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Vol. 57, No. 4, 2011
Issue release date: June 2011
Free Access
Gerontology 2011;57:295–303
(DOI:10.1159/000316577)

Coupling Vascular and Myocardial Inflammatory Injury into a Common Phenotype of Cardiovascular Dysfunction: Systemic Inflammation and Aging – A Mini-Review

Puntmann V.O.a · Taylor P.C.b · Mayr M.c
aCardiovascular Section, Department of Experimental Medicine, Division of Investigative Sciences, and bKennedy Institute of Rheumatology, Imperial College London, and cKing’s BHF Centre, King’s College London, London, UK
email Corresponding Author

Abstract

The rising epidemic of cardiovascular (CV) disease is fuelled by obesity, hypertension and diabetes and, independently and cumulatively, by an aging population. Extensive research identified immunoinflammatory mechanisms as key drivers in the initiation and progression of the disease, from early asymptomatic stages of vascular and myocardial injury leading to the clinically manifest dysfunction and remodeling in advanced stages. Underlying processes include endothelial dysfunction and extracellular matrix restructuration leading to increased vascular stiffness, as well as myocardial remodeling with dilatation and wall thinning. In this, overproduction of tumor necrosis factor-α, amongst others, contributes to generalized CV injury and dysfunction. Moreover, recent insights into the involvement of innate and adaptive immunity in atherosclerosis have shed light on many interesting parallels with chronic systemic inflammatory conditions, such as rheumatoid arthritis, with aggravated inflammation-induced vascular and myocardial injury. Besides, chronologic age has been identified as a potent, independent risk for reduced CV capacity and a plethora of heart diseases, with other modifiable risk factors acting as accelerators. We discuss the available evidence and propose that characterization of inflammatory CV responses might reveal a distinctive CV inflammatory phenotype. A comprehensive noninvasive bio-signature, comprising immunomic biomarkers and integrated noninvasive imaging, may serve as a potential tool in the early diagnosis and prognostication of CV risk.


 goto top of outline Key Words

  • Cardiovascular disease
  • Inflammation, myocardial
  • Imaging, integrated, noninvasive
  • Immunomics
  • Proteomics

 goto top of outline Abstract

The rising epidemic of cardiovascular (CV) disease is fuelled by obesity, hypertension and diabetes and, independently and cumulatively, by an aging population. Extensive research identified immunoinflammatory mechanisms as key drivers in the initiation and progression of the disease, from early asymptomatic stages of vascular and myocardial injury leading to the clinically manifest dysfunction and remodeling in advanced stages. Underlying processes include endothelial dysfunction and extracellular matrix restructuration leading to increased vascular stiffness, as well as myocardial remodeling with dilatation and wall thinning. In this, overproduction of tumor necrosis factor-α, amongst others, contributes to generalized CV injury and dysfunction. Moreover, recent insights into the involvement of innate and adaptive immunity in atherosclerosis have shed light on many interesting parallels with chronic systemic inflammatory conditions, such as rheumatoid arthritis, with aggravated inflammation-induced vascular and myocardial injury. Besides, chronologic age has been identified as a potent, independent risk for reduced CV capacity and a plethora of heart diseases, with other modifiable risk factors acting as accelerators. We discuss the available evidence and propose that characterization of inflammatory CV responses might reveal a distinctive CV inflammatory phenotype. A comprehensive noninvasive bio-signature, comprising immunomic biomarkers and integrated noninvasive imaging, may serve as a potential tool in the early diagnosis and prognostication of CV risk.

