Our results do not replicate those of previous studies showing associations between individual pathogens and atherosclerosis (e.g., [4
]). On the other hand, our null findings are consistent with results of a very large cohort study [28
] and those of a recent meta-analysis of randomized clinical trials [29
], both suggesting that antichlamydial antibiotic therapy does not reduce clinical atherosclerosis risk.
Pathogen burden, rather than individual pathogens, has been postulated as a risk factor for atherosclerosis and, indeed, several studies support its relationship with clinical coronary artery disease or death [15
], carotid atherosclerosis progression [13
], poor prognosis of patients with coronary artery disease [30
], ischemic stroke [31
], peripheral arterial disease [32
], and endothelial dysfunction [33
]. Yet, even after adjustment for multiple potential confounders, and in agreement with some other studies [34
], we could not observe an association of pathogen burden with proven markers of subclinical atherosclerosis.
Changes in the endothelium are related to infections [17
], and expression of cytokines in endothelial cells has been proposed as a mechanism linking infections to atherosclerosis [19
]. In addition, previous research suggests that pathogens may interact with inflammatory markers with regard to atherosclerosis [14
]. However, regardless of statistical significance, we only observed a clear-cut statistical interaction when examining the joint association of hepatitis A virus and s-ICAM-1 with Agatston score. Given the large number of interactions explored in the present analyses, this result may have been due to chance; however, its qualitative ('cross-over') nature warrants confirmation in future studies.
Among the strengths of our study are its population-based design, careful exposure, covariate and subclinical atherosclerosis measurements, and adjustment for multiple potential confounders. Among its limitations, inability to determine temporality given its cross-sectional nature is of particular concern, as antibodies may reflect prior, rather than current or chronic infections. Another possible reason for our null findings is past decreased survival for individuals with both infections and atherosclerosis, thus, resulting in survival bias at baseline. Because four of the five pathogens were measured in a random sample of about 20% of the cohort, insufficient statistical power may also explain our inability to detect associations; however, at least for Chlamydia, results for the whole cohort were also null. In addition, as prevalent cardiovascular disease was an exclusion criterion and as the distributions of some factors in the random sample and the whole cohort were not entirely comparable (), it is important to be cautious when generalizing the findings of the present study to the reference population.
In sum, we have investigated the link between individual pathogens, pathogen burden and subclinical atherosclerosis, and found no significant associations. It is possible that pathogen burden is related to a subset of the population prone to develop clinical manifestations of atherosclerosis, that is, those with both subclinical atherosclerosis and pathogen burden with its accompanying inflammatory process. Given the study’s limitations, longitudinal data on IMT progression, incidence and progression of coronary calcification, and incident cardiovascular events are needed to either confirm or reject our cross-sectional findings.