원저 Lab Med Online Vol. 6, No. 4: 221-227, October 2016 임상화학 건강검진자에서임상전단계관상동맥죽상경화증과혈중호모시스테인치와의연관성 Association of Homocysteine Levels with Subclinical Coronary Atherosclerosis in Asymptomatic Subjects 나은희 ¹ 조한익 ² 최중찬 ³ Eun-Hee Nah, M.D.¹, Han-Ik Cho, M.D.², Joong-Chan Choi, M.D.³ 한국건강관리협회진단검사의학과건강증진연구소 1, 한국건강관리협회 2, 한국건강관리협회영상의학과 3 Department of Laboratory Medicine and Health Promotion Research Institute 1, Korea Association of Health Promotion, Seoul; Korea Association of Health Promotion 2, Seoul; Department of Radiology 3, Korea Association of Health Promotion, Seoul, Korea Background: Progression of atherosclerotic plaques is known to be correlated with elevated circulating homocysteine (Hcy). However, whether the level of Hcy is related with coronary atherosclerosis in the subclinical state is unclear. Therefore, we performed this study to investigate the relationship between blood Hcy levels and subclinical atherosclerosis in asymptomatic self-referred subjects. Methods: We retrospectively enrolled 2,968 self-referred asymptomatic subjects (1,374 men, 1,594 women) who had undergone both coronary CT angiography (CCTA) and coronary artery calcium scoring. The relationships between atherosclerosis, Hcy, and other clinical factors were assessed. Results: Higher levels of Hcy were related with age, male gender, body mass index (BMI), waist circumference, blood pressure, high density lipoprotein (HDL), triglyceride, blood glucose, HbA1c, hscrp, and coronary artery calcium score (CACS). Coronary plaque was more frequently found in higher Hcy quartile groups (21.3%, 28.8%, 34.4%, and 34.3%, P <0.001). Significant coronary artery stenosis (stenosis>50%) was also more frequent in higher Hcy quartile groups (1.8%, 5.4%, 5.0%, and 6.6%, P <0.001). The factors associated with CACS included age, male gender, levels of HbA1c, Hcy and hscrp. Logistic regression analysis adjusted for gender and confounding factors showed that the third- and fourth-quartile Hcy groups had higher odds ratios [ odd ratio (OR) 3.980 (1.723-9.194), P =0.001, 7.355 (3.291-16.439), P <0.001, respectively] for high CACS (CACS >400) than the first quartile group. Conclusions: Blood Hcy levels were associated with an increased risk of the presence and extent of subclinical atherosclerosis in asymptomatic subjects. Key Words: Homocysteine, Subclinical coronary atherosclerosis, Coronary