Endocrinol Metab 26(1):44-52, March 2011 DOI: /EnM ORIGINAL ARTICLE 제 2 형당뇨병환자에서심혈관계자율신경병증과상완 - 발목맥파속도의상관관계 배영필 이병도 김봉건 박종화 권용섭 박자

Endocrinol Metab 26(1):44-52, March 2011 ORIGINAL ARTICLE 제 2 형당뇨병환자에서심혈관계자율신경병증과상완 - 발목맥파속도의상관관계 배영필 이병도 김봉건 박종화 권용섭 박자영 이창원 김보현 1 장재식 2 부산성모병원내과, 부산대학교의학전문대학원내과학교실내분비내과 1, 인제대학교부산백병원순환기내과 2 Relationships between Cardiac Autonomic Neuropathy and the Brachial-ankle Pulse Wave Velocity in Patients with Type 2 Diabetes Young Pil Bae, Byeong Do Yi, Bong-Gun Kim, Jong-Hwa Park, Yong Seop Kwon, Ja Young Park, Chang Won Lee, Bo Hyun Kim 1, Jae-Sik Jang 2 Department of Internal Medicine, Busan St. Mary s Medical Center, Busan; Division of Endocrinology and Metabolism, Department of Internal Medicine 1, Pusan National University School of Medicine Hospital, Busan; Division of Cardiology, Department of Internal Medicine 2, Pusan-Paik Hospital, Inje University College of Medicine, Busan, Korea Background: Cardiovascular disease is the leading cause of death in patients with type 2 diabetes. Clinically, evaluating cardiovascular autonomic neuropathy (CAN) is important to predict cardiovascular mortality because it is correlated with cardiovascular death. The pulse wave velocity (PWV) correlates well with arterial distensibility and stiffness. It is also a useful approach for evaluating the severity of systemic atherosclerosis in adults. So, we evaluated that the relationship between cardiac autonomic neuropathy and the brachial-ankle pulse wave velocity (bapwv) in patients with type 2 diabetes. Methods: We retrospectively analyzed 465 patients (209 men and 256 women) with type 2 diabetes. We checked the clinical characteristics and the laboratory tests and we assessed the diabetic complications. Standard tests for CAN were performed by DiCAN (Medicore, Seoul, Korea): 1) heart rate variability during deep breathing (the E/I ratio), 2) a Valsalva maneuver, 3) 30:15 ratio of R-R interval the blood pressure response to standing, and 5) the blood pressure response to handgrip. The CAN score was determined according to the results of the test as following: 0 = normal, 0.5 = borderline, 1 = abnormal. We also measured the bapwv by using a VP 1000 (Colin, Japan) and all the analyses were performed with the SPSS version 14.0. P values < 0.05 were considered significant. Results: The CAN score is associated with the maximal bapwv, age, systolic blood pressure, microalbuminuria, the duration of diabetes, angiotensin II receptor blocker treatment, calcium channel blocker treatment, β-blocker treatment and nephropathy. After adjusting for age, the bapwv is a independent predictor of the risk for CAN (β = 0.108, P = 0.021). Conclusion: The CAN is associated with the bapwv in patient with type 2 diabetes. (Endocrinol Metab 26:44-52, 2011) Key Words: Brachial-ankle pulse-wave velocity, Cardiovascular atonomic neuropathy, Type 2 diabetes 서론 전세계적으로제 2 형당뇨병환자의가장중요한사망원인은심 혈관계질환이며, 전체당뇨병으로인한사망원인중 40% 이상을 심근경색및뇌경색등이차지하고있다 [1]. 