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Echocardiography-based pressure–volume loop assessment in the evaluation for the effects of indoxyl sulfate on cardiovascular function

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Abstract

Background

Indoxyl sulfate (IS), a uremic toxin, has been reported to have hypertrophic effects on the heart. Previous studies, however, have shown no association between elevated IS levels and cardiovascular outcomes in hemodialysis patients. We hypothesized that, despite left ventricular (LV) hypertrophy, myocardial contractility and ventricular–arterial coupling would remain preserved, and that this would explain the reason for the absence of prognostic impact of IS.

Methods

We evaluated the association of IS with LV structure, contractility, vascular function, and mechanical efficiency (ventricular–arterial coupling and stroke work/pressure volume area) in 154 patients on hemodialysis, using echocardiography-based pressure–volume loop assessment.

Results

As expected, subjects in the high IS group (IS ≥ 33.8 μg/mL) had greater LV mass index and end-diastolic volume index compared to subjects in the low IS group (IS < 33.8 μg/mL). These differences remained significant after adjusting for age, sex, body mass index, diabetic nephropathy, duration of hemodialysis, and NT-proBNP levels, suggesting a potential role of elevated IS levels in LV remodeling. However, no differences in LV contractility (preload recruitable stroke work, peak power index, and systolic mitral annular velocity) and mechanical efficiency (ventricular–arterial coupling and stroke work/pressure volume area) were observed between the groups.

Conclusions

Deleterious effects of IS on LV remodeling are not accompanied by impaired LV contractility or mechanical efficiency, which could contribute to the absence of cardiovascular prognostic impact observed in previous studies performed on hemodialysis patients.

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References

  1. USRDS. Annual data report 2017: international comparisons. 2017. Available at: https://www.usrds.org/2017/view/v2_11.aspx. Accessed 6 July 2018.

  2. National Institute of Diabetes and Digestive and Kidney Diseases. Kidney disease statistics for the United States. Available at: https://www.niddk.nih.gov/health-information/health-statistics/kidney-disease. Accessed 6 July 2018.

  3. The Japanese Society for Dialysis Therapy. 2016 statistics of maintenance Dialysis therapy in Japan. 2016. Available at: http://docs.jsdt.or.jp/overview/pdf2017/p004.pdf. Accessed 6 July 2018.

  4. Foley RN, Collins AJ. End-stage renal disease in the United States: an update from the United States renal data system. J Am Soc Nephrol. 2007;18:2644–8.

    Article  PubMed  Google Scholar 

  5. Hung SC, Kuo KL, Wu CC, et al. Indoxyl sulfate: A novel cardiovascular risk factor in chronic kidney disease. J Am Heart Assoc. 2017;6:e005022.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Barreto FC, Barreto DV, Liabeuf S, et al. Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol. 2009;4:1551–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lekawanvijit S, Adrahtas A, Kelly DJ, et al. Does indoxyl sulfate, a uraemic toxin, have direct effects on cardiac fibroblasts and myocytes? Eur Heart J. 2010;31:1771–9.

    Article  CAS  PubMed  Google Scholar 

  8. Lekawanvijit S, Kompa AR, Manabe M, et al. Chronic kidney disease-induced cardiac fibrosis is ameliorated by reducing circulating levels of a non-dialysable uremic toxin, indoxyl sulfate. PLoS One. 2012;7:e41281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shimazu S, Hirashiki A, Okumura T, et al. Association between indoxyl sulfate and cardiac dysfunction and prognosis in patients with dilated cardiomyopathy. Circ J. 2013;77:390–6.

    Article  CAS  PubMed  Google Scholar 

  10. Sato B, Yoshikawa D, Ishii H, et al. Relation of plasma indoxyl sulfate levels and estimated glomerular filtration rate to left ventricular diastolic dysfunction. Am J Cardiol. 2013;111:712–6.

    Article  CAS  PubMed  Google Scholar 

  11. Obokata M, Sunaga H, Ishida H, et al. Independent and incremental prognostic value of novel cardiac biomarkers in chronic hemodialysis patients. Am Heart J. 2016;179:29–41.

