Advertisement

Myeloperoxidase levels predict accelerated progression of coronary atherosclerosis in diabetic patients: Insights from intravascular ultrasound

  • Author Footnotes
    1 Present address: South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA 5000, Australia.
    Yu Kataoka
    Correspondence
    Corresponding author. Tel.: +61 8 8116 4426.
    Footnotes
    1 Present address: South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA 5000, Australia.
    Affiliations
    Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Search for articles by this author
  • Mingyuan Shao
    Affiliations
    Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Search for articles by this author
  • Kathy Wolski
    Affiliations
    Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Search for articles by this author
  • Author Footnotes
    1 Present address: South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA 5000, Australia.
    Kiyoko Uno
    Footnotes
    1 Present address: South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA 5000, Australia.
    Affiliations
    Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Search for articles by this author
  • Rishi Puri
    Affiliations
    Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Search for articles by this author
  • E. Murat Tuzcu
    Affiliations
    Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Search for articles by this author
  • Stanley L. Hazen
    Affiliations
    Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA

    Department of Cell Biology, Cleveland Clinic and the Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Search for articles by this author
  • Steven E. Nissen
    Affiliations
    Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Search for articles by this author
  • Author Footnotes
    1 Present address: South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA 5000, Australia.
    Stephen J. Nicholls
    Footnotes
    1 Present address: South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA 5000, Australia.
    Affiliations
    Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Search for articles by this author
  • Author Footnotes
    1 Present address: South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA 5000, Australia.

      Highlights

      • We analyze the impact of MPO on plaque progression by intravascular ultrasound.
      • Increasing MPO level contributes to plaque progression in diabetics.
      • LDL-C lowering results in less progression in diabetics with low MPO level.
      • High-dose statin prevents plaque progression in diabetics with low MPO level.
      • These benefits are diminished in diabetics with high MPO level.

      Abstract

      Objective

      While inflammation has been proposed to contribute to the adverse cardiovascular outcome in diabetic patients, the specific pathways involved have not been elucidated. The leukocyte derived product, myeloperoxidase (MPO), has been implicated in all stages of atherosclerosis. The relationship between MPO and accelerated disease progression observed in diabetic patients has not been studied.

      Methods

      We investigated the relationship between MPO and disease progression in diabetic patients. 881 patients with angiographic coronary artery disease underwent serial evaluation of atherosclerotic burden with intravascular ultrasound. Disease progression in diabetic (n = 199) and non-diabetic (n = 682) patients, stratified by baseline MPO levels was investigated.

      Results

      MPO levels were similar in patients with and without diabetes (1362 vs. 1255 pmol/L, p = 0.43). No relationship was observed between increasing quartiles of MPO and either baseline (p = 0.81) or serial changes (p = 0.43) in levels of percent atheroma volume (PAV) in non-diabetic patients. In contrast, increasing MPO quartiles were associated with accelerated PAV progression in diabetic patients (p = 0.03). While optimal control of lipid and the use of high-dose statin were associated with less disease progression, a greater benefit was observed in diabetic patients with lower compared with higher MPO levels at baseline.

      Conclusions

      Increasing MPO levels are associated with greater progression of atherosclerosis in diabetic patients. This finding indicates the potential importance of MPO pathways in diabetic cardiovascular disease.

      Keywords

      Abbreviations:

      CAD (coronary artery disease), DM (diabetes mellitus), EEM (external elastic membrane), HDL (high-density lipoprotein), hsCRP (high sensitivity C-reactive protein), IVUS (intravascular ultrasound), LDL (low-density lipoprotein), MPO (myeloperoxidase), PAV (percent atheroma volume)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Huxley R.
        • Barzi F.
        • Woodward M.
        Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies.
        BMJ. 2006; 332: 73-78
        • Ho J.E.
        • Paultre F.
        • Mosca L.
        • Women's Pooling Project
        Is diabetes mellitus a cardiovascular disease risk equivalent for fatal stroke in women? Data from the Women's Pooling Project.
        Stroke. 2003; 34: 2812-2816
        • Nicholls S.J.
        • Tuzcu E.M.
        • Kalidindi S.
        • et al.
        Effect of diabetes on progression of coronary atherosclerosis and arterial remodeling: a pooled analysis of 5 intravascular ultrasound trials.
        J Am Coll Cardiol. 2008; 52: 255-262
        • Stamler J.
        • Vaccaro O.
        • Neaton J.D.
        • Wentworth D.
        Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.
        Diabetes Care. 1993; 16: 434-444
        • Duncan B.B.
        • Schmidt M.I.
        • Pankow J.S.
        • Atherosclerosis Risk in Communities Study
        • et al.
        Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study.
        Diabetes. 2003; 52: 1799-1805
        • Haffner S.M.
        Insulin resistance, inflammation, and the prediabetic state.
        Am J Cardiol. 2003; 92: 18J-26J
        • Moreno P.R.
        • Fuster V.
        New aspects in the pathogenesis of diabetic atherosclerosis.
        J Am Coll Cardiol. 2004; 44: 2293-2300
        • Koh K.K.
        • Han S.H.
        • Quon M.J.
        Inflammatory markers and the metabolic syndrome: insights from therapeutic interventions.
        J Am Coll Cardiol. 2005; 46: 1978-1985
        • Moreno P.R.
        • Murcia A.M.
        • Palacios I.F.
        • et al.
        Coronary composition and macrophage infiltration in atherectomy specimens from patients with diabetes mellitus.
        Circulation. 2000; 102: 2180-2184
        • Burke A.P.
        • Kolodgie F.D.
        • Zieske A.
        • et al.
        Morphologic findings of coronary atherosclerotic plaques in diabetics: a postmortem study.
        Arterioscler Thromb Vasc Biol. 2004; 24: 1266-1271
        • Mita T.
        • Watada H.
        • Uchino H.
        • et al.
        Association of C-reactive protein with early-stage carotid atherosclerosis in Japanese patients with early-stage type 2 diabetes mellitus.
        Endocr J. 2006; 53: 693-698
        • Sander D.
        • Schulze-Horn C.
        • Bickel H.
        • Gnahn H.
        • Bartels E.
        • Conrad B.
        Combined effects of hemoglobin A1c and C-reactive protein on the progression of subclinical carotid atherosclerosis: the INVADE study.
        Stroke. 2006; 37: 351-357
        • Nicholls S.J.
        • Hazen S.L.
        Myeloperoxidase and cardiovascular disease.
        Arterioscler Thromb Vasc Biol. 2005; 25: 1102-1111
        • Nicholls S.J.
        • Hazen S.L.
        Myeloperoxidase, modified lipoproteins, and atherogenesis.
        J Lipid Res. 2009; 50: S346-S351
        • Klebanoff S.J.
        Oxygen metabolism and the toxic properties of phagocytes.
        Ann Intern Med. 1980; 93: 480-489
        • Rausch P.G.
        • Pryzwansky K.B.
        • Spitznagel J.K.
        Immunocytochemicalidentification of azurophilic and specific granule markers in the giant granules of Chediak-Higashi neutrophils.
        N Engl J Med. 1978; 298: 693-698
        • Baldus S.
        • Eiserich J.P.
        • Brennan M.L.
        • Jackson R.M.
        • Alexander C.B.
        • Freeman B.A.
        Spatial mapping of pulmonary and vascular nitrotyrosinereveals the pivotal role of myeloperoxidase as a catalyst for tyrosine nitration in inflammatory diseases.
        Free Radic Biol Med. 2002; 33: 1010
        • Baldus S.
        • Eiserich J.P.
        • Mani A.
        • et al.
        Endothelial transcytosis of myeloperoxidase confers specificity to vascular ECM proteins as targets of tyrosine nitration.
        J Clin Invest. 2001; 108: 1759-1770
        • Hazen S.L.
        • Heinecke J.W.
        3-Chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima.
        J Clin Invest. 1997; 99: 2075-2081
        • Podrez E.A.
        • Schmitt D.