당뇨병은심혈관질환의 Received: 12 August 2010, Accepted: 14 September 2010 Corresponding author: Chang Won Lee Department of Internal Medicine, Busan St. Mary s Medical Center, 538-41 Yongho-dong, Nam-gu, Busan 608-838, Korea Tel: +82-51-933-7235, Fax: +82-51-932-8600, E-mail: koje94@hanmail.net 독립적인위험인자로, 당뇨병환자에서심혈관합병증의발생빈도는매년 1-3% 이며정상인에비하여 2-3배높다. 또한당뇨병으로인한전체사망률중약 75% 는심혈관합병증에기인하며, 죽상경화증 (atherosclerosis) 은이러한심혈관합병증의중요한요인으로여겨진다 [2]. 동맥의강직도는심혈관질환의독립된위험인자이며동맥의맥파속도 (pulse wave velocity, PWV) 는동맥의강직도를반영하는지표로서, 맥파속도의이상은전반적인동맥경화의지표가될수있다 [3]. 상완-발목맥파속도 (brachial-ankle pulse wave velocity, bapwv) 는동맥의죽상동맥경화증을측정하기위하여진동법 (os-

Relationships between CAN and the ba-pwv in Patients with Type 2 Diabetes 45 cillometric method) 에의해비침습적으로동맥의경직도를측정하는방법으로 [4,5] 비교적간단하게혈압과맥파속도를측정할수있다. 상완-발목맥파속도는대동맥맥파속도와달리대동맥및말초동맥의상태를모두반영하고혈관운동반사에영향을받기때문에대동맥맥파속도에비해미세혈관병증의상태및당뇨병의합병증과더큰연관성이있다고보고된다 [6]. 당뇨병성신경합병증중심혈관계자율신경병증은제2형당뇨병환자에서심혈관질환과관련된사망과깊은연관이있으나 [7], 초기에는최대 50% 까지신경병증의특징적인증상이없으므로 [8] 조기발견을위한관심이요구된다. 제2형당뇨병환자에서심혈관계자율신경병증동반시미세혈류장애를반영할수있는상완-발목맥파속도가도움이될것으로생각되나이에대한보고가드문실정이다. 이에본연구에서는자율신경병증검사와상완-발목맥파속도를측정한제2형당뇨병환자들을대상으로후향적으로검사결과를비교하여그상관관계에대해알아보고자하였다. 대상및방법이연구는임상윤리위원회의사전승인 (BSM 2009-03) 을받았다. 2008년 1월 1일부터 2009년 8월 31일까지제2형당뇨병으로외래또는입원치료중인 20세이상의환자중에서심혈관계자율신경병증검사및상완-발목맥파속도를동시에검사한 475명을대상으로하였다. 제2형당뇨병은미국당뇨병학회의진단기준에따랐으며, New York Heart Association (NYHA) Functional Classification III 이상의중증의심부전환자, 투석중인만성신부전환자, 심혈관계자율신경검사가미비했던 10명의환자는제외되었다. 모든대상자에서일반적인신체계측, 현병력을조사하였으며, 공복상태에서혈청지질검사를포함한일반화학검사를시행하였다. 이연구의비교군으로상완-발목맥파속도검사만을시행한환자는총 813명이었다. 심혈관계자율신경병증검사와상완-발목맥파속도를동시에시행한환자들은입원한상태였거나, 외래방문자의경우비교적다른합병증이동반된경우가많았다. 모든환자에서연령, 성별, 나이, 키, 몸무게, 허리둘레, 엉덩이둘레및체질량지수 (body mass index) 를평가하였고, 체질량지수는몸무게 (kg) 를키의제곱 (m 2 ) 으로나누어계산하였다. 수축기혈압, 이완기혈압은앙와위에서 5분간휴식후에좌, 우양측에서측정하였다. 당뇨병이환기간, 고혈압유무, 음주흡연의기왕력및인슐린사용여부및스타틴제, 항혈소판제, 안지오텐신전환효소억제제, 안지오텐신차단제, 베타차단제, 칼슘차단제및기타고혈압제복용유무에대해서도조사하였다. 당뇨병성말초신경병증의진단은환자가호소하는증상, 모노필라멘트검사 (10 g monofilament), 128헤르쓰음차를이용한진동각검사, 타건기를이용한심부각검사중한 가지이상을만족할때로정의하였다. 당뇨병성신증동반유무는요단백을정량화하기위해서 24시간뇨의채취가필요하나, 외래방문한환자를대상으로하였기때문에무작위소변에서알부민 / 크레아티닌비 (spot urinary albumin/creatinine ratio, ACR) 를측정하여반정량적인측정을하였다. ACR < 30 μg/mg인경우는정상, ACR 30 μg/mg인경우를당뇨병성신증으로정의하였다 [9]. 최소 8시간이상공복후혈액을채취하여공복혈당, 공복인슐린, 당화혈색소, 총콜레스테롤, 저밀도지단백콜레스테롤 (low density lipoprotein cholesterol, LDL-C), 고밀도지단백콜레스테롤 (high density lipoprotein cholesterol, HDL-C), 중성지방 (triglyceride, TG), high sensitivity C-reactive protein (hscrp), 미세알부민뇨, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (γ-gtp) 를측정하였다. 상완-발목맥파속도는가능한한일상생활중의상태를반영하기위해평소사용중인약물 ( 경구용혈당강하제혹은인슐린, 고혈압약제, 스타틴제, 항혈소판제등 ) 을그대로사용하는상태에서주간에특정시간의제한을두지않고측정하였다. 혈압과상완-발목맥파속도는누운자세에서최소 5분안정후자동파형분석기 (VP- 1000, Colin, Japan) 를사용하여측정하였다. 상완과발목에진동감지기를가진 cuff를감아혈압을측정하였고, 발목-상완지수는수축기혈압에대한발목대상완비로자동적으로계산하였다. 