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Chlamydia pneumoniae IgG and the severity of coronary atherosclerosis
European Journal of Internal Medicine 15 (2004) 508 – 510 www.elsevier.com/locate/ejim
Original article
Chlamydia pneumoniae IgG and the severity of coronary atherosclerosis P. J7remo*, A. Richter Department of Cardiology, Linko¨ping University Hospital, Linko¨ping, Sweden Received 15 March 2004; received in revised form 5 July 2004; accepted 12 July 2004
Abstract Background: The aim of this study was to compare Chlamydia pneumoniae IgG and the extent of coronary atherosclerosis. Methods: We investigated 92 patients with stable angina pectoris who underwent coronary angiography to assess chest pain. Before angiography, C. pneumoniae IgG was analyzed. The number of major coronary arteries (1–3) having at least one diameter narrowing (z50%) stenosis was determined. The patients were divided into two groups of equal size, according to C. pneumoniae IgG levels. One group included individuals with C. pneumoniae IgG levels exceeding 46 enzyme-immuno-units (EIU)/L and the other consisted of subjects with IgG concentrations below 46 EIU/L. Results: Subjects with higher antibody concentrations had a more severe disease. The number of diseased arteries was 2.1F0.8 (S.D.) and 1.4F0.6 (S.D.) for the two groups, respectively. The difference is highly significant ( pb0.0001). Conclusions: This study suggests a causative relationship between C. pneumoniae IgG and the degree of coronary atherosclerosis. It does not, however, prove causality. D 2004 Elsevier B.V. All rights reserved. Keywords: Atherosclerosis; Angina pectoris; Chlamydia pneumoniae; Coronary heart disease
1. Introduction Chlamydia pneumoniae is an obligate intracellular parasite. It shows a high prevalence and is spread around the world. In 1988, Saikku et al. [1] associated C. pneumoniae with coronary heart disease for the first time. The observation has been confirmed in many subsequent papers [2–4]. Negative studies have also been reported [5,6]. Shor et al. [7] were the first to identify C. pneumoniae in coronary plaques. This finding has been reported from both postmortem and surgically obtained tissue [8,9]. The role played by C. pneumoniae in the progression of atherosclerosis is still a matter of controversy. Consequently, the current study compares C.
* Corresponding author. Department of Internal Medicine, The Vrinnevi Hospital, S-601 82 Norrkfping, Sweden. Fax: +46 11125662. E-mail address: [email protected] (P. J7remo). 0953-6205/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2004.07.011
pneumoniae IgG and the extent of coronary atherosclerosis in stable angina pectoris.
2. Materials and methods Ninety-two patients with stable angina pectoris underwent coronary angiography to assess chest pain (Table 1). Exclusion criteria were age above75 years, an ongoing respiratory tract infection, diabetes mellitus, rheumatoid arthritis, and a history of myocardial infarction in the 3 months prior to inclusion in the study. Standard procedures were employed for coronary angiography [10]. Cases were defined as patients having at least one major coronary artery lesion occupying 50% or more of the luminal diameter. The number of affected major coronary arteries (1–3) was used as an experimental parameter. C. pneumoniae IgG was determined before angiography. A solidphase enzyme-immunoassay with the results expressed as enzyme-immuno-units (EIU; Labsystems OY, Finland) was
P. Ja¨remo, A. Richter / European Journal of Internal Medicine 15 (2004) 508–510 Table 1 Clinical and demographic characteristics of the patients studied
3. Results
Higher (N46 EIU/L) C. pneumoniae IgG levels
p-valuea Lower (b46 EIU/L) C. pneumoniae IgG levels
46 62F9 6/40 10 9
46 60F8 9/37 6 13
NS NS NS NS
14
12
NS
Medication at admission Aspirin, n 44 Beta-blockers, n 38 ACE-inhibitors, n 11 Ca2+ channel blockers, n 14 Prophylactic nitroglycerin, n 32 Lipid-lowering drugs, n 32
44 45 5 13 27 33
NS b0.05 NS NS NS NS
Number of patients Age Gender (female/male) Current smokers, n Previous myocardial infarction, n Hypertension requiring medical treatment, n
509
NS=not significant. EIU=enzyme-immuno-units. a Fisher’s exact test was used for statistical evaluation.
put to use for C. pneumoniae IgG. Fisher’s exact test and Student’s t-test for unpaired data were used for statistical evaluation. The local ethical committee approved the study.
