Discussion
Naproxen is a widely used drug for the treatment of pain and inflammatory conditions, and it is available in the United States without prescription. Its gastrointestinal side effects have been well documented, but recent investigation into its cardiovascular safety has been inconclusive. The majority of evidence favors either a negligible or slightly protective effect of the drug on cardiovascular risk,8 but its specific effects on the heart remain unclear. In addition, the effect of cardiovascular comorbidities on the safety profile of naproxen, such as chronic ischemia and hypercholesterolemia, is unknown. We have previously completed 2 studies that examined the specific effects of naproxen on chronically ischemic myocardium in comparison to non–drug treated controls. We found that, in normal diet swine, naproxen treatment increased myocardial blood flow, but also increased microvessel contraction responses to serotonin and endothelin-1, decreased tissue prostacyclin levels only, and seemed to inhibit angiogenesis and decrease VEGF and VEGFR2 expression.12 In contrast, in hypercholesterolemic swine, naproxen treatment had no effect on blood flow, but improved endothelium-dependent vasodilation, while inhibiting production of both prostacyclin and thromboxane (L.M. Chu, MD, unpublished data, 2011). Hypercholesterolemia clearly alters the effect of COX inhibition with naproxen. We designed this study in order to better elucidate the effects of hypercholesterolemia on COX inhibition. We revealed that hypercholesterolemia alters prostanoid balance and reduces perfusion in the ischemic territory of naproxen-treated swine. Myocardial perfusion is a predictor of angina frequency and quality of life in patients with chronic ischemia. In addition, decreased prostacyclin levels may predispose to thrombogenesis and atherosclerosis.13 These findings have important implications for cardiac patients taking NSAIDs.