양쪽손목에심전도유도를부착하여심전도를감시하였고, 흉골좌연의제3늑간에심음도마이크로폰을두어심음 S1 및 S2를기록하였다. 맥파속도를결정하는데필요한시간간격 ( T) 과측정지점간의거리 (L) 는모두파형분석기에서자동으로계산되었다. 거리는대상자의키 (cm) 를근거로하였다. 상완-발목맥파속도는상완-발목거리 (L) = 0.5934 키 (cm) + 14.4014 를상완및발목에서의맥파시작점간의시간간격 ( T) 으로나눈값 (L/ T) 이며자동으로계산되었다 [10]. 우측상완-발목맥파속도 (right brachial-ankle pulse wave velocity, Rt. bapwv), 좌측상완-발목맥파속도 (Lt. bapwv) 를측정하였고, 이중큰값을최대상완-발목맥파속도로정하였다. 모든계측치는규칙적인동성리듬동안측정되었다. 심혈관계자율신경기능검사는 DiCAN (Medicore, Seoul, Korea) 을이용하여발살바수기시, 체위변화시, 반복적인심호흡호기와흡기시심박동수의변화와기립시와악력주입시혈압변화를측정하였다. 발살바수기는압력계에연결된튜브를통하여 40 mmhg 가유지되도록호기하여가장긴 R-R 간격값을가장짧은 R-R 간격값으로나눈값 (E/I ratio) 으로정의하였다. 체위변화시는앙와위에서기립상태로변화시심박동수의변화를관찰하는검사로, ECG 에서 30회주위의가장긴 R-R 간격 /15 회주위의가장짧은 R-R 간격의비율 (30/15 ratio) 을구하였다. 심호흡시에는호기시가장긴 R-R 간격의평균값을흡기시가장짧은 R-R 간격의평균값으로나

46 Bae YP, et al. 눈값으로정의하였다 [11]. 직립후혈압반응은앙와위에서기립상태로자세변화시수축기혈압의하강정도를관찰하였다. 악력주입은악력운동계측기로최대악력의 30% 악력으로유지시키면서확장기혈압의변화를측정하였다. 심혈관계자율신경병증의점수는미국당뇨병학회의권고사항에따랐으며, E/I 비는연령과관련된참고치를이용하였다. 30:15 비는정상은 1.04 이상, 경계성이상은 1.011 이상 1.03 이하, 이상은 1.00 이하로정의하였다. 발살바비는정상은 1.21 이상, 경계성이상은 1.11 이상 1.20 이하, 이상은 1.10 이하로정의하였다. 심호흡후심박수변화는정상은 15 이상, 경계성이상은 11 이상 14 이하, 이상은 10 이하로정의하였다. 직립후혈압반응은수축기혈압의감소가정상은 10 이하, 경계성이상은 11 이상 29 이하, 이상은 30 이상으로정의하였다. 악력주입시는혈압상승이정상은 16 이상, 경계성이상은 11 이상 15 이하, 이상은 10 이하로정의하였다. 각다섯가지항목에대한정상은 0점, 경계성이상은 0.5점, 이상은 1점으로계산하였고 5점을최대값으로정의하였으며, 합계 1.5 점이상을심혈관계자율신경병증이있는것으로정의하였다. 통계분석은윈도우용 SPSS 14.0 (SPSS Inc., Chicago, IL, USA) 을이용하였고측정치는평균과표준편차로표시하였다. 심혈관계자율신경병증유무에따른여러인자들의차이를보기위해연속변수들은독립표본 t-검증을, 이변량변수들은카이제곱 (χ²) 검증을이용하였다. 심혈관계자율신경병증점수와발목-상완맥파속도에영향을미치는인자를확인하기위해서 Pearson 및 Spearman 상관분석을시행하였고, 통계적으로유의한결과를보인변수들은나이를제어변수로실시한편상관분석및다중회귀분석을실시하였다. P 값이 0.05 미만인경우에통계적으로유의성이있는것으로판정하였다. 결과입원또는외래를방문한 20세이상의제2형당뇨병환자 1278명중심혈관계자율신경병증검사를시행한군 (n=465) 과시행하지않은군 (n=813) 과의임상적인특성은다음과같았다 (Table 1). 검사시행군에서검사미실시군에비해여성의비율이높고체질량지수는적었으며몸무게가작았으나, 나이, 키, 허리둘레, 당뇨병유병기간, 흡연력, 음주력등은두군간에유의한차이는없었다. 또한, 검사시행군에서검사미실시군에비해인슐린치료중인환자가더많았고, 최대상완-발목맥파속도, 당화혈색소및공복시혈당, 저밀도지단백콜레스테롤, 고밀도지단백콜레스테롤, 총콜레스테롤이높았으나, 미세알부민뇨, 공복시인슐린수치, hscrp, AST, ALT, γ-gtp, 수축기혈압, 이완기혈압등은유의한차이가없었다. 말초신경병증, 당뇨병성신증도검사시행군에서더많았으나, 심혈관질환의과거력은유의한차이는없었다 (Table 1). 총 465 명의심혈관계자율신경병증검사군은총 465 명으로남자 환자 209 명, 여자환자 256 명이었으며, 이들의임상적특징은다음과 같았다 (Table 2). 전체환자의평균나이는 58.5 세였고, 체질량지수 는 24.7 ± 3.6 kg/m 2 였으며, 당뇨병유병기간은 8.7 ± 7.7 년이며, 당화 혈색소는 8.4 ± 2.2% 였다. 인슐린치료는 42% 의환자가받고있었 고, 스타틴제, 항혈소판제, alpha lipoic acid 는각각 41%, 43%, 47% 환자에서복용하고있었다. 안지오텐신전환효소억제제, 안지오텐 신차단제, 베타차단제, 칼슘차단제등의혈압강하제는각각 11%, 42%, 15%, 26% 에서사용중이었다. 344 명 (74%) 의환자에서말초신 경병증, 163 명 (35%) 의환자에서당뇨병성신증이동반되어있었으 Table 1. Baseline characteristics of the DiCAN test group and the control group Control group (n = 813) DiCAN test Test group (n = 465) P value Age (years) 58.08 ± 11.5 58.5 ± 11.9 0.532 Sex (M/F) (%) 49/51 45/55 0.041 Height (cm) 161.3 ± 8.9 160.7 ± 9.2 0.277 Weight (kg) 65.4 ± 10.9 63.9 ± 12.3 0.031 BMI (kg/m 2 ) 25.1 ± 3.4 24.7 ± 3.6 0.047 Waist (cm) 89.1 ± 8.2 88.6 ± 9.1 0.378 Duration