Effects of Chlamydia pneumonia infection on progression of coronary heart disease in elderly patients
Department of Cardiology, Liaocheng People's Hospital, Shandong University, Liaocheng, PR China
- *Corresponding Authors:
- Min Zhou
Department of Cardiology
Liaocheng People's Hospital, Shandong University
- Hengchen Yao
Department of Cardiology
Liaocheng People's Hospital, Shandong University
Accepted on December 1, 2016
This study explored the effects of Chlamydia pneumoniae (Cpn) infection in elderly patients with Coronary Heart Disease (CHD), as well as related treatment strategies. Serum levels of Endothelin-1 (ET-1), Interleukin-6 (IL-6), C-reactive protein, fibrinogen, soluble vascular cell adhesion molecule-1, and cardiac troponin-1 were determined in 81 elderly CHD patients with Cpn infection (group A) and 82 elderly CHD patients without Cpn infection (group B). Patients in group A were treated with oral azithromycin; serum Cpn-immunoglobulin (Ig) M and (Ig) G levels in group A were measured before and after treatment. Levels of various indicators in group A were higher than those in group B (P<0.05), while the titres of Cpn-IgA and Cpn-IgG in group A were lower than those in group B (P<0.05). Cpn infection may result in increases in inflammatory factors. Azithromycin treatment may reduce the antibody titer, which may reduce the incidence of adverse events in elderly patients with coronary heart disease.
Chlamydia pneumonia infection, Elderly patients, Coronary heart disease.
Coronary Heart Disease (CHD) is common in the elderly and results from atherosclerosis. Inflammatory reactions play a major role in CHD , and plaque inflammation is a key factor in plaque instability. The activation of inflammation and immune cells play key roles in the loss and rupture of collagen fiber caps [2,3], and plaque rupture could lead to adverse cardiovascular events . Chlamydia pneumoniae (Cpn) infection can cause an increase in inflammatory factors such as C-Reactive Protein (CRP) and others , which would promote the occurrence and development of plaque inflammation through inflammatory cytokines or pneumoniaassociated phospholipase D [6,7]. Cpn can cause pneumonia, bronchitis, myocarditis , endocarditis , and pericarditis , which can result in vascular inflammation , and may lead to acute cardiac and cerebrovascular events . However, the correlation between Cpn and CHD in the elderly remains unclear. We retrospectively analysed clinical data of 163 elderly patients with CHD, 81 of who received azithromycin for Cpn infection, and evaluated multiple inflammatory factors to determine the effects of Cpn infection on CHD in the elderly.
Materials and Methods
From April 2011 to June 2013, 163 elderly patients with CHD who were admitted to our hospital were recruited for the study. All patients had undergone coronary angiography or coronary computed tomography angiography. CHD was diagnosed if at least one large coronary branch had stenosis>50%. All patients had cardiac function grade II or above, left ventricular ejection fraction ≥ 50%, and left ventricular end diastolic diameter ≤ 50 mm. Patients with malignancy, other bacterial or viral infections, toxic diseases, liver and kidney dysfunction, or immune system diseases were excluded.
Of the 163 patients with CHD, 81 with Cpn infection were placed in group A, while the other 82 patients without Cpn infection were recruited as the control group. Patients in group A were administered azithromycin (500 mg/d) orally for a total of 3 days.
Fasting venous blood samples were collected in the morning, and serum was isolated by centrifugation at 1,500 rpm for 15 min and stored at-70°C. Radioimmunoassay was used to determine serum levels of Interleukin-6 (IL-6); plasma Fibrinogen (Fg) and serum CRP levels were detected using immunonephelometry. Enzyme-Linked Immunosorbent Assay (ELISA) was used to measure levels of Endothelin-1 (ET-1) (Biotech Co., Ltd, Shanghai, China) and soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) (Fangcheng Biotechnology Co. Ltd. Beijing), according to manufacturer’s instructions. Cardiac troponin-1 (c-TnI) levels were measured routinely in the clinical laboratory of our hospital. Cpn-Immunoglobulin (Ig) M and (Ig) G titers were measured in all patients the day after admission to determine whether Cpn infection was present; Cpn-IgM and IgG titers were also measured before and 1 month after azithromycin treatment for infection in group A.
