CLINICAL STUDIES
The prevalence of Chlamydia pneumoniae in atherosclerotic and nonatherosclerotic blood vessels of patients attending for redo and first time coronary artery bypass graft surgery
Yuk-ki Wong, BSc, MB, (Hons), ChB, MRCP*  ,
Martine Thomas, PhD*,
Victor Tsang, FRCS  ,
Patrick J. Gallagher, MD, PhD, FRCP and
Michael E. Ward, PhD*
* Molecular Microbiology, Southampton University Medical School, Southampton, England, United Kingdom
Wessex Cardiothoracic Unit, Southampton General Hospital, Southampton, England, United Kingdom
Present address: Great Ormond Street Children’s Hospital, London, England, United Kingdom
Department of Pathology, Southampton General Hospital, Southampton, England, United Kingdom
Manuscript received August 17, 1998;
revised manuscript received August 18, 1998,
accepted September 24, 1998.
Address for correspondence: Dr. Yuk-ki Wong, Wessex Cardiothoracic Unit, Southampton General Hospital, Tremona Road, Southampton, England, United Kingdom S016 6YD
YW2{at}soton.ac.uk
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Abstract
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Objectives. To determine if Chlamydia pneumoniae (C. pneumoniae) is more prevalent in atherosclerotic compared with normal blood vessels of patients requiring redo and first time coronary artery bypass graft surgery (CABG).
Background. Serological and pathological studies have associated atherosclerosis with C. pneumoniae infection. As atherosclerosis is one of the causes of graft failure following CABG, then it may be expected that the prevalence of the organism in failed grafts and diseased native vessels should be greater than in the new grafts.
Methods. Endarterectomy specimens and failed and new grafts were collected from 49 patients with late graft failure. Endarterectomy specimens and new grafts were also collected from nine patients having first time CABG. The presence of C. pneumoniae DNA was then checked for using a nested polymerase chain reaction.
Results. The prevalence of C. pneumoniae DNA in failed venous grafts (38.2%) was similar to that in endarterectomy specimens from native coronary arteries (38.5%) and greater than that in new saphenous vein grafts (11.8%). However, it was similar to that in new internal mammary artery grafts (30.0%). Also, the interval between surgery in redo patients was the same regardless of whether C. pneumoniae was present or not.
Conclusions. Cross sectional studies cannot determine whether C. pneumoniae is a cause of atherosclerosis since they do not show whether infection precedes or follows its development. However, our results suggest that the organism is not an important factor in graft failure or atherosclerosis.
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Abbreviations and Acronyms
| | CABG | = Coronary artery bypass graft surgery | | ICC | = immunocytochemistry | | IMA | = internal mammary artery | | PCR | = polymerase chain reaction | | SV | = saphenous vein |
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A serological association between antibodies to Chlamydia pneumoniae (C. pneumoniae) and coronary artery disease was first described in 1987 (1). This has been confirmed by many (2–4), but not all, studies (5). Furthermore, DNA and antigen detection methods such as the polymerase chain reaction (PCR) and immunocytochemistry (ICC), as well as other techniques such as electron microscopy and culture, have found evidence for the presence of C. pneumoniae in atherosclerotic blood vessels (6–12). In a recent systematic review, the organism was found in 52% of diseased but only 5% of normal blood vessels (13). One possible explanation of these serological and pathological findings is that C. pneumoniae has a direct causal role in atherosclerosis. Atherosclerosis is one cause of graft failure following coronary artery bypass graft surgery (CABG) (14). In this study we hypothesized that if C. pneumoniae causes atherosclerosis, then in patients with graft failure, it should be more prevalent in failed grafts compared with new saphenous vein (SV) and new internal mammary artery (IMA) grafts. Also, all other things being equal, graft failure should occur earlier in those patients with vascular C. pneumoniae infection. Similarly, for patients requiring first time CABG, C. pneumoniae should be more common in diseased native coronary arteries compared with new grafts.
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Methods
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Forty-nine consecutive patients presenting for elective redo (second) CABG were recruited between March 1996 and January 1998 following approval from the local research ethics committee. Another nine consecutive patients presenting for first time CABG but who, in addition, had coronary endarterectomy during their operation were also recruited. Demographic characteristics, smoking habits and medical history were recorded from each patient. From redo patients, a segment of one or more failed grafts was obtained. The decision as to whether or not to remove a failed graft and which failed graft to remove was left to the clinical discretion of the surgeon. From patients requiring first time CABG, endarterectomy specimens from native coronary arteries that were not grafted were obtained. In some cases, endarterectomy specimens were also available from redo patients. From all patients, we attempted to obtain surplus segments of newly harvested saphenous vein and internal mammary artery grafts. Vessel specimens (1 to 5 cms in length) were collected in the sterile environment of the operating theatre and processed immediately by dividing them into three portions, one for histology, one for PCR and the final portion stored in liquid nitrogen for future reference.
