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Mean platelet volume modifies the contribution of homocysteine to cardiovascular disease: A real-world study

  • Author Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors.
    Jing Li
    Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors.
    Affiliations
    Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
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  • Author Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors.
    Jianan Zhang
    Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors.
    Affiliations
    Department of Chronic Disease Management, Taicang Center for Disease Prevention and Control, Taicing, China
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  • Author Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors.
    Yan Chen
    Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors.
    Affiliations
    Department of Nephrology, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, China
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  • Linglin Gao
    Affiliations
    Department of Chronic Disease Management, Taicang Center for Disease Prevention and Control, Taicing, China
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  • Xiaoluan Yan
    Affiliations
    Department of Chronic Disease Management, Taicang Center for Disease Prevention and Control, Taicing, China
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  • Mingzhi Zhang
    Affiliations
    Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
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  • Fenchun Wang
    Affiliations
    Department of Chronic Disease Management, Taicang Center for Disease Prevention and Control, Taicing, China
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  • Yan He
    Affiliations
    Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
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  • Weidong Hu
    Correspondence
    Corresponding author. Department of Neurology, Second Affiliated Hospital of Soochow University, 1055 Sanxiang Rd, Gusu District, Suzhou, 215004, China.
    Affiliations
    Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, China
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  • Hao Peng
    Correspondence
    Corresponding author. Department of Epidemiology, School of Public Health, Medical College of Soochow University. 199 Renai Road, Industrial Park, Suzhou, 215123, China.
    Affiliations
    Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China

    Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou, China
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  • Author Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors.
Published:October 28, 2022DOI:https://doi.org/10.1016/j.numecd.2022.10.013

      Highlights

      • We are the first to examine the interactive effect of serum Hcy and platelet activation on the future risk of CVD.
      • We found that the association between Hcy and CVD events was significantly stronger in participants with a large MPV.
      • Both multiplicative and additive interactions between MPV and Hcy were significantly associated with incidence of CVD.
      • MPV may also need to be monitored and controlled in patients with hypertension, particularly those complicated with HHcy.

      Abstract

      Background and aims

      The effect of reductions in homocysteine (Hcy) on cardiovascular disease (CVD) was suggested to be modified by platelet activation, but the interaction between Hcy and platelet activation on CVD events is not well studied. Here, we aimed to examine the interaction between Hcy and platelet activation on CVD in a large, real-world population.

      Methods and results

      A total of 27,234 patients with hypertension (mean 63 years, 48% male) who were registered in Taicang city and free of CVD were prospectively followed up for new CVD events from 2017 to 2020. Hcy and platelet indices including mean platelet volume (MPV) were assayed at baseline. A total of 1063 CVD events were recorded during follow-up. Hcy at baseline was significantly associated with a higher risk of CVD (HR = 1.85, P < 0.001 for log-transformed Hcy). MPV showed a significant interaction effect with Hcy on CVD (HR = 1.20, P = 0.030 for the interaction term). The association between Hcy and CVD was significantly stronger in participants with a large (vs. small) MPV (HR = 2.71 vs. 1.32, P = 0.029 for log-transformed Hcy). For participants with both elevated Hcy and a large MPV, the attributable proportion of CVD events due to their interaction was 0.26 (95% CI: 0.06–0.45).

      Conclusions

      The association between Hcy and CVD was significantly stronger in patients with hypertension with a larger MPV. MPV may modify the contribution of Hcy to CVD events through synergistic interactions with Hcy. These findings suggest that MPV could be monitored and controlled in the prevention of CVD.

      Keywords

      Abbreviations:

      CVD (Cardiovascular disease), Hcy (Homocysteine), HHcy (hyperhomocysteinemia), HDL-C (High-density lipoprotein cholesterol), LDL-C (Low-density lipoprotein cholesterol), MTHFR (Methylenetetrahydrofolate reductase), MPV (Mean platelet volume), PLT (Platelet count), PCT (Plateletcrit), PDW (Platelet distribution width)
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      References

