원저접수번호 :08-113 인하대학교의과대학신경과학교실 Impact of Obstructive Sleep Apnea on Carotid Intima-Media Thickness Chang-Ho Yun, MD, So-Hyun Kim, MD, Ki-Hwan Ji, MD, Il-Gon Kim, MD, Choong-Kun Ha, MD Department of Neurology, College of Medicine, Inha University, Incheon, Korea Background: Obstructive sleep apnea (OSA) is known to be an independent risk for cardiovascular diseases. The carotid intima media thickness (IMT) is a surrogate marker of subclinical atherosclerosis. The aim of this study was to measure the carotid IMT in subjects with or without OSA and quantify its correlation with OSA severity. Methods: Subjects were categorized into OSA and non-osa groups based on polysomnography findings. The carotid IMT was considered a marker of atherosclerosis. The independent relationship between carotid IMT and OSA severity was analyzed using multiple linear regression. The presumed confounders were age, sex, body mass index, blood pressure, blood lipid and glucose profiles, smoking and alcohol drinking statuses, medications, being overweight, and having hypertension, diabetes mellitus, or hyperlipidemia. Results: The carotid IMT was larger in OSA subjects (n=82, 0.620±0.096 mm [mean±sd]) than in non-osa subjects (n=22, 0.551±0.078 mm; p=0.006), and was independently correlated with OSA severity (p<0.001). However, it was not affected by any of the other variables investigated. Conclusions: Subjects with OSA showed an increased IMT, with the thickness being correlated with the OSA severity. This finding suggests that accelerated atherosclerosis in OSA is the mechanism linking OSA and future cardiovascular events. J Korean Neurol Assoc 27(2):129-135, 2009 Key Words: Carotid artery, Hypoxia, Doppler ultrasonography 서론 수면은생존의필수현상으로인생의삼분의일을차지하는데, 성인인구의약 2~5% 는수면중기도저항의비정상적증가로폐쇄성수면무호흡증 (obstructive sleep apnea) 을경험하게된다. 1,2 수면무호흡증은심혈관질환의발병위험을증가시키는것으로알려져있다. 3 주요기전으로반복적저산소증, 산화손상 (oxidative injury), 교감신경계활성, 혈류역학적변화, 염증반응의증가등이보고되었다. 3 하지만, 무호흡증의발병위험인자인남성, 비만, 고령, 흡연, 적은신체활동은심혈관질환의 Received December 3, 2008 Revised March 2, 2009 Accepted March 3, 2009 *Chang-Ho Yun, MD Department of Neurology, Inha University Hospital 7-206, Sinheung-dong 3-ga, Jung-gu, Incheon, 400-711, Korea Tel: +82-32-890-3418 Fax: +82-32-890-3864 E-mail: ych333@chol.com 대표적위험인자이기도하다. 1,2,4-9 따라서, 혈관질환의발병위험증가측면에서무호흡증의독립적영향을평가하는데어려움이있다. 최근몇몇전향적관찰연구 (prospective observational study) 는수면무호흡증이뇌졸중과심혈관질환발병의독립적위험인자라는사실을뒷받침했고, 그주요기전으로동맥경화증을제시하였다. 10,11 이에저자들은무호흡증과대조군에서동맥경화증의척도로목동맥내중층두께 (carotid intima-media thickness, IMT) 를측정하여무호흡증과독립적상관관계를분석하였다. 대상과방법 1. 대상 2007 년 3월부터 2008 년 3월까지, 습관적코골이또는관찰된무호흡등수면중호흡이상 (sleep-disordered breathing) 을시사하는증상으로내원한만 20 세이상성인을대상으로선 J Korean Neurol Assoc Volume 27 No. 2, 2009 129
