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Chlamydophila pneumoniae in Cardiovascular Diseases: Clinical and Experimental Studies
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chlamydophila pneumoniae (C. pneumoniae) has been suggested as a stimulator of chronic inflammation in atherosclerosis. C. pneumoniae DNA was demonstrated in aortic biopsies in 50% of patients with stable angina pectoris or acute coronary syndrome undergoing coronary artery bypass grafting. C. pneumoniae mRNA, a marker of replicating bacteria, was demonstrated in 18% of the aortic biopsies.

Inflammation may have a role in the pathogenesis of thoracic aortic aneurysm, aortic dissection and aortic valve stenosis. C. pneumoniae DNA was demonstrated in aortic biopsies in 26% of thoracic aortic aneurysm patients and in 11% of aortic dissection patients undergoing thoracic surgery and in 22% of stenotic aortic heart valves from patients undergoing aortic valve replacement. No bacterial mRNA was demonstrated in these aortic biopsies, nor in the valves, suggesting that the infection has passed into a persistent state. C. pneumoniae DNA was demonstrated in peripheral blood mononuclear cells in only 5% of aortic valve stenosis patients and not in thoracic aortic aneurysm or aortic dissection patients, suggesting that the bacterium disseminated to the cardiovascular tissue long before the patient required surgery. The copper/zinc ratio in serum, a marker of infection/inflammation, was significantly elevated in thoracic aortic aneurysm patients, supporting an inflammatory pathogenesis. Patients positive for C. pneumoniae in the aortic valve had more advanced coronary atherosclerosis, further supporting a possible role for C. pneumoniae in atherosclerosis.

Mice were infected with C. pneumoniae that disseminated to all organs investigated (i.e. lungs, heart, aorta, liver and spleen). Trace element concentrations were altered in infected animals with an increased copper/zinc ratio in serum, a progressively increased iron concentration in the liver and a progressively decreased iron concentration in serum. Iron is important for C. pneumoniae metabolism, and a changed iron homeostasis was noted in infected mice by alterations in iron-regulating proteins, such as DMT1 and hepcidin.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2008. , p. 71
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 340
Keywords [en]
Communicable diseases, Chlamydophila pneumoniae, Chlamydia pneumoniae, trace elements, atherosclerosis, aortic valve stenosis, thoracic aortic aneurysm, aortic dissection, hepcidin, iron
Keywords [sv]
Infektionssjukdomar
Identifiers
URN: urn:nbn:se:uu:diva-8667ISBN: 978-91-554-7176-7 (print)OAI: oai:DiVA.org:uu-8667DiVA, id: diva2:171918
Public defence
2008-05-23, Hörsalen, Akademiska sjukhuset, ing. D1, Dag Hammarsköldsväg 17, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-04-25 Created: 2008-04-25Bibliographically approved
List of papers
1. Chlamydophila pneumonia: Specific mRNA in aorta ascendens in patients undergoing coronary artery by-pass grafting
Open this publication in new window or tab >>Chlamydophila pneumonia: Specific mRNA in aorta ascendens in patients undergoing coronary artery by-pass grafting
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2006 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 38, no 9, p. 758-763Article in journal (Refereed) Published
Abstract [en]

The objective of this prospective study was to investigate if Chlamydophila pneumoniae (Cp)-specific DNA and mRNA are present in tissue samples from the wall of aorta ascendens in patients undergoing by-pass surgery for coronary artery disease (CAD) that includes stable angina pectoris (SAP, 25 patients) and acute coronary syndrome (ACS, 19 patients). Viable Cp was detected in 8/44 (18%) patients using reversed transcriptase PCR (RT-PCR) against bacterial mRNA with detection of cDNA using real-time PCR against the MOMP gene. Cp DNA was detected by nested PCR in 22/44 (50%) patients and by real-time PCR in 13/44 (30%) patients. In total, 24/44 (55%) patients were positive for Cp nucleic acid in any PCR. Antibodies to Cp were detected in 13/24 (54%) Cp PCR-positive and in 15/20 (75%) Cp PCR-negative patients. Nested PCR was run on throat swabs from all patients. No significant differences were noted between SAP and ACS patients regarding PCR results or serology. It has been suggested that Cp may be a 'silent passenger' picked up by the atherosclerotic plaque. Our findings of viable and metabolically active bacteria in aortic tissue add further support to the hypothesis that Cp may have an active role in the pathogenesis of atherosclerosis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97115 (URN)10.1080/00365540600617058 (DOI)000240109600001 ()16938728 (PubMedID)
Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved
2. Chlamydophila pneumoniae in thoracic aortic aneurysm and aortic dissection
Open this publication in new window or tab >>Chlamydophila pneumoniae in thoracic aortic aneurysm and aortic dissection
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2008 (English)Other (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97116 (URN)
Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2010-11-08Bibliographically approved
3. Presence of Chlamydophila pneumoniae DNA but not mRNA in stenotic aortic heart valves
Open this publication in new window or tab >>Presence of Chlamydophila pneumoniae DNA but not mRNA in stenotic aortic heart valves
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2010 (English)In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 143, no 1, p. 57-62Article in journal (Refereed) Published
Abstract [en]

Background: The pathogenesis of aortic valve stenosis may involve inflammation and we have previously demonstrated Chlamydophila pneumoniae (C. pneumoniae) DNA in stenotic aortic heart valves. Dissemination of these bacteria is probably mediated by alveolar macrophages. Bacterial DNA alone does not indicate whether the bacteria are viable and replicating. This study aimed to investigate the presence of C. pneumoniae mRNA, a marker of replicating bacteria, and C. pneumoniae DNA in stenotic aortic valves and the prevalence of C. pneumoniae in peripheral blood mononuclear cells (PBMC).