        • Adachi H.
        • Hirai Y.
        • Fujiura Y.
        • Matsuoka H.
        • Satoh A.
        • Imaizumi T.
        Plasma homocysteine levels and atherosclerosis in Japan: epidemiological study by use of carotid ultrasonography.
        Stroke. 2002; 33: 2177-2181
        • Rodrigo R.
        • Passalacqua W.
        • Araya J.
        • Orellana M.
        • Rivera G.
        Homocysteine and essential hypertension.
        J Clin Pharmacol. 2003; 43: 1299-1306
        • Tyagi N.
        • Moshal K.S.
        • Lominadze D.
        • Ovechkin A.V.
        • Tyagi S.C.
        Homocysteine-dependent cardiac remodeling and endothelial-myocyte coupling in a 2 kidney, 1 clip Goldblatt hypertension mouse model.
        Can J Physiol Pharmacol. 2005; 83: 583-594
        • Stamler J.S.
        • Osborne J.A.
        • Jaraki O.
        • Rabbani L.E.
        • Mullins M.
        • Singel D.
        • Loscalzo J.
        Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen.
        J Clin Investig. 1993; 91: 308-318
        • Lentz S.R.
        Mechanisms of homocysteine-induced atherothrombosis.
        J Thromb Haemostasis : JTH. 2005; 3: 1646-1654
        • Kanani P.M.
        • Sinkey C.A.
        • Browning R.L.
        • Allaman M.
        • Knapp H.R.
        • Haynes W.G.
        Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans.
        Circulation. 1999; 100: 1161-1168
        • Shargorodsky M.
        • Boaz M.
        • Pasternak S.
        • Hanah R.
        • Matas Z.
        • Fux A.
        • Beigel Y.
        • Mashavi M.
        Serum homocysteine, folate, vitamin B12 levels and arterial stiffness in diabetic patients: which of them is really important in atherogenesis?.
        Diabetes Metab Res Rev. 2009; 25: 70-75
        • Wald D.S.
        • Law M.
        • Morris J.K.
        Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis.
        BMJ (Clin Res Ed). 2002; 325: 1202
        • Casas J.P.
        • Bautista L.E.
        • Smeeth L.
        • Sharma P.
        • Hingorani A.D.
        Homocysteine and stroke: evidence on a causal link from mendelian randomisation.
        Lancet (London, England). 2005; 365: 224-232
        • Clarke R.
        • Halsey J.
        • Bennett D.
        • Lewington S.
        Homocysteine and vascular disease: review of published results of the homocysteine-lowering trials.
        J Inherit Metab Dis. 2011; 34: 83-91
        • Albert C.M.
        • Cook N.R.
        • Gaziano J.M.
        • Zaharris E.
        • MacFadyen J.
        • Danielson E.
        • Buring J.E.
        • Manson J.E.
        Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial.
        JAMA. 2008; 299: 2027-2036
        • Armitage J.M.
        • Bowman L.
        • Clarke R.J.
        • Wallendszus K.
        • Bulbulia R.
        • Rahimi K.
        • Haynes R.
        • Parish S.
        • Sleight P.
        • Peto R.
        • Collins R.
        Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial.
        JAMA. 2010; 303: 2486-2494
      1. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial.
        Lancet Neurol. 2010; 9: 855-865
        • Bønaa K.H.
        • Njølstad I.
        • Ueland P.M.
        • Schirmer H.
        • Tverdal A.
        • Steigen T.
        • Wang H.
        • Nordrehaug J.E.
        • Arnesen E.
        • Rasmussen K.
        Homocysteine lowering and cardiovascular events after acute myocardial infarction.
        N Engl J Med. 2006; 354: 1578-1588
        • Kong X.
        • Huang X.
        • Zhao M.
        • Xu B.
        • Xu R.
        • Song Y.
        • Yu Y.
        • Yang W.
        • Zhang J.
        • Liu L.
        • Zhang Y.
        • Tang G.
        • Wang B.
        • Hou F.F.
        • Li P.
        • Cheng X.
        • Zhao S.
        • Wang X.
        • Qin X.
        • Li J.
        • Huo Y.
        Platelet count affects efficacy of folic acid in preventing first stroke.