Continuous variables are presented as mean ± standard deviation and were compared by one way Analysis of Variance (ANOVA). Categorical data are presented as percentages and were compared with the chi-square or Fisher’s exact test. All data were analysed using SPSS 13.0 software (SPSS, Inc., Chicago, IL, USA). P<0.05 was considered statistically significant.
A total of 163 elderly patients with CHD were recruited for the study. Group A comprised 81 patients with Cpn infection. Group B comprised 82 patients without Cpn infection, who were matched for sex, age, and history of diabetes, hypertension, smoking, and low-density lipoprotein cholesterol level. Basic data are shown in Table 1, and no significant differences were detected between the groups (P>0.05, respectively).
|Group A||Group B||Value||P|
|Male (%)||54 (66.7%)||54 (65.8%)||χ2=0.01||>0.05|
|Age (year)||71.38 ± 5.28||72.09 ± 5.32||t=0.86||>0.05|
|CHD history (years)||5-24 (17.38 ± 5.29)||5-25 (18.03 ± 5.22)||t=0.79||>0.05|
|Diabetes||38 (47%)||42 (51%)||χ2=0.30||>0.05|
|Hypertension||58 (72%)||54 (66%)||χ2=0.63||>0.05|
|Smoking||32 (40%)||35 (43%)||χ2=0.17||>0.05|
|LDL-c (mmol/l)||3.30 ± 1.14||3.18 ± 1.55||t=0.45||>0.05|
Data are present as mean ± S.D. or n (%): Baseline characteristics.
Comparison of ET-1, IL-6, CRP, Fg, and sVCAM-1 levels
ET-1, IL-6, CRP, Fg, and sVCAM-1 levels in group A were significantly higher than those in group B (P<0.05, respectively) (Table 2).
|Group A||Group B||Value||P|
|ET-1 (pg/ml)||51.23 ± 20.54||31.22 ± 10.08||t=3.526||<0.001|
|IL-6 (ng/L)||10.61 ± 3.46||6.72 ± 2.93||t=2.647||<0.01|
|CRP (mg/L)||3.54 ± 1.72||1.92 ± 1.03||t=2.161||<0.05|
|Fg (g/L)||2.98 ± 0.84||1.87 ± 0.92||t=2.624||0.01|
|sVCAM-1||27.33 ± 11.78||6.20 ± 1.38||t=3.668||<0.001|
|CK (IU/L)||159.67 ± 27.36||131.25 ± 30.69||t=3.258||<0.002|
|CK-MB (IU/L)||17.05 ± 6.32||13.68 ± 4.61||t=2.997||<0.005|
|CTnI (ng/ml)||0.26 ± 0.08||0.12 ± 0.03||t=2.648||<0.01|
Data are shown as mean ± SD. ET-1: Endothelial-1; IL-6: Interleukin-6; CRP: C-Reactive Protein; Fg: Fibrinogen; sVCAM-1: Soluble intercellular Cell Adhesion Molecule-I, CK: Creatine Kinase, CK-MB: Creatine Kinase-MB; CTnI: Cardiac Troponin I.
Comparison of myocardial biomarkers
Creatine Kinase (CK), CK-MB, c-TnT, and c-TnI levels were significantly higher in group A than in group B (P<0.05, respectively) (Table 2).
The titers of Cpn-IgM and Cpn-IgG in group A decreased significantly after treatment (P<0.05, respectively; Table 3).
|Group||n||Cpn-IgM (+) (%)||Cpn-IgG (+) (%)|
|Before treatment||After treatment||Before treatment||After treatment|
Data are shown as per centum (%). Cpn-IgM: Chlamydia pneumoniae-IgM; Cpn-IgG: Chlamydia pneumoniae-IgM.
