대한안과학회지 2016 년제 57 권제 7 호 J Korean Ophthalmol Soc 2016;57(7):1102-1108 ISSN 0378-6471 (Print) ISSN 2092-9374 (Online) http://dx.doi.org/10.3341/jkos.2016.57.7.1102 Original Article 한국인의건강검진에서발견되는대사증후군의구성요소와망막혈관변화와의관계 Association between Metabolic Syndrome and Retinal Vascular Changes in Koreans based on Health Check-ups 정경도 김재석 Kyeong Do Jeong, MD, Jae Suk Kim, MD, PhD 인제대학교상계백병원안과학교실 Department of Ophthalmology, Inje University Sanggye Paik Hospital, Seoul, Korea Purpose: To evaluate the associations between components of metabolic syndrome and retinal vascular changes in a Korean population based on data collected at health check-ups. Methods: Fundus photographs of 381 patients participating in a health check-up were examined to identify central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and arteriovenous ratio (AVR) by IVAN software. Retinal hemorrhage, arteriovenous nicking, and retinal exudate were also noted. The association between metabolic syndrome and each component was then analyzed. Results: Significant associations were shown between metabolic syndrome and CRAE (p = 0.032), central obesity and CRAE (p = 0.037), triglyceride and CRAE (p = 0.011), and triglyceride and AVR (p = 0.005), in addition to central obesity and arteriovenous nicking (odds ratio [OR] = 2.68, p = 0.013), central obesity and retinal exudate (OR = 2.30, p = 0.038), serum glucose and retinal hemorrhage (OR = 8.06, p = 0.030), and blood pressure and arteriovenous nicking (OR = 2.78, p = 0.007). Conclusions: Metabolic syndrome showed a significant relationship with retinal artery diameter. Central obesity showed the greatest relationship with retinal vascular changes among each of the components of metabolic syndrome. J Korean Ophthalmol Soc 2016;57(7):1102-1108 Keywords: Metabolic syndrome, Retinal artery, Retinal hemorrhage, Retinal vein 대사증후군은심혈관질환과제2형당뇨병의위험도를증가시키는복부비만, 고혈당증, 고혈압, 이상지혈증등의대사위험요인이군집성으로존재하는상태이다. 1-3 대사증후군의유병률은연구들마다차이가있지만미국성인에서는 24%, 한국성인에서는약 11-19% 로보고되고있다. 4,5 Received: 2016. 3. 10. Revised: 2016. 4. 30. Accepted: 2016. 6. 