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1 Original ORIGINAL Article ARTICLE Korean Circulation J 2005;35: ISSN c 2005, The Korean Society of Circulation 한국인성인에서심방세동과혈중 C-Reactive Protein 농도와의연관성 성균관대학교의과대학강북삼성병원순환기내과학교실, 1 진단검사의학과 2 황상준 1 성기철 1 이용수 1 윤장혁 1 김병진 1 김범수 1 강진호 1 이만호 1 박정로 1 금동극 2 Serum C-Reactive Protein Level and its Association with Atrial Fibrillation in Korean Adults Sang Jun Hwang, M.D. 1, Ki Chul Sung, M.D. 1, Yong Su Lee, M.D. 1, Jang Hyuk Yoon, M.D. 1, Byung Jin Kim, M.D. 1, Bum Soo Kim, M.D. 1, Jin Ho Kang, M.D. 1, Man Ho Lee, M.D. 1, Jung Ro Park, M.D. 1 and Dong Keuk Keum, M.D. 2 1 Division of Cardiology and 2 Laboratory Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea ABSTRACT Background and Objectives:Recent studies have implicated inflammation as playing an important role in the occurrence, persistence and recurrence of atrial fibrillation and that C-reactive protein is a useful marker of the inflammation. The purpose of this study is to evaluate the association between serum CRP levels and the risk of atrial fibrillation. Subjects and Methods:This study was performed on 9,487 subjects (5,263 men and 4,224 women; mean age: 58.8±6.6 years) who underwent medical check-ups at the Health Promotion Center in Kanbuk Samsung Hospital. 9,438 normal control subjects and 49 atrial fibrillation patients were included in the study. The CRP was measured using a highly sensitive Behring Nephelometer II. Results:When comparing the two groups, there were significant differences in age, gender and the presence of hypertension and cerebrovascular accident, and these are the previously known risk factors for atrial fibrillation. After adjustment was made for the clinical significant variables of atrial fibrillation, multiple regression analysis revealed that the hscrp levels were not associated with the risk for atrial fibrillation (p=0.52). Conclusion:The inflammatory markers (CRP, WBC count) were not predictive of a higher risk for atrial fibrillation in the Korean population. (Korean Circulation J 2005;35: ) KEY WORDS:Atrial fibrillation;c-reactive protein;inflammation. 