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Arterial Intima-Media Thickness in 13-Year-Old Adolescents and Previous Antichlamydial Antimicrobial Use: A Retrospective Follow-up Study

^a Research Centre of Applied and Preventive Cardiovascular Medicine
^b Departments of Pharmacology, Drug Development and Therapeutics
^c Pediatrics
^d Medicine
^e Virology
^g Clinical Physiology, University of Turku, Turku, Finland
^f Department of Health and Functional Capacity, National Public Health Institute, Turku, Finland

	ABSTRACT

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BACKGROUND. Children with persistent Chlamydia pneumoniae infection may be at increased risk for atherosclerosis. The impact of antimicrobial therapy for primary prevention of atherosclerotic cardiovascular disease is unsolved.

OBJECTIVE. The purpose of this study was to determine whether treatment with antimicrobial agents effective against C pneumoniae during childhood, regardless of indication, has a favorable influence on the arterial wall-thickness in children by the time they reach adolescence.

SUBJECTS AND METHODS. The association of macrolide, tetracycline, quinolone, and rifamycin use (number of exposure events) between ages 5 and 13 years with carotid and aortic intima-media thickness at age 13 years was investigated among 508 healthy children. Information about the use of medications was obtained from the Finnish prescription register. Arterial intima-media thickness was measured with a high-resolution ultrasound.

RESULTS. Mean aortic intima-media thickness showed a significant direct association with the number of antichlamydial antimicrobial exposure events also after controlling for established atherosclerotic risk factors. Elevated C-reactive protein level had an additional effect on aortic intima-media thickness in a multivariable model. Carotid intima-media thickness was not associated with the number of preceding antichlamydial treatments.

CONCLUSIONS. Recurrent antichlamydial treatments in childhood have no favorable influence on early vascular changes but are associated with increased intima-media thickness in the abdominal aorta. These findings suggest that the use of antimicrobial agents does not offer protection against the potential atherogenicity of repeated infectious insults.

Key Words: antimicrobial agents • atherosclerosis • infection • prevention • ultrasound

Abbreviations: CAD—coronary artery disease • IMT—intima-media thickness • aIMT—aortic intima-media thickness • cIMT—carotid intima-media thickness • STRIP—Special Turku Coronary Risk Factor Intervention Project • Ig—immunoglobulin • HDL—high-density lipoprotein • LDL—low-density lipoprotein • CRP—C-reactive protein • CI—confidence interval

Chronic Chlamydia pneumoniae infection and prevalent coronary artery disease (CAD) seem to be interrelated, as suggested by seroepidemiologic data^1,2 and by the demonstration of viable C pneumoniae in atherosclerotic arterial walls.³ C pneumoniae is also associated with impaired endothelial function⁴ and increased thickness of the carotid⁵ and aortic intima-media complex.⁶ These observations indicate a possible association between C pneumoniae infection and the early stages of atherogenesis. Therefore, it has been hypothesized that treatment with antimicrobial agents against C pneumoniae could prevent the progression of atherosclerotic lesions towards clinical CAD and reduce adverse events in patients with CAD. However, despite promising initial trial results,² standard antimicrobial agents have neither reduced the risk of first-time myocardial infarction⁷ nor proven to be beneficial for the secondary prevention of CAD.^8,9 On the other hand, antimicrobial agents improve arterial endothelial function in C pneumoniae–seropositive patients with CAD,¹⁰ halt C pneumoniae–induced acceleration of aortic intimal thickening in rabbits,¹¹ decelerate the progression of early carotid atherosclerosis in children with acute infections¹² and in adults with cerebrovascular disease,¹³ and reduce C pneumoniae counts within carotid atherosclerotic plaques.¹⁴

We have demonstrated recently that healthy children with persistent C pneumoniae seropositivity have increased intima-media thickness (IMT) in the abdominal aorta,⁶ the site of the first atherosclerotic lesions of the vasculature.¹⁵ Because of the contrasting results in the antimicrobial trials, we obtained information about the use of antichlamydial antimicrobial agents during childhood and related it to carotid IMT (cIMT) and aortic IMT (aIMT) in 13-year-old adolescents.

