SpringerLink
Log in

Long-term impact of high-sensitivity C-reactive protein in patients with intermittent claudication due to peripheral artery disease following endovascular treatment

  • Original Article
  • Published:
Heart and Vessels Aims and scope Submit manuscript

Abstract

Little is known about the prognostic impact of high-sensitivity C-reactive protein (hs-CRP) levels on causes of death during long-term follow-up. We, therefore, investigated the associations between hs-CRP and clinical outcomes in the patients with intermittent claudication. Three hundred thirty-five consecutive patients (mean age, 72 ± 8 years, 82% men) undergoing first intervention for de novo iliac and/or femoropopliteal artery lesions from 2009 to 2020 were studied. Patients were divided into 2 groups based on the optimal cutoff value of hs-CRP (> or ≤ 0.15 mg/dL). The median follow-up duration was 3.6 years (interquartile range, 1.0–6.2 years). Although the cumulative incidence rate of major adverse cardiovascular limb events was not significantly different between the higher and lower hs-CRP groups (29.0 and 22.1%, respectively; log-rank test, p = 0.410), that of all-cause death was significantly higher in the higher hs-CRP group than in the lower hs-CRP group (18.7 vs. 5.8%, log-rank test, p = 0.007), even in cardiovascular-related death and malignancy-related death (log-rank test, p = 0.030 and 0.046, respectively). Higher hs-CRP levels at the time of intervention were significantly associated with higher frequency of all-cause death, even after adjusting for other risk factors (hazard ratio 2.79; 95% confidence interval 1.66–7.17, p = 0.024). In addition, malignancy-related death was most frequent as high as 60% (21/35 deaths), and elevated hs-CRP levels and the Brinkman index were strongly independent predictors of malignancy-related death. In conclusion, elevated hs-CRP levels were significantly associated with cardiovascular-related and malignancy-related deaths in patients with intermittent claudication. Furthermore, the result that cancer mortality exceeds cardiovascular mortality is different from previous reports, so the present findings warrant further investigation.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Brevetti G, Giugliano G, Brevetti L, Hiatt WR (2010) Inflammation in peripheral artery disease. Circulation 122:1862–1875

    Article  Google Scholar 

  2. Libby P, Ridker PM (2004) Inflammation and atherosclerosis: role of C-reactive protein in risk assessment. Am J Med 116(Suppl 6A):9s–16s

    Article  Google Scholar 

  3. Karakas M, Koenig W (2009) CRP in cardiovascular disease. Herz 34:607–613

    Article  Google Scholar 

  4. Pepys MB, Hirschfield GM (2001) C-reactive protein and atherothrombosis. Ital Heart J 2:196–199

    CAS  PubMed  Google Scholar 

  5. Fordjour PA, Wang Y, Shi Y, Agyemang K, Akinyi M, Zhang Q, Fan G (2015) Possible mechanisms of C-reactive protein mediated acute myocardial infarction. Eur J Pharmacol 760:72–80

    Article  CAS  Google Scholar 

  6. Swastini DA, Wiryanthini IAD, Ariastuti NLP, Muliantara A (2019) Atherosclerosis prediction with high sensitivity C-reactive protein (hs-CRP) and related risk factor in patient with dyslipidemia. Open Access Maced J Med Sci 7:3887–3890

    Article  Google Scholar 

  7. Ridker PM (2007) C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J Am Coll Cardiol 49:2129–2138

    Article  CAS  Google Scholar 

  8. Kianoush S, Yakoob MY, Al-Rifai M, DeFilippis AP, Bittencourt MS, Duncan BB, Bensenor IM, Bhatnagar A, Lotufo PA, Blaha MJ (2017) Associations of cigarette smoking with subclinical inflammation and atherosclerosis ELSA-Brasil. (The Brazilian Longitudinal Study of Adult Health). J Am Heart Assoc 6(6):e005088

