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Association between Chlamydia pneumoniae and Acute Myocardial Infarction in Young Men in the United States Military: The Importance of Timing of Exposure Measurement

  1. Christine M. Arcari1,
  2. Charlotte A. Gaydos2,
  3. F. Javier Nieto1,
  4. Margot Krauss4, and
  5. Kenrad E. Nelson3
  1. 1University of Wisconsin Medical School, Madison;, Baltimore
  2. 2Johns Hopkins University School of Medicine, Baltimore
  3. 3Johns Hopkins University Bloomberg School of Public Health, Baltimore
  4. 4Walter Reed Army Institute of Research, Silver Spring, Maryland
  1. Reprints or correspondence: Dr. Christine M. Arcari, Population Health Sciences, 605 WARF, 610 Walnut St., Madison, WI 53726 (carcari{at}wisc.edu).
 
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Abstract

Background. Several investigators have found that Chlamydia pneumoniae and cytomegalovirus infections may be risk factors for coronary heart disease. However, the data remain controversial. To address this hypothesis, data and specimens were collected from a well-established prospective cohort of active-duty personnel from the US military.

Methods. A nested case-control study was conducted with 300 case patients and 300 matched control subjects. Case patients were men (age, 30–50 years) with a medically documented, first-time hospitalization for acute myocardial infarction (MI) and from whom a serum specimen had been drawn ⩾1 year before the time of the acute MI. Population-based control subjects were chosen from the same cohort and were individually matched by age, race, and time of specimen collection. Evidence of past infections with C. pneumoniae and cytomegalovirus were measured by microimmunofluorescence assay and enzyme-linked immunosorbent assay, respectively.

Results. Significant risk was associated with high titer (⩾1 : 64) to C. pneumoniae immunoglobulin A (IgA) (adjusted relative risk [RRadj], 1.67; 95% confidence interval [CI], 1.04–2.70). This increased risk was greatest when specimens were collected 1–5 years before the event (RRadj, 2.11; 95% CI, 1.06–4.21). High titer (⩾1 : 256) to C. pneumoniae immunoglobulin G (IgG) was also associated with an elevated risk (RRadj, 1.74; 95% CI, 0.90–3.34) after full adjustment for cardiovascular risk factors, whereas no independent risk for acute MI was associated with cytomegalovirus IgG seropositivity.

Conclusions. This study demonstrates a significant association between high titers to C. pneumoniae IgG and IgA and acute MI in a cohort of young men and suggests that recent or chronic active infections could be associated with an increased risk for MI.

Recent epidemiological research initiatives have investigated the relationship between a variety of infectious agents and coronary heart disease. Chlamydia pneumoniae and cytomegalovirus (CMV) infections have been reported to be associated with coronary heart disease, although some case-control and cohort studies have failed to find a significant association [1, 2]. However, the consistency of many different types of observations supports the biological plausibility that infectious agents—particularly C. pneumoniae—are etiologic factors or cofactors in coronary heart disease. In addition to the epidemiological data, other research demonstrates the occurrence of atherosclerosis in animals infected with C. pneumoniae and CMV and isolation of C. pneumoniae from atherosclerotic plaques in humans [3–14].

Some clinical trials have shown antibiotic therapy to be efficacious for prevention of cardiovascular events [15, 16]. Although the Weekly Intervention with Zithromax [Azithromycin] for Atherosclerosis and Its Related Disorders (WIZARD) study showed that azithromycin had no beneficial effects for secondary prevention of coronary heart disease [17], the patients in that study had advanced atherosclerosis. Therefore, the fact that azithromycin did not reduce the risk of recurrent coronary heart disease in the WIZARD trial cannot be used as evidence against an etiological role of C. pneumoniae in the early pathogenesis of atherosclerosis, and studies of younger populations are necessary.

We conducted a nested case-control study among active-duty US military personnel to investigate the hypothesis that previous C. pneumoniae or CMV infection is an independent risk factor for coronary heart disease. The young age and generally excellent health of this population and the existence of prediagnostic serum samples available through the Department of Defense serum repository made this population ideal for evaluation of this relationship.

