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Increased cystatin C levels as a risk factor of cardiovascular events in patients with preserved estimated glomerular filtration rate after elective percutaneous coronary intervention with drug-eluting stents

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Abstract

Chronic kidney disease (CKD) is an important risk factor for coronary artery disease (CAD) and cardiovascular events. Cystatin C (CysC) has been proposed as a sensitive marker for CKD. However, the predictive value of CysC for cardiovascular events in CAD patients with preserved estimated glomerular filtration rate (eGFR) is unclear. We enrolled 277 consecutive patients undergoing elective percutaneous coronary intervention with sirolimus-eluting stents (SES). Patients with an eGFR ≤60 ml/min/1.73 m2 were excluded. Serum CysC levels were measured immediately before SES implantation. Major adverse cardiac and cerebrovascular events (MACCE) were defined as cardiovascular death, acute coronary syndrome, stroke, and hospitalization because of congestive heart failure. After a median follow-up of 63 months, 29 patients had MACCE. The subjects were divided into 2 groups based on median serum CysC levels and eGFR (0.637 mg/L and 72.43 ml/min/1.73 m2, respectively). Kaplan–Meier curves showed that the high CysC group had a significantly higher occurrence of MACCE than the low CysC group (p = 0.006), although a low level of eGFR was not significantly associated with an increased risk for occurrence of MACCE. Multivariate analysis revealed that serum CysC levels were an independent predictor of MACCE [hazards ratio: 1.30 per 0.1 mg/L (1.01–1.63), p = 0.038]. These data suggested that serum CysC level is an independent predictor of MACCE, even in patients with preserved eGFR after elective SES implantation.

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References

  1. Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, McCullough PA, Kasiske BL, Kelepouris E, Klag MJ, Parfrey P, Pfeffer M, Raij L, Spinosa DJ, Wilson PW (2003) Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on kidney in cardiovascular disease, high blood pressure research, clinical cardiology, and epidemiology and prevention. Circulation 108:2154–2169

    Article  PubMed  Google Scholar 

  2. Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, White HD, Nordlander R, Maggioni A, Dickstein K, Zelenkofske S, Leimberger JD, Califf RM, Pfeffer MA (2004) Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 351:1285–1295

    Article  CAS  PubMed  Google Scholar 

  3. Ninomiya T, Kiyohara Y, Tokuda Y, Doi Y, Arima H, Harada A, Ohashi Y, Ueshima H, Japan Arteriosclerosis Longitudinal Study Group (2008) Impact of kidney disease and blood pressure on the development of cardiovascular disease: an overview from the Japan Arteriosclerosis Longitudinal Study. Circulation 118:2694–2701

    Article  PubMed  Google Scholar 

  4. Yagi H, Kawai M, Komukai K, Ogawa T, Minai K, Nagoshi T, Ogawa K, Sekiyama H, Taniguchi I, Yoshimura M (2011) Impact of chronic kidney disease on the severity of initially diagnosed coronary artery disease and the patient prognosis in the Japanese population. Heart Vessels 26:370–378

    Article  PubMed  Google Scholar 

  5. Otaki Y, Watanabe T, Takahashi H, Hasegawa H, Honda S, Funayama A, Netsu S, Ishino M, Arimoto T, Shishido T, Miyashita T, Miyamoto T, Konta T, Kubota I (2013) Acidic urine is associated with poor prognosis in patients with chronic heart faiure. Heart Vessels 28:735–741

    Article  PubMed  Google Scholar 

  6. Dohi T, Miyauchi K, Okazaki S, Yokoyama T, Tamura H, Kojima T, Yokoyama K, Kurata T, Daida H (2011) Long-term impact of mild chronic kidney disease in patients with acute coronary syndrome undergoing percutaneous coronary interventions. Nephrol Dial Transplant 26:2906–2911

    Article  PubMed  Google Scholar 

  7. Ogita M, Sasakura K, Nakamura T, Funayama H, Wada H, Naito R, Sugawara Y, Kubo N, Ako J, Momomura S (2012) Association between deteriorated renal function and long-term clinical outcome after perctaneous coronary intervention. Heart Vessels 27:460–467

    Article  PubMed  Google Scholar 

  8. Matsue Y, Matsumura A, Abe M, Ono M, Seya M, Nakamura T, Iwatsuka R, Mizukami A, Setoguchi M, Nagahori W, Ohno M, Suzuki M, Hashimoto Y (2013) Prognostic implications of chronic kidney disease and anemia after percutaneous coronary intervention in acute myocardial infarction patients. Heart Vessels 28:19–26

    Article  PubMed  Google Scholar 

  9. Hsu CY, Chertow GM, Curhan GC (2002) Methodological issues in studying the epidemiology of mild to moderate chronic renal insufficiency. Kidney Int 61:1567–1576