서 C-reactive protein 은급성반응단백 (acute phase protein) 의일종으로감염, 외상, 조직괴사, 종양및여러염증 론 논문접수일 :2004 년 10 월 5 일수정논문접수일 :2005 년 1 월 27 일심사완료일 :2005 년 13 월 4 일교신저자 : 성기철, 서울종로구평동 108 성균관대학교의과대학강북삼성병원순환기내과학교실전화 :(02) 전송 :(02) kcmd.sung@samsung.com 성질환에서증가함으로써염증상태를반영할뿐만아니라, 면역체계의구성요소로염증반응에서다양한역할을담당하는것으로알려져있다. 1-3) 최근에는 C-reactive protein 이관상동맥과뇌혈관, 말초동맥의동맥경화증의발생과연관성이있으며, 4) 급성관동맥증후군에서예후와관련된독립적인인자로서주목받고있다. 5) 이는동맥경화증이나급성관동맥증후군등이염증반응과관련됨을시사하며, 혈중 C-reactive protein 의상승은이를반영하는지표일뿐만아니라, 그자체가염증반응이나죽상반생성, 혈전발생등에관여할가능성이있다. 2)3) 309

2 310 Korean Circulation J 2005;35: 최근심방세동의발생, 지속및재발에있어전신적염증상태가중요한역할을하며, C-reactive protein 이이러한염증반응의지표로서유용할수있다는연구결과들이발표되고있다. 6-9) 이는전신적염증상태가동맥경화증이나급성관동맥증후군의발생에영향을미치듯이, 심방세동이라는심장내의전기생리학적인현상에도영향을미칠수있음을시사한다. 또한전신적염증상태가혈액내과다응고상태에기여하여, 심방세동으로인한뇌경색이나혈전색전증발생과관련된다는보고도있다. 10) 이는전신적염증상태가심방세동발생및이의합병증과도관련되어예후와관련될수있음을시사한다. 그러나이러한체내염증성변화를반영하는지표에대한연구들에서일치된결과를보여주고있지는못한상태이며, 8-10) 이러한연구들이대부분서양인을대상으로하였기때문에심방세동의발생및 C-reactive protein 에영향을줄수있는인자들의분포에차이가있을수있는동양인을대상으로한연구의필요성이있다. 이에저자들은건강검진을위해내원한한국인성인남녀를대상으로심방세동과전신적염증반응의지표들간의연관성을확인해봄으로써전신적염증반응의지표가심방세동의새로운위험인자가될수있을지확인해보고, 전신적염증반응와관련이되어있다고알려진대사증후군과심방세동간의연관성을확인해보고자하였다. 대상및방법 대상주로서울및경기지역에거주하며 2002 년 3월부터 2003 년 12월까지성균관대학교의과대학강북삼성병원에서건강검진을받았던 50세이상의수진자 9,487 명 ( 남자 5,263 명, 여자 4,224 명 ) 을대상으로하였다. 심방세동의발생및 hscrp 의혈중농도에영향을미칠수있는갑상선기능항진증, 급성및만성염증성질환, 최근의심근경색증또는불안정성협심증, 악성종양등이의심되는경우및 hscrp 의혈중농도를낮추는약물들 (statin, fibrate, niacin) 을복용하고있는환자들은배제하였다. 방법수진자 9,487 명을대상으로키, 체중, 허리둘레, 수축기와이완기혈압을측정하였으며, 문진을통하여고혈압, 당뇨및심방세동의과거력및흡연력을확인하였다. 12시간이상공복상태를확인후혈청포도당및인슐린농도, 혈청총콜레스테롤농도, 혈청중성지방농도, 혈청고밀도지단백콜레스테롤농도를측정하였다. 키, 체중은자동측정기를이용하였고, 허리둘레는직립자세에서제대부위에서측정하였으며, 혈청포도당농도, 혈청총콜레스테롤, 혈청중성지방농도, 혈청고밀도지단백콜 레스테롤농도는 Hitachi 사의자동분석기 (Hitachi 747) 를사용하였다. 혈청인슐린은방사면역계수측정법 (immunoradiometric assay, Biosource, Belgium) 으로측정하였다. hscrp(high-sensitivity C-reactive protein) 정량검사는면역비탁법 (immuno-nephelometry, Behring, Nephelometer Ⅱ,Germany) 으로측정하였으며, 측정의하한은 mg/l 이었다 년발표된 NCEP-ATPⅢ(The Third report of the National Cholesterol Education Program Expert panel on detection, evaluation and treatment of high blood cholesterol in adults(adults Treatment PanelⅢ)) 에근거하여대사증후군을정의하였고, 대사증후군과밀접히관련된인슐린저항성의지표로서 HOMA(homeostasis model assessment) 값을이용하였다. 심방세동의유무는문진및심전도를통해확인하였다. 통계분석자료의통계분석은 SAS version 8.0 및 SPSS version 10.0 을이용하였으며연속형변수자료는평균 ± 표준편차로제시하였다. 각변수들의정규분포여부는 Kolmogorov- Smirnov 검사를이용하여분석하였다. hscrp 는정규분포를하지않아로그변환후계산된평균치 (geometric mean) 을이용하였다. 