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Methods

The study population consisted of men aged 30–50 years who were on active duty in the US Army during the period of 1991–2000. Case patients (n = 300) were men who were hospitalized for a first myocardial infarction (MI; International Classification of Disease, Ninth Revision [ICD-9], code 410) for whom a serum sample had been available for ⩾1 year before the onset of MI. The US military maintains a repository of serum samples that contains residual serum left over from biannual screenings for HIV infection, which have been required of all active-duty military personnel since 1989 [18]. Case patients could not have any prior history of hospitalization for heart conditions (ICD-9 codes 401–429). Control subjects were individually matched to case patients by age (±1 year), race/ethnicity (“white non-Hispanic,” “black non-Hispanic,” and “other”), and availability of a serum specimen that had been collected within 60 days of collection of the case patient's specimen. Control subjects had not been hospitalized for cardiovascular disease (ICD-9 codes 401–429) before the date of the case event, and they were preferentially selected if they had undergone a Health Risk Appraisal (HRA). Hospitalization data were obtained from the Standard Inpatient Data Record, which is used in Department of Defense treatment facilities worldwide and which codes up to 8 diagnoses for each hospitalization on the basis of a health care provider's review and interpretation of test results, consultation data, and diagnostic and therapeutic procedures.

Information on health risk factors was obtained from the HRA, which was started by the Department of Defense in 1986 as part of a health promotion program and which includes self-reported information on past and current smoking habits, work stress, and diabetes, as well as measurements of height, weight, blood pressure, and serum cholesterol level [19]. Smoking status was categorized as “current,” “former,” and “never.” Responses to stress felt in the present work situation were “often,” “sometimes,” “seldom,” and “never.” Participants who had a systolic blood pressure ⩾140 mm Hg or a diastolic blood pressure ⩾90 mm Hg or who were currently receiving blood pressure medication were considered to be hypertensive; those with a serum total cholesterol level ⩾240 mg/dL were considered to be hypercholesterolemic. Height and weight were used to calculate body mass index, which was categorized as “desirable” (<25.0 kg/m2), “overweight” (25.0–29.9 kg/m2), or “obese” (⩾30.0 kg/m2).

Serum samples were tested for C. pneumoniae IgG and IgA antibodies using the microimmunofluorescence assay, titered to end point [20]. For both IgG and IgA, a threshold titer of ⩾1 : 16 was used to indicate evidence of past infection [20]. A high titer was defined as ⩾1 : 256 for C. pneumoniae IgG and as ⩾1 : 64 for C. pneumoniae IgA on the basis of previous literature and expert opinion. Evidence of previous infection with CMV was obtained using a commercially available ELISA (Wampole Laboratories) to measure IgG antibodies to CMV. All laboratory testing was performed by a single technician masked to the case-control status of the sample.

Statistical analyses were performed using SAS software, version 8.01 (SAS Institute). McNemar's test was used to examine differences in demographic characteristics between matched pairs in the full study population and to assess potential confounding variables. Multivariate conditional logistic regression was used to study the relationship between case-control status, infection status, and demographic covariates to identify important predictors of outcome [21]. Variable selection for final models was based on the results of the likelihood ratio test. Age was included in all final models to control for residual confounding. Stratification by age at the onset of acute MI and time between specimen collection and onset of acute MI was performed. To explore the role of established cardiovascular risk factors as confounders and effect modifiers, a subset of the study population with complete HRAs was used. Matching was ignored in the subset population to maximize sample size, but all matching variables were included in the multivariate model. The 2-sample Student's t test and the χ2 test were used to compare unmatched case patients and control subjects in the subset study population, and unconditional logistic regression was performed to study the relationship between case-control status, infection status, and demographic and cardiovascular risk factor covariates [21]. The study was reviewed and approved by the institutional review boards of Johns Hopkins University (Baltimore, MD) and the Walter Reed Army Institute of Research (Silver Spring, MD).