CT angiography, Coronary artery calcium score (CACS) 서론 관상동맥질환을비롯한심혈관질환은주요한사망원인중의하 Corresponding author: Eun-Hee Nah Department of Laboratory Medicine and Health Promotion Research Institute, Korea Association of Health Promotion, 350 Hwagok-ro, Gangseo-gu, Seoul 07653, Korea Tel: +82-2-2600-0107, Fax: +82-2-2690-4915, E-mail: cellonah@hanmail.net Received: August 5, 2015 Revision received: January 28, 2016 Accepted: April 1, 2016 This article is available from http://www.labmedonline.org 2016, Laboratory Medicine Online This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 나다. 심근경색에의한돌연사나심근경색발작후생존한심근경색환자의약삼분의이에서흉통, 운동시호흡곤란등의증상이없었다 [1, 2] 는점을고려할때임상증상이나오기전의임상전단계의관상동맥죽상경화증의위험인자들을찾아내는것이심혈관질환의예방과관리에필요하다. 호모시스테인이죽상경화증을일으키는정확한기전은알려져있지않지만, 혈중호모시스테인치의증가와죽상경화성혈관질환의발생위험이연관되어있다는것이알려져있다. Schaffer 등 [3] 은관상동맥조영술을받은환자들을대상으로한연구에서혈중호모시스테인수치와관상동맥질환의정도가관련이있다고하였고, Klerk 등 [4] 은메타분석에서증가된혈청호모시스테인농도와심혈관질환이연관이있다고하였다. 임상전단계의관상동맥죽상경화증과혈중호모시스테인과의관계에대한연구도진행되었는데, 이들연구에서일치된의견은없다. Rasouli 등 [5] 은증가된혈중 eissn 2093-6338 www.labmedonline.org 221
호모시스테인치와관상동맥질환의표지자인관상동맥석회화수치증가가관련이있다고하였고, Kullo 등 [6] 은다른심장관상동맥위험인자들의영향을배제한후에도혈중호모시스테인치가관상동맥석회화수치증가와연관이있다고하였다. 반면에호모시스테인과임상전단계관상동맥죽상경화증과연관이없다는연구결과들 [7, 8] 도있다. 이들연구들에서는대체로연구대상자들의수가적고, 주로젊은남성들을대상으로한것으로일반화하기에적당하지않았고, 관상동맥의죽상경화증진단방법에서도 CT scan 을이용한관상동맥석회화를측정한것이었다. 최근 multidetector-row computed tomography (MDCT) 의발전으로관상동맥CT조영술 (CCTA) 이관상동맥의협착정도와동맥경화반의성상을평가할수있는비침습적인방법으로서관상동맥질환의임상적증상이없는사람들에서도유용한진단방법이되었다. 그러므로본연구에서는관상동맥질환의증상이없는건강검진자를대상으로혈중호모시스테인치와 CCTA로평가한죽상경화증과의관련성을알아보고자하였다. 연구대상및방법 혈청호모시스테인은 Liquid Stable (LS) 2-Part Homocysteine reagent (Axis-Shield Diagnostics, Dundee, UK) 를사용하여효소법으로제조사의지시에따라 Hitachi 7600 (Hitachi, Tokyo, Japan) 으로측정하였다. 호모시스테인의측정범위는 0.3-65.0 μmol/l, 측정의정밀도는 2.5% 였다. 3. 관상동맥죽상경화증평가관상동맥의영상은 128-channel multi-detector CT scanner (Simens syngo CT 2011A, Erlangen, Germany) 을사용하여얻었으며, 영상의학전문의가분석하였다. 관상동맥석회화정도는 Agatston score [9] 에의한관상동맥석회화수치 (coronary artery calcium score, CACS) 를이용하였으며, 침습적인관상동맥조영술로확인검사를필요로하는 CACS >400인경우는관상동맥질환의심 (significant coronary disease) 으로하였다. 관상동맥의협착의정도는최대협착이 50% 이상인경우를의미있는 (significant) 협착, 70% 이상인경우를심한 (severe) 협착으로하였으며, 혈관내벽에또는혈관내에있는 1 mm² 이상의구조물을동맥경화반으로정의하였다 [10]. 1. 대상 2013년 1월부터 2014년 12월까지건강증진센터에서건강검진을목적으로관상동맥CT조영술을받은 20세이상성인 2,981명 ( 남, 1,374명 ; 여, 1,594명 ) 을대상으로하였다. 2. 혈액화학검사및혈청호모시스테인측정 10시간공복후채혈한혈액의혈청에서공복혈당, 중성지방, 총콜레스테롤, HDL콜레스테롤, LDL콜레스테롤, 고감도 C-반응단백질 (high sensitivity C-reactive protein, hscrp) 을 Hitachi 7600 (Hitachi, Tokyo, Japan) 으로측정하였다. 