	METHODS

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Study Design and Subjects
The design of the Special Turku Coronary Risk Factor Intervention Project (STRIP) has been published.¹⁶ Briefly, 1054 families with 1062 healthy 6-month-old infants volunteered in 1990–1992 to participate and were randomly assigned to an intervention group (n = 540) or to a control group (n = 522). The intervention group received detailed dietary and lifestyle counseling aiming at minimizing the children's exposure to environmental atherosclerosis risk factors. The study was conducted according to the Helsinki Declaration and approved by the local ethics committee. All of the parents gave their written informed consent.

A noninvasive ultrasound scanning to examine for the presence of early atherosclerosis was performed at age 13 years on 521 children (90% of the cohort remaining in the STRIP at that age [n = 578]) after an overnight fast. Data regarding the use of antimicrobial agents were gathered from the Finnish prescription register, maintained by the Social Insurance Institution of Finland since 1994.¹⁷ Because no prescription data were available for 13 of the 521 children who underwent ultrasound scanning, 508 children were eligible for final analysis of associations between ultrasound measures at age 13 years and antecedent antimicrobial use. An identical follow-up period for all of the study children born in 1989–1991 was determined according to the child with the briefest interval between the beginning of year 1994 (prescription register data first available) and the date of the ultrasound (8.2 years). Exposure to antimicrobial agents was then assessed for each child in this predefined window of exactly 8.2 years preceding the ultrasound scanning, that is, between the baseline age of 5 years (range: 4.6–5.1 years) and the ultrasound age of 13 years (range: 12.8–13.3 years).

As part of the STRIP, fasting blood samples were drawn annually from an antecubital vein of all of the participants. In this study, blood samples drawn at ages 5 and 13 years were used. The children had no apparent symptoms of respiratory tract infection at the times of blood sampling. Of the 508 study children, 111 had C pneumoniae immunoglobulin G (IgG) and IgA antibodies assessed at ages 5 and 11 years (later called the C pneumoniae subgroup).

One child with familial hypercholesterolemia and the 3 who had developed type 1 diabetes were excluded from this study. Children with asthma or asthma-like symptoms (n = 52) were included.

Ultrasound Measurements
The ultrasound scanning and the offline analysis of the scans were performed by 1 experienced operator blinded for the participant data.^6,18 An Acuson Sequoia 512 mainframe (Acuson, Mountain View, CA) with a 13.0-MHz linear-array transducer was used.

For cIMT, the far wall of the distal common carotid arteries 1 to 2 cm from the bulb on both sides was imaged from 2 angles. Two end-diastolic frames from both interrogation angles on both sides were analyzed for mean and maximum IMT. The average of these measurements was used as the mean cIMT, and the maximum cIMT was defined as the mean of the left and right maximum cIMTs. The between-visit coefficient of variation of the cIMT measurement was 3.9%.¹⁸

The aIMT was studied as described earlier,^6,18 that is, several images of the most distal 15 mm of the aortic far wall were captured at end-diastole for offline analysis. Two best images were chosen for the analysis. At least 4 measurements covering the entire far wall segment of interest were taken for each image. Maximum aIMT and the average of these measurements as mean aIMT were used. The between-visit coefficient of variation of the aIMT measurement was 4.9%.¹⁸

Exposure to Antimicrobial Agents
Because a physician's prescription is required for antimicrobial agents in Finland, information about their use was obtained by linking the personal social security code of each study participant with the respective data in the nationwide prescription register covering all permanent Finnish residents.¹⁷ This register is based on Anatomic Therapeutic Chemical codes¹⁹ and composes 97% of all reimbursed medication purchases from Finnish pharmacies. Antimicrobial drugs were defined in this study as those with Anatomical Therapeutic Chemical codes J01 (systemic antibacterials) and J04AB02-05 (rifamycins). In 2003, the prescription register captured 91% of outpatient consumption for macrolides and tetracyclines (except for doxycycline, which had a 40% capture rate but is seldom used in children aged 12 years), 90% for cephalosporins, 86% for fluoroquinolones, 73% for sulfonamides and trimethoprims, and 68% for penicillins (Jaana Martikainen, Pharm Lic, the Social Insurance Institution, Helsinki, Finland, oral communication, 2006).

Each prescription record provides full information on the drug (eg, active substance, quantity, and cost) and the date of purchase but contains no systematic information about the indication, prescribed daily dose, or duration of therapy. Several prescriptions of the same medicine redeemed simultaneously (composed of, eg, differently sized packages) were interpreted as a single course of therapy.

