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Genetic and Inflammatory Mechanisms in Stroke

Mitchell SV Elkind, MD, MS, FAAN, Associate Professor of Neurology, Columbia University College of Physicians and Surgeons; Associate Attending Neurologist, Department of Neurology, New York-Presbyterian Hospital, Columbia Presbyterian Medical Center, Neurological Institute
Richard Francis Carlino, MD, Resident Physician, Mid-Hudson Family Practice Program, Kingston Hospital, Kingston, New York

Updated: Jan 11, 2010

Introduction

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.[1 ]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

Inflammation, endothelial dysfunction, and atherogenesis

Atherogenesis is itself an inflammatory process. Recent evidence suggests 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.[1 ]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, serum biomarkers, such as high sensitivity C-reactive protein (hsCRP) and cytokine levels, predict progression of atherosclerosis and risk of stroke.[2,3 ]Recent infection may also serve as an acute precipitant of vascular events, including stroke.[4 ]

When endothelium is physically damaged or becomes dysfunctional, a cascade of immunologically-mediated events is precipitated. Potential causes of endothelial dysfunction 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).

Genetic and inflammatory mechanisms in stroke. Gr...

Genetic and inflammatory mechanisms in stroke. Gray background, subendothelium; white background, intraluminal smooth muscle cells (SMC).



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)-α, IL-1, proteolytic enzymes including matrix metalloproteinases (MMP), 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-α, and granulocyte-macrophage stimulating factor cause activated T cells to produce interferon γ, TNF-α, and TNF-β, leading to stimulation of macrophages and further up-regulation of leukocyte adhesion molecules. Cytokines like IL-1β and TNF-α are responsible for beginning the response, which is perpetuated by others in the cascade such as IL-6 and IL-8. This feedback amplifies the cycle of inflammation-mediated events and the release of acute phase reactants (see Image 2).[5,6 ]

Genetic and inflammatory mechanisms in stroke. G-...

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.


Regulation of adhesion molecules is also 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). 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 (lymphocyte function-associated antigen-1) 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.[5,7 ]

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. Next, PDGF, TGF-β, and fibroblast growth factor 2 act to cause smooth muscle cell migration to the site and proliferation. Next, the increased activity of specific chemokines and cytokines (IL-1, TNF-α, PDGF, TGF-β, and osteopontin) leads to formation of a fibrous cap on top of the necrotic core of lipid, leukocytes, and debris.

Plaque rupture, the acute precipitant of approximately 50% of clinical events related to large vessel atherosclerosis, occurs at sites of the fibrous plaque where macrophages stimulated by activated T cells enter, and may be encouraged by destruction of the fibrous cap through up-regulation and production of proteolytic enzymes, including collagenases, priming it for ulceration or rupture.[1,5 ]The profile of inflammatory cytokines in more advanced lesions, such as those taken from endarterectomy plaque specimens, is predominantly a proinflammatory T cell response.[8 ]

Inflammation in acute stroke

There is a wealth of information that inflammation contributes to injury after stroke. In stroke models, mice with CD4+ and/or CD8+ T-cell deficiency had better outcomes as measured by improved neurologic function 24 hours after reperfusion, decreased infarct volume, and reduced accumulation of leukocytes and platelets. B-cell deficient mice did not display the same protective effects, implicating a strong T-cell influence. Similarly, studies have shown better outcomes in animals deficient in ICAM-1 and selectin family members.[7,9,10 ]

Elevated levels of MMP-9 have been demonstrated to play an important role in both ischemic stroke and especially hemorrhagic stroke.[11 ]MMPs have been associated with worse stroke severity, including blood brain barrier dysfunction, increased vascular permeability, larger initial lesion size, growth of infarction, and hemorrhagic transformation. There is also growing evidence suggesting that the hemorrhagic complications of thrombolytic therapy might be mediated by MMP-related activity.[11 ]

Risk Factors And Mechanisms Of Injury

Infection as a Stroke Trigger

In light of the increasing acceptance of atherosclerosis as a chronic inflammatory disease, acute infections have been hypothesized to play a role in vascular disease. Acute or recent infections have been particularly well-studied as causes of stroke. 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[12,13 ], particularly in large vessel atherothrombotic and cardioembolic cases, even in those without vascular risk factors.[14,15 ]

There is a wide range of reported prevalence of infection in ischemic stroke, from 18-40% in the month preceding an event and from 10-35% in the week prior.[14,4 ]Both recent upper respiratory and urinary tract infections were associated with increased stroke risk among more than 50,000 stroke patients in the United Kingdom General Practice Research Database; investigators found that patients were more likely to have experienced stroke during the 90 days after these infections.[4 ]Using the case-series method, which controls for interindividual variability, stroke risk in the 3 days after infection was approximately 3 times as high as during infection-free periods, and gradually diminished during the following 3 months.