    Article  CAS  PubMed  Google Scholar 

  12. Lin CJ, Wu CJ, Pan CF, et al. Serum protein-bound uraemic toxins and clinical outcomes in haemodialysis patients. Nephrol Dial Transplant. 2010;25:3693–700.

    Article  CAS  PubMed  Google Scholar 

  13. Wu IW, Hsu KH, Hsu HJ, et al. Serum free p-cresyl sulfate levels predict cardiovascular and all-cause mortality in elderly hemodialysis patients–a prospective cohort study. Nephrol Dial Transplant. 2012;27:1169–75.

    Article  CAS  PubMed  Google Scholar 

  14. Lin CJ, Wu V, Wu PC, et al. Meta-analysis of the associations of p-Cresyl sulfate (PCS) and Indoxyl Sulfate (IS) with cardiovascular events and all-cause mortality in patients with chronic renal failure. PLoS One. 2015;10:e0132589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Borlaug BA, Lam CS, Roger VL, et al. Contractility and ventricular systolic stiffening in hypertensive heart disease insights into the pathogenesis of heart failure with preserved ejection fraction. J Am Coll Cardiol. 2009;54:410–8.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Obokata M, Kurosawa K, Ishida H, et al. Incremental Prognostic value of Ventricular–Arterial coupling over ejection fraction in patients with maintenance hemodialysis. J Am Soc Echocardiogr. 2017;30(444–453):e2.

    Google Scholar 

  17. Obokata M, Negishi K, Marwick TH, et al. Comparison of different interdialytic intervals among hemodialysis patients on their echocardiogram-based cardiovascular parameters. Am Heart J. 2015;169(523–30):e2.

    Google Scholar 

  18. Borlaug BA, Olson TP, Lam CS, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2010;56:845–54.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American society of echocardiography and the European association of cardiovascular imaging. J Am Soc Echocardiogr. 2015;28(1–39):e14.

    Google Scholar 

  20. Chen CH, Fetics B, Nevo E, et al. Noninvasive single-beat determination of left ventricular end-systolic elastance in humans. J Am Coll Cardiol. 2001;38:2028–34.

    Article  CAS  PubMed  Google Scholar 

  21. Saiki H, Eidem BW, Ohtani T, et al. Ventricular–arterial function and coupling in the adult fontan circulation. J Am Heart Assoc. 2016;5:e003887.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure. Heart Fail Clin. 2008;4:23–36.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Suga H. Ventricular energetics. Physiol Rev. 1990;70:247–77.

    Article  CAS  PubMed  Google Scholar 

  24. Takaoka H, Takeuchi M, Odake M, et al. Comparison of hemodynamic determinants for myocardial oxygen consumption under different contractile states in human ventricle. Circulation. 1993;87:59–69.

    Article  CAS  PubMed  Google Scholar 

  25. Kawaguchi M, Hay I, Fetics B, et al. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations. Circulation. 2003;107:714–20.

    Article  PubMed  Google Scholar 

  26. Wanner C, Amann K, Shoji T. The heart and vascular system in dialysis. Lancet. 2016;388:276–84.

    Article  PubMed  Google Scholar 

  27. Cao XS, Chen J, Zou JZ, et al. Association of indoxyl sulfate with heart failure among patients on hemodialysis. Clin J Am Soc Nephrol. 2015;10:111–9.

    Article  CAS  PubMed  Google Scholar 

  28. Fujii H, Nishijima F, Goto S, et al. Oral charcoal adsorbent (AST-120) prevents progression of cardiac damage in chronic kidney disease through suppression of oxidative stress. Nephrol Dial Transplant. 2009;24:2089–95.

    Article  CAS  PubMed  Google Scholar 

  29. Lin CY, Hsu YJ, Hsu SC, et al. CB1 cannabinoid receptor antagonist attenuates left ventricular hypertrophy and Akt-mediated cardiac fibrosis in experimental uremia. J Mol Cell Cardiol. 2015;85:249–61.