Coronary angiography revealed triple-artery disease in 20 participants, double-artery disease in 30, and singleartery disease in 42 individuals (Fig. 1). Patients with threevessel disease had the highest C. pneumoniae IgG levels. The subjects were then divided into two groups of equal size, according to C. pneumoniae IgG seroreactivity (Table 1). One group included subjects having C. pneumoniae IgG levels above 46 EIU/L and the other had subjects with IgG concentrations below 46 EIU/L. The two groups did not differ with respect to age, gender, or current smoking habits (Table 1). Medication differed slightly as patients with lower C. pneumoniae IgG used beta-blockers more frequently ( pb0.05). Individuals with higher IgG concentrations had more diseased coronary arteries [2.1F0.8 (S.D.) and 1.4F0.6 (S.D.) for the cohorts having higher and lower IgG titers, respectively, pb0.0001; Table 2].
4. Discussion This study demonstrates a highly significant relationship between C. pneumoniae IgG and the severity of coronary atherosclerosis (Table 2). In 1991, Thom et al. [11] already suggested that C. pneumoniae antibodies were associated
Fig. 1. C. pneumoniae IgG titers for individuals having one, two, and three diseased coronary arteries, respectively.
510
P. Ja¨remo, A. Richter / European Journal of Internal Medicine 15 (2004) 508–510
Table 2 Results (meanFS.D.) for the two groups having higher and lower C. pneumoniae IgG, respectively Higher (N46 EIU/L) Lower (b46 EIU/L) p-valuea C. pneumoniae C. pneumoniae IgG levels (n=46) IgG levels (n=46) C. pneumoniae 108F58 IgG titers (EIU) No. of diseased 2.1F0.8 coronary arteries
pneumoniae IgG and the degree of coronary atherosclerosis. The study does not prove causality, but it does suggest a link between the organism and the severity of the disease.
26F14
Acknowledgements 1.4F0.6
b0.0001
EIU=enzyme-immuno-units. a Student’s t-test for unpaired data was employed as statistics.
with severe coronary artery disease. However, the present close connection between C. pneumoniae IgG and the degree of coronary atherosclerosis is a new finding. Coronary involvement hardly indicates the extent of atherosclerosis. However, three affected major coronary arteries almost certainly denote more widespread disease in other parts of the body. Consequently, these patients more often experience silent plaque rupture in coronary and in other major arteries [12]. It is possible that plaque ruptures liberate C. pneumoniae, leading to an antigen challenge and elevated IgG levels [13]. Enhanced C. pneumoniae IgG is found with increased age, in males, and in smokers [3,5]. Our study groups did not differ with respect to age, current smoking, or sex distribution (Table 1). A substantial number of the participants were using lipid-lowering drugs. Thus, it is impossible to exclude the possibility that plasma cholesterol differs between the two groups. Whether elevated antibody levels reflect acute, past, or reactivated infection is unclear. Some authors have experience with the current C. pneumoniae IgG assay in the setting of an acute infection. Coronary heart disease is associated with a chronic infection [13]. Consequently, limits for seropositivity defined for acute infections were not employed, and the study cohort was divided according to C. pneumoniae IgG levels into two groups of equal size. Three subjects with one-vessel disease had high C. pneumoniae IgG (Fig. 1). This could reflect an ongoing exogenous infection. It is also possible that these patients had more severe atherosclerosis in other parts of the body. According to the manufacturer, the present immunoassay blocks antibodies to the most probable antigen for cross reactivity, i.e., the common lipopolysaccharides found in all chlamydial species. Consequently, the assay distinguishes C. pneumoniae from both C. trachomatis and C. psitticati. Although this study included a limited number of patients, it describes a robust association between C.
This study was supported by grants from the Health Research Council in the southeast of Sweden.
