ORIGINAL ARTICLE J Neurocrit Care 2016;9(2):139-143 eissn 2508-1349 비판막성심방세동환자에서 CHA 2 DS 2 -VASc 점수와좌심방확장및 D-dimer 의연관성 김태원 1 ㆍ정성우 1 ㆍ이광수 1 ㆍ박훈준 2 ㆍ김중석 1 ㆍ구자성 1 ㆍ송인욱 1 ㆍ오주희 1 ㆍ이양현 1 ㆍ전기평 1 ㆍ한시령 1 가톨릭대학교의과대학신경과학교실 1, 심장내과학교실 2 CHA 2 DS 2 -VASc Scores are Proportionally Associated with Left Atrial Enlargement and Serum D-dimer Levels in Patients with Non-valvular Atrial Fibrillation Taewon Kim, MD, PhD 1, Sung-Woo Jung, MD, PhD 1, Kwang-Soo Lee, MD, PhD 1, Hun-Jun Park, MD, PhD 2, Joong-Seok Kim, MD, PhD 1, Jaseong Koo, MD, PhD 1, In-Uk Song, MD, PhD 1, Ju-Hee Oh, MD 1, Yang-Hyun Lee, MD 1, Ki-Pyung Jeon, MD 1, and Si-Ryung Han, MD, PhD 1 Department of 1 Neurology, and 2 Division of Cardiology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea Background: Virchow s triad, consisting of atrial tissue damage, a hypercoagulable state, and blood stasis, has been used to explain the thrombogenic mechanisms of non-valvular atrial fibrillation (NVAF). Blood stasis is thought to be attributable to loss of left atrial systole and left atrial enlargement, while the hypercoagulable state is partly reflected by elevated serum D-dimer levels. The aim of this study was to evaluate the correlation between risk factors for CHA 2 DS 2 -VASc and left atrial enlargement/serum D-dimer levels in order to explore whether LAE with D-dimer elevation is one of the key factors in the thrombogenic mechanisms of atrial fibrillation. Methods: Consecutive patients with acute ischemic stroke due to NVAF who were anticoagulation-naïve were enrolled. All patients were evaluated for left atrial volume index (LAVI) by transthoracic echocardiography. The association between CHA 2 DS 2 -VASc scores and LAVI/D-dimer levels was evaluated. Results: A total of 98 anticoagulation-naïve patients who presented with acute ischemic stroke due to NVAF were enrolled in this study. CHA 2 DS 2 -VASc scores were significantly correlated with left atrial volume index (r=0.325, P =0.002). There was also a significant correlation between CHA 2 DS 2 -VASc scores and serum D-dimer levels (r=0.309, P=0.006). Conclusions: CHA 2 DS 2 -VASc scores were associated with left atrial enlargement (LAE) and increased D-dimer levels in anticoagulation-naïve patients with acute ischemic stroke due to NVAF. LAE may play a crucial role in the link between CHA 2 DS 2 -VASc risk factors and the development of ischemic stroke, and these hypercoagulable conditions seem to be reflected by an elevation in D-dimer levels. J Neurocrit Care 2016;9(2):139-143 Received Jun 1, 2016 Revised Jul 1, 2016 Accepted Jul 5, 2016 Corresponding Author: Si-Ryung Han, MD, PhD Department of Neurology, The Catholic University of Korea St. Vincent s Hospital, 93 Jungbu-daero, Paldal-gu, Suwon 16247, Korea Tel: +82-31-249-7156 E-mail: srhan@catholic.ac.kr Copyright 2016 The Korean Neurocritical Care Society Key words: Stroke; Atrial fibrillation; D-dimer 서론 심방세동은심장부정맥중에가장흔하며, 뇌경색및전신색 전증 (systemic thromboembolism) 과같은유해심혈관계질환 의위험성을높인다고알려져있다. 비판막성심방세동환자에 서, 다른혈관위험인자가없는소위고립성심방세동일경우 cc 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. www.e-jnc.org 139