Background Data (Collected at Ages 5 and 13 Years Unless Stated Otherwise)
Serum total cholesterol and triglyceride concentrations were determined enzymatically (CHOD-PAP and GPO-PAP kits, respectively [Olympus Diagnostica, Hamburg, Germany]) in an Olympus AU400 analyzer. Serum high-density lipoprotein (HDL) cholesterol concentration was measured after precipitation of low-density lipoprotein (LDL) and very LDL with dextran sulfate 500 000. The concentration of LDL cholesterol was calculated using the Friedewald equation. Triglyceride values in all of the children were <4 mmol/L. Serum C-reactive protein (CRP) concentration (at age 13 years) was determined using a high-sensitive immunoturbidimetric method and C pneumoniae–specific IgG and IgA antibodies (at ages 5 and 11 years) by an enzyme immunoassay, as described earlier.⁶ C pneumoniae seropositivity was defined as an IgG value of >45 enzyme immunounits and/or an IgA value of >12 enzyme immunounits.

Children were classified as pubertal (girls before menarche; boys in Tanner stage G3) or late pubertal (girls after menarche; boys >G3 (at age 13 years). Only 3 study children were prepubertal (Tanner stage M/G1 and P1). Blood pressure was measured after 10 minutes of rest with an automated sphygmomanometer (Omron M4, Omron Matsusaka, Matsusaka, Japan) from the right arm 3 times, and the readings were averaged for statistical analyses. Height to the nearest 0.1 cm was measured with a wall-mounted Harpenden stadiometer (Holtain, Crymych, United Kingdom), and weight to the nearest 0.1 kg was measured using an electronic scale (S10, Soehnle, Murrhardt, Germany) while the child was wearing light underwear. BMI was calculated as the weight (kilograms) divided by the square of the height (meters). The annual income of the family (below or above median [47 000 euros] in the year 1999) as a socioeconomic variable and the parents’ smoking habits were enquired by questionnaires. One child reported to be an active smoker at age 13 years.

Statistical Methods
Values are given as means and 95% confidence intervals (CIs), unless otherwise stated. The effects of the cumulative number of antichlamydial antimicrobial treatments on arterial IMT were assessed. Macrolides, tetracyclines, quinolones, and rifamycins were considered to be antichlamydial antimicrobial agents.²⁰

Univariate linear model or Wilcoxon rank-sum test, as appropriate, was used to study relations of established risk factors to ultrasound measures and antimicrobial use. Effects of the use of antimicrobial agents on arterial IMT were tested using univariate and multivariate regression analyses. Because of the association of antimicrobial use with CRP concentration, the models also included their interaction as an explanatory variable. The determinants of IMT and/or antichlamydial antimicrobial use that had an independent effect in the univariate model (P .10) and the use of other antimicrobial agents were controlled for. Multivariate linear regression technique with backward selection (P > .10 as an exclusion criterion) was used, resulting in an equation (the final model) in which only those covariates that significantly increase the predictability of the dependent variable (IMT) were included.

In the C pneumoniae subgroup, the relation between the number of antichlamydial treatments in subjects aged 5 to 11 years and changes in C pneumoniae antibody status (seropositive or seronegative) from 5 to 11 years of age was determined with Cochran-Mantel-Haenszel's method. The effect of the STRIP group on background variables at ages 5 and 13 years was tested using repeated-measures analysis of variance.

Because of their skewed distribution, the triglyceride and CRP concentrations were log transformed for analyses. SAS 9.1.3 (SAS Institute Inc, Cary, NC) was used for the statistical analyses. Differences were considered to be statistically significant at a 2-tailed P value of <.05.

	RESULTS

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A total of 467 (92%) of the 508 study children had received antimicrobial agents, and 305 children (60%) had used agents effective against C pneumoniae. During the follow-up period, the children experienced average of 1.4 (range: 0–13) and 4.3 (range: 0–25) antichlamydial and other antimicrobial exposure events, respectively. Macrolides were the most common antichlamydial antimicrobial agents used by the study children, and azithromycin topped the list of macrolides (Table 1). None had used rifamycins. The 6 most frequently used other antimicrobial agents were amoxicillin (n = 973), cephalexin (n = 272), trimethoprim/sulfadiazine (n = 265), amoxicillin/clavulanic acid (n = 225), phenoxymethylpenicillin (n = 165), and cefadroxil (n = 164).

