AUTHOR AND EDITOR INFORMATION

Section 1 of 8  

• Authors and Editors
• Introduction
• Atherogenesis: An Inflammatory Process
• Risk Factors And Mechanisms Of Injury
• Inflammatory Biomarkers As Predictors Of Stroke Risk
• Genetics And Stroke
• Multimedia
• References

INTRODUCTION

Section 2 of 8  

• Authors and Editors
• Introduction
• Atherogenesis: An Inflammatory Process
• Risk Factors And Mechanisms Of Injury
• Inflammatory Biomarkers As Predictors Of Stroke Risk
• Genetics And Stroke
• Multimedia
• References

Stroke is the third most common cause of death in the United States and the leading cause of serious, long-term disability. Attempts to modify traditional risk factors have not been entirely effective in reducing national stroke rates. After several decades of decline, the incidence of stroke is again on the rise. Despite advances in acute and prophylactic therapies, rates of stroke and stroke mortality continue to increase.

Evidence continues to accumulate to suggest important roles for inflammation and genetic factors in the process of atherosclerosis and specifically in stroke. According to the current paradigm, atherosclerosis is not a bland cholesterol storage disease, as previously thought, but a dynamic, chronic, inflammatory condition due to a response to endothelial injury (Libby and Theroux, 2005). Traditional risk factors, such as oxidized low-density lipoprotein (LDL) and smoking, contribute to this injury. More recently, it has been suggested that infections may also contribute to endothelial injury and atherosclerosis. Host genetic factors, moreover, may modify the response to these environmental challenges. Inherited risk for stroke is likely multigenic, although specific single-gene disorders with stroke as a component of the phenotype demonstrate the potency of genetics in determining stroke risk.

For excellent patient education resources, visit eMedicine's Stroke Center and Dementia Center. Also, see eMedicine's patient education articles Stroke and Stroke-Related Dementia.

ATHEROGENESIS: AN INFLAMMATORY PROCESS

Section 3 of 8  

• Authors and Editors
• Introduction
• Atherogenesis: An Inflammatory Process
• Risk Factors And Mechanisms Of Injury
• Inflammatory Biomarkers As Predictors Of Stroke Risk
• Genetics And Stroke
• Multimedia
• References

Inflammation, endothelial dysfunction, and atherogenesis

Atherogenesis is itself an inflammatory process (Libby and Theroux, 2005). When endothelium is physically damaged or becomes dysfunctional, a cascade of events is precipitated, initiating a cycle of injury, immunologic induction, and amplification. Causes of endothelial dysfunction are discussed in more detail in the next section, but they include sheer stress related to hypertension, oxidized low-density lipoprotein (LDL), homocysteine, and smoking. Dysfunctional endothelium leads to increased permeability to lipoproteins and up-regulation of leukocyte and endothelial adhesion molecules. In response to the presence of certain activating substances, including oxidized LDL, monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-8, and platelet-derived growth factor (PDGF), leukocytes migrate into the wall of the artery (see Image 1).

Induced by oxidized LDL, MCP-1 promotes diapedesis of monocytes across the endothelium. Granulocyte-macrophage colony-stimulating factor transforms monocytes into macrophages, which elaborate tumor necrosis factor (TNF) alpha, IL-1, proteolytic enzymes including matrix metalloproteinases, and growth factors, including PDGF and insulin-like growth factor (ILGF). These macrophages, in addition to smooth muscle cells, activate T cells by presenting antigens, including oxidized LDL. Other trophic factors such as IL-2, TNF alpha, and granulocyte-macrophage stimulating factor cause activated T cells to produce interferon (IFN) gamma, TNF alpha, and TNF beta, leading to stimulation of macrophages and further up-regulation of leukocyte adhesion molecules. This feedback amplifies the cycle of inflammation (see Image 2).

Regulation of adhesion molecules also is influenced by mechanical forces. Low shear stress up-regulates expression of vascular cell adhesion molecule 1 (VCAM-1), while increased shear stress can lead to increased gene expression of intercellular adhesion molecule 1 (ICAM-1), VCAM-1, and PDGF B chain. ICAM-1 and VCAM-1 are members of an immunoglobulin superfamily whose members have both a transmembrane region and a cytoplasmic tail. They are expressed on endothelial cells and bind to the integrins CD 11a/CD 18 and VLA-4, respectively. CD 11a/CD 18 are found on neutrophils, monocytes, macrophages, and lymphocytes, while VLA-4 is found on monocytes and lymphocytes.

Platelets attach to dysfunctional endothelium, macrophages, and exposed collagen. The activated platelets release granules containing cytokines and growth factors, causing conversion of arachidonic acid to both thromboxane A2, leading to further platelet aggregation, and leukotrienes, thereby amplifying the inflammatory process. Platelets also can be activated by platelet-activating factor (PAF), which is produced by monocytes, endothelial cells, and neutrophils. PAF causes platelet aggregation and degranulation, and also can promote leukocyte activation.

To summarize, the process of plaque formation initiates with one or more injurious factors. The resultant inflammatory cascade leads to incorporation of oxidized LDL into macrophages, forming foam cells, which, together with T cells, make fatty streaks. Next, PDGF, transforming growth factor (TGF) beta, and fibroblast growth factor 2 act to cause smooth muscle cell migration to the site. Next, the increased activity of specific chemokines and cytokines (IL-1, TNF alpha, PDGF, TGF beta, and osteopontin) leads to formation of a fibrous cap on top of the necrotic core of lipid, leukocytes, and debris. The continued presence of macrophages producing metalloproteinases and other proteolytic enzymes causes thinning of the fibrous cap, priming it for ulceration or rupture.

Importantly, the recognition of the importance of the inflammatory milieu within atherosclerotic plaque in precipitating plaque erosion and rupture leading to events has redirected attention away from the focus solely on the degree of stenosis in the arterial tree. Most acute myocardial infarctions, for example, occur in patients with substenotic lesions. According to the current model of atherosclerosis, initial plaque formation is abluminal, or external to the lumen, and is angiographically silent. Newer techniques such as intravascular ultrasound (Raggi, 2005) or contrast-enhanced carotid MRI (Weiss, 2001) can detect abnormal and active plaque even in the absence of stenosis.

Although established as the cause of coronary artery occlusion, and as a possible final mechanism of extracranial carotid artery occlusion, this ulceration/rupture is not typical of intracranial arterial occlusion (Lammie, 1999). Although atherosclerotic lesions in different vascular beds share many characteristics, mechanisms related to symptomatic conversion are likely site-specific. Most stroke risk associated with carotid stenosis, moreover, appears to be related to the degree of stenosis rather than other easily imaged characteristics.

Recent evidence implies that the risk of clinical events is related not only to local factors within the atherosclerotic plaque, such as the state of the necrotic core or the fibrous cap, but also to blood-borne, or systemic factors (Libby and Theroux, 2005). Thus, circulating levels of cytokines, prothrombotic factors or acute-phase reactants may play a role in precipitating acute stroke in the setting of diseased but not stenotic vessels. For example, evidence exists that markers such as CD40 ligand and CRP predict progression of atherosclerosis and risk of stroke (Novo, 2005; Corrado, 2006).

