Abstract
Vioxx (rofecoxib) was withdrawn from the market because of a higher rate of cardiovascular events. An increased risk of cardiovascular events has also been reported with valdecoxib in patients with coronary artery bypass grafting and in a recent colon cancer trial of high-dose celecoxib.
The reason for the propensity of COX-2 inhibitors to facilitate cardiovascular events remains unclear. One possible mechanism is an imbalance between prostacyclin (PGI2, antithrombotic) and thromboxane (TXA2, prothrombotic) since PGI2 production mainly depends on COX-2 activity. However, recent reports demonstrated that low-dose aspirin did not mitigate cardiovascular risk associated with COX-2 inhibitors. Co-administration of aspirin with a COX-2 inhibitor may restore the balance between PGI2 and TXA2 because low-dose aspirin selectively inhibits TXA2 production in platelets. Thus, the failure of low-dose aspirin to attenuate the cardiovascular risk associated with COX-2 inhibitors implies that the COX-2 inhibitor increases the risk of cardiovascular events, at least in part, by mechanisms unrelated to TXA2 production.
The heart has a remarkable ability to adapt to various stresses, such as ischemia, hypoxia, and oxidative stress. This is exemplified by ischemic preconditioning (IPC), the phenomenon whereby a sublethal ischemic stress greatly enhances the tolerance of the myocardium to subsequent ischemia. The occurrence of IPC has been shown in almost all mammalian tissues and has also been confirmed in humans, where it may play an important role in protecting the heart from coronary artery disease. We demonstrated that induction of COX-2 plays an obligatory role in the development of IPC, most likely via the production of cardioprotective prostanoids such PGI2 and PGE2. Since then, mounting evidence has accumulated which supports the concept that COX-2 is a cardioprotective protein that alleviates myocardial ischemia/reperfusion injury. We have suggested that induction of COX-2 is a fundamental mechanism whereby the heart adapts to stress. Importantly, low-dose aspirin does not interfere either with COX-2 or with IPC.
We propose another mechanism for the detrimental effects of COX-2 inhibitors, namely, that, in addition to their prothrombotic actions, these drugs may deprive the heart of its natural ability to adapt to ischemic stress (i.e., IPC), thereby increasing the susceptibility of the myocardium to infarction and stunning. We suggest that the biological effects of COX-2 may differ depending on the degree of its expression, cellular types where it is expressed (e.g., infiltrating cells vs. cardiac myocytes), and the ability of cells to metabolize COX-2-derived PGH2 into cytoprotective prostanoids.