Several potential biological mechanisms may explain how infections increase the risk of ischemic stroke. Infections increase platelet reactivity and platelet-leukocyte interactions, leading to an increased risk of platelet aggregation, potentially precipitating stroke. Platelet activation assessed by P-selectin expression, and platelet-leukocyte aggregates, are both increased in stroke patients compared with controls.[16 ]Platelet activation and platelet-leukocyte aggregates were also increased among 21 stroke patients with a history of infection within 1 week prior to the stroke compared with 37 stroke patients without recent infection. Severity of stroke was also greater among those with recent infection. Other organisms implicated in causing atherosclerosis and ischemic events have also been associated with platelet aggregation, including periodontal infections.[17 ]

Increased leukocyte count is independently associated in observational studies with carotid[18 ]and aortic arch plaque thickness[19 ]as well as with stroke risk, even after adjusting for smoking. In the Northern Manhattan Study (NOMAS), leukocyte count in healthy elderly individuals was predictive of first ischemic stroke after adjusting for vascular risk factors, including metabolic syndrome and socioeconomic factors.[20 ]Leukocyte count was also associated with progression of aortic arch atheroma, a risk factor for cardioembolic stroke, over 12 months.[21 ]Elevated leukocyte count was associated with increased risk of developing a first ischemic stroke or myocardial infarction even after correcting for traditional vascular risk factors.[6 ]

One of the most convincing analyses of the relationship of leukocyte count to recurrent stroke risk was conducted as a secondary analysis of the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial.[22 ]In that study, short-term changes in leukocyte count were associated with an increased period of stroke risk. Among 211 patients with ischemic stroke during follow-up, leukocyte levels in the prior week, but not earlier, were increased above baseline levels.

Observational studies also show evidence that vaccination against common infections, particularly viral influenza, may prevent stroke. In a case-control study among 370 consecutive stroke or TIA patients and an equal number of community controls, influenza vaccination during the previous season was associated with a 50% reduction in stroke risk after adjusting for other risk factors (a 19.2% vaccination rate in patients compared to a 31.4% rate in control subjects, P <0.0001).[23 ]In children and some adults, varicella infection appears to represent a period of increased stroke risk, and it is possible that vaccination against chickenpox will reduce this risk.[24 ]Recent guidelines recommend vaccination against influenza in patients with cardiovascular disease.[25 ]

Chlamydia

C pneumoniae is the infectious pathogen that has been most extensively studied in relation to atherosclerosis and stroke. C pneumoniae is present in the intima, media, macrophages, and smooth muscle of some carotid endarterectomy specimens. Detection of C pneumoniae in serum, however, correlates poorly with its detection in carotid plaques.[26 ]

Evidence also exists that patients with coronary disease[27 ]and stroke[28 ]are significantly more likely than control subjects to have elevated levels of immunoglobulin G (IgG) or immunoglobulin A (IgA) against C pneumoniae. T-cell proliferation of both CD4+ and CD8+ populations have been demonstrated in C pneumoniae antigen mediated (+ PCR) symptomatic atherosclerotic plaques.[5,110 ]However, prospective studies have not always confirmed these findings.[27 ]

In animal studies, C pneumoniae inoculation increases atherosclerosis, and azithromycin attenuates this effect.[29 ]It is unclear that the organism is causally related to atherosclerosis in humans, however. 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.[30,31 ]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 stroke risk. Some periodontal pathogens may invade tissue cultures of both human coronary artery endothelial cells and coronary artery smooth muscle cells.[32 ]In cross-sectional studies, periodontal infection appears to be associated with carotid atherosclerosis.[33 ]Case-control and prospective studies have found an association between periodontitis and stroke risk.[22 ]Several genes thought to play a role in periodontal disease may also be associated with carotid disease.

Herpes viruses

Other chronic viral infections 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.[34,35,36 ]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.[37 ]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

Epidemiological studies have shown that several inflammatory biomarkers are also associated with atherosclerosis and stroke. Even within the normal range, relative increases in these levels may serve as predictors of future risk.