총콜레스테롤, HDL콜레스테롤, 중성지방, 혈당은아산시약 (Asan Inc., Hwaseong, Korea) 을사용하여효소법으로, LDL콜레스테롤은 Daiichi 시약 (Daiichi Pure Chemicals Co., Tokyo, Japan) 을사용하여효소법으로, hscrp는 Daiichi 시약을사용하여혼탁면역법으로측정하였다. 총콜레스테롤, HDL콜레스테롤, 중성지방의측정시보정은로슈사의보정물질 (Roche Diagnostics, Mannheim, Germany) 을, LDL콜레스테롤측정의보정은 Daiichi의보정물질 (Daiichi Pure Chemicals Co., Tokyo, Japan) 을사용하였다. 지질검사의정밀도와정확도를평가하기위해서는정도관리물질인 Lyphocheck levels I, II (Bio-Rad Lab., Irvine, USA) 를사용하였고, 대한임상검사정도관리협회의외부정도관리사업에참여하여관리하였다. 당화혈색소 (HbA1c) 는고성능액체크로마토그래피법을이용한 HLC-723 G8 (Tosoh Corporation, Tokyo, Japan) 으로측정하였다. 4. 통계분석호모시스테인의사분위수에따른특성을비교하기위해일원분산분석및사후분석과교차분석을이용하였다. 관상동맥동맥경화반유무에따른특성을비교하기위해독립표본 T-검정 (Student s t-test) 과교차분석을, 관상동맥동맥경화반유무에영향을미치는인자를알아보기위해로지스틱회귀분석을하였다. 관상동맥석회화수치에따른대상군의특성을비교하기위해일원분산분석및사후분석과교차분석을이용하였으며, 관상동맥석회화수치를예측하는데유의한인자들을알아보기위해다중회귀분석을시행하였다. 관상동맥죽상경화증과호모시스테인과의연관성을알기위해로지스틱회귀분석을하였고, 오즈비 (odds ratio, OR) 와 95% 신뢰구간 (confidence interval, CI) 을구하였다. 통계프로그램은 SPSS version 17.0 (SPSS Inc., Chicago, IL, USA) 을이용하였고, P <0.05를통계적으로유의한것으로하였다. 결과 1. 호모시스테인사분위수에따른임상및대사지표의차이호모시스테인사분위수에따른남성의비율은제1사분위수에서 15.8%, 제2사분위수에서 38.6%, 제3사분위수에서 58.2%, 제4 사분위수에서 74.9% 로높은사분위수일수록남성의비율이높았다 (P <0.001). 호모시스테인사분위수에따른임상및대사지표의차이를보면, 연령, 체질량지수, 허리둘레, 혈압, 중성지방, 공복혈 222 www.labmedonline.org
Table 1. Clinical and laboratory characteristics in the subjects based on the homocysteine quartile group Q1 (N=784) Q2 (N=709) Q3 (N=780) Q4 (N=708) P value Hcy (μmol/l) 6.6±0.8 a 8.3±0.4 b 9.9±0.5 c 13.8±4.3 d <0.001 Age (yr) 56.6±8.4 a 57.8±9.5 a 59.4±9.5 b 60.3±10.4 b <0.001 Male (%) 15.8 38.7 58.2 74.9 <0.001 WC (cm) 79.6±8.4 a 82.2±8.8 b 83.5±8.3 c 85±8.7 d <0.001 BMI 24.1±3.0 a 24.7±3.1 b 24.8±3.0 b 24.8±3.1 b <0.001 SBP (mmhg) 121.6±14.0 a 123.4±13.6 a,b 124.8±13.3 a,b 126.7±14.0 b <0.001 DBP (mmhg) 73.5±9.1 a 74.6±9.0 a,b 75.3±8.5 a,b 76.2±9.4 b <0.001 TC 206.6±36.8 a,b 209.0±37.3 b 203.3±37.3 a,b 199.6±39.9 a <0.001 TG 121 ±101.2 a 118.6±69.3 a 122.1±74.7 a,b 135.1±110.2 b 0.003 HDL 58.9±14.4 b 57.9±14.9 b 54.7±12.5 a 53±13.4 a <0.001 LDL 119.2±38.0 a,b 123.2±39.9 b 121.2±38 a,b 115.8±40.2 a 0.003 FBS 101 ±17.8 a 103.2±18.8 a 103.6±18.8 a,b 106 ±22.3 b <0.001 HbA1c 5.7±0.7 a 5.8±0.7 a,b 5.8±0.8 a,b 5.9±0.8 b 0.010 hs-crp 0.14±0.3 a 0.19±0.5 a,b 0.16±0.3 a,b 0.21±0.5 b 0.006 CACS 17.5±79.5 a 35.6±159.8 a,b 56.5±208 b 95.8±279.1 c <0.001 presence of