Copyright © 2010 S. Karger AG, Basel


 goto top of outline References
  1. Libby P, Ridker PM, Hansson GK: Inflammation in atherosclerosis from pathophysiology to practice. J Am Coll Cardiol 2009;54:2129–2138.
  2. Lüscher TF, Steffel J, Eberli FR, Joner M, Nakazawa G, Tanner FC, Virmani R: Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. Circulation 2007;115:1051–1058.
  3. Cai H, Harrison DG: Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000;87:840–844.
  4. Püntmann VO, Hussain MB, Mayr M, Xu Q, Singer DR: Role of oxidative stress in angiotensin-II mediated contraction of human conduit arteries in patients with cardiovascular disease. Vascul Pharmacol 2005;43:277–282.
  5. Hussain MB, Puntmann VO, Mayr M, Khong T, Singer DRJ: The role of oxidant stress in angiotensin II-mediated contraction of human resistance arteries in the state of health and the presence of cardiovascular disease. Vascul Pharmacol 2006;45:395–399.
  6. Mitchell GF: Arterial stiffness and wave reflection: biomarkers of cardiovascular risk. Artery Res 2009;3:56–64.
  7. Mattace-Raso FUS, van der Cammen TJM, van der Meer IM, Schalekamp MADH, Asmar R, Hofman A, Witteman JCM: C-reactive protein and arterial stiffness in older adults: the Rotterdam Study. Atherosclerosis 2004;176:111–116.
  8. Van Leuven SI, Franssen R, Kastelein JJ, Levi M, Stroes ES, Tak PP: Systemic inflammation as a risk factor for atherothrombosis. Rheumatology 2008;47:3–7.
  9. Gonzalez-Gay MA, Gonzalez-Juanatey C, Pineiro A, Garcia-Porrua C, Testa A, Llorca J: High-grade C-reactive protein elevation correlates with accelerated atherogenesis in patients with rheumatoid arthritis. J Rheumatol 2005;32:1219–1223.
  10. Taylor PC, Sivakumar B: Hypoxia and angiogenesis in rheumatoid arthritis. Curr Opin Rheumatol 2005;17:293–298.
  11. Wick G, Knoflach M, Xu Q: Autoimmune and inflammatory mechanisms in atherosclerosis. Annu Rev Immunol 2004;22:361–403.
  12. Xu Q, Willeit J, Marosi M, Kleindienst R, Oberhollenzer F, Kiechl S, Stulnig T, Luef G, Wick G: Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis. Lancet 1993;341:255–325.
  13. Mayr M, Kiechl S, Willeit J, Wick G, Xu Q: Infections, immunity, and atherosclerosis: associations of antibodies to Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus with immune reactions to heat-shock protein 60 and carotid or femoral atherosclerosis. Circulation 2000;102:833–839.
  14. Liuzzo G, Kopecky SL, Frye RL, O’Fallon WM, Maseri A, Goronzy JJ, Weyand CM: Perturbation of the T-cell repertoire in patients with unstable angina. Circulation 1999;100:2135–2139.
  15. Metzler B, Mayr M, Dietrich H, Singh M, Wiebe E, Xu Q, Wick G: Inhibition of arteriosclerosis by T-cell depletion in normocholesterolemic rabbits immunized with heat shock protein 65. Arterioscler Thromb Vasc Biol 1999;19:1905–1911.
  16. Mann DL: Inflammatory mediators and the failing heart: past, present and foreseeable future. Circ Res 2002;91:988–998.
  17. Hamid T, Gu Y, Ortines RV, Bhattacharya C, Wang G, Xuan YT, Prabhu SD: Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-kappaB and inflammatory activation. Circulation 2009;119:1386–1397.
  18. Pauschinger M, Chandrasekharan K, Schultheiss HP: Myocardial remodeling in viral heart disease: possible interactions between inflammatory mediators and MMP-TIMP system. Heart Fail Rev 2004;9:21–31.
  19. Currie RW, Tanguay RM, Kingma JG Jr: Heat-shock response and limitation of tissue necrosis during occlusion/reperfusion in rabbit hearts. Circulation 1993;87:963–971.
  20. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, André-Fouët X, Revel D, Kirkorian G, Monassier JP, Derumeaux G, Ovize M: Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008;359:473–481.
  21. Bernhard D, Laufer G: The aging cardiomyocyte: a mini-review. Gerontology 2008;54:24–31.
  22. Li SY, Du M, Dolence EK, Fang CX, Mayer GE, Ceylan-Isik AF, LaCour KH, Yang X, Wilbert CJ, Sreejayan N, Ren J: Aging induces cardiac diastolic dysfunction, oxidative stress, accumulation of advanced glycation endproducts and protein modification. Aging Cell 2005;4:57–64.
  23. Barakat K, Wilkinson P, Deaner A, Fluck D, Ranjadayalan K, Timmis A: How should age affect management of acute myocardial infarction? A prospective cohort study. Lancet 1999;353:955–959.
