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

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 To examine the relationship between arginine-NO metabolites and CTRCD in a prospective cohort of 170 breast cancer patients treated with doxorubicin ± 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 following 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 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, 9.96) and 2.70 (95%CI 1.35, 5.41), respectively, and 0.78 (95%CI 0.64, 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.

Detailed phenotyping reveals distinct trajectories of cardiovascular function and symptoms with exposure to modern breast cancer therapy

“…Blood samples were collected at baseline and during each follow‐up visit, occurring every 4 to 6 weeks during treatment and annually. The visit schedule per treatment regimen has been described in detail previously …”

“…The visit schedule per treatment regimen has been described in detail previously. 13,15 Transthoracic echocardiograms were performed at standardized intervals according to the treatment regimen by a dedicated sonography team at an Intersocietal Accreditation Commission laboratory. Echocardiograms were performed at baseline, after completion of paclitaxel, and then annually in the doxorubicin group.…”

Plasma metabolites mediate the effect of HbA1c on incident cardiovascular disease

“…Glucose levels have a significant negative effect on endothelial function, and endothelial dysfunction is a key management of diabetes complications and CVD . It is also informed that endothelial dysfunction can make a metabolic dysregulation . The metabolites represent one of the downstream end products of the environment's interaction with the genome‐transcriptome‐proteome, and the endogenous metabolites level can sensitively reflect phenotype fluctuation for CVD …”

“…14,15 It is also informed that endothelial dysfunction can make a metabolic dysregulation. 16 The metabolites represent one of the downstream end products of the environment's interaction with the genome-transcriptome-proteome, and the endogenous metabolites level can sensitively reflect phenotype fluctuation for CVD. 17 However, the potential relationship among HbA1c, metabolites, and CVD is still unknown.…”

Precision Cardio-Oncology

“…These limitations compounded by a lack of biomarker specificity have motivated a search for more evidence-based biomarkers. For example, myeloperoxidase, growth differentiation factor-15, and asymmetric dimethylarginine have all been postulated as potentially useful biomarkers, as all play critical roles in oxidative stress or nitric oxide metabolism-potential mechanisms of anthracycline-induced cardiotoxicity (9,10). Additionally, a multimarker approach aimed at increasing sensitivity and specificity through the simultaneous evaluation of multiple contributory pathways has also been proposed, with elevations in troponin and myeloperoxidase demonstrating significant additive predictive value (9).…”