별하였다. 제외기준은다음과같다 : 중추성무호흡 ; 뇌혈관과심혈관질환의과거력 ; 만성기도폐쇄성폐질환 ; 신장, 간및혈액질환 ; 염증성질환 ; 자가면역질환또는종양 ; 최근 4주이내의외상 ; 편두통, 갑상선질환또는우울증등의정신질환 ; 비타민의복용. 제외기준에해당하지않으며본연구에동의한환자를최종대상으로선정하였다. 본연구는임상연구심의위원회 (Institutional Review Board) 의승인을받았다. 2. 수면무호흡증의평가대상자모두에게야간수면다원검사 (Comet XL Lab-based PSG, TWin PSG software, Grass-Telefactor, RI, USA) 를하였다. 수면의단계와각성의판정은뇌파 (C3-A2, C4-A1, O1-A2, O2-A1), 안전도 (ROC-A1, LOC-A2), 턱근전도 (Chin EMG) 에의거하였고, 호흡량은열전대 (oronasal thermistor) 와비압력감지기 (nasal pressure transducer) 로측정하였다. 흉곽과복부에장착한호흡유도계수체적기록계 (respiratory inductance plethysmography) 를이용하여호흡운동을측정하였고, 그외산소포화도 (finger pulse oximetry) 와체위센서, 심전도 (modified V2 lead), 양측전경골근근전도 (tibialis anterior EMG) 측정을병행하였다. 수면과호흡상태평가는이전의보고를따랐다. 12-14 폐쇄성수면무호흡 (obstructive sleep apnea) 은호흡운동이유지된상태에서호흡이 10초이상완전히멈춘경우로정의하였고, 저호흡 (hypopnea) 은호흡량진폭이 30% 이상감소한채 10초이상지속되고산소포화도가 3% 이상감소되는경우로정의하였다. 수면 1시간당발생하는폐쇄성무호흡과저호흡발생횟수를무호흡 -저호흡지수(apnea-hypopnea index, AHI) 로정의하였다. AHI, 수면중최저산소포화도 (lowest oxygen saturation), 저산소포화시간 (desaturation time, 산소포화도 90% 미만인상태에서수면을취한시간 ) 을무호흡증의중증도지표로사용하였다. 저산소포화시간은절대시간 ( 분 ) 과총수면시간 (total sleep time) 대비백분율로각각표시하였다. AHI 가 5 이상인경우폐쇄성수면무호흡증으로진단하였다. 15 또한 AHI에따라무호흡증을경증 (AHI<15), 중등도 (15 AHI<30), 중증 (AHI 30) 으로분류하였다. 중추성무호흡증이있는경우, 폐쇄성무호흡이존재하더라도본연구에서제외하였다. 중추성무호흡은중추성무호흡지수가 5 이상이거나 Cheyne-Stokes 호흡이상이관찰되는경우로정의하였다. 15 3. 연구대상자의임상평가체계화한설문지와면담을통해과거력과수면력을조사하였 고신체검진과신경학적검사를하였다. 조사대상에는질환력, 약물복용상태, 음주및흡연력, Epworth 졸음증척도 (Epworth Sleepiness Scale, ESS) 를포함하였고, ESS가 11점이상이면과도한주간졸음 (excessive daytime sleepiness) 이있는것으로정의하였다. 16 혈압은수면다원검사전검사실에서누운자세에서 2회이상 ( 최대 3회 ) 측정하였다. 15분이상휴식후 10분간격으로수은혈압계를이용하여표준화된방법으로측정하였다. 17 수축기와이완기혈압의평균을분석대상으로하였다. 체중 (kg) 과신장 (cm) 을함께측정하였고, 체질량지수 (kg/m 2 ) 를계산하였다. 8시간금식후아침에혈당, 콜레스테롤, 흉부방사선, 심전도검사를하였다. 체질량지수가 25 이상이면과체중으로정의하였다. 18 수축기혈압이 140 mm Hg 이상이거나이완기혈압이 90 mm Hg 이상, 또는고혈압치료제를복용하고있는경우, 고혈압이있다고하였다. 당뇨병의과거력이나당뇨병치료제를복용하고있으면당뇨병으로정의하였다. 공복콜레스테롤수치에이상 (total cholesterol>240 mg/dl 또는 LDL-cholesterol>160 mg/dl) 이있거나또는콜레스테롤강하제를복용하고있으면고지혈증이있다고하였다. 대상자가현재담배를피우고있거나금연한지 6개월미만이면흡연자로분류하였고, 남자가하루 4잔 ( 여자는하루 2잔 ) 이상술을마시고있으면습관성알코올복용으로정의하였다. 19 대상자의모든약물복용상태를함께기록하였다. 목동맥 IMT 는수면다원검사다음날아침에다음과같은방법으로측정하였다. 대상자의임상정보를알지못하는검사자가고화질 B 모드초음파기 (high-definition B-mode ultrasonography with a 10.0-MHz linear array transducer; 10L5, Terason 2000; Terason Ultrasound, Burlington, MA, USA) 를이용하여측정하였다. 먼저 IMT 를측정하기위해먼쪽온목동맥 (distal common carotid artery) 의종단면영상을확보한후, 목동맥분지하방 1 cm 아래, 초음파탐침 (probe) 반대측목동맥벽에서, 가장두꺼운부분을측정하였다. 단, 죽상경화판 (carotid plaque) 이있는부위는피하였다. 측정시에는기기에장착된소프트웨어 (Intimascope, Media Cross Co. Ltd., Tokyo, Japan) 를이용하였다. 검사자가정해진위치에서가장두꺼운부분을포함한영상을확보하면소프트웨어가 IMT 평균치를산출하였다. 양측 IMT 의평균치를대표값으로사용하였다. 죽상경화판은국소-IMT 두께가 1.2 mm 이상이면서목동맥벽횡단면전체를다포함하지않는경우로정의하였다. 죽상경화판의상태에따라아래와같이등급을정하였다 : 0= 죽상경화판이없는경우 ; 1= 혈관직경의 30% 미만두께의죽상경화판 ; 2= 직경의 30~50% 에해당하거나두개이상의 1등급죽상 130 대한신경과학회지제 27 권제 2 호, 2009
