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Relationships between sodium levels, haemodynamics and metalloproteinases in heart failure patients

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Abstract

To estimate the associations between dysnatraemia and inflammatory marker [including interleukin-6 (IL-6)], and tissue remodelling marker [matrix metalloproteinase (MMP)-9 and tissue inhibitor of MMP (TIMP)-1], the pulmonary capillary wedge pressure (PCWP), mean pulmonary artery pressure (PAP), and left ventricular end-diastolic pressure (EDP), and the prognostic relevance in patients with heart failure. The serum sodium level and circulating levels of IL-6, MMP-9, and TIMP-1 were measured in 173 heart failure patients. Dual heart catheterisation was performed to measure PCWP, mean PAP, and EDP. All-cause mortality was assessed during the follow-up period (mean 88 ± 49 months). Restricted cubic spline (RCS) regression showed a U-shaped association of serum sodium level with TIMP-1, with the lowest values in the 138–140 mmol/L range (P for effect = 0.042, P for non-linearity = 0.017). IL-6 and MMP-9 levels showed non-significant associations with serum sodium level. U-shaped associations of serum sodium level with PCWP (P for effect = 0.004, P for non-linearity = 0.001) and mean PAP (P for effect = 0.042, P for non-linearity = 0.017) were found with the RCS regression model. The random forest model revealed that TIMP-1, MMP-9, and IL-6 were important predictors for serum sodium levels. Restricted cubic spline Cox regressions demonstrated that TIMP-1 levels indicated a U-shaped, concaved, non-linear association with all-cause mortality (P for effect = 0.011, P for non-linearity = 0.022). Dysnatraemia is an index of TIMP-1 aggravation and elevated PCWP, mean PAP; hence, it is associated with worsening all-cause mortality.

Clinical Trial Registration: UMIN000023840.

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Data availability

The data underlying this article cannot be shared publicly due to the privacy of individuals that participated in the study. The data will be shared on reasonable request to the corresponding author. The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. De Luca L, Klein L, Udelson JE, Orlandi C, Sardella G, Fedele F, Gheorghiade M (2005) Hyponatremia in patients with heart failure. Am J Cardiol 96(12A):19L-23L. https://doi.org/10.1016/j.amjcard.2005.09.066

    Article  CAS  PubMed  Google Scholar 

  2. Bae MH, Kim JH, Jang SY, Park SH, Lee JH, Yang DH, Park HS, Cho Y, Chae SC (2017) Hyponatremia at discharge as a predictor of 12-month clinical outcomes in hospital survivors after acute myocardial infarction. Heart Vessels 32(2):126–133. https://doi.org/10.1007/s00380-016-0854-6

    Article  PubMed  Google Scholar 

  3. Gheorghiade M, Abraham WT, Albert NM, Gattis Stough W, Greenberg BH, O’Connor CM, She L, Yancy CW, Young J, Fonarow GC, Coordinators O-HIa (2007) Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry. Eur Heart J 28(8):980–988. https://doi.org/10.1093/eurheartj/ehl542

    Article  CAS  PubMed  Google Scholar 

  4. Kovesdy CP, Lott EH, Lu JL, Malakauskas SM, Ma JZ, Molnar MZ, Kalantar-Zadeh K (2012) Hyponatremia, hypernatremia, and mortality in patients with chronic kidney disease with and without congestive heart failure. Circulation 125(5):677–684. https://doi.org/10.1161/CIRCULATIONAHA.111.065391

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kusaka H, Sugiyama S, Yamamoto E, Akiyama E, Matsuzawa Y, Hirata Y, Fujisue K, Kurokawa H, Matsubara J, Sugamura K, Maeda H, Jinnouchi H, Matsui K, Ogawa H (2016) Low-normal serum sodium and heart failure-related events in patients with heart failure with preserved left ventricular ejection fraction. Circ J 80(2):411–417. https://doi.org/10.1253/circj.CJ-15-0878

    Article  CAS  PubMed  Google Scholar 

  6. Lu DY, Cheng HM, Cheng YL, Hsu PF, Huang WM, Guo CY, Yu WC, Chen CH, Sung SH (2016) Hyponatremia and worsening sodium levels are associated with long-term outcome in patients hospitalized for acute heart failure. J Am Heart Assoc 5(3):e002668. https://doi.org/10.1161/JAHA.115.002668

