title: Endothelial dysfunction plays a key role in increasing cardiovascular risk in type 2 diabetes: the Hoorn study.
abstract: In the pathogenesis of cardiovascular events, interaction between risk factors has seldom been identified. However, endothelial dysfunction on the one hand and type 2 diabetes mellitus, impaired glucose metabolism (IGM), and insulin resistance on the other may act synergistically (ie, interact) in the development of cardiovascular disease. We therefore investigated the interaction between endothelial dysfunction and type 2 diabetes mellitus, IGM, and insulin resistance with regard to risk of cardiovascular events. In a prospective population-based cohort (n=445; 69 years; 55% women; 23% type 2 diabetes mellitus, 28% IGM [by design]), endothelial dysfunction (brachial artery flow-mediated dilatation), glucose tolerance (oral glucose tolerance test), and insulin sensitivity (homeostasis model assessment for insulin resistance [HOMA2-IR]) were determined. After a median follow-up of 7.6 years, 106 participants had had a cardiovascular event. After adjustments, 1 SD less flow-mediated dilatation was associated with cardiovascular events in type 2 diabetes mellitus (hazard ratio 1.69 [95% confidence interval, 1.14-2.52]) and IGM (1.50 [0.95-2.37]) and among those in the highest HOMA2-IR tertile (1.92 [1.42-2.60]), but not in normal glucose metabolism (0.85 [0.63-1.16]) or among those in the lower 2 HOMA2-IR tertiles combined (0.85 [0.65-1.12]). Interaction between flow-mediated dilatation and type 2 diabetes mellitus, IGM, or insulin resistance was present on an additive (relative excess risk caused by interaction>0) and on a multiplicative scale (P interaction<0.05). Endothelial dysfunction and type 2 diabetes mellitus, IGM, or insulin resistance synergistically increase cardiovascular event risk. This identifies endothelial dysfunction as a key therapeutic target in these individuals.
authors.affiliation: From the Department of Medicine (T.T.v.S., R.M.A.H., M.T.S., C.D.A.S.), Cardiovascular Research Institute Maastricht (T.T.v.S., R.M.A.H., T.U., M.T.S., C.D.A.S.), and School for Nutrition, Toxicology and Metabolism (T.T.v.S.), Maastricht University Medical Centre, Maastricht, the Netherlands; and EMGO Institute for Health and Care Research (J.M.D., G.N.) and Department of Epidemiology and Biostatistics (J.M.D.), VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Thomas T
authors.initials: TT
authors.lastname: van Sloten
authors.affiliation: From the Department of Medicine (T.T.v.S., R.M.A.H., M.T.S., C.D.A.S.), Cardiovascular Research Institute Maastricht (T.T.v.S., R.M.A.H., T.U., M.T.S., C.D.A.S.), and School for Nutrition, Toxicology and Metabolism (T.T.v.S.), Maastricht University Medical Centre, Maastricht, the Netherlands; and EMGO Institute for Health and Care Research (J.M.D., G.N.) and Department of Epidemiology and Biostatistics (J.M.D.), VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Ronald M A
authors.initials: RM
authors.lastname: Henry
authors.affiliation: From the Department of Medicine (T.T.v.S., R.M.A.H., M.T.S., C.D.A.S.), Cardiovascular Research Institute Maastricht (T.T.v.S., R.M.A.H., T.U., M.T.S., C.D.A.S.), and School for Nutrition, Toxicology and Metabolism (T.T.v.S.), Maastricht University Medical Centre, Maastricht, the Netherlands; and EMGO Institute for Health and Care Research (J.M.D., G.N.) and Department of Epidemiology and Biostatistics (J.M.D.), VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Dekker
authors.affiliation: From the Department of Medicine (T.T.v.S., R.M.A.H., M.T.S., C.D.A.S.), Cardiovascular Research Institute Maastricht (T.T.v.S., R.M.A.H., T.U., M.T.S., C.D.A.S.), and School for Nutrition, Toxicology and Metabolism (T.T.v.S.), Maastricht University Medical Centre, Maastricht, the Netherlands; and EMGO Institute for Health and Care Research (J.M.D., G.N.) and Department of Epidemiology and Biostatistics (J.M.D.), VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Giel
authors.initials: G
authors.lastname: Nijpels
authors.affiliation: From the Department of Medicine (T.T.v.S., R.M.A.H., M.T.S., C.D.A.S.), Cardiovascular Research Institute Maastricht (T.T.v.S., R.M.A.H., T.U., M.T.S., C.D.A.S.), and School for Nutrition, Toxicology and Metabolism (T.T.v.S.), Maastricht University Medical Centre, Maastricht, the Netherlands; and EMGO Institute for Health and Care Research (J.M.D., G.N.) and Department of Epidemiology and Biostatistics (J.M.D.), VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.affiliation: From the Department of Medicine (T.T.v.S., R.M.A.H., M.T.S., C.D.A.S.), Cardiovascular Research Institute Maastricht (T.T.v.S., R.M.A.H., T.U., M.T.S., C.D.A.S.), and School for Nutrition, Toxicology and Metabolism (T.T.v.S.), Maastricht University Medical Centre, Maastricht, the Netherlands; and EMGO Institute for Health and Care Research (J.M.D., G.N.) and Department of Epidemiology and Biostatistics (J.M.D.), VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Miranda T
authors.initials: MT
authors.lastname: Schram
authors.affiliation: From the Department of Medicine (T.T.v.S., R.M.A.H., M.T.S., C.D.A.S.), Cardiovascular Research Institute Maastricht (T.T.v.S., R.M.A.H., T.U., M.T.S., C.D.A.S.), and School for Nutrition, Toxicology and Metabolism (T.T.v.S.), Maastricht University Medical Centre, Maastricht, the Netherlands; and EMGO Institute for Health and Care Research (J.M.D., G.N.) and Department of Epidemiology and Biostatistics (J.M.D.), VU University Medical Centre, Amsterdam, the Netherlands. cda.stehouwer@mumc.nl.
authors.forename: Coen D A
authors.initials: CD
authors.lastname: Stehouwer
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D001916:Brachial Artery / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000209:etiology / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007333:Insulin Resistance; D008297:Male; D009426:Netherlands / Q000453:epidemiology; D011159:Population Surveillance / Q000379:methods*; D011446:Prospective Studies; D012307:Risk Factors; D013997:Time Factors; D014655:Vascular Resistance / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology*
chemical_list: D001786:Blood Glucose
keywords: cardiovascular diseases; endothelium; epidemiology; insulin resistance; prospective studies; type 2 diabetes mellitus