  24. Puntmann VO: How-to guide on biomarkers: biomarker definitions, validation and applications with examples from cardiovascular disease. Postgrad Med J 2009;85:538–545.
  25. Mayr M, Grainger D, Mayr U, Leroyer AS, Leseche G, Sidibe A, Herbin O, Yin X, Gomes A, Madhu B, John R: Griffiths JR, Xu Q, Tedgui A and Boulanger CM: Proteomics, metabolomics, and immunomics on microparticles derived from human atherosclerotic plaques. Circ Cardiovasc Genet 2009;2:379–388.
  26. Puntmann VO, Taylor PC, Barr A, Schnackenburg B, Jahnke C, Paetsch I: Towards understanding the phenotypes of myocardial involvement in the presence of self-limiting and sustained systemic inflammation: a magnetic resonance imaging study. Rheumatology 2010;49:528–535.
  27. Mosedale DE, Chauhan A, Schofield PM, Grainger DJ: A pattern of anti-carbohydrate antibody responses present in patients with advanced atherosclerosis. J Immunol Methods 2006;309:182–191.
  28. Prokopi M, Pula G, Mayr U, Devue C, Gallagher J, Xiao Q, Boulanger CM, Westwood N, Urbich C, Willeit J, Steiner M, Breuss J, Xu Q, Kiechl S, Mayr M: Proteomic analysis reveals presence of platelet microparticles in endothelial progenitor cell cultures. Blood 2009;114:723–732.
  29. Xu QB, Oberhuber G, Gruschwitz M, Wick G: Immunology of atherosclerosis: cellular composition and major histocompatibility complex class II antigen expression in aortic intima, fatty streaks, and atherosclerotic plaques in young and aged human specimens. Clin Immunol Immunopathol 1990;56:344–359.
  30. Pham T, Gregg CJ, Karp F, Chow R, Padler-Karavani V, Cao H, Chen X, Witztum JL, Varki NM, Varki A: Evidence for a novel human-specific xeno-auto-antibody response against vascular endothelium. Blood 2009;114:5225–5235.
  31. Padler-Karavani V, Yu H, Cao H, Chokhawala H, Karp F, Varki N, Chen X, Varki A: Diversity in specificity, abundance, and composition of anti-Neu5Gc antibodies in normal humans: potential implications for disease. Glycobiology 2008;18:818–830.
  32. Binder CJ, Hörkkö S, Dewan A, Chang MK, Kieu EP, Goodyear CS, Shaw PX, Palinski W, Witztum JL, Silverman GJ: Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med 2003;9:736–743.
  33. Mayr M, Kiechl S, Tsimikas S, Miller E, Sheldon J, Willeit J, Witztum JL, Xu Q: Oxidized low-density lipoprotein autoantibodies, chronic infections, and carotid atherosclerosis in a population-based study. J Am Coll Cardiol 2006;47:2436–2443.
  34. Xu Q, Dietrich H, Steiner HJ, Gown AM, Schoel B, Mikuz G, Kaufmann SH, Wick G: Induction of arteriosclerosis in normocholesterolemic rabbits by immunization with heat shock protein 65. Arterioscler Thromb 1992;12:789–799.
  35. Maron R, Sukhova G, Faria AM, Hoffmann E, Mach F, Libby P, Weiner HL: Mucosal administration of heat shock protein-65 decreases atherosclerosis and inflammation in aortic arch of low-density lipoprotein receptor-deficient mice. Circulation 2002;106:1708–1715.
  36. Tonetti MS, D’Aiuto F, Nibali L, Donald A, Storry C, Parkar M, Suvan J, Hingorani AD, Vallance P, Deanfield J: Treatment of periodontitis and endothelial function. N Engl J Med 2007;356:911–920.
  37. Klein C, Nagel E, Gebker R, Kelle S, Schnackenburg B, Graf K, Dreysse S, Fleck E: Magnetic resonance adenosine perfusion imaging in patients after coronary artery bypass graft surgery. JACC Cardiovasc Imaging 2009;2:437–445.
  38. Von Birgelen C, Hartmann M, Mintz GS, van Houwelingen KG, Deppermann N, Schmermund A, Bose D, Eggebrecht H, Neumann T, Gossl M, Wieneke H, Erbel R: Relationship between cardiovascular risk as predicted by established risk scores versus plaque progression as measured by serial intravascular ultrasound in left main coronary arteries. Circulation 2004;110:1579–1585.
  39. Rieber J, Meissner O, Babaryka G, Reim S, Oswald M, Koenig A, Schiele TM, Shapiro M, Theisen K, Reiser MF, Klauss V, Hoffmann U: Diagnostic accuracy of optical coherence tomography and intravascular ultrasound for the detection and characterization of atherosclerotic plaque composition in ex-vivo coronary specimens: a comparison with histology. Coron Artery Dis 2006;17:425–430.
  40. Wick MC, Kremser C, Frischauf S, Wick G: In vivo molecular imaging of vascular stress. Cell Stress Chaperones 2008;13:263–273.