    Article  PubMed  PubMed Central  Google Scholar 

  7. Matsue Y, Yoshioka K, Suzuki M, Torii S, Yamaguchi S, Fukamizu S, Ono Y, Fujii H, Kitai T, Nishioka T, Sugi K, Onishi Y, Noda M, Kagiyama N, Satoh Y, Yoshida K, Goldsmith SR (2017) Prognostic importance of sodium level trajectory in acute heart failure. Heart Vessels 32(12):1498–1505. https://doi.org/10.1007/s00380-017-1020-5

    Article  PubMed  Google Scholar 

  8. Gheorghiade M, Rossi JS, Cotts W, Shin DD, Hellkamp AS, Piña IL, Fonarow GC, DeMarco T, Pauly DF, Rogers J, DiSalvo TG, Butler J, Hare JM, Francis GS, Stough WG, O’Connor CM (2007) Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE Trial. Arch Intern Med 167(18):1998–2005. https://doi.org/10.1001/archinte.167.18.1998

    Article  PubMed  Google Scholar 

  9. Forfia PR, Mathai SC, Fisher MR, Housten-Harris T, Hemnes AR, Champion HC, Girgis RE, Hassoun PM (2008) Hyponatremia predicts right heart failure and poor survival in pulmonary arterial hypertension. Am J Respir Crit Care Med 177(12):1364–1369. https://doi.org/10.1164/rccm.200712-1876OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Verbrugge FH, Steels P, Grieten L, Nijst P, Tang WH, Mullens W (2015) Hyponatremia in acute decompensated heart failure: depletion versus dilution. J Am Coll Cardiol 65(5):480–492. https://doi.org/10.1016/j.jacc.2014.12.010

    Article  CAS  PubMed  Google Scholar 

  11. Goldsmith SR, Francis GS, Cowley AW, Levine TB, Cohn JN (1983) Increased plasma arginine vasopressin levels in patients with congestive heart failure. J Am Coll Cardiol 1(6):1385–1390

    Article  CAS  Google Scholar 

  12. Park SJ, Shin JI (2013) Inflammation and hyponatremia: an underrecognized condition? Korean J Pediatr 56(12):519–522. https://doi.org/10.3345/kjp.2013.56.12.519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Swart RM, Hoorn EJ, Betjes MG, Zietse R (2011) Hyponatremia and inflammation: the emerging role of interleukin-6 in osmoregulation. Nephron Physiol 118(2):45–51. https://doi.org/10.1159/000322238

    Article  CAS  PubMed  Google Scholar 

  14. Nakaya R, Uzui H, Shimizu H, Nakano A, Mitsuke Y, Yamazaki T, Ueda T, Lee JD (2005) Pravastatin suppresses the increase in matrix metalloproteinase-2 levels after acute myocardial infarction. Int J Cardiol 105(1):67–73. https://doi.org/10.1016/j.ijcard.2004.12.024

    Article  PubMed  Google Scholar 

  15. Tsutamoto T, Hisanaga T, Wada A, Maeda K, Ohnishi M, Fukai D, Mabuchi N, Sawaki M, Kinoshita M (1998) Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol 31(2):391–398

    Article  CAS  Google Scholar 

  16. Yamazaki T, Lee JD, Shimizu H, Uzui H, Ueda T (2004) Circulating matrix metalloproteinase-2 is elevated in patients with congestive heart failure. Eur J Heart Fail 6(1):41–45. https://doi.org/10.1016/j.ejheart.2003.05.002

    Article  CAS  PubMed  Google Scholar 

  17. Formato M, Farina M, Spirito R, Maggioni M, Guarino A, Cherchi GM, Biglioli P, Edelstein C, Scanu AM (2004) Evidence for a proinflammatory and proteolytic environment in plaques from endarterectomy segments of human carotid arteries. Arterioscler Thromb Vasc Biol 24(1):129–135. https://doi.org/10.1161/01.ATV.0000104013.71118.53

    Article  CAS  PubMed  Google Scholar 

  18. Matsumura K, Morishita S, Taniguchi N, Takehana K, Takahashi H, Otagaki M, Yoshioka K, Yamamoto Y, Takagi M, Shiojima I (2019) Prognostic factors for long-term outcomes in acute decompensated heart failure patients under tolvaptan treatment. Heart Vessels 34(4):607–615. https://doi.org/10.1007/s00380-018-1290-6

    Article  PubMed  Google Scholar 

  19. Moriyama H, Kohno T, Kohsaka S, Shiraishi Y, Fukuoka R, Nagatomo Y, Goda A, Mizuno A, Fukuda K, Yoshikawa T, Tokyo Heart Failure Registry Investigators (2019) Length of hospital stay and its impact on subsequent early readmission in patients with acute heart failure: a report from the WET-HF Registry. Heart Vessels 34(11):1777–1788. https://doi.org/10.1007/s00380-019-01432-y

