Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199901143400207

Atherosclerosis — An Inflammatory Disease

Atherosclerosis is an Inflammatory Disease

Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis. Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors. Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease, but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance.

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Inflammation and Atherosclerosis

In 1998, the American Heart Association convened Prevention Conference V to examine strategies for the identification of high-risk patients who need primary prevention. Among the strategies discussed was the measurement of markers of inflammation.1 The Conference concluded that “many of these markers (including inflammatory markers) are not yet considered applicable for routine risk assessment because of: (1) lack of measurement standardization, (2) lack of consistency in epidemiological findings from prospective studies with endpoints, and (3) lack of evidence that the novel marker adds to risk prediction over and above that already achievable through the use of established risk factors.” The National Cholesterol Education Program Adult Treatment Panel III Guidelines identified these markers as emerging risk factors,1a which could be used as an optional risk factor measurement to adjust estimates of absolute risk obtained using standard risk factors. Since these publications, a large number of peer-reviewed scientific reports have been published relating inflammatory markers to cardiovascular disease (CVD). Several commercial assays for inflammatory markers have become available. As a consequence of the expanding research base and availability of assays, the number of inflammatory marker tests ordered by clinicians for CVD risk prediction has grown rapidly. Despite this, there has been no consensus from professional societies or governmental agencies as to how these assays of markers of inflammation should be used in clinical practice.

On March 14 and 15, 2002, a workshop titled “CDC/AHA Workshop on Inflammatory Markers and Cardiovascular Disease: Applications to Clinical and Public Health Practice” was convened in Atlanta, Ga, to address these issues. The goals of this workshop were to determine which of the currently available tests should be used; what results should be used to define high risk; which patients should be tested; and the indications for which the tests would be most useful. These …

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

Background Inflammation may be important in the pathogenesis of atherothrombosis. We studied whether inflammation increases the risk of a first thrombotic event and whether treatment with aspirin decreases the risk. Methods We measured plasma C-reactive protein, a marker for systemic inflammation, in 543 apparently healthy men participating in the Physicians' Health Study in whom myocardial infarction, stroke, or venous thrombosis subsequently developed, and in 543 study participants who did not report vascular disease during a follow-up period exceeding eight years. Subjects were randomly assigned to receive aspirin or placebo at the beginning of the trial. Results Base-line plasma C-reactive protein concentrations were higher among men who went on to have myocardial infarction (1.51 vs. 1.13 mg per liter, P<0.001) or ischemic stroke (1.38 vs. 1.13 mg per liter, P = 0.02), but not venous thrombosis (1.26 vs. 1.13 mg per liter, P = 0.34), than among men without vascular events. The men in the quartile wit...

https://www.nejm.org/doi/pdf/10.1056/NEJM199704033361401

Inflammation, Aspirin, and the Risk of Cardiovascular Disease in Apparently Healthy Men

Objective: To test the hypothesis that minor chronic insults such as smoking, chronic bronchitis, and two persistent bacterial infections may be associated with increases in C reactive protein concentration within the normal range and that variations in the C reactive protein concentration in turn may be associated with levels of cardiovascular risk factors and chronic coronary heart disease. Design: Population based cross sectional study. Setting: General practices in Merton, Sutton, and Wandsworth. Subjects: A random sample of 388 men aged 50-69 years from general practice registers. 612 men were invited to attend and 413 attended, of whom 25 non-white men were excluded. The first 303 of the remaining 388 men had full risk factor profiles determined. Interventions: Measurements of serum C reactive protein concentrations by in house enzyme linked immunosorbent assay (ELISA); other determinations by standard methods. Coronary heart disease was sought by the Rose angina questionnaire and Minnesota coded electrocardiograms. Main outcome measures: Serum C reactive protein concentrations, cardiovascular risk factor levels, and the presence of coronary heart disease. Results: Increasing age, smoking, symptoms of chronic bronchitis, Helicobacter pylori and Chlamydia pneumoniae infections, and body mass index were all associated with raised concentrations of C reactive protein. C Reactive protein concentration was associated with raised serum fibrinogen, sialic acid, total cholesterol, triglyceride, glucose, and apolipoprotein B values. C Reactive protein concentration was negatively associated with high density lipoprotein cholesterol concentration. There was a weaker positive relation with low density lipoprotein cholesterol concentration and no relation with apolipoprotein A I value. C Reactive protein concentration was also strongly associated with coronary heart disease. Conclusion: The body9s response to inflammation may play an important part in influencing the progression of atherosclerosis. The association of C reactive protein concentration with coronary heart disease needs testing in prospective studies. Key messages Factors that determine levels of inflammatory mediators in the normal general population have not been explored, nor has their relation to cardio- vascular risk factors Among 50-69 year old men many environmental and lifestyle risk factors for cardiovascular disease are associated with raised serum concentrations of C reactive protein Circulating concentrations of lipids, glucose, and clotting factors are also associated with serum C reactive protein concentrations The body9s response to inflammation may influence the development of atherosclerosis

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C reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study.

