Brain Trauma Stroke
evidence of CMV causing a vasculopathy is derived from the evidence of association of CMV and advanced progression of atherosclerosis and vasculopathy in heart-transplant recipients.16
but not all studies. Furthermore, specific strains of H. pylori, such as those expressing cytotoxin gene A (CagA-positive), are believed to specifically contribute to the atherosclerotic process.18
Helicobacter pylori Helicobacter pylori is a bacterium responsible for inflammation of the stomach lining, ulceration, and stomach cancer. H. pylori has been found at higher rates in carotid endarterectomy plaque samples compared with normal control samples derived from autopsy samples in some17
Mechanisms of Pathogen-mediated Effects on Atherosclerosis
Direct infection of cells lining arterial walls can lead to changes in transcription profiles and regulatory pathways that can result in endothelial dysfunction, smooth-muscle proliferation, or increased cytokine secretion.19
with the ability of cells to transport and metabolize cholesterol.21,22 has been shown to induce vascular injury23 smooth-muscle-cell proliferation24
and infection has been documented to interfere CMV
and double the rate of in rat models undergoing aortic
allografts. In in vitro studies of human arterial smooth-muscle tissue, CMV has been shown to replicate for prolonged periods compared with shorter observed survival in human lung fibroblasts.25
Pathogens may also exert non-specific effects on vessel walls, far removed from any localized infections. For example, research indicates that exposure early in life may be sufficient to pre-condition coronary arteries to atherosclerosis. A Swedish study of 175 autopsied children reported increased intima thickening in children with viral (32%) and bacterial (21%) infections compared with groups with no evidence of infection (16%).26
A case–control study from the same group found increased intima-media thickness (IMT) in cases (0.48±0.02mm) compared with controls (0.41±0.02mm), while no difference between groups was observed during the acute phase of infection.27
One
implication of this research is that atherosclerosis may be a delayed sequela of an acute infection. Other studies of non-specific effects of chronic infection have focused on elevated levels of serum cytokines that may affect atheromatous plaque progression by influencing macrophage activity. In vitro studies have shown C. pneumoniae to induce cytokine secretion in infected mononuclear cells that can directly affect atheroma progression28
and induce macrophage conversion to foam cells, a critical aspect of atherosclerotic plaque progression.29
Pathogen infection can also increase the risk for pro-thrombotic events by altering platelet activation and dynamics with leukocytes. The P-selectin adhesion molecule is the most critical determinant of platelet activation. In vitro analysis of human platelets incubated with C. pneumoniae found an increased expression of P-selectin using flow cytometry and the initiation of widespread aggregation as measured by lumiaggregometry.30
Platelet activation and platelet–leukocyte
aggregates were shown to be significantly elevated in recent stroke cases compared with controls of healthy employees.31
46
Evidence for an association between cumulative measures of infectious serologies (CMV, HSV1 and 2, hepatitis A virus [HAV], C. pneumoniae, and H. pylori) and endothelial dysfunction was observed in a cross-sectional study of 218 patients undergoing coronary angiography.32
In this study, endothelial reactivity was
assessed by measuring constriction in response to intracoronary administration of acetylcholine, and those individuals with more than four positive serologies had more vasoconstriction than those with fewer than four positive serologies.32
Another study consisting of
stroke cases with self-reported infection with an exclusion provision for suspected post-infective stroke found infection-exposed cases to have significantly higher P-selectin mean fluorescence units ± standard deviation (SD) (1.78±0.28 versus 1.49±0.36) and proportion of platelet–leukocyte aggregates (7.28±2.76 versus 4.96±2.58%) levels than those cases without a history of infection.32
HSV1 infection of human arterial smooth-muscle tissue causes decreased translation of cholesterol ester hydrolase messenger RNA (mRNA)20
Immune responses that target ‘self’ epitopes may be elicited by infection and have been implicated in atherogenesis. Heat-shock protein 60 (HSP60) is a highly conserved protein that is overexpressed in several cell types of atherosclerotic lesions.33,34
The ‘molecular
mimicry’ hypothesis suggests that exposure to bacterial or virally encoded HSPs homologous to the human variants can elicit an immune response that will target both pathogen and self HSPs. Clinical studies have shown that increased antibody titers to homologous C. pneumoniae HSP65 are associated with elevated coronary calcium.35
An alternative pathway of infection-mediated atherosclerotic effects is through the toll-like receptor (TLR) proteins. Infection increases expression of TLR, activating nuclear factor kappa beta (NF-κβ) and mitogen-activated protein kinase (MAPK) pathways that in turn set off a pro-inflammatory cascade.36
TLR proteins are overexpressed in
atheromatous plaque and may continue to be overexpressed post-infection even in the absence of the initiating pathogen.19
Host and Environmental Determinants of Risk An important consideration in evaluating IB and stroke is to account for potential confounding and interaction by host characteristics. Socioeconomic status (SES) may be associated with nutritional status, access to care, and many other factors that determine the ability to evoke a successful immune response against a pathogen and clear an infection. Health-seeking behavior may similarly confound the association. Socioeconomic disparities influence the seroprevalence of infection,37
and exposure to low education and chronic pyschosocial stress may increase antibody titer responses. Developing evidence shows SES may influence immune responses through influence on cortisol levels.38
However, studies have shown
that pathogen burden may be an independent predictor of cortisol levels after adjusting for demographics and socioeconomic position (SEP) measures,38
although residual influence of SES may continue to shape observed associations.
Underlying host genetic factors can also influence immune susceptibility and inflammatory responses to infection. Risk for CAD in those infected with C. pneumoniae has been shown to be elevated in patients with particular interleukin-1 (IL-1) polymorphisms, but IL-1
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