Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Optimal uric acid reduction to improve vascular endothelial function in patients with chronic heart failure complicated by hyperuricemia

Hypertension Research volume 46, pages 688–696 (2023)Cite this article

A Comment to this article was published on 28 December 2022

Abstract

Although an association of serum uric acid levels with endothelial function has been shown in various clinical settings, the optimal treatment target that would benefit vascular endothelial function has not been established. We, therefore, conducted a post hoc analysis of the Excited-UA study to identify an optimal target. Patients (N = 133) with chronic heart failure and comorbid hyperuricemia who enrolled in the Excited-UA study were divided into three tertiles based on their serum uric acid level 24 weeks after initiating xanthine oxidase inhibitor treatment with topiroxostat or allopurinol (i.e., groups with low, moderate, and high uric acid levels). Flow-mediated dilation (FMD) and reactive hyperemia index (RHI) values measured by reactive hyperemia peripheral arterial tonometry (RH-PAT) were compared among groups. The change from baseline in the FMD value 24 weeks after treatment was comparable among the three groups. In contrast, the change from baseline in the RHI was significantly different among the three groups (−0.153 ± 0.073, 0.141 ± 0.081 and −0.103 ± 0.104 in the low, moderate, and high uric acid level groups, respectively, P = 0.032). After adjustment for age, body mass index, and concomitant use of diuretics, which differed among the three groups, the change in the RHI in the moderate uric acid level group tended to be higher than that in the high uric acid level group (P = 0.057) and was significantly higher than that in the low uric acid level group (P = 0.020). These results indicate that targeting excessively low uric acid levels by treatment with xanthine oxidase inhibitors might be less beneficial for improving microvascular endothelial function in patients with chronic heart failure.

Comparisons of the changes from baseline in vascular endothelial function parameters at 24 weeks among the 3 groups of low, moderae and high uric acid levels achieved with xanthine oxidase inhibitors. After adjustment for confounding factors, such as age, body mass index and concomitant diuretic use, which showed differences among the 3 groups, the change in RHI in the moderate uric acid level group tended to be higher than that in the high uric acid level group and was significantly higher than that in the low uric acid level group.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359:1811–21.

    Article  CAS  Google Scholar 

  2. Li M, Hou W, Zhang X, Hu L, Tang Z. Hyperuricemia and risk of stroke: a systematic review and meta-analysis of prospective studies. Atherosclerosis. 2014;232:265–70.

    Article  CAS  Google Scholar 

  3. Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D, Knosalla C, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation. 2003;107:1991–97.

    Article  Google Scholar 

  4. Hamaguchi S, Furumoto T, Tsuchihashi-Makaya M, Goto K, Goto D, Yokota T.JCARE-CARD Investigators et al. Hyperuricemia predicts adverse outcomes in patients with heart failure. Int J Cardiol. 2011;151:143–47.

    Article  Google Scholar 

  5. Yu MA, Sanchez-Lozada LG, Johnson RJ, Kang DH. Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction. J Hypertens. 2010;28:1234–42.

    Article  Google Scholar 

  6. Mishima M, Hamada T, Maharani N, Ikeda N, Onohara T, Notsu T, et al. Effects of uric acid on the NO production of HUVECs and its restoration by urate-lowering agents. Drug Res. 2016;66:270–74.

    Article  CAS  Google Scholar 

  7. Mercuro G, Vitale C, Cerquetani E, Zoncu S, Deidda M, Fini M, et al. Effect of hyperuricemia upon endothelial function in patients at increased cardiovascular risk. Am J Cardiol. 2004;94:932–35.

    Article  CAS  Google Scholar 

  8. Kato M, Hisatome I, Tomikura Y, Kotani K, Kinugawa T, Ogino K, et al. Status of endothelial-dependent vasodilation in patients with hyperuricemia. Am J Cardiol. 2005;96:1576–78.

    Article  CAS  Google Scholar 

  9. Marti CN, Gheorghiade M, Kalogeropoulos AP, Georgiopoulou VV, Quyyumi AA, Butler J. Endothelial dysfunction, arterial stiffness, and heart failure. J Am Coll Cardiol. 2012;60:1455–69.

    Article  CAS  Google Scholar 

  10. Pacher P, Nivorozhkin A, Szabó C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharm Rev. 2006;58:87–114.

    Article  CAS  Google Scholar 

  11. Dopp JM, Philippi NR, Marcus NJ, Olson EB, Bird CE, Moran JJ, et al. Xanthine oxidase inhibition attenuates endothelial dysfunction caused by chronic intermittent hypoxia in rats. Respiration. 2011;82:458–67.

    Article  CAS  Google Scholar 

  12. Doehner W, Schoene N, Rauchhaus M, Leyva-Leon F, Pavitt DV, Reaveley DA, et al. Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation. 2002;105:2619–24.