of diabetes (years) 8.8 ± 6.6 8.7 ± 7.7 0.769 Smoking (%) 23 23 1.000 Alcohol (%) 33 32 0.618 Insulin treatment (%) 28 42 < 0.01 HbA1c (%) 7.5 ± 1.6 8.4 ± 2.2 < 0.01 Microalbuminuria (μg/mg crea) 171.2 ± 757.2 250.7 ± 891.0 0.095 Fasting plasma glucose (mg/dl) 141.1 ± 47.7 166.1 ± 68.2 < 0.01 Fasting insulin (mu/ml) 11.4 ± 10.4 11.6 ± 12.8 0.799 hscrp (mg/l) 1.97 ± 7.17 1.94 ± 3.67 0.938 Triglyceride (mg/dl) 149.4 ± 104.4 152.2 ± 93.6 0.624 LDL-C (mg/dl) 96.2 ± 32.8 102.9 ± 39.2 < 0.01 HDL-C (mg/dl) 47.5 ± 10.9 45.8 ± 12.0 0.015 Total cholesterol (mg/dl) 174.3 ± 40.0 179.3 ± 43.2 0.037 AST (U/L) 27.6 ± 16.5 28.1 ± 19.8 0.593 ALT (U/L) 28.2 ± 18.7 28.3 ± 19.1 0.896 γ-gtp (U/L) 45.4 ± 93.6 52.4 ± 90.8 0.195 SBP (mmhg) 133.2 ± 17.4 134.5 ± 19.4 0.218 DBP (mmhg) 78.9 ± 9.7 79.4 ± 10.5 0.411 Maximal bapwv (cm/sec) 1609 ± 377 1659 ± 365 0.021 Neuropathy (%) 54 74 < 0.01 CVD (%) 5 6 0.272 Nephropathy (%) 30 35 0.032 Data are mean ± SD. P value < 0.05 were considered significant. BMI, body mass index; HbA1c, hemoglobin A1c; hscrp, high sensitive C-reactive protein; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; AST, aspartate transferase; ALT, alanine transferase; γ-gtp, gammaglutamyltranspeptidase; SBP, systolic blood pressure; DBP, diastolic blood pressure; bapwv, brachial-ankle pulse wave velocity; CVD, cardiovascular diseases.

Relationships between CAN and the ba-pwv in Patients with Type 2 Diabetes 47 며, 28명 (6%) 의환자에서는심혈관질환의과거력이있었다. 말초신경병증진단시신경병증증상이동반된환자는 64%, 모노필라멘트검사양성인환자는 7%, 진동각검사양성인환자는 46%, 심부각검사양성인환자는 0.2% 였다 (Table 2). 심혈관계자율신경병증검사이상군과정상군의임상적특성을 분석한결과, 이상군에서정상군에비하여평균나이가많았고, 키와몸무게, 허리둘레가작았다. 당뇨병유병기간, 흡연력, 음주력등은두군간에유의한차이는없었다. 자율신경병증검사이상군에서 alpha lipoic acid 치료중인환자가더많았으나, 인슐린, 안지오텐신전환효소억제제, 안지오텐신차단제, 티아자이드이뇨제, 베타 Table 2. Baseline characteristics of the test group Absence of CAN (n = 209) Presence of CAN (n = 256) Total (n = 465) P value Age (years) 55.9 ± 12.0 60.4 ± 11.3 58.5 ± 11.9 < 0.01 Sex (M/F) (%) 47/53 43/57 45/55 0.329 Height (cm) 162.2 ± 9.0 159.5 ± 9.2 160.7 ± 9.2 < 0.01 Weight (kg) 65.3 ± 12.5 62.8 ± 11.9 63.9 ± 12.3 0.034 BMI (kg/m 2 ) 24.7 ± 3.6 24.5 ± 3.5 24.7 ± 3.6 0.686 Waist (cm) 88.6 ± 9.3 88.5 ± 9.0 88.6 ± 9.1 0.029 Duration of diabetes (years) 8.0 ± 7.6 9.3 ± 7.8 8.7 ± 7.7 0.093 Smoking (%) 23 23 23 1.000 Alcohol (%) 33 31 32 0.543 Insulin treatment (%) 40 44 42 0.449 Statin treatment (%) 42 41 41 0.924 Antiplatelet agent treatment (%) 41 44 43 0.647 ACE inhibitor treatment (%) 10 12 11 0.658 ARB treatment (%) 38 45 42 0.215 β-blocker treatment (%) 11 17 15 0.110 CCB treatment (%) 21 29 26 0.085 α-lipoic acid treatment (%) 37 54 47 < 0.01 HbA1c (%) 8.4 ± 2.4 8.4 ± 2.1 8.4 ± 2.2 0.975 Microalbuminuria (μg/mg crea) 139.9 ± 577.9 336.7 ± 1066.3 250.7 ± 891.0 0.012 Fasting plasma glucose (mg/dl) 170.2 ± 69.3 163.8 ± 67.4 166.1 ± 68.2 0.333 Fasting Insulin (mu/ml) 