경화판이있는경우 ; 3= 직경 50% 이상의죽상경화판또는두개이상의 2등급죽상경화판이있는경우로하였다. 20 4. 통계분석통계분석을통해 목동맥 IMT 와 무호흡증중증도지표 간의상관관계를검정하였다. 교란변수는연령, 성별, 체질량지수, 음주및흡연력, 혈압, 혈중콜레스테롤및혈당, 고혈압, 당뇨병, 약물복용력, 고지혈증이다. 모든결과는평균 (± 표준편차 ) 또는숫자 ( 분율 ) 로표시하였다. Kolomogorov-Smirnov 분석을통해연속변수의정규분포여부를검정하였다. 무호흡환자군과대조군의비교를위해, two-tailed Student s t-검정, 분산검정 (ANOVA), Pearson s chi square 또는 Fisher s exact 검정을사용하였다. 연속변수간의상관관계에대해 Pearson s correlation 분석을하였다. 단변량분석시 p<0.25 인변수를다변량분석 (multiple linear regression) 에포함하였다. 통계분석을통해 목동맥 IMT 와 무호흡증중증도지표 간의상관관계를 검정하였다. 교란변수는연령, 성별, 체질량지수, 음주및흡연력, 혈압, 혈중콜레스테롤및혈당, 고혈압, 당뇨병, 약물복용력, 고지혈증으로하였다. 모든통계분석과데이터관리에 SPSS 프로그램 (SPSS 12.0, SPSS Inc., Chicago, IL, USA) 을사용하였으며, p<0.05 인경우귀무가설을기각하였다. 결과 연구기간동안 185 명을대상으로무호흡증평가를하였다. 49명이제외기준에해당하여탈락하였고 23명이연구참여를거절하였다. 9명은혈액검사를하지않아탈락하였다. 총 102 명이연구에참여하였다. 이중 82명이무호흡증군에포함되었고 22명은대조군에해당하였다. 대상자의임상특성과검사결과를표에요약하였다 (Table 1). 분류기준에따라무호흡증군에서무호흡증중증지표와 Epworth 주간졸음척도가높았다. 16 그외, 연령, 성비, 체질량지수, 음주및흡연상태, 고혈압, 당뇨병, 및고지혈증의유병률, 혈압, 혈당, 콜레스테롤수치는양군 Table 1. Characteristics in OSA and non-osa group OSA (n=82) Non-OSA (n=22) p value Age 41.5±9.80 39.1±10.7 0.34 Male gender (%) 75 (91.5) 19 (86.4) 0.44 Hypertension (%) 30 (36.6) 07 (31.8) 0.68 SBP (mmhg) 124.7±14.50 124.1±13.50 0.87 DBP (mmhg) 82.5±11.2 81.5±10.1 0.70 DM (%) 6 (7.3) 1 (4.2) 1.00 Hyperlipidemia (%) 18 (22.0) 2 (9.1) 0.23 Current smoking (%) 45 (54.9) 14 (63.6) 0.46 Habitual alcohol drinking (%) 37 (45.1) 10 (45.5) 0.98 Overweight (%) 52 (63.4) 15 (68.2) 0.68 BMI (kg/m 2 ) 26.0±3.60 26.2±2.8 0.84 Antihypetensive (%) 18 (22.0) 05 (22.7) 0.94 Statin (%) 7 (8.5) 1 (4.5) 1.00 DM medication (%) 6 (7.3) 1 (4.5) 1.00 ESS 10.6±4.90 7.2±3.9 0.004* EDS (%) 38 (46.3) 04 (18.2) 0.02* AHI 39.8±23.5 2.2±1.4 <0.001* Desaturation time (min) 27.4±36.3 0.3±0.6 <0.001* Desaturation time (%) 08.6±11.8 0.1±0.1 <0.001* MinSaO 2 80.0±8.50 91.0±2.40 <0.001* F-glucose (mg/dl) 92.1±20.0 96.2±21.3 0.40 T-chol (mg/dl) 202.2±29.70 198.6±26.60 0.60 TG (mg/dl) 160.0±64.80 139.1±63.40 0.18 HDL (mg/dl) 50.8±10.3 48.6±7.50 0.35 LDL (mg/dl) 121.7±26.00 120.8±25.10 0.88 Carotid IMT (mm) 0.620±0.096 0.551±0.078 <0.006* *p<0.05, Student t-test, Pearson chi square test or Fisher s exact test, OSA; obstructive sleep apnea, SBP; systolic blood pressure, DBP; diastolic blood pressure, DM; diabetes mellitus, BMI; body mass index, overweight ; body mass index 25, AHI; apnea-hypopnea index, MinSaO 2; minimum oxygen saturation (%), ESS; Epworth Sleepiness Scale, EDS; excessive daytime sleepiness (ESS 11), F-glucose; fasting glucose, T-chol; total-cholesterol, TG; triglyceride, HDL; high density lipoprotein cholesterol, LDL; low density lipoprotein cholesterol, IMT; intima-media thickness J Korean Neurol Assoc Volume 27 No. 2, 2009 131
