Biomarker Studies in Acute Ischemic Stroke

Abstract

Stroke is defined by WHO as the clinical syndrome of rapid onset of focal (or global, as in subarachnoid haemorrhage) cerebral deficits lasting more than 24 hours or leading to death, with no apparent cause other than a vascular one. Of all strokes, 87% are ischemic, 10% are intracerebral hemorrhage, and 3% are subarachnoid hemorrhage strokes. The TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification is based on clinical symptoms as well as results of further investigations. Accordingly, a stroke is classified as either thrombosis or embolism due to atherosclerosis of a large artery, an embolism originating from the heart (cardiogenic stroke), a complete blockage of a small blood vessel (lacunar) or other determined/undetermined cause. Cardioembolic stroke accounts for 14-30% of ischemic strokes and atrial fibrillation (AF) is responsible for about 50% of cardiogenic strokes. Cardiac embolism causes more severe strokes than any other ischemic stroke subtypes resulting in more impairments (modified Rankin scale), more dependency (Barthel Index), and higher mortality. Several blood biomarkers have been emerged in the last decade in association of the evolution, diagnosis and prognosis of ischemic stroke. Some of them are organ specific (e.g. astrocyte damage marker - S100B), others reflect the preceding atherosclerosis such as hsCRP or indicators of endothelial dysfunction or thrombo-inflammation. S100B in the peripheral blood is a sensitive marker of both blood–brain barrier dysfunction and ischemic brain damage and predictor of stroke outcome. Increased high-sensitivity Creactive protein (hsCRP) in the subacute stage is an independent predictor of death. Thrombo-inflammatory molecules (tissue plasminogen activator [tPA], soluble CD40 ligand [sCD40L], P-selectin, interleukin-6, interleukin-8, monocyte chemoattractant protein-1 [MCP- 1]) connect the prothrombotic state, endothelial dysfunction, and systemic/ local inflammation in acute vascular events such as myocardial infarction or ischemic stroke. Besides other factors, MCP-1 plays a crucial role in atherogenesis. On the other hand, shear stress-induced overexpression of MCP-1 contributes significantly to the development of protective collaterals in the heart, but little is known about its role in the cerebral vasculature. Cardiac troponins (cTn) are sensitive and specific biomarkers used in the diagnosis of myocardial infarction (MI). Primarily, cTn is released into the bloodstream when cardiac myocytes are damaged by acute ischemia. Beside MI, there are several clinical conditions, such as stroke accompanied by troponin elevation. However, the exact mechanism of such increased concentration of cTn in stroke patients without apparent myocardial damage is not fully explored. Nitric oxide (NO) plays a role in maintaining vascular integrity. NO is synthetized by the oxidation of L-arginine, which can be inhibited by asymmetric dimethylarginine (ADMA). Symmetric dimethylarginine (SDMA) competes with arginine uptake and antagonizes the effects of L-arginine. The plasma concentration of L-arginine and its dimethylated derivatives ADMA and SDMA were associated with long- term mortality in patients followed up to 7 years after an acute ischemic stroke. In addition, SDMA level in the plasma was strongly associated with adverse clinical outcome during the first 30 days following ischemic stroke. Furthermore, a subacute elevation of both ADMA and SDMA proved to be predictors of poor functional outcome at 90 days. Several studies have demonstrated that a beat-to beat variation in the blood flow, which occurs in patients with AF, adversely affects the endothelial function by modulating the production of vasoactive substances produced by endothelial cells. Myocardial blood flow alterations caused by decreased production of nitric oxide (NO) lead to endothelial dysfunction. Emerging clinical and experimental evidences indicate that ADMA and SDMA are involved in the pathophysiology of endothelial dysfunction, atherosclerosis, oxidative stress, inflammation and apoptosis. All of these pathological processes play pivotal role in the development of AF.