In the present study, we found a significant association between pathogen burden and CMV seropositivity with CAD in the Asian Indian population, which is known to have higher risk for early development of the disease (20
). Serostatus was used as an indicator of previous infection with these pathogens. We also report that, in the presence of inflammatory markers, the risk association between burden of infection and CAD is augmented. Our results suggest that the levels of markers, such as hsCRP, IL-6, fibrinogen and sPLA2, show an association with anti-CMV antibody levels and the presence of these markers and, along with CMV infection, may enhance the susceptibility of the individual to cardiac events.
We found a high seropositivity for CMV (97.7%) in our study population compared with 50% to 85% in the western population (22
). However, the seropositivity was lower for C pneumoniae
in our population (26.2% versus 40% to 80% in the western population [25
]). The burden of infection showed a positive association with CAD, with the highest RR observed in the group with seropositivity for all the four pathogens studied, suggesting that pathogen burden is an important risk factor in the Asian Indian population. In a multiethnic study of atherosclerosis, Moyses Szkloa et al (28
), studied the cross sectional relationship between pathogen burden and subclinical atherosclerosis in a random sample of 1056 multiethnic individuals but failed to find an infectious etiology for subclinical atherosclerosis. A higher prevalence of infection in our population and the fact that we examined the clinical manifestation of the disease – not subclinical atherosclerosis – may explain the difference in the results
Pathogens can cause an increase in expression of proatherogenic markers such as acute phase proteins, chemokines, cytokines and adhesion molecules (15
). We chose CRP, sPLA2, IL-6 and fibrinogen as a few inflammatory markers to study the effect of these markers on infection associated risk of CAD. Interestingly, the risk association with seropositivity increased twofold in the presence of hsCRP, which has been extensively reported to have an association with cardiovascular diseases (29
). Although the ORs remained significant with the other three markers, we did not observe an increase in the RR. Thus, pathogen burden appears to be an important factor in determining the predisposition to CAD in Asian Indians and the addition of hsCRP levels can improve the identification of high-risk individuals in this population.
CMV seropositivity contributed independently to CAD risk as well as recurrent cardiac events in patients in this population. Several epidemiological studies have reported twofold or higher ORs for the association between CMV antibodies and CAD occurrence (22
). Increasing titres of CMV antibodies have been shown to be associated with severity of atherosclerosis, indicating a virus-mediated pathogenic mechanism for CAD (32
). This association appears most pronounced with coronary restenosis following angioplasty, graft rejection and transplantation (24
). High levels of anti-CMV antibodies are known to be associated with reactivation of a latent infection, a detrimental condition for atherosclerosis (35
). In our study, the basal level of CMV antibodies in CAD patients showed a direct association with mortality with significantly higher CMV antibodies in patients reporting a fatal event, suggesting that it could be one of the markers for the pathological complications.
and H pylori
serostatus were not associated with CAD in Indians. Our results are in agreement with a meta-analysis of 15 prospective studies; a pooled covariate adjusted OR of 1.15 (95% CI 0.97 to 1.36; P>0.1) was reported for the association of C pneumoniae
IgG antibodies and CAD (12
). The absence of risk association between CAD and C pneumoniae
antibodies may be explained by the fact that we measured only IgG antibodies and not IgA, which has been reported to be a better marker for recent exposure to infection in Indian and European populations (23
). Clinical reports on the association of CAD and H pylori
infection have also been inconsistent. These contradictory reports may, in part, be explained by the different genotypes of H pylori
among which only the cytotoxin-associated gene-A (Cag A
)-positive virulent strains show a disease association (37
). In our study, we could not establish any association between H pylori
infection and CAD, probably due to the estimation of antibody titres for H pylori
antigens and not specifically the CagA
Several mechanisms have been proposed to associate CMV infection with cardiovascular diseases. CMV can directly infect vessels, and its presence may induce smooth muscle cell proliferation, expression of inflammatory cytokines, increased uptake of lipoproteins and increased procoagulant activity of endothelial cells (15
). Expression of several genes involved in immune and inflammatory responses were found to be altered on CMV infection in normal mice (15
). Increased release of inflammatory cytokines in turn is believed to stimulate the release of sPLA2 from vascular smooth muscle cells (41
), which is also associated with the risk of coronary events (42
It is also suggested that individuals seropositive for CMV, with a subclinical inflammatory profile as estimated by CRP levels, are more susceptible to atherosclerosis compared with those without inflammation (44
). We observed a direct association between CMV antibody levels and mean levels of IL-6, fibrinogen, sPLA2 and hsCRP, suggesting a subclinical inflammatory profile for these individuals. Although the levels of the four inflammatory markers were higher in the highest quartile of CMV antibodies, the RR association of CMV antibodies increased only in the presence of hsCRP reiterating the importance of hsCRP in subclinical inflammation. The biomarkers IL-6, fibrinogen and sPLA2 increased the risk as well as the discriminatory power of CMV antibodies when included along with hsCRP, suggesting that a multi-marker-based model including CMV antibodies and inflammation may improve the prediction of CAD risk in this population.
It has also been reported that CMV reactivation may accelerate the process of atherogenesis (15
). During the process of reactivation, cross-reacting human peptides may be presented by the virus due to molecular mimicry resulting in hyperactivation of immune system (16
). Thus, CMV reactivation seems to be important in the physiological harm caused by the virus. The factors that can cause viral reactivation include stress, age, immunosuppression and coinfection, which may influence the risk association of CMV with CAD. Given the high CMV seropositivity in the Indian population, along with higher stress associated with the working class, the possibility of reactivation and CMV-induced pathogenesis may be an important risk factor for this population.