10.4 ± 9.7 12.5 ± 14.7 11.6 ± 12.8 0.088 hscrp (mg/l) 1.97 ± 3.67 1.91 ± 3.68 1.94 ± 3.67 0.879 Triglyceride (mg/dl) 145.1 ± 83.6 158.0 ± 100.7 152.2 ± 93.6 0.146 LDL-C (mg/dl) 106.1 ± 35.1 100.3 ± 42.1 102.9 ± 39.2 0.125 HDL-C (mg/dl) 47.0 ± 11.8 44.8 ± 12.1 45.8 ± 12.0 0.055 Total cholesterol (mg/dl) 180.2 ± 40.3 178.6 ± 45.1 179.3 ± 43.2 0.694 AST (U/L) 29.6 ± 23.0 27.0 ± 16.8 28.1 ± 19.8 0.022 ALT (U/L) 30.2 ± 20.2 26.8 ± 18.2 28.3 ± 19.1 0.018 r-gtp (U/L) 49.0 ± 68.6 55.1 ± 105.0 52.4 ± 90.8 0.476 SBP (mmhg) 132.3 ± 17.3 136.0 ± 20.7 134.5 ± 19.4 0.037 DBP (mmhg) 79.1 ± 10.6 79.7 ± 10.5 79.4 ± 10.5 0.558 Maximal bapwv (cm/sec) 1612 ± 363 1698 ± 387 1659 ± 365 < 0.01 Neuropathy (%) 69 79 74 0.015 Neuropathy symptoms (%) 57 69 64 < 0.01 Monofilament test (%) 3 10 7 < 0.01 Tuning fork test (%) 42 49 46 0.111 Ankle Jerk reflex (%) 0.4 0 0.2 0.439 CVD (%) 4 7 6 0.101 Nephropathy (%) 31 39 35 0.018 Data are mean ± SD. P value < 0.05 were considered significant. CAN, cardiovascular autonomic neuropathy; BMI, body mass index; ACE inhibitor, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; HbA1c, hemoglobin A1c; hscrp, high sensitive C-reactive protein; LDL- C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; AST, aspartate transferase; ALT, alanine transferase; γ-gtp, gamma-glutamyltranspeptidase; SBP, systolic blood pressure; DBP, diastolic blood pressure; bapwv, brachial-ankle pulse wave velocity; CVD, cardiovascular diseases.

48 Bae YP, et al. Table 3. Correlation between maximal bapwv and other variable factors Maximal bapwv Age-adjusted partial correlation r * P value β P value Age 0.538 < 0.01 DiCAN score 0.212 < 0.01 0.108 0.021 Height -0.258 < 0.01 0.039 0.411 Weight -0.268 < 0.01-0.066 0.163 SBP 0.568 < 0.01 0.580 < 0.01 Microalbuminuria 0.185 < 0.01 0.265 < 0.01 HDL-C -0.030 0.520-0.051 0.317 Triglyceride -0.040 0.395 0.052 0.314 AST -0.001 0.975 0.047 0.363 ALT -0.095 0.043 0.018 0.725 Duration of diabetes 0.326 < 0.01 0.198 < 0.01 ARB treatment 0.122 < 0.01 0.079 0.124 CCB treatment 0.196 < 0.01 0.128 0.012 β-blocker treatment 0.061 0.191 0.032 0.534 Neuropathy 0.092 0.047 0.025 0.623 P value < 0.05 were considered significant. *Pearson s and Spearman correlation coefficient; Standard coefficient. bapwv, brachial-ankle pulse wave velocity; SBP, systolic blood pressure; HDL- C, high density lipoprotein cholesterol; AST, aspartate transferase; ALT, alanine transferase; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; CVD, cardiovascular diseases. Maximal bapwv 3500.00 3000.00 2500.00 2000.00 1500.00 1000.00 0.0 2.0 4.0 CAN score Fig. 1. Relationship between maximal brachial-ankle pulse wave velocity and cardiovascular autonomic neuropathy score. There was significant positive correlation between maximal pulse wave velocity and cardiovascular autonomic neuropathy score (r = 0.212, P < 0.01). 