Background The clinical significance of the association between elevated anti– Chlamydia pneumoniae (Cp) antibody titres and coronary heart disease (CHD) is unclear. We explored the relationship between antibodies against Cp and future cardiovascular events in male survivors of myocardial infarction (MI). The effect of azithromycin antibiotic therapy was assessed in a subgroup of post-MI patients. Methods and Results We screened 220 consecutive male survivors of MI for anti-Cp antibodies. Of these, 213 patients were stratified into three groups: group Cp-ve (n=59), no detectable Cp antibodies; group Cp-I (n=74), intermediate titres of 1/8 to 1/32 dilution; and group Cp+ve (n=80), seropositive at ≥1/64 dilution. Patients with persisting seropositivity of ≥1/64 were randomized to either oral azithromycin (Cp+ve-A, 500 mg/d for 3 days [n=28] or 500 mg/d for 6 days [n=12]) or placebo (Cp+ve-P, n=20). Cp+ve-NR (n=20) represented patients not recruited into the antibiotic trial. The incidence of adverse cardiovascular events (over a mean follow-up period of 18±4 months) was recorded and shown to increase with increasing anti-Cp titre: Cp-ve, n=4 (7%); Cp-I, n=11 (15%); Cp+ve-NR, n=6 (30%); and Cp+ve-P, n=5 (25%). Cp+ve-NR and Cp+ve-P groups had a fourfold-increased risk for adverse cardiovascular events compared with the Cp-ve group (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.2 to 15.5; P =.03). In contrast, the OR for cardiovascular events in patients receiving azithromycin (Cp+ve-A, single or double course) was the same as in the Cp-ve group (OR, 0.9; 95% CI, 0.2 to 4.6, P =NS). Patients receiving azithromycin were more likely to experience a decrease in IgG anti-Cp titres than were those in the placebo group ( P =.02). Conclusions An increased anti-Cp antibody titre may be a predictor for further adverse cardiovascular events in post-MI patients. Taking a short course of azithromycin may lower this risk, possibly by acting against Cp.

Elevated Chlamydia pneumoniae Antibodies, Cardiovascular Events, and Azithromycin in Male Survivors of Myocardial Infarction

BACKGROUND--There is evidence suggesting that early life experience may influence adult risk of coronary heart disease (CHD). Chronic bacterial infections have been associated with CHD. OBJECTIVE--To determine whether Helicobacter pylori, a childhood acquired chronic bacterial infection, is associated with an increased risk of coronary heart disease in later life. DESIGN--Case-control study controlling for potential confounding variables with an opportunistically recruited control group. SUBJECTS--111 consecutive cases with documented CHD were recruited from a cardiology clinic and 74 controls from a general practice health screening clinic. All were white men aged 45-65. METHODS--Serum was analysed for the presence of H pylori specific IgG antibodies by ELISA (98% sensitive and 94% specific for the presence of infection). RESULTS--59% of the cases and 39% of the controls were seropositive for H pylori (odds ratio 2.28, chi 2 7.35, p = 0.007). After adjustment by multiple logistic regression for age, cardiovascular risk factors, and current social class, the effect of H pylori was little altered (odds ratio 2.15, p = 0.03). Further adjustment for various features of the childhood environment known to be risk factors for H pylori infection only slightly weakened the association (odds ratio 1.9). H pylori seropositivity was not related to the level of risk factors in the control population. CONCLUSION--In this pilot study the association of adult coronary heart disease with H pylori seropositivity suggests that the early childhood environment may be important in determining the risk of CHD in adult life. The association needs confirmation in other better designed studies. If H pylori itself is responsible for the association, then this is of great potential importance as the infection is treatable.

https://heart.bmj.com/content/heartjnl/71/5/437.full.pdf

Relation of Helicobacter pylori infection and coronary heart disease.

Objective: To investigate the relation between seropositivity to chronic infections with Helicobacter pylori and Chlamydia pneumoniae and both coronary heart disease and cardiovascular risk factors. Objective:To investigate the relation between seropositivity to chronic infections with Helicobacter pylori and Chlamydia pneumoniae and both coronary heart disease and cardiovascular risk factors. Setting: General practices in Merton, Sutton, and Wandsworth, south London. Subjects: 388 white south London men aged 50-69. Main outcome measures: Evidence of coronary risk factors and infection with H pylori or C pneumoniae. Results: 47 men (12.1%) had electrocardiographic evidence of ischaemia or infarction. 36 (76.6%) and 18 (38.3%) were seropositive for H pylori and C pneumoniae, respectively, compared with 155 (45.5%) and 62 (18.2%) men with normal electrocardiograms. Odds ratios for abnormal electrocardiograms were 3.82 (95% confidence interval 1.60 to 9.10) and 3.06 (12.33 to 7.01) in men seropositive for H pylori and C pneumoniae, respectively, after adjustment for a range of socioeconomic indicators and risk factors for coronary heart disease. Cardiovascular risk factors that were independently associated with seropositivity to H pylori included fibrinogen concentration and total leucocyte count. Seropositivity to C pneumoniae was independently associated with raised fibrinogen and malondialdehyde concentrations. Conclusions: Both H pylori and C pneumoniae infections are associated with coronary heart disease. These relations are not explained by a wide range of confounding factors. Possible mechanisms include an increase in risk factor levels due to a low grade chronic inflammatory response.

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Michael A. Mendall

Papers

C reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study.

Elevated Chlamydia pneumoniae Antibodies, Cardiovascular Events, and Azithromycin in Male Survivors of Myocardial Infarction

Relation of Helicobacter pylori infection and coronary heart disease.

Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors

Childhood living conditions and Helicobacter pylori seropositivity in adult life