Evaluating the utility of markers of thromboxane activity and oxidative stress in cardiovascular risk prediction

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Aspirin is a cornerstone therapy for coronary artery disease (CAD), with proven effects on reducing cardiovascular events and mortality 1. Aspirin is the most widely used antiplatelet agent and its usage is encouraged by guidelines for the spectrum of patients from those with stable CAD to acute coronary syndromes 2. However, not all individuals respond to aspirin in the same way 3.
Aspirin ‘resistance’ is defined as a lack of clinical or laboratory response to aspirin, although the term has no proper standardization. Moreover, genetic or pharmacologic factors influencing the response to aspirin have yet to be clearly described. Clinically, 10–20% of patients with cardiovascular disease have a recurrent vascular event while taking aspirin during long-term follow-up and these patients are described as having clinical aspirin ‘resistance’ 4.
Aspirin resistance can also be assessed by laboratory means. Thromboxane A2 (TxA2) is an important prostaglandin metabolite derived from arachidonic acid through the cyclooxygenase (COX) pathway 5. TxA2 is mainly produced by activated platelets and works as a vasoconstrictor and a pro-thrombotic agent that promotes the activation and subsequent aggregation of nearby platelets. Aspirin irreversibly acetylates COX-1 and even low doses of aspirin block 95% of COX-1 activity, resulting in the inhibition of TxA2 production 6. This is believed to be the primary mechanisms underlying the beneficial effects of aspirin in CAD treatment.
Routine measurement of TxA2 is, however, difficult because of its high instability and short half-life 7. Urinary 11-dehydrothromboxane B2 (11dhTxB2) is a stable downstream metabolite of TxA2 and a reliable biomarker for the assessment of platelet activity 8. Individuals with urinary 11dhTxB2 above 1500 pg/mg are defined as poor aspirin responders, whereas those below this threshold are considered aspirin ‘sensitive’ 6. Poor patient compliance with aspirin is an important but sometimes overlooked cause of aspirin resistance.
Nonetheless, other mediators such as the isoprostane 8-iso-prostaglandin F2α (8-iso-PGF2α) are formed through free radical-induced peroxidation of arachidonic acid formed during states of inflammation and can cause damage to the vascular system by activating the thromboxane receptor independent of TxA29–12. 8-iso-PGF2α is chemically stable, can be measured noninvasively in human urine, and has previously been shown to be a marker of CAD 13.
Is there evidence to support a link between laboratory aspirin resistance and increased risk of cardiovascular events? Eikelboom et al.14 reported the impact of urinary 11dhTxB2 in the subanalysis of Heart Outcomes Prevention Evaluation (HOPE) study. Of patients with available urine samples (n=5229), only those who were taking aspirin were included. Urinary 11dhTxB2 was assessed in cases (n=488) with subsequent cardiovascular events (myocardial infarction, stroke, or cardiovascular death) compared with sex-matched and age-matched controls (n=488) without cardiovascular events. Urinary 11dhTxB2 levels were significantly higher in cases with cardiovascular events. Those in the upper quartile of urinary 11dhTxB2 had a 1.8-times higher risk of events than those in the lower quartile (odds ratio, 1.8; 98% confidence interavl: 1.2–2.7; P=0.009). A substudy of Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance trial 15 showed increased CVD risk in patients with 11dhTxB2 in the upper quartile similar to what was reported previously by the HOPE study.
In the present issue of Coronary Artery Disease, Vasudevan et al.16 expands our understanding of aspirin resistance by examining the relationship of 11dhTxB2, 8-iso-PGF2α, and mortality in 447 patients with stable CAD under routine care at two Texas hospitals. Urinary samples were obtained on the day of enrollment and patients were followed for a median of 1149 days, with 14.9% of patients dying mostly of cardiovascular causes.

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