High-sensitivity C-reactive protein (hsCRP) and stroke risk

Acute-phase proteins, and hsCRP in particular, have been the most extensively studied markers of inflammation.[38 ]Other markers, including lipoprotein-associated phospholipase A2 (Lp-PLA2), serum amyloid A (SAA), interleukin-6 (IL-6), and CD40 ligand (CD40L), also may predict events. 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 more 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.[39 ]

HsCRP predicts incident cerebrovascular events in several populations, and much of the early literature on this topic has been reviewed in a European consensus statement.[40 ]In the Women’s Health Study, hsCRP, IL-6, soluble ICAM-1, and SAA all predicted cardiovascular events, including stroke.[36,41 ]In multivariate models, 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.[42,43 ]These initial studies focused on predominantly healthy middle-aged individuals without a significant burden of risk factors. However, in the Cardiovascular Health Study, which focuses on risk factors in elderly persons, hsCRP predicted a first ischemic stroke only modestly (adjusted hazard ratio for the highest quartile 1.60, 95% confidence interval [CI], 1.23-2.08).[44 ]

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] versus those in the lowest quartile) in the Physicians' Health Study, but the effect on stroke risk was less than the effect on cardiac risk and appeared to exhibit a threshold effect above the first quartile.[45 ]Among those older than 85 years, hsCRP was associated with risk of death from all causes as well as fatal stroke.[46 ]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.[47 ]

Among healthy Japanese American men, baseline 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.[48 ]Thus, hsCRP may be of greatest predictive value among those with low baseline risk and of least value in older populations and those with more risk factors. CRP gene polymorphisms were associated with hsCRP levels, and in white participants, the 1919T allele was associated with an increased risk of stroke and cardiovascular mortality.[49 ]Thus, the relationship of hsCRP to stroke risk is less certain than its relationship to myocardial infarction, and it appears to depend on study design and population. Validation in other populations is required.

Carotid artery disease

A growing body of literature suggests that inflammatory biomarkers can distinguish symptomatic from asymptomatic carotid plaques, and that these markers can be used to predict which patients with carotid stenosis are most likely to develop symptoms. Plaques from symptomatic patients undergoing carotid endarterectomy have significantly more inflammatory cells on immunohistochemical analysis than plaques from asymptomatic patients.[50 ]Doppler imaging may be a useful way to distinguish stable from unstable carotid plaques, and findings correlate with inflammatory biomarkers.

In one study, plaques in a group of stroke patients were predominantly echolucent, whereas those in the asymptomatic group were predominantly echogenic (P <0.05).[51 ]Irregular and ulcerated plaques were frequently found in stroke patients, while smooth plaques were frequently detected in asymptomatic patients (P <0.05). Serum levels of matrix metalloproteinase-9, soluble CD40L, and hsCRP were higher in stroke patients than in asymptomatic patients. In the Northern Manhattan Study (NOMAS), irregular and ulcerated plaques were more strongly associated with future stroke risk than smooth plaques.[52 ]

Recent studies have also used high-resolution carotid MRI as an alternative technique to assess the stability of carotid plaque, and visualized abnormalities are associated with levels of serum inflammatory markers.[53 ]Treatment to lower levels of LDL has also been associated with MRI-visualized carotid plaque regression.[54 ]Wiart and colleagues demonstrated the potential of using ultrasmall superparamagnetic particles of iron oxide (USPIO) to enhance MRI images in vivo by labeling inflammatory phagocytes of ischemic lesions.[55,56 ]

HsCRP and prognosis after stroke

The role of hsCRP and other inflammatory markers as prognostic markers after a first stroke has been investigated in few studies.[40 ]In a secondary analysis of nested case-control data from a multicenter secondary stroke prevention trial, the Perindopril Protection against Recurrent Stroke Study (PROGRESS), those in the highest tertile of hsCRP had a 40% increased risk of recurrent ischemic stroke.[57 ]The investigators did not fully adjust for diabetes mellitus. Fibrinogen and hsCRP were associated with increased risk of recurrent ischemic stroke, but not hemorrhagic stroke, after accounting for other risk factors and medications.

A more recent analysis in the same population found that each of these markers was associated with recurrent ischemic stroke.[58 ]When all markers, including hsCRP, were considered simultaneously, the effect appeared most prominent for TNF-α. The investigators argued that the acute phase response itself, rather than any particular marker, is associated with outcomes.