coronary plaque (%) 21.3 28.8 34.4 34.3 <0.001 Significant CAD (%) 1.8 5.4 5.0 6.6 <0.001 Severe CAD (%) 0.5 1.7 1.8 2.4 <0.001 P value derived from one-way ANOVA and χ 2 test was used for intergroup comparison. a, b, c, d : The same letters indicate a non-significant difference between groups based on Scheffe s multiple comparison test. Abbreviations: Q, quartile; Hcy, homocysteine; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; FBS, fasting blood sugar; HbA1c, hemoglobin A1c; hscrp, high sensitivity C-reactive protein; CACS, coronary artery calcium score; CAD, coronary artery disease. Presence of coronary plaque and significant CAD (%) 40 30 20 10 0 Coronary plaque 21.3 1.8 28.8 5.4 Significant coronary artery disease Q1 Q2 Q3 Q4 Fig. 1. Presence of coronary plaque and significant coronary artery disease (CAD) based on homocysteine quartile groups. 당, HbA1c, hscrp 등이호모시스테인사분위수가증가할수록더 높았고, HDL- 콜레스테롤은더낮았다 (P <0.01). 한편, 석회화수치 와관상동맥경화반의빈도및중등도이상의협착의빈도도호모 시스테인사분위수가증가할수록더높았다 (P <0.001) (Table 1, Fig. 1). 34.4 5.0 34.3 2. 관상동맥경화반유무에따른임상및대사지표의차이 관상동맥경화반을갖는사람들에서, 동맥경화반이없는사람 들에비해남성의비율, 연령, 체질량지수, 허리둘레, 혈압, 공복혈 당, HbA1c, 호모시스테인이더높았고, 총콜레스테롤, LDL-C, HDL-C 는더낮았다. 동맥경화반이없는경우에비해동맥경화반이있는 6.6 Table 2. Characteristics of subjects with/without coronary plaque Plaque (-) (N=2,099) Plaque (+) (N=882) P value Hcy (μmol/l) 9.4±3.2 10.0±3.8 <0.001 Age (yr) 57.1±9.8 61.8±8.1 <0.001 Male (%) 42 56.7 <0.001 WC (cm) 81.7±8.8 84.5±8.3 <0.001 BMI 24.4±3.1 25.1±3.1 <0.001 SBP (mmhg) 122.8±13.9 127.1±13.2 <0.001 DBP (mmhg) 74.4±9.2 76.0±8.5 <0.001 TC 206.4±37.5 200.5±38.7 <0.001 TG 123.4±95.3 125.6±78 0.554 HDL 56.5±14.4 55.2±13.1 0.024 LDL 121.6±37.9 115.6±41.6 <0.001 FBS 101.7 ±18.7 107.6±20.8 <0.001 HbA1c 5.7±0.7 5.9±0.8 <0.001 hs-crp 0.17±0.4 0.18±0.4 0.424 CACS 21 ±139.3 121.1±276.5 <0.001 Significant CAD (%) 1.3 28 <0.001 Severe CAD (%) 0.1 10.2 <0.001 P value derived from Student s t-test and χ 2 test was used for comparing subjects with/without coronary artery plaques. Abbreviations: Hcy, homocysteine; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; FBS, fasting blood sugar; HbA1c, hemoglobin A1c; hscrp, high sensitivity C-reactive protein; CACS, coronary artery calcium score; CAD, coronary artery disease. www.labmedonline.org 223