차단제, 칼슘차단제, 스타틴제, 항혈소판제치료병력은두군에서유 의한차이는없었다. 자율신경병증검사이상군에서당뇨병성신증, 말초신경병증및신경병증증상, 모노필라멘트검사이상이동반된 경우가많았으며, 심혈관질환의과거력은두군간에유의한차이 Table 4. Correlation between DiCAN score and other variable factors 가없었다. 최대상완 - 발목맥파속도와수축기혈압은심혈관계자 율신경병증검사이상군에서모두의미있게높았으나, 이완기혈압 은두군간의차이가없었다. AST 와미세알부민뇨는이상군에서 높은결과를보였으나이외의생화학적검사결과에서두군간의 차이는없었다 (Table 2). DiCAN score Age-adjusted partial correlation r * P value β P value Age 0.231 < 0.01 Height -0.140 < 0.01-0.021 0.648 Weight -0.098 0.034-0.011 0.812 SBP 0.130 < 0.01 0.087 0.064 Maximal bapwv 0.212 < 0.01 0.108 0.021 Microalbuminuria 0.121 < 0.01 0.142 < 0.01 HDL-C -0.118 0.012-0.119 0.020 Triglyceride 0.092 0.052 0.111 0.031 AST -0.107 0.022-0.095 0.063 ALT -0.111 0.018-0.069 0.181 Duration of diabetes 0.117 0.017 0.057 0.268 ARB treatment 0.122 < 0.01 0.122 0.017 CCB treatment 0.111 0.017 0.085 0.097 β-blocker treatment 0.129 < 0.01 0.144 < 0.01 α-lipoic acid treatment 0.146 < 0.01 0.123 < 0.01 Neuropathy 0.142 < 0.01 0.089 0.084 Neuropathy symptoms 0.094 0.042 0.076 0.102 Monofilament test 0.113 0.014 0.110 0.018 Tuning fork test 0.058 0.214 0.049 0.291 Ankle Jerk reflex -0.054 0.242-0.048 0.302 P value < 0.05 were considered significant. *Pearson s and Spearman correlation coefficient; Standard coefficient. SBP, systolic blood pressure; bapwv, brachial-ankle pulse wave velocity; HDL- C, high density lipoprotein cholesterol; AST, aspartate transferase; ALT, alanine transferase; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; CVD, cardiovascular diseases. 또한최대상완 - 발목맥파속도와여러인자들간의특성을상관 분석으로알아본결과심혈관계자율신경병증점수, 나이, 키, 몸무 게, 수축기혈압, 미세알부민뇨, 당뇨병유병기간, 안지오텐신차단제 사용, 칼슘차단제사용, 말초신경병증동반등이의미있는양의상 관관계를보였고, 키, 몸무게, ALT 는음의상관관계를보였다. 그외 고밀도지단백콜레스테롤, 중성지방, AST, 베타차단제사용등은 유의한상관관계가없었다 (Table 3). 나이를보정한이후에는심혈 관계자율신경병증점수, 수축기혈압, 미세알부민뇨, 당뇨병유병기 간, 칼슘차단제사용등이유의한연관관계를보였다 (Table 3). 심혈 관계자율신경병증점수와여러인자들간의연관성을상관분석으 로알아본결과, 최대상완 - 발목맥파속도 (r = 0.212, P < 0.01) (Fig. 1), 나이, 수축기혈압, 미세알부민뇨, 당뇨병유병기간, 안지오텐신

Relationships between CAN and the ba-pwv in Patients with Type 2 Diabetes 49 Table 5. Correlation between DiCAN score and maximal bapwv after adjusting confounding variables Confounding variables 차단제사용, 칼슘차단제사용, 베타차단제사용, alpha lipoic acid 사용, 말초신경병증동반및신경병증증상동반, 모노필라멘트검 사등이의미있는양의상관관계를보였고, 키, 몸무게, 고밀도지단 백콜레스테롤, AST, ALT 는음의상관관계를보였다 (Table 4). 그외 중성지방등은유의한상관관계를보이지않았다. 나이를보정한후 에는최대상완 - 발목맥파속도, 미세알부민뇨, 고밀도지단백콜레 스테롤, 중성지방, 안지오텐신차단제사용, 베타차단제사용, alpha lipoic acid 사용, 모노필라멘트검사등이유의한연관관계를보였 다 (Table 4). 키, 몸무게, 당뇨병유병기간, 수축기혈압, 안지오텐신차단제사 용, 칼슘차단제사용, 베타차단제사용, alpha lipoic acid 사용, 미세 알부민뇨, 말초신경병증등의요인을혼란변수로통제하여심혈관계 자율신경병증점수와최대상완 - 발목맥파속도의관계를편상관분 석한결과의미있는상관관계를보였다 (Table 5). 