RISK FACTORS AND MECHANISMS OF INJURY

Section 4 of 8  

• Authors and Editors
• Introduction
• Atherogenesis: An Inflammatory Process
• Risk Factors And Mechanisms Of Injury
• Inflammatory Biomarkers As Predictors Of Stroke Risk
• Genetics And Stroke
• Multimedia
• References

Factors leading to endothelial dysfunction, triggering the inflammatory cascade, include the following:

Hypertension

Hypertension confers a relative risk for stroke of 3- to 5-fold (Benson and Sacco, 2000). It continues to represent a significant public health risk. Recently, even high-normal blood pressures, 130-139/85-89 mm Hg, have been shown to be associated with elevated cardiovascular risk (Vasan et al, 2001). Hypertension can result in mechanical injury to endothelium through increased sheer stress, thereby increasing the number of endothelial adhesion molecules, which attract monocytes and lymphocytes.

Several other potential mechanisms exist by which hypertension may promote atherosclerosis. Angiotensin II often is elevated in patients with hypertension. Overactivity of the renin-angiotensin system has been implicated in the progression of atherosclerosis. Angiotensin II, in addition to being a potent vasoconstrictor, can lead to smooth muscle hypertrophy, extracellular matrix production, and induction of cytokines. Expression of angiotensin-converting enzyme (ACE) has been demonstrated in macrophages, lymphocytes, and microvessels neighboring carotid plaques (Fukuhara et al, 2000).

This suggests a role for ACE inhibitors as part of a prophylactic regimen for stroke. One study showed that patients with vascular disease who were treated with the ACE inhibitor ramipril had a lower stroke rate than patients treated with placebo (Heart Outcomes Prevention Evaluation Study investigators). Additionally, a substudy evaluating plaque progression using ultrasound suggested that ramipril also may retard atherosclerotic progression (Lonn et al, 2001).

Independent of the effects of angiotensin II, hypertension has been shown in animals to increase formation of hydrogen peroxide and free radicals, which in turn can increase leukocyte adhesion (Ross, 1999; Swei, 1997). Thus, additional pathophysiologic studies are needed.

Low-density lipoprotein

Oxidized LDL is a relatively active form of LDL, which attracts monocytes, increases adherence of monocytes, induces conversion of monocytes to macrophages, and decreases the motility of macrophages. While native LDL cannot be incorporated into a macrophage or smooth muscle cell, oxidized LDL can be taken up by scavenger receptor A (SRA), allowing for formation of foam cells. High plasma levels of LDL increase the entry rate of LDL into the intima. Serum high-density lipoprotein (HDL) exerts a protective effect by deterring LDL peroxidation.

Macrophages, smooth muscle cells, and endothelial cells can oxidize LDL. This leads to a spectrum of variably oxidized LDLs with a heterogeneity of deleterious effects. In culture, oxidized LDL is toxic to endothelial cells. Studies have shown the presence of oxidized LDL at sites of inflammation, raising a potential mechanism by which areas of inflammation may promote atherogenesis at remote sites. Several studies support a role for beta-hydroxy beta-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (ie, statins) in slowing the progression of intima media thickness, a frequently used surrogate for carotid atherosclerosis (Furberg, 1994; Crouse, 1995). Lowering of LDL has also been associated with reduction in plaque progression in studies using intravascular ultrasound (Nissen, 2006). The mechanism of this effect—whether lipid lowering per se, anti-inflammatory effects, or other as yet unidentified action—and its impact on large-vessel atherosclerotic stroke risk remain to be characterized.

Diabetes mellitus

Diabetes mellitus (DM) increases stroke risk by 1.5- to 3-fold. Not only does DM increase the risk of stroke, it also increases the rate of mortality from stroke. DM accelerates atherosclerosis and induces both microangiopathic changes and large-vessel atherosclerosis. Long-standing DM is associated with endothelial dysfunction, including reduction in endothelium-mediated vasodilator production. Additionally, acute hyperglycemia has been demonstrated to impair cerebrovascular reactivity mediated, at least in part, by endothelial production of nitric oxide and prostaglandins (Cipolla et al, 1997).

Smoking

Smoking represents a significant and modifiable risk factor. It almost doubles the risk of stroke. This is thought to occur by multiple mechanisms. Smoking leads to decreased arterial wall compliance, increased platelet aggregation, increased fibrinogen levels, and decreased HDL cholesterol levels. A small study recently showed that smokers had lower production of endogenous tissue plasminogen activator (tPA) antigen induced by substance P infusion, suggesting an impairment of endogenous fibrinolysis in smokers (Newby et al, 1999). Endogenous tPA can be released by endothelial cells to lyse subclinical clots, which may exist on denuded areas on the surface of atherosclerotic plaques.

Homocysteine

Those with genetic enzyme disorders, such as deficiencies in cystathionine beta-synthase, have elevated homocysteine levels and accelerated atherosclerosis associated with the disease homocysteinuria. This prompted researchers to investigate whether patients who had hyperhomocysteinemia without homocysteinuria had a higher-than-normal risk of atherosclerosis.

Elevated homocysteine level has been found to be an independent risk factor for vascular disease even in those without an enzymatic defect. Homocysteine has been shown to be prothrombotic and toxic to endothelial cells, to decrease nitrous oxide, and to increase collagen formation.

Homocysteine also has been postulated to cause a release of reactive oxygen species. Elevations of both homocysteine and lipid peroxide have been found in patients with acute stroke, while low levels of ascorbic acid have been detected. This suggests depletion of this potent antioxidant in the setting of increased oxidative stress (El Kossi et al, 2000). Increased levels of plasma homocysteine are associated with carotid plaques (Spence et al, 1999).

An association may exist between elevated homocysteine levels and large- and small-vessel strokes, but not with cardioembolic infarcts, lending support to the contribution of homocysteine in atherogenesis rather than as another mechanism of increased stroke risk (Eikelboom et al, 2000).

Elevated homocysteine levels can be attenuated by vitamins B-12, B-6, and folate. After coronary revascularization, treatment with these 3 vitamins decreases the rate of restenosis (Schnyder, 2001).

One study supported the role of vitamin therapy in carotid plaque regression (Hackam, 2000). In the multicenter Vitamin Intervention in Stroke Prevention (VISP) trial, there was no evidence of clinical benefit with a high-dose homocysteine-lowering vitamin regimen (Toole, 2004). Among 3680 patients with stroke randomized to receive either once-daily doses of high-dose vitamins (n = 1827) containing 25 mg of pyridoxine, 0.4 mg of cobalamin, and 2.5 mg of folic acid; or low-dose vitamins (n = 1853) containing 200 micrograms of pyridoxine, 6 micrograms of cobalamin, and 20 micrograms of folic acid, the 2-year ischemic stroke rates were about 9% in both groups. Risks of stroke, coronary heart disease, or death were about 18% in both groups, without any significant differences. Importantly, a 2 micromol/L reduction in homocysteine level occurred in the high-dose group. Baseline levels of homocysteine were associated with clinical outcomes.

The results of two recent clinical trials in high-risk populations confirm the absence of benefit with vitamin B-6, B-12, and folate therapy in reducing risk of vascular events overall (Bonaa, 2006; Lonn, 2006). Interestingly, however, there were trends toward a benefit in reducing the risk of stroke specifically in both studies. Nonetheless, because stroke was a secondary outcome in these studies, these findings need to be interpreted cautiously.

