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The serological evidence

[Lay reader: The body normally responds to the presence of infection by making specific antibodies to that infection as part of the protective immune response. Some antibodies (so-called IgG antibody for example) tend to persist for a long time after the infection has resolved. The presence of specific IgG antibody to an infection is therefore a valuable indication that that person has been infected, or at least exposed to infection, some time in the past. Other antibodies, such as IgA antibody, are not so persistent following resolution of an infection and may be a more valuable indicator of recent or current infection. Unfortunately the methods available for measuring antibody to C. pneumoniae and other Chlamydiales are imperfect [see: serology] causing difficulty in the interpretation of results].

To test the hypothesis that chronic C. pneumoniae infection is a cause of coronary artery disease, the presence of specific IgG has often been taken to be a marker of chronic infection or of past exposure to infection. There seems to be no limit to the patience of scientific journals accepting often very similar studies on the antibody responses to C. pneumoniae in coronary heart disease, but many of the studies are inadequate. As the references here show, numerous such studies, both cross sectional [lay reader: at one point in time] [Saikku et al., 1988; Leinonen et al., 1990; Blasi et al., 1997; Mendall et al., 1995; Leowatanna et al., 1999; Diedrichs et al., 1997; Mazzoli et al., 1998;  Dahlen et al., 1995; Thom et al., 1991, 1992; Patel et al., 1995; Thomas et al., 1992; Leinonen et al., 1994; Weiss et al., 1996; Kark et al., 1997; Linnanmaki et al., 1993; Anderson et al., 1998; Altman et al., 1999; Cellesi et al., 1999; Hoffmeister et al., 2000; Kaykov et al., 1999;   Hoffmeister et al., 2001; Nobel et al., 1999; Fang et al., 1998; Danesh et al., 1999; Wong, Dawkins & Ward, 1999; Myashita et al., 1998; Ericson et al., 2000; Romeo et al., 2000; Leowattana et al., 2000; Garcia et al., 2001; Shimada et al., 2001; Smieja et al. , 2001; Burian et al., 2001] and prospective studies [lay reader: seeing what happened in time after infection] [Saikku et al., 1992; Schiele et al., 2001; Kahler, et al., 2001; Zhu et al., 2001; Miettinen et al., 1996; Ossewaarde et al., 1998; Nieto et al., 1999; Siscovick et al., 2000; Roivainen et al., 2000; Muhlestein et al., 2000; Ridker et al., 1999a & b; Strachan et al., 1999; Danesh et al., 2000; Wald et al., 2000; Glader et al., 2000] have been reported and their results have been extensively reviewed [Wong, Gallagher & Ward, 1999; Danesh et al., 1997, 2000; Dunne,  2000]. A meta-analysis of results for IgA antibody to C. pneumoniae for 10 prospective studies [Danesh et al., 2002]  gave a combined odds ratio (+ or - 95% confidence interval) for coronary heart disease of 1.25 (1.03 - 1.53) compared to that previously reported for IgG antibody [Danesh et al., 2000] of 1.15 (0.97 - 1.36). Neither C. pneumoniae IgA nor IgG antibody titres in these combined studies were strongly predictive of coronary heart disease in the general population [Danesh et al., 2002]. 

In summary, there is general agreement that whereas cross sectional studies have suggested some sort of association, prospective studies have not [Siscovick et al., 2000]. It has been argued that the prospective studies were negative because serology was only tested at one time point several years before the development of disease. Therefore, controls may have developed chronic infection in the intervening years, so masking any association. Although ingenious, this seems an unlikely explanation. Firstly, annual infection rates in adults are low and that there is no convincing evidence that widespread epidemics occur in moderate latitudes. Secondly, prospective studies with relatively short follow up periods of 1.5 to 5 years [Nieto et al., 1999; Muhlestein et al., 2000; Ridker et al., 1999a] were just as likely to be negative as those with longer follow up. 

It is well known that negative studies are less likely to be published than positive ones.  It is therefore vital that any radical departure in the treatment and prevention of coronary heart disease should be based on rigorously evaluated data. In reviewing the literature, one way of detecting such publication bias is to construct funnel plots [Egger et al., 1997]. These are plots of the studies’ effect estimates against sample size (or study precision). Generally, the precision in estimating the underlying association will increase as the sample size increases. Results from small studies will scatter widely at the bottom of the graph with the spread narrowing among larger studies. In the absence of bias, the plot resembles a symmetrical inverted funnel but otherwise, the plot will often be skewed and asymmetrical. The Figure below shows a funnel plot for 33 cross sectional serological studies of antibody to C. pneumoniae and coronary heart disease.