23. Address reprint requests to Jae Suk Kim, MD, PhD Department of Ophthalmology, Inje University Sanggye Paik Hospital, #1342 Dongil-ro, Nowon-gu, Seoul 01757, Korea Tel: 82-2-950-1096, Fax: 82-2-935-6904 E-mail: 991027js@hanmail.net 대사증후군및각요소는심혈관질환과당뇨병발병률의위험도, 동맥경화를증가시킬수있다고알려져있으며, 최근에는미세혈관에도영향을줄수있다고보고되고있다. 6-8 망막은인체에서미세혈관을직접관찰할수있는유일한조직이다. 안저검사로망막과망막혈관을직접관찰하여미세혈관의병적변화를알수있다. 특히고해상도의안저사진은망막혈관의주행과방향, 굵기, 동정맥교차, 출혈, 삼출물등의병적변화를쉽게관찰할수있어망막혈관질환의진단에도움이된다. 이전연구에서고혈압, 심부전, 관상동맥질환, 뇌졸중, 당뇨, 고혈당등이망막혈관의직경에미치는영향에대해서보고가되었으며, 9-21 미 c2016 The Korean Ophthalmological Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 1102
- 정경도 김재석 : 대사증후군과망막혈관변화와의관계 - 국, 일본, 중국에서는 Atherosclerosis Risk in Communities (ARIC) study, Funagata study 등을통해대사증후군이망막혈관직경및망막출혈, 동정맥함요, 삼출물등의망막미세혈관변화와관련있다고보고되었다. 18,22,23 최근에는종합건강검진시대사증후군과관계된검사를시행하여조기에발견하고있으며, 대부분안과질환에대한선별검사로안저사진을촬영하고있다. 본연구에서는한국인에서대사증후군의구성요소와망막혈관의변화에대해기존에보고된바가없기에, 건강검진자료를활용하여대사증후군의구성요소와망막혈관변화와의관계를알아보고자하였다. 대상과방법 2014년 1월 1일부터 2014년 4월 30일까지인제대학교상계백병원종합건강검진센터에서건강검진을위하여내원한환자중무산동안저촬영을시행한 321명을대상으로후향적으로의무기록을분석하였고, 본원임상시험윤리위원회로부터심사면제판정을받았다. 과거력상다른전신질환을진단받은적이없는 20-80세를대상으로하며, 기존에망막변성, 망막혈관폐쇄, 나이관련황반변성등의망막질환, 포도막염, 유리체출혈, 유리체혼탁등의매체혼탁으로안저사진판독이어려운경우는제외하였다. 대상자들은암실에서안저사진촬영기 (TRC-NW200, Topcon, Tokyo, Japan) 로양안에서황반을중심으로 45 범위의안저를촬영하였다. 촬영한안저사진은이미지관리프로그램 (IMAGEnet2000, Topcon, Tokyo, Japan) 을이용하여압축하지않은 1,500 1,500 픽셀크기의 Tagged Image File (TIF) 로추출하였다. 모든안저사진의분석은환자의정보를모르는 1명의검사자에의하여시행되었다. 검사자는안저사진에서망막출혈유무, 동정맥함요유무, 망막삼출물유무를확인하였다. 망막혈관직경은반자동화망막혈관분석컴퓨터프로그램 (Interactive Vessel Analysis, IVAN; University of Wisconsin-Madison, Madison, WI, USA) 을이용하여디지털안저사진을분석하여측정하였다. 프로그램은안저사진에서시신경유두를인식하여시신경유두경계로부터 0.5에서 1 유두직경사이의범위에있는망막혈관을자동으로찾아낸다. 시신경유두의위치가잘못되거나망막혈관의종류와범위가틀린경우에는수동으로보정하였으며, 인식된망막혈관은자동으로직경이측정되고측정치에대한분석이이루어진다. Leung et al 24 의연구에서양안의망막혈관직경에유의한차이가없었다는보고를참고하여, 본연구에서는우안의안저사진을분석하는것을원칙 Figure 1. Fundus photograph centered at the optic disc of left eye, grader analysis measures arteries and veins, the largest six arteries (red) and veins (blue) are used to calculate the central retinal artery equivalent and central retinal vein equivalent by the Big 6 method. Yellow line is the vessel indicator of the IVAN. DD = disc diameter. 으로하고, 우안의안저사진화질이분석에적합하지않은경우좌안의안저사진을분석하였다. 망막혈관직경의계산은분석범위내의망막동맥과정맥중각각의가장굵은 6개의직경을계산하는 Big 6 법을이용하여이루어졌다. 