Methods: DNA was extracted from heart valves and PBMC and mRNA from heart valves from 76 patients undergoing aortic valve replacement surgery. C. pneumoniae DNA and mRNA were measured by real-time PCR targeting the ompA gene.

Results: C. pneumoniae DNA was demonstrated in 22% of heart valves and in 5% of PBMC. C. pneumoniae mRNA was not detected in any valve. Patients positive for C. pneumoniae in the valve underwent coronary artery by-pass grafting more often (p = 0.01) and suffered from angina pectoris (p = 0.02) and arterial hypertension (p = 0.03) more often than patients negative for C. pneumoniae in the valve.

Conclusions: These findings support a role for C. pneumoniae in the pathogenesis of aortic valve stenosis and indicate that the bacteria disseminate from the respiratory tract long before the patients were in need of surgery and that the valve infection thereafter entered into a persistent and non-replicative state. Moreover, patients positive for C. pneumoniae in the valve more often needed by-pass grafting because of more advanced coronary disease.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97117 (URN)10.1016/j.ijcard.2009.01.052 (DOI)000280010700010 ()
Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved
4. Trace element balance is changed in infected organs during acute Chlamydophila pneumoniae infection in mice
Open this publication in new window or tab >>Trace element balance is changed in infected organs during acute Chlamydophila pneumoniae infection in mice
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2008 (English)In: Biometals, ISSN 0966-0844, E-ISSN 1572-8773, Vol. 21, no 2, p. 229-237Article in journal (Refereed) Published
Abstract [en]

Most infectious diseases are accompanied by changed levels of several trace elements in the blood. However, sequential changes in trace elements in tissues harbouring bacterial infections have not been studied. In the present study the respiratory pathogen Chlamydophila pneumoniae (C. pneumoniae), adapted to C57BL/6J mice, was used to study whether the balance of trace elements is changed in infected organs. Bacteria were quantitatively measured by real-time PCR in the blood, lungs, liver, aorta, and heart on days 2, 5, and 8 of the infection. Concentrations of 13 trace elements were measured in the liver, heart, and serum by inductively coupled plasma mass-spectrometry (ICP-MS). Infected mice developed expected clinical signs of disease and bacteria were found in lungs, liver, and heart on all days. The number of bacteria peaked on day 2 in the heart and on day 5 in the liver. The copper/zinc (Cu/Zn) ratio in serum increased as a response to the infection. Cu increased in the liver but did not change in the heart. Iron (Fe) in serum decreased progressively, whereas in the heart it tended to increase, and in the liver it progressively increased. C. pneumoniae may thus cause a changed trace element balance in target tissues of infection that may be pivotal for bacterial growth.

Keywords
Bacterial infection, Heart, Liver, Serum, Trace elements
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97118 (URN)10.1007/s10534-007-9114-7 (DOI)000254087000015 ()17712530 (PubMedID)
Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved
5. Chlamydophila pneumoniae changes iron homeostasis in infected tissues
Open this publication in new window or tab >>Chlamydophila pneumoniae changes iron homeostasis in infected tissues
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2008 (English)In: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 298, no 7-8, p. 635-44Article in journal (Refereed) Published
Abstract [en]

Many bacteria, including Chlamydophila pneumoniae (C. pneumoniae), are dependent on iron (Fe) for their growth. However, it is not known whether bacterial infections affect gastrointestinal uptake and uptake of trace elements in infected tissues. A human C. pneumoniae strain adapted to C57BL/6J mice was used to study hepcidin gene expression in the liver and divalent metal transporter 1 (DMT1) content in the liver and intestine and whether Fe is concomitantly changed in serum, liver, and intestine. The copper/zinc (Cu/Zn) ratio in the serum was used as a marker for infection. Bacterial DNA, mRNA, and hepcidin were measured by real-time PCR, DMT1 by Western blot, and trace elements by ICP-MS on days 2, 5, and 8 of the infection. C. pneumoniae DNA was found in the liver on all days but the number of viable bacteria peaked on day 8. Hepcidin expression increased on days 2 and 5, whereas DMT1 content in the liver increased on day 8. Fe decreased in serum, increased in the liver but was not changed in the intestine during the disease. In the serum, the Cu/Zn ratio peaked on day 5. The peak of viable bacteria in the liver was associated with increased DMT1 and Fe contents and increased hepcidin expression, but this did not affect intestinal Fe uptake. Thus, growth of C. pneumoniae in tissues parallels a redistribution of Fe to those tissues resulting in a changed body homeostasis of Fe.

Keywords
Chlamydophila pneumoniae, Chlamydia pneumoniae, DMT1, Hepcidin, Iron, Liver
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97119 (URN)10.1016/j.ijmm.2008.01.014 (DOI)000260142400009 ()18436480 (PubMedID)
Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved

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