References [1] Saikku P, Leinonen M, Mattila K, et al. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet 1988;2:983 – 6. [2] Saikku P, Leinonen M, Tenkanen L, et al. Chronic Chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart Study. Ann Intern Med 1992;16:273 – 8. [3] Patel P, Mendall MA, Carrington D, et al. Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors. BMJ 1995;11:711 – 4. [4] Ossewaarde JM, Feskens EJM, De Vries A, et al. Chlamydia pneumoniae is a risk factor for coronary heart disease in symptomfree elderly men, but Helicobacter pylori and cytomegalovirus are not. Epidemiol Infect 1998;20:93 – 9. [5] Ridker PM, Kundsin RB, Stampfer MJ, et al. Prospective study of Chlamydia pneumoniae IgG seropositivity and risks of future myocardial infarction. Circulation 1999;9:1161 – 4. [6] Danesh J, Whincup P, Walker M, et al. Chlamydia pneumoniae IgG titres and coronary heart disease: prospective study and meta-analysis. BMJ 2000;21:208 – 13. [7] Shor A, Kuo CC, Patton DL. Detection of Chlamydia pneumoniae in coronary arterial fatty streaks and atheromatous plaques. S Afr Med J 1992;2:158 – 61. [8] Kuo CC, Shor A, Campbell LA, et al. Demonstration of Chlamydia pneumoniae in atherosclerotic lesions of coronary arteries. J Infect Dis 1993;67:841 – 9. [9] Vink A, Pasterkamp G, Poppen M, et al. The adventitia of atherosclerotic coronary arteries frequently contains Chlamydia pneumoniae. Atherosclerosis 2001;57:117 – 22. [10] J7remo P, Lindahl TL, Milovanovic M, et al. Inverse relationship between platelet density and reactivity at coronary angiography. Haemostasis 2001;31:55 – 60. [11] Thom DH, Wang SP, Grayston JT, et al. Chlamydia pneumoniae strain TWAR antibody and angiographically demonstrated coronary artery disease. Arterioscler Thromb 1991;11:547 – 51. [12] Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992;326:42 – 50. [13] J7remo P. Evidence that Chlamydia pneumoniae affects platelet activity in patients with acute myocardial infarction and ST-elevations. Scand J Infect Dis 2001;33:747 – 8.
Original article
Chlamydia pneumoniae IgG and the severity of coronary atherosclerosis P. J7remo*, A. Richter Department of Cardiology, Linko¨ping University Hospital, Linko¨ping, Sweden Received 15 March 2004; received in revised form 5 July 2004; accepted 12 July 2004
Abstract Background: The aim of this study was to compare Chlamydia pneumoniae IgG and the extent of coronary atherosclerosis. Methods: We investigated 92 patients with stable angina pectoris who underwent coronary angiography to assess chest pain. Before angiography, C. pneumoniae IgG was analyzed. The number of major coronary arteries (1–3) having at least one diameter narrowing (z50%) stenosis was determined. The patients were divided into two groups of equal size, according to C. pneumoniae IgG levels. One group included individuals with C. pneumoniae IgG levels exceeding 46 enzyme-immuno-units (EIU)/L and the other consisted of subjects with IgG concentrations below 46 EIU/L. Results: Subjects with higher antibody concentrations had a more severe disease. The number of diseased arteries was 2.1F0.8 (S.D.) and 1.4F0.6 (S.D.) for the two groups, respectively. The difference is highly significant ( pb0.0001). Conclusions: This study suggests a causative relationship between C. pneumoniae IgG and the degree of coronary atherosclerosis. It does not, however, prove causality. D 2004 Elsevier B.V. All rights reserved. Keywords: Atherosclerosis; Angina pectoris; Chlamydia pneumoniae; Coronary heart disease
1. Introduction Chlamydia pneumoniae is an obligate intracellular parasite. It shows a high prevalence and is spread around the world. In 1988, Saikku et al. [1] associated C. pneumoniae with coronary heart disease for the first time. The observation has been confirmed in many subsequent papers [2–4]. Negative studies have also been reported [5,6]. Shor et al. [7] were the first to identify C. pneumoniae in coronary plaques. This finding has been reported from both postmortem and surgically obtained tissue [8,9]. The role played by C. pneumoniae in the progression of atherosclerosis is still a matter of controversy. Consequently, the current study compares C.
