Pathophysiological Mechanisms of Carotid Plaque Vulnerability: Impact on Ischemic Stroke
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REVIEW
Pathophysiological Mechanisms of Carotid Plaque Vulnerability: Impact on Ischemic Stroke Jaroslav Pelisek • Hans-Henning Eckstein Alma Zernecke
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Received: 5 April 2012 / Accepted: 6 August 2012 / Published online: 4 September 2012 Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2012
Abstract Stroke is among the major causes of mortality and disabilities in the world. About 80 % of all strokes in the anterior circulation are ischemic and up to 20 % of all ischemic strokes are caused by extracranial atherosclerotic carotid artery stenosis. The prevalence of a cervical internal carotid artery stenosis increases with age and can be found in 6.9 % of the elderly population ([65 years). Atherosclerotic changes of the carotid vessel wall can lead to plaque vulnerability and may result in arterio-arterial embolism, which frequently underlie carotid-related cerebrovascular ischemic events. Carotid atherosclerosis is characterised by inflammation, extensive degradation of extracellular matrix components, neovascularization, and as recently recognised is also affected by epigenetic changes. These factors accelerate the progression of atherosclerosis towards vulnerable plaques and increase the risk of ischemic stroke. In this review, the main pathophysiological mechanisms leading to rupture-prone carotid artery plaques and successive ischemic stroke are considered. It is important to recognise the heterogeneity of atherosclerosis and that various pathophysiological processes dissected in this review are not acting individually, but rather in a complementary manner. The identification and careful integration of all relevant factors will be
J. Pelisek (&) H.-H. Eckstein A. Zernecke Clinic for Vascular and Endovascular Surgery, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Ismaninger Str. 22, 81675 Munich, Germany e-mail: [email protected]; [email protected] A. Zernecke Rudolf Virchow-Center/DFG-Research Center for Experimental Medicine, University of Wu¨rzburg, 97080 Wu¨rzburg, Germany
required for the development of future diagnostic and therapeutic strategies. Keywords Carotid atherosclerosis Vulnerable carotid plaque Ischemic stroke
Abbreviations ADAM A disintegrin and metalloprotease domain ADAMTS ADAM-related metalloproteases with a thrombospondin domain AGEs Advanced glycation end products Ang-1, -2 Angiopoietins-1 and -2 CEA Carotid endarterectomy CKD Chronic kidney disease DM Diabetes mellitus ECM Extracellular matrix Eph Ephrins FGF Fibroblast growth factor ICA Internal carotid artery HDL High density lipoproteins HIF-1 Hypoxia-inducible growth factor IL Interleukin INF-c Interferon-gamma LDL Low density lipoproteins oxLDL Oxidised low density lipoproteins LDL(-) Electronegatively charged low density lipoproteins MP Metalloprotease MMP Matrix metalloprotease PDGF Platelet-derived growth factor PGs Proteoglycans RAGE AGE receptor TNF-a Tumour necrosis factor-alpha VSMCs Vascular smooth muscle cells
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VEGF VEGFR
Arch. Immunol. Ther. Exp. (2
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