원저 새롭게진단된한국인제2 형당뇨병환자에서내피세포의존성 / 비의존성혈관확장반응의경동맥내중막두께와의연관성 을지의과대학교내과학교실 최정호 민경완 김효정 구보경 임채영 김현진 박강서 한경아 김응진 Relationship between Endothelial-dependent/-independent Vasodilation and Carotid Intimalmedia Thickness in Newly-diagnosed Korean Type 2 Diabetic Patients Jung-Ho Choi, Kyung Wan Min, Hyo-Jeong Kim, Bo kyung Koo, Chae Young Lim, Hyun-Jin Kim Gang Seo Pak, Kyung Ah Han, Eung Jin Kim Department of Internal Medicine, Eulji University School of Medicine Abstract Background: The relative effect of diabetes on the risk of cardiovascular disease in Asian population is much the same as that in Western populations. Although multiple atherosclerotic risk factors have been documented in Asia, precise estimates of vascular reactivity might provide more critical informations for the prevention and the control of diabetes-related cardiovascular mortality and morbidity. The aims of this study were to estimate the vascular reactivity directly and evaluate its relationship with other cardiovascular risk factors and carotid intimal-media thickness (IMT) in newly-diagnosed Korean type 2 diabetic patients. Methods: We measured flow-mediated vasodilation (FMD) and endothelial-independent vasodilation (EID) of the brachial artery using high-resolution ultrasonography in total of 121 (M; N = 68, F; N = 53) diabetic patients. We assessed conventional cardiovascular risk factors such as age, smoking, obesity, hypertension, hyperlipidemia or family history of cardiovascular disease and analyzed the association among FMD/EID with cardiovascular risk factors, carotid IMT or the total number of risk factors. Results: The mean values of age, smoking, BMI, waist, systolic blood pressure and diastolic blood pressure were 51.2 ± 12.3 years, 11.0 ± 15.8 pack years, 25.0 ± 3.2 kg/m 2, 86 ± 9 cm, 123 ± 16 mmhg and 79 ± 12 mmhg. The mean values of HbA1c, fasting blood glucose, total cholesterol, triglyceride, LDL-cholesterol and HDL-cholesterol were 8.4 ± 2.0%, 166 ± 51 mg/dl, 187 ± 37 mg/dl, 166 ± 143 mg/dl, 114 ± 30 mg/dl and 46 ± 12 mg/dl. FMD and EID were estimated by 6.1 ± 2.8% and 16.6 ± 5.6% respectively. The mean/maximal carotid IMT were 0.63 ± 0.12/0.76 ± 0.16 mm and the number of risk factors besides diabetes mellitus were 2.3 ± 1.3. After adjusting age, FMD was associated only with smoking, but EID was associated with smoking, systolic/diastolic blood pressure, mean/maximal carotid IMT and number of risk factors by partial correlations. Age, smoking and EID were independent risk variables for carotid IMT, analyzed by multiple regression test. Conclusion: These findings suggest that impaired vascular reactivity detected by EID is closely related to carotid IMT, an useful surrogate marker for atherosclerosis, in newly-diagnosed Korean type 2 diabetic patients. (J Kor Diabetes Assoc 31:498~506, 2007) Key Words: Intimal-media thickness (IMT), Endothelial-independent vasodilation (EID), Flow-mediated vasodilation (FMD), Newly-diagnosed Type 2 Diabetes 접수일자 : 2007 년 9 월 5 일, 통과일자 : 2007 년 10 월 31 일, 책임저자 : 한경아, 을지의과대학교내과학교실 * 본연구는한국당뇨병임상연구소의지원에의하여이루어진것임 498
