Skip to main content

Advertisement

SpringerLink
Log in

Change of walking distance in intermittent claudication: impact on inflammation, oxidative stress and mononuclear cells: a pilot study

  • Original Paper
  • Published:
Clinical Research in Cardiology Aims and scope Submit manuscript

Abstract

Background

Atherosclerosis is a chronic inflammatory process involving the immune system and formation of reactive oxygen species (ROS). We investigated changes of mononuclear blood cells and ROS production in relation to the walking distance of patients with intermittent claudication during home-based exercise training.

Methods

Forty patients with intermittent claudication were asked to perform a home-based exercise training for a mean time of 12 months. ROS formation was measured using the luminol analogue L-012. Peripheral blood leucocytes [monocytes, polymorphonuclear neutrophils (PMN) and dendritic cells (DC)] were analysed by flow cytometry and analysed for the expression of major inflammatory surface molecules.

Results

At follow-up, patients showed an increased walking distance and reduced ROS production upon stimulation with a phorbol ester derivative (PDBu) (p < 0.01). Monocytes changed their inflammatory phenotype towards an increased anti-inflammatory CD14++CD16− subpopulation (p < 0.0001). Adhesion molecules CD11b, CD11c and TREM-1 on monocytes and PMN decreased (all p < 0.01). On DC expression of HLA-DR, CD86 or CD40 decreased at follow-up. Inflammatory markers like fibrinogen, C-reactive protein or soluble TREM-1 (sTREM-1) decreased over the observation period. Finally, we found a close relation of sTREM-1 with the walking distance, fibrinogen and ROS production.

Conclusions

We observed an amelioration of the proinflammatory phenotype on monocytes, DC and PMN, as well as a reduced ROS production in PAD patients under home-based exercise, paralleled by an increased walking distance. Our data suggest that a reduced inflammatory state might be achieved by regular walking exercise, possibly in a dimension proportionately to changes in walking distance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

ACE:

Angiotensin converting enzyme

AT1 :

Angiotensin receptor 1

BMT:

Best medical treatment

CAD:

Coronary artery disease

DC:

Dendritic cells

ECL:

Enhanced chemiluminescence

FSC/SSC:

Forward scatter/sideward scatter

EPC:

Endothelial progenitor cells

IC:

Intermittent claudication

IMT:

Intima-media thickness

LV-EF:

Left ventricular ejection fraction

mDC:

Myeloid DC

MFI:

Mean fluorescence intensity

NOX:

NADPH oxidase

PAD:

Peripheral arterial disease

PBMC:

Peripheral blood mononuclear cells

pDC:

Plasmacytoid DC

PDBu:

Phorbol 12,13-dibutyrate

PMN:

Polymorphonuclear neutrophils

PTA:

Percutaneous transluminal angioplasty

ROS:

Reactive oxygen species

sTREM:

Soluble TREM

TREM:

Triggering receptor expressed on myeloid cells

References

  1. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, Bell K, Caporusso J, Durand-Zaleski I, Komori K, Lammer J, Liapis C, Novo S, Razavi M, Robbs J, Schaper N, Shigematsu H, Sapoval M, White C, White J, Clement D, Creager M, Jaff M, Mohler E 3rd, Rutherford RB, Sheehan P, Sillesen H, Rosenfield K (2007) Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg 33(Suppl 1):S1–75. doi:10.1016/j.ejvs.2006.09.024

    Article  PubMed  Google Scholar 

  2. Bhatt DL, Steg PG, Ohman EM, Hirsch AT, Ikeda Y, Mas JL, Goto S, Liau CS, Richard AJ, Rother J, Wilson PW (2006) International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 295(2):180–189. doi:10.1001/jama.295.2.180

