Advertisement

Influence of smoking and smoking cessation on biomarkers of endothelial function and their association with mortality

  • Graciela E. Delgado
    Affiliations
    Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
    Search for articles by this author
  • Bernhard K. Krämer
    Affiliations
    Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

    European Center for Angioscience ECAS, Medical Faculty Mannheim of the University Heidelberg, Mannheim, Germany
    Search for articles by this author
  • Rüdiger Siekmeier
    Affiliations
    Drug Regulatory Affairs, Pharmaceutical Institute, Bonn University, Bonn, Germany
    Search for articles by this author
  • Babak Yazdani
    Affiliations
    Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
    Search for articles by this author
  • Winfried März
    Affiliations
    Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

    Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Graz, Austria

    SYNLAB Academy, SYNLAB Holding Deutschland GmbH, Augsburg and Mannheim, Germany
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
    Jan Leipe
    Correspondence
    Corresponding author. Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

    Division of Rheumatology and Clinical Immunology, Medizinische Klinik and Poliklinik IV, University of Munich, 80336 Munich, Germany
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
    Marcus E. Kleber
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

    European Center for Angioscience ECAS, Medical Faculty Mannheim of the University Heidelberg, Mannheim, Germany
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.

      Highlights

      • Smokers exhibited higher concentrations of sICAM-1, sE-selectin, sP-selectin.
      • Smokers exhibited lower concentrations of sL-selectin and sVCAM-1.
      • sL-selectin was reduced even after 20 years of smoking abstinence.
      • sL-selectin was inversely associated with mortality in active smokers.
      • sL-selectin significantly improved risk prediction in smokers.

      Abstract

      Background and aims

      Endothelial dysfunction precedes atherosclerosis and smoking is a well-known risk factor for the development of endothelial dysfunction. The aim of our study was to analyse the effect of smoking on circulating markers of endothelial function and to investigate whether such effects have an influence on the potential use of these markers to estimate cardiovascular risk.

      Methods

      Stratified for smoking, levels of sE-/sP-/sL-selectin, von Willebrand (vWF), sICAM-1 and sVCAM-1, their association with mortality using Cox regression, and their accuracy of risk prediction using area-under-the-ROC-curve and net-reclassification-index were analysed in 1926 participants from the Ludwigshafen Risk and Cardiovascular Health (LURIC) – a prospective case-control study in patients who underwent coronary angiography with a median mortality follow-up of 10.6 years.

      Results

      In smokers, higher concentrations of sICAM-1, sE-selectin sP-selectin, but lower concentrations of sL-selectin and sVCAM-1, were detected compared to never-smokers. A direct association with mortality was found for levels of sICAM-1, sVCAM-1 and vWF regardless of smoking. Low sL-selectin levels were inversely associated with mortality in heavy and light smokers, with hazard ratios of 0.72 and 0.67 per 1-SD increase, adjusted for cardiovascular risk factors. Adding sL-selectin to a model based on traditional risk factors significantly improved AUC from 0.725 to 0.752 (p = 0.034) with an NRI of 43% (16.9%–62.3%).

      Conclusions

      Smoking alters the concentration of circulating markers of endothelial function. sL-selectin is decreased in smokers, inversely associated with risk, and could be a useful marker to improve risk prediction.