에서유사하였다 (Table 1). 고혈압치료약물과스타틴 (statin) 의복용빈도도차이가없었다. 23 명의혈압약복용자중 15명은한가지, 7명은두가지, 1명은세가지약제를복용하였다. 14명은안지오텐신수용체차단제 (angiotensin receptor blocker) 를, 2명은안지오텐신전환효소억제제 (angiotensin-converting enzyme inhibitor) 를, 10명은칼슘채널차단제 (calcium channel blocker) 를, 5명은베타차단제 (beta blocker) 를, 1명은이뇨제 (hydrochlorothiazide) 를복용하였다. 무호흡증군에서 7명은스타틴을, 1명은섬유산 (fibric acid) 을복용하였고, 대조군 1명은스타틴을복용하였다. 80명에서목동맥도플러초음파검사 (carotid Doppler study) 를하였다 ( 대조군 18명, 81.8%; 무호흡증 62명, 75.6%; p=0.54). 양군간임상특성의차이가없던반면, 목동맥 IMT 는무호흡군에서유의하게높았다 (0.620± 0.096 mm vs. 0.551±0.078 mm; p=0.006, Table 1). 무호흡증의중증도와목동맥 IMT 사이의독립적정량관계를평가하기위하여, 대상을 AHI 에따라, 정상과경증, 중등도, 중증무호흡군으로세분하였다 (Table 2). 분류기준에따라 AHI 를 포함한중증도지표가네군간에차이가있었다 (p<0.001). 각군간, 연령, 성비, 고혈압, 당뇨병, 주간졸음증의유병률, 흡연및음주상태, 약물복용력, 공복혈당과콜레스테롤수치는유사하였다 (p>0.05, Table 2). 반면, 체질량지수 (p=0.01), 과체중비율 ( 체질량지수 25, p=0.01), 중성지방 (p=0.03), Epworth 주간졸음척도 (p=0.03) 는달랐다. 무호흡증중증도지표, 수축기혈압, 중성지방, 체질량지수, 고지혈증, 스타틴복용, 과체중, 음주및흡연상태를독립변수로, 목동맥 IMT 를종속변수로하여다중선형회귀 (multiple linear regression) 분석을하였다. Epworth 주간졸음증척도와주간졸음증은무호흡증중증도에따라달라지므로다중선형회귀분석에포함하지않았다. AHI, 최저산소포화도, 저산소포화시간중하나씩중증도지표로선택해서다중선형회귀분석을반복하였다. 목동맥 IMT 는 AHI (r= 0.76, p<0.001), 저산소포화시간 (r=0.60, p<0.001), 최저산소포화도 (r=0.65, p<0.001) 과독립적상관관계가있었다 (Table 3, Fig.). 그외인자들은유의한상관관계가없었다. 생물학적임상맥락에서다중선형회귀분석에포함된일부변 Table 2. Clinical features and carotid atherosclerosis depending on the OSA severity Non-OSA Mild OSA Moderate OSA Severe OSA (n=22) (n=18) (n=16) (n=48) p value Age 39.1±10.7 42.8±10.9 40.5±11.1 41.3±9.10 0.79* Male gender (%) 19 (86.4) 17 (94.4) 13 (81.3) 45 (93.8) 0.41* Hypertension (%) 7 (31.8) 5 (27.8) 9 (56.3) 16 (33.3) 0.30* SBP 124.1±13.50 118.8±9.700 129.7±19.20 125.3±13.90 0.16* DBP 81.5±10.1 79.3±13.4 82.9±11.1 83.6±10.3 0.53* DM (%) 1 (4.2) 1 (5.6) 0 (0) 0 05 (10.4) 0.49* Hyperlipidemia (%) 2 (9.1) 1 (5.6) 0 (0) 0 17 (35.4) 0.001* Current smoking (%) 14 (63.6) 06 (33.3) 09 (56.3) 30 (62.5) 0.17* Habitual alcohol drinking (%) 10 (45.5) 4 (22.2) 6 (37.5) 27 (57.4) 0.09* BMI (kg/m 2 ) 26.2±2.8 23.7±2.80 26.2±5.00 26.8±2.90 0.01* Overweight (%) 15 (68.2) 6 (33.3) 9 (56.3) 37 (77.1) 0.01* Antihypertensive (%) 5 (22.7) 4 (22.2) 5 (31.3) 9 (18.8) 0.78* Statin (%) 1 (4.5) 0 (0) 00 0 (0) 00 7 (14.6) 0.10* DM medication (%) 1 (4.5) 1 (5.6) 0 0 (0) 00 5 (10.4) 0.49* AHI 2.2±1.4 12.5±3.90 22.1±3.10 56.0±16.8 <0.001* Desaturation time (min) 0.3±0.6 2.68±6.37 3.99±4.02 43.7±39.3 <0.001* Desaturation time (%) 0.1±0.1 0.8±1.8 1.2±1.2 14.0±12.9 <0.001* MinSaO 2 (%) 91.0±2.40 87.3±3.40 85.0±4.10 75.6±8.10 <0.001* ESS 7.2±3.9 9.9±4.5 11.0±5.00 10.7±5.10 0.03* EDS (%) 4 (18.2) 7 (38.9) 8 (50.0) 23 (47.9) 0.10* F-glucose (mg/dl) 96.2±21.3 93.8±14.8 90.1±11.9 92.1±23.7 0.81* T-chol (mg/dl) 198.6±26.60 195.3±26.80 195.0±19.60 207.2±32.70 0.30* TG (mg/dl) 139.1±63.40 136.8±40.30 138.8±52.00 175.7±72.00 0.03* HDL (mg/dl) 48.6±7.50 52.9±12.6 52.9±12.6 49.4±10.2 0.39* LDL (mg/dl) 120.8±25.10 115.7±19.90 116.3±20.00 125.8±29.10 0.41* Carotid IMT (mm) 0.551±0.078 0.500±0.047 0.589±0.046 0.685±0.059 <0.001* *p<0.05, ANOVA test or Pearson chi square test, OSA; obstructive sleep apnea, SBP; systolic blood pressure, DBP; diastolic blood pressure, DM; diabetes mellitus, BMI; body mass index, overweight; body mass index 25, AHI; apnea-hypopnea index, MinSaO 2; minimum oxygen saturation, ESS; Epworth Sleepiness Scale, EDS; excessive daytime sleepiness (ESS 11), F-glucose; fasting glucose, T-chol; total-cholesterol, TG; triglyceride, HDL; high density lipoprotein cholesterol, LDL; low density lipoprotein cholesterol, IMT; carotid intima-media thickness 132 대한신경과학회지제 27 권제 2 호, 2009
Table 3. Relationship of sleep apnea severity with carotid intima-media thickness Carotid IMT (mm) β SE p value AHI -0.003 0.000 <0.001* Lowest oxygen saturation (%) -0.007 0.002 <0.001* Desaturation time (%) -0.004 0.001 <0.001* *p<0.05, multiple regression analysis, Result was adjusted for systolic blood pressure, triglyceride level, body mass index (kg/m 2 ), hyperlipidemia, overweight (body mass index 25), statin use, alcohol drinking, and smoking. AHI; apnea-hypopnea index, IMT; intima-media thickness 수들은서로밀접한연관관계가있었다. 예를들어, 체질량지수와과체중, 고지혈증과중성지방등이다. 따라서, 이를고려한통계모델에서다중선형회귀분석을다시하였다. 이모델은독립변수로무호흡중증도, 수축기혈압, 흡연, 음주, 스타틴복용을포함하였다. 스타틴복용은고지혈증과관련되나, 목동맥 IMT 에대한스타틴의고유효과가알려져있으므로포함시켰다. 21 분석한통계모델은비만또는과체중한개변수와고지혈증또는중성지방중한가지변수를번갈아포함한총네개모델이었다. 각모델에서모든무호흡증중증도지표는목동맥 IMT 와독립적연관관계가있었다. IMT 는무호흡증중증도와상관관계가있었지만, 경증무호흡에서 IMT 수치가정상군보다유의하게낮았다 (p=0.03, Table 2). 경증무호흡군에비해대조군에서체질량지수 (p=0.01) 와흡연율 (p=0.06) 이높았다. 죽상경화판은 15명에서관찰할수있었다. 11명 ( 대조군 1, 경증무호흡 3, 중등도 1, 중증 6) 에서는 1등급, 4명의중증무호흡에서는 2등급이었다. 죽상경화판의빈도는대조군 (1, 5.6%), 경증무호흡 (3, 18.8%), 중등도 (1, 10.0%), 중증 (10, 27.8%) 사이에유의한차이가없었다 (chi-square test, p=0.42). 초음파검사는대조군 18명 (81.8%), 경증무호흡 16명 (88.9%), 중등도 10명 (62.5%), 중증무호흡 36명 (75.0%) 에서시행하였고, 각군에서검사빈도의차이는없었다 (p=0.29). 수면무호흡증은저산소증외에수면분절 (sleep fragmentation) 을통해서도장애를초래한다. 22 따라서, 각성지수 (arousal index) 와 IMT 간의상관관계를다변량분석하였다. 위에기술한통계모델에서수면중증도지표를제외한경우, 각성지수와 IMT 간에유의한상관관계 (r=0.73, p<0.001) 가있었으나, 수면중증도지표를포함한모델에서는중증도지표만이 IMT 와유의한상관관계가있었다. 고찰 본연구를통해폐쇄성수면무호흡과목동맥 IMT 사이의독립적상관관계를규명하였다. 목동맥 IMT 는동맥경화증의주요지표로알려져있다. 비침습적으로측정이가능하며비징후성동맥경화증의조직학적소견과잘일치하기때문이다. 23 또한 IMT 의증가는동맥경화성심혈관및뇌혈관질환발병위험과연관된다. 24 따라서, 본연구결과는무증상성동맥경화증이무호흡증에존재하며, 그정도가무호흡증의중증도와정량적상관관계가있음을규명하였다. 이는현재까지알려진폐쇄성수면무호흡증과동맥경화성심장및뇌혈관질환의상관관계를뒷받침한다. 3 무호흡증에의해직접초래되는저산소증 (hypoxia) 과재산소화 (reoxygenation) 의반복은산소화손상 (oxidative Figure. Scatter plot of apnea severity and carotid intima-media thickness (IMT). All severity indices including apnea-hypopnea index (AHI), lowest oxygen saturation, and desaturation time independently correlate with carotid IMT. J Korean Neurol Assoc Volume 27 No. 2, 2009 133
