In a recent review by Hansson, published on Sep 6 in the journal "Atherosclerosis", vast evidence is presented describing atherosclerosis as an inflammatory disease. This article reviews the emergence of this concept from studies of patients and their lesions, experimental animal models, and epidemiological cohorts. Immunohistochemical studies identified immune cells and mediators and provided evidence for inflammatory activation in the atherosclerotic lesion. In parallel, cell culture studies demonstrated the capacity of vascular cells to interact with immune cells. Subsequent studies of clinical and epidemiological materials have identified inflammatory markers and immunoregulatory genes as contributors of risk for myocardial infarction and stroke. Finally, experiments using gene-targeted mice have provided mechanistic understanding of the disease process. Intensified inflammatory activation may lead to local proteolysis, plaque rupture, thrombus formation, ischemia and infarction. The conclusion is that novel therapeutic opportunities may emerge from understanding the role of inflammation in atherosclerosis.
Statins stabilize atherosclerotic lesions in animal models of advanced atherosclerosis, but there is little evidence to suggest that they have a preventive effect on plaque rupture itself. A study by Nakamura and coauthors (Atherosclerosis. 2008 Jul 15) demonstrated that statin prevents plaque disruption in apoE-knockout mouse model through pleiotropic effect on acute inflammation. They examined the effect of fluvastatin on plaque disruption using a simple and quick method of plaque disruption in carotid artery lesions in apolipoprotein E-deficient mice. Fluvastatin administration decreased matrix metalloproteinase-9 expression, gelatinolytic activity, endothelial adhesion molecules expression and neutrophil infiltration, and increased type I collagen content. In summary, fluvastatin was found to prevent plaque disruption through pleiotropic effect on acute inflammation in an animal model.
Increased levels of the inflammatory biomarker C-reactive protein predict cardiovascular events. Paul Ridker from Brigham and Women's Hospital, Boston and coauthors presented data on the successful use of osuvastatin to prevent vascular events in men and women with elevated C-reactive protein (CRP) (see New England Journal of Medicine, Nov 9, 2008). Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, they hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment.The investigators randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.
In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events, of LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. Consistent effects were observed in all subgroups evaluated. As a result of the positive effect on the patients, the 5-year trial was stopped after 1.9 years.
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A study was released by Cairo and co-authors showing an association between severe periodontal disease and initial stage of atherosclerosis in young otherwise healthy individuals. Atherosclerotic plaque formation in 90 subjects (as carotid artery intima-media thickness, IMT) was measured by ultrasonography. Traditional cardiovascular risk factors for atherosclerosis were also evaluated. The study demonstrated that severe periodontitis is associated with more than 8-fold increased risk for sub-clinical atherosclerosis in young systemically healthy patients (Source: Cairo and co-authors, Severe periodontitis in young adults is associated with sub-clinical atherosclerosis, J Clin Periodontol. 2008 Jun;35(6):465-72)
A variety of microbes may be present in atherosclerotic plaques and chronic bacterial infection increases the risk of atherosclerosis by mechanisms that remain vague. One possible mechanism is that bacteria or bacterial products activate plaque mast cells that are known to participate in the pathogenesis of atherosclerosis. In a study released in February 2008, the investigators show by different methods that pathogenic bacteria, Chlamydia pneumoniae (Cpn) and Aggregatibacter actinomycetemcomitans (Aa), both induce inflammation in human mast cells. The authors conclude that atherosclerosis-promoting bacteria induce a proinflammatory response in cultured human cells and act similarly in animal model of atherosclerotic disease (Source: Oksaharju and co-autors, Proatherogenic lung and oral pathogens induce an inflammatory response in human and mouse mast cells, J Cell Mol Med. 2008 Feb 24).
Peripheral vascular disease (PVD) is a common disabling condition associated with many of the same risk factors as coronary heart disease. It has been suggested that periodontal disease is a risk factor for coronary heart disease but its relationship to peripheral vascular disease is under-researched. In this investigation, the authors evaluated the relationship of periodontal disease to PVD. The study population consisted of 3585 participants who were 40 years or older. It was found that individuals with tooth attachment loss had more than twice increased risk for PVD. Systemic markers of inflammation were also associated with PVD, and were also significantly associated with tooth attachment loss. Inflammation may therefore be a pathway linking peripheral vascular disease with periodontal disease (Source: Lu and coauthors, Relationship of periodontal attachment loss to peripheral vascular disease: An analysis of NHANES 1999-2002 data, Atherosclerosis. 2008 Feb 7).
Several studies support an association between periodontal disease and atherosclerosis with a crucial role for the bacterial pathogen Porphyromonas gingivalis. The authors aim at investigating the proteolytic and oxidative activity of this pathogen on low-density lipoprotein (LDL) in human blood using a proteomic approach and analysing the effects of the modified LDL on cell proliferation. The cellular effects of the bacteria in human whole blood were assessed using lumi-aggregometry analysing reactive oxygen species. Incubation of whole blood with bacteria caused an extensive blood cell aggregation, reactive oxygen species production and markedly increased the growth of fibroblasts. Inhibition of bacterial enzymes suppressed the modification of LDL. The authors conclude that the ability of the periodontal bacteria to change the properties of LDL may represent a crucial event in periodontitis-associated atherosclerosis (Source: Bengtsson and coauthors, The periodontal pathogen Porphyromonas gingivalis cleaves apoB-100 and increases the expression of apoM in LDL in whole blood leading to cell proliferation, J Intern Med. 2008 May;263(5):558-71).
The concentration of antibodies in blood specific for periodontal bacteria has been shown to be elevated in coronary heart disease patients. The aim of this study is to examine whether serum antibody levels to the periodontal bacteria Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans are higher in type 1 diabetic patients and are associated with coronary artery calcification, a measure of atherosclerosis. For this, 400 type 1 diabetic patients and non-diabetic subjects with coronary artery calcification were studied. Serum antibody levels to the bacteria were measured by enzyme-linked immunosorbent assay. The authors found that elevated antibody levels were associated with higher blood pressure and with coronary artery calcification in all subjects combined and in diabetic subjects examined separately. Therefore, the association of elevated levels of serum IgG to P. gingivalis and A. actinomycetemcomitans with coronary artery atherosclerosis reflects a role for periodontal infection in coronary atherosclerosis, particularly in patients with type 1 diabetes (Source: Colhoun and coauthors, Antibodies to periodontal pathogens and coronary artery calcification in type 1 diabetic and nondiabetic subjects, J Periodontal Res. 2008 Feb;43(1):103-10).
Certain types of chronic infection increase the plasma level of the particularly atherogenic (advancing atherosclerotic development) low-density lipoprotein (LDL). In this study, the authors examined whether aggressive forms of periodontitis are associated with these atherogenic lipoproteins. Twelve healthy control subjects without periodontitis and 24 subjects with periodontitis were studied. Lipoprotein subclass levels were determined using nuclear magnetic resonance methodology. The authors found that the mean periodontal pocket depth correlated positively with very-low-density lipoprotein levels in blood. These results indicate that periodontal infection is associated with elevated plasma levels of atherogenic LDL. This association may account for the increased risk of periodontitis patients for cardiovascular disease (Source: Rufail and coauthors, Atherogenic lipoprotein parameters in patients with aggressive periodontitis, J Periodontal Res. 2007 Dec;42(6):495-502).