* Corresponding author. Department of Internal Medicine, The Vrinnevi Hospital, S-601 82 Norrkfping, Sweden. Fax: +46 11125662. E-mail address: [email protected] (P. J7remo). 0953-6205/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2004.07.011
pneumoniae IgG and the extent of coronary atherosclerosis in stable angina pectoris.
2. Materials and methods Ninety-two patients with stable angina pectoris underwent coronary angiography to assess chest pain (Table 1). Exclusion criteria were age above75 years, an ongoing respiratory tract infection, diabetes mellitus, rheumatoid arthritis, and a history of myocardial infarction in the 3 months prior to inclusion in the study. Standard procedures were employed for coronary angiography [10]. Cases were defined as patients having at least one major coronary artery lesion occupying 50% or more of the luminal diameter. The number of affected major coronary arteries (1–3) was used as an experimental parameter. C. pneumoniae IgG was determined before angiography. A solidphase enzyme-immunoassay with the results expressed as enzyme-immuno-units (EIU; Labsystems OY, Finland) was
P. Ja¨remo, A. Richter / European Journal of Internal Medicine 15 (2004) 508–510 Table 1 Clinical and demographic characteristics of the patients studied
3. Results
Higher (N46 EIU/L) C. pneumoniae IgG levels
p-valuea Lower (b46 EIU/L) C. pneumoniae IgG levels
46 62F9 6/40 10 9
46 60F8 9/37 6 13
NS NS NS NS
14
12
NS
Medication at admission Aspirin, n 44 Beta-blockers, n 38 ACE-inhibitors, n 11 Ca2+ channel blockers, n 14 Prophylactic nitroglycerin, n 32 Lipid-lowering drugs, n 32
44 45 5 13 27 33
NS b0.05 NS NS NS NS
Number of patients Age Gender (female/male) Current smokers, n Previous myocardial infarction, n Hypertension requiring medical treatment, n
509
NS=not significant. EIU=enzyme-immuno-units. a Fisher’s exact test was used for statistical evaluation.
put to use for C. pneumoniae IgG. Fisher’s exact test and Student’s t-test for unpaired data were used for statistical evaluation. The local ethical committee approved the study.
Coronary angiography revealed triple-artery disease in 20 participants, double-artery disease in 30, and singleartery disease in 42 individuals (Fig. 1). Patients with threevessel disease had the highest C. pneumoniae IgG levels. The subjects were then divided into two groups of equal size, according to C. pneumoniae IgG seroreactivity (Table 1). One group included subjects having C. pneumoniae IgG levels above 46 EIU/L and the other had subjects with IgG concentrations below 46 EIU/L. The two groups did not differ with respect to age, gender, or current smoking habits (Table 1). Medication differed slightly as patients with lower C. pneumoniae IgG used beta-blockers more frequently ( pb0.05). Individuals with higher IgG concentrations had more diseased coronary arteries [2.1F0.8 (S.D.) and 1.4F0.6 (S.D.) for the cohorts having higher and lower IgG titers, respectively, pb0.0001; Table 2].
4. Discussion This study demonstrates a highly significant relationship between C. pneumoniae IgG and the severity of coronary atherosclerosis (Table 2). In 1991, Thom et al. [11] already suggested that C. pneumoniae antibodies were associated
Fig. 1. C. pneumoniae IgG titers for individuals having one, two, and three diseased coronary arteries, respectively.
510
P. Ja¨remo, A. Richter / European Journal of Internal Medicine 15 (2004) 508–510
Table 2 Results (meanFS.D.) for the two groups having higher and lower C. pneumoniae IgG, respectively Higher (N46 EIU/L) Lower (b46 EIU/L) p-valuea C. pneumoniae C. pneumoniae IgG levels (n=46) IgG levels (n=46) C. pneumoniae 108F58 IgG titers (EIU) No. of diseased 2.1F0.8 coronary arteries
pneumoniae IgG and the degree of coronary atherosclerosis. The study does not prove causality, but it does suggest a link between the organism and the severity of the disease.