injury) 등을통해동맥경화증을유발한다. 3 본연구결과무호흡의중증도지표인 AHI, 최저산소포화도, 저산소포화시간과 IMT 사이의독립적정량관계는이를뒷받침한다. 또한, 무호흡증은전신염증반응 (systemic inflammation) 을유도하는것으로알려져있다. 무호흡환자에게서염증성사이토카인 (cytokine) 인종양괴사성인자 (tumor necrosis factor alpha), 인터루킨-6 (interleukin-6), C-반응단백 (c-reactive protein) 의증가와염증매개물질인 nuclear factor-κb 와세포간접착분자 (intercellular adhesion molecule-1), E-셀렉틴 (E-selectin) 의높은발현이알려져있다. 25-28 염증은동맥경화증의중요한발병기전이다. 29 따라서, 무호흡증에의한전신염증반응의증가가목동맥경화증을가속화한다고추정할수있다. 또한, 코골이의진동에너지가목동맥의동맥경화진행에영향을끼친다고도알려져있다. 동물모델에서코골이에의한목동맥에너지전달이확인되었고, 저산소증이없는경증의무호흡증환자에게서목동맥동맥경화증의정도가저산소성지표및 AHI 와무관하게코골이와관련됨이보고되었다. 30,31 그외에도교감신경항진등이동맥경화증을초래하는것으로알려져있다. 3,25 무호흡증과동맥경화증의인과관계는지속적양압호흡기 (continuous positive airway pressure) 치료를통한목동맥 IMT 의개선연구결과를통해서도확인할수있다. 이전의연구에서 4개월간지속적양압호흡기치료후목동맥직경의변화를관찰하였는데, 효과적양압치료만으로도목동맥경화증이유의하게감소하였다. 25 이는전신염증반응과교감신경의활성감소와관계가있고, 혈압또는혈중콜레스테롤수치변화와는무관하였다. IMT 의감소정도가기존스타틴등고지혈증치료제효과보다월등하였다는점은주목할만한다. 25,32,33 본연구에서는치료후변화를관찰하지못하였다. 현재국내의료보험이양압호흡기치료에대해의료급여를인정하지않고, 수술적치료에만급여를인정하고있기때문이다. 본연구에참여한환자중 25.6% 만이양압호흡기치료를받았고, 두명을제외한모두가수술적치료를받았다. 수술은기법에따라효과차이가많고양압호흡기치료보다치료성적이매우좋지않다. 34 본연구에는혈관질환위험인자가있는대상도포함하였다. 동맥경화증에대한폐쇄성수면무호흡증만의영향을규명하기위해서는다른혈관질환위험인자, 예를들어과체중, 고혈압, 당뇨병, 고지혈증, 흡연력및과도한음주력이없는대상자를선별하여연구를하는것이이상적이다. 하지만, 무호흡환자중다수가과체중이고, 과체중은다른혈관위험인자를흔히동반하므로무호흡증만있는환자를선별하기어렵다는문제가있다. 따라서, 본연구와같이, 무호흡증환자와위험인자를짝짓기한대조군과결과변수를비교하거나, 통계적보정을하는 것이연구의방법이될수있다. 이런방식의연구는무호흡증과다른위험인자들사이의상호작용을알아볼수있는장점이있다. 실제무호흡증과고혈압, 고지혈증등의상호작용이심혈관질환또는대사이상을가중시킨다는것이보고되었다. 35-38 또한고혈압과무호흡증이목동맥경화증에끼치는상승작용도보고되었다. 39 한편, 본연구에서무호흡증중증도만이 IMT 와상관관계를보였다고해서, 고혈압, 당뇨병, 고지혈증, 흡연등이 IMT, 즉동맥경화증과연관이없다는것을의미하지는않는다. 연구설계상환자와대조군간교란변수분포균형이이들영향을확인하기어렵게만들었을것으로생각한다. 본연구의다른제한점은대조군선정에있다. 습관성코골이또는목격된무호흡등을평가하기위해서수면클리닉에내원한환자중수면다원검사상 AHI 가 5 미만인경우, 즉단순코골이환자를대조군에포함시켰기때문이다. 하지만, 코골이자체가목동맥경화증을초래함에도불구하고코골이가있는대조군보다무호흡환자군에서유의하게 IMT 가높았다는것은무호흡증이중요함을시사한다. 30,31 본연구를통해확인된폐쇄성무호흡증과동맥경화증의독립적연관관계는폐쇄성무호흡증이각종심혈관질환의발병위험인자임을뒷받침한다. 따라서, 수면무호흡증을적극적으로진단하고치료하는것이필요하다. REFRENENCES 1. Kim J, In K, You S, Kang K, Shim J, Lee S, et al. Prevalence of sleepdisordered breathing in middle-aged Korean men and women. Am J Respir Crit Care Med 2004;170:1108-1113. 2. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328:1230-1235. 3. Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, et al. Sleep apnea and cardiovascular disease: an American Heart Association/american College Of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council On Cardiovascular Nursing. In collaboration with the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health). Circulation 2008;118:1080-1111. 4. Bixler EO, Vgontzas AN, Lin HM, Ten Have T, Rein J, Vela-Bueno A, et al. Prevalence of sleep-disordered breathing in women: effects of gender. Am J Respir Crit Care Med 2001;163:608-613. 5. Tishler PV, Larkin EK, Schluchter MD, Redline S. Incidence of sleepdisordered breathing in an urban adult population: the relative importance of risk factors in the development of sleep-disordered breathing. JAMA 2003;289:2230-2237. 6. Newman AB, Foster G, Givelber R, Nieto FJ, Redline S, Young T. Progression and regression of sleep-disordered breathing with changes 134 대한신경과학회지제 27 권제 2 호, 2009
