In this cross-sectional analysis, we found an association between a weighted measure of infectious burden, previously shown to be associated with stroke risk in our population (29
), and carotid plaque thickness, a known risk factor cerebrovascular events. This analysis provides indirect evidence that, if infectious burden is associated with stroke risk, then atherosclerosis, as measured by carotid plaque thickness, may be a mechanism for this increased risk. Therefore, this study enhances the validity of infectious burden as an independent risk predictor of stroke through its effects on atherosclerosis. Infectious burden may be a modifiable marker of stroke risk and measurement of carotid plaque thickness may offer a way to assess the effects of anti-infective strategies. In particular, our secondary findings suggest that infectious burden may be associated measures of plaque instability, such as irregular plaque.
The infectious diseases that comprise the NOMAS IB index are common chronic infections that were reported to contribute to atherosclerosis and to have an association with stroke risk. C. pneumoniae
is an obligate intracellular prokaryote and represents the most studied infectious risk factor for vascular outcomes associated with atherosclerosis. Epidemiological, pathological, and animal studies support an association of C. pneumoniae
with atheroma development (6
), but not all studies have found this association. (31
) Previous studies found C. pneumoniae
IgA to be more strongly associated with stroke risk than IgG. (7
, a well-characterized infectious agent responsible for chronic gastric inflammation; moreover, it has been linked to stroke caused by small-artery occlusion in case-control studies. (11
) Additionally, many viral pathogens in the herpesviridae family, characterized by latent or persistent infection, were implicated in increased stroke risk. (16
) For example, CMV was associated with increased stroke risk in some (34
), but not all studies. (36
) Other members of this family, such HSV 1 and HSV 2, have an unclear association with stroke risk, demonstrating inconsistent relationships with stroke risk. (10
The mechanism for the association of infectious burden with atherosclerosis is uncertain. It is possible that infectious organisms directly invade the vascular wall. For example, a small (n=85) case-control study used PCR to evaluate the presence of persistent infection in atherosclerotic lesions of samples excised from patients undergoing coronary bypass grafting, endarterectomy, or surgery of the abdominal aorta; C. pneumoniae
DNA was found in 26% of cases and H. pylori
in 37% of cases, whereas no pathogen DNA was found in controls. (38
) Animal models also implicated infection in enhancing the risk for neointimal response to endothelial and smooth muscle injury, without direct endothelial localization. (39
) Other potential mechanisms include enhanced macrophage lipid uptake (40
); increased gene expression and cell-surface localization of adhesion molecules and inflammatory cytokines (41
); increased smooth cell proliferation (42
); localized hypercoagulability (43
); macrophage activation and plaque destabilization (44
); and molecular mimicry, whereby pathogens contain proteins homologous to vascular self-epitopes. (45
The combined use of multiple serological tests for infectious diseases, to obtain a composite indicator of infectious burden, was used previously in secondary prospective analyses of data from clinical trials, such as the Heart Outcomes Prevention Evaluation (HOPE) trial, (18
) and in observational studies, including the Framingham Heart Study (46
). In these studies there was limited evidence of association with stroke as a primary outcome. However, in prior analyses in the NOMAS cohort, the weighted IB was associated with stroke risk. (29
Previous studies also sought to elucidate the relationship between positive infectious disease serological results and plaque progression. In one study, serological testing for 8 infectious agents (HSV1/2, CMV, Epstein-Barr virus, Hemophilus influenzae, C. pneumoniae, M. pneumoniae
, and H. pylori
) were used to compile an independent infectious burden measure, with a score ranging from 1–8, to predict plaque progression as assessed by multiple diagnostic measures including angiography and Doppler. This simple score was associated with progression of atherosclerosis after adjusting for age, sex, and cardiovascular risk factors. (16
) In another study, 504 patients were evaluated for both carotid artery intima-media thickness (IMT) and infectious disease serology at baseline and follow-up time points. (17
) Infectious burden predicted IMT progression of ≥0.1 mm/year with an OR= 2.89, 95% CI of 1.14–7.28 in the group with 6–8 positive serological results, as compared to the reference group with 0–3 positive serological results. (17
) Limitations of these studies include the apparent post-hoc nature of the thresholds for measuring infectious burden, the non-quantitative approach that assumes the effect of all infections is equal, and the absence of adjustment for socio-economic status.
The major strength of our study is the use of a weighted measure to characterize the aggregate effect of infectious disease burden on atherogenesis. Our approach does not assume equal effects for each pathogen. Additional strengths include the use of a large, multi-ethnic and urban population-based study, with a predominant Hispanic population, capturing a traditionally underrepresented group. In addition, we assessed the potential confounding by additional markers of inflammation, including hs-CRP and leukocyte counts.
Weaknesses of our approach include performing a cross-sectional analysis and the use of serological measures of infection and carotid plaque thickness at a single time point. Therefore, we cannot assess the temporal relationship between increased MCPT and IB. Future studies in our cohort and others may evaluate the ability of weighted infectious burden measures as they relate to repeated measures of plaque progression. In addition, the NOMAS cohort lacks systematically collected clinical information regarding preexisting inflammatory conditions, infection status, and immune-related interventions that may confound the relationship of IB and atherosclerosis. Nonetheless, most members of our population are healthy, without significant autoimmune or infectious diseases. Finally, the NOMAS sub-population under study in this analysis is significantly younger and has a greater proportion of Hispanics than the overall NOMAS cohort, potentially limiting the generalizability of our findings.
Recent clinical trials found no evidence that antibiotic treatment of C. pneumoniae
and other infections reduce vascular risk. (47
) These studies, however, remain subject to weaknesses due to restrictions to cardiac patients, inclusion of participants without serological evidence of infection, and use of antibiotic treatment late after disease onset. Meanwhile, evidence that infection can be a stimulus for atherothrombosis continues to accumulate. These observations, along with the results of this current study lend support to the notion that past or chronic exposure to common infections, perhaps by exacerbating inflammation, may be an important etiologic factor of atherosclerosis. Future studies are needed to confirm these findings and to define optimal measures of infectious burden as a vascular risk factor. Ultimately, clinical trials employing enhanced measurement tools, such as the Infectious Burden index, that better capture total infectious burden will be required to test whether preventive or anti-infective strategies can modify the risk of vascular disease associated with infection.