Skip to main content

Advertisement

SpringerLink
Log in

Increased plasma xanthine oxidoreductase activity deteriorates coronary artery spasm

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

Abstract

Increased reactive oxygen species (ROS) contributes to the development of endothelial dysfunction, which is involved in coronary artery spasm (CAS). Xanthine oxidoreductase (XOR) plays a pivotal role in producing both uric acid and ROS. However, the association between plasma XOR activity and CAS has not been elucidated. The aim of this study was to investigate whether plasma XOR activity is associated with CAS. We measured XOR activity in 104 patients suspected for CAS, who presented without significant coronary artery stenosis and underwent intracoronary acetylcholine provocation tests. CAS was provoked in 44 patients and they had significantly higher XOR activity as compared with those without CAS. The patients were divided into three groups based on the XOR activity. The prevalence rate of CAS was increased with increasing XOR activity. A multivariate logistic regression analysis showed that the 3rd tertile group exhibited a higher incidence of CAS as compared with the 1st tertile group [odds ratio (OR) 6.9, P = 0.001) and the 2nd tertile group (OR 3.2, P = 0.033) after adjustment for conventional CAS risk factors, respectively. The C index was significantly improved by the addition of XOR activity to the baseline model based on CAS risk factors. Furthermore, the 3rd tertile group had the highest incidence of severe spasm defined as total obstruction, flow-limiting stenosis, diffuse spasm, multivessel spasm, and/or lethal arrhythmia. This is a first report to elucidate the association of plasma XOR activity with CAS. Increased plasma XOR activity is significantly associated with CAS.

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

References

  1. Finegold JA, Asaria P, Francis DP (2013) Mortality from ischaemic heart disease by country, region, and age: statistics from World Health Organisation and United Nations. Int J Cardiol 168:934–945

    Article  PubMed  PubMed Central  Google Scholar 

  2. Yasue H, Nakagawa H, Itoh T, Harada E, Mizuno Y (2008) Coronary artery spasm–clinical features, diagnosis, pathogenesis, and treatment. J Cardiol 51:2–17

    Article  PubMed  Google Scholar 

  3. Pristipino C, Beltrame JF, Finocchiaro ML, Hattori R, Fujita M, Mongiardo R, Cianflone D, Sanna T, Sasayama S, Maseri A (2000) Major racial differences in coronary constrictor response between japanese and caucasians with recent myocardial infarction. Circulation 101:1102–1108

    Article  CAS  PubMed  Google Scholar 

  4. Lanza GA, Careri G, Crea F (2011) Mechanisms of coronary artery spasm. Circulation 124:1774–1782

    Article  PubMed  Google Scholar 

  5. Hung MJ, Hu P, Hung MY (2014) Coronary artery spasm: review and update. Int J Med Sci 11:1161–1171

    Article  PubMed  PubMed Central  Google Scholar 

  6. Munzel T, Camici GG, Maack C, Bonetti NR, Fuster V, Kovacic JC (2017) Impact of oxidative stress on the heart and vasculature: Part 2 of a 3-Part series. J Am Coll Cardiol 70:212–229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, Krotova K, Block ER, Prabhakar S, Johnson RJ (2005) Hyperuricemia induces endothelial dysfunction. Kidney Int 67:1739–1742

    Article  PubMed  Google Scholar 

  8. Battelli MG, Bolognesi A, Polito L (2014) Pathophysiology of circulating xanthine oxidoreductase: new emerging roles for a multi-tasking enzyme. Biochim Biophys Acta 1842:1502–1517

    Article  CAS  PubMed  Google Scholar 

  9. Otaki Y, Watanabe T, Kinoshita D, Yokoyama M, Takahashi T, Toshima T, Sugai T, Murase T, Nakamura T, Nishiyama S, Takahashi H, Arimoto T, Shishido T, Miyamoto T, Kubota I (2017) Association of plasma xanthine oxidoreductase activity with severity and clinical outcome in patients with chronic heart failure. Int J Cardiol 228:151–157

    Article  PubMed  Google Scholar 

  10. Nishino M, Mori N, Yoshimura T, Nakamura D, Lee Y, Taniike M, Makino N, Kato H, Egami Y, Shutta R, Tanouchi J, Yamada Y (2014) Higher serum uric acid and lipoprotein(a) are correlated with coronary spasm. Heart Vessels 29:186–190