25,26 망막동맥의직경은 central retinal artery equivalent (CRAE), 망막정맥의직경은 central retinal vein equivalent (CRVE), arteriovenous ratio (AVR) 는 CRAE/CRVE로망막혈관의동정맥비율을나타내는값으로 IVAN 프로그램은망막혈관을설정하면 CRAE, CRVE, AVR을자동으로측정해준다 (Fig. 1). 키와몸무게는신발을벗은상태로가벼운옷차림으로측정하였으며허리둘레는배꼽위치에서측정하였다. 모든대상자는 10시간공복을시행후혈액을채취하였으며혈당, 중성지방, 고밀도콜레스테롤은혈액검사장비 (AU5800, Beckman Coulter, Brea, CA, USA) 를이용하여측정하였다. 혈압은앉은자세로 5분간휴식을시행한후자동혈압계 (FT-500, Jawon Medical, Guri, Korea) 로측정하였다. 대사증후군의정의는 National Cholesterol Education Program Adult Treatment Panel III (NCEP III) 를참고하여다음중 3가지이상을만족하는경우로정하였다. 2 - 복부비만 central obesity: 남성 90 cm 이상, 여성 85 cm 이상 - 중성지방 triglyceride: 150 mg/dl 이상 1103
- 대한안과학회지 2016 년제 57 권제 7 호 - Table 1. Demographics of participants with or without metabolic syndrome, defined with National Cholesterol Education Program Adult Treatment Panel III (NCEP III) criteria Metabolic syndrome Present (N = 52) Absent (N = 269) p-value * Age (years) 58.5 ± 10.8 54.6 ± 10.0 0.012 Gender (% male) 37 (71.2) 165 (59.5) 0.122 Height (kg) 165.8 ± 9.7 163.8 ± 8.7 0.135 Weight (cm) 73.9 ± 11.8 64.6 ± 10.2 <0.001 Body mass index (kg/m2) 26.8 ± 2.7 24.0 ± 2.6 <0.001 Waist circumference (cm) 89.9 ± 7.15 79.7 ± 8.5 <0.001 Systolic blood pressure (mm Hg) 129.4 ± 6.1 119.5 ± 9.7 <0.001 Diastolic blood pressure (mm Hg) 78.1 ± 5.6 74.3 ± 5.9 <0.001 Triglyceride (mg/dl) 189.2 ± 84.0 114.2 ± 66.8 <0.001 HDL cholesterol (mg/dl) 40.9 ± 7.6 51.5 ± 10.7 <0.001 Fasting glucose (mg/dl) 118.3 ± 36.0 94.5 ± 14.6 <0.001 Values are presented as mean ± SD unless otherwise indicated. HDL = high density lipoprotein. * Independent t-test. Table 2. Relationship of retinal vascular calibers with metabolic syndrome factors CRAE (μm) CRVE (μm) AVR Waist circumference 90 cm (M), 85 cm (F) 144.63 ± 18.56 209.00 ± 25.30 0.70 ± 0.11 <90 cm (M), <85 cm (F) 150.85 ± 17.26 211.85 ± 20.42 0.72 ± 0.09 p-value 0.037 0.602 0.250 Triglyceride 150 mg/dl 144.80 ± 16.10 212.06 ± 20.27 0.69 ± 0.08 <150 mg/dl 151.07 ± 17.98 210.95 ± 22.02 0.72 ± 0.10 p-value 0.011 0.566 0.005 HDL cholesterol 40 mg/dl (M), 50 mg/dl (F) 149.45 ± 18.08 210.75 ± 21.52 0.71 ± 0.09 >40 mg/dl (M), >50 mg/dl (F) 149.50 ± 17.60 211.41 ± 21.63 0.71 ± 0.09 p-value 0.994 0.864 0.958 Glucose 110 mg/dl 146.49 ± 16.51 213.07 ± 24.06 0.69 ± 0.08 <110 mg/dl 149.93 ± 17.86 