(lone atrial fibrillation) 뇌경색위험이높지않지만, CHA 2 DS 2 - VASc 위험인자 ( 심부전, 고혈압, 고령, 당뇨, 뇌졸중 / 일과성허혈증후군, 말초혈관질환, 관상동맥병, 대동맥궁혈전, 여성 ) 가더해질경우정상인에비해최소 5배이상의높은뇌경색위험성을갖게된다. 1 그러나 CHA 2 DS 2 -VASc 위험인자들은뇌경색을발생시키는직접적인원인인자들이아니라여러관찰연구를토대로뇌경색을예측하기위해고안된연관인자들이다. 어떻게 CHA 2 DS 2 -VASc 위험인자들이더해질수록뇌경색위험성이높아지는지는혈전형성기전측면에서 Virchow s triad 로설명되고있다. 심방세동에서의 Virchow s triad는심방조직손상 (atrial tissue damage), 응고항진상태 (hypercoagulable state), 혈류의정체 (blood stasis) 로구성된다. 2,3 이중에서응고항진상태는 D-이합체, 트롬빈-항트롬빈복합체, 프로트롬빈, 인터루킨, C반응성단백 (C-reactive protein, CRP) 의증가로나타나는데, 특히 D-이합체는심방세동에서유의하게증가된다고알려져있으며, 4 또한유해심혈관계질환의발생과독립적으로연관되어있다고알려져있다. 5 심방세동에서혈전형성의가장중요한기전중하나인혈류의정체는좌심방의수축기능상실 (loss of left atrial systole) 과좌심방확장 (left atrial enlargement) 때문에기인한다. 2,3 좌심방확장역시뇌경색발생의독립적인예측인자일뿐만아니라, 6-10 심한뇌경색을일으켜뇌경색의중증도와도관련있음이알려졌다. 11 이연구의목적은다음과같다. 첫째, CHA 2 DS 2 -VASc 위험인자들의점수와좌심방확장의연관성을밝힘으로써, 좌심방확장이 CHA 2 DS 2 -VASc 점수증가와혈전발생위험의중요한중간연결고리의역할을할수있음을알아보고자하였다. 또한만약연관성이있다면 CHA 2 DS 2 -VASc 위험인자들중에어떤인자들이좌심방확장과가장연관성이있는지알아보고자하였다. 둘째는, CHA 2 DS 2 -VASc 위험인자들의점수와 D-이합체의연관성을평가함으로써, CHA 2 DS 2 -VASc 점수의증가가혈전형성의한기전인응고항진상태의심화와관련있음을알고자하였다. 대상및방법 대상이연구과제는서울성모병원의윤리위원회의승인을받아진행되었다. 2010년 9월부터 2013년 10월까지비판막성심방세동에의해발생한급성뇌경색으로연속적으로입원한환자중 에항응고제를투여하지않은 98명의환자를대상으로하였다. 환자들은다음의조건들을모두만족하면포함되었다 : (1) 발생 2일이내의뇌경색이고, 이는임상적증상과일치하는뇌병변이확산자기공명영상에서확인되어야함, (2) 이전에심방세동과거력이있거나, 응급실, 뇌졸중집중치료실, 홀터모니터검사에서심방세동이보이는경우, (3) 항응고제는 D-이합체수치를저하시키기때문에, 12 최근 3개월동안항응고제를복용하지않았으며입원시활성화부분트롬보플라스틴시간 (activated partial thromboplastin time, aptt) 과프로트롬빈시간국제표준화비율 (prothrombin time international normalized ratio, PT INR) 이정상소견을보이는환자, (4) 심장초음파에서판막질환이없는경우. 다음의조건들이한가지라도있는환자들은제외되었다 : (1) 뇌경색병변과관련있는뇌혈관의근위부에 artery-toartery embolism을시사하는국소적인동맥경화협착이있는경우, (2) 감염성, 염증성, 혈관염성, 탈수초성, 또는결합조직병 (connective tissue disease) 을시사할만한진단검사또는임상양상이있는경우, (3) 3개월이내에뇌졸중기왕력이있는경우, (4) 가역적인심방세동일때 ( 갑상선호르몬이상또는전신마취수술후 2주이내 ). 포함된환자들의나이, 성별, 흡연, 고혈압, 당뇨, 심부전, 관상동맥병, 말초혈관질환및이전에뇌졸중기왕력의임상정보가조사되었으며, 모든환자들은자세한신체검사및신경학적검사, D-이합체를포함한혈액검사, 흉부 X선, 12리드심전도, 심전도지속모니터, 홀터모니터검사, 경흉부심장초음파 ( 필요한환자는경식도심장초음파 ), 뇌자기공명영상, 뇌자기공명혈관조영술 (MR Angiography) 또는전산화단층촬영혈관조영술 (CT angiography) 를시행하였다. 이연구에서사용한각환자의 CHA 2 DS 2 -VASc 점수는급성뇌경색발생전의위험인자의과거력 (pre-stroke CHA 2 DS 2 -VASc score) 으로분석하였다. 좌심방 용적지수 (left atrial volume index) 의평가심장전문의 (HJP) 가초음파를이용하여좌심방용적지수를측정하였다. 좌심방용적은 American Society of Echocardiography standard guidelines를준수하여 biplane area-length method를이용하여측정하였으며, 13 좌심방용적지수는이렇게구한좌심방용적을각환자의체표면적 (body surface area) 으로나누어얻었다. 자료처리통계적분석은 Statistical Package for the Social Sciences 140