In the C pneumoniae subgroup, C pneumoniae seropositivity did not covary significantly with the number of antichlamydial exposure events (Cochran-Mantel-Haenszel P = .39 for a general association). Interestingly, 52% of those who seroconverted between ages 5 and 11 years to C pneumoniae IgG and/or IgA positivity had received antichlamydial antimicrobial agents.

Antichlamydial Antimicrobial Use, CRP, and Arterial IMT
The mean aIMT showed significant association with the number of antichlamydial exposure events during the study period (β = .010; P < .001), whereas the mean cIMT was not significantly associated with the number of antichlamydial treatments (β = .0006; P = .68) (Fig 1). The thickening of the aortic intima-media was further enhanced in the presence of an elevated CRP concentration (n = 484 with complete data; number of courses and CRP interaction β = .010; P = .001). There was no significant relationship between CRP and aIMT in children without any antimicrobial treatments (n = 41; β = 1.207; P = .48) or, interestingly, in those with antimicrobial but without antichlamydial treatments (n = 152; β = 1.148; P = .11).

View larger version (7K): [in this window] [in a new window]   FIGURE 1 Aortic (solid line) and carotid (interrupted line) IMT in healthy 13-year-old adolescents according to the number of antichlamydial antimicrobial treatments (AAT). Values are crude means ± SEMs.

Multivariate Analyses
A multivariate analysis that modeled the mean aIMT with the number of antichlamydial exposure events was run with the following covariates: BMI, blood pressure, CRP, LDL cholesterol, triglycerides, asthma, interaction between the number of antichlamydial antimicrobial treatments and CRP, and the number of antimicrobial courses other than those active against C pneumoniae. The final model included significant effects of interaction between the number of antichlamydial treatments and CRP (β = .008; P = .01), the number of antichlamydial treatments (β = .018; P < .001), and BMI (β = .012; P < .001). CRP did not provide any additional, significant independent effect on aIMT in the final model (P = .56). Adding a term for the interaction between the number of antichlamydial treatments and gender to the multivariate model did not change the outcome.

Regarding the mean cIMT, the association with the number of antichlamydial treatments remained insignificant in multivariate analysis (P = .83). Neither aIMT nor cIMT was significantly associated with the number of antimicrobial courses other than those active against C pneumoniae, which were included in the multivariate models. All of the associations between antichlamydial antimicrobial use and aIMT or cIMT were unchanged when the maximum IMTs were used instead of the mean IMTs or when the actively smoking child was excluded from the analyses (data not shown).

	DISCUSSION

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Increased cIMT is a significant predictor of cardiovascular morbidity and mortality.^23,24 However, because autopsy studies show that the earliest morphologic alterations in the arterial wall emerge in the abdominal aorta,¹⁵ aIMT with a higher variability may provide an even better index of preclinical atherosclerosis than cIMT.¹⁸

We found that there is a direct association between the number of antichlamydial antimicrobial courses that the child has taken and his or her aIMT assessed at age 13 years. Furthermore, the proportion of C pneumoniae–seropositive children does not decrease with drug use. These findings may support the concept that cumulative arterial injuries by repeated infectious insults of any origin result in the development of atherosclerosis. Activation of persistent infection not covered by standard antimicrobial treatment in the vascular wall might provide a plausible underlying mechanism. Indeed, antichlamydial antimicrobial agents cannot completely eradicate C pneumoniae from continuously infected epithelial cells²⁵ and the pathogen in circulating human monocytes enters a persistent state and becomes refractory to antimicrobial treatment.²⁶ Monocytes can, thus, transport C pneumoniae from granulocytes, alveolar epithelial cells, and macrophages to the aortic wall,²⁷ also after antimicrobial treatment. Interestingly, a recent in vitro study showed that first-choice antichlamydial antimicrobial agents at subinhibitory concentrations could in fact induce persistence of C pneumoniae.²⁸ This finding presents a novel mechanism of interaction between underlying acute infections and antimicrobial agents. We also showed that a combination of numerous antichlamydial therapies and a higher CRP value was associated with a greater aIMT than was antimicrobial use in connection with a low serum CRP. In adults, the C pneumoniae infection-related risk of coronary events and progression of IMT have similarly increased in the presence of an elevated CRP value,^5,29 underscoring the importance of inflammation for both early and advanced atherogenesis.