Cpn is an important cause of human respiratory tract infection, and the infection rate increases with age. It has been reported that Cpn infection promotes the transformation of macrophages to foam cells [13,14] and destabilizes atherosclerotic plaques , which can result in occlusion of coronary arteries, and induce myocardial infarction. Persistent Cpn infection may lead to arteriosclerosis [16,17] and endothelial dysfunction , may promote the development of atherosclerotic plaque inflammation , and may be involved in the pathogenesis of acute coronary syndrome , thus increasing the risk for CHD . High levels of Heat shock protein 60 (Hsp60) and Cpn antibodies are independent risk factors for coronary atherosclerosis . CHD is common in the elderly, and the morbidity associated with CHD increases with changes in life style and diet, as well as with an increase in life expectancy. Atherosclerosis, an important pathological characteristic in CHD, is closely correlated with inflammation ; in other words, inflammation mediates atherosclerosis . Among the inflammatory cytokines in our study, ET-1 is produced by activated macrophages and facilitates coronary plaque rapture, induces major adverse cardiac events , and reduces the sensitivity of coronary artery smooth muscle cells to Ca2+, resulting in vascular insufficiency . ET-1 recruits monocytes in the circulation and activates macrophages, leading to damage of vascular endothelial cells. ET-1 also promotes smooth muscle cell proliferation and aggravates arteriosclerosis. IL-6 can activate inflammatory cells, enhance macrophage expression [27,28], and stimulate liver cells to synthesize CRP and Fg . As an independent and sensitive predictor of cardiovascular disease, IL-6 not only directly damages vascular endothelium, leading to release of abundant adhesion cells that are involved in arteriosclerosis and thrombosis, causing plaque rapture, but also induces increased sVCAM-1 production, which is associated with multiple risk factors for CHD and atherosclerotic disease [30,31]. The binding of IL-6 to monocytes or T cells can promote leukocyte adhesion and aggravate pathological damage. Fg, an acutephase protein, can enter the artery wall via the circulation as a coagulation factor and transform into fibrin, which directly damages vascular endothelial cells, increases the incidence of thrombosis, and promotes development of atherosclerotic plaques . Fg can also accumulate in the vascular wall to accelerate arteriosclerosis. In our research, we found that elderly patients with CHD complicated by Cpn infection had significantly higher levels of inflammatory factors and c-TnI than CHD patients without Cpn infection, indicating that inflammatory lesions induced by Cpn infection influence the progression of arteriosclerosis in CHD or even result in plaque rupture to cause myocardial infarction. Treatment for Cpn infection facilitates reduction in inflammatory factors, thus slowing the progression of atherosclerosis. Azithromycin is a newer macrolide, and affects protein synthesis by binding to the 50 S ribosomal subunit of pathogenic bacteria; moreover, it may improve vascular endothelial function to a certain extent . Cpn-IgA and Cpn-IgG are common indicators of chronic Cpn infection. Cpn-IgA titer was markedly higher in an Acute Coronary Syndrome (ACS) group than in a non-ACS group . These two indicators reflect severity of Cpn infection to some extent. In conclusion, we believe that Cpn infection may closely correlate with CHD in elderly patients; increased Cpninduced inflammatory cytokines may promote atherosclerosis and enhance the morbidity of myocardial infarction. These patients were treated with drug therapy to control high-risk factors for atherosclerosis, and received clinical education. Treatment of chlamydial infection might improve the prognosis of elderly patients with CHD.
Conflict of Interests
No conflict of interests to declare.
- Mehran R, Dangas G, Parise H, Guagliumi G, Witzenbichler B, Grinfeld L. Prognostic impact of the baseline white blood cell count in patients with acute myocardial infarction undergoing primary PCI: Results from the HORIZONS-AMI trial. Circulation 2008; 118: 973.
- Shah PK. Inflammation and plaque vulnerability. Cardiovasc Drugs Ther 2009; 23: 31-40.
- Mosolygo T, Spengler G, Endresz V, Laczi K, Perei K, Burian K. IL-17E production is elevated in the lungs of balb/c mice in the later stages of chlamydia muridarum infection and re-infection. In Vivo 2013; 27: 787-792.