Fig 1. Funnel plot for 33 cross sectional studies investigating the association between coronary heart disease and IgG seropositivity for C. pneumoniae. Methodology of Egger et al., 1997. [Double click on thumb-nailed figure].

* The Estimates precision is the reciprocal of the standard error (the standard error can be calculated from the 95% confidence interval limits).  Figure © Y. Wong, 2001.

Of these 33 studies, 17 found no significant association (although some of these 17 were reported as positive because apart from IgG, other markers of infection such as IgA were used). It can be seen that the plot is highly asymmetrical. In fact, it is almost half of a funnel plot, suggesting that the majority of negative studies have not been published [Egger et al., 1997]. More importantly the plot demonstrates  that the studies with the greatest statistical precision (the larger studies towards the top of the vertical axis) show little effect (odds ratios close to 1). 

Problems with the serological evidence

Serology prompted the initial hypothesis that C. pneumoniae might be a cause of cornonary heart disease, but the evidence has not stood the test of time. Kalayoglu et al., 2002 have neatly summarised the problems associated with sero-epidemiological studies of the association of C. pneumoniae infection with coronary heart disease [and indeed with other chronic diseases].

• The high prevalence of C. pneumoniae exposure makes it very difficult to identify true seropositives, particularly in cardiovascular disease which becomes apparent in an age group where nearly 80% of people have antibody to the organism.

• The main serological test used, micro immunfluorescence, has major shortcomings including poor inter laboratory reproducibility and varying criteria of positivity

• The original studies were based on detecting chlamydial immune complexes or lipopolysaccharide. Cross reactions with other antigens such as cardiolipin, itself associated with coronary artery disease, may well explain the observed association

• Many studies did not adjust for important confounding factors, such as cigarette smoking. There may also be unknown confounding risk factors for C. pneumoniae infection.

[YW] [Updated [MEW] August 2003]

NEXT: Direct detection of C. pneumoniae in atheromatous tissues

References

Altman, R., Rouvier, J., Scazziota, A,. Absi, R. S. & Gonzalez, C. (1999). Lack of association between prior infection with Chlamydia pneumoniae and acute or chronic coronary artery disease. Clinical Cardiology 22, 85 - 90. [Argentina. Cross sectional study]

Anderson, J. L., Carlquist, J. F., Muhlestein, J. B., Horne, B. D. &  Elmer, S. P. (1998). Evaluation of C-reactive protein, an inflammatory marker, and infectious serology as risk factors for coronary artery disease and myocardial infarction. Journal of the American College of Cardiology 32, 35 - 41. [US. Cross sectional. Seropositivity to both C. pneumoniae and H. pylori (but not one agent alone) may predict increased risk and may be associated with higher CRP levels, but infectious serology may be less predictive than previously suggested]

Blasi, F., Cosentini, R., Raccanelli, R., Massari, F. M., Arosio, C., Tarsia, P. et al. (1997). A possible association of Chlamydia pneumoniae infection and acute myocardial infarction in patients younger than 65 years of age. Chest 112, 309 - 312. [Milan. Cross sectional.] Full article

Burian, K., Kis, Z., Virok, D., Endresz, V., Prohaszka, Z., Duba, J. et al. (2001). Independent and joint effects of antibodies to human heat-shock protein 60 and Chlamydia pneumoniae infection in the development of coronary atherosclerosis. Circulation 103, 1503 - 1508. [Hungary. Cross sectional. High level antibody to human heat shock protein 60 and to C. pneumoniae are independent risk factors for coronary atherosclerosis.  Their simultaneous presence substantially increases risk]

Cellesi, C., Sansoni, A., Casini, S., Migliorini, L., Zacchini, F., Gasparini, R. et al. (1999). Chlamydia pneumoniae antibodies and angiographically demonstrated coronary artery disease in a sample population from Italy. Atherosclerosis 145, 81 - 85.[Siena. Small cross sectional study. No association]

Dahlen, G. H., Boman, J., Birgander, L. S. & Lindblom, B. (1995). Lp(a) lipoprotein, IgG, IgA and IgM antibodies to Chlamydia pneumoniae and HLA class II genotype in early coronary artery disease. Atherosclerosis 114, 165 - 174. [Host HLA genotype, lipoprotein a levels and Ch. pneumoniae infection may interact causing heart disease etc]

Danesh, J., Collins, R.& Peto, R. (1997). Chronic infections and coronary heart disease: is there a link? Lancet 350, 430 - 436. [Plus editorial. Good review by respected Oxford epidemiologists of the earlier data. Concludes role of C. pneumoniae not proven. Since superseded by meta-analysis of Danesh et al., (2000).] 