    Article  PubMed  Google Scholar 

  20. Morishita T, Uzui H, Mitsuke Y, Amaya N, Kaseno K, Ishida K, Fukuoka Y, Ikeda H, Tama N, Yamazaki T, Lee JD, Tada H (2017) Association between matrix metalloproteinase-9 and worsening heart failure events in patients with chronic heart failure. ESC Heart Fail 4(3):321–330. https://doi.org/10.1002/ehf2.12137

    Article  PubMed  PubMed Central  Google Scholar 

  21. McKee PA, Castelli WP, McNamara PM, Kannel WB (1971) The natural history of congestive heart failure: the Framingham study. N Engl J Med 285(26):1441–1446. https://doi.org/10.1056/NEJM197112232852601

    Article  CAS  PubMed  Google Scholar 

  22. Harrell FE Jr (2019). rms: Regression Modeling Strategies. R package version 5.1-3.1. https://CRAN.R-project.org/package=rms

  23. Kanda Y (2013) Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant 48(3):452–458. https://doi.org/10.1038/bmt.2012.244

    Article  CAS  PubMed  Google Scholar 

  24. Kelly D, Khan SQ, Thompson M, Cockerill G, Ng LL, Samani N, Squire IB (2008) Plasma tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9: novel indicators of left ventricular remodelling and prognosis after acute myocardial infarction. Eur Heart J 29(17):2116–2124. https://doi.org/10.1093/eurheartj/ehn315

    Article  PubMed  Google Scholar 

  25. Loncar G, Springer J, Anker M, Doehner W, Lainscak M (2016) Cardiac cachexia: hic et nunc. J Cachexia Sarcopenia Muscle 7(3):246–260. https://doi.org/10.1002/jcsm.12118

    Article  PubMed  PubMed Central  Google Scholar 

  26. Morishita T, Uzui H, Sato Y, Mitsuke Y, Tada H (2021) Associations between cachexia and metalloproteinases, haemodynamics and mortality in heart failure. Eur J Clin Investig 51(4):e13426. https://doi.org/10.1111/eci.13426

    Article  CAS  Google Scholar 

  27. Dörr O, Walther C, Liebetrau C, Keller T, Tabert H, Boeder N, Bayer M, Bauer P, Möllmann H, Gaede L, Troidl C, Voss S, Bauer T, Hamm CW, Nef H (2018) Specific biomarkers of myocardial inflammation and remodeling processes as predictors of mortality in high-risk patients undergoing percutaneous mitral valve repair (MitraClip). Clin Cardiol 41(4):481–487. https://doi.org/10.1002/clc.22900

    Article  PubMed  PubMed Central  Google Scholar 

  28. Konstam MA, Gheorghiade M, Burnett JC, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C, EoVAiHFOSWTE I (2007) Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 297(12):1319–1331. https://doi.org/10.1001/jama.297.12.1319

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank the Mses. Hiromi Nishimura, Yumie Yasusaki, Motoko Oku, Mari Kurata, and Yoshiko Kurose for providing excellent technical assistance. We would like to thank Editage (http://www.editage.com) for English language editing. The first author would also like to express his gratitude to his wife and daughter for their moral support and constant encouragement.

Funding

This work was partially supported by a research grant from the University of Fukui.

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka, Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan

    Tetsuji Morishita, Hiroyasu Uzui, Kaori Hisazaki, Yasuhiko Mitsuke, Taketoshi Yamazaki & Hiroshi Tada

  2. Department of Cardiovascular Medicine, National Hospital Organization Awara Hospital, 238-1 Kitagata, Awara, Fukui, 910-4272, Japan

    Tetsuji Morishita & Yasuhiko Mitsuke

  3. Department of Internal Medicine, Matsunami General Hospital, Gifu, 501-6062, Japan

    Tetsuji Morishita

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  1. Tetsuji Morishita
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Correspondence to Hiroyasu Uzui.

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Approval from the ethics committee of our institution was obtained prior to conducting the study. The institutional review board waived the need for informed consent for these administrative data, because of the retrospective nature of this study.

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Morishita, T., Uzui, H., Hisazaki, K. et al. Relationships between sodium levels, haemodynamics and metalloproteinases in heart failure patients. Heart Vessels 37, 986–993 (2022). https://doi.org/10.1007/s00380-021-02004-9

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  • DOI: https://doi.org/10.1007/s00380-021-02004-9

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