There is also evidence, perhaps not surprisingly, that hsCRP predicts mortality after stroke.[59,60 ]These studies require confirmation in large, multicenter studies with prospectively defined thresholds for marker levels. At present, testing for hsCRP after stroke to predict prognosis or to recommend treatment cannot be routinely recommended.[40 ]

Lipoprotein-associated phospholipase A2 (Lp-PLA2) and stroke risk

Lp-PLA2 is a macrophage-derived enzyme involved in metabolism of LDL in arterial walls that is responsible for release of inflammatory mediators. Recent epidemiologic studies have provided evidence that relative elevations in serum levels of Lp-PLA2 are associated with increased risk of incident ischemic stroke.[61,62 ]This risk appears to be independent of the effect of hsCRP. In NOMAS, hsCRP and LP-PLA2 were assessed as predictors of stroke recurrence, other vascular events, and death among 467 patients with incident stroke.[28 ]Those in the highest quartile of Lp-PLA2 were at about double the risk of recurrent stroke. They also had an increased risk of the combined outcome of recurrent stroke, myocardial infarction, or vascular death (adjusted HR 1.86, 95% CI, 1.01-3.42). After adjusting for other prognostic factors, hsCRP was not associated with recurrent stroke or other vascular events, but was associated with mortality.

From this data, it appears that inflammatory markers are associated with prognosis after first ischemic stroke, but that different markers offer complementary information. LP-PLA2 may be a stronger predictor of recurrent stroke risk and therefore more specific for vascular inflammation, while hsCRP, an acute phase reactant, increases with stroke severity, is less specific for vascular inflammation, and is associated with mortality to a greater degree than recurrence.[63 ]

Potential therapeutic implications

Elevations in inflammatory marker levels could be used to target patients for therapy with secondary prevention medications, including antiplatelets, antihypertensives, and statins. This approach is consistent with the paradigm in primary and secondary prevention, according to which overall baseline level of risk, rather than specific risk factors, should be treated with all drugs efficacious in reducing risk of vascular events.[20 ]Several trials demonstrate that hydroxymethylglutaryl-coenzyme A reductase inhibitors or statins reduce levels of hsCRP and Lp-PLA2 independently of effects on cholesterol levels.[64,65 ]

Some recent evidence suggests reduction in hsCRP and Lp-PLA2 may be associated with a reduction in risk of vascular disease.[66,67 ]In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial of atorvastatin, hsCRP levels were related to stroke risk over the next 16 weeks. Of note, however, stroke risk was related to hsCRP only in the placebo group, providing indirect evidence that statin treatment can reduce the risk associated with elevated hsCRP.[68 ]

In the JUPITER trial, which examined the benefits of rosuvastatin therapy in participants with an elevated hsCRP level but low LDL, there was a significant reduction in cardiovascular events, including stroke, in the rosuvastatin treated group compared with the controls.[69 ]The effect appeared independent of lowering LDL. More studies are required to determine what the true extent of the anti-inflammatory role of statin therapy is and whether any modification of current guidelines would be warranted to incorporate measuring additional markers such as hsCRP. Because the benefit of statins did not seem dependent on hsCRP levels and the limited inclusion criteria, there is still no consensus on what these results mean in terms of primary prevention and treatment.

Because secondary stroke prevention guidelines do not state that all stroke patients should be treated with statin therapy, and because stroke is a heterogeneous condition, hsCRP or Lp-PLA2 may be useful as additional markers to help determine which stroke patients should be started on statins. The decision to measure hsCRP, Lp-PLA2, or other markers in stroke patients may be based on the CDC/AHA guidelines until further data are available.[38 ]

Genetics And Stroke

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, may also be modified by genetics.

Single-Gene Disorders

Single-gene stroke disorders, while rare, do occur.

Homocystinuria
Homocystinuria is a genetically heterogeneous disease that results in accumulation of homocysteine and premature atherosclerosis. Homocystinuria is well established as a contributor to endothelial damage, proatherosclerotic and thromboembolic generation, lipoprotein oxidation, vascular smooth muscle proliferation, and even arterial dissection.[70,71 ]The most common defect is in the enzyme cystathionine beta synthase (CBS), coded for by chromosome subband 21q22.3, which normally converts homocysteine to cystathionine.