 goto top of outline Author Contacts

Dr. Valentina O. Puntmann, Cardiovascular Section
Department of Experimental Medicine, Division of Investigative Sciences
Imperial College London, Hammersmith Campus, Burlington Danes Building
5th Floor, Du Cane Road, London W12 0NN (UK)
Tel. +44 207 594 6825, Fax +44 207 594 7393, E-Mail v.puntmann@imperial.ac.uk


 goto top of outline Article Information

Received: November 5, 2009
Accepted: April 7, 2010
Published online: June 11, 2010
Number of Print Pages : 9
Number of Figures : 2, Number of Tables : 0, Number of References : 40


 goto top of outline Publication Details

Gerontology (International Journal of Experimental, Clinical, Behavioural and Technological Gerontology)

Vol. 57, No. 4, Year 2011 (Cover Date: June 2011)

Journal Editor: Wick G. (Innsbruck)
ISSN: 0304-324X (Print), eISSN: 1423-0003 (Online)

For additional information: http://www.karger.com/GER


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

The rising epidemic of cardiovascular (CV) disease is fuelled by obesity, hypertension and diabetes and, independently and cumulatively, by an aging population. Extensive research identified immunoinflammatory mechanisms as key drivers in the initiation and progression of the disease, from early asymptomatic stages of vascular and myocardial injury leading to the clinically manifest dysfunction and remodeling in advanced stages. Underlying processes include endothelial dysfunction and extracellular matrix restructuration leading to increased vascular stiffness, as well as myocardial remodeling with dilatation and wall thinning. In this, overproduction of tumor necrosis factor-α, amongst others, contributes to generalized CV injury and dysfunction. Moreover, recent insights into the involvement of innate and adaptive immunity in atherosclerosis have shed light on many interesting parallels with chronic systemic inflammatory conditions, such as rheumatoid arthritis, with aggravated inflammation-induced vascular and myocardial injury. Besides, chronologic age has been identified as a potent, independent risk for reduced CV capacity and a plethora of heart diseases, with other modifiable risk factors acting as accelerators. We discuss the available evidence and propose that characterization of inflammatory CV responses might reveal a distinctive CV inflammatory phenotype. A comprehensive noninvasive bio-signature, comprising immunomic biomarkers and integrated noninvasive imaging, may serve as a potential tool in the early diagnosis and prognostication of CV risk.



 goto top of outline Author Contacts

Dr. Valentina O. Puntmann, Cardiovascular Section
Department of Experimental Medicine, Division of Investigative Sciences
Imperial College London, Hammersmith Campus, Burlington Danes Building
5th Floor, Du Cane Road, London W12 0NN (UK)
Tel. +44 207 594 6825, Fax +44 207 594 7393, E-Mail v.puntmann@imperial.ac.uk


 goto top of outline Article Information

Received: November 5, 2009
Accepted: April 7, 2010
Published online: June 11, 2010
Number of Print Pages : 9
Number of Figures : 2, Number of Tables : 0, Number of References : 40


 goto top of outline Publication Details

Gerontology (International Journal of Experimental, Clinical, Behavioural and Technological Gerontology)

Vol. 57, No. 4, Year 2011 (Cover Date: June 2011)

Journal Editor: Wick G. (Innsbruck)
ISSN: 0304-324X (Print), eISSN: 1423-0003 (Online)