    Article  CAS  Google Scholar 

  13. Tanaka A, Nakamura T, Sato E, Node K. Clinical effects of topiroxostat on renal and endothelial function in a patient with chronic kidney disease and hyperuricemic arteriopathy: a case report. Drugs R D. 2017;17:97–101.

    Article  CAS  Google Scholar 

  14. Sakuma M, Toyoda S, Arikawa T, Koyabu Y, Kato T, Adachi T, et al. for Excited UA study Investigators. The effects of xanthine oxidase inhibitor in patients with chronic heart failure complicated with hyperuricemia: a prospective randomized controlled clinical trial of topiroxostat versus allopurinol-study protocol. Clin Exp Nephrol. 2018;22:1379–86.

    Article  CAS  Google Scholar 

  15. Sakuma M, Toyoda S, Arikawa T, Koyabu Y, Kato T, Adachi T, et al. for Excited UA study Investigators. Topiroxostat versus allopurinol in patients with chronic heart failure complicated by hyperuricemia. PLoS One. 2022;17:e0261445.

    Article  CAS  Google Scholar 

  16. Inoue T, Matsuoka H, Higashi Y, Ueda S, Sata M, Shimada KE, et al. Vascular Failure Workshop Group. Flow-mediated vasodilation as a diagnostic modality for vascular failure. Hypertens Res. 2008;31:2105–13.

    Article  Google Scholar 

  17. Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Lavi S, Nelson RE, et al. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J. 2010;31:1142–48.

    Article  Google Scholar 

  18. Tomiyama H, Yoshida M, Higashi Y, Takase B, Furumoto T, Kario K, et al. sub-group study of FMD-J. Autonomic nervous activation triggered during induction of reactive hyperemia exerts a greater influence on the measured reactive hyperemia index by peripheral arterial tonometry than on flow-mediated vasodilatation of the brachial artery in patients with hypertension. Hypertens Res. 2014;37:914–18.

    Article  Google Scholar 

  19. Tajima E, Sakuma M, Tokoi S, Matsumoto H, Saito F, Watanabe R, et al. The comparison of endothelial function between conduit artery and microvasculature in patients with coronary artery disease. Cardiol J. 2020;27:38–46.

    Article  Google Scholar 

  20. Sakata K, Hashimoto T, Ueshima H, Okayama A. NIPPON DATA 80 Research Group. Absence of an association between serum uric acid and mortality from cardiovascular disease: NIPPON DATA 80, 1980–1994. National integrated projects for prospective observation of non‑communicable diseases and its trend in the aged. Eur J Epidemiol. 2001;17:461–68.

    Article  CAS  Google Scholar 

  21. Feig DI, Mazzali M, Kang DH, Nakagawa T, Price K, Kannelis J, et al. Serum uric acid: a risk factor and a target for treatment? J Am Soc Nephrol. 2006;17:S69–S73.

    Article  CAS  Google Scholar 

  22. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004; 109:III-27-32.

  23. Inoue T, Matsuoka H, Higashi Y, Ueda S, Sata M, Shimada K, et al. Flow-mediated vasodilation as a diagnostic modality for vascular failure. Hypertens Res. 2008;31:2105–13.

    Article  Google Scholar 

  24. Hamburg NM, Palmisano J, Larson MG, Sullivan LM, Lehman BT, Vasan RS, et al. Relation of brachial and digital measures of vascular function in the community: the Framingham heart study. Hypertension. 2011;57:390–96.

    Article  CAS  Google Scholar 

  25. Karatzis EN, Ikonomidis I, Vamvakou GD, Papaioannou TG, Protogerou AD, Andreadou I, et al. Long-term prognostic role of flow-mediated dilatation of the brachial artery after acute coronary syndromes without ST elevation. Am J Cardiol. 2006;98:1424–28.

    Article  Google Scholar 

  26. Otani N, Toyoda S, Sakuma M, Ouchi M, Fujita T, Anzai N, et al. Effects of uric acid on vascular endothelial function -from bedside to bench-. Hypertens Res. 2018;41:923–31.

    Article  Google Scholar 

  27. Fischer D, Rossa S, Landmesser U, Spiekermann S, Engberding N, Hornig B, et al. Endothelial dysfunction in patients with chronic heart failure is independently associated with increased incidence of hospitalization, cardiac transplantation, or death. Eur Heart J. 2005;26:65–69.

    Article  CAS  Google Scholar 

  28. Meyer B, Mortl D, Strecker K, Hulsmann M, Kulemann V, Neunteufl T, et al. Flow-mediated vasodilation predicts outcome in patients with chronic heart failure: Comparison with B-type natriuretic peptide. J Am Coll Cardiol. 2005;46:1011–18.