CADASIL
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.[72 ]Characteristic imaging findings include white matter lesions in the external capsule and anterior temporal poles.[73 ]

Genetic linkage analyses have identified several associated mutations of the Notch3 gene, which is located on chromosome band 19q12.[72 ]Most of these mutations result from a missense mutation altering the number of cysteine residues expressed in an extracellular receptor domain.[74 ] 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. While the defective receptors usually do not interfere with phenotypic signaling, they have been shown to accumulate in the basilar lamina of arterial vasculature.[75,76 ]Skin biopsy revealing granular osmiophilic material (GOM) can be pathognomonic for the diagnosis, sometimes detecting the disease in patients who have normal findings on imaging studies and negative genetic test results for the most common mutations.[77 ]

Familial amyloid angiopathy

 Mutations in cystatin C have been implicated in familial amyloid angiopathy.[78 ]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.[79 ]Abnormalities in other basement membrane proteins may be reasonable candidates for other genetic stroke disorders.

MELAS
The syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disorder characterized by strokelike episodes often involving the cortex, typically in the occipitoparietal region; migraine headaches; nausea; and vomiting. Multiple organ systems can be affected, leading to short stature, hearing loss, developmental delay, diabetes mellitus, and other problems. Imaging of the vasculature within the lesions reveals no embolic or stenotic mechanisms but rather a vasogenic impairment of microvascular blood flow autoregulation or metabolism, not limited to particular vascular territories. The significant heterogeneity in the phenotype of family members is thought to arise from heteroplasmy, the variable expression of mutated mitochondrial DNA within different tissues. The most commonly reported genetic defect is an A3243G substitution within a t RNA gene in 80% of cases.[80 ]

Connective tissue disorders
Cerebrovascular complications are commonly associated manifestations with several hereditary connective tissue diseases. The autosomal dominant diseases Marfan syndrome and Ehlers-Danlos syndrome are caused by mutations in the fibrillin-1 (FBN-1) and collagen type-III (COL3A1) genes respectively, and carry a risk of vascular dissections, ischemic infarcts, aneurysms, and cardiovascular disease. Carotid disease has also been reported in other conditions such as osteogenesis imperfecta, pseudoxanthoma elasticum, and neurofibromatosis type 1.[70 ]

Fabry disease
Fabry disease is an X-linked deficiency (both missense and non-sense GLA mutations) in the lysosomal α-galactosidase A enzyme, resulting in the systemic accumulation of glycosphingolipids. Cerebrovascular involvement typically occurs in both large and small vessels and a preference in the posterior circulation, especially of younger stroke patients.[70 ]

Sickle cell disease
Sickle cell disease represents the most common cause of childhood stroke, with the highest incidence before age 5 years. By the onset of early adulthood, the risk of ischemic stroke is surpassed by the increased incidence of hemorrhagic stroke, and as many as 25% of Hb-S homozygous patients will have a stroke by age 45 years. These patients often have both large vessel thrombus formation and vessel remodeling as well as smaller vessel border zone and subcortical region disease. Stroke recurrence is fairly common as are multiple silent infarcts evident by imaging.[70 ]

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.[81 ]Genetic influence appears to be more substantial in younger patients.[82,83 ]A relationship appears to exist between parental stroke and silent cerebral infarcts in their offspring. 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[84 ], 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.

Analysis of genome-wide association studies have recently provided possible candidate genes for common cardiovascular disease.[85 ]The most notable association was reported for chromosome 9p21, which has been associated with risk of myocardial infarction and coronary heart disease. Polymorphic variants on chromosome 9p21, located near the genes CDKN2A and CDKN2B, were significantly associated with risk of ischemic stroke as well.[86 ]

Gretarsdottir et al reported a strong association between gene variations that confer an increased risk of atrial fibrillation and ischemic stroke, especially those originating from cardioembolic sources.[87 ]Interestingly, there was also a significant association in the noncardiogenic classified events, which the authors speculate is due to the underdiagnosis of atrial fibrillation. One major limitation of the study was that the subjects being studied were primarily of a Northern European-derived population, so it is unknown how generalizable the findings are.

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.[88 ]The gene that resides in the STRK1 locus region of chromosome 5q12 was associated with both cardiogenic and carotid origin strokes. Some North American studies have found that polymorphisms in the PDE4D gene are also associated with increased stroke risk.[89 ]Since studies in other populations have yielded inconsistent results, a wide range of ethnic hereditary and environmental influence is likely.[70 ]

A related protein, arachidonate 5-lipoxygenase activating protein (FLAP), is also associated with risk of stroke in the Icelandic population and some select Northern European populations.[90 ]FLAP, encoded from the ALOX5AP gene, is an important mediator in the leukotriene activation pathway with roles in atherosclerosis proliferation. There was a 1.8 fold increase in risk of myocardial infarction and stroke with the Icelandic population.[90 ]

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 (IMT) and also with risk of stroke in some populations.[91 ]Variants of the hepatic enzymes microsomal P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) have been identified to have a significant affect on a patient’s sensitivity to warfarin.[92,93 ]

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.[94 ]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.[95 ]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.