For additional information: http://www.karger.com/GER


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Libby P, Ridker PM, Hansson GK: Inflammation in atherosclerosis from pathophysiology to practice. J Am Coll Cardiol 2009;54:2129–2138.
  2. Lüscher TF, Steffel J, Eberli FR, Joner M, Nakazawa G, Tanner FC, Virmani R: Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. Circulation 2007;115:1051–1058.
  3. Cai H, Harrison DG: Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000;87:840–844.
  4. Püntmann VO, Hussain MB, Mayr M, Xu Q, Singer DR: Role of oxidative stress in angiotensin-II mediated contraction of human conduit arteries in patients with cardiovascular disease. Vascul Pharmacol 2005;43:277–282.
  5. Hussain MB, Puntmann VO, Mayr M, Khong T, Singer DRJ: The role of oxidant stress in angiotensin II-mediated contraction of human resistance arteries in the state of health and the presence of cardiovascular disease. Vascul Pharmacol 2006;45:395–399.
  6. Mitchell GF: Arterial stiffness and wave reflection: biomarkers of cardiovascular risk. Artery Res 2009;3:56–64.
  7. Mattace-Raso FUS, van der Cammen TJM, van der Meer IM, Schalekamp MADH, Asmar R, Hofman A, Witteman JCM: C-reactive protein and arterial stiffness in older adults: the Rotterdam Study. Atherosclerosis 2004;176:111–116.
  8. Van Leuven SI, Franssen R, Kastelein JJ, Levi M, Stroes ES, Tak PP: Systemic inflammation as a risk factor for atherothrombosis. Rheumatology 2008;47:3–7.
  9. Gonzalez-Gay MA, Gonzalez-Juanatey C, Pineiro A, Garcia-Porrua C, Testa A, Llorca J: High-grade C-reactive protein elevation correlates with accelerated atherogenesis in patients with rheumatoid arthritis. J Rheumatol 2005;32:1219–1223.
  10. Taylor PC, Sivakumar B: Hypoxia and angiogenesis in rheumatoid arthritis. Curr Opin Rheumatol 2005;17:293–298.
  11. Wick G, Knoflach M, Xu Q: Autoimmune and inflammatory mechanisms in atherosclerosis. Annu Rev Immunol 2004;22:361–403.
  12. Xu Q, Willeit J, Marosi M, Kleindienst R, Oberhollenzer F, Kiechl S, Stulnig T, Luef G, Wick G: Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis. Lancet 1993;341:255–325.
  13. Mayr M, Kiechl S, Willeit J, Wick G, Xu Q: Infections, immunity, and atherosclerosis: associations of antibodies to Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus with immune reactions to heat-shock protein 60 and carotid or femoral atherosclerosis. Circulation 2000;102:833–839.
  14. Liuzzo G, Kopecky SL, Frye RL, O’Fallon WM, Maseri A, Goronzy JJ, Weyand CM: Perturbation of the T-cell repertoire in patients with unstable angina. Circulation 1999;100:2135–2139.
  15. Metzler B, Mayr M, Dietrich H, Singh M, Wiebe E, Xu Q, Wick G: Inhibition of arteriosclerosis by T-cell depletion in normocholesterolemic rabbits immunized with heat shock protein 65. Arterioscler Thromb Vasc Biol 1999;19:1905–1911.
  16. Mann DL: Inflammatory mediators and the failing heart: past, present and foreseeable future. Circ Res 2002;91:988–998.
  17. Hamid T, Gu Y, Ortines RV, Bhattacharya C, Wang G, Xuan YT, Prabhu SD: Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-kappaB and inflammatory activation. Circulation 2009;119:1386–1397.
  18. Pauschinger M, Chandrasekharan K, Schultheiss HP: Myocardial remodeling in viral heart disease: possible interactions between inflammatory mediators and MMP-TIMP system. Heart Fail Rev 2004;9:21–31.
  19. Currie RW, Tanguay RM, Kingma JG Jr: Heat-shock response and limitation of tissue necrosis during occlusion/reperfusion in rabbit hearts. Circulation 1993;87:963–971.
  20. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, André-Fouët X, Revel D, Kirkorian G, Monassier JP, Derumeaux G, Ovize M: Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008;359:473–481.
  21. Bernhard D, Laufer G: The aging cardiomyocyte: a mini-review. Gerontology 2008;54:24–31.
  22. Li SY, Du M, Dolence EK, Fang CX, Mayer GE, Ceylan-Isik AF, LaCour KH, Yang X, Wilbert CJ, Sreejayan N, Ren J: Aging induces cardiac diastolic dysfunction, oxidative stress, accumulation of advanced glycation endproducts and protein modification. Aging Cell 2005;4:57–64.
  23. Barakat K, Wilkinson P, Deaner A, Fluck D, Ranjadayalan K, Timmis A: How should age affect management of acute myocardial infarction? A prospective cohort study. Lancet 1999;353:955–959.