Danesh, J., Wong, Y., Ward M. E. & Muir, J. (1999). Chronic infection with Helicobacter pylori, Chlamydia pneumoniae, or cytomegalovirus: population based study of coronary heart disease. Heart 81, 245 - 247. [UK general practice. Large study. No associations  CHD with C. pneumoniae, H. pylori or CMV]

Danesh, J., Whincup, P., Walker, M., Lennon, L., Thomson, A., Appleby, P.,  Wong, Y., Bernades-Silva, M. & Ward, M. E. (2000). Chlamydia pneumoniae IgG titres and coronary heart disease: prospective study and meta-analysis. British Medical Journal 2000;321:208-13.   Full article [Plus associated journal editorial and commentary on and offline. One of the largest prospective studies, general practice based, plus meta-analysis of previous data including Wald et al., 2000. Concludes that contribution of C. pneumoniae to coronary heart disease must be small if anything.]

Danesh, J., Whincup, P., Lewington, S., Walker, M., Lennon, L., Thomson, A., Wong, Y. K., Zhou, X. & Ward, M. E. (2002). Chlamydia pneumoniae IgA titres and coronary heart disease. Prospective study and meta-analysis. European Heart Journal 23, 371 - 375. [Large prospective study and meta-analysis of previous data. Results for IgA antibodies similar to those for IgG above].

Diedrichs, H., Schneider, C. A., Scharkus, S., Pfister, H. &  Erdmann, E. (1997). Prevalence of Chlamydia antibodies in patients with coronary heart disease. Herz Kreislauf 29, 304 - 307.

Dunne, M. (2000). The evolving relationship between Chlamydia pneumoniae and atherosclerosis. Current Opinion in Infectious Diseases 13, 583 - 591. [Review]

Egger, M., Davey Smith, G., Schneider, M. & Minder, C. (1997). Bias in meta-analysis detected by a simple, graphical test. British Medical Journal 315, 629 - 634. Full article  [Funnel plots (plots of effect estimates against sample size) provide a useful test to detect bias in meta-analyses that were later contradicted by large trials].

Ericson, K., Saldeen, T. G., Lindquist, O., Pahlson, C. & Mehta, J. L. (2000). Relationship of Chlamydia pneumoniae infection to severity of human coronary atherosclerosis. Circulation 101, 2568 - 2571. [No relationship antibody levels and severity of atherosclerosis] Full article  

Fang, J. C., Kinlay, S., Kundsin, R. & Ganz, P. (1998). Chlamydia pneumoniae infection is frequent but not associated with coronary arteriosclerosis in cardiac transplant recipients. American Journal of Cardiology 82, 1479 - 1483. [Unlike CMV]

Garcia, J. B., Martinez, P. M., Rodriguez, J. F. M., Carpente, M. D., Bustamante, R. B., Peral, A. B. G. et al. (2001). Inflammation and infection in stable coronary disease and the acute coronary syndrome. Revista Espanola de Cardiologia 54, 453 - 459. Full article   [In Spanish. Small cross sectional study. No association].

Glader, C. A., Boman, J., Saikku, P., Stenlund, H., Weinehall, L., Hallmanns, G. et al. (2000). The proatherogenic properties of lipoprotein(a) may be enhanced through the formation of circulating immune complexes containing Chlamydia pneumoniae-specific IgG antibodies. European Heart Journal 21, 639 - 646. [Exploring an under-researched area].

Hoffmeister, A., Rothenbacher, D., Wanner, P., Bode, G., Persson, K., Brenner, H. et al. (2000). Seropositivity to chlamydial lipopolysaccharide and Chlamydia pneumoniae, systemic inflammation and stable coronary artery disease - Negative results of a case-control study. Journal of the American College of Cardiology 35, 112 - 118. [Ulm, Germany. Large cross sectional study. No association]

Hoffmeister, A., Rothenbacher, D., Bode, G., Persson, K., Marz, W., Nauck, M. A. et al. (2001). Current infection with Helicobacter pylori, but not seropositivity to Chlamydia pneumoniae or cytomegalovirus, is associated with an atherogenic, modified lipid profile. Atherosis Thrombosis and Vascular Biology 21,427 - 432.

