Ubiquinol Improves Endothelial Function in Patients with Heart Failure with Reduced Ejection Fraction: A Single-Center, Randomized Double-Blind Placebo-Controlled Crossover Pilot Study

Abstract

Background

Endothelial dysfunction is reportedly associated with worse outcomes in patients with chronic heart failure. Ubiquinol is a reduced form of coenzyme Q10 (CoQ10) that may improve endothelial function.

Objective

We assessed the hypothesis that ubiquinol improves peripheral endothelial function in patients with heart failure with reduced ejection fraction (HFrEF).

Methods

In this randomized, double-blind, placebo-controlled, crossover pilot study, 14 patients with stable HFrEF were randomly and blindly allocated to ubiquinol 400 mg/day or placebo for 3 months. After a 1-month washout period, patients were crossed over to the alternative treatment. Before and after each treatment, we assessed peripheral endothelial function using the reactive hyperemia index (RHI) and analyzed it using the natural logarithm of RHI (LnRHI).

Results

Peripheral endothelial function as assessed by LnRHI tended to improve with ubiquinol 400 mg/day for 3 months (p = 0.076). Original RHI values were also compared, and RHI significantly improved with ubiquinol treatment (pre-RHI 1.57 [interquartile range (IQR) 1.39–1.80], post-RHI 1.74 [IQR 1.63–2.02], p = 0.026), but not with placebo (pre-RHI 1.67 [IQR 1.53–1.85], post-RHI 1.51 [IQR 1.39–2.11], p = 0.198).

Conclusions

Ubiquinol 400 mg/day for 3 months led to significant improvement in peripheral endothelial function in patients with HFrEF. Ubiquinol may be a therapeutic option for individuals with HFrEF. Large-scale randomized controlled trials of CoQ10 supplementation in patients with HFrEF are needed.

Clinical Trial Registration

Japanese University Hospital Medical Information Network (UMIN-ICDR). Clinical Trial identifier number UMIN000012604.

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References

  1. 1.

    Meta-analysis Global Group in Chronic Heart Failure. The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis. Eur Heart J. 2012;33:1750–7.

    Article  Google Scholar 

  2. 2.

    Sharma A, Fonarow GC, Butler J, Ezekowitz JA, Felker GM. Coenzyme Q10 and heart failure: a state-of-the-art review. Circ Heart Fail. 2016;9:e002639.

    CAS  Article  Google Scholar 

  3. 3.

    Mortensen SA, Vadhanavikit S, Muratsu K, Folkers K. Coenzyme Q10: clinical benefits with biochemical correlates suggesting a scientific breakthrough in the management of chronic heart failure. Int J Tissue React. 1990;12:155–62.

    CAS  PubMed  Google Scholar 

  4. 4.

    Mortensen SA. Perspectives on therapy of cardiovascular diseases with coenzyme Q10 (ubiquinone). Clin Investig. 1993;71:S116–23.

    CAS  Article  Google Scholar 

  5. 5.

    Folkers K, Vadhanavikit S, Mortensen SA. Biochemical rationale and myocardial tissue data on the effective therapy of cardiomyopathy with coenzyme Q10. Proc Natl Acad Sci USA. 1985;82:901–4.

    CAS  Article  Google Scholar 

  6. 6.

    Mortensen SA, Rosenfeldt F, Kumar A, Dolliner P, Filipiak KJ, Pella D, et al. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC Heart Fail. 2014;2:641–9.

    Article  Google Scholar 

  7. 7.

    Tiano L, Belardinelli R, Carnevali P, Principi F, Seddaiu G, Littarru GP. Effect of coenzyme Q10 administration on endothelial function and extracellular superoxide dismutase in patients with ischaemic heart disease: a double-blind, randomized controlled study. Eur Heart J. 2007;28:2249–55.

    CAS  Article  Google Scholar 

  8. 8.

    Hamilton SJ, Chew GT, Watts GF. Coenzyme Q10 improves endothelial dysfunction in statin-treated type 2 diabetic patients. Diabetes Care. 2009;32:810–2.

