Prediction of myocardial infarction, stroke and cardiovascular mortality with urinary biomarkers of oxidative stress: Results from a large cohort study
Introduction
There is increasing evidence showing that oxidative stress is involved in the pathogenesis and development of a wide range of chronic and degenerative diseases, including type 2 diabetes, cancer and cardiovascular diseases (CVD) [[1], [2], [3]]. Cardiovascular diseases (CVD), such as coronary artery disease (CAD) and stroke, are the leading cause of death globally, and contribute substantially to the escalating costs of health care [4,5]. In most cases, the underlying cause of CVD is atherosclerosis [6,7], which usually progresses slowly and remains asymptomatic for decades. Common features of atherosclerosis include low-density lipoprotein (LDL) oxidation, endothelial dysfunction, and inflammation [8]. Importantly, these three features of atherosclerosis all involve reactive oxygen species (ROS) in their pathophysiology [9].
However, ROS cannot be directly measured in serum or urine samples because of their short half-lives and instead products of lipid or DNA oxidation like measurements of 8-isoprostane or oxidized guanine/guanosine (OxGua) concentrations are being used. These biomarkers are most stable in urine samples. Measurement of 8-isoprostane levels in urine has emerged as one of the most accurate approaches to assess oxidative stress status in vivo because of their long-term stability [10]. The 8-isoprostane molecule and other F2-isoprostanes are non-enzymatic free radical catalyzed peroxidation products of arachidonic acid [11]. The 8-isoprostane levels have been shown to be a promising biomarker of coronary artery disease [12], ischemic stroke [13] and diabetes [14]. OxGua molecules, including 8-hydroxyguanine (8-OHGua) and its nucleoside forms 8-hydroxy-2′-deoxyguanosine (8-OHdGuo) and 8-hydroxyguanosine (8-OHGuo), are formed from the attack of hydroxyl radicals on the guanine nucleobase of the DNA or RNA strand [15]. Base excision repair processes are initiated to correct the damages and the OxGua species are released into the urine [16]. 8-OHdGuo has been demonstrated to be associated with various CVDs [17].
However, due to the limited number of publications that focus on the hard endpoints of CVDs, we assessed the association of OxGua and 8-isoprostane levels with incident MI, incident stroke and CVD mortality, using data from a large, population-based study of older adults from Germany with long-term follow-up. In addition, we evaluated the predictive value of these two biomarkers of oxidative stress for risk prediction with respect to 10-year CVD mortality.
Section snippets
Study population
The research questions were addressed by using data of the ESTHER study [Epidemiologische Studie zu Chancen der Verhütung, Früherkennung und optimierten Therapie chronischer Erkrankungen in der älteren Bevölkerung (German)], an ongoing population-based cohort study, conducted in the federal state of Saarland, located in Southwest Germany. Details of the study design have been reported previously [18]. Briefly, 9949 male and female residents of Saarland aged 50–75 years and with sufficient
Results
Baseline characteristics of the 8354 included study participants are shown in Table 1. The cohort comprised more women (57.4%) than men and the median age was 62 years. OxGua levels were higher in subjects aged 65–75 than in younger study participants. The 8-isoprostane levels did not vary much by age but nevertheless minimal differences in the age groups led to a statistically significant finding. Both oxidative stress biomarkers were statistically significantly higher in women than in men.
Discussion
In this population-based cohort study of older adults, we showed that both 8-isoprostane and OxGua levels were significantly associated with CVD mortality. In addition, OxGua levels were associated with stroke incidence and 8-isoprostane levels with fatal stroke. Both oxidative stress markers were not statistically associated with MI incidence in the total population but in obese subjects. Generally, associations were stronger for fatal outcomes and in older and obese individuals. Moreover,
Conclusion
This large cohort study observed associations of both high OxGua and 8-isoprostane levels with MI and stroke incidence as well as CVD mortality (especially in obese subjects and individuals aged 60 years and older). The results suggest an important contribution of an imbalanced redox system to the etiology of CVD. In addition, OxGua and 8-isoprostane measurements were shown to be useful for an improvement of CVD mortality prediction.
Acknowledgement of grant support
This project was funded by a grant from the German Research Foundation (grant No. SCHO 1545/3-1) and a scholarship from the China Scholarship Council (CSC) to Yang Xuan. The ESTHER study was funded by grants from the Saarland state Ministry for Social Affairs, Health, Women and Family Affairs (Saarbrücken, Germany), the Baden-Württemberg state Ministry of Science, Research and Arts (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany) and the Federal Ministry of
Conflicts of interests
The authors report no relationships that could be construed as a conflict of interest.
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