Rebound phenomenon of inflammatory response may be a major mechanism responsible for increased cardiovascular events after abrupt cessation of statin therapy

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Summary

Inflammation has been recognized as having an important role in the development and progression of atherosclerosis. Statins reduce cardiovascular events mainly by cholesterol lowering. A large number of investigations have demonstrated that administration of statin could modify inflammatory response with a concurrent fall in cardiovascular events.

Despite the known benefit of statin therapy, many cardiac patients abruptly discontinue therapy because of financial constraints, forgetfulness, or side effects. More recently, several studies have shown that abrupt cessation of statin therapy during treatment could increase the incidence of cardiac events in patients with atherosclerotic heart disease. However, the mechanisms of the increased incidence of cardiovascular events after abruptly stopping statin therapy are still unknown. A few data suggest that abrupt withdrawal of statin therapy deteriorates endothelial function, result in expression of pro-inflammatory gene involved in the development and progression of atherosclerosis.

We hypothesis that rebound phenomenon of inflammatory response may be a major mechanism responsible for increased cardiovascular events after abrupt cessation of statin therapy. Our very recent data showed that abrupt termination of statin therapy resulted in a rapid increased C-reactive protein (CRP) and interleukin-6 (IL-6) levels in patients with hypercholesterolemia. This finding may be of important interest in the connection between inflammatory response and abrupt withdrawal of statin therapy in patients with coronary artery disease.

Introduction

There is mounting evidence that inflammation plays an important role in the initiation, development as well as progression of atherosclerosis [1], [2], [3], [4], [5], [6], [7], [8], [9]. In addition to lowering lipid profile, statins have pleiotropic effects on improving vascular function in patients with cardiovascular diseases. There is increasing interest in the non-lipid-lowering effects of statins and their effect on outcomes in patients with coronary artery diseases [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25]. It has been suggested that withdrawal of statin therapy during an acute coronary syndrome may attenuate any benefits of pretreatment, therefore providing indirect evidence of the importance of their non-lipid-lowering effects [26], [27], [28], [29], [30], [31], [32], [33], [34].

Changes of these pleiotropic effects and their relationship to lipid profile after withdrawal of statin treatment remained unclear. Several data suggest that withdrawal of chronic statin treatment during acute coronary syndromes may impair vascular function independent of lipid-lowering effects and thus increase cardiac event rate. In this article, we hypotheses that rebound phenomenon of inflammatory response may be a major mechanism responsible for increased cardiovascular events after abrupt cessation of statin therapy.

Section snippets

Inflammation and atherosclerosis

Although atherosclerosis has been considered to be a multi-factorial disease in which genetic, environmental, metabolic factors have been implicated, gaps remain in our knowledge of the etiopathogenesis of atherosclerosis. More recently, there is mounting evidence that inflammation plays an important role in the development and progression of atherosclerosis. The data from animals as well as humans indicated that an inflammatory process was involved in all stages of atherosclerosis that

Effects of statins on inflammatory response

Statin drugs have previously been shown to very significantly reduce cardiovascular events in a number of large clinical trials. As a result, statins are now considered to represent one of the most powerful classes of agents for the treatment of cardiovascular disease [10], [11], [12], [13], [14], [15], [16], [17]. Statins are rapidly becoming frontline therapy for diabetes mellitus, hypertension, and other known cardiovascular disease risk factors.

Originally, reductions in cardiovascular

Withdrawal of statins and cardiovascular events

Statins are postulated to provide cardiovascular protection by a number of different mechanisms. Although low-density lipoprotein (LDL) cholesterol reduction via inhibition of the HMG-CoA reductase enzyme is likely the most important mechanism, it may not account for all benefits associated with statin therapy. A number of pleiotropic effects of statins have been proposed. Statins have been shown to upregulate endothelial NO synthase, resulting in improved vasodilatation. Endothelial

Clinical implications

Increasing evidence has showed that atherosclerosis is closely linked to inflammation. Inflammation stress, due to a variety of factors, may induce atherosclerosis and trigger acute cardiovascular events. Accumulating recent data suggested that the inflammation process is sustained long after the coronary event has resolved, and that ongoing inflammation is associated with an increase in subsequent coronary events. In addition, increasing evidence has shown that the acute coronary event is a

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