    Article  PubMed  Google Scholar 

  10. Knight EL, Verhave JC, Spiegelman D, Hillege HL, de Zeeuw D, Curhan GC, de Jong PE (2004) Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int 65:1416–1421

    Article  CAS  PubMed  Google Scholar 

  11. Macdonald J, Marcora S, Jibani M, Roberts G, Kumwenda M, Glover R, Barron J, Lemmy A (2006) GFR estimation using cystatin C is not independent of body composition. Am J Kidney Dis 48:712–719

    Article  CAS  PubMed  Google Scholar 

  12. Shlipak MG, Sarnak MJ, Katz R, Fried LF, Seliger SL, Newman AB, Siscovick DS, Stehman-Breen C (2005) Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med 352:2049–2060

    Article  CAS  PubMed  Google Scholar 

  13. Sarnak MJ, Katz R, Stehman-Breen CO, Fried LF, Jenny NS, Psaty BM, Newman AB, Siscovick D, Shlipak MG, Cardiovascular Health Study (2005) Cystatin C concentration as a risk factor for heart failure in older adults. Ann Intern Med 142:497–505

    Article  CAS  PubMed  Google Scholar 

  14. Shlipak MG, Katz R, Fried LF, Jenny NS, Stehman-Breen C, Newman AB, Siscovick D, Psaty BM, Sarnak MJ (2005) Cystatin-C and mortality in elderly persons with heart failure. J Am Coll Cardiol 45:268–271

    Article  CAS  PubMed  Google Scholar 

  15. Ix JH, Shlipak MG, Chertow GM, Whooley MA (2007) Association of cystatin C with mortality, cardiovascular events, and incident heart failure among persons with coronary heart disease: data from the Heart and Soul Study. Circulation 115:173–179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Koenig W, Twardella D, Brenner H, Rothenbacher D (2005) Plasma concentrations of cystatin C in patients with coronary heart disease and risk for secondary cardiovascular events: more than simply a marker of glomerular filtration rate. Clin Chem 51:321–327

    Article  CAS  PubMed  Google Scholar 

  17. Jernberg T, Lindahl B, James S, Larsson A, Hansson LO, Wallentin L (2004) Cystatin C: a novel predictor of outcome in suspected or confirmed non-ST-elevation acute coronary syndrome. Circulation 110:2342–2348

    Article  CAS  PubMed  Google Scholar 

  18. Windhausen F, Hirsch A, Fischer J, van der Zee PM, Sanders GT, van Straalen JP, Cornel JH, Tijssen JG, Verheugt FW, de Winter RJ, Invasive versus Conservative Treatment in Unstabe Coronary Syndromes (ICTUS) investigators (2009) Cystatin C for enhancement of risk stratification in non-ST elevation acute coronary syndrome patients with an increased troponin T. Clin Chem 55:1118–1125

    Article  CAS  PubMed  Google Scholar 

  19. Menon V, Shlipak MG, Wang X, Coresh J, Greene T, Stevens L, Kusek JW, Beck GJ, Collins AJ, Levey AS, Sarnak MJ (2007) Cystatin C as a risk factor for outcomes in chronic kidney disease. Ann Intern Med 147:19–27

    Article  PubMed  Google Scholar 

  20. Hou ZQ, Sun ZX, Su CY, Tan H, Zhong X, Hu B, Zhou Y, Shang DY (2013) Effect of lipo-prostaglandin E1 on cystatin C, β2-microglobulin, and estimated glomerular filtration rate in patients with decompensated heart failure and renal dysfunction: a single-center, nonrandomized controlled study. Heart Vessels 28:589–595

    Article  PubMed  Google Scholar 

  21. Imai E, Horio M, Watanabe T, Iseki K, Yamagata K, Hara S, Ura N, Kiyohara Y, Moriyama T, Ando Y, Fujimoto S, Konta T, Yokoyama H, Makino H, Hishida A, Matsuo S (2009) Prevalence of chronic kidney disease in the Japanese general population predicted by the MDRD equation modified by a Japanese coefficient. Clin Exp Nephrol 13:621–630

    Article  PubMed  Google Scholar 

  22. Miyazaki T, Shimada K, Miyauchi K, Kume A, Tanimoto K, Kiyanagi T, Sumiyoshi K, Hiki M, Mokuno H, Okazaki S, Sato H, Kurata T, Daida H (2010) Effects of fenofibrate on lipid profiles, cholesterol ester transfer activity, and in-stent intimal hyperplasiain patients after elective coronary stenting. Lipids Health Dis 9:122

    Article  PubMed  PubMed Central  Google Scholar 

  23. Leung-Tack J, Tavera C, Gensac MC, Martinez J, Colle A (1990) Modulation of phagocytosis-associated respiratory burst by human cystatin C: role of the N-terminal tetrapeptide Lys-Pro-Pro-Arg. Exp Cell Res 188:16–22