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Results

A comparison of case patients and control subjects in the full study population of 300 individually matched case-control pairs is shown in table 1. Case patients were statistically more likely to be of lower military rank, to be less educated, and to be married than were control subjects. Table 2 shows the distribution of the results of serological testing for C. pneumoniae IgG and IgA and CMV IgG. Complete information on established risk factors for cardiovascular disease (i.e., elevated cholesterol level, smoking, hypertension, obesity, and stress) was available for 168 case patients (56.0%) and 259 control subjects (86.3%). Case patients with complete HRAs tended to be older (mean age, 41.0 vs. 39.2 years; P = .002) and were more likely to have a college education or greater (42.9% vs. 28.5%; P = .01), compared with case patients without HRAs or with incomplete HRAs. There were no differences in demographic characteristics between control subjects with and without complete HRAs.

Table 1
Table 1

Demographic characteristics of the full population of case patients and control subjects.

Table 2
Table 2

Results of serologic tests for the full study population.

For case patients and control subjects in the subset population with complete cardiovascular risk factor data, case patients were slightly older than control subjects (table 3). No differences were observed by race or military rank, but case patients were less likely to have greater than a college education than were control subjects. As expected, there were significant differences between the 2 groups with regard to cholesterol level (P < .0001), smoking status (P < .0001), and stress in the present work situation (P = .004). No statistically significant differences were observed for the other established cardiovascular risk factors, hypertension and obesity. Only 2 control subjects and no case patients reported a history of diabetes.

Table 3
Table 3

Demographic characteristics and cardiovascular risk factors for the subset study population.

In the full study population, there was no association between high C. pneumoniae IgG titer (⩾1 : 256) or CMV IgG seropositivity and acute MI (table 4). There was also no association observed for a C. pneumoniae IgG titer of ⩾1 : 64 (adjusted relative risk [RRadj], 1.04; 95% CI, 0.68–0.59) (data not shown). However, a high titer to C. pneumoniae IgA was found in significantly more case patients than control subjects (P = .03), an association that persisted after adjustment for age, military rank, education, and marital status (RRadj, 1.67; 95% CI, 1.04–2.70).

Table 4
Table 4

Crude relative risk (RR) and adjusted relative risk (RRadj) for acute myocardial infarction, by infection status, for the full and subset study populations

The subset of the study population with complete cardiovascular risk factor information was used to assess the effects of established cardiovascular risk factors on the relationship between serum antibodies and coronary heart disease (table 4). For C. pneumoniae IgA, RRs for acute MI by infection status were similar to the results seen in the full study population, including a statistically significant increased risk associated with high titer even after full adjustment for cardiovascular risk factors (RRadj, 1.78; 95% CI, 1.00–3.18). Unlike the results for the full study population, in the subset population, the unadjusted RR for C. pneumoniae IgG was significant (RR, 1.87; 95% CI, 1.04–3.34) and remained elevated after adjustment for demographic characteristics and cardiovascular risk factors, although it was no longer statistically significant (RRadj, 1.74; 95% CI, 0.90–3.34).

Additional analyses of C. pneumoniae IgG and IgA were conducted for the full study population to investigate the importance of time between measurement of infection status and onset of acute MI and the role of age at time of acute MI (table 5). To explore the temporal importance of exposure measurement, the study population was stratified on the basis of the length of calendar time between measurement of infection status and the onset of acute MI (1–5 years for 161 case-control pairs and ⩾5 years for 139 case-control pairs).

Table 5
Table 5

Adjusted relative risks (RRadj) for acute myocardial infarction (MI), by infection status, time of specimen collection before onset of MI, and age at time of MI, for the full study population.