210.96 ± 21.21 0.72 ± 0.10 p-value 0.543 0.279 0.169 Blood pressure 130/85 mm Hg 147.77 ± 16.90 209.21 ± 25.03 0.71 ± 0.10 <130/85 mm Hg 150.65 ± 18.18 212.58 ± 18.83 0.71 ± 0.09 p-value 0.360 0.316 0.755 Metabolic syndrome Yes 144.08 ± 15.83 209.99 ± 22.30 0.69 ± 0.08 No 150.54 ± 17.89 211.47 ± 21.46 0.72 ± 0.10 p-value 0.032 0.750 0.084 Values are presented as mean ± SD unless otherwise indicated. All components are adjusted for age and gender. CRAE = central retinal artery equivalent; CRVE = central retinal vein equivalent; AVR = arteriovenous ratio; M = male; F = female; HDL = high density lipoprotein. - 고밀도콜레스테롤 high density lipoprotein (HDL) cholesterol: 남성 40 mg/dl 미만, 여성 50 mg/dl 미만 - 공복혈당 fasting plasma glucose: 110 mg/dl 이상 - 혈압 blood pressure: 130/85 mmhg 이상각군간의 CRAE, CRVE, AVR의비교를위해공분산분석, 각군간의망막출혈여부, 동정맥함요여부, 망막 삼출물여부의비교를위해로지스틱회귀분석을통계프로그램 Statistical Analysis Software (SAS) version 5.1 (SAS Institute Inc., Cary, NC, USA) 로분석하였으며, p-value가 0.05 미만인경우를통계적으로의미있는것으로해석하였다. 모든분석은연령과성별을보정하여시행하였다. 1104
- 정경도 김재석 : 대사증후군과망막혈관변화와의관계 - Table 3. Odds ratio (95% confidence interval) for components of metabolic syndrome Retinal hemorrhage Arteriovenous nicking Retinal exudate Waist circumference 0.59 (0.06-5.58) 2.68 (1.23-5.83) 2.30 (1.06-4.03) 90 cm (M), 85 cm (F) p = 0.642 p = 0.013 p = 0.038 Triglyceride 1.89 (0.31-11.65) 0.98 (0.44-2.20) 0.68 (0.26-1.78) 150 mg/dl p = 0.493 p = 0.957 p = 0.431 HDL-cholesterol 0.60 (0.07-5.54) 0.95 (0.44-2.08) 0.57 (0.22-1.49) 40 mg/dl (M), 50 mg/dl (F) p = 0.654 p = 0.898 p = 0.250 Glucose 8.06 (1.22-53.05) 0.78 (0.25-2.41) 1.03 (0.35-2.98) 110 mg/dl p = 0.030 p = 0.665 p = 0.962 Blood pressure 0.72 (0.12-4.56) 2.78 (1.33-5.84) 1.34 (0.60-2.98) 130/85 mm Hg p = 0.729 p = 0.007 p = 0.479 Metabolic syndrome 1.02 (0.11-9.52) 1.53 (0.64-3.66) 0.82 (0.29-2.34) p = 0.988 p = 0.337 p = 0.713 All components are adjusted for age and gender. M = male; F = female; HDL = high density lipoprotein. 결과 검사대상자전체 321명의평균연령은 55.3세 ( 최소 20 세, 최대 80세 ) 이며, 남자가 197명, 여자가 124명이다. 대사증후군각인자의 NCEP III 기준을만족하는대상자는복부비만 70명, 중성지방 81명, 고밀도콜레스테롤 89명, 공복혈당 41명, 혈압 129명으로 3가지이상을만족하는경우는 52명이다 (Table 1). 전체대상자의망막혈관직경은 CRAE 149.49 ± 17.70 μm, CRVE 211.23 ± 21.57 μm, AVR 0.71 ± 0.09이다. 