최정호외 8 인 : 새롭게진단된한국인제 2 형당뇨병환자에서내피세포의존성 / 비의존성혈관확장반응의경동맥내중막두께와의연관성 서론제2형당뇨병환자에서는심혈관계질환이가장많은사망원인이고, 관상동맥질환, 뇌졸중, 말초혈관질환의위험이 2~4배증가하며, 조기에죽상경화가진행된다 1). 인슐린저항성과고인슐린혈증, 고혈당등이죽상경화성심혈관질환과연관되어있음이밝혀지면서당뇨병환자에서조기에죽상경화증을진단하는것에관심이모아지고있다 2). 죽상경화증을조기에진단하기위한여러가지방법중에서경동맥초음파를이용한경동맥내중막두께의측정은많은연구에서심근경색과뇌경색을포함한혈관질환의예측인자로서유용성이입증되었다 3,4). 최근내피세포의존성혈관확장반응 (Endothelial-dependent, Flow-mediated vasodilation: FMD) 에관한많은연구에서혈관내피세포기능의이상이관상동맥질환과연관되어있으며 5-7) 내피세포비의존성혈관확장반응 (Endothelial-independent vasodilation: EID, Nitrate mediated dilation: NMD) 역시성인에서죽상경화증의독립적인위험인자임이밝혀지고있다 8-11). 그러나혈관확장반응의중요한조절인자인혈관내피세포나평활근의기능이상이당뇨병환자에서조기죽상경화증을평가하는중요한예측인자인지는잘평가되어있지않다 12). 국내의경우신등이평균유병기간이 10.5년인제2형당뇨병환자들의 FMD 수치가정상대조군에비해유의하게감소되어있고 hscrp 농도와 fibrinogen이내피세포기능장애를예측하는독립적인위험인자임을보고한바있다 13). 본연구에서는새롭게진단된한국인제2형당뇨병환자에서 FMD 및 EID 를측정하고, 기존에알려진심혈관질환위험인자들및조기죽상경화증의지표로잘알려져있는경동맥내중막두께와의연관성을고찰하고자하였다. 대상및방법 1. 연구대상 2005년 10월부터 2007년 3월까지을지병원당뇨센터를내원하여새롭게제2형당뇨병을진단받은 20~80세환자들을대상으로하였다. 당뇨병의진단은 1997년미국당뇨병학회에서제시한진단기준에근거하여내원당시공복혈당이 126 mg/dl 이상이거나 75그램경구당부하검사두시간후혈당이 200 mg/dl 이상인경우로하였다. 연구에포함된대상자들은 121명 ( 남자 68명, 여자 53명 ) 이었고평균연령은 51.2 ± 12.3세였다. 2. 연구방법본연구는단일기관단면조사연구로대상환자들을 10시간금식시킨후 FMD 및 EID를시행하였고, 혈관확장반응 과기존에알려진심혈관질환위험인자들및경동맥내중막두께의연관성을평가하였다. 1) 신체계측신장및체중을측정한후체질량지수 (BMI) 는체중 (kg)/ [ 신장 (m)] 2 으로계산하였고허리둘레는마지막늑골하단과배꼽상방의가장짧은둘레를측정하였다. 혈압은대상자를 5분이상충분히안정시킨후두차례측정하여평균값을구하였다. 2) 심혈관질환위험인자평가혈관확장반응과연관성이있는인자들을분석하기위해심혈관질환의위험인자로잘알려져있는연령 (M: 45세, F: 55세 ), 흡연, 비만 (BMI 25 kg/m 2 ), 고혈압 (BP 130/80 mmhg 또는항고혈압약제복용 ), 고지혈증 [Total cholesterol 200 mg/dl 또는 triglyceride 150 mg/dl 또는 LDL cholesterol 100 mg/dl 또는 HDL-cholesterol (M: < 40 mg/dl, F: < 50 mg/dl) 또는지질강하제복용 ] 및심혈관질환의조기발병가족력 (M: < 55세, F: < 65세 ) 을조사하였다. 위험인자의수가증가할수록혈관내피세포의기능이감소하는지를평가하기위해당뇨병을제외한위험인자들을수 (N) 로산정하였다. 3) 생화학적검사대상환자들을 10시간이상금식시킨후다음날아침공복상태에서채혈하였다. 당화혈색소는 high performance liquid chromatography 법 (Tosch Gn, Japan) 을이용하여측정하였고, 공복혈당, 총콜레스테롤, 중성지방, 저밀도지단백콜레스테롤, 고밀도지단백콜레스테롤은자동분석기 (Hitachi 7150 autochemistry analyzer, Japan) 을이용하여효소법으로측정하였다. 4) 혈관내피세포의존성 / 비의존성혈관확장반응고해상도 B형초음파기기인 LOGIC 400 CL PRO (GE) 를이용하여내피세포의존성혈관확장반응 (Endothelial dependent vasodilation, Flow-mediated vasodilation, FMD) 과내피세포비의존성혈관확장반응 (Endothelial independent vasodilation, EID) 을이등 14) 과 Corretti 등 15) 이권고한방법에따라측정하였다. 검사에대한영향을배제하기위해대상자에서검사 10시간전부터음식뿐아니라알코올, 카페인, 담배를중단하도록하였고, 검사 24시간전부터칼슘길항제나베타차단제, 질산염, 안지오텐신전환효소억제제를중단하도록하였다. 대상자를최소한 10분간누운채로안정시키고오른팔을펼쳐움직이지않게한후상박동맥을팔오금 5~10 cm 상방에서 11 MHz의고해상도초음파로관찰하였다. 혈관의내측과외측이평행하게보이도록기저 499