in weight: the Sleep Heart Health Study. Arch Intern Med 2005;165: 2408-2413. 7. Bixler EO, Vgontzas AN, Ten Have T, Tyson K, Kales A. Effects of age on sleep apnea in men: I. Prevalence and severity. Am J Respir Crit Care Med 1998;157:144-148. 8. Wetter DW, Young TB, Bidwell TR, Badr MS, Palta M. Smoking as a risk factor for sleep-disordered breathing. Arch Intern Med 1994;154: 2219-2224. 9. Quan SF, O Connor GT, Quan JS, Redline S, Resnick HE, Shahar E, et al. Association of physical activity with sleep-disordered breathing. Sleep Breath 2007;11:149-157. 10. Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005;353:2034-2041. 11. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365:1046-1053. 12. Rechtschaffen A, Kale A. A manual of standardized technology, techniques and scoring system for sleep stages for human subjects. Los Angeles: Brain information service/brain research institute, University of California-Los Angeles, 1968. 13. EEG arousals: scoring rules and examples: a preliminary report from the Sleep Disorders Atlas Task Force of the American Sleep Disorders Association. Sleep 1992;15:173-184. 14. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep 1999;22: 667-689. 15. American Academy of Sleep Medicine. Obstructive sleep apnea syndromes. In: International classification of sleep disorders. Diagnostic and coding manual. 2nd ed. Westchester, Illinois: American Academy of Sleep Medicine, 2005: 51-59. 16. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540-545. 17. Recommendations for routine blood pressure measurement by indirect cuff sphygmomanometry. American Society of Hypertension. Am J Hypertens 1992;5:207-209. 18. World Health Organization. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. Geneva: World Health Organization, 2000. 19. Kloner RA, Rezkalla SH. To drink or not to drink? That is the question. Circulation 2007;116:1306-1317. 20. Silvestrini M, Rizzato B, Placidi F, Baruffaldi R, Bianconi A, Diomedi M. Carotid artery wall thickness in patients with obstructive sleep apnea syndrome. Stroke 2002;33:1782-1785. 21. Kang S, Wu Y, Li X. Effects of statin therapy on the progression of carotid atherosclerosis: a systematic review and meta-analysis. Atherosclerosis 2004;177:433-442. 22. Thomas RJ. Sleep fragmentation and arousals from sleep-time scales, associations, and implications. Clin Neurophysiol 2006;117:707-711. 23. Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation 1986;74:1399-1406. 24. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007;115:459-467. 25. Minoguchi K, Yokoe T, Tazaki T, Minoguchi H, Tanaka A, Oda N, et al. Increased carotid intima-media thickness and serum inflammatory markers in obstructive sleep apnea. Am J Respir Crit Care Med 2005;172: 625-630. 26. Ryan S, Taylor CT, McNicholas WT. Predictors of elevated nuclear factor-kappab-dependent genes in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2006;174:824-830. 27. Ohga E, Nagase T, Tomita T, Teramoto S, Matsuse T, Katayama H, et al. Increased levels of circulating ICAM-1, VCAM-1, and L-selectin in obstructive sleep apnea syndrome. J Appl Physiol 1999;87:10-14. 28. Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med 2002;165:934-939. 29. Lusis AJ. Atherosclerosis. Nature 2000;407:233-241. 30. Amatoury J, Howitt L, Wheatley JR, Avolio AP, AmisTC. Snoringrelated energy transmission to the carotid artery in rabbits. J Appl Physiol 2006;100:1547-1553. 31. Lee SA, Amis TC, Byth K, Larcos G, Kairaitis K, Robinson TD, et al. Heavy snoring as a cause of carotid artery atherosclerosis. Sleep 2008;31: 1207-1213. 32. Amarenco P, Labreuche J, Lavallee P, Touboul PJ. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke 2004;35:2902-2909. 33. Yokoyama H, Kawasaki M, Ito Y, Minatoguchi S, Fujiwara H. Effects of fluvastatin on the carotid arterial media as assessed by integrated backscatter ultrasound compared with pulse-wave velocity. J Am Coll Cardiol 2005;46:2031-2037. 34. Won CH, Li KK, Guilleminault C. Surgical treatment of obstructive sleep apnea: upper airway and maxillomandibular surgery. Proc Am Thorac Soc 2008;5:193-199. 35. Elmasry A, Lindberg E, Berne C, Janson C, Gislason T, Awad Tageldin M, et al. Sleep-disordered breathing and glucose metabolism in hypertensive men: a population-based study. J Intern Med 2001;249:153-161. 36. Savransky V, Nanayakkara A, Li J, Bevans S, Smith PL, Rodriguez A, et al. Chronic intermittent hypoxia induces atherosclerosis. Am J Respir Crit Care Med 2007;175:1290-1297. 37. Drager LF, Bortolotto LA, Figueiredo AC, Silva BC, Krieger EM, Lorenzi- Filho G. Obstructive sleep apnea, hypertension, and their interaction on arterial stiffness and heart remodeling. Chest 2007;131:1379-1386. 38. Lavie L, Lavie P. Smoking interacts with sleep apnea to increase cardiovascular risk. Sleep Med 2008;9:247-253. 39. Drager LF, Bortolotto LA, Krieger EM, Lorenzi-Filho G. Additive effects of obstructive sleep apnea and hypertension on early markers of carotid atherosclerosis. Hypertension 2009;53:64-69. J Korean Neurol Assoc Volume 27 No. 2, 2009 135