군에서석회화수치가더높았으며, 50% 이상관상동맥협착된경 우도의의있게더많았다 (P <0.001) (Table 2). 3. 관상동맥경화반에관련된인자 관상동맥경화반과관련된인자는남성, 연령, 허리둘레, 수축기 혈압, 공복혈당, 관상동맥석회화수치였다 (Table 3). 4. 관상동맥석회화수치와관련된인자들 관상동맥석회화수치에따른남성의비율, 연령, 공복혈당, HbA1c, 요산, hscrp 는높은석회화수치군일수록높았고, HDL- 콜레스테 롤은더낮았다 (P <0.001). 체질량지수, 허리둘레, 혈압, 중성지방 Table 3. Logistic regression analysis for the variables affecting the presence of coronary plaque Variables OR (95% CI) P value Age 1.051 (1.039-1.064) <0.001 Male 1.800 (1.454-2.227) <0.001 WC 1.018 (1.006-1.030) 0.004 SBP 1.012 (1.005-1.020) <0.001 FBS 1.006 (1.002-1.011) 0.010 Hcy 0.972 (0.942-1.003) 0.080 CACS 1.002 (1.001-1.003) <0.001 This model was adjusted for age, sex, body mass index, waist circumference, blood pressure, blood lipid, fasting blood glucose and HbA1c level. Abbreviations: OR, odds ratio; CI, confidence interval; WC, waist circumference; SBP, systolic blood pressure; FBS, fasting blood sugar; Hcy, homocysteine; CACS, coronary artery calcium score. 등은관상동맥석회화수치 400 미만인군에서높은석회화수치군 일수록더높았다 (P <0.001) (Table 4). 관상동맥석회화수치를예 측하는데유의한인자들을알아보기위해다중회귀분석을시행 하였을때, 연령, 남성, HbA1c, 호모시스테인, hscrp 가통계적으로 유의한인자였다 (P <0.001) (Table 5). 5. 호모시스테인사분위수에따른관상동맥죽상경화증과의 연관성 관상동맥석회화수치 400 이상과관련이있는인자들을알아보 기위한로지스틱회귀분석에서연령, 남성, HbA1c, 호모시스테인 이연관되어있었고, 연령, 성별, HbA1c 등을통제하였을때, 제 1 사 분위수에비해호모시스테인제 3 사분위수에서는 3.98 배 (95% 신 Table 5. Association of the coronary artery calcium score with metabolic and demographic variables Variables R² B t P value Age 0.0492 3.878 9.32 <0.001 Male 0.0670 39.110 4.65 <0.001 HbA1C 0.0788 28.364 5.43 <0.001 Hcy 0.0857 4.783 4.08 <0.001 hs CRP 0.0898 31.708 3.51 <0.001 LDL 0.0922-0.262-2.37 0.018 HDL 0.0942 0.661 2.32 0.020 P value derived from multiple linear regression analysis. Abbreviations: HbA1c, hemoglobin A1c; Hcy, homocysteine; hscrp, high sensitivity C-reactive protein; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol. Table 4. Clinical and laboratory characteristics based on the coronary artery calcium score group in subjects CACS<1 (N=1,934) 1 CACS<101 (N=715) 101 CACS<401 (N=229) CACS 401 (N=90) Hcy (μmol/l) 9.2±3.3 10.1±3.1 10.6±3.9 12±3.9 <0.001 Age (yr) 56.3±9.3 a 61.8±7.7 b 65.1±7.0 c 67.2±7.6 c <0.001 Male (%) 39.7 56.5 59.39 74.44 <0.001 WC (cm) 81.6±8.9 a 83.8±8.2 a 86.2±8.1 b 83.8±8.3 a <0.001 BMI 24.4±3.1 a 24.9±3.0 a,b 25.5±3.0 b 24.4±2.8 a <0.001 SBP (mmhg) 122.6±14.0 a 126.2±13.2 a,b 129±13.0 b 127.5±12.8 b <0.001 DBP (mmhg) 74.5±9.2 a 75.9±8.9 a 75.9±8.3 a 74.2±8.2 a 0.001 TC 207.6±36.9 b 201.6±39.4 a,b 194±37.0 a 194.9±41.3 a <0.001 TG 124.4±97.6 124±75.4 127±82.4 114.6±62.1 0.761 HDL 56.9±14.0 a 54.6±13.9 a 54.6±14.1 a 54.7±12.8 a 0.001 LDL 122.1±38.3 b 118.9±39.7 a,b 108.9±39.3 a 110.3±44.3 a <0.001 FBS 101.2 ±17.5 a 106.6±20.2 b 108 ±22.4 b 116.1±33.2 c <0.001 HbA1c 5.7±0.7 a 5.9±0.7 a,b 6±0.9 b 6.3±1.2 c <0.001 hs-crp 0.161±0.306 a 0.2±0.523 a 0.164±0.252 a 0.317±0.989 b 0.003 Number of plaque 0.1±0.398 a 1.484±1.584 b 3.672±2.994 c 4.933±4.618 d <0.001 P value derived from one-way ANOVA and χ 2 test was used for intergroup comparison. a, b, c, d : The same letters indicate non-significant differences between groups based on Scheffe s multiple comparison test. Abbreviations: Hcy, homocysteine; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; FBS, fasting blood sugar; HbA1c, hemoglobin A1c; hscrp, high sensitivity C-reactive protein; CACS, coronary artery calcium score. P value 224 www.labmedonline.org
Table 6. Multiple logistic regression analysis for the effect of homocysteine quartile on significant coronary disease (CACS > 400) Variables OR (95% CI) P value Age 1.134 (1.096-1.173) <0.001 Male 3.503 (1.964-6.248) <0.001 HbA1c 1.565 (1.265-1.936) <0.001 Hcy Quartile Q1 Q2 Q3 Q4 뢰구간 ; 1.723-9.195) (P = 0.001), 제 4 사분위수에서는 7.355 배 (95% 신뢰구간 ; 3.291-16.439) (P <0.001) 더관상동맥석회화수치 400 이상과연관성이높았다 (Table 6). 고찰 본연구결과호모시스테인이기준범위일지라도높은사분위수 에있는경우에낮은사분위수인경우에비해관상동맥석회화수 치도높고, 관상동맥협착도많았다. 죽상경화증의표지자로서의 관상동맥경화반 (Plaque) 또는관상동맥석회화수치 (Coronary Artery Calcium Score: CACS) 와혈중호모시스테인치와의연관성을 알아보았을때, 연령, 성별, 심혈관계질환위험인자들의영향을배 제한후에는호모시스테인치와관상동맥경화반과는연관이없었 으나관상동맥석회화수치와는연관성이있었다. 특히관상동맥석 회화수치 400 이상인경우에는혈중호모시스테인사분위수가증 가할수록연관성이더높았다. 1 2.073 (0.823-5.226) 3.980 (1.723-9.194) 7.355 (3.291-16.439) 0.122 0.001 <0.001 This model was adjusted for age, sex, body mass index, waist circumference, blood pressure, blood lipid, fasting blood glucose and HbA1c. Abbreviations: OR, odds ratio; CI, confidence interval; HbA1c, hemoglobin A1c; Hcy, homocysteine; Q, quartile. Lin 등 [11] 의연구에서당뇨병이나고혈압, 흡연, 고지혈증, 심장 관상동맥의가족력등의심혈관계질환위험인자를최소 1 개이상 가진건강검진자에서혈중호모시스테인치와관상동맥경화반유 무및협착이경도의연관은있었으나, 다른심혈관계질환위험인 자를배제한후에는이러한연관성이없어져서호모시스테인치가 심장관상동맥경화증의독립된예견인자는아니라고하였다. Schaffer 등 [3] 의 6 년여동안의전향적코호트연구에서, 진단방법을침 습적인관상동맥조영술 (invasive coronary angiography) 을사용하 였을때심장관상동맥질환발생과높은혈중호모시스테인치가 연관성이있다고하였다. 침습적인관상동맥조영술은대부분심혈 관계질환의고위험군에서흉통등의증상이있는경우에시행하 는검사방법으로, Schaffer 등의연구에서의대상자는건강검진자 를대상으로한본연구대상자와는차이가있다. 