- Narula J, Nakano M, Virmani R, Kolodgie FD, Petersen R, Newcomb R, Malik S, Fuster V, Finn AV. Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and non-invasive detection of vulnerable plaques. J Am Coll Cardiol 2013; 61: 1041-1051.
- Kilic ZB, Poyraz O, Kilic AT. Investigation of Chlamydophila pneumoniae seropositivity and risk factors in patients with atherosclerotic vascular disease in Sivas, Turkey. Mikrobiyol Bul 2012; 46: 156-158.
- Benagiano M, Munari F, Ciervo A, Amedei A, Paccani SR, Mancini F, Ferrari M, Della Bella C, Ulivi C, DElios S, Baldari CT, Prisco D, de Bernard M, DElios MM. Chlamydophila pneumoniae phospholipase D (CpPLD) drives Th17 inflammation in human atherosclerosis. Proc Natl Acad Sci USA 2012; 109: 1222-1227.
- Calabrn P, Golia E, Yeh ET. CRP and the risk of atherosclerotic events. Semin Immunopathol 2009; 31: 79-94.
- Tong CY, Potter F, Worthington E, Mullins P. Chlamydia pneumoniae myocarditis. Lancet 1995; 346: 710-711.
- Norton R, Schepetiuk S, Kok TW. Chlamydia pneumoniae pneumonia with endocarditis. Lancet 1995; 345: 1376-1377.
- Suesaowalak M, Cheung MM, Tucker D, Chang AC, Chu J, Arrieta A. Chlamydophila pneumoniae myopericarditis in a child. Pediatr Cardiol 2009; 30: 336-339.
- Monno R, Fumarola L, Trerotoli P, Giannelli G, Correale M. Seroprevalence of Chlamydophila pneumoniae in ischaemic heart disease. New Microbiol 2010; 33: 381-385.
- Tiszlavicz Z, Endresz V, Nemeth B, Megyeri K, Orosz L, Seprenyi G, Mandi Y. Inducible expression of human beta- defensin 2 by Chlamydophila pneumoniae in brain capillary endothelial cells. Innate Immun 2011; 17: 463-469.
- Herrera VL, Shen L, Lopez LV, Didishvili T, Zhang YX, Ruiz-Opazo N. Chlamydia pneumoniae accelerates coronary artery disease progression in transgenic hyperlipidemia- genetic hypertension rat model. Mol Med 2003; 9: 135-142.
- Campbell LA, Lee AW, Rosenfeld ME, Kuo CC. Chlamydia pneumoniae induces expression of pro-atherogenic factors through activation of the lectin-like oxidized LDL receptor-1. Pathog Dis 2013.
- Legan M, Vraspir-Porenta O, Kese D, Zorc-Pleskovic R, Zorc M. Histopathologic signs for the inflammatory role of Chlamydia pneumoniae in the high-grade atherosclerotic coronary artery wall. Angiology 2004; 55: 525-531.
- Yavuz MT, Yavuz O, Yazici M, Guler S, Ozhan H, Albayrak S, Coskun A. Interaction between Chlamydia pneumoniae seropositivity, inflammation and risk factors for atherosclerosis in patients with severe coronary stenosis. Scand J Clin Lab Invest 2006; 66: 523-534.
- Player MS, Mainous AG 3rd, Everett CJ, Diaz VA, Knoll ME. Chlamydia pneumoniae and progression of subclinical atherosclerosis. Eur J Prev Cardiol 2014; 21: 559-565.
- Birck MM, Pesonen E, Odermarsky M, Hansen AK, Persson K, Frikke-Schmidt H, Heegaard PM, Liuba P. Infection-induced coronary dysfunction and systemic inflammation in piglets are dampened in hypercholesterolemic milieu. Am J Physiol Heart Circ Physiol 2011; 300: 1595-1601.
- Schumacher A, Seljeflot I, Lerkerrd AB, Sommervoll L, Otterstad JE. Chlamydia LPS and MOMP seropositivity are associated with different cytokine profiles in patients with coronary heart disease. Eur J Clin Invest 2005; 35: 431-437.
