Claudio Bozzoli

Association of serum C3 levels with the risk of myocardial infarction

PURPOSE Serum complement and IgA levels have been found to be retrospectively associated with the presence of diffuse atherosclerosis. This study was performed to assess whether serum immunoglobulins and complement components are predictive of future ischemic events. PATIENTS AND METHODS The baseline values of IgG, IgA, IgM, C3, and C4 were measured in the sera from a cohort of 860 inhabitants of the town of Brisighella, Italy. They were 444 men and 416 women, mean age 53.9 years (SD 12.4, range 23 to 84), who had not had any ischemic events (myocardial infarction [MI], angina pectoris, stroke, transient ischemic attack, or intermittent claudication) at the time of blood sampling in 1984. Their baseline values for the main recognized risk factors for atherosclerosis were known at baseline and for 4 years of follow-up. Multiple logistic regression analysis was performed for associations between ischemic events and immunologic variables (including serum IgG, IgA, IgM, C3, and C4) and risk factors for atherosclerosis (including age, sex, diastolic blood pressure, cigarette consumption, Quetelet index, total cholesterol, HDL cholesterol, triglycerides and blood glucose). RESULTS During follow-up, 57 subjects experienced ischemic events, including 28 cases of coronary heart disease (17 MI and 11 angina pectoris). Of the immunologic variables studied, only serum C3 was found to be independently associated with ischemic events (P < 0.005 for any ischemic events, coronary heart disease, and MI). The population was divided into thirds according to C3 values. The cumulative incidence of MI was 7.1/1,000 in the low third, 10.6/1,000 in the middle third and 40.8/1,000 in the high third (risk ratio for high versus middle plus low = 4.2 after adjustment for age and sex; 95% CI 1.5 to 11.7). A separate analysis for the sexes showed that serum C3 was a particularly powerful predictor of MI in men. Men whose C3 levels were in the top third had a 72.6/1,000 incidence of MI while the incidence in the rest of the male population was 6.2/1,000 (risk ratio 10.7 after adjustment for age; 95% CI 2.3 to 49.0). When similar analyses were performed for angina pectoris, stroke, and intermittent claudication, no significant increase in risk was found to be associated with serum C3. CONCLUSION C3 levels measured in sera from male subjects without previous ischemic events are independently associated with the risk of MI.

Complement Components and Fibrinogen: Correlations and Association with Previous Myocardial Infarction

Serum complement levels have been found to be predictive of myocardial infarction up to 4 years before the acute event. To assess whether they are a marker of a hypercoagulable state, the serum or plasma levels of C3, C4, C3a, C4a, C1 inactivator, antithrombin III, protein S, protein C, fibrinogen and tissue plasminogen activator were measured in 31 patients with previous myocardial infarction and 33 controls (all males, 40-60 years old). C3, C4 and fibrinogen (which share the common characteristic of being acute phase proteins) were correlated and were associated with previous myocardial infarction, although this association persisted only for C4 in multivariate analysis. None of the coagulative variables directly involved in the complement system differed significantly in the two groups.

Increased Serum IgA Levels in Subjects with Previous Myocardial Infarction or Other Major Ischemic Events

To ascertain whether the increase in serum IgA, which has been found to be associated with the presence of severe atherosclerotic disease, precedes or follows the occurrence of major ischemic events (MIE), we studied the serum levels of IgA as well as IgG and IgM in 145 subjects with acute or previous ischemic events and 34 controls. The subjects with previous myocardial infarction had higher IgA levels with respect to the controls, the patients with angina pectoris and those with acute myocardial infarction, while no significant differences concerning IgG and IgM were found. In the subjects with previous extracoronary events, immunoglobulin levels tended to be even higher. Overall, 30% of the subjects with previous MIE and only 3% of the controls had IgA levels over 4.5 g/l (p = 0.0018). This study indicates that total serum IgA is a marker of previous major ischemic events (protracted immune response to denatured proteins?), rather than a factor predisposing to atherosclerosis development.

Association of serum IgA antibodies to milk antigens with severe atherosclerosis

The presence of antibodies of the IgA class against dietary antigens (bovine IgG (BGG), beta-lactoglobulin, casein, alpha-lactalbumin and xanthine oxidase, chicken ovalbumin and crude gliadin) was checked in the sera of 23 severely atherosclerotic subjects (ATS) and 20 highly selected controls (C). In these subjects an association between serum IgA levels and atherosclerosis had previously been shown. Determinations were performed by a micro-ELISA method and results were expressed as absorbances at 405 nm x 1000. Higher levels of IgA antibodies were found in ATS with respect to C against beta-lactoglobulin (respectively, 113.4 +/- 152.4 (1 SD) vs. 40.0 +/- 34.2; P less than 0.005) and casein (69.8 +/- 35.5 vs. 52.4 +/- 27.5; P less than 0.05). There was no difference in IgG and IgM against these 2 proteins between the 2 groups. Significant differences of prevalence of IgA antibodies were found for the following antigens: beta-lactoglobulin (4 C and 16 ATS over the limit value of 51; P less than 0.002), xanthine oxidase (1 C and 9 ATS over 289; P less than 0.01), BGG (7 C and 17 ATS over 87; P less than 0.02) and casein (5 C and 14 ATS over 60; P less than 0.02). These data suggest an association between anti-milk IgA antibodies and atherosclerosis. Its relevance and significance deserves further investigation.

Chronic ischemic heart disease: prevention and therapy

In the term of “chronic ischemic heart disease” a series of different nosological, physiopathologic and etiological forms are included, which can differ even considerably in their therapy. Among these, stable, unstable, variant and microvascular angina are the most common, as well as the various forms in which chest pain is absent or is not the main symptom, such as “silent” ischemic heart disease and the arrhythmic or congestive forms. While at present the causes of microvascular angina are not well known, the forms affecting large epicardial vessels are mostly due to coronary atherosclerosis, although arterial diseases caused by different etiologies (infectious, dysreactive, malformative) may occasionally be involved. Therefore, from the point of view of both practical feasibility and interest due to incidence, the prevention of chronic ischemic heart disease actually coincides with atherosclerosis prevention.