    Article  CAS  PubMed  Google Scholar 

  3. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, Hiratzka LF, Murphy WR, Olin JW, Puschett JB, Rosenfield KA, Sacks D, Stanley JC, Taylor LM Jr, White CJ, White J, White RA, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Hunt SA, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B (2006) ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 113(11):e463–e654. doi:10.1161/CIRCULATIONAHA.106.174526

    Article  PubMed  Google Scholar 

  4. Naruko T, Ueda M, Haze K, van der Wal AC, van der Loos CM, Itoh A, Komatsu R, Ikura Y, Ogami M, Shimada Y, Ehara S, Yoshiyama M, Takeuchi K, Yoshikawa J, Becker AE (2002) Neutrophil infiltration of culprit lesions in acute coronary syndromes. Circulation 106(23):2894–2900. doi:10.1161/01.cir.0000042674.89762.20

    Article  PubMed  Google Scholar 

  5. Bobryshev YV, Lord RSA (1998) Mapping of vascular dendritic cells in atherosclerotic arteries suggests their involvement in local-inflammatory reactions. Cardiovasc Res 37:799–810

    Article  CAS  PubMed  Google Scholar 

  6. Cutrona SL, Choudhry NK, Stedman M, Servi A, Liberman JN, Brennan T, Fischer MA, Brookhart MA, Shrank WH (2010) Physician effectiveness in interventions to improve cardiovascular medication adherence: a systematic review. J Gen Intern Med 25(10):1090–1096. doi:10.1007/s11606-010-1387-9

    Article  PubMed Central  PubMed  Google Scholar 

  7. Weber C, Zernecke A, Libby P (2008) The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol 8(10):802–815. doi:10.1038/nri2415

    Article  CAS  PubMed  Google Scholar 

  8. Weber C, Noels H (2011) Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 17(11):1410–1422. doi:10.1038/nm.2538

    Article  CAS  PubMed  Google Scholar 

  9. Nathan C (2002) Points of control in inflammation. Nature 420(6917):846–852. doi:10.1038/nature01320

    Article  CAS  PubMed  Google Scholar 

  10. Fischer MA, Stedman MR, Lii J, Vogeli C, Shrank WH, Brookhart MA, Weissman JS (2010) Primary medication non-adherence: analysis of 195,930 electronic prescriptions. J Gen Intern Med 25(4):284–290. doi:10.1007/s11606-010-1253-9

    Article  PubMed Central  PubMed  Google Scholar 

  11. Tendera M, Aboyans V, Bartelink ML, Baumgartner I, Clement D, Collet JP, Cremonesi A, De Carlo M, Erbel R, Fowkes FG, Heras M, Kownator S, Minar E, Ostergren J, Poldermans D, Riambau V, Roffi M, Rother J, Sievert H, van Sambeek M, Zeller T (2011) ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J 32(22):2851–2906. doi:10.1093/eurheartj/ehr211

    Article  PubMed  Google Scholar 

  12. Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK (2013) Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 127(13):1425–1443. doi:10.1161/CIR.0b013e31828b82aa

    Article  PubMed  Google Scholar 

  13. Bendermacher BL, Willigendael EM, Teijink JA, Prins MH (2006) Supervised exercise therapy versus non-supervised exercise therapy for intermittent claudication. Cochrane Database Syst Rev (2):CD005263. doi:10.1002/14651858.CD005263.pub2

  14. Laufs U, Werner N, Link A, Endres M, Wassmann S, Jurgens K, Miche E, Bohm M, Nickenig G (2004) Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation 109(2):220–226. doi:10.1161/01.CIR.0000109141.48980.37

    Article  CAS  PubMed  Google Scholar 

  15. Jaumdally RJ, Goon PK, Varma C, Blann AD, Lip GY (2010) Effects of atorvastatin on circulating CD34+/CD133+/CD45− progenitor cells and indices of angiogenesis (vascular endothelial growth factor and the angiopoietins 1 and 2) in atherosclerotic vascular disease and diabetes mellitus. J Intern Med 267(4):385–393. doi:10.1111/j.1365-2796.2009.02151.x