    Article  Google Scholar 

  29. Katz SD, Hryniewicz K, Hriljac I, Balidemaj K, Dimayuga C, Hudaihed A, et al. Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure. Circulation. 2005;111:310–14.

    Article  Google Scholar 

  30. Fujisue K, Sugiyama S, Matsuzawa Y, Akiyama E, Sugamura K, Matsubara J, et al. Prognostic significance of peripheral microvascular endothelial dysfunction in heart failure with reduced left ventricular ejection fraction. Circ J. 2015;79:2623–31.

    Article  Google Scholar 

  31. Waku R, Tokoi S, Toyoda S, Kitahara K, Naganuma J, Yazawa H, et al. Flow-mediated vasodilation and reactive hyperemia index in heart failure with reduced or preserved ejection fraction. Tohoku J Exp Med. 2020;252:85–93.

    Article  Google Scholar 

  32. Zhang W, Iso H, Murakami Y, Miura K, Nagai M, Sugiyama D.EPOCH-JAPAN GROUP et al. Serum uric acid and mortality form cardiovascular disease: EPOCH-JAPAN study. J Atheroscler Thromb. 2016;23:692–703.

    Article  CAS  Google Scholar 

  33. Verdecchia P, Schillaci G, Reboldi G, Santeusanio F, Porcellati C, Brunetti P. Relation between serum uric acid and risk of cardiovascular disease in essential hypertension: the PIUMA study. Hypertension. 2000;36:1072–78.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

To conduct this trial, an outsourcing agreement was signed between Dokkyo Medical University and Sanwa Kagaku Kenkyusho, Co., Ltd., Aichi, Japan. The funders had no role in the study design, data collection, and analysis, decision to publish, or preparation of the manuscript.

for the Excited UA study investigators

Masashi Sakuma1, Shigeru Toyoda1, Takuo Arikawa1, Yota Koyabu1, Teruo Inoue1, Toru Kato6, Taichi Adachi2, Hideaki Suwa2, Jun-ichi Narita7, Koetsu Anraku7, Kimihiko Ishimura7, Fumitake Yamauchi4, Yasunori Sato8

Author information

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Dokkyo Medical University School of Medicine, Mibu, Japan

    Jin Naganuma, Masashi Sakuma, Keijiro Kitahara, Jun Yokomachi, Riri Inoue, Keitaro Iida, Yuto Kohno, Koki Inoue, Nobuo Koshiji, Shichiro Abe, Shigeru Toyoda, Teruo Inoue, Masashi Sakuma, Takuo Arikawa, Yota Koyabu & Teruo Inoue

  2. Department of Cardiology, National Hospital Organization Tochigi Medical Center, Utsunomiya, Japan

    Jin Naganuma, Toru Kato, Taichi Adachi & Hideaki Suwa

  3. Regenerative Medicine Center, Dokkyo Medical University Hospital, Mibu, Japan

    Masashi Sakuma & Teruo Inoue

  4. Department of Cardiology, Yuai Memorial Hospital, Koga, Japan

    Jun Yokomachi & Fumitake Yamauchi

  5. Critical Care Center, Dokkyo Medical University Hospital, Mibu, Japan

    Nobuo Koshiji

  6. Department of Clinical Research, National Hospital Organization Tochigi Medical Center Utsunomiya, Mibu, Japan

    Toru Kato

  7. Department of Internal Medicine, Tochigi Medical Center Tochinoki, Tochigi, Japan

    Jun-ichi Narita, Koetsu Anraku & Kimihiko Ishimura

  8. Department of Preventive Medicine and Public Health, Keio University School of 18 Medicine, Shinanomachi, Japan

    Yasunori Sato

Authors
  1. Jin Naganuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masashi Sakuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Keijiro Kitahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toru Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jun Yokomachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fumitake Yamauchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Riri Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Keitaro Iida
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yuto Kohno
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Koki Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nobuo Koshiji
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shichiro Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Shigeru Toyoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Teruo Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the Excited UA study investigators

  • Masashi Sakuma
  • , Shigeru Toyoda
  • , Takuo Arikawa
  • , Yota Koyabu
  • , Teruo Inoue
  • , Toru Kato
  • , Taichi Adachi
  • , Hideaki Suwa
  • , Jun-ichi Narita
  • , Koetsu Anraku
  • , Kimihiko Ishimura
  • , Fumitake Yamauchi
  •  & Yasunori Sato

Corresponding author

Correspondence to Masashi Sakuma.

Ethics declarations

Conflict of interest

The authors declare that they have 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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Naganuma, J., Sakuma, M., Kitahara, K. et al. Optimal uric acid reduction to improve vascular endothelial function in patients with chronic heart failure complicated by hyperuricemia. Hypertens Res 46, 688–696 (2023). https://doi.org/10.1038/s41440-022-01116-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-022-01116-7

Keywords

Search

Advanced search

Quick links