대사증후군과 CRAE의감소 (p=0.032), 복부비만과 CRAE의감소 (p=0.037), 중성지방과 CRAE의감소 (p=0.011), 중성지방과 AVR의감소 (p=0.005) 는유의한관계가있었으나고밀도콜레스테롤, 공복혈당, 혈압은 CRAE, CRVE, AVR과의미있는관계를보이지않았다 (Table 2). 전체대상자들의안저사진에서망막출혈 5명, 동정맥함요 36명, 망막삼출물 29명이관찰되었다. 대사증후군과망막출혈, 동정맥함요, 망막삼출물의유무는의미있는관계를보이지않았다. 복부비만과동정맥함요 ( 교차비 2.68, p=0.013), 복부비만과망막삼출물 ( 교차비 2.30, p=0.038), 공복혈당과망막출혈 ( 교차비 8.06, p=0.030), 혈압과동정맥함요의유무 ( 교차비 2.78, p=0.007) 는유의한관계를보였다 (Table 3). 고찰 The National Cholesterol Education Program s ATP III 보고에서는대사증후군을여러가지대사위험요인을포함하는하나의군집으로보았으며, 이는심혈관을비롯한전신혈관에영향을준다고하였다. 2 본연구는대사증후군이 망막혈관에미치는영향을알아보기위해건강검진을시행한 321명의한국인을대상으로연구를진행하였다. 망막혈관과아무런관련성을보이지않은고밀도콜레스테롤을제외한대사증후군의각인자들을살펴보면다음과같다. 복부비만은 CRAE의감소, 동정맥함요, 망막삼출물의유무와연관성을보였으며중성지방은 CRAE와 AVR의감소와유의한관계를보였다. 비만상태로만든 Zucker rat을이용한동물실험에서는혈관내피의존적인혈관확장과인슐린에의해활성화되는산화질소합성이억제되어혈관수축이발생하며, 기능적인변화외에도혈관벽의경화로인한구조적인변화가동반되어동맥의협착이발생한다고보고하였다. 27 또한신체용적의증가와동반되어발생하는전체체혈량의증가와렙틴에의한미세혈관자동조절의손상또한망막혈관에영향을줄수있다고보고되었다. 28 본연구에서공복혈당은망막출혈의유무는관련성을보였으나다른인자들과는의미있는관련성을보이지않았다. Klein et al 29 은당뇨환자에서망막동맥이더가늘어진다고보고하였고 Tikellis et al 30 은망막동맥이더굵어진다고보고하였다. Curtis et al 31 은당뇨초기단계에서혈관평활근이온통로의혼란으로망막동맥의혈관수축이발생하고후기에는혈관주위세포나평활근의사멸로인한자동조절의변화로동맥혈관이확장된다고보고하였다. 당뇨환자에서망막정맥혈관두께에대한이전연구들은대부분증가하는경향을보였는데고혈당, 저산소증, 염증반응, 그리고일산화질소수치의증가가혈관확장을일으킨다고알려져있다. 21 본연구에서공복혈당과혈관직경은연관성을보이지않았는데, 이는본연구의검사대상자들은오랜기간당뇨가있던것이아니라건강검진에서공복혈당의상승이처음발견되었기때문에기존연구들과차이를보인것으로생각된다. 1105
- 대한안과학회지 2016 년제 57 권제 7 호 - 혈압이높은군에서동정맥함요가나타날가능성이높으나다른인자들과의미있는관계를보이지않았다. Liew et al 19 이조사한모든연구들에서는혈압이높을수록동맥직경은가늘어진다고보고하였다. 고혈압이정맥두께에미치는영향은이전연구들에서정맥두께를넓힌다고보고하였지만일관된연관성을나타내지않았다. 32 고혈압이망막혈관두께변화에미치는병리생리학적기전은아직정확하게밝혀져있지않다. 하지만고혈압에서의세동맥두께감소는대동맥의탄성감소와연관된다고알려져있다. 33 본연구에서도동맥직경은혈압이높은군에서감소하는경향을보였으나의미있는차이를보이지는않았다 (p=0.155). 이는연구대상자들이기존에고혈압이장기간이있던상태가아니라혈압상승이처음발견되었기때문으로생각된다. 대사증후군의 3가지조건을만족하는경우에는망막동맥직경이감소하는것을확인할수있는데이는일본, 중국, 미국에서시행한연구와도일치하는부분이다. 망막동맥직경외에일본의 Funagata study와미국의 ARIC study 에서는대사증후군이있을경우망막정맥직경이증가하고동정맥함요와망막병증이발견될가능성이증가한다고하였으나본연구와중국의연구에서는망막정맥직경의증가는있으나유의한차이를보이지는않았다. 다른연구들과의차이를보이는이유는명확하지않다. 다만다른연구에서는대사증후군의진단을위해 International Diabetes Federation (IDF) 또는 NECP III criteria를각국가의사정에맞게변형하여사용하였는데이는본연구에서활용한기준과차이가있다. 일본의 Funagata study는공복혈당의기준이 100 mg/dl 이상, 복부비만의기준이남성은 85 cm 이상, 여성은 90 cm 이상을기준으로두었으며, 중국의연구는공복혈당의기준이 100 mg/dl 이상, 복부비만의기준이남성 90 cm 이상, 여성 80 cm 이상으로, 미국의 ARIC study는복부비만의기준이남성 102 cm 이상, 여성 88 cm 이상을대사증후군의기준으로삼아본연구와는차이를보인다. 