영상을얻어도플러로혈류를확인한후동맥의기저직경을 2회측정하였다. 기저영상을얻은뒤 FMD를측정하기위해우측상박에혈압계를감은후압력을올려 180 mmhg 로 5분간유지하였고, 이후급격히압력을감소시켜반응성충혈을유발하였다. 상박동맥의혈류가증가하기시작한시점부터 50초후에혈류증가에의한혈관확장반응을초음파영상으로기록하였다. EID는 FMD를측정한후환자를 10분간안정시킨후시행하였고위와같은방법으로기저동맥의직경을다시측정하였다. 니트로글리세린 1 정 (0.4 mg) 을설하투여한시점부터 3분후에확장된동맥의두께를초음파영상으로기록하였다. 5) 경동맥내중막두께측정경동맥내중막두께는고해상도 B형초음파기기인 LOGIC 400 CL PRO (GE) 의 11 MHz 선형탐촉자를사용하여측정하였다. 오른쪽과왼쪽에서종단면을따라내경동맥, 경동맥분지, 총경동맥부위에서측정하였고 6부위의산술평균값 (mean carotid IMT) 과 6부위중최대값 (maxiamal carotid IMT) 을구하였다 16). 6) 통계분석모든자료는평균 ± 표준편차로표시하였으며통계분석은 SPSS 12.0 프로그램 (SPSS Inc, Chicago, IL) 을사용하였다. 혈관확장반응과여러심혈관질환위험인자들의연관성은 Pearsons' correlation test와 partial correlation test를이용하여분석하였으며내피세포의존성 / 비의존성혈관확 장반응및경동맥내중막두께에영향을주는독립적인위험인자는선형회귀분석을이용하여분석하였다. P value 0.05 미만을통계적으로유의성이있는것으로판정하였다. 결과 1. 대상자의임상적특성대상환자의임상적특징은표에나타내었다 (Table 1). 본연구에포함된각심혈관질환위험인자의유병률은연령인자 (M: 45, F: 55) 59.5%, 흡연인자 24.8%, 비만 (BMI 25 kg/m 2 ) 45.0%, 고혈압 (BP 130/80 mmhg 또는항고혈압약제복용 ) 42.1%, 고지혈증 [Total cholesterol 200 mg/dl 또는 triglyceride 150 mg/dl 또는 LDL cholesterol 100 mg/dl 또는 HDL-cholesterol (M: < 40 mg/dl, F: < 50 mg/dl) 또는지질강하제복용 ] 57.0% 였으며심혈관질환의가족력은 4.1% 였다 (Fig. 1A). 대상환자의심혈관질환위험인자수는 0~5개로각수에따른환자의빈도는 9.2%, 20.8%, 20.8%, 31.7%, 11.7%, 5.8% 였고 6개의위험인자를모두가진환자는없었다 (Fig. 1B). 2. 내피세포의존성혈관확장반응과여러심혈관위험인자들의연관성내피세포의존성혈관확장반응은연령 (r = -0.299, P < 0.01), 흡연갑년 (r = -0.214, P < 0.05), 수축기혈압 (r = -0.256, P < 0.01), 이완기혈압 (r = -0.218, P < 0.05), 경동 Table 1. Clinical characteristics of 121 newly diagnosed diabetic patients Mean ± S.D. Range Age (years) 51.2 ± 12.3 20 ~ 79 Smoking (pack years) 11.0 ± 15.8 0 ~ 90 BMI (kg/m 2 ) 25.0 ± 3.2 16.4 ~ 36.1 Waist circumference (cm) 86 ± 9 62 ~ 111 HbA1c (%) 8.4 ± 2.0 5.4 ~ 15.4 FPG (mg/dl) 166 ± 51 95 ~ 305 Total cholesterol (mg/dl) 187 ± 37 68 ~ 298 Triglyceride (mg/dl) 166 ± 143 33 ~ 1080 LDL cholesterol (mg/dl) 114 ± 30 54 ~ 187 HDL cholesterol (mg/dl) 46 ± 12 26 ~ 80 SBP (mmhg) 123 ± 16 90 ~ 175 DBP (mmhg) 79 ± 12 44 ~ 100 FMD (%) 6.1 ± 2.8 0.9 ~ 19.1 EID (%) 16.6 ± 5.6 7.1 ~ 34.5 Mean carotid IMT (mm) 0.63 ± 0.12 0.40 ~ 0.97 Maximal carotid IMT (mm) 0.76 ± 0.16 0.50 ~ 1.30 Number of risk factors (N) 2.3 ± 1.3 0 ~ 5 BMI, body mass index; FPG, fasting plasma glucose; SBP, systolic blood pressure; DBP, diastolic blood pressure; FMD, flow-mediated vasodilation; EID, endothelium-independent vasodilation; IMT, carotid intimal-media thickness. 500
