Thromboxane and Prostaglandin Metabolite Levels and Inflammation Phenotypes in Coronary Artery Disease Patients

Purpose:  Inflammation plays a major role in the development of acute coronary syndrome (ACS) events in stable coronary artery disease (CAD) patients. In addition to regulating platelet activation, cyclooxygenase-derived thromboxane (TxA2) and prostacyclin (PGI2) have potent pro- and anti-inflammatory effects, respectively. Although low-dose aspirin suppresses platelet-derived TxA2, this prostanoid is synthesized by other cell types and initiates inflammatory processes that predispose CAD patients to increased risk of ACS events. Therefore, we evaluated associations between TxA2, PGI2 and the TxA2/PGI2 ratio and inflammation phenotypes predictive of prognosis.

Methods:  Using a cross-sectional design, we collected blood and urine from 123 patients with stable, angiographically-confirmed CAD after fasting, withholding morning medications, and withholding NSAID use for at least 7 days. Stable urine metabolites of thromboxane (Tx-M) and prostacyclin (PGI-M) were quantified by ELISA and normalized to creatinine. Relationships with circulating cellular adhesion molecules (CAMs: E-selectin, P-selectin), monocyte (MCP-1) and neutrophil (ENA-78) chemokines, and C-reactive protein (hs-CRP) were quantified by Spearman rank correlation (r_s) and regression.

Results:  Subjects were 60±10 years old, 70% male and 17% African-American, clinically stable, and 98% were receiving low-dose aspirin. Unadjusted correlations are reported below. Similar results were obtained when adjusting for demographic and clinical covariates, including aspirin dose (81 or 325 mg).

Prostanoid	hsCRP		ENA-78		P-Selectin		E-Selectin		MCP-1
	rs	P	rs	P	rs	P	rs	P	rs	P
Tx-M	0.264	0.003	0.264	0.003	0.288	0.001	0.233	0.010	0.140	0.124
PGI-M	-0.178	0.049	-0.258	0.004	-0.058	0.526	-0.100	0.276	-0.050	0.582
Tx-M/PGI-M	0.279	0.002	0.362	<.001	0.191	0.036	0.195	0.032	0.108	0.236

Conclusion:  Elevated Tx-M levels are associated with activated inflammation phenotypes, suggesting TxA2 biosynthesis is an important driver of inflammation in stable CAD patients on aspirin therapy. Future studies are needed to identify the origin of TxA2 biosynthesis and develop interventions that attenuate inflammation in this high-risk population.