A striking difference was observed for high titer to C. pneumoniae IgA. After adjustment for age, military rank, education, and marital status, the RRadj for C. pneumoniae IgA when the specimen had been collected 1–5 years before the onset of acute MI was 2.11 (95% CI, 1.06–4.21), compared with an RRadj of 1.34 (95% CI, 0.67–2.65) when the specimen had been collected ⩾5 years before onset of acute MI. This pattern remained even after a second stratification by age at onset of MI (data not shown). Statistical tests for interaction between time of specimen collection and C. pneumoniae titer level did not yield significant results. There was little difference in risk between time periods for high titer to C. pneumoniae IgG.

Age at the time of onset of acute MI was 30.0–39.9 years for 142 case-control pairs and 40.0–50.0 years for 158 case-control pairs. Elevated RRs were observed at high titers to C. pneumoniae IgA regardless of age at the time of onset of acute MI, although they were slightly higher in the 40.0–50.0-year age group. The RRadj for high C. pneumoniae IgA titer among case-control pairs with an age at onset of acute MI of 30.0–39.9 years—the younger group—was 1.62 (95% CI, 0.81–3.24), and it was 1.82 (95% CI, 0.93–3.58) for case-control pairs in the older group.

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Discussion

We found that a high titer to C. pneumoniae IgA antibodies was independently associated with incidence of acute MI in the full study population. This relationship was maintained in the subset study population after further adjustment for cardiovascular risk factors. No association between acute MI and C. pneumoniae IgG was observed, with or without adjustment for demographic characteristics, in the full study population. However, in the subset study population, a significant increased risk for acute MI at high C. pneumoniae IgG titer was noted, although the association did not remain significant after full adjustment for demographic characteristics and cardiovascular risk factors. No association between acute MI and CMV IgG was detected in either the full or subset study populations. These data suggest that a recent or chronic active C. pneumoniae infection before a first MI might be related to coronary heart disease.

Stratification based on the time of specimen collection before onset of acute MI showed a strong relationship with C. pneumoniae IgA only among case-control pairs for whom the specimen had been collected 1–5 years before the onset of acute MI and was not seen in the case-control pairs for whom the specimen had been collected ⩾5 years before the onset of acute MI. This indicates the possible importance between the time of infection and the date of the actual cardiac event. Although the results of the test for interaction were not statistically significant, the markedly different RR estimates suggest the possibility of true interaction and should be confirmed by a study with sufficient power to detect it.

The published literature rarely accounts for the issue of time of infection, with the exception of an early study by Saikku et al. [22]. In that study, exposure measurement 6 months before onset of MI had an elevated OR for high titer (⩾1 : 64) to C. pneumoniae IgA (adjusted OR, 2.4; 95% CI, 0.9–6.6). This relationship was not seen for specimens that had been collected more remote from the time of MI onset (adjusted OR, 1.2; 95% CI, 0.5–2.9). Long intervals between C. pneumoniae antibody measurement before an MI may explain some of the discordant results and insignificant findings of earlier studies.

There are many studies in the literature that have explored the relationship between C. pneumoniae IgG and coronary heart disease, and the results remain inconclusive. Many of these studies have been conducted with older populations. High rates of previous infection, the presence of atherosclerosis, and other comorbidities found in older populations make it difficult to study any association between infection and coronary heart disease. Adjustment for cardiovascular risk factors and other potential confounders is not standardized. Methods to measure infection differ between studies, and there is no general consensus for the definition of seropositivity. In the present study, with use of a C. pneumoniae IgG titer of ⩾1 : 64, the RRadj in the full study population was comparable to the result from a combined analysis of 15 prospective studies, which produced an overall OR for C. pneumoniae IgG of 1.15 (95% CI, 0.97–1.36) [23]. These data seem to exclude the possibility of a strong effect of C. pneumoniae IgG. However, previous studies have shown an association between high titer to C. pneumoniae IgG and coronary heart disease, which is similar to the results of the present study with a C. pneumoniae IgG titer of ⩾1 : 256 [24, 25].