최정호외 8 인 : 새롭게진단된한국인제 2 형당뇨병환자에서내피세포의존성 / 비의존성혈관확장반응의경동맥내중막두께와의연관성 A B Fig. 1. Prevalence of risk factors besides diabetes (A) and incidence of patients who had CVD risk factors (B). Table 2. Correlations among clinical variables with FMD or EID FMD r age-controlled (r) r age-controlled (r) Age -0.299 - -0.358 - Smoking -0.214 * -0.190 * -0.230 * -0.208 * BMI -0.108-0.140-0.028-0.071 Waist circumference -0.163-0.151-0.165-0.153 HbA1c -0.003-0.087 0.068-0.007 FPG 0.082-0.035 0.114-0.024 Total cholesterol 0.133 0.081 0.052-0.025 Ln_Triglyceride -0.061-0.099-0.068-0.129 HDL cholesterol 0.110 0.109 0.071 0.091 LDL cholesterol 0.181 * 0.173 0.148 0.118 SBP -0.256-0.170-0.305-0.203 * DBP -0.218 * -0.145-0.285-0.213 * Mean carotid IMT -0.263-0.115-0.398-0.252 Maximal carotid IMT -0.266-0.131-0.381-0.244 Number of risk factors -0.184 * -0.118-0.301-0.244 Ln_Triglyceride, Triglyceride transformed by log-scale. *P < 0.05. P < 0.01. P < 0.001. Analyzed by Pearsons' correlation test (r) and partial correlations [age-controlled(r)]. EID 맥내중막두께의평균값 (r = -0.263, P < 0.01) 과최대값 (r = -0.266, P < 0.01), 심혈관질환위험인자수 (r = -0.184, P < 0.05) 와음의상관관계가있었고, 저밀도지단백콜레스테롤과는양의상관관계가있었다 (r = 0.181, P < 0.05). 연령을보정하였을때내피세포의존성혈관확장반응은흡연과음의상관관계가있었다 (r = -0.190, P < 0.05) (Table 2). 3. 내피세포비의존성혈관확장반응과여러심혈관위험인자들의연관성내피세포비의존성혈관확장반응은연령 (r = -0.358, P < 0.001), 흡연갑년 (r = -0.230, P < 0.05), 수축기혈압 (r = -0.305, P < 0.01), 이완기혈압 (r = -0.285, P < 0.01), 경동맥내중막두께의평균값 (r = -0.398, P < 0.001) 과최대값 (r = -0.381, P < 0.001), 심혈관질환위험인자수 (r = -0.301, P < 0.01) 와음의상관관계가있었다. 연령을보정하였을때내피세포비의존성혈관확장반응은흡연 (r = -0.208, P < 0.05), 수축기혈압 (r = -0.203, P < 0.05), 이완기혈압 (r = -0.213, P < 0.05), 경동맥내중막두께의평균값 (r = -0.252, P < 0.01) 과최대값 (r = -0.244, P < 0.01), 심혈관질환위험인자수 (r = -0.244, P < 0.01) 와음의상관관계가있었다 (Table 2) (Fig. 2). 501
A B Fig. 2. Correlations between endothelium-independent vasodilation (EID) and mean carotid IMT (A) or number of CVD risk factors besides diabetes (B). Table 3. Multiple regression analysis for mean carotid IMT as dependent variables beta t P value Age 0.541 6.070 < 0.001 Smoking 0.188 2.329 < 0.05 BMI 0.103 1.093 0.277 HbA1c 0.077 0.973 0.333 Ln_triglyceride 0.117 1.300 0.196 LDL cholesterol -0.022-0.269 0.789 Systolic BP -0.044-0.490 0.625 FMD 0.012 0.146 0.884 EID -0.183-2.134 < 0.05 Number of risk factors -0.044-0.401 0.689 Dependent variable: mean carotid IMT, r 2 = 0.43 P < 0.001, Ln_Triglyceride, Triglyceride transformed by log-scale. 4. 조기동맥경화증의예측인자로서비의존성혈관확장반응의유용성연령, 흡연갑년, 체질량지수, 당화혈색소, 중성지방, 저밀도지단백콜레스테롤, 수축기혈압, 혈관세포의존성 / 비의존성혈관확장반응, 심혈관질환위험인자의수를독립변수로하고조기동맥경화증의지표인경동맥내중막두께를종속변수로하여다중회귀분석을시행하였을때경동맥내중막두께에독립적으로영향을주는인자는연령, 흡연력및내피세포비의존성혈관확장반응이었다 (Table 3). 고찰혈관은주변의물리적또는화학적자극에반응하여혈류와혈관의긴장상태를조절하는능력이있다. 혈류가증가하면혈관의내피세포에서산화질소가분비되어혈관확장반응을일으키는데이를혈류가증가됨으로서유발되는내피세포의존성혈관반응이라한다. 이에대한기전은확실히알 려지진않았으나내피세포의산화질소생성효소 (endothelial nitric oxide synthase, enos) 17), 비대칭성디메칠아르기닌 (asymmetric dimethylarginine, ADMA) 18), 유리산소 19), TNF-α 20) 등과의연관성이밝혀져있으며여러연구에서죽상경화증및심혈관질환의발생을예측하는표지자로보고되고있다. 최근에는혈관수축능력감소와혈관벽의재구성시혈관평활근의감소가죽상경화증의발생기전과연관되어있음이보고되면서 FMD을억제한뒤혈관평활근에의한혈관반응성을살펴보는 EID에대한연구도활발히진행되고있다. 당뇨병이없는심혈관질환환자들을대상으로한이연구들에서는 FMD와 EID가동시에유의하게감소하였고 EID의감소원인을혈관평활근중층의쇠퇴, 세포내 guanylate cyclase와 cyclic GMP 활성의감소, 과거에질산염제제사용으로인한내성등으로분석하였다 8-11). Celermajer 등이외부에서니트로글리세린을투여하여 EID를같이측정한것은혈류에의한혈관확장반응이평활근세포의손상이아닌순수한내피세포의영향인지를판단하기위한것으로통상적으로죽상경화증의초기에는 EID 502
