Novel Biomarker of Oxidative Stress Is Associated With Risk of Death in Patients With Coronary Artery Disease

Abstract

Background Free radical scavengers have failed to improve patient outcomes promoting the concept that clinically important oxidative stress (OS) may be mediated by alternative mechanisms. We sought to examine the association of emerging aminothiol markers of non-free radical mediated oxidative stress with clinical outcomes. Methods and Results Plasma levels of reduced (cysteine and glutathione) and oxidized (cystine and glutathione disulphide) aminothiols were quantified by high performance liquid chromatography in 1411 patients undergoing coronary angiography (mean age 63 years, male 66%). All patients were followed for a mean of 4.7±2.1 years for the primary outcome of all-cause death (n=247). Levels of cystine (oxidized) and glutathione (reduced) were associated with risk of death (p<0.001 both) before and after adjustment for covariates. High cystine and low glutathione levels (>+1 SD & <−1 SD respectively) were associated with higher mortality (adjusted HR 1.63 (95% CI 1.19–2.21; HR 2.19 (95% CI 1.50–3.19), respectively) compared to those outside these thresholds. Furthermore, the ratio of cystine/glutathione was also significantly associated with mortality (adjusted HR 1.92 (95% CI 1.39–2.64) and was independent of and additive to hs-CRP level. Similar associations were found for other outcomes of cardiovascular death and combined death and myocardial infarction. Conclusions A high burden of OS, quantified by the plasma aminothiols, cystine, glutathione and their ratio is associated with mortality in patients with CAD, a finding that is independent of and additive to the inflammatory burden. Importantly, this data supports the emerging role of non-free radical biology in driving clinically important oxidative stress.

Oxidative stress and frailty: A systematic review and synthesis of the best evidence

“…Both higher OS in the periphery and frailty are accompanied by several negative outcomes, such as higher mortality and multi-morbidity (9,28). Our systematic review suggests that frailty is associated with higher OS and lower anti-oxidant peripheral parameters.…”

“…The deteriorations related to OS rank first among causes of aging (4), and may lead to development of age-related diseases, such as macular degeneration, sarcopenia, cerebrovascular diseases, Alzheimer's disease (AD), Parkinson's disease, cancer, and consequently mortality (5,28), although the direction of this relationship is motive of debate. Furthermore, anti-oxidants have been proposed as novel therapeutic targets for several aging-associated diseases, due in part to their cardioprotective, chemotherapeutic, and neuroprotective effects (29).…”

“…Furthermore, anti-oxidants have been proposed as novel therapeutic targets for several aging-associated diseases, due in part to their cardioprotective, chemotherapeutic, and neuroprotective effects (29). Nowadays, effects of both OS and anti-oxidant parameters on the initiation and progression of age-related diseases remain unclear; however, clinical and experimental studies have intensively investigated this topic (4,5,(27)(28)(29).…”

“…In addition, predominantly inflammatory cytokines may influence frailty status either directly by promoting protein degradation, or indirectly by affecting important metabolic pathways (34). Third, frail and pre-frail participants have a higher prevalence of various medical disorders, including cardiovascular diseases, stroke, dementia and diabetes mellitus, all of which are both strongly associated with frailty and could also increase the generation of OS products (5,28). These chronic diseases, arising mainly in later life, may increase resting metabolic rate in order to maintain cellular homeostasis, which drive the generation of ROS by dysregulated mitochondria, ultimately leading to homeostatic deregulation and then loss of muscle strength (14).…”

Selected oxidative stress biomarkers in antenatal diagnosis as 11–14 gestational weeks

“…The decreased GSH levels were reported by other authors in patients with rheumatoid arthritis, alopecia areata, prediabetes, gestational diabetes, coronary heart disease and in preterm termination of pregnancy. Importantly, oxidative processes may be altered even at subclinical stages of these diseases [34][35][36][37][38][39]. Based on that, it can be hypothesized that redox imbalance may disturb foetal development, even at the absence of clinically manifested abnormalities.…”