Infection

In light of the increasing acceptance of atherosclerosis as a chronic inflammatory disease, it has been hypothesized that acute and chronic infections may play a role in vascular disease. Increased leukocyte counts are associated in observational studies with carotid thickness (Elkind, 2001) and aortic arch plaque thickness (Elkind, 2002) in some populations as well as with clinical stroke (Elkind, 2005). In a clinical trial in which leukocyte levels were followed repeatedly over time, evidence suggested that those patients who had recurrent clinical events were more likely to have had recent elevations in their leukocyte counts (Grau, Stroke 2004:1147-52). These findings indirectly implicate infection in the pathogenesis of plaque formation and stroke risk.

Several studies provide evidence that patients with stroke are more likely than control subjects to have had an upper respiratory infection within the previous 2 weeks (Bova, 1996; Grau, 1999). This suggests a plausible role for infection in the conversion of an asymptomatic to a symptomatic plaque.

Chlamydia

C pneumoniae is the infectious pathogen that has been most extensively studied in relation to atherosclerosis and stroke.

The presence of C pneumoniae in the intima, media, macrophages, and smooth muscle of some carotid endarterectomy specimens is evident. Detection of C pneumoniae in serum, however, correlates poorly with its detection in carotid plaques (LaBiche, 2001).

Evidence also exists that patients with coronary disease (Kalayoglu, 2002) and stroke (Elkind, 2006) are significantly more likely than control subjects to have elevated levels of immunoglobulin G (IgG) or immunoglobulin A (IgA) against C pneumoniae. However, prospective studies have not always confirmed these findings (Kalayoglu, 2002).

In an animal study, inoculation with C pneumoniae increases atherosclerosis, and azithromycin attenuates this effect (Muhlestein, 2000).

While evidence of C pneumoniae in atherosclerotic plaque specimens exists, it is unclear that the organism is causally related to atherosclerosis. Large-scale clinical trials have not demonstrated a benefit of antichlamydial therapy in reducing risk of vascular events in patients with established coronary artery disease (Cannon, 2005; Grayston, 2005). It is possible that other antibiotic regimens, or treatment of patients at an earlier stage of disease, would still provide benefit.

Periodontitis

Periodontal disease has also been linked to atherosclerosis and stroke. Some periodontal pathogens have been demonstrated to invade tissue cultures of both human coronary artery endothelial cells and coronary artery smooth muscle cells (Dorn, 1999). In cross-sectional studies, periodontal infection appears to be associated with carotid atherosclerosis (Engebretson, 2005). Case-control and prospective studies have found an association between periodontitis and stroke risk (Grau, 1995; Grau, 1997). Several genes thought to play a role in periodontal disease may also be associated with carotid disease.

Herpes

Viruses have been hypothesized to play a pathogenic role in atherosclerosis as well. Although results have been mixed, some prospective studies found associations between serological evidence of infection with cytomegalovirus (CMV) and herpes simplex virus (HSV) and subsequent stroke (Danesh, 1999; Nicholson and Hajjar, 1998; Ridker, 1998). In chickens, the herpes virus that causes Marek disease has been shown to induce atherosclerosis even in normocholesterolemic animals, while vaccines against the virus have been shown to block this response (Fabricant and Fabricant, 1999). While the animal data are provocative, human studies have failed to consistently support an association between herpes and atherosclerosis.

INFLAMMATORY BIOMARKERS AS PREDICTORS OF STROKE RISK

Section 5 of 8  

• Authors and Editors
• Introduction
• Atherogenesis: An Inflammatory Process
• Risk Factors And Mechanisms Of Injury
• Inflammatory Biomarkers As Predictors Of Stroke Risk
• Genetics And Stroke
• Multimedia
• References

Acute-phase proteins, high-sensitivity C-reactive protein (hsCRP) in particular, have been the most extensively studied markers of inflammation (Pearson, 2003). CRP is produced not only by the liver but also in vascular smooth muscle cells and adipocytes. Because it is a stable protein, its measurement is not greatly affected by freezing and thawing cycles in large, epidemiological studies. It has little diurnal variation, and it can be measured in the nonfasting state. HsCRP therefore qualifies as a good, reproducible assay, and currently widely available, standardized, FDA-approved assays are available. However, the assay is nonspecific; acute increases in hsCRP may therefore occur in acute infection or other illness.

Whether CRP is directly causative of atherosclerosis or simply an epiphenomenon, ie, a marker of the inflammation that is present in atherosclerosis but not directly responsible for it, remains uncertain. Increasing evidence suggests that CRP may play a direct or causative role, or serve as another risk factor, for atherosclerosis. In vitro, CRP upregulates and stimulates the release of several cytokines and growth factors and also downregulates nitric oxide, a potent vasodilator (Verma, 2004). Conformational rearrangements in CRP may be required for its proinflammatory actions, again implicating a direct role (Khreiss, 2004).

HsCRP predicts first cardiovascular events in several populations. In women, hsCRP, IL-6, soluble ICAM-1, and serum amyloid A (SAA) all predicted incident cardiovascular events, including stroke (Ridker, Circulation 1998:731-3; Ridker, 2000). HsCRP was the only inflammatory marker that independently predicted risk, and the inclusion of hsCRP improved the predictive ability of the models over those containing lipid values and other risk factors alone (p <0.001) in several studies (Ridker, 2002; Ridker, Circulation 1998:1557-65). These initial studies focused on predominantly healthy middle-aged individuals without a significant burden of risk factors. In the Cardiovascular Health Study, however, which focuses on risk factors in elderly persons, hsCRP predicted a first ischemic stroke modestly (adjusted hazard ratio for the highest quartile 1.60, 95% confidence interval [CI], 1.23 to 2.08) (Cao, 2003).

The association of hsCRP with stroke risk may depend on the population studied. HsCRP levels measured prior to onset of clinical disease were an independent predictor of first ischemic stroke (relative risk 1.9 for those in the highest quartile [CRP> 2.1] vs those in the lowest quartile) in the Physicians' Health Study, but the effect on stroke risk was less than on cardiac risk and appeared to exhibit a threshold effect above the first quartile (Ridker, 1997). Among those older than 85 years, hsCRP was associated with risk of death from all causes as well as fatal stroke (Gussekloo, 2000). In Framingham, men in the highest quartile of hsCRP had twice the risk of stroke of those in the lowest and women had 3 times the risk. For men, the increased risk was not statistically significant after adjusting for confounders (Rost, 2001).

Among healthy Japanese American men, hsCRP was associated with increased risk of stroke after 10-15 years of follow-up only among those younger than 55 years, without

hypertension, or without diabetes (Curb, 2003). Thus, hsCRP may be of greatest value among those with low baseline risk, and of least value in older populations and those with more risk factors.

Other inflammatory markers have recently been described as predictors of risk of stroke. Lipoprotein-associated phospholipase A2, or Lp-PLA2, is a macrophage-derived enzyme involved in the metabolism of LDL in arterial walls that is responsible for the release of inflammatory mediators, including lysophosphatidylcholine and free fatty acids. It is associated with ischemic stroke risk in large epidemiologic studies (Oei, 2005; Ballantyne, 2005). In other, smaller studies, circulating levels of specific subsets of T lymphocytes, also present in rheumatoid arthritis, may be associated with recurrence after first stroke (Nadareishvili, 2004).