이처럼연구결과 들의불일치는연구대상자들의차이, 관상동맥검사방법의차이를 생각해볼수있다. Agatston 등 [9] 은관상동맥석회화수치가혈관내경화반의석회화정도와범위를나타내는것으로서관상동맥의죽상경화를나타내는표지자이며관상동맥질환의협착정도를나타낸다고하였다. 즉, 더높은관상동맥석회화수치일수록심장혈관질환의위험이증가하여, 관상동맥석회화수치는심장혈관질환의이환율및이로인한사망률과연관되어있는것으로생각되고있다. 특히관상동맥석회화수치 400 이상은침습적인관상동맥조영술을고려해볼수도있는경우 [12] 로, Kunita 등 [13] 은관상동맥석회화수치에따른심장혈관질환의생존곡선에서, 관상동맥석회화수치가 0 인경우에비해 400 이상인경우의심장혈관질환위험비 (hazard ratio) 가 8.75배라고하였다. 본연구에서관상동맥석회화수치와혈중호모시스테인치는연관성이있었다. 특히관상동맥석회화수치가 400 이상인경우에는연령, 성별, 당화혈색소치등의교란효과를배제한후에도연관성이있었고, 호모시스테인사분위수가증가할수록오즈비 (odds ratio) 는증가하였다. 호모시스테인이동맥경화증에영향을미치는기전은아직도이견이많치만, 대체로혈관내피세포에산화적인손상을입히고혈관근세포의증식을일으키며 [14, 15] 혈관벽안에염증과혈전을생기게함으로써 [16-18] 죽상경화증에이르게한다고알려져있다. Kullo 등 [19] 은 Framingham risk score에따른관상동맥질환의 10년위험률을 3부류로나누어심장관상동맥석회화수치 (CACS) 와혈중호모시스테인치와의연관성을본연구에서, 중등도의위험군에서는 CACS와호모시스테인치는연관성이있었으나저위험군과고위험군에서는연관성이없다고하였다. 이에저자들은혈중호모시스테인치가 조건부적인위험인자 (conditional risk factor) 로서호모시스테인이죽상경화증을나타내기위해서는고전적인위험인자들이어느수준이상이되어야한다고하였고, 이를뒷받침하는다른연구들 [20-23] 의결과에서고혈압이나흡연등, 고전적인위험인자들을가지고있을때이들인자에의해심혈관질환의위험이증가한점을제시하였다. 본연구에서도석회화수치 (CACS) 가 100 이상인경우와호모시스테인치와의연관성을보기위한로지스틱회귀분석에서는성별, 연령, 다른심혈관계질환위험인자들의교란효과를배제한후에는연관성이없었다 ( 자료제시안함 ). 이는호모시스테인치와죽상경화증과의연관성은석회화수치가어느정도수치이상인경우에연관성이있는것으로추측된다. 본연구는몇가지제한점을가지고있다. 첫째, 본연구의대상자는대부분무증상인사람들로, 건강검진을위해자발적으로참여한사람들이므로전체인구집단을대표한다고볼수는없다. 둘째, 연구대상자들이한국인들로서, 본연구의결과가다른인종들에는적용이안될수도있다. 섯째, 본연구는단면연구로, 호모시스테인과죽상경화사이의인과관계는증명할수없었다. 넷째, 본연 www.labmedonline.org 225
구에서는이상지질혈증에대한스타틴제사용유무를조사할수없었다. 본연구결과관상동맥증후군의증상이없는건강검진자에서혈중호모시스테인치와관상동맥석회화수치는연관성이있었고, 특히관상동맥석회화수치가 400 이상인경우에혈중호모시스테인치는석회화수치와독립적인연관성이있었다. 요약 배경 : 혈중호모시스테인의증가는혈전생성과혈관의산화적인손상및혈관내피세포의기능장애을일으키며, 이는죽상경화반의진행과관련이있다고알려져있다. 그러나임상전단계의관상동맥죽상경화증과혈중호모시스테인치의연관성은불분명하다. 그러므로본연구에서는무증상의건강검진자들에서임상전단계의죽상경화증과혈중호모시스테인치의관련성을알아보고자하였다. 방법 : 관상동맥 CT조영술 (coronary CT angiography) 을받은 20세이상성인 2,968명 ( 남자, 1,374명 ; 여자, 1,594명 ) 을대상으로하였고, 이들을혈중호모시스테인치에따라사분위수로나누었다. 로지스틱회귀분석을이용하여, 호모시스테인사분위수에따른관상동맥석회화수치, 관상동맥경화반, 관상동맥협착과의연관성을알아보았다. 결과 : 높은사분위수의호모시스테인은연령, 남성, 체질량지수, 허리둘레, 혈압, 고밀도콜레스테롤, 중성지방, 혈당, 당화혈색소, 고감도 C반응성단백질및관상동맥석회화지수와유의하게관련이있었다. 관상동맥경화반도더높은사분위수인경우에더많이관찰되었고 (21.3%, 28.8%, 34.4%, 34.3%; P <0.001), 관상동맥의 50% 이상협착도더많이관찰되었다 (1.8%, 5.4%, 5.0%, 6.6%; P < 0.001). 관상동맥석회화수치와연관된인자는연령, 호모시스테인, 당화혈색소및고감도 C반응성단백질이었고, 석회화수치 >400인경우와호모시스테인과의연관성은제1사분위수에비해제3사분위수에서는 3.980배 (95% 신뢰구간 : 1.723-9.195) (P = 0.001), 제4사분위수에서는 7.355 배 (95% 신뢰구간 : 3.291-16.439) (P <0.001,) 더높았다. 