PCR.
To prevent DNA contamination, different laboratories were used for pre- and post-PCR handling. Dedicated hoods, UV sterilization of equipment and filter pipette tips were used. DNA was obtained from specimens using conventional methods. Briefly, samples were digested with Proteinase K followed by phenol chloroform extraction and ethanol-sodium acetate precipitation. The DNA obtained was resuspended in 50 µl of purified water. To check for PCR inhibitors in extracted DNA, 5 pg of lambda phage DNA was added to 3 µl of extracted DNA and subjected to PCR with lambda specific primers (Table 1). Inhibitors were considered to be present if there was no amplification, and extracted DNA was then diluted by a factor of 10 and the PCR repeated. For detection of C. pneumoniae DNA, a nested PCR with primer sets from the C. pneumoniae omp 1 gene was used (15). A positive control and one negative control for every five to six samples were included in each experiment. PCR products were visualized with ethidium bromide after electrophoresis on a 2% agarose gel. Polymerase chain reaction products were also slot blotted and hybridised to a digoxigenin-deoxy-uridine triphosphate labelled DNA probe consisting of a 242 bp VS4 fragment that spanned the target sequence. Hybridization products were detected colorimetrically using nitro blue tetrazolium and X-Phosphate according to the manufacturer’s instructions (Boehringer Mannheim, Lewes, United Kingdom). All C. pneumoniae PCRs were carried out in triplicate.
Statistical analysis.
The  2 test was used to compare proportions of categorical variables. The two sample t test (2 tailed, assuming equal variance) was used to compare continuous variables from two populations. A significance level of p = 0.05 was used.
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Results
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Redo CABG patients.
The characteristics of the 49 patients who underwent redo CABG are shown in Table 2. The time interval between CABG operations was at least six years for all patients except for one (three years). Therefore, this represents a group of patients with late graft failure. We obtained at least one failed vein graft from each of 47 patients. Of the other two patients, an endarterectomy sample was available from one, but no diseased vessel was available from the other. Endarterectomy samples were available from three patients in total. We obtained at least one new saphenous vein graft from each of 41 patients. Of the other eight patients, new IMA grafts were available for two, but no undiseased vessel was available from six patients. New IMA grafts were available from 15 patients in total. Eleven patients (22.4%) had C. pneumoniae DNA in a failed graft or endarterectomy specimen only, two patients (4%) had C. pneumoniae in a new IMA or SV graft only and five patients (10.2%) had C. pneumoniae DNA in both failed and new grafts. The presence of C. pneumoniae DNA was not associated with age, gender, smoking, hypertension or hyperlipidaemia (Table 2), and the interval between CABG operations was the same in patients with and without C. pneumoniae DNA in their vessels.
First time CABG patients.
Nine patients were recruited with an average age of 70.4 ± 9.2 years (4 males, 5 females). At least one new SV graft and one endarterectomy specimen was obtained from every patient but a new IMA graft was obtained from only five patients. Four patients had an endarterectomy specimen that was positive for C. pneumoniae, and, of these, one also had a new IMA graft that was positive and another had a new IMA and a new SV graft that was positive.
It can be seen from Table 3 that, in all patients, the prevalence of C. pneumoniae in diseased vessels (failed grafts and endarterectomy specimens) was similar to that in new IMAs but greater than that in new SV grafts (p = 0.001).
PCR inhibition.
DNA samples extracted from atherosclerotic vessels were more likely to show inhibition to PCR compared with nonatherosclerotic vessels (29/68 vs. 19/71, P = 0.05). However, on repeat PCR for C. pneumoniae, positive atherosclerotic vessels were more likely to be positive on two or more occasions than positive nonatherosclerotic vessels (13/26 vs. 3/12) although this was not statistically significant. This may be because the quantity of C. pneumoniae DNA is greater in diseased vessels. Inhibition was eliminated in all cases by tenfold dilution of the DNA sample. Although dilution inevitably dilutes the amount of DNA, 14 of 48 inhibited samples (29.2%) were positive at least once compared with 24 of 91 uninhibited samples (26.3%). Also, inhibited samples were just as likely to be positive on two or more occasions as uninhibited samples (7/14 vs. 9/24).
