Impact of exercise training on inflammation and platelet activation in patients with intermittent claudication
BACKROUND: Serum markers of inflammation and platelet activation are related to cardiovascular risk. Cardiovascular risk reduction is a major treatment goal in patients with peripheral arterial disease (PAD). Although current guidelines recommend supervised exercise training (SET) for PAD patients with intermittent claudication, its contribution to risk reduction remains unclear. Aim of the present study was to assess the impact of SET on inflammation and platelet activation as surrogates for cardiovascular risk.
METHODS: 53 patients with intermittent claudication were randomly assigned to SET on top of best medical treatment (BMT) for 6 months (SET-group) or to BMT only (BMT-group). High sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and fibrinogen as well as soluble P-selectin (sP-sel), prothrombin fragment 1+2 (F1.2) and monocyte-platelet aggregates (MPA) were determined at study entry, after 3, 6 and 12 months.
RESULTS: While clinical improvement, reflected by an increase of walking capacity, was observed upon SET, no lasting changes of markers of inflammation and platelet activation were found within the SET-group during the training period. Compared to the BMT-group no improvements of these markers were observed in response to training at any time point (all p >0.05).
CONCLUSION: Regular SET added no further anti-inflammatory effect and had no effect on platelet activation when provided on top of BMT in PAD patients with intermittent claudication.
- Lusis AJ. Atherosclerosis. Nature. 2000;407(6801):233–41.
- Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105(9):1135–43.
- Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med. 1999;340(2):115–26.
- Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res. 2001;89(9):763–71.
- Danenberg HD, Kantak N, Grad E, Swaminathan RV, Lotan C, Edelman ER. C- reactive protein promotes monocyte-platelet aggregation: an additional link to the inflammatory-thrombotic intricacy. Eur J Haematol. 2007;78(3):246–52.
- Schillinger M, Exner M, Amighi J, Mlekusch W, Sabeti S, Rumpold H, et al. Joint effects of C-reactive protein and glycated hemoglobin in predicting future cardiovascular events of patients with advanced atherosclerosis. Circulation. 2003;108(19):2323–8.
- Sabeti S, Exner M, Mlekusch W, Amighi J, Quehenberger P, Rumpold H, et al. Prognostic impact of fibrinogen in carotid atherosclerosis: nonspecific indicator of inflammation or independent predictor of disease progression? Stroke. 2005;36(7):1400–4.
- Luc G, Bard JM, Juhan-Vague I, Ferrieres J, Evans A, Amouyel P, et al. C-reactive protein, interleukin-6, and fibrinogen as predictors of coronary heart disease: the PRIME Study. Arterioscler Thromb Vasc Biol. 2003;23(7):1255–61.
- Varughese GI, Patel JV, Tomson J, Blann AD, Hughes EA, Lip GY. Prognostic value of plasma soluble P-selectin and von Willebrand factor as indices of platelet activation and endothelial damage/dysfunction in high-risk patients with hypertension: a sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial. J Intern Med. 2007;261(4):384–91.
- Caro J, Migliaccio-Walle K, Ishak KJ, Proskorovsky I. The morbidity and mortality following a diagnosis of peripheral arterial disease: long-term follow-up of a large database. BMC Cardiovasc Disord. 2005;5:14.
- Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, et al. ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary 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. J Am Coll Cardiol. 2006;47(6):1239–312.
- Schlager O, Giurgea A, Schuhfried O, Seidinger D, Hammer A, Groger M, et al. Exercise training increases endothelial progenitor cells and decreases asymmetric dimethylarginine in peripheral arterial disease: A randomized controlled trial. Atherosclerosis. 2011;217(1):240–8.
- Murphy TP, Cutlip DE, Regensteiner JG, Mohler ER, Cohen DJ, Reynolds MR, et al. Supervised exercise versus primary stenting for claudication resulting from aortoiliac peripheral artery disease: six-month outcomes from the claudication: exercise versus endoluminal revascularization (CLEVER) study. Circulation. 2012;125(1):130–9.
- Pamukcu B, Oflaz H, Acar RD, Umman S, Koylan N, Umman B, et al. The role of exercise on platelet aggregation in patients with stable coronary artery disease: exercise induces aspirin resistant platelet activation. J Thromb Thrombolysis. 2005;20(1):17–22.
- Lara Fernandes J, Serrano CV Jr., Toledo F, Hunziker MF, Zamperini A, Teo FH, et al. Acute and chronic effects of exercise on inflammatory markers and B-type natriuretic peptide in patients with coronary artery disease. Clin Res Cardiol. 2011;100(1):77–84.