Compared with C. pneumoniae IgG, far fewer studies have been reported in the literature on the association between C. pneumoniae IgA and coronary heart disease. A review of 10 studies of C. pneumoniae IgA and nonfatal MI or death due to coronary heart disease revealed that the association between C. pneumoniae IgA and coronary heart disease was stronger than that with C. pneumoniae IgG, with a summary OR of 1.24 (95% CI, 1.02–1.51), although these studies faced the same limitations as the IgG studies [26]. It has been hypothesized that IgA may be a better marker of chronic infection or recent reinfection, because the half-life of serum IgA is only 5–6 days [27].

Many studies that have examined the relationship between CMV infection and coronary heart disease, including ours, have not found an association between CMV IgG antibodies and MI. One study has shown an increased risk of atherosclerosis at the highest CMV antibody levels and also reported a strong interaction between high antibody levels of CMV and diabetes [28]. A quantitative test for CMV IgG was not used in the present study, but the fact that the association found was inverse makes finding a similar association unlikely. Diabetes was rare in the present study population, making it impossible to evaluate an interaction between CMV and diabetes. It has also been reported that a direct relationship between CMV infection and coronary heart disease has been seen in female subjects but not in male subjects, which may be related to sex-related differences in immune response to CMV [29]. There are several studies that show positive significant relationships between CMV and increased risk of both posttransplantation atherosclerosis and restenosis, which may be different diseases [30]. CMV is persistent in the body in a latent state, and perhaps acute endothelial damage or an immunocompromised state is needed for reactivation.

Confidence in the results of this study comes, in large part, from the strengths of the US military cohort. The study population was young: 35% of the case patients were <40 years of age at time of onset of acute MI, and the other case patients were 40–50 years of age and were generally healthy). High rates of asymptomatic coronary heart disease in control subjects, a problem in older populations in particular, may explain some of the negative results found in the literature. The young age of this study population allows for exploration of the role of infections in coronary heart disease at earlier stages of the natural history of atherosclerosis and may not be generalizable to older populations. Despite their youth, it is still possible that some of the control subjects in our study may have had asymptomatic coronary heart disease or have been hospitalized for acute MI, because control subjects were not contacted to confirm the absence of hospitalization for acute MI. As with previous studies, the resulting misclassification would make estimates of the RR conservative.

The large size of the US military cohort allowed us to choose closely matched control population-based subjects. The resource of the Department of Defense serum repository is unparalleled. It was possible to match case patients and control subjects on the basis of time of specimen collection and to establish the temporality of exposure and outcome.

The presence of antibodies to C. pneumoniae or CMV in the serum does not guarantee the persistence of active infection at any site in the body or persistent exposure of the coronary arteries to any type of insult. C. pneumoniae and CMV antibody titers may decrease substantially within a few years after seroconversion and may increase substantially if reinfection occurs, making it difficult to interpret antibody levels measured at only a single point in time. It is unclear when in the coronary heart disease process infections are most likely to exert a negative impact. Different stages of infection (acute, chronic, latent, or recurrent infection) may or may not be involved in pathogenesis or may be involved in different ways. Infections may produce plaque instability, leading to rupture at later stages of disease, or infections may play a part in the initiation and early promotion of atherosclerosis at a young age. A better understanding of antibody level and the stage of the infectious process represented is essential. This is the next necessary step that must be taken to further investigate the association between infection and coronary heart disease.

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Acknowledgments

We are grateful to Colonel Patrick Kelley and Colonel Mark Rubertone from the Department of Defense for their invaluable assistance in accessing data and specimens. We thank Mellisa Theodore, Billie Jo Wood, Justin Hardick, Jeff Holden, and Anthony Quinn from the Johns Hopkins International Chlamydia Research Laboratory for technical assistance.

Financial support. American Heart Association (grant AHA 0240103N).

Potential conflicts of interest. All authors: no conflicts.

  • Received June 9, 2004.
  • Accepted December 3, 2004.
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  1. Clin Infect Dis. (2005) 40 (8): 1123-1130. doi: 10.1086/428730
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