      Graphical abstract

      Keywords

      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

        • Bonetti P.O.
        • Lerman L.O.
        • Lerman A.
        Endothelial dysfunction: a marker of atherosclerotic risk.
        Arterioscler. Thromb. Vasc. Biol. 2003; 23: 168-175
        • Galley H.F.
        • Webster N.R.
        Physiology of the endothelium.
        Br. J. Anaesth. 2004; 93: 105-113
        • Messner B.
        • Bernhard D.
        Smoking and cardiovascular disease: mechanisms of endothelial dysfunction and early atherogenesis.
        Arterioscler. Thromb. Vasc. Biol. 2014; 34: 509-515
        • Csiszar A.
        • Podlutsky A.
        • Wolin M.S.
        • et al.
        Oxidative stress and accelerated vascular aging: implications for cigarette smoking.
        Front. Biosci. 2009; 14: 3128-3144
        • Sugiura T.
        • Dohi Y.
        • Takase H.
        • et al.
        Oxidative stress is closely associated with increased arterial stiffness, especially in aged male smokers without previous cardiovascular events: a cross-sectional study.
        J. Atheroscler. Thromb. 2017; 24: 1186-1198
        • Carnevale R.
        • Sciarretta S.
        • Violi F.
        • et al.
        Acute impact of tobacco vs electronic cigarette smoking on oxidative stress and vascular function.
        Chest. 2016; 150: 606-612
        • Celermajer D.S.
        • Sorensen K.E.
        • Georgakopoulos D.
        • et al.
        Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults.
        Circulation. 1993; 88: 2149-2155
        • Collaborators, GBDRF
        Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.
        Lancet. 2018; 392: 1923-1994
        • Halvorsen B.
        • Lund Sagen E.
        • Ueland T.
        • et al.
        Effect of smoking cessation on markers of inflammation and endothelial cell activation among individuals with high risk for cardiovascular disease.
        Scand. J. Clin. Lab. Investig. 2007; 67: 604-611
        • Gearing A.J.
        • Newman W.
        Circulating adhesion molecules in disease.
        Immunol. today. 1993; 14: 506-512
        • Garton K.J.
        • Gough P.J.
        • Raines E.W.
        Emerging roles for ectodomain shedding in the regulation of inflammatory responses.
        J. Leukoc. Biol. 2006; 79: 1105-1116
        • Tardif J.C.
        • Tanguay J.F.
        • Wright S.R.
        • et al.
        Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-ST-segment elevation myocardial infarction: results of the SELECT-ACS trial.
        J. Am. Coll. Cardiol. 2013; 61: 2048-2055
        • Swirski F.K.
        • Nahrendorf M.
        Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure.
        Science. 2013; 339: 161-166
        • Winkelmann B.R.
        • Marz W.
        • Boehm B.O.
        • et al.
        Rationale and design of the LURIC study--a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease.
        Pharmacogenomics. 2001; 2: S1-73
        • Cosentino F.
        • Grant P.J.
        • Aboyans V.
        • et al.
        ESC Guidelines on Diabetes, Pre-diabetes, and Cardiovascular Diseases Developed in Collaboration with the EASD.
        European heart journal, 2019 (2019)
        • Kim S.
        Overview of cotinine cutoff values for smoking status classification.
        Int. J. Environ. Res. Public Health. 2016; 13: 1236
        • Benowitz N.L.
        • Bernert J.T.
        • Foulds J.
        • et al.
        Biochemical verification of tobacco use and abstinence: 2019 update.
        Nicotine Tob. Res.: Off. J. Soc. Res. Nicotine Tob. 2019;
        • Tukey J.W.
        • Ciminera J.L.
        • Heyse J.F.
        Testing the statistical certainty of a response to increasing doses of a drug.
        Biometrics. 1985; 41: 295-301
        • R Core Team
        R: A Language and Environment for Statistical Computing.
        Foundation for Statistical Computing, Vienna, Austria2018
