Role of C-reactive Protein in Cerebrovascular Disease
Role of C-reactive Protein in Cerebrovascular Disease
C-reactive protein (CRP) is a blood marker of inflammation and a hallmark of the acute-phase response. Its elevation bears negative prognostic implications for many conditions and it has also been shown to be a nonspecific predictor of long-term risk of cerebrovascular disease (CVD) in several populations, while elevations of CRP associated with the major acute-phase response following ischemic or hemorrhagic stroke are associated with death and vascular complications. High-sensitivity assays that accurately measure levels of CRP have been proposed for use in risk assessment for CVD and as a prognostic marker after an acute event, although the pathogenic and clinical significance of these associations is controversial. In this article, we critically review the literature in narrative format and describe major epidemiological studies, novel experiments and possible future developments that may inform the debate. In our discussion, we will distinguish the different pathophysiological roles of high circulating CRP concentrations in individuals with acute stroke from the modestly and persistently increased levels of CRP concentration in generally healthy subjects. However, before any clinical application is possible, a critical appraisal of the strengths and deficiencies of the accumulated evidence is required, both to consider the current state of knowledge and to inform the design of future research.
More than 795,000 individuals suffer a stroke annually in the USA. Stroke is the second most common cause of death in Europe (1.24 million annually) and in the EU (508,000 annually), and the third cause of death in Canada (~14,000 deaths annually) and the USA (4.3 per 100,000 annually). Meanwhile, 1.8% of Asians aged 18 years and older have had a stroke.
Inflammation has been proposed to contribute to cerebrovascular disease (CVD) in several ways, including:
C-reactive protein (CRP), the classical acute-phase protein, is the most extensively studied systemic marker of inflammation. In previous decades, CRP has been the focus of intense investigation to identify its complex role in CVD after the introduction of high-sensitivity (hs)-CRP assays able to detect low levels of blood CRP. hs-CRP has been used as a CVD risk biomarker, as a pathogenetic determinant with a direct causal role in stroke pathogenesis, and as a short- and long-term predictor of stroke outcomes. Although a number of articles related to the hs-CRP test have been published, no review has comprehensively addressed the relevance of hs-CRP test results in a variety of scenarios encountered in stroke medicine – primary prevention, stroke pathogenesis and secondary prevention. The objective of this article is to provide a critical review of the available evidence on associations of CRP with CVD and to highlight emerging approaches that may help to clarify the uncertainties described above.
Abstract and Introduction
Abstract
C-reactive protein (CRP) is a blood marker of inflammation and a hallmark of the acute-phase response. Its elevation bears negative prognostic implications for many conditions and it has also been shown to be a nonspecific predictor of long-term risk of cerebrovascular disease (CVD) in several populations, while elevations of CRP associated with the major acute-phase response following ischemic or hemorrhagic stroke are associated with death and vascular complications. High-sensitivity assays that accurately measure levels of CRP have been proposed for use in risk assessment for CVD and as a prognostic marker after an acute event, although the pathogenic and clinical significance of these associations is controversial. In this article, we critically review the literature in narrative format and describe major epidemiological studies, novel experiments and possible future developments that may inform the debate. In our discussion, we will distinguish the different pathophysiological roles of high circulating CRP concentrations in individuals with acute stroke from the modestly and persistently increased levels of CRP concentration in generally healthy subjects. However, before any clinical application is possible, a critical appraisal of the strengths and deficiencies of the accumulated evidence is required, both to consider the current state of knowledge and to inform the design of future research.
Introduction
More than 795,000 individuals suffer a stroke annually in the USA. Stroke is the second most common cause of death in Europe (1.24 million annually) and in the EU (508,000 annually), and the third cause of death in Canada (~14,000 deaths annually) and the USA (4.3 per 100,000 annually). Meanwhile, 1.8% of Asians aged 18 years and older have had a stroke.
Inflammation has been proposed to contribute to cerebrovascular disease (CVD) in several ways, including:
The lifelong process of atherogenesis;
The acute atherothrombotic event, which causes ischemic necrosis in acute cerebral infarction and the brain damage following ischemic stroke;
Delayed brain injury after intracerebral hemorrhage (ICH);
Vasospasm after subarachnoid hemorrhage.
C-reactive protein (CRP), the classical acute-phase protein, is the most extensively studied systemic marker of inflammation. In previous decades, CRP has been the focus of intense investigation to identify its complex role in CVD after the introduction of high-sensitivity (hs)-CRP assays able to detect low levels of blood CRP. hs-CRP has been used as a CVD risk biomarker, as a pathogenetic determinant with a direct causal role in stroke pathogenesis, and as a short- and long-term predictor of stroke outcomes. Although a number of articles related to the hs-CRP test have been published, no review has comprehensively addressed the relevance of hs-CRP test results in a variety of scenarios encountered in stroke medicine – primary prevention, stroke pathogenesis and secondary prevention. The objective of this article is to provide a critical review of the available evidence on associations of CRP with CVD and to highlight emerging approaches that may help to clarify the uncertainties described above.