    Article  PubMed  Google Scholar 

  11. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F (2014) 2013 ESH/ESC practice guidelines for the management of arterial hypertension. Blood Press 23:3–16

    Article  PubMed  Google Scholar 

  12. Murase T, Nampei M, Oka M, Miyachi A, Nakamura T (2016) A highly sensitive assay of human plasma xanthine oxidoreductase activity using stable isotope-labeled xanthine and LC/TQMS. J Chromatogr B Analyt Technol Biomed Life Sci 1039:51–58

    Article  CAS  PubMed  Google Scholar 

  13. Sugano Y, Anzai T, Yagi T, Noma S (2010) Impact of high-density lipoprotein cholesterol level in patients with variant angina pectoris. Int J Cardiol 140:175–181

    Article  PubMed  Google Scholar 

  14. Li YH, Lin GM, Lin CL, Wang JH, Chen YJ, Han CL (2013) Relation of serum uric acid and body mass index to mortality in high-risk patients with established coronary artery disease: a report from the ET-CHD registry, 1997-2006. J Cardiol 62:354–360

    Article  PubMed  Google Scholar 

  15. Li M, Hu X, Fan Y, Li K, Zhang X, Hou W, Tang Z (2016) Hyperuricemia and the risk for coronary heart disease morbidity and mortality a systematic review and dose-response meta-analysis. Sci Rep 6:19520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Puddu P, Puddu GM, Cravero E, Vizioli L, Muscari A (2012) Relationships among hyperuricemia, endothelial dysfunction and cardiovascular disease: molecular mechanisms and clinical implications. J Cardiol 59:235–242

    Article  PubMed  Google Scholar 

  17. Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA (2005) Uric acid and oxidative stress. Curr Pharm Des 11:4145–4151

    Article  CAS  PubMed  Google Scholar 

  18. Cantu-Medellin N, Kelley EE (2013) Xanthine oxidoreductase-catalyzed reactive species generation: a process in critical need of reevaluation. Redox Biol 1:353–358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hellsten-Westing Y (1993) Immunohistochemical localization of xanthine oxidase in human cardiac and skeletal muscle. Histochemistry 100:215–222

    Article  CAS  PubMed  Google Scholar 

  20. Chen C, Lü J-M, Yao Q (2016) Hyperuricemia-related diseases and xanthine oxidoreductase (XOR) inhibitors: an overview. Med Sci Monit 22:2501–2512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Forstermann U, Xia N, Li H (2017) Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis. Circ Res 120:713–735

    Article  CAS  PubMed  Google Scholar 

  22. Lefroy DC, Crake T, Uren NG, Davies GJ, Maseri A (1993) Effect of inhibition of nitric oxide synthesis on epicardial coronary artery caliber and coronary blood flow in humans. Circulation 88:43–54

    Article  CAS  PubMed  Google Scholar 

  23. Spiekermann S (2003) Electron spin resonance characterization of vascular xanthine and NAD(P)H oxidase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation. Circulation 107:1383–1389

    Article  CAS  PubMed  Google Scholar 

  24. Radi R, Beckman JS, Bush KM, Freeman BA (1991) Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. J Biol Chem 266:4244–4250

    CAS  PubMed  Google Scholar 

  25. George J, Carr E, Davies J, Belch JJ, Struthers A (2006) High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation 114:2508–2516

    Article  CAS  PubMed  Google Scholar 

  26. Nakagawa H, Morikawa Y, Mizuno Y, Harada E, Ito T, Matsui K, Saito Y, Yasue H (2009) Coronary spasm preferentially occurs at branch points: an angiographic comparison with atherosclerotic plaque. Circ Cardiovasc Interv 2:97–104

    Article  CAS  PubMed  Google Scholar 

  27. Morita S, Mizuno Y, Harada E, Nakagawa H, Morikawa Y, Saito Y, Katoh D, Kashiwagi Y, Yoshimura M, Murohara T, Yasue H (2014) Differences and interactions between risk factors for coronary spasm and atherosclerosis–smoking, aging, inflammation, and blood pressure. Intern Med 53:2663–2670

