Pflügers Archiv - European Journal of Physiology

, Volume 455, Issue 6, pp 1081–1088 | Cite as

Beneficial effects of cardiac rehabilitation and exercise after percutaneous coronary intervention on hsCRP and inflammatory cytokines in CAD patients

  • Young-Joo Kim
  • Young-Oh Shin
  • Jun-Sang Bae
  • Jeong-Beom LeeEmail author
  • Joo-Hyun Ham
  • Youn-Jung Son
  • Jung-Kyu Kim
  • Chul Kim
  • Byoung-Kwon Lee
  • Jae-Keun Oh
  • Timothy Othman
  • Young-Ki Min
  • Hun-Mo Yang
Exercise, Temperature Regulation


Recent studies showed that tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), as well as high-sensitive C-reactive protein (hsCRP) levels are predictive factors of cardiovascular risk. However, the effect of cardiac rehabilitation (CR) intervention in coronary artery disease (CAD) patients on these factors is not known. The aim of this study was to evaluate the effects of CR and exercise on hsCRP and inflammatory cytokine levels in patients with CAD after percutaneous coronary intervention (PCI). CAD patients who underwent PCI were divided into a CR and exercise group (CRE, n = 29) or a control group (CON, n = 10). CR and exercise consisted of 6 weeks supervised exercise training and 8 weeks home-based, self-managed exercise. Compared to pre-experimental levels, TNF-α (by 20.4%; p = 0.006) and IL-6 (by 49.0%; p < 0.0001), as well as hsCRP (by 59.4%; p < 0.0001), were markedly decreased after CR and exercise in CAD patients but not in control group, except for IL-6 (by 41.6%; p = 0.001). However, there was no significant alteration of adiposity-related variables such as BMI, percent body fat, and waist circumferences, in both groups. We suggest that CR and exercise in CAD patients after PCI induce significant reduction in hsCRP and inflammatory cytokines (TNF-α and IL-6), and marked increase in exercise tolerance and capacity.


Cardiac rehabilitation Exercise High-sensitive C-reactive protein Inflammatory cytokines Coronary artery disease Percutaneous coronary intervention Tumor necrosis factor- α Interleukin-6 



This work was supported by the Regional Innovation Center (RIC) of Soonchunhyang University. Young-Joo Kim, Young-Oh Shin, and Jun-Sang Bae contributed equally to this work.