        • Olivera D.S.
        • Boggs S.E.
        • Beenhouwer C.
        • et al.
        Cellular mechanisms of mainstream cigarette smoke-induced lung epithelial tight junction permeability changes in vitro.
        Inhal. Toxicol. 2007; 19: 13-22
        • Bergmann S.
        • Siekmeier R.
        • Mix C.
        • et al.
        Even moderate cigarette smoking influences the pattern of circulating monocytes and the concentration of sICAM-1.
        Respir. Physiol. 1998; 114: 269-275
        • Scott D.A.
        • Stapleton J.A.
        • Wilson R.F.
        • et al.
        Dramatic decline in circulating intercellular adhesion molecule-1 concentration on quitting tobacco smoking.
        Blood Cells Mol. Dis. 2000; 26: 255-258
        • Tsai J.S.
        • Guo F.R.
        • Chen S.C.
        • et al.
        Changes of serum adiponectin and soluble intercellular adhesion molecule-1 concentrations after smoking cessation, Clinical chemistry and laboratory medicine.
        CCLM/FESCC. 2012; 50: 1063-1069
        • Xue C.
        • Chen Q.Z.
        • Bian L.
        • et al.
        Effects of smoking cessation with nicotine replacement therapy on vascular endothelial function, arterial stiffness, and inflammation response in healthy smokers.
        Angiology. 2019; (3319719853458)
        • Palmer R.M.
        • Stapleton J.A.
        • Sutherland G.
        • et al.
        Effect of nicotine replacement and quitting smoking on circulating adhesion molecule profiles (sICAM-1, sCD44v5, sCD44v6).
        Eur. J. Clin. Investig. 2002; 32: 852-857
        • Spencer C.G.
        • Gurney D.
        • Blann A.D.
        • et al.
        Von Willebrand factor, soluble P-selectin, and target organ damage in hypertension: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).
        Hypertension. 2002; 40: 61-66
        • Osterud B.
        • Elvevoll E.O.
        • Brox J.
        • et al.
        Haemostatic parameters related to lipids and adhesion molecules.
        Blood Coagul. Fibrinolysis: Int. J. Haemostasis Thrombosis. 1999; 10: 465-470
        • Takeuchi N.
        • Kawamura T.
        • Kanai A.
        • et al.
        The effect of cigarette smoking on soluble adhesion molecules in middle-aged patients with Type 2 diabetes mellitus.
        Diabet. Med.: J. Br. Diabet. Assoc. 2002; 19: 57-64
        • Roldan V.
        • Marin F.
        • Lip G.Y.
        • et al.
        Soluble E-selectin in cardiovascular disease and its risk factors. A review of the literature.
        Thromb. Haemost. 2003; 90: 1007-1020
        • Berardi C.
        • Decker P.A.
        • Kirsch P.S.
        • et al.
        Plasma and serum L-selectin and clinical and subclinical cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA).
        Transl. Res.: J. Lab. Clin. Med. 2014; 163: 585-592
        • Scott D.A.
        • Palmer R.M.
        The influence of tobacco smoking on adhesion molecule profiles.
        Tob. Induc. Dis. 2002; 1: 7-25
        • Kleber M.E.
        • Siekmeier R.
        • Delgado G.
        • et al.
        C-reactive protein and lipoprotein-associated phospholipase A2 in smokers and nonsmokers of the Ludwigshafen Risk and Cardiovascular Health study.
        Adv. Exp. Med. Biol. 2015; 832: 15-23
        • Wannamethee S.G.
        • Lowe G.D.
        • Shaper A.G.
        • et al.
        Associations between cigarette smoking, pipe/cigar smoking, and smoking cessation, and haemostatic and inflammatory markers for cardiovascular disease.
        Eur. Heart J. 2005; 26: 1765-1773
        • Gallus S.
        • Lugo A.
        • Suatoni P.
        • et al.
        Effect of tobacco smoking cessation on C-reactive protein levels in A cohort of low-dose computed tomography screening participants.
        Sci. Rep. 2018; 8: 12908
        • Pedersen K.M.
        • Colak Y.
        • Ellervik C.
        • et al.
        Smoking and increased white and red blood cells.
        Arterioscler. Thromb. Vasc. Biol. 2019; 39: 965-977