26F14
Acknowledgements 1.4F0.6
b0.0001
EIU=enzyme-immuno-units. a Student’s t-test for unpaired data was employed as statistics.
with severe coronary artery disease. However, the present close connection between C. pneumoniae IgG and the degree of coronary atherosclerosis is a new finding. Coronary involvement hardly indicates the extent of atherosclerosis. However, three affected major coronary arteries almost certainly denote more widespread disease in other parts of the body. Consequently, these patients more often experience silent plaque rupture in coronary and in other major arteries [12]. It is possible that plaque ruptures liberate C. pneumoniae, leading to an antigen challenge and elevated IgG levels [13]. Enhanced C. pneumoniae IgG is found with increased age, in males, and in smokers [3,5]. Our study groups did not differ with respect to age, current smoking, or sex distribution (Table 1). A substantial number of the participants were using lipid-lowering drugs. Thus, it is impossible to exclude the possibility that plasma cholesterol differs between the two groups. Whether elevated antibody levels reflect acute, past, or reactivated infection is unclear. Some authors have experience with the current C. pneumoniae IgG assay in the setting of an acute infection. Coronary heart disease is associated with a chronic infection [13]. Consequently, limits for seropositivity defined for acute infections were not employed, and the study cohort was divided according to C. pneumoniae IgG levels into two groups of equal size. Three subjects with one-vessel disease had high C. pneumoniae IgG (Fig. 1). This could reflect an ongoing exogenous infection. It is also possible that these patients had more severe atherosclerosis in other parts of the body. According to the manufacturer, the present immunoassay blocks antibodies to the most probable antigen for cross reactivity, i.e., the common lipopolysaccharides found in all chlamydial species. Consequently, the assay distinguishes C. pneumoniae from both C. trachomatis and C. psitticati. Although this study included a limited number of patients, it describes a robust association between C.
This study was supported by grants from the Health Research Council in the southeast of Sweden.
References [1] Saikku P, Leinonen M, Mattila K, et al. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet 1988;2:983 – 6. [2] Saikku P, Leinonen M, Tenkanen L, et al. Chronic Chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart Study. Ann Intern Med 1992;16:273 – 8. [3] Patel P, Mendall MA, Carrington D, et al. Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors. BMJ 1995;11:711 – 4. [4] Ossewaarde JM, Feskens EJM, De Vries A, et al. Chlamydia pneumoniae is a risk factor for coronary heart disease in symptomfree elderly men, but Helicobacter pylori and cytomegalovirus are not. Epidemiol Infect 1998;20:93 – 9. [5] Ridker PM, Kundsin RB, Stampfer MJ, et al. Prospective study of Chlamydia pneumoniae IgG seropositivity and risks of future myocardial infarction. Circulation 1999;9:1161 – 4. [6] Danesh J, Whincup P, Walker M, et al. Chlamydia pneumoniae IgG titres and coronary heart disease: prospective study and meta-analysis. BMJ 2000;21:208 – 13. [7] Shor A, Kuo CC, Patton DL. Detection of Chlamydia pneumoniae in coronary arterial fatty streaks and atheromatous plaques. S Afr Med J 1992;2:158 – 61. [8] Kuo CC, Shor A, Campbell LA, et al. Demonstration of Chlamydia pneumoniae in atherosclerotic lesions of coronary arteries. J Infect Dis 1993;67:841 – 9. [9] Vink A, Pasterkamp G, Poppen M, et al. The adventitia of atherosclerotic coronary arteries frequently contains Chlamydia pneumoniae. Atherosclerosis 2001;57:117 – 22. [10] J7remo P, Lindahl TL, Milovanovic M, et al. Inverse relationship between platelet density and reactivity at coronary angiography. Haemostasis 2001;31:55 – 60. [11] Thom DH, Wang SP, Grayston JT, et al. Chlamydia pneumoniae strain TWAR antibody and angiographically demonstrated coronary artery disease. Arterioscler Thromb 1991;11:547 – 51. [12] Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992;326:42 – 50. [13] J7remo P. Evidence that Chlamydia pneumoniae affects platelet activity in patients with acute myocardial infarction and ST-elevations. Scand J Infect Dis 2001;33:747 – 8.