    Article  CAS  PubMed  Google Scholar 

  16. Adams V, Lenk K, Linke A, Lenz D, Erbs S, Sandri M, Tarnok A, Gielen S, Emmrich F, Schuler G, Hambrecht R (2004) Increase of circulating endothelial progenitor cells in patients with coronary artery disease after exercise-induced ischemia. Arterioscler Thromb Vasc Biol 24(4):684–690. doi:10.1161/01.ATV.0000124104.23702.a0

    Article  CAS  PubMed  Google Scholar 

  17. Mobius-Winkler S, Hilberg T, Menzel K, Golla E, Burman A, Schuler G (1985) Adams V (2009) Time-dependent mobilization of circulating progenitor cells during strenuous exercise in healthy individuals. J Appl Physiol 107(6):1943–1950. doi:10.1152/japplphysiol.00532.2009

    Article  Google Scholar 

  18. Laufs U, Urhausen A, Werner N, Scharhag J, Heitz A, Kissner G, Bohm M, Kindermann W, Nickenig G (2005) Running exercise of different duration and intensity: effect on endothelial progenitor cells in healthy subjects. Eur J Cardiovasc Prev Rehabil 12(4):407–414

    Article  PubMed  Google Scholar 

  19. Mantel-Teeuwisse AK, Klungel OH, Egberts TC, Verschuren WM, Porsius AJ, de Boer A (2004) Failure to continue lipid-lowering drug use following the withdrawal of cerivastatin. Drug Saf 27(1):63–70

    Article  CAS  PubMed  Google Scholar 

  20. Gardner AW, Poehlman ET (1995) Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis. JAMA 274(12):975–980

    Article  CAS  PubMed  Google Scholar 

  21. Nishinaka Y, Aramaki Y, Yoshida H, Masuya H, Sugawara T, Ichimori Y (1993) A new sensitive chemiluminescence probe, L-012, for measuring the production of superoxide anion by cells. Biochem Biophys Res Commun 193(2):554–559. doi:10.1006/bbrc.1993.1659

    Article  CAS  PubMed  Google Scholar 

  22. Daiber A, Oelze M, August M, Wendt M, Sydow K, Wieboldt H, Kleschyov AL, Munzel T (2004) Detection of superoxide and peroxynitrite in model systems and mitochondria by the luminol analogue L-012. Free Radic Res 38(3):259–269

    Article  CAS  PubMed  Google Scholar 

  23. Daiber A, August M, Baldus S, Wendt M, Oelze M, Sydow K, Kleschyov AL, Munzel T (2004) Measurement of NAD(P)H oxidase-derived superoxide with the luminol analogue L-012. Free Radic Biol Med 36(1):101–111. doi:10.1016/j.freeradbiomed.2003.10.012

    Article  CAS  PubMed  Google Scholar 

  24. Dopheide JF, Obst V, Doppler C, Radmacher MC, Scheer M, Radsak MP, Gori T, Warnholtz A, Fottner C, Daiber A, Munzel T, Espinola-Klein C (2012) Phenotypic characterisation of pro-inflammatory monocytes and dendritic cells in peripheral arterial disease. Thromb Haemost 108(6):1198–1207. doi:10.1160/TH12-05-0327

    Article  PubMed  Google Scholar 

  25. Dopheide JF, Doppler C, Scheer M, Obst V, Radmacher MC, Radsak MP, Gori T, Warnholtz A, Fottner C, Munzel T, Daiber A, Espinola-Klein C (2013) Critical limb ischaemia is characterised by an increased production of whole blood reactive oxygen species and expression of TREM-1 on neutrophils. Atherosclerosis 229(2):396–403. doi:10.1016/j.atherosclerosis.2013.05.029