Taewon Kim, et al. CHA2DS2-VASc scores and left atrial enlargement with D-dimer (SPSS) software package version 15.0 (SPSS Inc., Chicago, IL, USA) 을이용하였다. CHA 2 DS 2 -VASc 점수와좌심방용적지수 및 D- 이합체의연관성은상관관계분석 (correlation coefficient Table 1. Demographic and clinical characteristics of anticoagulation-naïve patients with acute ischemic stroke due to nonvalvular AF Characteristic Total (N=98) Age (yr.) 72.2±9.1 Male, No. (%) 64 (65.3) Initial NIHSS score 8.4±7.5 Location of stroke in left hemisphere, No. (%) 48 (49.0) Posterior circulation infarction *, No. (%) 16 (16.3) Hypertension, No. (%) 63 (64.3) Diabetes mellitus, No. (%) 25 (25.5) Smoking, No. (%) 37 (37.8) Previous stroke, No. (%) 12 (12.2) Ischemic heart disease, No. (%) 19 (19.4) Peripheral vascular disease, No. (%) 2 (2.0) Body mass index 23.8±3.5 History of taking antiplatelet agents, No. (%) 50 (51.0) Statin use, No. (%) 20 (20.4) Diagnosed as AF previously, No. (%) 45 (45.9%) Pre-stroke CHA 2 DS 2 -VASc scores 0 8 (8.2%) 1 17 (17.3%) 2 12 (12.2%) 3 26 (26.5%) 4 18 (18.4%) 5 9 (9.2%) 6 4 (4.1%) 7 2 (2%) 8 2 (2%) PT INR 1.1±0.1 D-dimer (µg/ml) mean (SD) 2.6±5.0 Left atrium volume index (ml/m 2 ) 57.1±25.4 Median (Interquartile range) 52.3 (39.3-67.1) Left ventricular ejection fraction (%) 58.0±10.6 Values are presented as mean ± SD unless otherwise indicated. Analyses were performed with the independent sample t-test, Fisher s exact test, or χ 2 test. AF, atrial fibrillation; NIHSS, National Institudes of Health Stroke Scale; PT INR, prothrombin time international normalized ratio; T, total participants; M, male; F, female. *Posterior circulation infarction includes infarction in the regions of the vertebral, basilar, and/or posterior cerebral arteries; P<0.05; P<0.01. analysis) 을이용하여평가하였으며, CHA 2 DS 2 -VASc 위험인자 들중에어떤인자들이좌심방용적지수와가장독립적으로연 관성이있는지알아보고자다중선형회귀분석 (multiple linear regression analysis) 을이용하였다. 결과 전체환자의특성 항응고제를투여하지않은비판막성심방세동에의한급 성뇌경색환자총 98 명이대상이되었다. 총환자중에 64 명 2 ) Figure 1. Scatterplot and the result of correlation coefficient analysis between CHA 2 DS 2 -VASc scores and left atrial volume index. Figure 2. Scatterplot and the result of correlation coefficient analysis between CHA 2 DS 2 -VASc scores and serum D-dimer levels. 141