최정호외 8 인 : 새롭게진단된한국인제 2 형당뇨병환자에서내피세포의존성 / 비의존성혈관확장반응의경동맥내중막두께와의연관성 변화는없는것으로받아들여져왔다. 그러나 221개연구의메타분석에서 FMD가심혈관질환의 10년위험도가 2.8% 미만인저위험군에서만기존의심혈관질환위험요인들과연관성을보였고고위험군에서는내피세포의기능을온전히반영하지못한다고보고하여 21) 심혈관질환과동등한정도의고위험군으로분류되는당뇨병환자의경우 FMD 수치의결과를주의깊게해석할필요가있음을상기시켰다. 또한최근에, 평균유병기간 10년정도인당뇨병환자에서 FMD가정상대조군에비해감소되어있으나경동맥내중막두께와유의한상관관계는없다고보고되어 22) FMD가오래된당뇨병환자나심혈관질환고위험군환자에서죽상경화증을예측하는인자로유용한지에대한평가가필요함을시사하였다. 본연구에서는새롭게진단된한국인제2형당뇨병환자에서 FMD 및 EID와기존에알려진심혈관질환위험인자들및조기죽상경화증의지표로잘알려져있는경동맥내중막두께와의연관성을고찰하고자하였다. 본연구결과, FMD는연령, 흡연력, 저밀도지단백콜레스테롤, 혈압, 경동맥내중막두께, 기존에알려진심혈관질환위험인자의수와유의한연관성이있었으나연령의영향을배제하였을때흡연력만이유의한연관인자였고, EID는연령의영향을배제하였을때도흡연력, 혈압, 경동맥내중막두께및심혈관질환위험인자의수와유의한연관성이있었다. 본연구에서심혈관질환위험인자의수가증가함에따라 EID는유의하게감소하였고경동맥내중막두께를종속변수로하여다중회귀분석을시행하였을때도 EID는연령, 흡연력과함께경동맥내중막두께상승의독립적인영향인자였다. 이는주로 FMD의감소를유의한심혈관질환의예측인자로보고한초기의논문들 5-7) 과는다른결과이다. 그러나증상이없는죽상경화증의고위험군환자 800명을대상으로한연구에서 FMD와 EID는유의하게연관되어있었고당뇨병, 기저혈관의직경및 FMD가 EID의독립적인영향인자로보고되었다 9). 또한미세알부민뇨, 현성단백뇨, 말기신부전등당뇨병성신장병증의단계에따라서도 FMD의감소, 또는 FMD와 EID의동시감소등다른결과가보고되고있어 23-26) 당뇨병환자중대상환자의심혈관질환위험인자에따라결과에차이가있음을알수있다. 본연구에서 FMD가연령, 흡연외에다른심혈관질환위험인자들과뚜렷한연관성을보이지않았던것은내피세포의기능에연령, 흡연이가장주요한위험인자로작용할가능성과다른심혈관질환위험인자가동반되어있는당뇨병환자의특성상진단당시부터내피세포에미치는영향이감소해있었을가능성을배제할수없다. FMD는단기간에유발된고혈당, 고혈압, 고지혈증, 비만중한가지만있어도감소되어있었고 27-30) 제2형당뇨병이나조기관상동맥질환의가족력이있는경우에도감소되어있었다 31,32). 본연구에서는당뇨병외의위험인자를 1개이상가진환자가 90.8%, 2개이 상의위험인자를가진환자가 70.0% 였고, 고혈압, 고지혈증의비율이당뇨병유병기간이본연구보다길었던다른연구들과유사하여당뇨병진단당시부터내피세포기능이유의하게감소되어있었을것으로추정할수있다. 본연구에서심혈관질환위험인자수가 2가지이상일때부터 FMD는추가적인감소를보이지않았으나, EID는심혈관질환의위험인자의수가증가할수록유의하게감소하였다. 혈류증가에의한유리라디칼이나내인성및외인성산화질소등내피세포의기능과연관된인자들이비교적초기에작용하여위험인자가증가하여도 FMD의추가적인감소를보이지않 으며 17) 내피세포의기능저하단계를넘어서면혈관의섬유 화, 평활근수축등의미세한구조변화와니트로글리세린에대한반응성감소등이원인이되어 33,34) 혈관에초음파로병변이발견되기전에 EID가감소할것으로생각된다. 이전의많은연구들에서이미심혈관질환과경동맥내중막두께의강력한상관관계와심혈관예측인자로서경동맥내중막의유용성은입증되어있다. 본연구에서경동맥내중막두께는 FMD 및 EID와통계적으로유의한음의상관관계를보였으나경동맥내중막두께에독립적으로영향을주는인자는연령, 흡역력다음으로 EID였고 FMD는유의한영향인자가아니었다. 또한 EID는통상적으로유의한경동맥내중막두께의기준치로사용되고있는 1.0 mm 미만에서도유의한역상관관계가성립하여저자들은새롭게진단된당뇨병환자에서이미잘알려져있는 FMD보다는 EID 가심혈관질환의예측인자로서더유용하다고판단할수있었다. 본연구에서당뇨병환자의혈관반응을정상대조군과비교하지는못하였다. 각각의연구에서대상의특성에차이가있어직접적인비교는어려우나본연구의 FMD의평균값은 6.1% 로다른논문에서보고된정상대조군이나직계가족중에당뇨병이있는당뇨병이없는젊은연령층의값보다는감소되어있었고 31) 미세알부민뇨가있는당뇨병환자보다는증가되어있었다 23). Enderle 등 35) 은관상동맥질환의 95% 양성예측률의 cut-off를 4.5% 로보고하였고 Kubin 등 36) 은 95% 음성예측률의 cut-off를 10% 로보고한바있다. Xiang-yu 등은체질량지수가유의하게높은환자들을대상으로하였음에도미세알부민뇨가없는당뇨병환자에서평균 FMD 값을 11.4% 로보고하였는데이연구의대상환자들은 ACE 억제제를평균 3.8년사용한환자들이었다는점에서본연구와차이가있다. 본연구결과, 새롭게진단받은당뇨병환자에서 EID가동반된심혈관질환위험인자의수및조기죽상경화증의지표로잘알려진경동맥내중막두께와유의한연관성이있음을알수있었다. 향후건강한성인을대상으로한한국에서의기준치가제시되어야할것이며전향적인연구를통해혈관반응의감소가심혈관질환의발생을예측할수있는지검증 503