Kahler, J., Gerth, S., Schafer, P., Boersma, E., Koster, R., Terres, W. et al. (2001). Antibodies to chlamydial lipopolysaccharides in unstable angina pectoris. American Journal of Cardiology 87, 1150 - 1153. [Hamburg. Large study. No correlation between antichlamydial antibody titers and C-reactive protein or troponin T]

Kalayoglu, M. V., Libby, P. & Byrne, G. I. (2002). Chlamydia pneumoniae as an emerging risk factor in cardiovascular disease. JAMA. 288, 2724 - 2731. Full article

Kanamoto, Y., Ouchi, K., Mizui, M., Ushio, M. & Usui, T. (1991). Prevalence of antibody to Chlamydia pneumoniae TWAR in Japan. Journal of Clinical Microbiology 29, 816 - 818.

Kark, J. D., Leinonen, M., Paltiel, O. &  Saikku, P. (1997). Chlamydia pneumoniae and acute myocardial infarction in Jerusalem. International Journal of Epidemiology 26, 730 - 738. [Large population based study. No association C. pneumoniae antibody and acute myocardial infarction]

Kaykov, E., Abbou, B., Friedstrom, S., Hermoni, D., Roguin, N. (1999). Chlamydia preumoniae in ischemic heart disease. Israel Medical Association Journal 1, 225 - 227.[Small cross sectional study showing association]

Leinonen, M., Linnanmaki, E., Mattila, K., Nieminen, M. S., Valtonen, V., Leirisalorepo, M. et al. (1990). Circulating immune complexes containing Chlamydial lipopolysaccharide in acute myocardial infarction. Microbial Pathogenesis 9, 67 - 73. [Early paper showing association with myocardial infarction]

Leinonen, M., Mattila, K., Kohlmeier, L. & Saikku, P. (1994). Chlamydia pneumoniae specific antibodies and immune complexes in German patients with acute myocardial infarction. In: Orfila, J., Byrne, G. I., Chernesky, M. et al., eds. Chlamydial Infections. Proceedings of the Eighth International Symposium on Human Chlamydial Infections. Paris, published Editrice Esculapio, Bologna, pages 209 - 211.

Leowattana, W., Mahanonda, N., Bhuripunyo, K., Leelarasamee, A., Pokum, S. &  Suwimol, B. (1999). The prevalence of Chlamydia pneumoniae antibodies in Thai patients with coronary artery disease. Journal of the Medical Association of Thailand 82, 792 - 797.

Leowattana, W., Mahanonda, N., Bhuripanyo, K., Pokium, S. & Kiartivich, S. (2000).  Chlamydia pneumoniae antibodies and angiographically demonstrated coronary artery disease in Thailand. Journal of the Medical Association of Thailand 83, 1054 - 1058.

Linnanmaki, E., Leinonen, M., Mattila, K., Nieminen, M. S., Valtonen, V. & Saikku, P. (1993). Chlamydia pneumoniae-specific circulating immune complexes in patients with chronic coronary heart disease. Circulation 87, 1130 - 1134.

Mazzoli, S., Tofani, N., Fantini, A., Semplici, F., Bandini, F., Salvi, A. et al. (1998). Chlamydia pneumoniae antibody response in patients with acute myocardial infarction and their follow-up. American Heart Journal 135, 15 - 20. [Italy. Small cross sectional study, positive association]

Mendall, M.A., Carrington, D., Strachan, D., Patel, P., Molineaux, N., Levi, J. et al. (1995). Chlamydia pneumoniae: risk factors for seropositivity and association with coronary heart disease. Journal of Infectious Diseases 30, 121 - 128. [Small general practice study, UK. Positive association]

Miettinen, H., Lehto, S., Saikku, P., Haffner, S. M., Ronnemaa, T., Pyorala, K. et al. (1996). Association of Chlamydia pneumoniae and acute coronary heart disease events in non-insulin dependent diabetic and non-diabetic subjects in Finland. European Heart Journal 17, 682 - 688.[E Finland. Positive association]

Miyashita, N., Toyota, E., Sawayama, T., Matsumoto, A., Mikami, Y., Kawai, N. et al. (1998). Association of chronic infection of Chlamydia pneumoniae and coronary heart disease in the Japanese. Internal Medicine 37, 913 - 916.[Small cross sectional study. Positive association with myocardial infarction]

Muhlestein, J. B., Horne, B. D., Carlquist, J. F., Madsen, T. E., Bair, T. L., Pearson, R. R. et al. (2000). Cytomegalovirus seropositivity and C-reactive protein have independent and combined predictive value for mortality in patients with angiographically demonstrated coronary artery disease. Circulation 102, 1917 - 1923. [Large prospective study over 1.4 - 4 years only. CMV but not Ch. pneumoniae was predictive of death from heart disease].