    Article  Google Scholar 

  9. 9.

    Dai YL, Luk TH, Yiu KH, Wang M, Yip PM, Lee SW, et al. Reversal of mitochondrial dysfunction by coenzyme Q10 supplement improves endothelial function in patients with ischaemic left ventricular systolic dysfunction: a randomized controlled trial. Atherosclerosis. 2011;216:395–401.

    CAS  Article  Google Scholar 

  10. 10.

    Frei B, Kim MC, Ames BN. Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations. Proc Natl Acad Sci USA. 1990;87:4879–83.

    CAS  Article  Google Scholar 

  11. 11.

    Langsjoen PH, Langsjoen AM. Comparison study of plasma coenzyme Q10 levels in healthy subjects supplemented with ubiquinol versus ubiquinone. Clin Pharmacol Drug Dev. 2014;3:13–7.

    CAS  Article  Google Scholar 

  12. 12.

    Garcia-Corzo L, Luna-Sanchez M, Doerrier C, Ortiz F, Escames G, Acuna-Castroviejo D, et al. Ubiquinol-10 ameliorates mitochondrial encephalopathy associated with CoQ deficiency. Biochim Biophys Acta. 2014;1842:893–901.

    CAS  Article  Google Scholar 

  13. 13.

    Yoritaka A, Kawajiri S, Yamamoto Y, Nakahara T, Ando M, Hashimoto K, et al. Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme Q10 for Parkinson’s disease. Parkinsonism Relat Disord. 2015;21:911–6.

    Article  Google Scholar 

  14. 14.

    Yen CH, Chu YJ, Lee BJ, Lin YC, Lin PT. Effect of liquid ubiquinol supplementation on glucose, lipids and antioxidant capacity in type 2 diabetes patients: a double-blind, randomised, placebo-controlled trial. Br J Nutr. 2018;120:57–63.

    CAS  Article  Google Scholar 

  15. 15.

    Perez-Sanchez C, Aguirre MA, Ruiz-Limon P, Abalos-Aguilera MC, Jimenez-Gomez Y, Arias-de la Rosa I, et al. Ubiquinol effects on antiphospholipid syndrome prothrombotic profile: a randomized, placebo-controlled trial. Arterioscler Thromb Vasc Biol. 2017;37:1923–32.

    CAS  Article  Google Scholar 

  16. 16.

    Matsuzawa Y, Sugiyama S, Sumida H, Sugamura K, Nozaki T, Ohba K, et al. Peripheral endothelial function and cardiovascular events in high-risk patients. J Am Heart Assoc. 2013;2:e000426.

    Article  Google Scholar 

  17. 17.

    Matsuzawa Y, Sugiyama S, Sugamura K, Nozaki T, Ohba K, Konishi M, et al. Digital assessment of endothelial function and ischemic heart disease in women. J Am Coll Cardiol. 2010;55:1688–96.

    Article  Google Scholar 

  18. 18.

    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 

  19. 19.

    Akiyama E, Sugiyama S, Matsuzawa Y, Konishi M, Suzuki H, Nozaki T, et al. Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction. J Am Coll Cardiol. 2012;60:1778–86.

    Article  Google Scholar 

  20. 20.

    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;57:390–6.

    CAS  Article  Google Scholar 

  21. 21.

    Matsuzawa Y, Kwon TG, Lennon RJ, Lerman LO, Lerman A. Prognostic value of flow-mediated vasodilation in brachial artery and fingertip artery for cardiovascular events: a systematic review and meta-analysis. J Am Heart Assoc. 2015. https://doi.org/10.1161/JAHA.115.002270.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Kumar A, Kaur H, Devi P, Mohan V. Role of coenzyme Q10 (CoQ10) in cardiac disease, hypertension and Meniere-like syndrome. Pharmacol Ther. 2009;124:259–68.

    CAS  Article  Google Scholar 

  23. 23.

    Pepe S, Marasco SF, Haas SJ, Sheeran FL, Krum H, Rosenfeldt FL. Coenzyme Q10 in cardiovascular disease. Mitochondrion. 2007;7(Suppl):S154–67.