- Liu R, Moroi M, Yamamoto M, Kubota T, Ono T, Funatsu A, Komatsu H, Tsuji T, Hara H, Hara H, Nakamura M, Hirai H, Yamaguchi T. Presence and severity of Chlamydia pneumoniae and Cytomegalovirus infection in coronary plaques are associated with acute coronary syndromes. Int Heart J 2006; 47: 511-519.
- Roivainen M, Viik-Kajander M, Palosuo T, Toivanen P, Leinonen M. Infections, inflammation, and the risk of coronary heart disease. Circulation 2000; 101: 252-257.
- Burian K, Kis Z, Virok D, Endresz V, Prohaszka Z, Duba J, Berencsi K, Boda K, Horvath L, Romics L, Fust G, Gonczol E. Independent and joint effects of antibodies to human heat-shock protein 60 and Chlamydia pneumoniae infection in the development of coronary atherosclerosis. Circulation 2011; 103: 1503-1508.
- Bucher HC, Richter W, Glass TR, Magenta L, Wang Q, Cavassini M, Vernazza P, Hirschel B, Weber R, Furrer H, Battegay M, Bernasconi E. Small dense lipoproteins, apolipoprotein B, and risk of coronary events in HIV-infected patients on antiretroviral therapy: The Swiss HIV Cohort Study. JAIDS 2012; 60: 135-142.
- Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105: 1135-1143.
- Burg MM, Soufer A, Lampert R, Collins D, Soufer R. Autonomic contribution to endothelin-1 increase during laboratory anger- recall stress in patients with coronary artery disease. Mol Med 2011; 17: 495-501.
- Emter CA, Tharp DL, Ivey JR, Ganjam VK, Bowles DK. Low-intensity interval exercise training attenuates coronary vascular dysfunction and preserves Ca (2)- sensitive K current in miniature swine with LV hypertrophy. Am J Physiol Heart Circ Physiol 2011; 301: 1687-1694.
- Yudkin JS, Kumari M, Humphries SE, Mohamed-Ali V. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 2000; 148: 209-214.
- Fraser A, May M, Lowe G, Rumley A, Smith GD. Interleukin-6 and incident coronary heart disease: results from the British Womens Heart and Health Study. Atherosclerosis 2009; 202: 567-572.
- Schumacher A, Seljeflot I, Sommervoll L, Christensen B, Otterstad JE. Increased levels of markers of vascular inflammation in patients with coronary heart disease. Scand J Clin Lab Invest 2002; 62: 59-68.
- Shai I, Pischon T, Hu FB, Ascherio A, Rifai N, Rimm EB. Soluble intercellular adhesion molecules, soluble vascular cell adhesion molecules, and risk of coronary heart disease. Obesity (Silver Spring) 2006; 14: 2099-2106.
- Bellmann-Weiler R, Schroll A, Engl S, Nairz M, Talasz H, Seifert M, Weiss G. Neutrophil gelatinase-associated lipocalin and interleukin-10 regulate intramacrophage Chlamydia pneumoniae replication by modulating intracellular iron homeostasis. Immunobiology 2013; 218: 969-978.
- Lockhart PB, Bolger AF, Papapanou PN, Osinbowale O, Trevisan M, Levison ME, Taubert KA, Newburger JW, Gornik HL, Gewitz MH, Wilson WR, Smith SC Jr, Baddour LM. Periodontal disease and atherosclerotic vascular disease: Does the evidence support an independent association? A scientific statement from the American heart association. Circulation 2012; 125: 2520-2544.
- Parchure N, Zouridakis EG, Kaski JC. Effect of azithromycin treatment on endothelial function in patients with coronary artery disease and evidence of Chlamydia pneumoniae infection. Circulation 2002; 105: 1298-1303.
- Liu R, Yamamoto M, Moroi M, Kubota T, Ono T, Funatsu A, Komatsu H, Tsuji T, Hara H, Hara H, Nakamura M, Hirai H, Yamaguchi T. Chlamydia pneumoniae immunoreactivity in coronary artery plaques of patients with acute coronary syndromes and its relation with serology. Am Heart J 2005; 150: 681-688.