Nieto, F. J., Folsom, A. R., Sorlie, P. D., Grayston, J. T., Wang, S. P, & Chambless, L. E. (1999). Chlamydia pneumoniae infection and incident coronary heart disease: the Atherosclerosis risk in Communities Study. American Journal of Epidemiology 150,149 - 156. [Community based study. C. pneumoniae not a risk factor]

Nobel, M., DeTorrente, A., Peter, O., & Genne, D. (1999). No serological evidence of association between Chlamydia pneumoniae infection and acute coronary heart disease. Scandinavian Journal of Infectious Diseases 31, 261 - 264. [Small Swiss cross sectional study, no association]

Ossewaarde, J. M., Feskens, E. J., de Vries A,, Vallinga. C, E. & Kromhout, D. (1998). Chlamydia pneumoniae is a risk factor for coronary heart disease in symptom-free elderly men, but Helicobacter pylori and cytomegalovirus are not. Epidemiol Infect 120, 93 - 99.

Patel, P., Mendall, M. A., Carrington, D., Strachan, D. P., Leatham, E., Molineaux, N. et al. (1995). Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors. British Medical Journal 311, 711 - 714. Full article [Small study. Positive association for H. pylori and C. pneumoniae]

Ridker, P. M., Kundsin, R. B., Stampfer, M. J., Poulin, S. & Hennekens, C. H. (1999). Prospective study of Chlamydia pneumoniae IgG seropositivity and risks of future myocardial infarction. Circulation 99, 1161 - 1164. [Large prospective study. No association] Full article

Ridker, P. M., Hennekens, C. H., Buring, J. E., Kundsin, R. & Shih, J. (1999a). Baseline IgG antibody titers to Chlamydia pneumoniae, Helicobacter pylori, Herpes simplex virus, and cytomegalovirus and the risk for cardiovascular disease in women. Annals of Internal Medicine 131, 573 - 577. [Rare prospective nested case control study of women; infection had no effect].

Roivainen, M., Viik-Kajander, M., Palosuo, T., Toivanen, P., Leinonen, M., Saikku, P. et al. (2000). Infections, inflammation, and the risk of coronary heart disease. Circulation 101, 252 - 257. [Rework of the prospective Helsinki heart study. HSV1 and Ch. pneumoniae increase risk] Full article

Romeo, F., Martuscelli, E., Chirieolo, G., Cerabino, L. M., Ericson, K., Saldeen, T. G. et al. (2000). Seropositivity against Chlamydia pneumoniae in patients with coronary atherosclerosis. Clinical Cardiology 23, 327 - 330.

Saikku, P., Mattila, K., Nieminen, M. S., Huttunen, J. K., Leinonen, M., Ekman, M. R. et al. (1988). Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet 1988 vol 2, 983 - 986. [The paper that started the ball rolling]

Saikku, P., Leinonen, M., Tenkanen, L., Linnanmaki, E., Ekman, M. R., Manninen, V. et al. (1992). Chronic Chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart Study. Annals of Internal Medicine 116, 273 - 278. [The first major prospective study, but now superseded by more powerful studies].

Schiele, F., Batur, M. K., Seronde, M. F., Meneveau, N., Sewoke, P., Bassignot, A. et al. (2001). Cytomegalovirus, Chlamydia pneumoniae, and Helicobacter pylori IgG antibodies and restenosis after stent implantation: an angiographic and intravascular ultrasound study. Heart 85, 304 - 311. [Previous infection with cytomegalovirus, C. pneumoniae, or H. pylori not a contributing factor in the process of restenosis after stent implantation]

Shimada, K., Daida, H., Mokuno, H., Watanabe, Y., Sawano, M., Iwama, Y. et al. (2001). Association of seropositivity for antibody to Chlamydia- specific lipopolysaccharide and coronary artery disease in Japanese men. Japanese Circulation Journal - English Edition 65, 182 - 187. [Japan. Medium sized cross sectional study suggesting an association with myocardial infarction].

Siscovick, D. S., Schwartz, S. M., Corey, L., Grayston, J. T., Ashley, R., Wang, S. P. et al. (2000). Chlamydia pneumoniae, Herpes simplex virus type 1, and cytomegalovirus and incident myocardial infarction and coronary heart disease death in older adults : the cardiovascular health study.  Circulation 102, 2335 - 2240. [Prospective study showing association for HSV antibody and for high level antibody to C. pneumoniae].

