Oxidative/nitrosative stress and endothelial dysfunction are hypothesized to be central to cancer therapeutics–related cardiac dysfunction (CTRCD). However, the relationship between circulating arginine-nitric oxide (NO) metabolites and CTRCD remains unstudied.
Objectives
This study sought to examine the relationship between arginine-NO metabolites and CTRCD in a prospective cohort of 170 breast cancer patients treated with doxorubicin with or without trastuzumab.
Methods
Plasma levels of arginine, citrulline, ornithine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and N-monomethylarginine (MMA) were quantified at baseline, 1 month, and 2 months after doxorubicin initiation. Determinants of baseline biomarker levels were identified using multivariable linear regression, and Cox regression defined the association between baseline levels and 1- or 2-month biomarker changes and CTRCD rate in 139 participants with quantitated echocardiograms at all time points.
Results
Age, hypertension, body mass index, and African-American race were independently associated with ≥1 of baseline citrulline, ADMA, SDMA, and MMA levels. Decreases in arginine and citrulline and increases in ADMA were observed at 1 and 2 months (all p < 0.05). Overall, 32 participants experienced CTRCD over a maximum follow-up of 5.4 years. Hazard ratios for ADMA and MMA at 2 months were 3.33 (95% confidence interval [CI]: 1.12 to 9.96) and 2.70 (95% CI: 1.35 to 5.41), respectively, and 0.78 (95% CI: 0.64 to 0.97) for arginine at 1 month.
Conclusions
In breast cancer patients undergoing doxorubicin therapy, early alterations in arginine-NO metabolite levels occurred, and early biomarker changes were associated with a greater CTRCD rate. Our findings highlight the potential mechanistic and translational relevance of this pathway to CTRCD.
This work was supported by National Heart, Lung, and Blood Institute (NHLBI) grant R01-HL118018 (Dr. Ky), the McCabe Fellow Award (Dr. Ky), American Cancer Society institutional research grant 78-002-30 (Dr. Ky), NHLBI grant K23-HL095661 (Dr. Ky), NHLBI grant R01-HL103931 (Dr. Tang), and National Institute of Child Health and Development grant T32-HD060550 (Dr. Narayan). The funders had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript. Dr. Putt has reported owning stock in Roche. Dr. Ky has received consulting fees from Roche. All other authors have reported that they have no relationships relevant to the contents of this paper to report. This study was presented in part at the Global Cardio-Oncology Summit, in Vancouver, Canada, on September 23, 2016. Drs. Finkelman and Putt contributed equally to this work.
