Coronary Vasomotor Function Is Abnormal in First-Degree Relatives of Patients With Type 2 Diabetes KUMIKO HIRATA, MD 1 AMUDHA KADIRVELU, MB, PHD 2 MARCO DI TULLIO, MD 1 SHUNICHI HOMMA, MD, FACC 1 ANNA MARIA CHOY, MB, FRCP, FACC 1,3 CHIM C. LANG, MD, FRCP, FACC 1,3 N ondiabetic first-degree relatives of patients with type 2 diabetes are at increased risk of developing diabe- tes (1) and cardiovascular disease (CVD) (2). Endothelial dysfunction is regarded as an early step in the development of ath- erosclerosis (3). Abnormal peripheral en- dothelial dysfunction detected by flow- mediated, endothelium-dependent, forearm-mediated dilatation (FMD) has been reported in first-degree relatives (4,5). The abnormal FMD could not be explained by confounding variables in- cluding age, sex, ethnicity, obesity, lipids, blood pressure, glycemia, or insulin resis- tance (5). However, endothelial dysfunc- tion detected in brachial arteries may not reflect the condition of the coronary vasculature, as brachial and coronary cir- culations differ in terms of the microvas- cular architecture, pattern of blood flow, their metabolic regulation, and the path- ways that are activated to induce hyperemia (6). Coronary flow reserve measurement has been considered to be a useful physi- ologic index for coronary circulation (6). In this study, we report for the first time impaired coronary flow reserve in young nonobese normoglycemic first-degree rel- atives compared with healthy control subjects. RESEARCH DESIGN AND METHODS — The study subjects were healthy volunteers recruited by ad- vertisements for the University of Malaya. All gave written informed consent to par- ticipate in the study, which was approved by the local ethics committee. To be eligi- ble as a first-degree relative, subjects had to have one or more parent with type 2 diabetes. To avoid any confounding influ- ence on endothelial function, subjects were excluded if they had a history of smoking, manifest type 2 diabetes, hyper- tension, hypercholesterolemia (serum cholesterol 6.5 mmol/l), and concur- rent CVD, including current or previous history of myocardial infarction and an- gina. None were on regular medication. At the screening visit, subjects underwent a standard 75-g oral glucose tolerance test (OGTT), and those with impaired glucose tolerance (IGT) according to American Diabetes Association criteria (7) were identified. On the first visit, subjects were stud- ied following an overnight fast and had the following procedures: a blood draw, an OGTT, and measurement of FMD. Blood was drawn for measurement of serum glucose, lipids, serum inflamma- tory markers (interleukin-6 [IL-6] and high-sensitivity C-reactive protein), and soluble intercellular adhesion molecule-1 (sICAM-1), a measure of endothelial cell activation (8). Following the blood draw, a standard OGTT was performed with ve- nous blood sampling at 0, 15, 30, 60, 90, and 120 min to measure plasma glucose and serum insulin and to allow determi- nation of insulin resistance using the ho- meostatic model of insulin resistance (9). Following the OGTT, peripheral endo- thelial function was determined using the FMD method as described by Celermajer et al. (10). Subjects returned for a second study visit to assess the coronary flow re- serve. Coronary flow reserve was assessed by transthoracic Doppler echocardiogra- phy as we previously described (11,12). In women, investigations were made dur- ing the menstrual phase because the men- strual cycle may affect vascular reactivity (12). In brief, echocardiography was per- formed with the Acuson Sequoia 512 (Siemens Medical Solutions USA, Moun- tain View, CA) initially using a 3.5-MHz probe to assess left ventricular structure and function. None had left ventricular hypertrophy, and all had normal left ven- tricular function. Thereafter, a 7.0-MHz transducer was used to visualize coronary blood flow in the left anterior descending coronary artery by color Doppler echo- cardiography. Baseline spectral Doppler signals were recorded in the distal portion of the left anterior descending coronary artery over five cardiac cycles at end expi- ration by transthoracic Doppler echocar- diography. Intravenous adenosine was then administered (140 g  kg -1  min -1 i.v.) for 2 min to record spectral Doppler signals during hyperemic conditions. Mean diastolic velocities were measured at baseline and peak hyperemic condi- tions measured from the Doppler signal recordings. Measurements were averaged over three cardiac cycles. Coronary flow reserve velocity (CFVR) was defined as the ratio of hyperemic to basal mean dia- stolic velocity. All echocardiographic as- sessments were performed and analyzed by an experienced investigator (K.H.) who was blinded to the clinical informa- tion of the subjects. ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the 1 Department of Medicine, Columbia University, New York, New York; the 2 Department of Med- icine, University of Malaya, Kuala Lumpur, Malaysia; and the 3 Department of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee, Scotland, U.K. Address correspondence and reprint requests to Professor Chim C. Lang, MD, FRCP, FACC, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, U.K. E-mail: c.c.lang@dundee.ac.uk. Received for publication 21 July 2006 and accepted in revised form 30 September 2006. Abbreviations: CFVR, coronary flow velocity reserve; CVD, cardiovascular disease; FMD, forearm- mediated dilatation; IGT, impaired glucose tolerance; IL-6, interleukin-6; OGTT, oral glucose tolerance test; sICAM-1, soluble intercellular adhesion molecule-1. A table elsewhere in this issue shows conventional and Syste `me International (SI) units and conversion factors for many substances. DOI: 10.2337/dc06-1529 © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Pathophysiology/Complications B R I E F R E P O R T 150 DIABETES CARE, VOLUME 30, NUMBER 1, JANUARY 2007 Downloaded from http://diabetesjournals.org/care/article-pdf/30/1/150/594138/zdc00107000150.pdf by guest on 16 November 2023