두군간의비교에서연속변수의비교에는 indepentent sample t-test 를, 명목변수의비교에서는카이제곱법을사용하였다. 각변수들의상관관계를확인하기위하여 Spearman correlation test 를사용하였으며, 심방세동발생유무에영향을미치는인자들을분석하기위해서는다중회귀분석을이용하였다. p-value 가 0.05 미만을통계적으로유의하다고판정하였다. 결과 대상군에포함된총 9,487 명중남자는 5,263 명, 여자는 4,224 명이었고, 연령은 50세부터 88세에걸쳐분포하였으며, 평균연령은 58.8±6.6 세였다. hscrp 의평균농도는 1.38±0.2 mg/l 였다. 체질량지수는 15.2 kg/m 2 부터 40.6 kg/m 2 에걸쳐분포하였으며, 평균치는 24.5 kg/m 2 이었다. 전체연구대상자의임상적특징을보면, 대조군과비교하여심방세동을가진군에서연령이높았으며, 남성의비율및고혈압및뇌혈관질환의유병률이높았다. 그러나심전도및과거력상발견할수있는관상동맥질환유무의비교에서는차이가없었다. NCEP-ATP Ⅲ 정의에의한대사증후군인자들각각에서심방세동유무를비교한결과허리둘레를제외한다른인자들에서는통계학적으로유의한차이를보이지않았다. 대사증후군의유무및인슐린저항성의지표인 HOMA index 에대한비교에서도양군간에유의한차이를보이지않았

3 Sang Jun Hwang, et al:crp in Atrial Fibrillation 311 Table 1. Comparison of the baseline characteristics between the control group and patients with atrial fibrillation Characteristic Control group (n=9438) Atrial fibrillation group (n=49) p Age (years) 058.7± ±6.60 < * Male sex-no. (%) 5226 (55.4%) 38 (79.2%) < * History of diabetes-no. (%) 0343 (03.6%) 02 (04.2%) <0.844 History of hypertension-no. (%) 1168 (12.4%) 11 (22.9%) < History of smoking-no. (%) 0998 (10.6%) 03 (06.3%) <0.331 History of CAD-no. (%) 0097 (01.0%) 01 (02.1%) <0.471 History of CVA-no. (%) 0025 (00.3%) 01 (02.1%) <0.016 * Metabolic syndrome-no. (%) 0912 (20.3%) 05 (21.7%) <0.861 Systolic blood pressure (mmhg).124.2± ±18.0 <0.533 Diastolic blood pressure (mmhg) 078.7± ±13.5 <0.126 Body mass index 024.5± ±3.0 <0.184 Waist circumference (cm) 082.7± ±8.6 <0.047 * HOMA index 01.90± ±2.2 <0.304 HsCRP (mg/l) 001.4± ±0.25 <0.257 WBC count (10 3 /mm 3 ) 06.05± ±1.72 <0.009 * Total cholesterol (mg/dl) 238.4± ±36.4 <0.021 * Fasting glucose (mg/dl) 100.0± ±300. <0.281 Triglyceride (mg/dl) 155.8± ±54.8 <0.108 HDL-cholesterol (mg/dl) 055.9± ±11.1 <0.544 LDL-cholesterol (mg/dl) 125.3± ±31.3 <0.479 Values are expressed as mean±se. CAD: coronary artery disease, CVA: cerebrovascular accident, HOMA index: homeostasis model assessment index, hscrp: high-sensitivity C-reactive protein, HDL: high density lipoprotein, LDL: low density lipoprotein, WBC: white blood cell, HsCRP: high-sensitivity C-reactive protein. *: p<0.05, significant difference from control group Table 2. Spearman s correlation coefficients among age, BMI, hscrp, WBC count, HOMA index and individual components