        J Am Coll Cardiol. 2018; 71: 2136-2146
        • Riba R.
        • Nicolaou A.
        • Troxler M.
        • Homer-Vaniasinkam S.
        • Naseem K.M.
        Altered platelet reactivity in peripheral vascular disease complicated with elevated plasma homocysteine levels.
        Atherosclerosis. 2004; 175: 69-75
        • Spencer C.G.
        • Martin S.C.
        • Felmeden D.C.
        • Blann A.D.
        • Beevers G.D.
        • Lip G.Y.
        Relationship of homocysteine to markers of platelet and endothelial activation in "high risk" hypertensives: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial.
        Int J Cardiol. 2004; 94: 293-300
        • Sloan A.
        • Gona P.
        • Johnson A.D.
        Cardiovascular correlates of platelet count and volume in the Framingham Heart Study.
        Ann Epidemiol. 2015; 25: 492-498
        • Zhang J.
        • Li J.
        • Chen S.
        • Gao L.
        • Yan X.
        • Zhang M.
        • Yu J.
        • Wang F.
        • Peng H.
        Modification of platelet count on the association between homocysteine and blood pressure: a moderation analysis in Chinese hypertensive patients.
        Int J Hypertens. 2020; 20205983574
        • Yang B.
        • Fan S.
        • Zhi X.
        • Wang Y.
        • Wang Y.
        • Zheng Q.
        • Sun G.
        Prevalence of hyperhomocysteinemia in China: a systematic review and meta-analysis.
        Nutrients. 2015; 7: 74-90
        • Hallqvist J.
        • Ahlbom A.
        • Diderichsen F.
        • Reuterwall C.
        How to evaluate interaction between causes: a review of practices in cardiovascular epidemiology.
        J Intern Med. 1996; 239: 377-382
        • Coppola A.
        • Davi G.
        • De Stefano V.
        • Mancini F.P.
        • Cerbone A.M.
        • Di Minno G.
        Homocysteine, coagulation, platelet function, and thrombosis.
        Semin Thromb Hemost. 2000; 26: 243-254
        • He S.
        • Lei W.
        • Li J.
        • Yu K.
        • Yu Y.
        • Zhou L.
        • Zhang X.
        • He M.
        • Guo H.
        • Yang H.
        • Wu T.
        Relation of platelet parameters with incident cardiovascular disease (the dongfeng-Tongji cohort study).
        Am J Cardiol. 2019; 123: 239-248
        • Faeh D.
        • Chiolero A.
        • Paccaud F.
        Homocysteine as a risk factor for cardiovascular disease: should we (still) worry about?.
        Swiss Med Wkly. 2006; 136: 745-756
        • Hozyasz K.K.
        • Mostowska A.
        • Szaflarska-Poplawska A.
        • Lianeri M.
        • Jagodzinski P.P.
        Polymorphic variants of genes involved in homocysteine metabolism in celiac disease.
        Mol Biol Rep. 2012; 39: 3123-3130
        • Dusitanond P.
        • Eikelboom J.W.
        • Hankey G.J.
        • Thom J.
        • Gilmore G.
        • Loh K.
        • Yi Q.
        • Klijn C.J.
        • Langton P.
        • van Bockxmeer F.M.
        • Baker R.
        • Jamrozik K.
        Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous transient ischemic attack or stroke: a randomized substudy of the VITATOPS trial.
        Stroke. 2005; 36: 144-146
        • Toole J.F.
        • Malinow M.R.
        • Chambless L.E.
        • Spence J.D.
        • Pettigrew L.C.
        • Howard V.J.
        • Sides E.G.
        • Wang C.H.
        • Stampfer M.
        Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial.
        JAMA. 2004; 291: 565-575
        • Lonn E.
        • Yusuf S.
        • Arnold M.J.
        • Sheridan P.
        • Pogue J.
        • Micks M.
        • McQueen M.J.
        • Probstfield J.
        • Fodor G.
        • Held C.
        • Genest Jr., J.
        Homocysteine lowering with folic acid and B vitamins in vascular disease.
        N Engl J Med. 2006; 354: 1567-1577
        • Wang L.
        • Cui W.
        • Nan G.
        • Yu Y.
        Meta-analysis reveals protective effects of vitamin B on stroke patients.
