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Plasma cystine/methionine ratio is associated with left ventricular diastolic function in patients with heart disease

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Abstract

Elevated circulating homocysteine (Hcy) is a well-known risk factor for cardiovascular diseases (CVDs), including coronary artery disease (CAD) and heart failure (HF). It remains unclear how Hcy and its derivatives relate to left ventricular (LV) diastolic function. The aim of the present study was to investigate the relationship between plasma Hcy-related metabolites and diastolic dysfunction (DD) in patients with heart disease (HD). A total of 62 HD patients with preserved LV ejection fraction (LVEF ≥ 50%) were enrolled. Plasma Hcy and its derivatives were measured by liquid chromatography‒mass spectrometry (LC–MS/MS). Spearman’s correlation test and multiple linear regression models were used to analyze the associations between metabolite levels and LV diastolic function. The cystine/methionine (CySS/Met) ratio was positively correlated with LV diastolic function, which was defined from the ratio of mitral inflow E and mitral e′ annular velocities (E/e′) (Spearman’s r = 0.43, p < 0.001). When the subjects were categorized into two groups by E/e′, the high-E/e′ group had a significantly higher CySS/Met ratio than the low-E/e′ group (p = 0.002). Multiple linear regression models revealed that the CySS/Met ratio was independently associated with E/e′ after adjustment for age, sex, body mass index (BMI), diabetes mellitus, hypertension, chronic kidney disease (CKD),　hemoglobin, and lipid peroxide (LPO) {standardized β (95% CI); 0.14 (0.04–0.23); p = 0.005}. Hcy, CySS, and Met did not show a significant association with E/e′ in the same models. A high plasma CySS/Met ratio reflected DD in patients with HD.

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Data availability

The datasets related to this study are available from the corresponding author on reasonable request.

References

  1. MacDonald MR, Tay WT, Teng TK, Anand I, Ling LH, Yap J, Tromp J, Wander GS, Naik A, Ngarmukos T, Siswanto BB, Hung CL, Richards AM, Lam CSP, dagger A-Fi and investigatorsdagger A-F (2020) Regional variation of mortality in heart failure with reduced and preserved ejection fraction across Asia: outcomes in the ASIAN-HF registry. J Am Heart Assoc 9:e012199

    Article  PubMed  Google Scholar 

  2. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Piepoli MF, Price S, Rosano GMC, Ruschitzka F, Skibelund AK, Group ESCSD (2022) 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC. Rev Esp Cardiol (Engl Ed) 75:523

    PubMed  Google Scholar 

  3. Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Cheng S, Delling FN, Elkind MSV, Evenson KR, Ferguson JF, Gupta DK, Khan SS, Kissela BM, Knutson KL, Lee CD, Lewis TT, Liu J, Loop MS, Lutsey PL, Ma J, Mackey J, Martin SS, Matchar DB, Mussolino ME, Navaneethan SD, Perak AM, Roth GA, Samad Z, Satou GM, Schroeder EB, Shah SH, Shay CM, Stokes A, VanWagner LB, Wang NY, Tsao CW, American Heart Association Council on E (2021) Prevention statistics C and stroke statistics S. Heart disease and stroke statistics-2021 update: a report from the American Heart Association. Circulation 143:e254–e743

    Article  PubMed  Google Scholar 

  4. Vasan RS, Xanthakis V, Lyass A, Andersson C, Tsao C, Cheng S, Aragam J, Benjamin EJ, Larson MG (2018) Epidemiology of left ventricular systolic dysfunction and heart failure in the Framingham study: an echocardiographic study over 3 decades. JACC Cardiovasc Imaging 11:1–11

    Article  PubMed  Google Scholar 

  5. Del Buono MG, Buckley L, Abbate A (2018) Primary and secondary diastolic dysfunction in heart failure with preserved ejection fraction. Am J Cardiol 122:1578–1587

    Article  PubMed  PubMed Central  Google Scholar 

  6. Rush CJ, Berry C, Oldroyd KG, Rocchiccioli JP, Lindsay MM, Touyz RM, Murphy CL, Ford TJ, Sidik N, McEntegart MB, Lang NN, Jhund PS, Campbell RT, McMurray JJV, Petrie MC (2021) Prevalence of coronary artery disease and coronary microvascular dysfunction in patients with heart failure with preserved ejection fraction. JAMA Cardiol 6:1130–1143

    Article  PubMed  Google Scholar 

  7. Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, Graham I (1991) Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 324:1149–1155

    Article  CAS  PubMed  Google Scholar 

  8. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE (1997) Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 337:230–236