    Article  Google Scholar 

  9. Skoglund PH, Arpegård J, Ostergren J, Svensson P (2014) Amino-terminal pro-B-type natriuretic peptide and high-sensitivity C-reactive protein but not cystatin C predict cardiovascular events in male patients with peripheral artery disease independently of ambulatory pulse pressure. Am J Hypertens 27:363–371

    Article  CAS  Google Scholar 

  10. Urbonaviciene G, Frystyk J, Flyvbjerg A, Urbonavicius S, Henneberg EW, Lindholt JS (2012) Markers of inflammation in relation to long-term cardiovascular mortality in patients with lower-extremity peripheral arterial disease. Int J Cardiol 160:89–94

    Article  Google Scholar 

  11. Vidula H, Tian L, Liu K, Criqui MH, Ferrucci L, Pearce WH, Greenland P, Green D, Tan J, Garside DB, Guralnik J, Ridker PM, Rifai N, McDermott MM (2008) Biomarkers of inflammation and thrombosis as predictors of near-term mortality in patients with peripheral arterial disease, a cohort study. Ann Intern Med 148:85–93

    Article  Google Scholar 

  12. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, Group TIW (2007) Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg 45(Suppl S):S5–S67

    Article  Google Scholar 

  13. Abu Dabrh AM, Steffen MW, Undavalli C, Asi N, Wang Z, Elamin MB, Conte MS, Murad MH (2015) The natural history of untreated severe or critical limb ischemia. J Vasc Surg 62:1642-1651 e3

    Article  Google Scholar 

  14. Umemura S, Arima H, Arima S, Asayama K, Dohi Y, Hirooka Y, Horio T, Hoshide S, Ikeda S, Ishimitsu T, Ito M, Ito S, Iwashima Y, Kai H, Kamide K, Kanno Y, Kashihara N, Kawano Y, Kikuchi T, Kitamura K, Kitazono T, Kohara K, Kudo M, Kumagai H, Matsumura K, Matsuura H, Miura K, Mukoyama M, Nakamura S, Ohkubo T, Ohya Y, Okura T, Rakugi H, Saitoh S, Shibata H, Shimosawa T, Suzuki H, Takahashi S, Tamura K, Tomiyama H, Tsuchihashi T, Ueda S, Uehara Y, Urata H, Hirawa N (2019) The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019). Hypertens Res 42(9):1235–1481

    Article  Google Scholar 

  15. Kinoshita M, Yokote K, Arai H, Iida M, Ishigaki Y, Ishibashi S, Umemoto S, Egusa G, Ohmura H, Okamura T, Kihara S, Koba S, Saito I, Shoji T, Daida H, Tsukamoto K, Deguchi J, Dohi S, Dobashi K, Hamaguchi H, Hara M, Hiro T, Biro S, Fujioka Y, Maruyama C, Miyamoto Y, Murakami Y, Yokode M, Yoshida H, Rakugi H, Wakatsuki A, Yamashita S (2018) Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017. J Atheroscler Thromb 25(9):846–984

    Article  Google Scholar 

  16. International Expert Committee (2009) International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 32(7):1327–1334

    Article  Google Scholar 

  17. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A (2009) Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53:982–992

    Article  CAS  Google Scholar 

  18. Blackwell DL, Lucas JW, Clarke TC (2014) Summary health statistics for U.S. adults: national health interview survey, 2012. Vital Health Stat 10:1–161

    Google Scholar 

  19. Hata K, Nakagawa T, Mizuno M, Yanagi N, Kitamura H, Hayashi T, Irokawa M, Ogami A (2012) Relationship between smoking and a new index of arterial stiffness, the cardio-ankle vascular index, in male workers: a cross-sectional study. Tob Induc Dis 10:11

    Article  Google Scholar 

  20. Krankenberg H, Zeller T, Ingwersen M, Schmalstieg J, Gissler HM, Nikol S, Baumgartner I, Diehm N, Nickling E, Müller-Hülsbeck S, Schmiedel R, Torsello G, Hochholzer W, Stelzner C, Brechtel K, Ito W, Kickuth R, Blessing E, Thieme M, Nakonieczny J, Nolte T, Gareis R, Boden H, Sixt S (2017) Self-expanding versus balloon-expandable stents for iliac artery occlusive disease: the randomized ICE trial. JACC Cardiovasc Interv 10:1694–1704