    Article  CAS  PubMed  Google Scholar 

  26. Della Bella S, Giannelli S, Taddeo A, Presicce P, Villa ML (2008) Application of six-color flow cytometry for the assessment of dendritic cell responses in whole blood assays. J Immunol Methods 339(2):153–164

    Article  CAS  PubMed  Google Scholar 

  27. Haselmayer P, Daniel M, Tertilt C, Salih HR, Stassen M, Schild H, Radsak MP (2009) Signaling pathways of the TREM-1- and TLR4-mediated neutrophil oxidative burst. J Innate Immun 1(6):582–591. doi:10.1159/000231973

    Article  CAS  PubMed  Google Scholar 

  28. Rohde G, Radsak MP, Borg I, Buhl R, Schultze-Werninghaus G, Taube C (2012) Levels of soluble triggering receptor expressed on myeloid cells 1 in infectious exacerbations of chronic obstructive pulmonary disease. Respir Int Rev Thorac Dis 83(2):133–139. doi:10.1159/000328413

    Google Scholar 

  29. Stocker R, Keaney JF Jr (2005) New insights on oxidative stress in the artery wall. J Thromb Haemost 3(8):1825–1834. doi:10.1111/j.1538-7836.2005.01370.x

    Article  CAS  PubMed  Google Scholar 

  30. Brass EP (2013) Intermittent claudication: new targets for drug development. Drugs 73(10):999–1014. doi:10.1007/s40265-013-0078-3

    Article  CAS  PubMed  Google Scholar 

  31. Walsh NP, Gleeson M, Shephard RJ, Woods JA, Bishop NC, Fleshner M, Green C, Pedersen BK, Hoffman-Goetz L, Rogers CJ, Northoff H, Abbasi A, Simon P (2011) Position statement. Part one: immune function and exercise. Exerc Immunol Rev 17:6–63

    PubMed  Google Scholar 

  32. Walsh NP, Gleeson M, Pyne DB, Nieman DC, Dhabhar FS, Shephard RJ, Oliver SJ, Bermon S, Kajeniene A (2011) Position statement. Part two: maintaining immune health. Exerc Immunol Rev 17:64–103

    PubMed  Google Scholar 

  33. Edwards AJ, Bacon TH, Elms CA, Verardi R, Felder M, Knight SC (1984) Changes in the populations of lymphoid cells in human peripheral blood following physical exercise. Clin Exp Immunol 58(2):420–427

    PubMed Central  CAS  PubMed  Google Scholar 

  34. Ho CS, Lopez JA, Vuckovic S, Pyke CM, Hockey RL, Hart DN (2001) Surgical and physical stress increases circulating blood dendritic cell counts independently of monocyte counts. Blood 98(1):140–145

    Article  CAS  PubMed  Google Scholar 

  35. Hong S, Mills PJ (2008) Effects of an exercise challenge on mobilization and surface marker expression of monocyte subsets in individuals with normal vs. elevated blood pressure. Brain Behav Immun 22(4):590–599. doi:10.1016/j.bbi.2007.12.003

    Article  CAS  PubMed  Google Scholar 

  36. Steppich B, Dayyani F, Gruber R, Lorenz R, Mack M, Ziegler-Heitbrock HW (2000) Selective mobilization of CD14(+)CD16(+) monocytes by exercise. Am J Physiol Cell Physiol 279(3):C578–C586

    CAS  PubMed  Google Scholar 

  37. Timmerman KL, Flynn MG, Coen PM, Markofski MM, Pence BD (2008) Exercise training-induced lowering of inflammatory (CD14+CD16+) monocytes: a role in the anti-inflammatory influence of exercise? J Leukoc Biol 84(5):1271–1278

    Article  CAS  PubMed  Google Scholar 

  38. van Eeden SF, Granton J, Hards JM, Hogg JC (1999) Expression of the cell adhesion molecules on leukocytes that demarginate during acute maximal exercise. J Appl Physiol 86(3):970–976

