur studies demonstrate for the first time the effect of CT drugs on human MV function and may lead to methods of preventing additional adverse CV side effects from CT.Support or Funding InformationThis work was supported by NIH R01 HL133029, We Care Foundation Grant; MCW‐Cardiovascular Center Pre‐PPG grant, Advancing a Healthier Wisconsin – Redox Biology Grant.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.