of metabolic syndrome Log (hscrp) HOMA WBC count Age SBP DBP BMI Waist circumference (cm) Triglyceride (mg/dl) HDL-cholesterol (mg/dl) FBS (mg/dl) All correlation p< SBP: systolic blood pressure, DBP: diastolic blood pressure, BMI: body mass index, HDL: high density lipoprotein, FBS: fasting blood glucose, log (hscrp): log transformation of hscrp, WBC: white blood cell count (10 3 /mm 3 ). HOMA: Homeostasis model assessment 다. 전신적염증성반응의지표로측정한 hscrp 의혈중농도는심방세동을가진군에서높게나타났으나통계학적으로유의한차이를보이지는못했으며 (p=0.257), 말초혈액백혈구수는심방세동을가진군에서높게나타났다 (p=0.009)(table 1). 전체를대상으로연령, 체질량지수및대사증후군의인자들과 hscrp 의 log 값, HOMA index, 말초혈액백혈구수간의상관관계를관찰한결과, 모두에서통계학적으로유의한상관관계를보였으며 (p<0.001), hscrp 농도와가장상관성이높은인자는허리둘레 (r=0.242) 였으며, HOMA index Table 3. Multiple regression analysis between the presence of atrial fibrillation and some variables including hscrp Regression coefficient Standard error (S.E) Chi-square value hscrp Age Sex SBP DBP BMI History of HTN History of DM History of CAD History of CVA hscrp: high-sensitivity C-reactive protein, SBP: systolic blood pressure, DBP: diastolic blood pressure, BMI: body mass index, HTN: hyper-tension, DM: diabetes mellitus, CAD: coronary artery disease, CVA: cerebrovascular accident 는체질량지수 (r=0.356) 와, 말초혈액백혈구수는중성지방농도 (r=0.212) 와의상관관계가가장높게나타났다 (Table 2). 다중회귀분석으로연령, 성별, 혈압, 체질량지수및고혈압, 당뇨병, 관상동맥질환, 뇌혈관질환의유무등의교란변수들을보정하였을때, hscrp 농도는심방세동발생을예측할수없었다 (p=0.52)(table 3). HOMA index 및말초혈액백혈구수의경우도심방세동발생을예측할수없었다 (data not shown). hscrp 값에따라대상군을사등분하여가장낮은군에대 p

4 312 Korean Circulation J 2005;35: Table 4. Odds ratio for presence of atrial fibrillation according to CRP quartiles CRP quartiles (mg/dl) AF cases/no. at Risk Unadjusted OR (95% CI) p Adjusted* OR (95%CI) p < / to / ( ) ( ) to / ( ) ( ) > / ( ) ( ) *: variables considered in the multivariate analyses included age, sex, systoloic and diastolic blood pressures, body mass index, history of hypertension, diabetes mellitus, coronary artery disease, cerebro-vascular disease and smoking. CRP: C-reactive protein, AF: atrial fibrillation, OR: odd ratio, CI: confidence index 해심방세동의위험도를비교하였을때, hscrp 값이높아질수록교차비가증가하였으나, 통계학적인유의성은없었다 (Table 4). 혈중 hscrp 농도에따른심방세동유병률의선형적관계를다시확인하기위하여 χ 2 for linear trend test 를하였으나통계학적인유의성은없었다 (p=0.317)(data not shown). 고 심방세동은가장흔한부정맥이지만그발생기전에대해서는잘알려져있지않다. 