The restriction of the relation of aIMT to the number of exposure events for children with previous antichlamydial antimicrobial use may suggest that repeated exposure to antichlamydial agents, per se, affects atherosclerosis. Accordingly, in a recent trial, cardiovascular mortality increased significantly among clarithromycin-treated CAD patients followed up for 3 years.⁹ Furthermore, when the authors pooled the data of the secondary prevention trials in which patients were monitored for >2 years,^9,30,31 antichlamydial therapy was associated with increased mortality. However, why antichlamydial antimicrobial agents might be atherogenic remains unclear. The present data also cannot be used to assess whether the recurrent infections or the use of antimicrobial agents in children led to increased aIMT.

Our findings contradict previous observations that suggested that early structural atherosclerotic changes, be they C pneumoniae infection-related aortic intimal thickenings in rabbits or carotid exacerbations in children or in C pneumoniae–seropositive adults with cerebrovascular disease, are responsive to treatment with antimicrobial agents.^11–13 Differences in study design and study population may account for these discrepancies. For example, the only available earlier study in children was composed of subjects with acute infections followed up for 3 months and treated with cephalosporins or penicillins.¹² Furthermore, in patients with stroke, progression of carotid atherosclerosis was decelerated by roxithromycin therapy only temporarily,³² and, in a rabbit model, vascular chlamydial antigen could not be eliminated by azithromycin therapy,¹¹ indicating persistence.

The prescription register only became available in 1994, and we did not have information on antimicrobial use during the study children's first 5 years of life. Moreover, because of the low cost of penicillins and sulfonamides/trimethoprims, they were often not reimbursed and, thus, failed to be entered into the register, leading to underestimation of their use. This may have hampered opportunities to observe changes in IMT after the use of antimicrobial agents other than those effective against C pneumoniae. However, the main aim of this study was to assess effects on IMT of the use of antichlamydial antimicrobial agents, of which the overall coverage approached 90% in the register.

	CONCLUSIONS

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In a meta-analysis of the effects of clarithromycin, azithromycin, roxithromycin, or gatifloxacin therapy in the secondary prevention of CAD, there was no overall benefit of treatment in reducing mortality or cardiovascular events.⁸ Retrospective trials on the association between tetracycline or quinolone use and the risk of subsequent first myocardial infarction have yielded contradictory results; inverse relations between the use of antimicrobial agents and myocardial infarction have only been seen in low-risk populations.^7,33 Thus, despite some inconsistency, together these findings support the view that antichlamydial antimicrobial agents do not improve major clinical outcomes of CAD. The present study confirms these findings and extends them to apply to the earliest stages of atherosclerotic development in apparently healthy children and adolescents and accordingly discourages the use of standard antimicrobial agents in the primary prevention of atherosclerotic cardiovascular disease.

	ACKNOWLEDGMENTS

 
This study was financially supported by the Academy of Finland grants 73582 and 206374, the Special Federal Grants for Turku University Central Hospital, the Emil Aaltonen Foundation, the Regional Fund of Varsinais-Suomi of the Finnish Cultural Foundation, the Päivikki and Sakari Sohlberg Foundation, the Turku University Foundation, and the Maud Kuistila Memorial Fund.

We thank Kristiina Tyrkkö (The Social Insurance Institution, Helsinki, Finland) for her excellent data management skills.

	FOOTNOTES

 
Accepted May 5, 2008.

Address correspondence to Iina Volanen, MD, PhD, Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. E-mail: iina.volanen{at}utu.fi

The authors have indicated they have no financial relationships relevant to this article to disclose.

This trial has been registered at www.clinicaltrials.gov (identifier NCT00223600).

What's Known on This Subject Chlamydia pneumoniae infection has been associated with the initiation and progression of atherosclerosis, but standard antimicrobial agents have not helped in the secondary prevention of coronary artery disease. Little is known about the impact of antimicrobial therapy for the primary prevention of atherosclerosis.

 

What This Study Adds This study adds to the controversy over the role of antimicrobial agents in the prevention of atherosclerosis. It shows that antichlamydial treatments are not protective of vascular changes and, thus, discourages the use of standard antimicrobial agents in the primary prevention of atherosclerosis.

 

	REFERENCES

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