하는단계가필요할것으로생각된다. 요약연구배경 : 당뇨병환자에서심혈관질환의위험을예측할수있는여러위험인자들이제시되고있으나직접혈관의반응성을평가하는것이조기동맥경화증을진단하고당뇨병과관련된심혈관질환의발생을예측하는가장좋은방법일것이다. 본연구는새로진단받은제2형당뇨병환자들의내피세포의존성 / 비의존성혈관반응을측정하고기존에알려진심혈관질환위험인자들및조기죽상경화증의지표로잘알려져있는경동맥내중막두께와의연관성을고찰하고자하였다. 방법 : 당뇨병을새로진단받은 121명 ( 남자 68명, 여자 53 명 ) 의상박동맥에서고해상도초음파를이용하여내피세포의존성 / 비의존성혈관확장반응을측정하였고, 연령인자, 흡연인자, 비만, 고혈압, 고지혈증, 심혈관질환가족력같은고전적인심혈관질환위험인자의수를산정하였고조기동맥경화증의지표로잘알려져있는경동맥내중막두께를측정하였다. 내피세포의존성 / 비의존성혈관확장반응과다른심혈관위험인자와의연관성은 Pearsons' correlation test와 partial correlation test를이용하여분석하였고내피세포의존성 / 비의존성혈관확장반응이경동맥내중막두께의독립적인영향인자인지를평가하기위해다중회귀분석을시행하였다. P value 0.05 미만을통계적으로유의성이있는것으로판정하였다. 결과 : 연구대상의평균연령, 흡연력, 체질량지수, 허리둘레, 수축기및이완기혈압은각각 51.2 ± 12.3세, 11.0 ± 15.8 갑년, 25.0 ± 3.2 kg/m 2, 86 ± 9 cm, 123 ± 16 mmhg, 79 ± 12 mmhg였다. 평균당화혈색소, 공복혈당, 총콜레스테롤, 중성지방, 저밀도지단백콜레스테롤, 고밀도지단백콜레스테롤은각각 8.4 ± 2.0%, 166 ± 51 mg/dl, 187 ± 37 mg/dl, 166 ± 143 mg/dl, 114 ± 30 mg/dl, 46 ± 12 mg/dl였다. 평균 FMD와 EID는 6.1 ± 2.8 %, 16.6 ± 5.6% 였고, 경동맥내중막두께의평균값과최대값은각각 0.63 ± 0.12/0.76 ± 0.16 mm였다. 본연구에서산정한심혈관질환위험인자의수는당뇨병을제외하고 2.3 ± 1.3개였다. 연령변수를보정하였을때, FMD는흡연력과만유의한상관관계가있었고, EID는흡연력외에수축기및이완기혈압, 경동맥내중막두께의평균값및최대값, 심혈관질환위험인자의수와연관성이있었다. 조기동맥경화증의지표중하나인경동맥내중막두께를종속변수로하여다중회귀분석을시행하였을때연령, 흡연력및 EID가경동맥내중막두께의유의한영향인자였다. 결론 : 새롭게진단받은제2형당뇨병환자에서혈관확장반응의감소는고전적인심혈관질환위험인자들의영향을 잘반영하였다. 특히 EID는조기동맥경화증의지표로잘알려진경동맥내중막두께와유의한연관성이있었다. 참고문헌 1. Kannel WB, McGee DL: Diabetes and cardiovascular risk factors: the Framingham study. Circulation 59:8-13, 1979 2. Almdal T, Scharling H, Jensen JS, Vestergaard H: The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death; a population -based study of 13,000 men and women with 20 years of follow-up. Arch Intern Med 164: 1422-6, 2004 3. Eric de Groot GKH, Albert Wiegman, Patrick Duriez, Andries J. Smit, Jean-Charles Fruchart and John J.P. Kastelein: Measurement of arterial wall thickness as a surrogate marker for atherosclerosis. Circulation 109:33-8, 2004 4. O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK: Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 340:14-22, 1999. 5. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE: Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340:1111-5, 1992 6. Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, Lieberman EH, Ganz P, Creager MA, Yeung AC, et al: Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol 26:1235-41, 1995 7. Neunteufl T, Katzenschlager R, Hassan A, Klaar U, Schwarzacher S, Glogar D, Bauer P, Weidinger F: Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis 129:111-8, 1997 8. Xiang-yu Zhang, Shui-ping Zhao, Xiang-ping Li, Mei Gao, Qi-Chang Zhou: Endothelium-dependent and -independent functions are impaired in patients with coronary heart disease. Atherosclerosis 149:19-24, 2000 9. Adams MR, Robinson J, McCredie R, Seale JP, Sorensen KE, Deanfield JE, Celermajer DS: Smooth 504
