Circulating concentrations of endothelin-1 predict coronary heart disease in women but not in men: a longitudinal observational study in the Vara-Skövde Cohort

Bledar Daka, Josefin Olausson, Charlotte A Larsson, Margareta I Hellgren, Lennart Råstam, Per-Anders Jansson, Ulf Lindblad, Bledar Daka, Josefin Olausson, Charlotte A Larsson, Margareta I Hellgren, Lennart Råstam, Per-Anders Jansson, Ulf Lindblad

Abstract

Background: The vasoconstricting peptide endothelin-1 has been proposed to be a marker of cardiovascular disease. Our aim was to investigate whether circulating endothelin-1 levels predict coronary heart disease (CHD) in Sweden.

Methods: In 2002-2005, 2816 adult participants (30-74 years) were randomly selected from two municipalities in south-western Sweden. Cardiovascular risk factors and endothelin-1 levels were assessed at baseline, and incident CHD was followed-up in all participants through 2011. After exclusion of 50 participants due to known CHD at baseline and 21 participants because of unsuccessful analysis of endothelin-1, 2745 participants were included in the study. In total, 72 CHD events (52 in men and 20 in women) were registered during the follow-up time.

Results: We showed that baseline circulating endothelin-1 levels were higher in women with incident CHD than in women without CHD (3.2 pg/ml, SE: 0.36 vs 2.4 pg/ml, SE: 0.03, p = 0.003) whereas this difference was not observed in men (2.3 pg/ml, SE: 0.16 vs 2.3 pg/ml, SE: 0.04, p = 0.828). An age-adjusted Cox proportional regression analysis showed an enhanced risk of CHD with increasing baseline endothelin-1 levels in women (hazard ratio (HR) = 1.51, 95 % CI = 1.1-2.1, p = 0.015) but not in men (HR = 0.98, 95 % CI = 0.8-1.2, p = 0.854). Furthermore, the predictive value of endothelin-1 for incident CHD in women was still significant after adjustments for age, HOMA-IR, apolipoprotein (apo)B/apoA1 and smoking (HR = 1.53, CI = 1.1-1.2, p = 0.024).

Conclusion: Circulating endothelin-1 levels may predict CHD in women.

Figures

Fig 1
Fig 1
Schematic overview of study design and follow-up of the study. CHD; coronary heart disease, ET-1; endothelin-1, PCI; percutaneous coronary intervention, CABG; coronary artery bypass grafting
Fig 2
Fig 2
Circulating concentrations of endothelin-1 at baseline separated by age in the Vara-Skövde Cohort in (a) men and (b) women. c Endothelin-1 levels at baseline comparing participants with incident CHD (men n = 52, women n = 20) and participants without coronary heart disease (CHD) (men n = 1307, women n = 1386) at the follow-up. General linear model was used in statistical analyses, mean ± SEM
Fig 3
Fig 3
Kaplan-Meier survival plots comparing time to the first coronary heart disease (CHD) event between participants with the highest tertile of endothelin-1 (ET-1) and the remaining population in (a) men (highest tertile n = 453, two lower tertiles combined n = 906) and (b) women (highest tertile n = 469, two lower tertiles combined n = 938). + = Censored