  24. Puntmann VO: How-to guide on biomarkers: biomarker definitions, validation and applications with examples from cardiovascular disease. Postgrad Med J 2009;85:538–545.
  25. Mayr M, Grainger D, Mayr U, Leroyer AS, Leseche G, Sidibe A, Herbin O, Yin X, Gomes A, Madhu B, John R: Griffiths JR, Xu Q, Tedgui A and Boulanger CM: Proteomics, metabolomics, and immunomics on microparticles derived from human atherosclerotic plaques. Circ Cardiovasc Genet 2009;2:379–388.
  26. Puntmann VO, Taylor PC, Barr A, Schnackenburg B, Jahnke C, Paetsch I: Towards understanding the phenotypes of myocardial involvement in the presence of self-limiting and sustained systemic inflammation: a magnetic resonance imaging study. Rheumatology 2010;49:528–535.
  27. Mosedale DE, Chauhan A, Schofield PM, Grainger DJ: A pattern of anti-carbohydrate antibody responses present in patients with advanced atherosclerosis. J Immunol Methods 2006;309:182–191.
  28. Prokopi M, Pula G, Mayr U, Devue C, Gallagher J, Xiao Q, Boulanger CM, Westwood N, Urbich C, Willeit J, Steiner M, Breuss J, Xu Q, Kiechl S, Mayr M: Proteomic analysis reveals presence of platelet microparticles in endothelial progenitor cell cultures. Blood 2009;114:723–732.
  29. Xu QB, Oberhuber G, Gruschwitz M, Wick G: Immunology of atherosclerosis: cellular composition and major histocompatibility complex class II antigen expression in aortic intima, fatty streaks, and atherosclerotic plaques in young and aged human specimens. Clin Immunol Immunopathol 1990;56:344–359.
  30. Pham T, Gregg CJ, Karp F, Chow R, Padler-Karavani V, Cao H, Chen X, Witztum JL, Varki NM, Varki A: Evidence for a novel human-specific xeno-auto-antibody response against vascular endothelium. Blood 2009;114:5225–5235.
  31. Padler-Karavani V, Yu H, Cao H, Chokhawala H, Karp F, Varki N, Chen X, Varki A: Diversity in specificity, abundance, and composition of anti-Neu5Gc antibodies in normal humans: potential implications for disease. Glycobiology 2008;18:818–830.
  32. Binder CJ, Hörkkö S, Dewan A, Chang MK, Kieu EP, Goodyear CS, Shaw PX, Palinski W, Witztum JL, Silverman GJ: Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med 2003;9:736–743.
  33. Mayr M, Kiechl S, Tsimikas S, Miller E, Sheldon J, Willeit J, Witztum JL, Xu Q: Oxidized low-density lipoprotein autoantibodies, chronic infections, and carotid atherosclerosis in a population-based study. J Am Coll Cardiol 2006;47:2436–2443.
  34. Xu Q, Dietrich H, Steiner HJ, Gown AM, Schoel B, Mikuz G, Kaufmann SH, Wick G: Induction of arteriosclerosis in normocholesterolemic rabbits by immunization with heat shock protein 65. Arterioscler Thromb 1992;12:789–799.
  35. Maron R, Sukhova G, Faria AM, Hoffmann E, Mach F, Libby P, Weiner HL: Mucosal administration of heat shock protein-65 decreases atherosclerosis and inflammation in aortic arch of low-density lipoprotein receptor-deficient mice. Circulation 2002;106:1708–1715.
  36. Tonetti MS, D’Aiuto F, Nibali L, Donald A, Storry C, Parkar M, Suvan J, Hingorani AD, Vallance P, Deanfield J: Treatment of periodontitis and endothelial function. N Engl J Med 2007;356:911–920.
  37. Klein C, Nagel E, Gebker R, Kelle S, Schnackenburg B, Graf K, Dreysse S, Fleck E: Magnetic resonance adenosine perfusion imaging in patients after coronary artery bypass graft surgery. JACC Cardiovasc Imaging 2009;2:437–445.
  38. Von Birgelen C, Hartmann M, Mintz GS, van Houwelingen KG, Deppermann N, Schmermund A, Bose D, Eggebrecht H, Neumann T, Gossl M, Wieneke H, Erbel R: Relationship between cardiovascular risk as predicted by established risk scores versus plaque progression as measured by serial intravascular ultrasound in left main coronary arteries. Circulation 2004;110:1579–1585.
  39. Rieber J, Meissner O, Babaryka G, Reim S, Oswald M, Koenig A, Schiele TM, Shapiro M, Theisen K, Reiser MF, Klauss V, Hoffmann U: Diagnostic accuracy of optical coherence tomography and intravascular ultrasound for the detection and characterization of atherosclerotic plaque composition in ex-vivo coronary specimens: a comparison with histology. Coron Artery Dis 2006;17:425–430.
  40. Wick MC, Kremser C, Frischauf S, Wick G: In vivo molecular imaging of vascular stress. Cell Stress Chaperones 2008;13:263–273.