    Article  CAS  PubMed  Google Scholar 

  24. Sukhova GK, Shi GP, Simon DI, Chapman HA, Libby P (1998) Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J Clin Invest 102:576–583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Oorni K, Sneck M, Bromme D, Pentikainen MO, Lindstedt KA, Mayranpaa M, Aitio H, Kovanen PT (2004) Cysteine protease cathepsin F is expressed in human atherosclerotic lesions, is secreted by cultured macrophages, and modifies low density lipoprotein particles in vitro. J Biol Chem 279:34776–34784

    Article  PubMed  Google Scholar 

  26. Lutgens E, Lutgens SP, Faber BC, Heeneman S, Gijbels MM, de Winther MP, Frederik P, van der Made I, Daugherty A, Sijbers AM, Fisher A, Long CJ, Saftig P, Black D, Daemen MJ, Cleutjens KB (2006) Disruption of the cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation. Circulation 113:98–107

    Article  CAS  PubMed  Google Scholar 

  27. Liu J, Sukhova GK, Sun JS, Xu WH, Libby P, Shi GP (2004) Lysosomal cysteine proteases in atherosclerosis. Arterioscler Thromb Vasc Biol 24:1359–1366

    Article  CAS  PubMed  Google Scholar 

  28. Shi GP, Sukhova GK, Grubb A, Ducharme A, Rhode LH, Lee RT, Ridker PM, Libby P, Chapman HA (1999) Cystatin C deficiency in human atherosclerosis and aortic aneurysms. J Clin Invest 104:1191–1197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bengtsson E, To F, Hakansson K, Grubb A, Branen L, Nilsson J, Jovinge S (2005) Lack of the cysteine protease inhibitor cystatin C promotes atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 25:2151–2156

    Article  CAS  PubMed  Google Scholar 

  30. Shlipak MG, Katz R, Cushman M, Sarnak MJ, Stehman-Breen C, Psaty BM, Siscovick D, Tracy RP, Newman A, Fried L (2005) Cystatin-C and inflammatory markers in the ambulatory elderly. Am J Med 118:1416

    Article  PubMed  Google Scholar 

  31. Naruse H, Ishii J, Kawai T, Hattori K, Ishikawa M, Okumura M, Kan S, Nakano T, Matsui S, Nomura M, Hishida H, Ozaki Y (2009) Cystatin C in acute heart failure without advanced renal impairment. Am J Med 122:566–573

    Article  CAS  PubMed  Google Scholar 

  32. Abrahamson M, Olafsson I, Palsdottir A, Ulvsback M, Lundwall A, Jensson O, Grubb A (1990) Structure and expression of the human cystatin C gene. Biochem J 268:287–294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Maurer MS, Burkhoff D, Fried LP, Gottdiener J, King DL, Kitzman DW (2007) Ventricular structure and function in hypertensive participants with heart failure and a normal ejection fraction: the Cardiovascular Health Study. J Am Coll Cardiol 49:972–981

    Article  PubMed  Google Scholar 

  34. Lassus J, Harjola VP, Sund R, Siirila-Waris K, Melin J, Peuhkurinen K, Pulkki K, Nieminen MS, FINN-AKVA Study group (2007) Prognostic value of cystatin C in acute heart failure in relation to other markers of renal function and NT-proBNP. Eur Heart J 28:1841–1847

    Article  CAS  PubMed  Google Scholar 

  35. Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, Coresh J, Gansevoort RT (2010) Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 375:2073–2081

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors thank Yumi Nozawa and Ayako Onodera for secretarial assistance.

Conflict of interest

The authors have no conflicts of interests to declare, financial or otherwise.

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Authors and Affiliations

  1. Department of Cardiology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo, 113-8421, Japan

    Eiryu Sai, Kazunori Shimada, Katsumi Miyauchi, Yoshiyuki Masaki, Takahiko Kojima, Tadashi Miyazaki, Takeshi Kurata, Manabu Ogita, Shuta Tsuboi, Takuma Yoshihara, Tetsuro Miyazaki & Hiroyuki Daida

  2. Department of Transfusion Medicine and Stem Cell Regulation, Juntendo University School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo, 113-8421, Japan

    Akimichi Ohsaka

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  1. Eiryu Sai
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Correspondence to Kazunori Shimada.

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Sai, E., Shimada, K., Miyauchi, K. et al. Increased cystatin C levels as a risk factor of cardiovascular events in patients with preserved estimated glomerular filtration rate after elective percutaneous coronary intervention with drug-eluting stents. Heart Vessels 31, 694–701 (2016). https://doi.org/10.1007/s00380-015-0674-0

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