Editorial [Hot Topic:Stabilizing the Vulnerable Plaque: The Search for the Magic Bullet (Executive Editors: G. Pasterkamp and M. Daemen)]

Atherosclerotic disease remains the number one killer of the aging population in Western Society and numbers of cardiovascular events are strongly increasing in developing countries. Worldwide, about 20 million deaths per year are caused by this inflammatory disease and the costs for health care and loss of productivity are impressive. Despite the advances in treatment of cardiovascular disease, the increasing incidence of type II diabetes in developed countries deserves careful consideration, since this will surely enhance morbidity and mortality rates due to cardiovascular disease. Improvement of our understanding of the mechanisms that lead to atherosclerotic disease has resulted in innovative modalities that may help diagnose, prevent and treat this life threatening disease. Pathological studies revealed that next to atherosclerotic plaque burden, also the plaque phenotype is a major determinant of acute coronary thrombotic occlusion. Plaque rupture or plaque erosion may lead to activation of coagulation cascades and induce a thrombotic occlusion of the lumen. Cross-sectional studies demonstrated that plaques that are associated with thrombotic occlusion often encompass large lipid cores with a thin fibrous cap and a large number of inflammatory cells that secrete matrix degrading proteases and destabilize the plaque. Stabilizing this so called vulnerable plaque is one of the major challenges in the research domain of cardiovascular diseases. Many pharmaceutical companies run research and development programs to image, detect and stabilize the plaques prone to induce an adverse coronary event. The stakes are high. However, there is an ongoing debate how to define the vulnerable plaque and whether the patient is a vulnerable entity himself and should be treated accordingly. In this issue of Current Pharmaceutical Design you will find research papers that cover the current status and remaining issues in this very active field of the research on the vulnerable atherosclerotic plaque. Atherosclerosis: An Inflammatory Disease: It is now well established that atherosclerosis is an inflammatory disease and that the body's immune system plays a central role in the initiation and progression of atherosclerotic lesion development [1]. The recent insights into how the immune system recognizes endogenous and exogenous ligands and how ligation of innate immune receptors results in a local inflammatory response have opened exciting new therapeutic avenues [2]. Local plaque inflammation is now considered as a major determinant of destabilisation of the advanced atherosclerotic lesion. Cross-sectional studies demonstrated that atherosclerotic plaques that are associated with thrombotic occlusion often encompass large lipid cores with a thin fibrous cap and a large number of inflammatory cells that secrete matrix degrading proteases and destabilize the plaque. Macrophages express proteases like MMP1, MMP9 and cathepsins that degrade the collagen and elastin structures of the arterial wall and thereby induce expansive remodelling and breakdown of the fibrous cap [3-6]. Subsequently, the plaque may rupture and the now uncovered atheromatous core induces a strong coagulatory response. Thrombotic occlusion of the coronary artery may be the fatal consequence of these events. Stabilizing the atheromatous inflammatory vulnerable plaque is one of the major challenges in cardiovascular research. Stabilising the Vulnerable Plaque: the Natural History of the Disease: Although plaque rupture is associated with the presence of a large lipid pool, macrophages and a thin fibrous cap, the predictive value of these histopathological determinants for the occurrence of rupture of the so-called “vulnerable plaque” is unknown. In fact, since prospective studies have not yet been performed, we do not really know the phenotype and natural development of the vulnerable plaque. For successful application of new imaging techniques to visualize the vulnerable plaque that will predict a clinical event, many questions merit careful attention among which are the following: (1) How specific are the established histological features that have been considered representative for “the vulnerable plaque”, i.e. a large lipid core and cap inflammation, for the development of plaque rupture? (2) Are the histopathological determinants of ruptured plaques locally or systemically observed phenomena? In other words, could sampling for the presence of arterial wall inflammation or lipid-core formation be extrapolated to the total coronary atherosclerotic circulation? (3) If a vulnerable plaque ruptures, what is the chance that this plaque rupture eventually leads to a clinical syndrome? More questions like this could be raised but these questions all share the same denominator that can be summarized as follows: “What is the natural history of human atherosclerotic disease?” There is no doubt that longitudinal studies including imaging may help answering this question [7]. Until then, scientific experimental evidence in non human experimental models will point to potential molecular targets that may stabilize the vulnerable plaque and patient.