The role of hsCRP and other inflammatory markers as prognostic markers after a first stroke has been investigated in few studies (Di Napoli, 2005). In a secondary analysis of nested case-control data from a multicenter secondary stroke prevention trial, those in the highest tertile of hsCRP had a 40% increased risk of recurrent ischemic stroke (Woodward, 2005). The investigators did not fully adjust for diabetes mellitus.

There is also evidence, perhaps not surprisingly, that hsCRP predicts mortality after stroke. HsCRP greater than 10.1 mg/L measured within 72 hours of stroke predicted increased mortality over 4 years in one study (Muir, 1999). In another, hsCRP level greater than 15 mg/L at discharge was significantly associated with occurrence of a new vascular event or death at 1 year (Di Napoli, 2001). HsCRP measured at least 3 months after ischemic stroke or TIA was associated with an increased risk of subsequent stroke or MI in another study (Arenillas, 2003). These studies require confirmation in large, multicenter studies with prospectively defined thresholds for marker levels. At present, according to a consensus statement of the CRP Pooling Project, testing for hsCRP after stroke to predict prognosis or to recommend treatment cannot be routinely recommended (Di Napoli, 2005).

If inflammatory biomarkers are found to have prognostic significance in stroke patients, then it is plausible that therapeutic implications would be present. Several trials demonstrate that hydroxymethylglutaryl-coenzyme A reductase inhibitors, or statins, reduce levels of hsCRP and Lp-PLA2 independently of effects on cholesterol levels (Albert MA, 2001; Ridker, 2001). Some recent evidence suggests reduction in hsCRP and Lp-PLA2 may be associated with a reduction in risk of vascular disease (Ridker, 2005; O'Donoghue, 2006).

In a prespecified secondary analysis of a large comparative statin trial among cardiac patients, lower event rates were observed in patients in whom hsCRP levels were lowered to less than 2 mg/L by 30 days after treatment initiation, independently of the LDL lowering effect. The lowest event rates were seen in those with LDL less than 70 mg/dL and hsCRP less than 1 mg/L, suggesting an additive benefit of lowering lipid and inflammatory measures. Other agents, including angiotensin-converting enzyme inhibitors, peroxisome-proliferator activator receptor agonists, and certain antiplatelet agents also appear to lower inflammatory marker levels. The effects of lowering these levels in stroke patients remain to be studied.

GENETICS AND STROKE

Section 6 of 8  

• Authors and Editors
• Introduction
• Atherogenesis: An Inflammatory Process
• Risk Factors And Mechanisms Of Injury
• Inflammatory Biomarkers As Predictors Of Stroke Risk
• Genetics And Stroke
• Multimedia
• References

While the genetic contribution to traditional cardiovascular risk factors, such as hypertension, diabetes mellitus (DM), and high cholesterol, has been thoroughly investigated, the role of genetics in causing stroke itself remains controversial. Several novel genetic determinants of stroke have been discovered in the past few years, though the findings have not always been consistent across populations. The genetics of nontraditional risk factors, including inflammation, have also been increasingly studied in recent years. The effect of exposure to toxins, such as cigarette smoke and infectious agents, is also modified by an individual's genetic make-up.

Single-gene disorders

Single-gene stroke disorders, while rare, do occur. Homocysteinuria is a genetically heterogeneous disease, which results in accumulation of homocysteine and premature atherosclerosis. The most common defect is in the enzyme cystathione beta synthase, coded for by chromosome subband 21q22.3, which normally converts homocysteine to cystathione.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) causes granular degeneration of the media of small vessels and a prominent and progressive leukoencephalopathy. The phenotype is characterized by migrainelike headaches, depression and psychosis, and recurrent strokes, often leading to pseudobulbar palsy and subcortical dementia (Tournier-Lasserve and Iba-Zizen, 1991). Characteristic imaging findings include white matter lesions in the external capsule and temporal poles (Yousry et al, 1999). Genetic linkage analyses have identified several associated mutations of the Notch 3 gene, which is located on chromosome band 19q12 (Tournier-Lasserve, 1991). Notch3 is widely expressed in the body and plays an important role in development, but the role of Notch3 in normal smooth muscle and why the disease clinically affects only the nervous system, is unknown. Skin biopsy revealing granular osmiophilic material (GOM) can be helpful in the diagnosis, sometimes

detecting the disease in patients who have normal findings on imaging studies and negative genetic tests for the most common mutations (Ebke, 1997). Notch3 mutations do not account for most white matter disease (Dong, 2003).

Mutations in cystatin C have been implicated in familial amyloid angiopathy (Levy, 2006). A recent study has also implicated a mutation in the gene (COL4A1) encoding a basement membrane protein, type 4 collagen alpha-1, in rare families with intracranial hemorrhage, leukoencephalopathy, and retinal arteriolar abnormalities (Gould, 2006). Abnormalities in other basement membrane proteins may be reasonable candidates for other genetic stroke disorders.

The syndrome of mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS) is a mitochondrial disorder characterized by strokelike episodes, typically in the occipitoparietal region; migraine headaches; nausea; and vomiting. Multiple organ systems can be affected, leading to short stature, developmental delay, diabetes mellitus, and other problems. The significant heterogeneity in the phenotype of family members is thought to arise from heteroplasmy (de Vries, 1994), the variable expression of mutated mitochondrial DNA within different tissues. The most commonly reported genetic defect is an A3243G substitution (Enter, 1991).

These diseases are representative of single-gene disorders that manifest largely with stroke symptoms. Additionally, many single-gene disorders, including sickle cell disease and Fabry disease, include stroke as part of their phenotype.

Common ischemic stroke

There is evidence that garden variety stroke is also associated with familial, and possibly genetic, factors. Twin studies support this theory, demonstrating a 17.7% concordance rate for monozygotic twins and only 3.6% for dizygotic twins (Brass, 1992). Genetic influence appears to be more substantial in younger patients (Brass, 1998; Jood, 2005). A relationship appears to exist between parental stroke and silent cerebral infarcts in their offspring (Morrison, 2000). The MRI finding of T2 hyperintensities consistent with small-vessel ischemic disease in the elderly has concordance rates of 0.61 for monozygotic twins and 0.38 for dizygotic twins (Carmelli, 1998), possibly suggesting a genetic susceptibility to a particular stroke mechanism.

Familial influence is more easily demonstrated in coronary artery disease than in stroke. Stroke is an umbrella term for several mechanistically disparate diseases (eg, large vessel atherosclerosis, small vessel or lacunar disease, cardioembolism). In contrast, coronary artery disease is most often a disease of native vessel atherosclerosis. Epidemiological studies are thus limited by a heterogeneous phenotype among ischemic stroke subtypes, not to mention the distinctions between ischemic and hemorrhagic stroke.

Mutations in several genes have recently been associated with common stroke types. For example, linkage analysis in the Icelandic population established the phosphodiesterase 4D (PDE4D) gene as a risk factor for stroke in that population (Gretarsdottir, 2002). Some North American studies have found that polymorphisms in the PDE4D gene are also associated with increased stroke risk (Meschia, 2005).