Siscovick, D. S., Schwartz, S. M., Caps, M., Wang, S. P. & Grayston, J. T. (2000). Chlamydia pneumoniae and atherosclerotic risk in populations: The role of seroepidemiology. Journal of Infectious Diseases (Supplement) 181, S417 - S420. [Points out that results on seroepidemiological studies on the contribution of Ch. pneumoniae to atherosclerotic disease are inconclusive compared with other data and suggests why this might be]. 

Smieja, M., Cronin, L., Levine, M., Goldsmith, C. H., Yusuf, S. & Mahoney, J. B. (2001). Previous exposure to Chlamydia pneumoniae, Helicobacter pylori and other infections in Canadian patients with ischemic heart disease. Canadian Journal of Cardiology 17, 270 - 276. [Smallish cross sectional study. Canada. Association for C. pneumoniae not H. pylori or CMV]

Strachan, D. P., Carrington, D., Mendall, M. A., Ballam, L., Morris, J., Butland, B. K. et al. (1999b). Relation of Chlamydia pneumoniae serology to mortality and incidence of ischaemic heart disease over years in the Caerphilly prospective heart disease study. British Medical Journal 318, 1035 - 1039. [Large prospective. Weak association for IgA but not IgG antibody to C. pneumoniae] Full article  

Thom, D. H., Wang, S. P., Grayston, J. T., Siscovick, D. S., Stewart, D. K., Kronmal, R. A. & Weiss, N. S. (1991). Chlamydia pneumoniae strain TWAR antibody and angiographically demonstrated coronary artery disease. Arteriosclerosis and Thrombosis 11, 547 - 551. [Early cross sectional study supporting association]

Thom, D. H., Grayston, J. T., Siscovick, D. S., Wang, S. P., Weiss, N. S. &  Daling, J. R. (1992). Association of prior infection with Chlamydia pneumoniae and angiographically demonstrated coronary artery disease. Journal of the American Medical Association (JAMA) 268, 68 - 72. [Early cross sectional study supporting association]

Thomas, G. N., Scheel, O., Koehler, A. P., Bassett, D. C., Cheng, A. F. (1997). Respiratory chlamydial infections in a Hong Kong teaching hospital and association with coronary heart disease. Scandinavian Journal of Infectious Diseases Supplement 104, 30 - 33.

Wald, N. J., Law, M. R., Morris, J. K., Zhou, X., Wong, Y. & Ward, M. E. (2000). Chlamydia pneumoniae infection and mortality from ischaemic heart disease: large prospective study. British Medical Journal  321, 204 - 207.   Full article   [Currently the largest prospective trial, performed on an homogeneous upper socio-economic class group.  Showed no effect of prior C. pneumoniae infection on coronary heart events in a long term study.]

Weiss, S. M,. Roblin, P. M., Gaydos, C. A., Cummings, P., Patton, D. L., Schulhoff, N. et al. (1996). Failure to detect Chlamydia pneumoniae in coronary atheromas of patients undergoing atherectomy. Journal of Infectious Diseases 173, 957 - 962. [Small cross sectional study. Antibody to C. pneumoniae, unusually, higher in controls than patients]

Wong, Y. K., Gallagher, P. J. & Ward, M. E. (1999). Chlamydia pneumoniae and atherosclerosis. Heart 81, 232 - 238. [A review critical of the evidence that C. pneumoniae is an important cause of coronary heart disease. Found that although the majority of serological studies had shown an association between C. pneumoniae and atherosclerosis, the number of cases in studies that have reported a positive association when using strict criteria for chronic infection is similar to the number of cases in studies which found no association.]

Wong, Y. K., Dawkins, K. D. & Ward, M. E. (1999). Circulating Chlamydia pneumoniae DNA as a predictor of coronary artery disease. Journal of the American College of Cardiology 34, 1435 - 1439. [see hyperlink for related comment / editorial]

Zhu, J. H., Nieto, F. J., Horne, B. D., Anderson, J. L., Muhlestein, J. B. & Epstein, S. E. (2001). Prospective study of pathogen burden and risk of myocardial infarction or death. Circulation 103, 45 - 51. [Overall pathogen burden associated with increased risk of death from myocardial infarction]

NEXT: Direct detection of C. pneumoniae in atheromatous tissues