  1. 1.
    Ades PA (2001) Cardiac rehabilitation and secondary prevention of coronary heart disease. N Engl J Med 345:892–902PubMedCrossRefGoogle Scholar
  2. 2.
    Albert MA, Danielson E, Rifai N, Ridker PM, PRINCE Investigators (2001) Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 286:64–70PubMedCrossRefGoogle Scholar
  3. 3.
    Bhagat K, Vallance P (1997) Inflammatory cytokines impair endothelium-dependent dilatation in human veins in vivo. Circulation 96:3042–3047PubMedGoogle Scholar
  4. 4.
    Biasucci LM, Vitelli A, Liuzzo G, Altamura S, Caligiuri G, Monaco C, Rebuzzi AG, Ciliberto G, Maseri A (1996) Elevated levels of interleukin-6 in unstable angina. Circulation 94:874–877PubMedGoogle Scholar
  5. 5.
    Bickel C, Rupprecht HJ, Blankenberg S, Espiniola-Klein C, Schlitt A, Rippin G, Hafner G, Treude R, Othman H, Hofmann KP, Meyer J, AtheroGene Investigators (2002) Relation of markers of inflammation (C-reactive protein, fibrinogen, von Willebrand factor, and leukocyte count) and statin therapy to long-term mortality in patients with angiographically proven coronary artery disease. Am J Cardiol 89:901–908PubMedCrossRefGoogle Scholar
  6. 6.
    Blake GJ, Ridker PM (2002) Inflammatory bio-markers and cardiovascular risk prediction. J Intern Med 252:283–294PubMedCrossRefGoogle Scholar
  7. 7.
    Cesari M, Penninx BW, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K, Rubin SM, Ding J, Simonsick EM, Harris TB, Pahor M (2003) Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation 108:2317–2322PubMedCrossRefGoogle Scholar
  8. 8.
    Conraads VM, Beckers P, Bosmans J, De Clerck LS, Stevens WJ, Vrints CJ, Brutsaert DL (2002) Combined endurance/resistance training reduces plasma TNF-α receptor levels in patients with chronic heart failure and coronary artery disease. Eur Heart J 23:1854–1860PubMedCrossRefGoogle Scholar
  9. 9.
    Ferri C, Desideri G, Valenti M, Bellini C, Pasin M, Santucci A, de Mattia G (1999) Early upregulation of endothelial adhesion molecules in obese hypertensive men. Hypertension 34:568–573PubMedGoogle Scholar
  10. 10.
    Geffken DF, Cushman M, Burke GL, Polak JF, Sakkinen PA, Tracy RP (2001) Association between physical activity and markers of inflammation in a healthy elderly population. Am J Epidemiol 153:242–250PubMedCrossRefGoogle Scholar
  11. 11.
    Gielen S, Adams V, Mobius-Winkler S, Linke A, Erbs S, Yu J, Kempf W, Schubert A, Schuler G, Hambrecht R (2003) Anti-inflammatory effects of exercise training in the skeletal muscle of patients with chronic heart failure. J Am Coll Cardiol 42:861–868PubMedCrossRefGoogle Scholar
  12. 12.
    Harris TB, Ferrucci L, Tracy RP, Corti MC, Wacholder S, Ettinger WH Jr, Heimovitz H, Cohen HJ, Wallace R (1999) Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 106:506–512PubMedCrossRefGoogle Scholar
  13. 13.
    Hasdai D, Scheinowitz M, Leibovitz E, Sclarovsky S, Eldar M, Barak V (1996) Increased serum concentrations of interleukin-1 beta in patients with coronary artery disease. Heart 76:24–28PubMedCrossRefGoogle Scholar
  14. 14.
    Hwang SJ, Ballantyne CM, Sharrett AR, Smith LC, Davis CE, Gotto AM Jr, Boerwinkle E (1997) Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study. Circulation 96:4219–4225PubMedGoogle Scholar
  15. 15.
    Kennedy MD, Haykowsky M, Daub B, Van Lohuizen K, Knapik G, Black B (2003) Effects of a comprehensive cardiac rehabilitation program on quality of life and exercise tolerance in women: a retrospective analysis. Curr Control Trials Cardiovasc Med 4:1 (Abstract)PubMedCrossRefGoogle Scholar
  16. 16.
    Kinlay S, Schwartz GG, Olsson AG, Rifai N, Leslie SJ, Sasiela WJ, Szarek M, Libby P, Ganz P, Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study Investigators (2003) High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation 108:1560–1566PubMedCrossRefGoogle Scholar
  17. 17.
    Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A, Hutchinson WL, Pepys MB (1999) C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 99:237–242PubMedGoogle Scholar
  18. 18.
    Oh KK, Son JW, Han JY, Kim DS, Han SH, Han TH, Choi IS, Park GS, Shin EK (2003) Comparative effects of diet and simvastatin on markers of thrombogenicity in patients with coronary artery disease. Am J Cardiol 91:1231–1234CrossRefGoogle Scholar
  19. 19.
    Koukkunen H, Penttila K, Kemppainen A, Halinen M, Penttila I, Rantanen T, Pyorala K (2001) C-reactive protein, fibrinogen, interleukin-6 and tumour necrosis factor-alpha in the prognostic classification of unstable angina pectoris. Ann Med 33:37–47PubMedGoogle Scholar
  20. 20.
    Leon AS, Franklin BA, Costa F, Balady GJ, Berra KA, Stewart KJ, Thompson PD, Williams MA, Lauer MS, American Heart Association; Council on Clinical Cardiology (Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention); Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity); American association of Cardiovascular and Pulmonary Rehabilitation (2005) Cardiac rehabilitation and secondary prevention of coronary heart disease: an American Heart Association scientific statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity), in collaboration with the American association of Cardiovascular and Pulmonary Rehabilitation. Circulation 111:369–376PubMedCrossRefGoogle Scholar
  21. 21.
    Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105:1135–1143PubMedCrossRefGoogle Scholar
  22. 22.