Mutations in genes related to common stroke risk factors, including lipids and hypertension, have been associated with stroke risk. Hepatic lipase has been associated with increased intima-media thickness (Rundek, 2002) and also with risk of stroke in some populations (Shimo-Nakanishi, 2001). An intron 16 insertion/deletion polymorphism in the ACE gene has been associated with increased stroke risk in some studies; however, results are conflicting (Sharma, 1998). Apparently the ACE gene polymorphism may have a greater influence over lacunes than large-vessel infarcts (Markus, 1995); however, a prospective study failed to show an association between stroke occurrence and ACE gene polymorphism (Zee, 1999).

Mutations in genes involved in the regulation of inflammation have been increasingly inculpated in genetic studies of stroke risk. Interleukin 6 polymorphisms are associated with carotid intima-media wall thickness (IMT) (Rundek, 2002) and carotid atheroma (Chapman, 2003).

Interleukin 1 receptor antagonist (IL-1ra) is an anti-inflammatory cytokine that has been implicated in atherosclerosis in several animal studies (Devlin, 2002). Polymorphisms in noncoding regions of the gene have been associated with carotid atherosclerosis (Worrall, 2003). Mutations in this gene have also been associated with severe periodontitis (Kornman, 1999), providing potential insight into the association of this infection with atherosclerosis. Early studies of recombinant IL-1ra in acute stroke suggest that it is safe and may be an effective neuroprotectant (Emsley, 2005).

Cyclooxygenase 2 induces production of prostaglandins, which activate matrix metalloproteinases that appear to be important in the destabilization of plaques. Recent evidence suggests that polymorphisms in the gene for COX2 are associated with reduced levels of CRP and risk of both MI and stroke (Cipollone, 2004). Expression of COX-2 and MMPs was significantly lower in atherosclerotic plaques from participants carrying the mutant allele.

Fatty acids are a source of inflammatory mediators, including leukotrienes. The enzyme 5-lipoxygenase (5-LO) participates in the synthesis of leukotrienes and is expressed in vascular tissue. Certain high-risk polymorphisms in the 5-LO gene are associated with increased carotid IMT as well as with increased levels of inflammatory markers (Dwyer, 2004). Importantly, the gene may interact with diet, as polyunsaturated n-6 fatty acids are associated with increased IMT, while marine n-3 fatty acids typically associated with reduced vascular risk and reduced leukotriene levels were associated with reduced IMT.

A related protein, arachidonate 5-lipoxygenase activating protein (FLAP), is also associated with risk of stroke in the Icelandic population (Helgadottir, 2004).

Infection and gene interaction

Genetics play a role in susceptibility to infections. Host defenses are modified by genetics, with certain human leukocyte antigen (HLA) classes being more associated with autoimmune responses. A ubiquitous infectious agent thus may cause an inflammatory response in some individuals but not others. This could explain some of the discrepancies in the literature on the association of infectious agents with atherosclerosis. Polymorphisms of the mannose-binding lectin (MBL) gene, which codes for a protein designed to help facilitate phagocytosis, have been shown to increase the risk of infection in humans. These polymorphisms were also found to correlate with the presence and size of carotid atherosclerotic plaques (Hegele, 2000). Similarly, mutations in the IL-1ra gene discussed above modify the risk of coronary artery disease associated with Chlamydia pneumoniae infection (Momiyama, 2001).

Similarly, the toll-like receptor-4 (TLR4) is expressed on macrophages, endothelial cells, and vascular smooth cells. It binds to bacterial lipopolysaccharide and plays an important role in the innate immune response, and it also binds to other ligands including modified LDL and fibrinogen. Ligand binding to this receptor initiates an inflammatory cascade including the release of cytokines, chemokines, and adhesion molecules. The TLR4 polymorphism Asp299Gly is associated with a reduction in inflammatory mediators, atherosclerosis assessed by noninvasive studies, and risk of clinical events (Kiechl, 2002).

Taken together, these findings provide evidence that inflammation-related genes play an important role in atherosclerosis. Further work is needed to confirm many of these findings in other populations. The proinflammatory genotype, resulting in a high cytokine response, may have been an evolutionary advantage. In the past, it likely promoted wound healing and eradication of infections during times of nutritional deficiency. In today's society, with longer life spans, these previously advantageous traits may contribute to atherosclerosis and insulin resistance. In the future, therapies directed at downregulating or inhibiting inflammation may reduce atherosclerosis and its complications, including stroke.

MULTIMEDIA

Section 7 of 8  

• Authors and Editors
• Introduction
• Atherogenesis: An Inflammatory Process
• Risk Factors And Mechanisms Of Injury
• Inflammatory Biomarkers As Predictors Of Stroke Risk
• Genetics And Stroke
• Multimedia
• References

Media file 1:  Genetic and inflammatory mechanisms in stroke. Gray background, subendothelium; white background, intraluminal smooth muscle cells (SMC).
	View Full Size Image
Media type:  Photo

Media file 2:  Genetic and inflammatory mechanisms in stroke. G-M, granulocyte-monocyte; IFN, interferon; IL, interleukin; ILGF, insulin-like growth factor; LDL, low-density lipoprotein; MMP, matrix metalloproteinases; PDGF, platelet-derived growth factor; TNF, tumor necrosis factor.
	View Full Size Image
Media type:  Image

Media file 3:  Genetic and inflammatory mechanisms in stroke. The inflammatory cascade.
	View Full Size Image
Media type:  Image

REFERENCES

Section 8 of 8

• Authors and Editors
• Introduction
• Atherogenesis: An Inflammatory Process
• Risk Factors And Mechanisms Of Injury
• Inflammatory Biomarkers As Predictors Of Stroke Risk
• Genetics And Stroke
• Multimedia
• References