    Article  PubMed  Google Scholar 

  28. Ishii M, Kaikita K, Sato K, Tanaka T, Sugamura K, Sakamoto K, Izumiya Y, Yamamoto E, Tsujita K, Yamamuro M, Kojima S, Soejima H, Hokimoto S, Matsui K, Ogawa H (2015) Acetylcholine-provoked coronary spasm at site of significant organic stenosis predicts poor prognosis in patients with coronary vasospastic angina. J Am Coll Cardiol 66:1105–1115

    Article  CAS  PubMed  Google Scholar 

  29. Yamagishi M, Miyatake K, Tamai J, Nakatani S, Koyama J, Nissen SE (1994) Intravascular ultrasound detection of atherosclerosis at the site of focal vasospasm in angiographically normal or minimally narrowed coronary segments. J Am Coll Cardiol 23:352–357

    Article  CAS  PubMed  Google Scholar 

  30. Battelli MG, Polito L, Bolognesi A (2014) Xanthine oxidoreductase in atherosclerosis pathogenesis: not only oxidative stress. Atherosclerosis 237:562–567

    Article  CAS  PubMed  Google Scholar 

  31. Tsushima Y, Nishizawa H, Tochino Y, Nakatsuji H, Sekimoto R, Nagao H, Shirakura T, Kato K, Imaizumi K, Takahashi H, Tamura M, Maeda N, Funahashi T, Shimomura I (2013) Uric acid secretion from adipose tissue and its increase in obesity. J Biol Chem 288:27138–27149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Patetsios P, Song M, Shutze WP, Pappas C, Rodino W, Ramirez JA, Panetta TF (2001) Identification of uric acid and xanthine oxidase in atherosclerotic plaque. Am J Cardiol 88(188–191):a186

    Google Scholar 

  33. Shimokawa H, Takeshita A (2005) Rho-kinase is an important therapeutic target in cardiovascular medicine. Arterioscler Thromb Vasc Biol 25:1767–1775

    Article  CAS  PubMed  Google Scholar 

  34. Crea F, Lanza GA (2011) New light on a forgotten disease: vasospastic angina. J Am Coll Cardiol 58:1238–1240

    Article  CAS  PubMed  Google Scholar 

  35. George J, Struthers AD (2009) Role of urate, xanthine oxidase and the effects of allopurinol in vascular oxidative stress. Vasc Health Risk Manag 5:265–272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was in part supported by the consigned research fund from Sanwa Kagaku Kenkyusho Co., Ltd and by Japan Society for Promotion of Science KAKENHI (Grant No. 17K15984, 18K08025, 18K08059, and 18K15838). We also would like to thank Editage (https://www.editage.jp) for the English language review.

Author information

Authors and Affiliations

  1. Department of Cardiology, Pulmonology and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan

    Ken Watanabe, Tetsuro Shishido, Yoichiro Otaki, Tetsu Watanabe, Takayuki Sugai, Taku Toshima, Tetsuya Takahashi, Miyuki Yokoyama, Daisuke Kinoshita, Masahiro Wanezaki, Harutoshi Tamura, Satoshi Nishiyama, Hiroki Takahashi, Takanori Arimoto, So Yamauchi, Tamon Yamanaka, Takuya Miyamoto, Isao Kubota & Masafumi Watanabe

  2. Radioisotope and Chemical Analysis Center, Sanwa Kagaku Kenkyusho Co., Ltd, Mie, Japan

    Takayo Murase

  3. Pharmacological Study Group, Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd, Mie, Japan

    Takashi Nakamura

Authors
  1. Ken Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tetsuro Shishido
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoichiro Otaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tetsu Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takayuki Sugai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Taku Toshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tetsuya Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Miyuki Yokoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Daisuke Kinoshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Takayo Murase
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takashi Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Masahiro Wanezaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Harutoshi Tamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Satoshi Nishiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Hiroki Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Takanori Arimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. So Yamauchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Tamon Yamanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Takuya Miyamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Isao Kubota
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Masafumi Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tetsuro Shishido.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Watanabe, K., Shishido, T., Otaki, Y. et al. Increased plasma xanthine oxidoreductase activity deteriorates coronary artery spasm. Heart Vessels 34, 1–8 (2019). https://doi.org/10.1007/s00380-018-1207-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00380-018-1207-4

Keywords

Search

Navigation