    Article  CAS  PubMed  Google Scholar 

  9. Homocysteine Studies C (2002) Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 288:2015–2022

    Article  Google Scholar 

  10. May HT, Alharethi R, Anderson JL, Muhlestein JB, Reyna SP, Bair TL, Horne BD, Kfoury AG, Carlquist JF, Renlund DG (2007) Homocysteine levels are associated with increased risk of congestive heart failure in patients with and without coronary artery disease. Cardiology 107:178–184

    Article  CAS  PubMed  Google Scholar 

  11. Vasan RS, Beiser A, D’Agostino RB, Levy D, Selhub J, Jacques PF, Rosenberg IH, Wilson PW (2003) Plasma homocysteine and risk for congestive heart failure in adults without prior myocardial infarction. JAMA 289:1251–1257

    Article  CAS  PubMed  Google Scholar 

  12. Sundstrom J, Sullivan L, Selhub J, Benjamin EJ, D’Agostino RB, Jacques PF, Rosenberg IH, Levy D, Wilson PW, Vasan RS, Framingham Heart S (2004) Relations of plasma homocysteine to left ventricular structure and function: the Framingham Heart Study. Eur Heart J 25:523–530

    Article  CAS  PubMed  Google Scholar 

  13. Rallidis LS, Katsimardos A, Kosmas N, Rallidi T, Zapantiotis D, Varounis C, Kountouri A (2022) Differential prognostic value of resistin for cardiac death in patients with coronary artery disease according to the presence of metabolic syndrome. Heart Vessels 37(5):713–719

    Article  PubMed  Google Scholar 

  14. Takahara M, Iida O, Soga Y, Kodama A, Terashi H, Azuma N (2021) Impact of homocysteine levels on mortality risk in patients with chronic limb-threatening ischemia undergoing revascularization. Heart Vessels 36:1825–1829

    Article  PubMed  Google Scholar 

  15. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, Flachskampf FA, Gillebert TC, Klein AL, Lancellotti P, Marino P, Oh JK, Popescu BA, Waggoner AD (2016) Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American society of echocardiography and the European association of cardiovascular imaging. J Am Soc Echocardiogr 29:277–314

    Article  PubMed  Google Scholar 

  16. Yoshikawa S, Nagao M, Toh R, Shinohara M, Iino T, Irino Y, Nishimori M, Tanaka H, Satomi-Kobayashi S, Ishida T, Hirata KI (2022) Inhibition of glutaminase 1-mediated glutaminolysis improves pathological cardiac remodeling. Am J Physiol Heart Circ Physiol 322:H749–H761

    Article  CAS  PubMed  Google Scholar 

  17. Yagi K (1976) A simple fluorometric assay for lipoperoxide in blood plasma. Biochem Med 15:212–216

    Article  CAS  PubMed  Google Scholar 

  18. Bannai S (1984) Transport of cystine and cysteine in mammalian cells. Biochim Biophys Acta 779:289–306

    Article  CAS  PubMed  Google Scholar 

  19. McCully KS (1969) Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 56:111–128

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Luo JL, Chien KL, Hsu HC, Su TC, Lin HJ, Chen PC, Chen MF, Lee YT (2017) Association between plasma homocysteine concentration and the risk of all-cause death in adults with diastolic dysfunction in a community: a 13-year cohort study. Medicine (Baltimore) 96:e6716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shi Y, Zhao L, Zhang Y, Qin Q, Cong H, Guo Z (2021) Homocysteine promotes cardiac fibrosis by regulating the Akt/FoxO3 pathway. Ann Transl Med 9:1732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Raad M, AlBadri A, Wei J, Mehta PK, Maughan J, Gadh A, Thomson L, Jones DP, Quyyumi AA, Pepine CJ, Bairey Merz CN (2020) Oxidative stress is associated with diastolic dysfunction in women with ischemia with no obstructive coronary artery disease. J Am Heart Assoc 9:e015602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Keith M, Geranmayegan A, Sole MJ, Kurian R, Robinson A, Omran AS, Jeejeebhoy KN (1998) Increased oxidative stress in patients with congestive heart failure. J Am Coll Cardiol 31:1352–1356

    Article  CAS  PubMed  Google Scholar 

  24. McMurray J, Chopra M, Abdullah I, Smith WE, Dargie HJ (1993) Evidence of oxidative stress in chronic heart failure in humans. Eur Heart J 14:1493–1498

    Article  CAS  PubMed  Google Scholar 

  25. Sorop O, Heinonen I, van Kranenburg M, van de Wouw J, de Beer VJ, Nguyen ITN, Octavia Y, van Duin RWB, Stam K, van Geuns RJ, Wielopolski PA, Krestin GP, van den Meiracker AH, Verjans R, van Bilsen M, Danser AHJ, Paulus WJ, Cheng C, Linke WA, Joles JA, Verhaar MC, van der Velden J, Merkus D, Duncker DJ (2018) Multiple common comorbidities produce left ventricular diastolic dysfunction associated with coronary microvascular dysfunction, oxidative stress, and myocardial stiffening. Cardiovasc Res 114:954–964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mosharov E, Cranford MR, Banerjee R (2000) The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes. Biochemistry 39:13005–13011