• Albert MA, Danielson E, Rifai N. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA. Jul 4 2001;286(1):64-70. [Medline].
• American Heart Association. 2001 Heart and Stroke Statistical Update. Dallas, Tex:. American Heart Association;2000.
• Arenillas JF, Alvarez-Sabin J, Molina CA. C-reactive protein predicts further ischemic events in first-ever transient ischemic attack or stroke patients with intracranial large-artery occlusive disease. Stroke. Oct 2003;34(10):2463-8. [Medline].
• Ballantyne CM, Hoogeveen RC, Bang H. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Arch Intern Med. Nov 28 2005;165(21):2479-84. [Medline].
• Benson RT, Sacco RL. Stroke prevention: hypertension, diabetes, tobacco, and lipids. Neurol Clin. May 2000;18(2):309-19. [Medline].
• Bitsch A, Klene W, Murtada L, et al. A longitudinal prospective study of soluble adhesion molecules in acute stroke. Stroke. Oct 1998;29(10):2129-35. [Medline].
• Boers GH, Smals AG, Trijbels FJ. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med. Sep 19 1985;313(12):709-15. [Medline].
• Bonaa KH, Njolstad I, Ueland PM. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. Apr 13 2006;354(15):1578-88. [Medline].
• Bova IY, Bornstein NM, Korczyn AD. Acute infection as a risk factor for ischemic stroke. Stroke. Dec 1996;27(12):2204-6. [Medline].
• Brass LM, Isaacsohn JL, Merikangas KR. A study of twins and stroke. Stroke. Feb 1992;23(2):221-3. [Medline].
• Brass LM, Page WF, Lichtman JH. Stroke in twins III: a follow-up study. Stroke. 1998;29 (Suppl):256.
• Cannon CP, Braunwald E, McCabe CH. Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med. Apr 21 2005;352(16):1646-54. [Medline].
• Cao JJ, Thach C, Manolio TA. C-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study. Circulation. Jul 15 2003;108(2):166-70. [Medline].
• Carmelli D, DeCarli C, Swan GE, et al. Evidence for genetic variance in white matter hyperintensity volume in normal elderly male twins. Stroke. Jun 1998;29(6):1177-81. [Medline].
• Chapman CM, Beilby JP, Humphries SE. Association of an allelic variant of interleukin-6 with subclinical carotid atherosclerosis in an Australian community population. Eur Heart J. Aug 2003;24(16):1494-9. [Medline].
• Cipolla MJ, Porter JM, Osol G. High glucose concentrations dilate cerebral arteries and diminish myogenic tone through an endothelial mechanism. Stroke. Feb 1997;28(2):405-10; discussion 410-1. [Medline].
• Cipollone F, Toniato E, Martinotti S. A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke. JAMA. May 12 2004;291(18):2221-8. [Medline].
• Cook PJ, Honeybourne D, Lip GY, et al. Chlamydia pneumoniae antibody titers are significantly associated with acute stroke and transient cerebral ischemia: the West Birmingham Stroke Project. Stroke. Feb 1998;29(2):404-10. [Medline].
• Corrado E, Rizzo M, Tantillo R. Markers of inflammation and infection influence the outcome of patients with baseline asymptomatic carotid lesions: a 5-year follow-up study. Stroke. Feb 2006;37(2):482-6. [Medline].
• Crouse JR 3rd, Byington RP, Bond MG. Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC- II). Am J Cardiol. Mar 1 1995;75(7):455-9. [Medline].
• Curb JD, Abbott RD, Rodriguez BL. C-reactive protein and the future risk of thromboembolic stroke in healthy men. Circulation. Apr 22 2003;107(15):2016-20. [Medline].
• Danesh J, Wong Y, Ward M, et al. Chronic infection with Helicobacter pylori, Chlamydia pneumoniae, or cytomegalovirus: population based study of coronary heart disease. Heart. Mar 1999;81(3):245-7. [Medline].
• DeGraba TJ. The role of inflammation after acute stroke: utility of pursuing anti- adhesion molecule therapy. Neurology. Sep 1998;51(3 Suppl 3):S62-8. [Medline].
• Devlin CM, Kuriakose G, Hirsch E. Genetic alterations of IL-1 receptor antagonist in mice affect plasma cholesterol level and foam cell lesion size. Proc Natl Acad Sci U S A. Apr 30 2002;99(9):6280-5. [Medline].
• Di Napoli M, Schwaninger M, Cappelli R. Evaluation of C-reactive protein measurement for assessing the risk and prognosis in ischemic stroke: a statement for health care professionals from the CRP Pooling Project members. Stroke. Jun 2005;36(6):1316-29. [Medline].
• Dong Y, Hassan A, Zhang Z. Yield of screening for CADASIL mutations in lacunar stroke and leukoaraiosis. Stroke. Jan 2003;34(1):203-5. [Medline].
• Dorn BR, Dunn WA Jr, Progulske-Fox A. Invasion of human coronary artery cells by periodontal pathogens. Infect Immun. Nov 1999;67(11):5792-8. [Medline].
• Dwyer JH, Allayee H, Dwyer KM. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med. Jan 1 2004;350(1):29-37. [Medline].
• Ebke M, Dichgans M, Bergmann M, et al. CADASIL: skin biopsy allows diagnosis in early stages. Acta Neurol Scand. Jun 1997;95(6):351-7. [Medline].
• Eikelboom JW, Hankey GJ, Anand SS. Association between high homocyst(e)ine and ischemic stroke due to large- and small-artery disease but not other etiologic subtypes of ischemic stroke. Stroke. May 2000;31(5):1069-75. [Medline].
• El Kossi MM, Zakhary MM. Oxidative stress in the context of acute cerebrovascular stroke. Stroke. Aug 2000;31(8):1889-92. [Medline].
• Elkind MS, Lin IF, Grayston JT, et al. Chlamydia pneumoniae and the risk of first ischemic stroke: The Northern Manhattan Stroke Study. Stroke. Jul 2000;31(7):1521-5. [Medline].
• Elkind MS, Cheng J, Boden-Albala B, et al. Elevated white blood cell count and carotid plaque thickness: the northern manhattan stroke study. Stroke. Apr 2001;32(4):842-9. [Medline].
• Elkind MS, Sciacca RR, Boden-Albala B. Relative elevation in baseline leukocyte count predicts first cerebral infarction. Neurology. Jun 28 2005;64(12):2121-5. [Medline].
• Elkind MS, Sciacca R, Boden-Albala B. Leukocyte count is associated with aortic arch plaque thickness. Stroke. Nov 2002;33(11):2587-92. [Medline].
• Emsley HC, Smith CJ, Georgiou RF. A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry. Oct 2005;76(10):1366-72. [Medline].
• Engebretson SP, Lamster IB, Elkind MS. Radiographic measures of chronic periodontitis and carotid artery plaque. Stroke. Mar 2005;36(3):561-6. [Medline].
• Enter C, Muller-Hocker J, Zierz S. A specific point mutation in the mitochondrial genome of Caucasians with MELAS. Hum Genet. Dec 1991;88(2):233-6. [Medline].
• Fabricant CG, Fabricant J. Atherosclerosis induced by infection with Marek''s disease herpesvirus in chickens. Am Heart J. Nov 1999;138(5 Pt 2):S465-8. [Medline].
• Fagerberg B, Gnarpe J, Gnarpe H, et al. Chlamydia pneumoniae but not cytomegalovirus antibodies are associated with future risk of stroke and cardiovascular disease: a prospective study in middle-aged to elderly men with treated hypertension. Stroke. Feb 1999;30(2):299-305. [Medline].
• Fukuhara M, Geary RL, Diz DI, et al. Angiotensin-converting enzyme expression in human carotid artery atherosclerosis. Hypertension. Jan 2000;35(1 Pt 2):353-9. [Medline].