기존의연구에있어서, 심방세동의발생에는다발성회귀파기전 (multiple-wavelet hypothesis) 이나국소성급속자극기전 (focal rapid firing theory) 등의전기생리학적인측면으로설명되고있었으나, 최근전신적또는국소적염증반응이이에관여할수있다는보고들이있다. 심장수술후 11) 나급성심장막염후 12) 에심방세동이잘발생하며, 이에대한기전으로보체계의활성화나사이토카인의분비등염증반응의역할이언급되면서, 11)13) 실험적연구로확인하려는시도도있었다. 14)15) 비록소규모집단을대상으로한연구이나 Sata 등 16) 은심방세동발생후 hscrp 를포함한전신적염증반응의지표들이정상심율동전환후에도감소되지않고지속적으로상승되어있다는결과에서염증반응이심방세동의원인일가능성을지적하였다. 이는심장내의국소적인염증반응뿐만아니라, 전신적인염증상태도심방세동발생과연관성이있음을시사하는것이다. 이러한기전으로, 전신적또는국소적염증반응이심방내국소자극형성을촉발하며, 심방재형성에관여하여심방세동의지속및재발에영향을미칠수있다는보고가 17)18) 있으나아직이에대해서확실한결론은없는상태이다. 최근이러한염증반응의표지자로서 hscrp 와심방세동과의연관성에대한연구들이보고되고있는바, Aviles 등 6) 은 hscrp 가다른위험인자들과독립적으로심방세동의존재및향후발생가능성을예측한다고하였다. Dernellis 등 8) 은발작성심방세동의유지와관련되어 hscrp 가정상심율동전환의결정인자가될수있다고보고하였다. hscrp 는표준화된측정방법이있고, 비교적재현성이좋은검사방법이기때문에, 19-22) 심방세동과염증반응과의관계를반 찰 영할수있다면심방세동의일차또는이차예방이나치료효과를모니터링할수있는지표로서유용하게사용될가능성이있다. 그러나, 본연구에서는 hscrp 의혈중농도는대조군과심방세동을가진군간에통계학적으로유의한차이가없었으며, 나이, 성별, 혈압, 체질량지수, 흡연력및고혈압, 당뇨, 심혈관질환, 뇌혈관질환등의과거력등을보정한후에도 hscrp 의혈중농도가심방세동유무를예측하지못하였다. 이는기존의연구결과와는비교되는것으로, hscrp 와심방세동발생에영향을미칠수있는다른요인들의차이를고려해야한다. Avile 등 6) 의연구에서는 hscrp 의평균이 3.64±6.31 mg/l 로심혈관질환의고위험군 21) 에해당하는미국인이었던반면, 본연구에서는대상군의 hscrp 의평균이 1.38±0.2 mg/l 으로상대적으로낮은수치를보였다. 심혈관질환의위험인자들이심방세동발생에영향을미칠가능성을고려할때, 대상군간의 hscrp 의차이는심방세동발생에영향을미치는인자들의분포에차이가있음을시사한다. 또한, 심방세동에서혈전생성이잘생기는원인으로혈역학적측면외에, 과다응고상태로의진행이중요하며, 염증반응이이에관여된다는보고들 23-25) 에서지적했듯이, hscrp 나 Interleukin-6 와같은염증지표의상승은심방세동과직접적으로관련이있다기보다는과다응고상태와관련된동반질환에의해영향을받을수있다. 심방세동에서염증반응의지표로 hscrp 외에도 interleukin-6, fibrinogen, 말초혈액백혈구수등에대한보고들 9)26) 이있으나결과에있어서발표자간에차이가있다. 본연구에서말초혈액백혈구수는대조군과심방세동을가진군간의비교에서통계학적으로유의한차이가있었으나, 교란변수를보정한후에는심방세동의발생과유의한상관관계를보여주지못하였다 (data not shown). 대사증후군의특징인인슐린저항성의지표로측정한 HOMA index 역시심방세동발생에영향을미치는독립적인인자로서작용하지는못하였다 (data not shown). 그러나대사증후군인자들각각에대해심방세동유무를비교한결과복부비만을나타내는허리둘레가유의한차이를보였는데이것은지방세포에서분비되는사이토카인인 interleukin(il)-6, tumor necrosis factor-α 등이전신적염증

5 Sang Jun Hwang, et al:crp in Atrial Fibrillation 313 반응을유발함으로써대사증후군이발생한다는보고들 27-29) 에서보듯이복부비만이전신적염증반응과관련되어심방세동의발생에영향을미칠가능성을배제할수없다. 또한심방세동의발생이비만과관련있다고알려진폐쇄수면무호흡증을가진환자에서유의하게증가되어있다는보고도이에대한설명이될수있을것이다. 30) 따라서심방세동의발생에있어복부비만의연관성에대한연구가향후필요하리라생각된다. 본연구는몇가지제한점이있었다. 첫째, 단면적연구설계가가지는한계이고, 둘째, 심방세동을가진군에서건강검진시시행한심전도소견만을참조하였기때문에발작성, 지속성, 고립성등의심방세동분류에따라비교할수없어서, 심방세동의발생, 유지및재발의각각의경우로나누어 hscrp 와의연관성을확인해볼수없었다는점이다. 셋째, hscrp 는기존의 CRP 측정에비해매우예민한검사방법이나동일인을대상으로측정하더라고측정방법에따라차이가날수있는것으로알려져있다. 