최정호외 8 인 : 새롭게진단된한국인제 2 형당뇨병환자에서내피세포의존성 / 비의존성혈관확장반응의경동맥내중막두께와의연관성 muscle dysfunction occurs independently of impaired endothelium-dependent dilation in adults at risk of atherosclerosis. J Am Coll Cardiol 32:123-7, 1998 10. Jarvisalo M, Lehtimaki T, Raitakari OT: Determinants of arterial nitrate-mediated dilation in children; Role of low-density lipoprotein, endothelial function, and carotid intima-media thickness. Circulation 109: 2885-9, 2004 11. Raitakari OT, Seale JP, Celermajer DS: Impaired vascular responses to nitroglycerin in subjects with coronary atherosclerosis. Am J Cardiol 87:217-9, 2001. 12. Vita JA, Keaney JF, Jr: Endothelial function; a barometer for cardiovascular risk? Circulation 106: 640-2, 2002 13. 신장열, 이미영, 고장현, 김장영, 신영구, 정춘희 : 제2형당뇨병환자에서혈관내피세포기능장애와만성염증표지자인 High Sensitivity C-reactive Protein과의연관성. 당뇨병 29:467-78, 2005 14. 이인규 : 혈관내피세포기능평가. 당뇨병 25:406-23, 2001 15. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R: Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 39:257-65, 2002 16. 박태선, 이길홍, 임성의, 이승호, 백홍선, 정경호 : 인슐린비의존형당뇨병환자에서경동맥초음파로측정한경동맥중막-내막두께와죽상경화증위험인자와의관계. 당뇨병 20:145-52, 1996 17. Komatsu M, Kawagishi T, Emoto M, Shoji T, Yamada A, Sato K, Hosoi M, Nishizawa Y: enos gene polymorphism is associated with endotheliumdependent vasodilation in Type 2 diabetes. Am J Physiol Heart Circ Physiol 283:H557-61, 2002 18. Takiuchi S, Fujii H, Kamide K, Horio T, Nakatani S, Hiuge A, Rakugi H, Ogihara T, Kawano Y: Plasma asymmetric dimethylarginine and coronary and peripheral endothelial dysfunction in hypertensive patients. Am J Hypertens 17:802-8, 2004 19. Graiser WF, Posch K, Eleonore F, Wascher TC, Kostner GM: Increased superoxide anion formation in endothelial cells during hyperglycemia: an adaptive response or initial step of vascular dysfunction? Diabetes Res Clin Pract 45:153-60, 1999 20. Martens FM, Rabelink TJ, op 't Roodt J, de Koning EJ, Visseren FL: TNF-alpha induces endothelial dysfunction in diabetic adults, an effect reversible by the PPAR-gamma agonist pioglitazone. Eur Heart J 27:1605-9, 2006 21. Witte DR, Westerink J, de Koning EJ, van der Graaf Y, Grobbee DE, Bots ML: Is the association between flow-mediated dilation and cardiovascular risk limited to low-risk populations? J Am Coll Cardiol 45:1987-93, 2005 22. Chan L, Shaw AG, Busfield F, Haluska B, Barnett A, Kesting J, Short L, Marczak M, Shaw JT: Carotid artery intimal medial thickness, brachial artery flowmediated vasodilation and cardiovascular risk factors in diabetic and non-diabetic indigenous Australians. Atherosclerosis. 