Table 2. Associations of left atrial volume index with CHA 2 DS 2 -VASc risk factors as determined by multiple linear regression analysis in patients with acute ischemic stroke due to non-valvular AF Variables β ± SE t value P-value Congestive heart failure 28.615±14.034 2.039 0.045 * Hypertension 12.482±4.964 2.515 0.014 * Age -0.442±0.287-1.539 0.127 Diabetes mellitus 3.780±5.435 0.695 0.489 Prior Stroke or TIA or thromboembolism 12.443±7.514 1.656 0.102 Ischemic heart disease -4.091±6.140-0.666 0.507 Peripheral vascular disease 66.705±17.310 3.853 0.000 Female sex 7.319±5.004-1.463 0.147 AF, atrial fibrillation; SE, standard error; TIA, transient ischemic attack. *Adjusted R 2 =0.286; F=5.550 (P=0.000). (65.3%) 은남자였으며, 평균나이는 72.2±9.1 ( 범위, 46-92) 세 였다. 고혈압 (n=63, 64.3%) 이가장흔한위험인자였으며, 그다 음으로담배 (n=37, 37.8%), 당뇨 (n=25, 25.5%), 고지혈증 (n=20, 20.4%), 허혈성심장질환 (n=19, 19.4%), 허혈성뇌졸중 (n=12, 12.2%), 그리고말초혈관질환 (n=2, 2%) 순이었다. 평균체표면적은 23.8 ± 3.5 kg/m 2 (16 36) 였다. 총 45 명이입 원전에비판막성심방세동으로진단받은적이있었으며, 이 중에 25 명은항혈소판제제를복용하고있었다. 평균좌심방용 적지수는 57.1± 25.4 ml/m 2 였다. 전체환자의특성은 Table 1 에 요약되어있다. CHA 2 DS 2 -VASc 점수와좌심방용적지수및 D- 이합체의연관성 상관계수분석을하였을때 CHA 2 DS 2 -VASc 점수는유의하게 좌심방용적지수와비례적인관련이있었다 (r=0.325, P=0.002) (Fig. 1). 다중선형회귀분석에서는 CHA 2 DS 2 -VASc 위험인자중 에고혈압 (t=2.5, P=0.014), 심부전 (t=2.0, P=0.045), 말초혈관 질환 (t=3.9, P<0.001) 이좌심방용적지수와독립적인연관성을 보였다 (Table 2). 혈액의 D- 이합체수치또한상관계수분석에 서 CHA 2 DS 2 -VASc 점수와비례적인연관성이있었다 (r=0.309, P=0.006) (Fig. 2). 고찰 비판막성심방세동에의한급성뇌경색환자를대상으로한 이연구에서, CHA 2 DS 2 -VASc 점수는유의하게좌심방확장과 비례적인연관성을보였으며, CHA 2 DS 2 -VASc 위험인자중에서 도특히고혈압, 심부전, 말초혈관질환이좌심방확장과유의한연관성을보였다. 또한 CHA 2 DS 2 -VASc 점수는 D-이합체의증가와도비례적인연관성을보였다. 이연구의결과는 CHA 2 DS 2 -VASc 점수의증가와좌심방직경의증가가유의한연관성을보인한연구내용과일치한다. 14 그러나그연구는좌심방확장을평가하기위해용적보다는직경을측정하였는데, 이는용적에비해부정확하다고알려져있으며, 15 그래서 The Guidelines and Standards Committee of the American Society of Echocardiography에서는직경보다는용적을평가하는것을추천하고있다. 13 그러므로좌심방확장의측정측면에서이연구는타연구에비해강점을가지고있다. 이연구의결과에서보인 CHA 2 DS 2 -VASc와좌심방확장의유의한연관성의가장큰의미는심방세동에서 CHA 2 DS 2 -VASc 증가가뇌경색위험성의증가로연결되는중요한연결고리역할을좌심방확장이할수있음을나타낸다. 이연구와다른연구의결과를종합해보면, CHA 2 DS 2 -VASc 위험인자들이더해질수록좌심방이확장되고, 이렇게커지고정상적인수축기능또한상실된좌심방에서는난류가심해지고정체된혈류의용적과표면적이증가하면서혈전생성을촉진시키는것으로가설을세울수있다. 11 CHA 2 DS 2 -VASc 위험인자중에서도특히고혈압, 심부전, 말초혈관질환이좌심방확장에가장영향력이있었다. 고혈압및심부전이진행하면좌심방이비대해지는것은어떻게보면당연하지만, 거꾸로생각해본다면 CHA 2 DS 2 -VASc 위험인자들중에고혈압, 심부전, 말초혈관질환이혈전생성의중요한기전중에하나인좌심방확장에있어서가장중요한인자임을시사한다고볼수있다. 또한 CHA 2 DS 2 -VASc 점수의증가와 D-이합체의증가가유의한상관관계를보였는데, 이는아마도좌심방이비대해지면서혈전생성이잘만들어지는환경을 D-이합체가대변한것일수 142
Taewon Kim, et al. CHA2DS2-VASc scores and left atrial enlargement with D-dimer 도있고, 또는 CHA 2 DS 2 -VASc 위험인자들이더해지면서응고항진상태가진행하는것을독립적으로나타내는것일수도있다. 이를확인하기위해서는더많은연구가필요하다고생각된다. 이연구에서의 CHA 2 DS 2 -VASc 점수와좌심방용적지수및 D- 이합체의유의한상관관계는, 좌심방용적지수및 D-이합체가 CHA 2 DS 2 -VASc처럼향후뇌경색의발생을예측하는데한가지예측인자로적용할수있음을시사한다. 이미 D-이합체를 CHA 2 DS 2 -VASc에넣어서뇌경색의발생을예측했을때더좋은결과를보인연구결과가있었으며, 5 본연구는이의결과를더뒷받침한다. 이연구는여러가지한계점을가지고있다. 첫째는, 항응고제효과를배제하기위해항응고제를복용하지않는환자를모았는데, 예상보다많은환자를모으지못한이유가되었다. 둘째는심초음파를시행한환자들만포함시킴으로써, 심초음파조차시행할수없을정도의심한뇌졸중환자는배제되어표본선택편의 (selection bias) 의여지가있다. 결론적으로항응고제를투여하지않았었던비판막성심방세동에의한급성뇌경색환자를대상으로한이연구에서, CHA 2 DS 2 -VASc 점수의증가는좌심방확장및 D-이합체증가와유의한연관성이있었고, 좌심방확장및 D-이합체는혈전형성및뇌경색의발생에있어서향후중요한잠재적인예측인자로적용될수있을것으로생각된다. REFERENCES 1. