Arginine-Nitric Oxide Metabolites and Cardiac Dysfunction in Patients With Breast Cancer

J Am Coll Cardiol. 2017 Jul 11;70(2):152-162. doi: 10.1016/j.jacc.2017.05.019.

Abstract

Background: 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.

Keywords: arginine metabolism; cardio-oncology; cardiotoxicity; doxorubicin; nitrosative stress; trastuzumab.

MeSH terms

  • Adult
  • Antibiotics, Antineoplastic / adverse effects
  • Antibiotics, Antineoplastic / therapeutic use
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use
  • Arginine / blood*
  • Biomarkers, Tumor / blood
  • Breast Neoplasms / blood*
  • Breast Neoplasms / complications
  • Breast Neoplasms / drug therapy
  • Cardiomyopathies / blood
  • Cardiomyopathies / chemically induced*
  • Doxorubicin / adverse effects*
  • Doxorubicin / therapeutic use
  • Female
  • Follow-Up Studies
  • Humans
  • Middle Aged
  • Nitric Oxide / blood*
  • Oxidative Stress*
  • Prospective Studies
  • Time Factors
  • Trastuzumab / adverse effects*
  • Trastuzumab / therapeutic use

Substances

  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Nitric Oxide
  • Doxorubicin
  • Arginine
  • Trastuzumab