결론 : 혈중호모시스테인치는임상전단계의죽상경화증과연관이있었다. REFERENCES 1. Choi EK, Choi SI, Rivera JJ, Nasir K, Chang SA, Chun EJ, et al. Coronary computed tomography angiography as a screening tool for the detection of occult coronary artery disease in asymptomatic individuals. J Am Coll Cardiol 2008;52:357-65. 2. Myerburg RJ, Interian A Jr, Mitrani RM, Kessler KM, Castellanos A. Frequency of sudden cardiac death and profiles of risk. Am J Cardiol 1997; 80:10-9F. 3. Schaffer A, Verdoia M, Cassetti E, Marino P, Suryapranata H, De Luca G, et al. Relationship between homocysteine and coronary artery disease. Results from a large prospective cohort study. Thromb Res 2014; 134:288-93. 4. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR 677C-->T polymorphism and risk of coronay heart disease: a meta-analysis. JAMA 2002;288:2023-31. 5. Rasouli ML, Nasir K, Blumenthal RS, Park R, Aziz DC, Budoff MJ. Plasma homocysteine predicts progression of atherosclerosis. Atherosclerosis 2005;181:159-65. 6. Kullo IJ, Bielak LF, Bailey KR, Sheedy PF II, Peyser PA, Li G, et al. Association of plasma homocysteine with coronary artery calcification in different categories of coronary heart disease risk. Mayo Clin Proc 2006; 81:177-82. 7. Taylor AJ, Feuerstein I, Wong H, Barko W, Brazaitis M, O Malley PG. Do conventional risk factors predict subclinical coronary artery disease? Results from the Prospective Army Coronary Calcium Project. Am Heart J 2001;141:463-8. 8. Hunt ME, O Malley PG, Vernalis MN, Feuerstein IM, Taylor AJ. C-reactive protein is not associated with the presence or extent of calcified subclinical atherosclerosis. Am Heart J 2001;141:206-10. 9. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15:827-32. 10. Austen WG, Edwards JE, Frye RL, Gensini GG, Gott VL, Griffith LS. A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association. Circulation 1975;51(4 Suppl):5-40. 11. Lin T, Liu JC, Chang LY, Shen CW. Association of C-reactive protein and homocysteine with subclinical coronary plaque subtype and stenosis using low-dose MDCT coronary angiography. Atherosclerosis 2010;21:501-6. 12. Nasir K and Clouse M. Role of nonenhanced multidetector CT coronary artery calcium testing in asymptomatic and symptomatic individuals. Radiology 2012;264:637-49. 13. Kunita E, Yamamoto H, Kitagawa T, Ohashi N, Oka T, Utsunomiya H, et al. Prognostic value of coronary artery calcium and epicardial adi- 226 www.labmedonline.org
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