180:319-26, 2005 23. Jawa A, Nachimuthu S, Pendergrass M, Asnani S, Fonseca V: Impaired vascular reactivity in African- American patients with type 2 diabetes mellitus and microalbuminuria or proteinuria despite angiotensinconverting enzyme inhibitor therapy. J Clin Endocrinol Metab 91:31-5, 2006 24. Chan WB, Chan NN, Lai CW, So WY, Lo MK, Lee KF, Chow CC, Metreweli C, Chan JC: Vascular defect beyond the endothelium in type II diabetic patients with overt nephropathy and moderate renal insufficiency. Kidney Int. 70:711-6, 2006 25. Stehouwer CD, Henry RM, Dekker JM, Nijpels G, Heine RJ, Bouter LM: Microalbuminuria is associated with impaired brachial artery, flow-mediated vasodilation in elderly individuals without and with diabetes. Kidney Int Suppl 92:S42-4, 2004 26. Papaioannou GI, Seip RL, Grey NJ, Katten D, Taylor A, Inzucchi SE, Young LH, Chyun DA, Davey JA, Wackers FJ, Iskandrian AE, Ratner RE, Robinson EC, Carolan S, Engel S, Heller GV: Brachial artery reactivity in asymptomatic patients with type 2 diabetes mellitus and microalbuminuria (from the Detection of Ischemia in Asymptomatic Diabetics- brachial artery reactivity study). Am J Cardiol. 2004 Aug 1;94(3):294-9 27. 이상준, 이동욱, 이인규 : 제2형당뇨병환자에서급성고혈당이혈관내피세포기능에미치는효과. 당뇨병 24: 574-86, 2000 28. T, Saito N, Dong J, Mikami T, Fujii S, Kitabatake A: Association of cardiovascular risk factors and endothelial 505
dysfunction in japanese hypertensive patients; implications for early atherosclerosis. Furumoto Hypertens Res 25:475-80, 2002 29. Lundman P, Eriksson MJ, Stühlinger M, Cooke JP, Hamsten A, Tornvall P: Mild- to-moderate hypertriglycemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine. J Am coll Cardiol 38:111, 2001 30. Al Suwaidi J, Higano ST, Holmes DR Jr, Lennon R, Lerman A: Obsesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries. J Am Coll Cardiol 37:1523, 2001 31. Balletshofer BM, Rittig K, Enderle MD, Volk A, Maerker E, Jacob S, Matthaei S, Rett K, Häring HU: Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance. Circulation 101:1780-4, 2000 32. Clarkson P, Celermajer DS, Powe AJ, Donald AE, Henry RM, Deanfield JE: Endothelium-dependent dilatation is impaired in young healthy subjects with a family history of premature coronary disease. Circulation 96:3378, 1997 33.Lee RT, Kamm RD: Vascular mechanics for the cardiologist. J Am Coll cardiol 23:1289-95, 1994 34. Gibbon GH, Dzau VJ: The emerging concept of vascular remodeling. New Engl J Med 330:1431-8, 1994 35. Enderle M, Benda N, Schmuelling R, Haering HU, Pfohl M: Preserved endothelial function in IDDM patients, but not in NIDDM patients, compared with healthy subjects. Diabetes Care 21:271-7, 1998 36. Kuvin JT, Patel AR, Sliney KA, Pandian NG, Rand WM, Udelson JE, Karas RH: Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease. J Am Coll Cardiol 38:1843-9, 2001 506