References

    1. Faxon DP, Creager MA, Smith SC, Jr, Pasternak RC, Olin JW, Bettmann MA, et al. Atherosclerotic Vascular Disease Conference: Executive summary: Atherosclerotic Vascular Disease Conference proceeding for healthcare professionals from a special writing group of the American Heart Association. Circulation. 2004;109:2595–604. doi: 10.1161/01.CIR.0000128517.52533.DB.
    1. Nichols M, Townsend N, Scarborough P, Rayner M. Cardiovascular disease in Europe 2014: epidemiological update. Eur Heart J. 2014;35(42):2929. doi: 10.1093/eurheartj/ehu378.
    1. Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003;23:168–75. doi: 10.1161/01.ATV.0000051384.43104.FC.
    1. Moreau P. Endothelin in hypertension: a role for receptor antagonists? Cardiovasc Res. 1998;39:534–42. doi: 10.1016/S0008-6363(98)00154-0.
    1. Zeiher AM, Goebel H, Schachinger V, Ihling C. Tissue endothelin-1 immunoreactivity in the active coronary atherosclerotic plaque. A clue to the mechanism of increased vasoreactivity of the culprit lesion in unstable angina. Circulation. 1995;91:941–7. doi: 10.1161/01.CIR.91.4.941.
    1. Zouridakis EG, Schwartzman R, Garcia-Moll X, Cox ID, Fredericks S, Holt DW, et al. Increased plasma endothelin levels in angina patients with rapid coronary artery disease progression. Eur Heart J. 2001;22:1578–84. doi: 10.1053/euhj.2000.2588.
    1. Kanaya AM, Barrett-Connor E, Wassel Fyr CL. Endothelin-1 and prevalent coronary heart disease in older men and women (the Rancho Bernardo Study) Am J Cardiol. 2007;99:486–90. doi: 10.1016/j.amjcard.2006.09.096.
    1. Ruo B, Tripputi MT, Hsue PY, Saigo M, Ouyang P, Waters DD. Usefulness of serum endothelin levels in predicting death and myocardial infarction but not coronary progression in postmenopausal women with coronary disease (from the Women’s Angiographic Vitamin and Estrogen [WAVE] study) Am J Cardiol. 2005;96:335–8. doi: 10.1016/j.amjcard.2005.03.071.
    1. Novo G, Sansone A, Rizzo M, Guarneri FP, Pernice C, Novo S. High plasma levels of endothelin-1 enhance the predictive value of preclinical atherosclerosis for future cerebrovascular and cardiovascular events: a 20-year prospective study. J Cardiovasc Med (Hagerstown) 2014;15:696–701. doi: 10.2459/JCM.0000000000000121.
    1. Larsson CA, Daka B, Gullberg B, Rastam L, Lindblad U. Clusters of AMI risk factors and their association with left ventricular hypertrophy: a population-based study within the Skaraborg Project, Sweden. Int J Cardiol. 2013;168:5416–21. doi: 10.1016/j.ijcard.2013.08.047.
    1. Hellgren MI, Daka B, Jansson PA, Lindblad U, Larsson CA. Insulin resistance predicts early cardiovascular morbidity in men without diabetes mellitus, with effect modification by physical activity. Eur J Prev Cardiol. 2015;22(7):940–9. doi: 10.1177/2047487314537917.
    1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206-52. [PubMed].
    1. Haffner SM, Miettinen H, Stern MP. The homeostasis model in the San Antonio Heart Study. Diabetes Care. 1997;20:1087–92. doi: 10.2337/diacare.20.7.1087.
    1. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998;15:539–53. doi: 10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>;2-S.
    1. Andersen L, Dinesen B, Jorgensen PN, Poulsen F, Roder ME. Enzyme immunoassay for intact human insulin in serum or plasma. Clin Chem. 1993;39:578–82.
    1. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84:3666–72. doi: 10.1210/jcem.84.10.6079.
    1. Rinaldi S, Geay A, Dechaud H, Biessy C, Zeleniuch-Jacquotte A, Akhmedkhanov A, et al. Validity of free testosterone and free estradiol determinations in serum samples from postmenopausal women by theoretical calculations. Cancer Epidemiol Biomarkers Prev. 2002;11:1065–71.
    1. Merlo J, Lindblad U, Pessah-Rasmussen H, Hedblad B, Rastam J, Isacsson SO, et al. Comparison of different procedures to identify probable cases of myocardial infarction and stroke in two Swedish prospective cohort studies using local and national routine registers. Eur J Epidemiol. 2000;16:235–43. doi: 10.1023/A:1007634722658.
    1. Lindblad U, Rastam L, Ranstam J, Peterson M. Validity of register data on acute myocardial infarction and acute stroke: the Skaraborg Hypertension Project. Scand J Soc Med. 1993;21:3–9.
    1. Melander O, Newton-Cheh C, Almgren P, Hedblad B, Berglund G, Engstrom G, et al. Novel and conventional biomarkers for prediction of incident cardiovascular events in the community. JAMA. 2009;302:49–57. doi: 10.1001/jama.2009.943.
    1. Polderman KH, Stehouwer CD, van Kamp GJ, Dekker GA, Verheugt FW, Gooren LJ. Influence of sex hormones on plasma endothelin levels. Ann Intern Med. 1993;118:429–32. doi: 10.7326/0003-4819-118-6-199303150-00006.
    1. Morey AK, Razandi M, Pedram A, Hu RM, Prins BA, Levin ER. Oestrogen and progesterone inhibit the stimulated production of endothelin-1. Biochem J. 1998;330(Pt 3):1097–105. doi: 10.1042/bj3301097.
    1. Lin CL, Dumont AS, Wu SC, Wang CJ, Howng SL, Huang YF, et al. 17beta-estradiol inhibits endothelin-1 production and attenuates cerebral vasospasm after experimental subarachnoid hemorrhage. Exp Biol Med (Maywood) 2006;231:1054–7.
    1. Ding D, Starke RM, Dumont AS, Owens GK, Hasan DM, Chalouhi N, et al. Therapeutic implications of estrogen for cerebral vasospasm and delayed cerebral ischemia induced by aneurysmal subarachnoid hemorrhage. Biomed Res Int. 2014;2014:727428.
    1. Caballero AE, Arora S, Saouaf R, Lim SC, Smakowski P, Park JY, et al. Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes. 1999;48:1856–62. doi: 10.2337/diabetes.48.9.1856.
    1. Maeda S, Tanabe T, Miyauchi T, Otsuki T, Sugawara J, Iemitsu M, et al. Aerobic exercise training reduces plasma endothelin-1 concentration in older women. J Appl Physiol (1985) 2003;95:336–41. doi: 10.1152/japplphysiol.01016.2002.
    1. Schiffrin EL. State-of-the-Art lecture. Role of endothelin-1 in hypertension. Hypertension. 1999;34:876–81. doi: 10.1161/01.HYP.34.4.876.
    1. Shichiri M, Hirata Y, Ando K, Emori T, Ohta K, Kimoto S, et al. Plasma endothelin levels in hypertension and chronic renal failure. Hypertension. 1990;15:493–6. doi: 10.1161/01.HYP.15.5.493.
    1. Schneider MP, Boesen EI, Pollock DM. Contrasting actions of endothelin ET(A) and ET(B) receptors in cardiovascular disease. Annu Rev Pharmacol Toxicol. 2007;47:731–59. doi: 10.1146/annurev.pharmtox.47.120505.105134.
    1. Hiatt WR, Stoll S, Nies AS. Effect of beta-adrenergic blockers on the peripheral circulation in patients with peripheral vascular disease. Circulation. 1985;72:1226–31. doi: 10.1161/01.CIR.72.6.1226.
    1. Ingram DM, House AK, Thompson GH, Stacey MC, Castleden WM, Lovegrove FT. Beta-adrenergic blockade and peripheral vascular disease. Med J Aust. 1982;1:509–11.
    1. Wedel H, Demets D, Deedwania P, Fagerberg B, Goldstein S, Gottlieb S, et al. Challenges of subgroup analyses in multinational clinical trials: experiences from the MERIT-HF trial. Am Heart J. 2001;142:502–11. doi: 10.1067/mhj.2001.117600.

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