또한상관분석에 서통계적으로의의가있었던인자들로심혈관계자율신경병증점 수와최대상완 - 발목맥파속도를다중회귀분석을시행한결과나 이와수축기혈압을동시에통제한경우 (Model 5) 를제외하고는유 의한연관관계를보였다 (Table 6). Confounding factor adjusted partial correlation 고찰 본연구에서는심혈관계자율신경병증이합병된제 2 형당뇨병환 자에서상완 - 발목맥파속도와심혈관계자율신경병증과의상관관 계를알아보기위해상완 - 발목맥파속도와심혈관계자율신경병증 점수를동시에측정한 465 명의환자를대상으로비교연구한결과 심혈관계자율신경병증과최대상완 - 발목맥파속도사이에유의한 r * P value Height 0.184 < 0.01 Weight 0.193 < 0.01 Duration of diabetes 0.195 < 0.01 SBP 0.169 < 0.01 ARB treatment 0.189 < 0.01 CCB treatment 0.195 < 0.01 β-blocker treatment 0.210 < 0.01 α-lipoic acid treatment 0.226 < 0.01 Microalbuminuria 0.202 < 0.01 Neuropathy 0.202 < 0.01 P value < 0.05 were considered significant. *Pearson s and Spearman correlation coefficient. bapwv, brachial-ankle pulse wave velocity; SBP, systolic blood pressure; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker. Table 6. Multiple regression analysis of the relationship between DiCAN score and maximal bapwv after adjusting variables 양의상관관계가있음을알수있었다. 동맥강직도는맥압, 경동맥내중막두께, 동맥맥파속도등을측 정하여평가할수있고, 그중측정이용이하고비침습적이고재연성 이뛰어난장점이있는동맥맥파속도는혈액의맥파가인체동맥계 의서로다른두지점을통과할때두지점의거리를맥파가통과하 는데걸리는시간으로나눈값이다 [12]. 상완 - 발목맥파속도는대동 맥동맥맥파속도와달리대동맥및말초동맥의상태를모두반영 하고혈관운동반사에영향을받기때문에대동맥동맥맥파속도에 비해미세혈관병증의상태및당뇨병의합병증과더큰연관성이 있다고보고된다 [8]. 동맥맥파속도에영향을미치는인자에대해서 여러연구가진행되어왔다. 상완 - 발목맥파속도에가장강력한영 향을미치는인자로나이, 수축기혈압, 성별이알려져있고 [13], Aso 등 [6] 은상완 - 발목맥파속도는나이, 수축기혈압뿐만아니라당뇨병 유병기간도강력한양의연관성을가지고, 알부민뇨증, 말초신경병 증, 자율신경병증, 망막병증과관련이있음을보고하였다. Lee 등 [14] 은제 2 형당뇨병환자를대상으로한연구에서상완 - 발목맥파 속도가수축기혈압과나이에가장영향을받는다고보고하였으며, Yun 등 [15] 은제 2 형당뇨병환자에서 1 년간격으로측정한상완 - 발 목맥파속도의변화에혈압변화가가장큰영향을미친다고보고 하였다. 본연구에서는상완 - 발목맥파속도는심혈관계자율신경병 증점수, 나이, 키, 몸무게, 수축기혈압, 미세알부민뇨, 당뇨병유병 기간, 안지오텐신차단제사용, 칼슘차단제사용, 말초신경병증동반 등이유의한연관관계를보였다. 나이를보정한이후에는심혈관계 자율신경병증점수, 수축기혈압, 미세알부민뇨, 당뇨병유병기간, 칼 슘차단제사용등이유의한연관관계를보였다. β * P value Model 1 Age, height, weight, sex 0.119 0.029 Model 2 SBP, ACE treatment, ARB treatment, CCB 0.186 0.001 treatment, β-blocker treatment Model 3 Age, height, weight, neuropathy, α-lipoic acid 0.143 0.018 treatment Model 4 SBP, height, weight, triglyceride, ALT, HDL 0.183 0.003 Model 5 Age, SBP 0.090 0.167 P value < 0.05 were considered significant. *Standard coefficient. bapwv, brachial-ankle pulse wave velocity; SBP, systolic blood pressure; ACE, inhibitor: angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; ALT, alanine transferase; HDL, high density lipoprotein.

50 Bae YP, et al. 당뇨병으로인한합병증중에서당뇨병성신경병증은다양한증상을보이며여러형태로신경계를침범하는대표적인만성합병증이다. 당뇨병성신경병증중심각한합병증하나가심혈관계자율신경병증이며, 안정시빈맥, 기립성저혈압, 실신, 운동불응성 (exercise intolerance), 수술중불안정성 (perioperative instability), 무증상허혈, 심근경색, 좌심실수축, 이완기부전, 신장질환의위험성증가, 만성신부전, 뇌졸중, 급사 [16] 등의다양한임상양상을통해환자의삶의질을저하시키게된다. 심장과혈관에공급되는자율신경에손상을주어맥박조절과혈관역동성 (vascular dynamics) 에이상을초래하여, 무증상허혈, 심근경색등 [17] 과연관되어사망률을증가 [7] 시키는것으로알려져있으며, 가장치명적인결과는심장교감신경계이상으로인한 Q-T 간격연장과이로인한돌발성부정맥및돌연사로 [18-20], 다른합병증이동반되지않은제1형당뇨병환자에서자율신경기능이정상인경우와비정상인경우 8년생존율이각각 97% 와 77% 로크게차이가있다는보고도있다 [20]. 대규모의메타분석에서도급사와사망률이심혈관계자율신경병증의존재시정상에비해 3배이상증가함을보여주었다 [7]. 그러나심혈관계자율신경병증을가진대부분의환자는대부분무증상으로수십년간을지내게되고증상이있는기립성저혈압환자는 1% 이하로알려져있다 [21]. 이러한점이환자들의질병에대한이해도를낮게하여심각한합병증에도불구하고조기진단이늦어지는원인으로생각된다. 