        • Hoff H.F.
        • Hazen S.L.
        Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro.
        J Clin Invest. 1999; 103: 1547-1560
        • Zheng L.
        • Nukuna B.
        • Brennan M.L.
        • et al.
        Apolipoprotein A-1 is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subject with cardiovascular disease.
        J Clin Invest. 2004; 114: 529-541
        • Shao B.
        • Oda M.N.
        • Bergt C.
        • et al.
        Myeloperoxidase impairs ABCA1-dependent cholesterol efflux through methionine oxidation and site-specific tyrosine chlorination of apolipoprotein A-I.
        J Biol Chem. 2006; 281: 9001-9004
        • Undurti A.
        • Huang Y.
        • Lupica J.A.
        • Smith J.D.
        • DiDonato J.A.
        • Hazen S.L.
        Modification of high density lipoprotein by myeloperoxidase generates a pro-inflammatory particle.
        J Biol Chem. 2009; 284: 30825-30835
        • Eiserich J.P.
        • Baldus S.
        • Brennan M.L.
        • et al.
        Myeloperoxidase, a leukocyte-derived vascular NO oxidase.
        Science. 2002; 296: 2391-2394
        • Vita J.A.
        • Brennan M.L.
        • Gokce N.
        • et al.
        Serum myeloperoxidase levels independently predict endothelial dysfunction in humans.
        Circulation. 2004; 110: 1134-1139
        • Abu-Soud H.M.
        • Hazen S.L.
        Nitric oxide modulates the catalytic activity of myeloperoxidase.
        J Biol Chem. 2000; 275: 5425-5430
        • Sorrentino S.A.
        • Besler C.
        • Rohrer L.
        • et al.
        Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy.
        Circulation. 2010; 121: 110-122
        • Nicholls S.J.
        • Tuzcu E.M.
        • Sipahi I.
        • Schoenhagen P.
        • Nissen S.E.
        Intravascular ultrasound in cardiovascular medicine.
        Circulation. 2006; 114: e55-e59
        • Nissen S.E.
        • Tuzcu E.M.
        • Schoenhagen P.
        • REVERSAL Investigators
        • et al.
        Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.
        JAMA. 2004; 291: 1071-1080
        • Nissen S.E.
        • Tuzcu E.M.
        • Libby P.
        • CAMELOT Investigators
        • et al.
        Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial.
        JAMA. 2004; 292: 2217-2225
        • Nissen S.E.
        • Tuzcu E.M.
        • Brewer H.B.
        • ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE) Investigators
        • et al.
        Effect of ACAT inhibition on the progression of coronary atherosclerosis.
        N Engl J Med. 2006; 354: 1253-1263
        • Nicholls S.J.
        • Tang W.H.
        • Brennan D.
        • et al.
        Risk prediction with serial myeloperoxidase monitoring in patients with acute chest pain.
        Clin Chem. 2011; 57: 1762-1770
        • Brennan M.L.
        • Penn M.S.
        • Van Lente F.
        • et al.
        Prognostic value of myeloperoxidase in patients with chest pain.
        N Engl J Med. 2003; 349: 1595-1604
        • Baldus S.
        • Heeschen C.
        • Meinertz T.
        • CAPTURE Investigators
        • et al.
        Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes.
        Circulation. 2003; 108: 1440-1445
        • Meuwese M.C.
        • Stroes E.S.
        • Hazen S.L.
        • et al.
        Serum myeloperoxidase levels are associated with the future risk of coronary artery disease in apparently healthy individuals: the EPIC-Norfolk Prospective Population Study.
        J Am Coll Cardiol. 2007; 50: 159-165
        • Zhang R.
        • Brennan M.L.
        • Fu X.
        • et al.
        Association between myeloperoxidase levels and risk of coronary artery disease.
        JAMA. 2001; 286: 2136-2142
        • Heslop C.L.
        • Frohlich J.J.
        • Hill J.S.
        Myeloperoxidase and C-reactive protein have combined utility for long-term prediction of cardiovascular mortality after coronary angiography.
        J Am Coll Cardiol. 2010; 55: 1102-1109
        • Zhang C.
        • Yang J.
        • Jennings L.K.
        Leukocyte-derived myeloperoxidase amplifies high-glucose-induced endothelial dysfunction through interaction with high-glucose-stimulated, vascular non-leukocyte-derived reactive oxygen species.
        Diabetes. 2004; 53: 2950-2959
        • Nicholls S.J.
        • Hsu A.
        • Wolski K.
        • et al.
        Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome.
        J Am Coll Cardiol. 2010; 55: 2399-2407