    Article  Google Scholar 

  21. Aung PP, Maxwell HG, Jepson RG, Price JF, Leng GC (2007) Lipid-lowering for peripheral arterial disease of the lower limb. Cochrane Database Syst Rev 2007:Cd000123

    PubMed Central  Google Scholar 

  22. Momsen AH, Jensen MB, Norager CB, Madsen MR, Vestersgaard-Andersen T, Lindholt JS (2009) Drug therapy for improving walking distance in intermittent claudication: a systematic review and meta-analysis of robust randomised controlled studies. Eur J Vasc Endovasc Surg 38:463–474

    Article  CAS  Google Scholar 

  23. Kumbhani DJ, Steg PG, Cannon CP, Eagle KA, Smith SC Jr, Goto S, Ohman EM, Elbez Y, Sritara P, Baumgartner I, Banerjee S, Creager MA, Bhatt DL (2014) Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the REACH registry. Eur Heart J 35:2864–2872

    Article  CAS  Google Scholar 

  24. Nanto K, Iida O, Fujihara M, Yokoi Y, Tomoi Y, Soga Y, Fujita M, Masuda M, Okamoto S, Ishihara T, Kanda T, Tsujimura T, Matsuda Y, Okuno S, Mano T (2019) Five-year patency and its predictors after endovascular therapy for aortoiliac occlusive disease. J Atheroscler Thromb 26:989–996

    Article  Google Scholar 

  25. Indes JE, Pfaff MJ, Farrokhyar F, Brown H, Hashim P, Cheung K, Sosa JA (2013) Clinical outcomes of 5358 patients undergoing direct open bypass or endovascular treatment for aortoiliac occlusive disease: a systematic review and meta-analysis. J Endovasc Ther 20:443–455

    Article  Google Scholar 

  26. Stavroulakis K, Torsello G, Manal A, Schwindt A, Hericks C, Stachmann A, Schönefeld E, Bisdas T (2016) Results of primary stent therapy for femoropopliteal peripheral arterial disease at 7 years. J Vasc Surg 64:1696–1702

    Article  Google Scholar 

  27. Stone PA, Schlarb H, Campbell JE, Williams D, Thompson SN, John M, Campbell JR, AbuRahma AF (2014) C-reactive protein and brain natriuretic peptide as predictors of adverse events after lower extremity endovascular revascularization. J Vasc Surg 60:652–660

    Article  Google Scholar 

  28. Vrsalović M, Vučur K, Car B, Krčmar T, Vrsalović Presečki A (2015) C-reactive protein, renal function, and cardiovascular outcome in patients with symptomatic peripheral artery disease and preserved left ventricular systolic function. Croat Med J 56:351–356

    Article  Google Scholar 

  29. Schlager O, Amighi J, Haumer M, Sabeti S, Dick P, Mlekusch W, Loewe C, Koppensteiner R, Minar E, Schillinger M (2009) Inflammation and adverse cardiovascular outcome in patients with renal artery stenosis and peripheral artery disease. Atherosclerosis 205:314–318

    Article  CAS  Google Scholar 

  30. Sartipy F, Sigvant B, Lundin F, Wahlberg E (2018) Ten year mortality in different peripheral arterial disease stages: a population based observational study on outcome. Eur J Vasc Endovasc Surg 55:529–536

    Article  Google Scholar 

  31. Sprengers RW, Janssen KJ, Moll FL, Verhaar MC, van der Graaf Y (2009) Prediction rule for cardiovascular events and mortality in peripheral arterial disease patients. Data from the prospective Second Manifestations of ARTerial disease (SMART) cohort study. J Vasc Surg 50:1369–1376