    PubMed  Google Scholar 

  39. Peake JM (2002) Exercise-induced alterations in neutrophil degranulation and respiratory burst activity: possible mechanisms of action. Exerc Immunol Rev 8:49–100

    PubMed  Google Scholar 

  40. Wang JS (2004) Strenuous, acute exercise suppresses polymorphonuclear leukocyte respiratory burst under adherence to surface-adherent platelets in men. Thromb Haemost 92(5):1076–1085. doi:10.1267/THRO04051076

    CAS  PubMed  Google Scholar 

  41. Haselmayer P, Grosse-Hovest L, von Landenberg P, Schild H, Radsak MP (2007) TREM-1 ligand expression on platelets enhances neutrophil activation. Blood 110(3):1029–1035. doi:10.1182/blood-2007-01-069195

    Article  CAS  PubMed  Google Scholar 

  42. Muhlestein JB (2010) Effect of antiplatelet therapy on inflammatory markers in atherothrombotic patients. Thromb Haemost 103(1):71–82. doi:10.1160/TH09-03-0177

    Article  CAS  PubMed  Google Scholar 

  43. Radsak MP, Taube C, Haselmayer P, Tenzer S, Salih HR, Wiewrodt R, Buhl R, Schild H (2007) Soluble triggering receptor expressed on myeloid cells 1 is released in patients with stable chronic obstructive pulmonary disease. Clin Dev Immunol 2007:52040. doi:10.1155/2007/52040

    Article  PubMed Central  PubMed  Google Scholar 

  44. Saurer L, Rihs S, Birrer M, Saxer-Seculic N, Radsak M, Mueller C, Swiss IBDCS (2012) Elevated levels of serum-soluble triggering receptor expressed on myeloid cells-1 in patients with IBD do not correlate with intestinal TREM-1 mRNA expression and endoscopic disease activity. J Crohn’s Colitis 6(9):913–923. doi:10.1016/j.crohns.2012.02.010

    Article  Google Scholar 

  45. Jackevicius CA, Li P, Tu JV (2008) Prevalence, predictors, and outcomes of primary nonadherence after acute myocardial infarction. Circulation 117(8):1028–1036. doi:10.1161/CIRCULATIONAHA.107.706820

    Article  PubMed  Google Scholar 

  46. Brehm W, Wagner P, Sygusch R, Schonung A, Hahn U (2005) Health promotion by means of health sport–a framework and a controlled intervention study with sedentary adults. Scand J Med Sci Sports 15(1):13–20. doi:10.1111/j.1600-0838.2003.00369.x

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This paper contains in part data reported in the medical thesis of Martin Scheer.

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Author information

Author notes

    Authors and Affiliations

    1. Department of Internal Medicine II, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany

      Jörn F. Dopheide, Martin Scheer, Christopher Doppler, Viviane Obst, Markus Vosseler, Nico Abegunewardene, Tommaso Gori, Thomas Münzel, Andreas Daiber & Christine Espinola-Klein

    2. Department of Internal Medicine III, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

      Markus P. Radsak

    3. Institute for Immunology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

      Pamela Stein & Markus P. Radsak

    Authors
    1. Jörn F. Dopheide
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Martin Scheer
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Christopher Doppler
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Viviane Obst
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Pamela Stein
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Markus Vosseler
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Nico Abegunewardene
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Tommaso Gori
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Thomas Münzel
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Andreas Daiber
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Markus P. Radsak
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Christine Espinola-Klein
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Jörn F. Dopheide.

    Additional information

    M. P. Radsak and C. Espinola-Klein contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Dopheide, J.F., Scheer, M., Doppler, C. et al. Change of walking distance in intermittent claudication: impact on inflammation, oxidative stress and mononuclear cells: a pilot study. Clin Res Cardiol 104, 751–763 (2015). https://doi.org/10.1007/s00392-015-0840-5

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00392-015-0840-5

    Keywords

    Search

    Navigation