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.[96 ]Similarly, mutations in the IL-1ra gene modify the risk of coronary artery disease associated with C pneumoniae infection.[97 ]

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, fibrinogen, and NF-κB. 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.[98,5,99,100 ]Defective TLR variations have been observed with an increased incidence of myocardial infarctions.

An innate susceptibility for an inflammatory response is demonstrated through an MHC class II receptor polymorphism. T cells expressing defective binding sites can be activated in a receptor independent manner. This mechanism can be triggered by multiple infectious agents including even Staph and Strep antigens.[101 ]

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

Genetic and inflammatory mechanisms in stroke. Gr...

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

Genetic and inflammatory mechanisms in stroke. G-...

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.

Genetic and inflammatory mechanisms in stroke. Th...

Media file 3: Genetic and inflammatory mechanisms in stroke. The inflammatory cascade.

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Keywords

cerebrovascular accident, cerebral infarction, atherosclerosis, atherogenesis, C-reactive protein, endothelial dysfunction, inflammation, infection, lipoprotein-associated phospholipase A2, Chlamydia pneumoniae, vascular disease, genetics, stroke, statins

Contributor Information and Disclosures

Author

Mitchell SV Elkind, MD, MS, FAAN, Associate Professor of Neurology, Columbia University College of Physicians and Surgeons; Associate Attending Neurologist, Department of Neurology, New York-Presbyterian Hospital, Columbia Presbyterian Medical Center, Neurological Institute
Mitchell SV Elkind, MD, MS, FAAN is a member of the following medical societies: American Academy of Neurology, American Medical Association, Massachusetts Medical Society, Medical Society of the State of New York, National Headache Foundation, National Stroke Association, and Stroke Council of the American Heart Association
Disclosure: BMS-Sanofi Pharmaceutical Partnership Grant/research funds Independent contractor; diaDexus, Inc. Grant/research funds Independent contractor; BMS-Sanofi Pharmaceutical Partnership Honoraria Speaking and teaching; Boehringer-Ingelheim, Inc. Honoraria Speaking and teaching; Pfizer Consulting fee Consulting; GlaxoSmithKline Consulting fee Consulting; Daichi Sankyo  Consulting; Jarvik Heart Consulting fee Consulting

Coauthor(s)

Richard Francis Carlino, MD, Resident Physician, Mid-Hudson Family Practice Program, Kingston Hospital, Kingston, New York
Richard Francis Carlino, MD is a member of the following medical societies: American Academy of Family Physicians and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Richard M Zweifler, MD, Chief of Neurology, Sentara Healthcare, Norfolk, VA; Professor of Neurology, Eastern Virginia Medical School, Norfolk, VA
Richard M Zweifler, MD is a member of the following medical societies: American Academy of Neurology, American Heart Association, American Medical Association, American Stroke Association, Royal Society of Medicine, and Stroke Council of the American Heart Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Howard S Kirshner, MD, Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center
Howard S Kirshner, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Heart Association, American Medical Association, American Neurological Association, American Society of Neurorehabilitation, National Stroke Association, Phi Beta Kappa, and Tennessee Medical Association
Disclosure: Boehringer Ingelheim Honoraria Speaking and teaching; BMS/Sanofi Honoraria Speaking and teaching; Novartis Honoraria Speaking and teaching

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Helmi L Lutsep, MD, Professor, Department of Neurology, Oregon Health & Science University; Associate Director, Oregon Stroke Center
Helmi L Lutsep, MD is a member of the following medical societies: American Academy of Neurology and American Stroke Association
Disclosure: Co-Axia Consulting fee Review panel membership; Talecris Consulting fee Review panel membership; AGA Medical Consulting fee Review panel membership; Boehringer Ingelheim Honoraria Speaking and teaching; Concentric Medical Consulting fee Review panel membership; Abbott Consulting fee Consulting; Sanofi  Consulting

Acknowledgments

The authors acknowledge the work of previous authors Devin Brown, MD, and Bradford Burke Worrall, MD.

Further Reading

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