이러한대사증후군의선정기준의차이때문에각연구에서대사증후군세부항목이망막미세혈관변화에미치는영향에차이를보이는것으로생각된다. 18,22,23 본연구의결과를종합하면대사증후군과각인자들중에서망막미세혈관변화와가장많은연관성을보이는것은복부비만이다. 이는대상자선정시기존에당뇨, 고혈압이있던사람을제외하였기때문으로생각된다. 혈당과혈압상승은검진시처음발견된것이므로대상자가장기간에영향을받았을가능성이낮으며, 복부비만은검진전부터기존에있었을가능성이높아장기간의망막미세혈관의변화를반영할수있을것으로생각된다. 본연구에는몇가지제한점이있다. 산동하지않은상 태에서무산동안저촬영을시행하여매체혼탁등의안구자체적인문제때문이아니라사진촬영기술의문제로연구에서배제된대상자들이있다. 그리고한쪽눈을대상으로만연구를진행하였다. 비록양안의망막혈관직경은전반적으로일치한다는연구가있으나, 24 이는망막출혈, 삼출물등과같은망막병증을저평가했을수있다. 또한본원을내원한환자만을대상으로하여다른연구에비해대상군의수가적어 (ARIC study 11,265명 18, Funagata study 1,961명 22 ) 전체인구의특성을반영하지못한다. 그리고본연구에서망막혈관분석에사용한 IVAN 프로그램은시신경유두직경을 1,850 μm로인식한후혈관의직경을구하게되어, 시신경유두직경이 1,850 μm보다클경우실제혈관직경보다작게측정되거나시신경유두직경이 1,850 μm 보다작을경우실제혈관직경보다크게측정이될수있다. 26 또한굴절이상에따른안저사진의보정을시행하지않아이러한요인들이혈관직경의측정에영향을주었을수있다. 34 대사증후군은망막동맥직경의감소와유의한관계가있다. 대사증후군의각인자들중에서복부비만은망막동맥직경의감소및동정맥함요, 망막삼출물의유무와연관이있어망막미세혈관변화와가장많은연관성을보인다. 따라서특별한병력이없어건강해보이더라도복부비만이있을경우망막미세혈관에변화가발생할수있음을염두에둬야한다. 앞으로많은인구를대상으로다양한인자들을분석하는대규모연구를통하여대사증후군의구성요소들이망막혈관변화에미치는영향에대하여알아볼필요가있을것으로생각된다. REFERENCES 1) Timar O, Sestier F, Levy E. Metabolic syndrome X: a review. Can J Cardiol 2000;16:779-89. 2) National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation 2002;106:3143-421. 3) Grundy SM, Brewer HB Jr, Cleeman JI, et al. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004;109:433-8. 4) Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287:356-9. 5) Park JS, Park HD, Yun JW, et al. Prevalence of the metabolic syndrome as defined by NCEP - ATPⅢ among the urban Korean population. Korean J Med 2002;63:290-8. 1106
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- 대한안과학회지 2016 년제 57 권제 7 호 - = 국문초록 = 한국인의건강검진에서발견되는대사증후군의구성요소와망막혈관변화와의관계 목적 : 한국인의건강검진에서발견되는대사증후군의구성요소와망막혈관변화와의관계를알아보고자하였다. 대상과방법 : 381 명을대상으로망막출혈, 동정맥함요, 망막삼출물의유무및 IVAN 프로그램으로측정한망막동맥직경, 망막정맥직경, 동정맥비율과대사증후군및각인자들과의관계를분석하였다. 결과 : 대사증후군, 복부비만, 중성지방은망막동맥직경의감소 (p=0.032, 0.037, 0.011) 와유의한관계가있었으며, 중성지방은동정맥비율의감소 (p=0.005) 와유의한관계가있었다. 복부비만과동정맥함요 ( 교차비 2.68, p=0.013), 복부비만과망막삼출물 ( 교차비 2.30, p=0.038), 혈당과망막출혈 ( 교차비 8.06, p=0.030), 혈압과동정맥함요 ( 교차비 2.78, p=0.007) 는유의한관계를보였다. 결론 : 대사증후군은망막동맥직경의감소와유의한관계가있으며, 대사증후군의구성요소중복부비만은망막미세혈관변화와가장많은연관성을보인다. < 대한안과학회지 2016;57(7):1102-1108> 1108