20) 아울러이에영향을줄수있는여러변수들의영향을통제해야하는것이중요하다. 본연구에서는 AHA/CDC 에서제시한 21) hscrp 에영향을미칠수있는변수들을가능한고려하려고하였다. 그러나 hscrp 농도에영향을미친다고알려져있는알콜섭취량이나운동정도, 최근의체중감소, 여성에있어호르몬대체요법등은문진시이를확인하지못하여이로인한영향을반영하지못한한계점이있었다. 이상의제한점에도불구하고, 본연구는심방세동과염증반응의지표들사이의관계를알아본국내첫보고이고, 비교적많은인원을대상으로했으며, 전신적염증상태와관련이있다고알려진대사증후군과심방세동의관계를규명하려시도하였다는점에서그의의가있다하겠다. 결론적으로본연구에서는기존의서양에서행해진연구결과와달리, 상대적으로저위험군인동양인에서전신적염증상태의지표로서 hscrp 와말초혈액백혈구수는심방세동발생을예측할수없었다. 대사증후군과인슐린저항성의지표인 HOMA index 도심방세동의유무와유의한관계를보이지못했으나, 대사증후군의인자들중복부비만을나타내는허리둘레가심방세동의유무와유의한관계를나타내었다. 따라서앞으로심방세동과관계되는염증반응의정도를반영할수있는새로운지표의연구가필요하며, 심방세동과염증반응의인과관계를규명할수있도록전향적인연구가필요할것으로생각된다. 요약 배경및목적 : 최근심방세동의발생및지속, 재발에있어전신적염증상태가중요한역할을하며, C-reactive protein 이이러한염증반응의지표로서유용하다는연구결과들이있다. 본 연구에서는한국인성인남녀를대상으로심방세동의유무와전신적염증반응의지표들간의연관성을확인해보고자하였다. 방법 : 2002 년 3월부터 2003 년 12월까지서울의강북삼성병원에서건강검진을받았던 50세이상의수진자 9,487 명 ( 남자 5,263 명, 여자 4,224 명 ) 을대상으로하였으며평균연령은 58.8±6.6 세였다. 건강대조군과심방세동군으로나누어임상양상을비교하였으며, hscrp 방법으로측정한염증반응의활성도로서염증반응의정도와심방세동의유무와의관련성을분석하였다. 결과 : 건강대조군과심방세동군간의비교에서심방세동의위험인자로알려진연령, 성별, 고혈압및뇌혈관질환유무등에서통계학적으로유의한차이를보였으나, 관상동맥질환유무의비교에서는차이가없었다. 대사증후군의유무도양군간에유의한차이를보이지않았으며, 대사증후군인자들각각의비교에서허리둘레만이유의한차이를보였다. 전체를대상으로연령, 체질량지수및대사증후군의인자들과 hscrp, 말초혈액백혈구수, HOMA index 간의상관관계를관찰한결과, 모두에서통계학적으로유의한상관관계를보였으나다중회귀분석으로교란변수들을보정하였을때, hscrp 및말초혈액백혈구수, HOMA index 모두심방세동의유무를예측할수없었다. hscrp 값에따라대상군을사등분하여가장낮은군에대해심방세동의위험도를비교하였을때, hscrp 값이높아질수록교차비가증가하였으나, 통계학적인유의성은없었다. 결론 : 본연구에서전신적염증상태의지표로서 hscrp 와말초혈액백혈구수는심방세동유무를예측할수없었다. 따라서앞으로심방세동과염증반응의연관성및인과관계를규명할수있도록전향적인연구가필요할것으로생각된다. 중심단어 : 심방세동 ;C-reactive protein; 염증반응. REFERENCES 1) Volanakis JE. Acute phase proteins in rheumatic disease. In: Koopman WJ editor. Arthritis and Allied Conditions: a textbook of rheumatology. 13th ed. Baltimore: Williams & Wilkins; p ) Ballou SP, Lozanski G. Induction of inflammatory cytokine release from cultured human monocytes by C-reactive protein. Cytokine 1992;4: ) Cermak J, Key NS, Bach RR, Balla J, Jacob HS, Vercellotti GM. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 1993;82: ) Heinrich J, Schulte H, Schofeld R, Koler E, Assmann G. Association of variables of coagulation, fibrinolysis and acute-phase with atherosclerosis in coronary and peripheral arteries and those arteries supplying the brain. Thromb Haemost 1995;73:

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