- Tendera M, Aboyans V, Bartelink ML, Baumgartner I, Clement D, Collet JP, et al. 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. 2011;32(22):2851–906.
- Stewart KJ, Hiatt WR, Regensteiner JG, Hirsch AT. Exercise training for claudication. N Engl J Med. 2002;347(24):1941–51.
- Cachovan M, Rogatti W, Creutzig A, Diehm C, Heidrich H, Scheffler P, et al. Treadmill testing for evaluation of claudication: comparison of constant-load and graded-exercise tests. Eur J Vasc Endovasc Surg. 1997;14(4):238–43.
- Steiner S, Speidl WS, Pleiner J, Seidinger D, Zorn G, Kaun C, et al. Simvastatin blunts endotoxin-induced tissue factor in vivo. Circulation. 2005;111(14):1841–6.
- Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med. 1984;311(8):501–5.
- Kesten F, Aschwanden M, Gubser P, Glatz K, Daikeler T, Hess C. Giant cell arteritis – a changing entity. Swiss Med Wkly. 2011;141:w13272.doi: 10.4414/smw.2011.13272.
- Tzoulaki I, Murray GD, Lee AJ, Rumley A, Lowe GD, Fowkes FG. C-reactive protein, interleukin-6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the general population: Edinburgh Artery Study. Circulation. 2005;112(7):976–83.
- Milani RV, Lavie CJ, Mehra MR. Reduction in C-reactive protein through cardiac rehabilitation and exercise training. J Am Coll Cardiol. 2004;43(6):1056–61.
- Kasapis C, Thompson PD. The effects of physical activity on serum C-reactive protein and inflammatory markers: a systematic review. J Am Coll Cardiol. 2005;45(10):1563–9.
- Yakeu G, Butcher L, Isa S, Webb R, Roberts AW, Thomas AW, et al. Low-intensity exercise enhances expression of markers of alternative activation in circulating leukocytes: roles of PPARgamma and Th2 cytokines. Atherosclerosis. 2010;212(2):668–73.
- Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab. 1998;83(3):847–50.
- Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol. 1999;19(4):972–8.
- Coen PM, Flynn MG, Markofski MM, Pence BD, Hannemann RE. Adding exercise to rosuvastatin treatment: influence on C-reactive protein, monocyte toll-like receptor 4 expression, and inflammatory monocyte (CD14+CD16+) population. Metabolism. 2010;59(12):1775–83.
- Ridker PM, Buring JE, Rifai N. Soluble P-selectin and the risk of future cardiovascular events. Circulation. 2001;103:491–5.
- McEver RP. Selectins. Curr Opin Immunol. 1994;6(1):75–84.
- Michelson AD, Barnard MR, Krueger LA, Valeri CR, Furman MI. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation. 2001;104(13):1533–7.
- Aronson DL, Stevan L, Ball AP, Franza BR Jr., Finlayson JS. Generation of the combined prothrombin activation peptide (F1-2) during the clotting of blood and plasma. J Clin Invest. 1977;60(6):1410–8.
- Paramo JA, Orbe J, Beloqui O, Benito A, Colina I, Martinez-Vila E, et al. Prothrombin fragment 1+2 is associated with carotid intima-media thickness in subjects free of clinical cardiovascular disease. Stroke. 2004;35(5):1085–9.
- Niessner A, Richter B, Penka M, Steiner S, Strasser B, Ziegler S, et al. Endurance training reduces circulating inflammatory markers in persons at risk of coronary events: Impact on plaque stabilization? Atherosclerosis. 2006;186(1):160–5.
- Adamopoulos S, Parissis J, Karatzas D, Kroupis C, Georgiadis M, Karavolias G, et al. Physical training modulates proinflammatory cytokines and the soluble fas/soluble fas ligand system in patients with chronic heart failure. J Am Coll Cardiol. 2002;39(4):653–63.
- Watson L, Ellis B, Leng GC. Exercise for intermittent claudication. Cochrane Database Syst Rev. 2008;(4):CD000990.
- Leng GC, Fowler B, Ernst E. Exercise for intermittent claudication. Cochrane Database Syst Rev. 2000;(2):CD000990.
- Nicolai SP, Hendriks EJ, Prins MH, Teijink JA. Optimizing supervised exercise therapy for patients with intermittent claudication. J Vasc Surg. 2010;52(5):1226–33.