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Discussion
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Detection of C. pneumoniae in atherosclerotic vessels.
The most common methods for detecting C. pneumoniae in atherosclerotic vessels are PCR and antigen detection techniques such as ICC. However, the specificity and sensitivity of these methods are unknown. Ideally, infection by C. pneumoniae should be confirmed by culture and the results of PCR and ICC compared to this. Unfortunately, culture of C. pneumoniae from atherosclerotic vessels is technically difficult and there have only been three reports of this. In the first study, C. pneumoniae was cultured from a coronary artery and this was confirmed by three of four laboratories using PCR and one of two laboratories using ICC (9). In the second study, C. pneumoniae was isolated from a carotid artery but both PCR and ICC were negative (16). Finally, multiple serial passage was used to isolate C. pneumoniae from 11 of 70 arteries and all 11 results were confirmed by PCR (7), but ICC was not used. Therefore, there is insufficient data in the literature to assess whether PCR or ICC is the most sensitive for detection of vascular C. pneumoniae. Generally, ICC reports more positive results than PCR (11,16), but this is not always the case (9,17). The concern is that antibodies used in ICC may cross-react with components of atherosclerotic tissue, and in some studies results have depended on the antibody used. Genus-specific antibodies against lipopolysaccharide have been reported to give more positive results than species-specific antibodies (18,19) and some species-specific antibodies appear to be more sensitive than others (20). Furthermore, the results of these different antibodies do not necessarily correlate with each other. For example, a genus specific antibody found 79.8% of 114 samples to be positive for C. pneumoniae compared with 53.2% using a species-specific antibody, but the kappa statistic was only 0.047 (18). We had intended to use ICC, but preliminary studies failed to convince us of its specificity. Background staining was also high, and other groups have reported this (10). The advantage of PCR is that positive results can be confirmed by sequencing of PCR products or by Southern hybridization, but PCR also has disadvantages. Atherosclerotic tissue has many inhibitors of PCR as has been illustrated in this study. The DNA extraction process is important, and techniques must achieve a balance between maximal DNA extraction and removal of potential inhibitors. In a study that compared different methods of extracting DNA from atherosclerotic vessels, phenol chloroform extraction was found to be superior to many commercial kits (21). We also used dilution to eliminate inhibition and although this inevitably results in DNA dilution, inhibited samples were just as likely to be positive for C. pneumoniae as uninhibited samples. All our specimens were tested in triplicate, and although most were not positive on all occasions, we counted them as positive because our negative controls were consistently negative. It is likely that the inconsistent results were due to a combination of small amounts of DNA and low sample volumes. Inconsistent results have also been reported by other groups (9), but these problems of reduced sensitivity do not detract from the fact that we found a high prevalence of C. pneumoniae DNA in new IMA grafts.
C. pneumoniae in arteries and veins.
The main finding of this study was that C. pneumoniae was more common in the arterial circulation (including failed venous grafts) than in saphenous veins, but it was not more common in atherosclerotic vessels than in nonatherosclerotic IMAs. Another study has now also reported that C. pneumoniae can be found in IMAs (22). At first sight, this appears to contradict previous studies. Thus, Muhlestein et al. (8) detected C. pneumoniae in 79% of atherectomy specimens compared with 4% of nonatherosclerotic coronary arteries. A study of young adult deaths (11) reported similar findings. However, whereas these studies have compared patients with and without atherosclerosis, we have compared atherosclerotic and nonatherosclerotic blood vessels from patients with atherosclerosis. Taken together, these data may imply that C. pneumoniae is more common in blood vessels of patients with atherosclerosis but that, in such patients, it may be present in any artery including those which are not normally subject to atherosclerosis. Thus, of the seven redo patients in this study who had C. pneumoniae in a new graft, five also had C. pneumoniae in a failed graft. Likewise, both of the first time CABG patients who had C. pneumoniae in a new graft also had an endarterectomy specimen that was positive. In a post mortem study of C. pneumoniae in atherosclerotic coronary arteries (23), the organism was also detected in noncardiovascular tissue (lung, liver and spleen), although less frequently. However, the prevalence of the organism in normal arteries and veins was not specifically addressed. It is uncertain as to why the prevalence of C. pneumoniae is greater in the arterial rather than the venous circulation. It has been hypothesized that C. pneumoniae is primarily a cause of respiratory infection and enters the circulation after being ingested by alveolar macrophages. In this case, organisms will enter the arterial circulation first after reaching the heart from the lungs. We speculate that chlamydiae may effectively be filtered out in the capillaries or alternatively, that haemodynamic factors, such as higher blood pressure, are important in making arteries more susceptible to colonization with C. pneumoniae.