심혈관계자율신경병증과임상적특성간의관계에대한연구는그결과가다양하게보고되고있으며, 나이, 당뇨병유병기간, 부적절한혈당조절등이연관성이높다는결과가있었다 [22]. 본연구에서는최대상완-발목맥파속도, 나이, 수축기혈압, 미세알부민뇨, 당뇨병유병기간, 안지오텐신차단제사용, 칼슘차단제사용, 베타차단제사용, alpha lipoic acid 사용, 말초신경병증동반, 신경병증증상동반및모노필라멘트검사등이심혈관계자율신경병증점수와유의한상관관계를보였고, 나이를보정한후에는최대상완-발목맥파속도, 미세알부민뇨, 고밀도지단백콜레스테롤, 중성지방, 안지오텐신차단제사용, 베타차단제사용, alpha lipoic acid 사용, 모노필라멘트검사등이유의한연관관계를보였다. 항고혈압약제가당뇨병성신경병증에영향을미치는것으로알려져있다. Quinapril을 12개월사용한군 [23] 및 losartan 100 mg을 12개월간사용한군 [24] 에서심혈관계자율신경병증이호전되었으며, 제2형당뇨환자에서칼슘차단제가교감신경활성을감소시켰다는보고도있었다 [25]. 고혈압환자에서베타차단제사용시단기심박수변이를증가시키고부교감신경계의항진을유도한다고알려져있으며 [26], 베타차단제를복용한고령의당뇨환자에서 1년사망률이감소되었다는보고도있었다 [27]. 본연구에서도항고혈압제사용이많은것으로나타났고, 심혈관계자율신경병증검사시행군에서이들약제가많이사용되고있음을알수있었다. 고혈압약제들 을혼란변수를통제한후에도심혈관계자율신경병증점수와최대상완-발목맥파속도는유의한상관관계가있음을보여주었다. 심혈관계자율신경병증이당뇨환자에서사망의주요원인과관련된관상동맥죽상경화증같은대혈관합병증과어떻게연관되어있는지를설명하는몇가지연구가있었다. 한연구에서는자율신경기능부전이관상동맥질환의중요한위험인자중하나인고혈압의발병을촉진한다고하였다 [16]. 두개의다른연구는심혈관계자율신경병증이동맥의팽창성의감소 [17] 및혈관기능부전 [22] 과연관있음을보여주었다. 더욱이낮아진심박수변이성은당뇨환자에서관상동맥질환의발전과연관이있고, 이것은심장자율신경의부적절한통제가관상동맥질환의위험을증가시킨다는것을보여준다 [28]. 당뇨병성신경병증과죽상동맥경화증이항산화스트레스 (oxidative stress) 와연관이되어있다는보고도이를뒷받침해준다 [29-31]. 본연구에서도심혈관계자율신경병증과최대상완-발목맥파속도는유의한연관성을나타내었으며이는심혈관계자율신경병증과동맥경화증과의연관성을보인다고생각해볼수있었다. 본연구의제한점으로는정상대조군과의비교가없이제2형당뇨병환자만을대상으로연구가이루어져서정상군과의직접적인비교가어려웠다는점과비교적당뇨유병기간이긴환자군을대상으로하여자율신경병증이보다진행된상태에서상완-발목맥파속도가측정되었을가능성이높다는점으로추후정상군과의비교및조기에당뇨병이진단된환자군을대상으로의연구가필요할것으로사료된다. 결론적으로제2형당뇨병환자에서최대상완-발목맥파속도는심혈관계자율신경병증과연관성이있었으며, 나이를보정한이후에도심혈관계자율신경병증을독립적인예측인자로나타났다. 요약배경 : 당뇨병환자에서동맥경화증은관상동맥질환이나뇌졸중, 기타말초혈관질환을초래하여이환율과사망률의주요원인이되고있다. 또한심혈관계자율신경병증은당뇨병환자뿐만아니라심장질환환자에서도심혈관질환의위험성을나타내는표지자이다. 동맥맥파속도는동맥의팽창성및강직도와잘연관되어있고성인에서동맥경화증의상태를평가하는데유용한방법이다. 이에본연구에서는제2형당뇨병환자들을대상으로보다간편하게동맥강직도를측정할수있는지표인상완-발목맥파속도 (brachial-ankle PWV) 와심혈관계자율신경병증과의관련성을규명하고자하였다. 방법 : 심혈관계자율신경병증및상완-발목맥파속도를동시에검사한 20세이상의제2형당뇨병환자 465명을대상으로하였으며병력및신체계측치, 혈액검사등을후향적으로조사하였다. 심혈관계자율신경병증은 DiCAN (Medicore, Seoul, Korea) 을이용하여반복적인심호흡호기와흡기시, 체위변화시, 발살바수기시심박

Relationships between CAN and the ba-pwv in Patients with Type 2 Diabetes 51 동수의변화와기립시와악력주입시혈압변화를측정하였다. 각 다섯가지항목에대한정상은 0 점, 경계성이상은 0.5 점, 이상은 1 점 으로계산하였고 1.5 점이상을심혈관계자율신경병증으로정의하 였다. 상완 - 발목맥파속도는 VP-1000 (Colin, Japan) 을이용하여측 정하였다. 통계처리는윈도우용 SPSS 14.0 을이용하였다. 결과 : 심혈관계자율신경병증점수와여러인자들간의연관성을 상관분석으로알아본결과, 최대상완 - 발목맥파속도 (r = 0.212, P < 0.01), 나이 (r = 0.232, P < 0.01), 수축기혈압, 미세알부민뇨, 당뇨병 유병기간, 안지오텐신차단제사용, 칼슘차단제사용, 베타차단제사 용, alpha lipoic acid 사용, 말초신경병증동반및신경병증증상동 반, 모노필라멘트검사등이의미있는양의상관관계를보였고, 키, 몸무게, 고밀도지단백콜레스테롤, AST, ALT 는음의상관관계를보 였다. 나이를보정한후에도심혈관계자율신경병증점수는최대상 완 - 발목맥파속도 (β = 0.108, P = 0.021) 와유의한상관관계를보였다. 결론 : 제 2 형당뇨병환자에서심혈관계자율신경병증과상완 - 발 목맥파속도는유의한상관관계를보였다. 참고문헌 1. American Heart Association: Heart Disease and Stroke Statistics-2005 update, Dallas, Tex, American Heart Association, 2005 2. Gu K, Cowie CC, Harris MI: Mortality in adults with and without diabetes in a national cohort of the U.S. population, 1971-1993. Diabetes Care 21:1138-1145, 1998 3. 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