        Transl Neurosci. 2015; 6: 150-156
        • Ji Y.
        • Tan S.
        • Xu Y.
        • Chandra A.
        • Shi C.
        • Song B.
        • Qin J.
        • Gao Y.
        Vitamin B supplementation, homocysteine levels, and the risk of cerebrovascular disease: a meta-analysis.
        Neurology. 2013; 81: 1298-1307
        • Sansanayudh N.
        • Anothaisintawee T.
        • Muntham D.
        • McEvoy M.
        • Attia J.
        • Thakkinstian A.
        Mean platelet volume and coronary artery disease: a systematic review and meta-analysis.
        Int J Cardiol. 2014; 175: 433-440
        • Gheissari A.
        • Dehghan B.
        • Ghaed Sharafi B.
        • Abedini A.
        • Merrikhi A.
        • Madihi Y.
        • Mehrkash M.
        Importance of mean platelet volume in predicting cardiac mechanics parameters and carotid-intima media thickness in children with end-stage renal disease and comparison with healthy children.
        Ther Apher Dial Off Peer Reviewed J Int Soc Apheresis Jpn Soc Apheresis Jpn Soc Dialysis Ther. 2019; 23: 451-459
        • He S.
        • Lei W.
        • Li J.
        • Yu K.
        • Yu Y.
        • Zhou L.
        • Zhang X.
        • He M.
        • Guo H.
        • Yang H.
        • Wu T.
        Relation of platelet parameters with incident cardiovascular disease (the dongfeng-Tongji cohort study).
        Am J Cardiol. 2019; 123: 239-248
        • Ibrahim H.
        • Kleiman N.S.
        Platelet pathophysiology, pharmacology, and function in coronary artery disease.
        Coron Artery Dis. 2017; 28: 614-623
        • Vagdatli E.
        • Gounari E.
        • Lazaridou E.
        • Katsibourlia E.
        • Tsikopoulou F.
        • Labrianou I.
        Platelet distribution width: a simple, practical and specific marker of activation of coagulation.
        Hippokratia. 2010; 14: 28-32
        • Citirik M.
        • Beyazyildiz E.
        • Simsek M.
        • Beyazyildiz O.
        • Haznedaroglu I.C.
        MPV may reflect subcinical platelet activation in diabetic patients with and without diabetic retinopathy.
        Eye. 2015; 29: 376-379
        • Wu W.
        • Liu J.
        • Yu H.
        • Jiang Z.
        Antiplatelet therapy with or without PPIs for the secondary prevention of cardiovascular diseases in patients at high risk of upper gastrointestinal bleeding: a systematic review and meta-analysis.
        Exp Ther Med. 2020; 19: 3595-3603
        • Tsoumani M.E.
        • Tatsidou P.T.
        • Ntalas I.V.
        • Goudevenos J.A.
        • Tselepis A.D.
        Dynamic platelet adhesion in patients with an acute coronary syndrome: the effect of antiplatelet therapy.
        Platelets. 2016; 27: 812-820
        • Sibbing D.
        • Schulz S.
        • Braun S.
        • Morath T.
        • Stegherr J.
        • Mehilli J.
        • Schömig A.
        • von Beckerath N.
        • Kastrati A.
        Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement.
        J Thromb Haemostasis JTH. 2010; 8: 250-256
        • Haungsaithong R.
        • Udommongkol C.
        • Nidhinandana S.
        • Chairungsaris P.
        • Chinvarun Y.
        • Suwantamee J.
        • Sithinamsuwan P.
        The changes in mean platelet volume after using of antiplatelet drugs in acute ischemic stroke: a randomized controlled trial.
        J Med Assoc Thailand Chotmaihet Thangphaet. 2015; 98: 852-857
        • Hankey G.J.
        • Eikelboom J.W.
        • Yi Q.
        • Lees K.R.
        • Chen C.
        • Xavier D.
        • Navarro J.C.
        • Ranawaka U.K.
        • Uddin W.
        • Ricci S.
        • Gommans J.
        • Schmidt R.
        • Vts group
        Antiplatelet therapy and the effects of B vitamins in patients with previous stroke or transient ischaemic attack: a post-hoc subanalysis of VITATOPS, a randomised, placebo-controlled trial.
        Lancet Neurol. 2012; 11: 512-520