Graft failure.
Generally, IMA grafts last substantially longer than SV grafts as they are less prone to develop atherosclerosis (14). However, we found that new IMA grafts were more likely than new SV grafts to be infected with C. pneumoniae (Table 3). Furthermore, redo patients whose failed grafts were found to be infected with C. pneumoniae did not present for their second operation any earlier than those patients whose failed grafts were not infected (Table 2). Taken together, these data suggest that C. pneumoniae is not an important risk factor in graft failure. In this study, patients undergoing redo or first time CABG were of similar age and the prevalence of C. pneumoniae was also similar in both groups. In contrast, in a study of patients undergoing directional atherectomy (12), it was reported that C. pneumoniae was more likely to be found in restenotic compared with primary lesions although this was not statistically significant. However, whereas late graft failure is mainly due to atherosclerosis, the cause of restenosis following atherectomy is incompletely understood (24). It was suggested that C. pneumoniae might be important in restenosis but another atherectomy study found that the only clinical predictor of the presence of C. pneumoniae was the presence of a primary nonrestenotic lesion (8).
Native coronary atherosclerosis.
Several processes contribute to vein graft failure including thrombosis in the early stages and fibrointimal hyperplasia and graft atherosclerosis in the later stages. Our patients were mainly those with late graft failure requiring redo surgery. It could be argued that although graft atherosclerosis has many similarities to native coronary atherosclerosis there are differences (14); therefore, C. pneumoniae may still be important in native coronary atherosclerosis. However, in the nine first time CABG patients, the presence of C. pneumoniae DNA in endarterectomy specimens was no greater than that in new IMA grafts. Also, there was a high prevalence of C. pneumoniae in the IMA from all patients and this is a vessel which is not prone to any form of atherosclerosis.
In summary, in patients undergoing first time or redo CABG, C. pneumoniae can be found in both atherosclerotic and nonatherosclerotic arteries and, to a lesser extent, in new saphenous vein grafts. This suggests that C. pneumoniae is not important in causing late graft failure or disease of native coronary arteries. However, cross sectional studies such as this give no information on the temporal sequence of events. It is not known whether C. pneumoniae infection preceded or followed the development of atherosclerosis. It is possible that if C. pneumoniae infects a preexisting lesion, it may cause disease progression rather than initiate atherosclerosis itself. Thus, in New Zealand White Rabbits fed a diet supplemented with small amounts of cholesterol, intranasal inoculation with C. pneumoniae was found to increase the size of atheromatous aortic lesions and this could be prevented by azithromycin (25). In two other studies using New Zealand White Rabbits fed normal diets, intranasal inoculation resulted in aortic changes consistent with atherosclerosis, but such changes were early and compatible with arteritis (26,27). Aortic changes were not seen in a fourth study (28). Two secondary prevention trials have also suggested that C. pneumoniae may have a role in atherosclerosis (29,30). Patients given macrolide antibiotics were found to be at lower risk for further adverse cardiovascular events and this benefit was seen as early as one month (30) after onset of treatment. However, both studies were small, with just over 200 patients each, and preliminary results after six months of follow up from a third, similar sized study have not shown any such benefit (31). A fourth study recruited 34 men who had previously had CABG and randomized them to placebo or doxycycline for four months. No evidence of any effect on forearm basal nitric oxide production or C. pneumoniae antibody titres was seen (32). It is evident that further research, including larger antibiotic intervention trials, is required to determine if C. pneumoniae plays a significant pathological role in atherosclerosis.
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Acknowledgments
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We wish to thank Mr. J. Monro, Mr. R. Lamb and Mr. S. Livesey, consultant cardiothoracic surgeons at the Wessex Cardiothoracic Unit for providing surgical specimens. We are grateful to the British Heart Foundation who supported this project and to Wessex Cardiac Trust who funded a research fellowship for Y. Wong.
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Footnotes
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This work was supported by a grant from the British Heart Foundation. Dr. Yuk-ki Wong is supported by a grant from Wessex Cardiac Trust.
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References
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Abstract
Methods