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137:263-72. 2. Castellano JM, Chinitz J, Willner J, Fuster V. Mechanisms of stroke in atrial fibrillation. Card Electrophysiol Clin 2014;6:5-15. 3. Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow s triad revisited. Lancet 2009;373:155-66. 4. Gustafsson C, Blombäck M, Britton M, Hamsten A, Svensson J. Coagulation factors and the increased risk of stroke in nonvalvular atrial fibrillation. Stroke 1990;21:47-51. 5. Christersson C, Wallentin L, Andersson U, Alexander JH, Ansell J, De Caterina R, et al. D-dimer and risk of thromboembolic and bleeding events in patients with atrial fibrillation- -observations from the ARISTOTLE trial. J Thromb Haemost 2014;12:1401-12. 6. Barnes ME, Miyasaka Y, Seward JB, Gersh BJ, Rosales AG, Bailey KR, et al. Left atrial volume in the prediction of first ischemic stroke in an elderly cohort without atrial fibrillation. Mayo Clin Proc 2004;79:1008-14. 7. Moller JE, Hillis GS, Oh JK, Seward JB, Reeder GS, Wright RS, et al. Left atrial volume: a powerful predictor of survival after acute myocardial infarction. Circulation 2003;107:2207-12. 8. Osranek M, Bursi F, Bailey KR, Grossardt BR, Brown RD Jr, Kopecky SL, et al. Left atrial volume predicts cardiovascular events in patients originally diagnosed with lone atrial fibrillation: threedecade follow-up. Eur Heart J 2005;26:2556-61. 9. Tsang TS, Barnes ME, Bailey KR, Leibson CL, Montgomery SC, Takemoto Y, et al. Left atrial volume: important risk marker of incident atrial fibrillation in 1655 older men and women. Mayo Clin Proc 2001;76:467-75. 10. Tsang TS, Barnes ME, Gersh BJ, Takemoto Y, Rosales AG, Bailey KR, et al. Prediction of risk for first age-related cardiovascular events in an elderly population: the incremental value of echocardiography. J Am Coll Cardiol 2003;42:1199-205. 11. Kim TW, Jung SW, Song IU, Koo J, Choi HS, Lee KS, et al. Left atrial dilatation is associated with severe ischemic stroke in men with non-valvular atrial fibrillation. J Neurol Sci 2015;354:97-102. 12. Lip GY, Lowe GD, Rumley A, Dunn FG. Increased markers of thrombogenesis in chronic atrial fibrillation: effects of warfarin treatment. Br Heart J 1995;73:527-33. 13. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440-63. 14. Hrynkiewicz-Szymanska A, Dluzniewski M, Platek AE, Szymanski FM, Syska-Suminska J, Klos-Szadryn A, et al. Association of the CHADS and CHA 2DS-VASc scores with left atrial enlargement: a prospective cohort study of unselected atrial fibrillation patients. Thromb Thrombolysis 2015;40:240-7. 15. Jiamsripong P, Honda T, Reuss CS, Hurst RT, Chaliki HP, Grill DE, et al. Three methods for evaluation of left atrial volume. Eur J Echocardiogr 2008;9:351-5. 143