• Furberg CD, Adams HP Jr, Applegate WB. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Circulation. Oct 1994;90(4):1679-87. [Medline].
• Gould DB, Phalan FC, van Mil SE. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med. Apr 6 2006;354(14):1489-96. [Medline].
• Grau AJ, Buggle F, Heindl S, et al. Recent infection as a risk factor for cerebrovascular ischemia. Stroke. Mar 1995;26(3):373-9. [Medline].
• Grau AJ, Boddy AW, Dukovic DA. Leukocyte count as an independent predictor of recurrent ischemic events. Stroke. May 2004;35(5):1147-52. [Medline].
• Grau AJ, Becher H, Ziegler CM. Periodontal disease as a risk factor for ischemic stroke. Stroke. Feb 2004;35(2):496-501. [Medline].
• Grau AJ, Buggle F, Becher H. Recent bacterial and viral infection is a risk factor for cerebrovascular ischemia: clinical and biochemical studies. Neurology. Jan 1998;50(1):196-203. [Medline].
• Grayston JT, Kuo CC, Coulson AS, et al. Chlamydia pneumoniae (TWAR) in atherosclerosis of the carotid artery. Circulation. Dec 15 1995;92(12):3397-400. [Medline].
• Grayston JT, Kronmal RA, Jackson LA. Azithromycin for the secondary prevention of coronary events. N Engl J Med. Apr 21 2005;352(16):1637-45. [Medline].
• Gretarsdottir S, Sveinbjornsdottir S, Jonsson HH. Localization of a susceptibility gene for common forms of stroke to 5q12. Am J Hum Genet. Mar 2002;70(3):593-603. [Medline].
• Gussekloo J, Schaap MC, Frolich M. C-reactive protein is a strong but nonspecific risk factor of fatal stroke in elderly persons. Arterioscler Thromb Vasc Biol. Apr 2000;20(4):1047-51. [Medline].
• Hackam DG, Peterson JC, Spence JD. What level of plasma homocyst(e)ine should be treated? Effects of vitamin therapy on progression of carotid atherosclerosis in patients with homocyst(e)ine levels above and below 14 micromol/L. Am J Hypertens. Jan 2000;13(1 Pt 1):105-10. [Medline].
• Hassan A, Markus HS. Genetics and ischaemic stroke. Brain. Sep 2000;123 (Pt 9):1784-812. [Medline].
• Hegele RA, Ban MR, Anderson CM, et al. Infection-susceptibility alleles of mannose-binding lectin are associated with increased carotid plaque area. J Investig Med. May 2000;48(3):198-202. [Medline].
• Helgadottir A, Manolescu A, Thorleifsson G. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet. Mar 2004;36(3):233-9. [Medline].
• Huang Z, Huang PL, Panahian N. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science. Sep 23 1994;265(5180):1883-5. [Medline].
• Hwang SJ, Ballantyne CM, Sharrett AR, et al. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study. Circulation. Dec 16 1997;96(12):4219-25. [Medline].
• Jamrozik K, Broadhurst RJ, Anderson CS, et al. The role of lifestyle factors in the etiology of stroke. A population- based case-control study in Perth, Western Australia. Stroke. Jan 1994;25(1):51-9. [Medline].
• Jood K, Ladenvall C, Rosengren A. Family history in ischemic stroke before 70 years of age: the Sahlgrenska Academy Study on Ischemic Stroke. Stroke. Jul 2005;36(7):1383-7. [Medline].
• Kalayoglu MV, Libby P, Byrne GI. Chlamydia pneumoniae as an emerging risk factor in cardiovascular disease. JAMA. Dec 4 2002;288(21):2724-31. [Medline].
• Kessler C, Spitzer C, Stauske D, et al. The apolipoprotein E and beta-fibrinogen G/A-455 gene polymorphisms are associated with ischemic stroke involving large-vessel disease. Arterioscler Thromb Vasc Biol. Nov 1997;17(11):2880-4. [Medline].
• Khreiss T, Jozsef L, Potempa LA. Conformational rearrangement in C-reactive protein is required for proinflammatory actions on human endothelial cells. Circulation. Apr 27 2004;109(16):2016-22. [Medline].
• Kiechl S, Lorenz E, Reindl M. Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med. Jul 18 2002;347(3):185-92. [Medline].
• Kornman KS, Pankow J, Offenbacher S, et al. Interleukin-1 genotypes and the association between periodontitis and cardiovascular disease. J Periodontal Res. Oct 1999;34(7):353-7. [Medline].
• Kostulas N, Pelidou SH, Kivisakk P, et al. Increased IL-1beta, IL-8, and IL-17 mRNA expression in blood mononuclear cells observed in a prospective ischemic stroke study. Stroke 1999. 30;2174-9.
• LaBiche R, Koziol D, Quinn TC, et al. Presence of Chlamydia pneumoniae in human symptomatic and asymptomatic carotid atherosclerotic plaque. Stroke. Apr 2001;32(4):855-60. [Medline].
• Lammie GA, Sandercock PA, Dennis MS. Recently occluded intracranial and extracranial carotid arteries. Relevance of the unstable atherosclerotic plaque. Stroke. Jul 1999;30(7):1319-25. [Medline].
• Levy E, Jaskolski M, Grubb A. The role of cystatin C in cerebral amyloid angiopathy and stroke: cell biology and animal models. Brain Pathol. Jan 2006;16(1):60-70. [Medline].
• Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation. Jun 28 2005;111(25):3481-8. [Medline].
• Lonn E, Yusuf S, Dzavik V. Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE). Circulation. Feb 20 2001;103(7):919-25. [Medline].
• Lonn E, Yusuf S, Arnold MJ. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. Apr 13 2006;354(15):1567-77. [Medline].
• Margaglione M, Seripa D, Gravina C, et al. Prevalence of apolipoprotein E alleles in healthy subjects and survivors of ischemic stroke: an Italian Case-Control Study. Stroke. Feb 1998;29(2):399-403. [Medline].
• Markus HS, Barley J, Lunt R, et al. Angiotensin-converting enzyme gene deletion polymorphism. A new risk factor for lacunar stroke but not carotid atheroma. Stroke. Aug 1995;26(8):1329-33. [Medline].
• Melnick SL, Shahar E, Folsom AR, et al. Past infection by Chlamydia pneumoniae strain TWAR and asymptomatic carotid atherosclerosis. Atherosclerosis Risk in Communities (ARIC) Study Investigators. Am J Med. Nov 1993;95(5):499-504. [Medline].
• Mendall MA, Patel P, Ballam L, et al. C reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study. BMJ. Apr 27 1996;312(7038):1061-5. [Medline].
• Meschia JF, Brott TG, Brown RD. Phosphodiesterase 4D and 5-lipoxygenase activating protein in ischemic stroke. Ann Neurol. Sep 2005;58(3):351-61. [Medline].
• Momiyama Y, Ohmori R, Taniguchi H. Association of Mycoplasma pneumoniae infection with coronary artery disease and its interaction with chlamydial infection. Atherosclerosis. Sep 2004;176(1):139-44. [Medline].
• Morrison AC, Fornage M, Liao D, et al. Parental history of stroke predicts subclinical but not clinical stroke: the Atherosclerosis Risk in Communities Study. Stroke. Sep 2000;31(9):2098-102. [Medline].
• Muhlestein JB, Anderson JL, Hammond EH, et al. Infection with Chlamydia pneumoniae accelerates the development of atherosclerosis and treatment with azithromycin prevents it in a rabbit model. Circulation. Feb 24 1998;97(7):633-6. [Medline].
• Muhlestein JB, Anderson JL, Carlquist JF, et al. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease: primary clinical results of the ACADEMIC study. Circulation. Oct 10 2000;102(15):1755-60. [Medline].