    Liuzzo G, Baisucci LM, Gallimore JR, Caligiuri G, Buffon A, Rebuzzi AG, Pepys MB, Maseri A (1999) Enhanced inflammatory response in patients with preinfarction unstable angina. J Am Coll Cardiol 34:1696–1703PubMedCrossRefGoogle Scholar
  23. 23.
    Mattusch F, Dufaux B, Heine O, Mertens I, Rost R (2000) Reduction of the plasma concentration of C-reactive protein following nine months of endurance training. Int J Sports Med 21:21–24PubMedCrossRefGoogle Scholar
  24. 24.
    Milani RV, Lavie CJ, Mehra MR (2004) Reduction in C-reactive protein through cardiac rehabilitation and exercise training. J Am Coll Cardiol 43:1056–1061PubMedCrossRefGoogle Scholar
  25. 25.
    Musial J, Undas A, Gajewski P, Jankowski M, Sydor W, Szczeklik A (2001) Anti-inflammatory effects of simvastatin in subjects with hypercholesterolemia. Int J Cardiol 77:247–253PubMedCrossRefGoogle Scholar
  26. 26.
    Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group (2005) High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 294:2437–2445PubMedCrossRefGoogle Scholar
  27. 27.
    Resnick N, Gimbrone MA Jr (1995) Hemodynamic forces are complex regulators of endothelial gene expression. FASEB J 9:874–882PubMedGoogle Scholar
  28. 28.
    Ridker PM (2001) High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 103:1813–1818PubMedGoogle Scholar
  29. 29.
    Ridker PM, Buring JE, Rifai N (2001) Soluble P-selectin and the risk of future cardiovascular events. Circulation 103:491–495PubMedGoogle Scholar
  30. 30.
    Ridker PM, Hennekens CH, Buring JE, Rifai N (2000) C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342:836–843PubMedCrossRefGoogle Scholar
  31. 31.
    Ridker PM, Stampfer MJ, Rifai N (2001) Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 285:2481–2485PubMedCrossRefGoogle Scholar
  32. 32.
    Romano M, Sironi M, Toniatti C, Polentarutti N, Fruscella P, Ghezzi P, Faggioni R, Luini W, van Hinsbergh V, Sozzani S, Bussolino F, Poli V, Ciliberto G, Mantovani A (1997) Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 6:315–325PubMedCrossRefGoogle Scholar
  33. 33.
    Seki E, Watanabe Y, Sunayama S, Iwama Y, Shimada K, Kawakami K, Sato M, Sato H, Mokuno H, Daida H (2003) Effects of phase III cardiac rehabilitation programs on health-related quality of life in elderly patients with coronary artery disease: Juntendo Cardiac Rehabilitation Program (J-CARP). Circulation 67:73–77CrossRefGoogle Scholar
  34. 34.
    Smith JK, Dykes R, Douglas JE, Krishnaswamy G, Berk S (1999) Long-term exercise and atherogenic activity of blood mononuclear cells in persons at risk of developing ischemic heart disease. JAMA 281:1722–1727PubMedCrossRefGoogle Scholar
  35. 35.
    Adamopoulos S, Parissis J, Karatzas D, Kroupis C, Georgiadis M, Karavolias G, Paraskevaidis J, Koniavitou K, Coats AJ, Kremastinos DT (2002) Physical training modulates proinflammatory cytokines and the soluble Fas/soluble Fas ligand system in patients with chronic heart failure. J Am Coll Cardiol 39(4):653–663PubMedCrossRefGoogle Scholar
  36. 36.
    Varin R, Mulder P, Richard V, Tamion F, Devaux C, Henry JP, Lallemand F, Lerebours G, Thuillez C (1999) Exercise improves flow-mediated vasodilatation of skeletal muscle arteries in rats with chronic heart failure. Role of nitric oxide, prostanoids, and oxidant stress. Circulation 99:2951−2957PubMedGoogle Scholar
  37. 37.
    Vasan RS, Sullivan LM, Roubenoff R, Dinarello CA, Harris T, Benjamin EJ, Sawyer DB, Levy D, Wilson PW, D’Agostino RB; Framingham Heart Study (2003) Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study. Circulation 107:1486–1491PubMedCrossRefGoogle Scholar
  38. 38.
    Yoshida T, Yoshida K, Yamamoto C, Nagasaka M, Tadaura H, Meguro T, Sato T, Kohzuki MM (2001) Effects of a two-week, hospitalized phase II cardiac rehabilitation program on physical capacity, lipid profiles and psychological variables in patients with acute myocardial infarction. Jpn Circ J 65:87–93PubMedCrossRefGoogle Scholar
  39. 39.
    Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW (1999) 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 19:972–978PubMedGoogle Scholar
  40. 40.
    Ziccardi P, Nappo F, Giugliano G, Esposito K, Marfella R, Cioffi M. D’Andrea F, Molinari AM, Giugliano D (2002) Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 105:804–809PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Young-Joo Kim
    • 4
  • Young-Oh Shin
    • 1
  • Jun-Sang Bae
    • 1
  • Jeong-Beom Lee
    • 1
    Email author
  • Joo-Hyun Ham
    • 1
  • Youn-Jung Son
    • 2
  • Jung-Kyu Kim
    • 3
  • Chul Kim
    • 4
  • Byoung-Kwon Lee
    • 5
  • Jae-Keun Oh
    • 6
  • Timothy Othman
    • 7
  • Young-Ki Min
    • 1
  • Hun-Mo Yang
    • 1
  1. 1.Department of Physiology, College of MedicineSoonchunhyang UniversityCheonanRepublic of Korea
  2. 2.Department of Nursing, College of MedicineSoonchunhyang UniversityCheonanRepublic of Korea
  3. 3.Department of Leisure SportsKangwon National UniversitySamcheokRepublic of Korea
  4. 4.Department of Rehabilitation Medicine, College of MedicineInje UniversitySeoulRepublic of Korea
  5. 5.Department of Internal Medicine, College of MedicineInje UniversitySeoulRepublic of Korea
  6. 6.Department of Sports MedicineKorea National Sport UniversitySeoulRepublic of Korea
  7. 7.Huntingdon Life SciencesPrinceton Research CenterSomersetUSA

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