Elsevier

Heart Rhythm

Volume 14, Issue 12, December 2017, Pages 1849-1855
Heart Rhythm

Clinical
Atrial Fibrillation
Association between oxidative stress and atrial fibrillation

https://doi.org/10.1016/j.hrthm.2017.07.028Get rights and content

Background

Oxidative stress (OS) may be a key mechanism underlying the development of atrial fibrillation (AF) in experimental studies, but data in humans remain limited.

Objective

Systemic OS can be estimated by measurements of circulating levels of the aminothiols including glutathione, cysteine, and their oxidized products. We tested the hypothesis that the redox potentials of glutathione (EhGSH) and cysteine will be associated with prevalent and incident AF.

Methods

Plasma levels of aminothiols were measured in 1439 patients undergoing coronary angiography, of whom 148 (10.3%) had a diagnosis of AF. After a median follow-up of 6.3 years, 104 of 917 patients (11.5%) developed incident AF. Multivariate logistic regression and Cox regression models were used to determine whether OS markers were independent predictors of prevalent and incident AF after adjustment for traditional risk factors, heart failure, coronary artery disease, and high-sensitivity C-reactive protein level.

Results

For each 10% increase in EhGSH, the odds of prevalent AF was 30% higher (odds ratio [OR] 1.3; 95% confidence interval [CI] 1.1–1.7; P = .02) and 90% higher (OR 1.9; 95% CI 1.3–2.7; P = .004) when the median was used as a cutoff. The EhGSH level above the median was more predictive of chronic AF (OR 4.0; 95% CI 1.3–12.9; P = .01) than of paroxysmal AF (OR 1.7; 95% CI 1.1–2.7; P = .03). Each 10% increase in EhGSH level was associated with a 40% increase in the risk of incident AF (hazard ratio 1.4; 95% CI 1.1–1.7; P = .01).

Conclusion

Increased OS measured by the redox potentials of glutathione is associated with prevalent and incident AF. Therapies that modulate OS need to be investigated to treat and prevent AF.

Introduction

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice. Although its pathophysiology is incompletely understood, oxidative stress (OS) and inflammation appear to be important triggers.1, 2, 3 OS increases when the production of reactive oxygen species (ROS) overwhelms endogenous antioxidant defenses, causing tissue injury. ROS are derived from many sources including mitochondria, xanthine oxidase, uncoupled nitric oxide synthases, and nicotinamide adenine dinucleotide phosphate oxidases.4 Increased oxidation results in cell dysfunction, necrosis, apoptosis, and alterations in cellular proteins and signaling pathways.5 Because of the short half-life of ROS, the focus has been on measuring stable markers in the circulation that reflect cellular and systemic OS. These include markers of lipid peroxidation (isoprostanes), oxidized phospholipids, malondialdehyde, nitrotyrosine, myeloperoxidase, and aminothiol compounds. Aminothiols play a crucial role in redox signaling and can be quantified in plasma.6 Of these, cysteine and glutathione and their oxidized disulfide compounds (cystine and glutathione disulfide) constitute the major extra- and intracellular reduced thiol pools, respectively. The redox potentials of both glutathione and cysteine pools can be calculated using the Nernst equation to estimate the OS burden in vivo6 or simply calculating the ratio of cystine to oxidized glutathione, which has been shown to improve risk discrimination of adverse clinical outcomes.7 Because the plasma glutathione disulfide concentration is low (<200 μM), we have developed a method using high performance liquid chromatography with fluorescence detection that directly measure the low nanomolar plasma concentration of glutathione.

We have shown that increased systemic OS, measured as higher levels of cystine, lower levels of reduced glutathione, or altered ratios of oxidized to reduced aminothiols, has been associated with aging, risk factors for cardiovascular disease including hypertension and smoking, endothelial dysfunction, arterial stiffness and thickness, prevalent and incident cardiovascular disease, and increased pulmonary arterial pressures.7, 8, 9 Experimental studies have shown that increased systemic OS is associated with AF,1, 2 but the evidence in humans remains limited.3 To investigate the role of OS in AF, we tested the hypothesis that increased OS, measured as changes in circulating aminothiol levels, will be associated with prevalent and incident AF.

Section snippets

Study design

Between 2004 and 2008, plasma levels of aminothiols were measured in 1439 subjects aged between 18 and 90 years who were enrolled in the Emory Cardiovascular Biobank, a prospective registry of patients undergoing elective or emergent cardiac catheterization for suspected or known coronary artery disease (CAD) at 3 Emory Healthcare sites.10 Subjects were excluded if they had a history of heart transplantation, immunosuppressant use, malignancy, or significant infections. Patients' demographic

Results

The age of the cohort was 63.4 ± 11.3 years; 67% were men, 33% had diabetes, 69% had hypertension and/or hyperlipidemia, and 67.8% were smokers. Approximately three-quarters had significant CAD (≥50% luminal stenosis) on angiography and 10% presented with acute myocardial infarction (Table 1). Of 1439 patients enrolled in this study, 148 (10.3%) had a diagnosis of AF (86% nonvalvular and 77% paroxysmal). The relationship between markers of OS and clinical features are provided in the

Discussion

In this large prospective cohort study of patients undergoing evaluation for CAD, OS assessed as EhGSH was associated with an increased risk of prevalent and incident AF. A 10% increase in EhGSH level was associated with a 30% increase in prevalent and incident AF. This association was independent of hsCRP level and other clinical predictors of AF. In subjects with AF, OS markers correlated with CHA2DS2-VASc score, which is a power predictor of stroke risk. To our knowledge, this is the first

Conclusion

Increased OS, measured as EhGSH, was associated with a high risk of prevalent and incident AF. Whether reduction of OS will prevent AF needs to be investigated further.

Acknowledgments

We thank Shuai Zheng, PhD, for his assistance with database.

References (34)

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Dr Quyyumi was supported by the National Institutes of Health (grant nos. 5P01HL101398-02, 1P20HL113451-01, 1R56HL126558-01, 1RF1AG051633-01, R01 NS064162-01, R01 HL89650-01, HL095479-01, 1U10HL110302-01, 1DP3DK094346-01, and 2P01HL086773-06A1). Dr Tahhan was supported by the Abraham J. & Phyllis Katz Foundation (Atlanta, GA) and the National Institutes of Health/National Institutes of Aging (grant no. AG051633).

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