• Muir KW, Weir CJ, Alwan W. C-reactive protein and outcome after ischemic stroke. Stroke. May 1999;30(5):981-5. [Medline].
• Nadareishvili ZG, Li H, Wright V. Elevated pro-inflammatory CD4+CD28- lymphocytes and stroke recurrence and death. Neurology. Oct 26 2004;63(8):1446-51. [Medline].
• Newby DE, Wright RA, Labinjoh C, et al. Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction. Circulation. Mar 23 1999;99(11):1411-5. [Medline].
• Nicholson AC, Hajjar DP. Herpesvirus in atherosclerosis and thrombosis: etiologic agents or ubiquitous bystanders?. Arterioscler Thromb Vasc Biol. Mar 1998;18(3):339-48. [Medline].
• Nissen SE, Nicholls SJ, Sipahi I. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. Apr 5 2006;295(13):1556-65. [Medline].
• Novo S, Basili S, Tantillo R. Soluble CD40L and cardiovascular risk in asymptomatic low-grade carotid stenosis. Stroke. Mar 2005;36(3):673-5. [Medline].
• O'Donoghue M, Morrow DA, Sabatine MS. Lipoprotein-associated phospholipase A2 and its association with cardiovascular outcomes in patients with acute coronary syndromes in the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction. Circulation. Apr 11 2006;113(14):1745-52. [Medline].
• Oei HH, van der Meer IM, Hofman A. Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study. Circulation. Feb 8 2005;111(5):570-5. [Medline].
• Patel P, Mendall MA, Carrington D, et al. Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors. BMJ. Sep 16 1995;311(7007):711-4. [Medline].
• Pearson TA, Mensah GA, Alexander RW. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. Jan 28 2003;107(3):499-511. [Medline].
• Raggi P, Taylor A, Fayad Z. Atherosclerotic plaque imaging: contemporary role in preventive cardiology. Arch Intern Med. Nov 14 2005;165(20):2345-53. [Medline].
• Ridker PM, Hennekens CH, Stampfer MJ, et al. Prospective study of herpes simplex virus, cytomegalovirus, and the risk of future myocardial infarction and stroke. Circulation. Dec 22-29 1998;98(25):2796-9. [Medline].
• Ridker PM, Cushman M, Stampfer MJ. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. Apr 3 1997;336(14):973-9. [Medline].
• Ridker PM, Buring JE, Shih J. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation. Aug 25 1998;98(8):731-3. [Medline].
• Ridker PM, Hennekens CH, Buring JE. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. Mar 23 2000;342(12):836-43. [Medline].
• Ridker PM, Rifai N, Rose L. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. Nov 14 2002;347(20):1557-65. [Medline].
• Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation. May 26 1998;97(20):2007-11. [Medline].
• Ridker PM, Rifai N, Lowenthal SP. Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia. Circulation. Mar 6 2001;103(9):1191-3. [Medline].
• Ridker PM, Cannon CP, Morrow D. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. Jan 6 2005;352(1):20-8. [Medline].
• Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. Jan 14 1999;340(2):115-26. [Medline].
• Rost NS, Wolf PA, Kase CS, et al. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study. Stroke. Nov 2001;32(11):2575-9. [Medline].
• Rundek T, Elkind MS, Pittman J. Carotid intima-media thickness is associated with allelic variants of stromelysin-1, interleukin-6, and hepatic lipase genes: the Northern Manhattan Prospective Cohort Study. Stroke. May 2002;33(5):1420-3. [Medline].
• Schmidt R, Schmidt H, Fazekas F, et al. Apolipoprotein E polymorphism and silent microangiopathy-related cerebral damage. Results of the Austrian Stroke Prevention Study. Stroke. May 1997;28(5):951-6. [Medline].
• Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med. Nov 29 2001;345(22):1593-600. [Medline].
• Sharma P. Meta-analysis of the ACE gene in ischaemic stroke. J Neurol Neurosurg Psychiatry. Feb 1998;64(2):227-30. [Medline].
• Spence JD, Malinow MR, Barnett PA. Plasma homocyst(e)ine concentration, but not MTHFR genotype, is associated with variation in carotid plaque area. Stroke. May 1999;30(5):969-73. [Medline].
• Swei A, Lacy F, DeLano FA, et al. Oxidative stress in the Dahl hypertensive rat. Hypertension. Dec 1997;30(6):1628-33. [Medline].
• The Heart Outcomes Prevention Evaluation Study Investigators. Correction: Effects of An Angiotensin-Converting-Enzyme Inhibitor, Ramipril, on Cardiovascular Events in High-Risk Patients. N Engl J Med. Mar 9 2000;342(10):748. [Medline].
• Toole JF, Malinow MR, Chambless LE. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA. Feb 4 2004;291(5):565-75. [Medline].
• Torzewski M, Rist C, Mortensen RF, et al. C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis. Arterioscler Thromb Vasc Biol. Sep 2000;20(9):2094-9. [Medline].
• Tournier-Lasserve E, Iba-Zizen MT, Romero N, Bousser MG. Autosomal dominant syndrome with strokelike episodes and leukoencephalopathy. Stroke. Oct 1991;22(10):1297-302. [Medline].
• Vasan RS, Larson MG, Leip EP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med. Nov 1 2001;345(18):1291-7. [Medline].
• Verma S, Szmitko PE, Yeh ET. C-reactive protein: structure affects function. Circulation. Apr 27 2004;109(16):1914-7. [Medline].
• Weiss CR, Arai AE, Bui MN. Arterial wall MRI characteristics are associated with elevated serum markers of inflammation in humans. J Magn Reson Imaging. Dec 2001;14(6):698-704. [Medline].
• Wimmer ML, Sandmann-Strupp R, Saikku P, et al. Association of chlamydial infection with cerebrovascular disease. Stroke. Dec 1996;27(12):2207-10. [Medline].
• Woodward M, Lowe GD, Campbell DJ. Associations of inflammatory and hemostatic variables with the risk of recurrent stroke. Stroke. Oct 2005;36(10):2143-7. [Medline].
• Worrall BB, Azhar S, Nyquist PA, et al. Interleukin-1 receptor antagonist gene polymorphisms in carotid atherosclerosis. Stroke. Mar 2003;34(3):790-3. [Medline].
• Yamashita K, Ouchi K, Shirai M, et al. Distribution of Chlamydia pneumoniae infection in the athersclerotic carotid artery. Stroke. Apr 1998;29(4):773-8. [Medline].
• Yousry TA, Seelos K, Mayer M, et al. Characteristic MR lesion pattern and correlation of T1 and T2 lesion volume with neurologic and neuropsychological findings in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). AJNR Am J Neuroradiol. Jan 1999;20(1):91-100. [Medline].
• Zee RY, Ridker PM, Stampfer MJ, et al. Prospective evaluation of the angiotensin-converting enzyme insertion/deletion polymorphism and the risk of stroke. Circulation. Jan 26 1999;99(3):340-3. [Medline].
• Zhu Y, Yang GY, Ahlemeyer B. Transforming growth factor-beta 1 increases bad phosphorylation and protects neurons against damage. J Neurosci. May 15 2002;22(10):3898-909. [Medline].
• Zweifler RM. Management of acute stroke. South Med J. Apr 2003;96(4):380-5. [Medline].
• deVries D, deWijs I, Ruitenbeek W, et al. Extreme variability of clinical symptoms among sibs in a MELAS family correlated with heteroplasmy for the mitochondrial A3243G mutation. J Neurol Sci. 1994;124:77-82.

Article Last Updated: Jun 14, 2006