    Article  CAS  PubMed  Google Scholar 

  27. Chen XX, Wu Y, Ge X, Lei L, Niu LY, Yang QZ, Zheng L (2022) In vivo imaging of heart failure with preserved ejection fraction by simultaneous monitoring of cardiac nitric oxide and glutathione using a three-channel fluorescent probe. Biosens Bioelectron 214:114510

    Article  CAS  PubMed  Google Scholar 

  28. Garcia MC, Amankwa-Sakyi M, Flynn TJ (2011) Cellular glutathione in fatty liver in vitro models. Toxicol In Vitro 25:1501–1506

    Article  CAS  PubMed  Google Scholar 

  29. Persa C, Pierce A, Ma Z, Kabil O, Lou MF (2004) The presence of a transsulfuration pathway in the lens: a new oxidative stress defense system. Exp Eye Res 79:875–886

    Article  CAS  PubMed  Google Scholar 

  30. Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M (2008) How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. Neurotoxicology 29:190–201

    Article  CAS  PubMed  Google Scholar 

  31. Vitvitsky V, Thomas M, Ghorpade A, Gendelman HE, Banerjee R (2006) A functional transsulfuration pathway in the brain links to glutathione homeostasis. J Biol Chem 281:35785–35793

    Article  CAS  PubMed  Google Scholar 

  32. Righetti M, Serbelloni P, Milani S, Ferrario G (2006) Homocysteine-lowering vitamin B treatment decreases cardiovascular events in hemodialysis patients. Blood Purif 24:379–386

    Article  CAS  PubMed  Google Scholar 

  33. Sun J, Wen S, Zhou J, Ding S (2017) Association between malnutrition and hyperhomocysteine in Alzheimer’s disease patients and diet intervention of betaine. J Clin Lab Anal 31(5):e22090

    Article  PubMed  Google Scholar 

  34. Cao P, Zhang W, Wang G, Zhao X, Gao N, Liu Z, Xu R (2021) Low dose of folic acid can ameliorate hyperhomocysteinemia-induced cardiac fibrosis and diastolic dysfunction in spontaneously hypertensive rats. Int Heart J 62:627–635

    Article  CAS  PubMed  Google Scholar 

  35. Park JH, Saposnik G, Ovbiagele B, Markovic D, Towfighi A (2016) Effect of B-vitamins on stroke risk among individuals with vascular disease who are not on antiplatelets: a meta-analysis. Int J Stroke 11:206–211

    Article  Google Scholar 

  36. Spence JD, Yi Q, Hankey GJ (2017) B vitamins in stroke prevention: time to reconsider. Lancet Neurol 16:750–760

    Article  CAS  PubMed  Google Scholar 

  37. Li Y, Huang T, Zheng Y, Muka T, Troup J, Hu FB (2016) Folic acid supplementation and the risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. J Am Heart Assoc 5(8):e003768

    Article  PubMed  PubMed Central  Google Scholar 

  38. Cui R, Iso H, Date C, Kikuchi S, Tamakoshi A and Japan Collaborative Cohort Study G (2010) Dietary folate and vitamin b6 and B12 intake in relation to mortality from cardiovascular diseases: Japan collaborative cohort study. Stroke 41:1285–1289

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank Emiko Yoshida for providing technical assistance.

Funding

This research was supported by the Hyogo Science and Technology Association, a Grant-in-Aid for Scientific Research (C) (22K08205), and a Grant-in-Aid for Young Scientists (20K17081) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

    Junko Asakura, Sachiko Yoshikawa, Takuya Iino, Yutaro Seto, Hidekazu Tanaka, Seimi Satomi-Kobayashi, Tatsuro Ishida & Ken-ichi Hirata

  2. Division of Evidence-Based Laboratory Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Manabu Nagao, Ken-ichi Hirata & Ryuji Toh

  3. Division of Molecular Epidemiology, Kobe University Graduate School of Medicine, Kobe, Japan

    Masakazu Shinohara & Makoto Nishimori

  4. The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Kobe, Japan

    Masakazu Shinohara

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  1. Junko Asakura
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Correspondence to Manabu Nagao.

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Manabu Nagao and Ryuji Toh belong to the Division of Evidence-based Laboratory Medicine, Kobe University Graduate School of Medicine which was established by an endowment fund from Sysmex Corporation, Japan.

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Asakura, J., Nagao, M., Shinohara, M. et al. Plasma cystine/methionine ratio is associated with left ventricular diastolic function in patients with heart disease. Heart Vessels 38, 1422–1430 (2023). https://doi.org/10.1007/s00380-023-02302-4

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