    Article  Google Scholar 

  32. Leng GC, Fowkes FG, Lee AJ, Dunbar J, Housley E, Ruckley CV (1996) Use of ankle brachial pressure index to predict cardiovascular events and death: a cohort study. BMJ 313:1440–1444

    Article  CAS  Google Scholar 

  33. Xu Z, Qi F, Wang Y, Jia X, Lin P, Geng M, Wang R, Li S (2018) Cancer mortality attributable to cigarette smoking in 2005, 2010 and 2015 in Qingdao. China. PLoS One 13:e0204221

    Article  Google Scholar 

  34. Chang CM, Corey CG, Rostron BL, Apelberg BJ (2015) Systematic review of cigar smoking and all cause and smoking related mortality. BMC Public Health 15:390

    Article  Google Scholar 

  35. Botteri E, Iodice S, Bagnardi V, Raimondi S, Lowenfels AB, Maisonneuve P (2008) Smoking and colorectal cancer: a meta-analysis. JAMA 300:2765–2778

    Article  CAS  Google Scholar 

  36. Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, Danesh J (2010) C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality. An individual participant meta-analysis. Lancet 375:132–140

    Article  Google Scholar 

  37. Kianoush S, Bittencourt MS, Lotufo PA, Bensenor IM, Jones SR, DeFilippis AP, Toth PP, Otvos JD, Tibuakuu M, Hall ME, Harada PHN, Blaha MJ (2017) Association between smoking and serum GlycA and high-sensitivity C-reactive protein levels: the Multi-Ethnic Study of Atherosclerosis (MESA) and Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). J Am Heart Assoc 6(8):e006545

    Article  Google Scholar 

  38. Tibuakuu M, Kamimura D, Kianoush S, DeFilippis AP, Al Rifai M, Reynolds LM, White WB, Butler KR, Mosley TH, Turner ST, Kullo IJ, Hall ME, Blaha MJ (2017) The association between cigarette smoking and inflammation: the Genetic Epidemiology Network of Arteriopathy (GENOA) study. PLoS ONE 12:e0184914

    Article  Google Scholar 

  39. McEvoy JW, Nasir K, DeFilippis AP, Lima JA, Bluemke DA, Hundley WG, Barr RG, Budoff MJ, Szklo M, Navas-Acien A, Polak JF, Blumenthal RS, Post WS, Blaha MJ (2015) Relationship of cigarette smoking with inflammation and subclinical vascular disease: the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol 35:1002–1010

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are grateful to the staff of the Department of Cardiovascular Medicine at Juntendo University. The authors also appreciate the secretarial assistance of Ms. Yumi Nozawa.

Funding

This research received no grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Tatsuya Fukase, Tomotaka Dohi, Yoshiteru Kato, Yuichi Chikata, Norihito Takahashi, Hirohisa Endo, Shinichiro Doi, Hiroki Nishiyama, Iwao Okai, Hiroshi Iwata, Shinya Okazaki, Kikuo Isoda, Katsumi Miyauchi, Hiroyuki Daida & Tohru Minamino

  2. Japan Agency for Medical Research and Development-Core Research for Evolutionary Medical Science and Technology (AMED-CREST), Japan Agency for Medical Research and Development, Tokyo, Japan

    Tohru Minamino

Authors
  1. Tatsuya Fukase
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomotaka Dohi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshiteru Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuichi Chikata
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Norihito Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hirohisa Endo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shinichiro Doi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiroki Nishiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Iwao Okai
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hiroshi Iwata
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shinya Okazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kikuo Isoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Katsumi Miyauchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hiroyuki Daida
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Tohru Minamino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tomotaka Dohi.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fukase, T., Dohi, T., Kato, Y. et al. Long-term impact of high-sensitivity C-reactive protein in patients with intermittent claudication due to peripheral artery disease following endovascular treatment. Heart Vessels 36, 1670–1678 (2021). https://doi.org/10.1007/s00380-021-01863-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00380-021-01863-6

Keywords

Search

Navigation