        • Kawada T.
        Smoking-induced leukocytosis can persist after cessation of smoking.
        Arch. Med. Res. 2004; 35: 246-250
        • Mehta H.
        • Nazzal K.
        • Sadikot R.T.
        Cigarette smoking and innate immunity.
        Inflamm. Res. 2008; 57: 497-503
        • Qiu F.
        • Liang C.L.
        • Liu H.
        • et al.
        Impacts of cigarette smoking on immune responsiveness: up and down or upside down?.
        Oncotarget. 2017; 8: 268-284
        • Jaspers I.
        Cigarette smoke effects on innate immune mechanisms in the nasal mucosa. Potential effects on the microbiome.
        Ann Am Thorac Soc. 2014; 11: S38-42
        • Boldt J.
        • Wollbruck M.
        • Kuhn D.
        • et al.
        Do plasma levels of circulating soluble adhesion molecules differ between surviving and nonsurviving critically ill patients?.
        Chest. 1995; 107: 787-792
        • Tchalla A.
        • Wellenius G.A.
        • Boyer S.
        • et al.
        High levels of an endothelial dysfunction marker (sVCAM-1) are associated with injurious and recurrent falls and mortality over a 5-year interval in an older population.
        Exp. Gerontol. 2018; 106: 1-7
        • Rozenberg I.
        • Sluka S.H.
        • Mocharla P.
        • et al.
        Deletion of L-selectin increases atherosclerosis development in ApoE-/- mice.
        PLoS One. 2011; 6 (e21675)
        • Fassbender K.
        • Mossner R.
        • Motsch L.
        • et al.
        Circulating selectin- and immunoglobulin-type adhesion molecules in acute ischemic stroke.
        Stroke: J. Cereb. Circulation. 1995; 26: 1361-1364
        • Albertini J.P.
        • Valensi P.
        • Lormeau B.
        • et al.
        Soluble L-selectin level is a marker for coronary artery disease in type 2 diabetic patients.
        Diabetes Care. 1999; 22: 2044-2048
        • Patiar S.
        • Slade D.
        • Kirkpatrick U.
        • et al.
        Smoking causes a dose-dependent increase in granulocyte-bound L-selectin.
        Thromb. Res. 2002; 106: 1-6
        • Schwab N.
        • Schneider-Hohendorf T.
        • Posevitz V.
        • et al.
        L-selectin is a possible biomarker for individual PML risk in natalizumab-treated MS patients.
        Neurology. 2013; 81: 865-871
        • Schwab N.
        • Schneider-Hohendorf T.
        • Pignolet B.
        • et al.
        PML risk stratification using anti-JCV antibody index and L-selectin.
        Mult. Scler. 2016; 22: 1048-1060
        • Lieberman L.A.
        • Zeng W.
        • Singh C.
        • et al.
        CD62L is not a reliable biomarker for predicting PML risk in natalizumab-treated R-MS patients.
        Neurology. 2016; 86: 375-381
        • Wei Y.S.
        • Lan Y.
        • Meng L.Q.
        • et al.
        The association of L-selectin polymorphisms with L-selectin serum levels and risk of ischemic stroke.
        J. Thromb. Thrombolysis. 2011; 32: 110-115
        • Siminiak T.
        • Smielecki J.
        • Dye J.F.
        • et al.
        Increased release of the soluble form of the adhesion molecules L-selectin and ICAM-1 but not E-selectin during attacks of angina pectoris.
        Heart Vessel. 1998; 13: 189-194
        • Atalar E.
        • Aytemir K.
        • Haznedaroglu I.
        • et al.
        Increased plasma levels of soluble selectins in patients with unstable angina.
        Int. J. Cardiol. 2001; 78: 69-73
        • Gregorczyk-Maga I.
        • Maga M.
        • Wachsmann A.
        • et al.
        Air pollution may affect the assessment of smoking habits by exhaled carbon monoxide measurements.
        Environ. Res. 2019; 172: 258-265
        • McDonagh E.M.
        • Wassenaar C.
        • David S.P.
        • et al.
        PharmGKB summary: very important pharmacogene information for cytochrome P-450, family 2, subfamily A, polypeptide 6.
        Pharmacogenet. Genom. 2012; 22: 695-708