    Article  CAS  PubMed  Google Scholar 

  30. de Simone G, Devereux RB, Koren MJ, et al. Midwall left ventricular mechanics. An independent predictor of cardiovascular risk in arterial hypertension. Circulation. 1996;93:259–65.

    Article  PubMed  Google Scholar 

  31. Hensen LCR, Goossens K, Delgado V, et al. Prognostic Implications of Left Ventricular Global Longitudinal Strain in Predialysis and Dialysis Patients. Am J Cardiol. 2017;120:500–4.

    Article  PubMed  Google Scholar 

  32. de Simone G, Devereux RB, Roman MJ, et al. Assessment of left ventricular function by the midwall fractional shortening/end-systolic stress relation in human hypertension. J Am Coll Cardiol. 1994;23:1444–51.

    Article  PubMed  Google Scholar 

  33. Aurigemma GP, Silver KH, Priest MA, et al. Geometric changes allow normal ejection fraction despite depressed myocardial shortening in hypertensive left ventricular hypertrophy. J Am Coll Cardiol. 1995;26:195–202.

    Article  CAS  PubMed  Google Scholar 

  34. Dou L, Jourde-Chiche N, Faure V, et al. The uremic solute indoxyl sulfate induces oxidative stress in endothelial cells. J Thromb Haemost. 2007;5:1302–8.

    Article  CAS  PubMed  Google Scholar 

  35. Yamamoto H, Tsuruoka S, Ioka T, et al. Indoxyl sulfate stimulates proliferation of rat vascular smooth muscle cells. Kidney Int. 2006;69:1780–5.

    Article  CAS  PubMed  Google Scholar 

  36. Ky B, French B, May Khan A, et al. Ventricular–arterial coupling, remodeling, and prognosis in chronic heart failure. J Am Coll Cardiol. 2013;62:1165–72.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Hansson NH, Sorensen J, Harms HJ, et al. Myocardial oxygen consumption and efficiency in aortic valve stenosis patients with and without heart failure. J Am Heart Assoc. 2017;6:e004810.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan

    Masaru Obokata, Koji Kurosawa, Masahiko Kurabayashi & Kazuaki Negishi

  2. Menzies Research Institute Tasmania, Hobart, Australia

    Kazuaki Negishi

  3. Hidaka Hospital, Takasaki, Gunma, Japan

    Hideki Ishida, Kyoko Ito, Tetsuya Ogawa & Yoshitaka Ando

  4. Department of Nephrology, Heisei-Hidaka Clinic, Takasaki, Gunma, Japan

    Kyoko Ito

  5. Department of Medicine, Tokyo Women’s Medical University Medical Center East, Tokyo, Japan

    Tetsuya Ogawa

Authors
  1. Masaru Obokata
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  2. Koji Kurosawa
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  3. Hideki Ishida
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  4. Kyoko Ito
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  5. Tetsuya Ogawa
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  6. Yoshitaka Ando
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  7. Masahiko Kurabayashi
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  8. Kazuaki Negishi
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Corresponding author

Correspondence to Masaru Obokata.

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Conflict of interest

Dr. Obokata received research funding from Kureha Corporation, Tokyo, Japan. The sponsor was not involved in the study design, data collection, analysis and interpretation, and preparation of manuscript. Dr. Negishi was supported by an award from the Select Foundation, which has no role in the preparation of this manuscript. Drs. Kurosawa, Ishida, Ito, Ogawa, Ando, and Kurabayashi declare that they have no conflict of interest.

Ethical approval

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later revisions.

Informed consent

Informed consent was obtained from all patients for being included in the study.

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Obokata, M., Kurosawa, K., Ishida, H. et al. Echocardiography-based pressure–volume loop assessment in the evaluation for the effects of indoxyl sulfate on cardiovascular function. J Echocardiogr 17, 35–43 (2019). https://doi.org/10.1007/s12574-018-0385-5

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  • DOI: https://doi.org/10.1007/s12574-018-0385-5

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