    CAS  Article  Google Scholar 

  24. 24.

    Belardinelli R, Mucaj A, Lacalaprice F, Solenghi M, Seddaiu G, Principi F, et al. Coenzyme Q10 and exercise training in chronic heart failure. Eur Heart J. 2006;27:2675–81.

    CAS  Article  Google Scholar 

  25. 25.

    Yamashita S, Yamamoto Y. Simultaneous detection of ubiquinol and ubiquinone in human plasma as a marker of oxidative stress. Anal Biochem. 1997;250:66–73.

    CAS  Article  Google Scholar 

  26. 26.

    Brant LC, Barreto SM, Passos VM, Ribeiro AL. Reproducibility of peripheral arterial tonometry for the assessment of endothelial function in adults. J Hypertens. 2013;31:1984–90.

    CAS  Article  Google Scholar 

  27. 27.

    McCrea CE, Skulas-Ray AC, Chow M, West SG. Test-retest reliability of pulse amplitude tonometry measures of vascular endothelial function: implications for clinical trial design. Vasc Med. 2012;17:29–36.

    Article  Google Scholar 

  28. 28.

    Mortensen SA. Overview on coenzyme Q10 as adjunctive therapy in chronic heart failure. Rationale, design and end-points of “Q-symbio”—a multinational trial. Biofactors. 2003;18:79–89.

    CAS  Article  Google Scholar 

  29. 29.

    Hasin T, Matsuzawa Y, Guddeti RR, Aoki T, Kwon TG, Schettle S, et al. Attenuation in peripheral endothelial function after continuous flow left ventricular assist device therapy is associated with cardiovascular adverse events. Circ J. 2015;79:770–7.

    Article  Google Scholar 

  30. 30.

    Takishima I, Nakamura T, Hirano M, Kitta Y, Kobayashi T, Fujioka D, et al. Predictive value of serial assessment of endothelial function in chronic heart failure. Int J Cardiol. 2012;158:417–22.

    Article  Google Scholar 

  31. 31.

    Chew GT, Watts GF. Coenzyme Q10 and diabetic endotheliopathy: oxidative stress and the ‘recoupling hypothesis’. QJM. 2004;97:537–48.

    CAS  Article  Google Scholar 

  32. 32.

    Fan L, Feng Y, Chen GC, Qin LQ, Fu CL, Chen LH. Effects of coenzyme Q10 supplementation on inflammatory markers: a systematic review and meta-analysis of randomized controlled trials. Pharmacol Res. 2017;119:128–36.

    CAS  Article  Google Scholar 

  33. 33.

    Turunen M, Olsson J, Dallner G. Metabolism and function of coenzyme Q. Biochim Biophys Acta. 2004;1660:171–99.

    CAS  Article  Google Scholar 

  34. 34.

    Gao L, Mao Q, Cao J, Wang Y, Zhou X, Fan L. Effects of coenzyme Q10 on vascular endothelial function in humans: a meta-analysis of randomized controlled trials. Atherosclerosis. 2012;221:311–6.

    CAS  Article  Google Scholar 

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Acknowledgements

Kaneka, Japan, supplied the ubiquinol and matching placebo capsules used in this study.

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Corresponding author

Correspondence to Yasushi Matsuzawa.

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Funding

No sources of funding were used to conduct this study or prepare this manuscript.

Conflict of interest

C.K., Y.M., M. Konishi, E.A., H.S., R.S., H.N., S.K., Y.K., N.M., N.I., K.H., M. Kosuge, T.E., K.T., and K.K. have no conflicts of interest that are directly relevant to the content of this study.

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Kawashima, C., Matsuzawa, Y., Konishi, M. et al. Ubiquinol Improves Endothelial Function in Patients with Heart Failure with Reduced Ejection Fraction: A Single-Center, Randomized Double-Blind Placebo-Controlled Crossover Pilot Study. Am J Cardiovasc Drugs 20, 363–372 (2020). https://doi.org/10.1007/s40256-019-00384-y

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