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1 대한내과학회지 : 제 81 권제 4 호 2011 특집 (Special Review) - 심방세동의이해와치료 심방세동의기전 연세대학교의과대학내과학교실심장내과 정보영 Mechanism of Atrial Fibrillation Boyoung Joung Department of Internal Medicine, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea Atrial fibrillation (AF) remains the most common adult rhythm disorder, and it associated with a substantial rate of morbidity and economic burden. AF involves a wide spectrum of arrhythmias from lone AF to paroxysmal to chronic AF. It is likely that AF comprises a spectrum of disease with no single mechanism adequate enough to comprehensively explain AF and its variability. Mechanism of fibrillation is explained by multiple wavelets and focal activation theories. Electrical, contractile and mechanical remodeling is involved in AF progression. Atrial remodeling may also increase in atrial fibrosis which can slow conduction velocity and can shorten the refractory period in atria with long-standing AF. Mechanical remodeling manifests as decreased atrial contractility and increased atrial compliance which leads to a stretch of the atrial myocardium. Abnormal intracellular calcium dynamics is observed in AF. Modulating factors such as genetic factors, age, obesity, sleep apnea, inflammation, autonomic factors and atrial and pulmonary vein stretch only partially account for the increase in AF. It is still unclear whether initiation of AF activates direct inflammatory effects or whether the presence of a pre-existing systemic inflammatory state promotes further persistence of AF. Although significant progress in understanding the mechanism of this arrhythmia has been accomplished, the pathophysiology of AF is complex and likely has many possible mechanisms which may be interrelated. (Korean J Med 2011;81: ) Keywords: Atrial fibrillation; Arrhythmia mechanism; Remodeling; Risk factor Correspondence to Boyoung Joung, M.D., Ph.D. Department of Internal Medicine, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine, 250 Seongsan-ro, Seodaemun-gu, Seoul , Korea Tel: , Fax: , cby6908@yuhs.ac * This study was supported in part by a faculty research grant from Yonsei University College of Medicine ( , , ) and by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology ( )

2 - The Korean Journal of Medicine: Vol. 81, No. 4, 서론심방세동 (atrial fibrillation) 은임상적으로가장흔한부정맥으로국내의정확한통계는없지만, 미국의경우 2.3백만명이상의환자가있는것으로알려져있다. 심방세동은다른동반질환이없이발생하는경우 (lone AF) 부터만성적으로발생한경우까지다양한스펙트럼을보인다. 울혈성심부전, 판막질환, 뇌졸중, 좌심방확장, 고혈압, 고령이심방세동발생의중요한독립적인자로알려져있다. 최근에는비만, 수면무호흡증, 장기간의음주등이심방세동의증가와연관됨이밝혀졌다. 심방세동의기전에대하여는지금까지많은연구들이이루어져왔지만아직까지는정확한기전은밝혀지지않았고, 한가지기전이아니라다양한기전이연관되어있을것으로생각한다. 본론세동을설명하는두가지대표적이론심방세동기전은 multiple wavelets 와 focal activation 의이론에의하여설명이되고있다. Multiple wavelets 이론은다수의무질서하게움직이는 (wandering) 회귀성소파형들이서로부딪히고, 자발적으로종료되고, 새롭게만들어지면서심방세동을만든다는이론이다 [1]. Focal activation 이론은 국소적으로빠르게박동을형성하는부위 (rotor) 가있으며, 주변조직으로세동전도 (fibrillatory conduction) 가되어서발생한다는이론이다 (Fig. 1). Rotor의발생기전은다시 ectopic focus 혹은 single reentry 기전으로세분화할수있다. 이러한이론들은심방세동의치료효과를설명하는데도중요하다. Multiple wavelets 이론의경우불응기를증가시키는부정맥약제와 Maze 수술의효과를설명하는데도움이된다. 이에반하여 focal activation 이론은도관 (catheter) 을이용한국소적치료의효과를설명할수있다. Focal activation 의기전중 ectopic focus 는 automaticity 를억제하는약물, 그리고 single reentry 인경우불응기를연장하고, 회귀를억제하는약물의치료효과를설명가능하다. Multiple wavelets 이론은지금까지심방세동을설명하는가장중요한이론이었다. 하지만심방세동의발생과지속에폐정맥 (pulmonary vein) 의중요함이밝혀지고, 폐정맥을포함하는도자절제술이좋은치료효과를보이면서 [2] 최근에는 focal activation 이일부심방세동을설명하는중요한기전으로제시되고있다. 동물실험에도심방세동이유발된동물에서일차적박동형성부 (rotor) 가관찰되었고, 이부위는 ectopic focus 혹은 single reentry 를보였다 [3,4]. 또한심방세동을지속하는데좌심방에 dominant rotor가존재하고, 우심방은수동적으로활성화됨이관찰되었다 [3,4]. 흥미롭게도 dominant rotor 부위 A B Figure 1. The mechanism of atrial fibrillation. (A) Multiple wavelets. (B) Focal activation

- Boyoung Joung. Mechanism of atrial fibrillation - Figure 2. Pathophysiology of AF promotion by atrial tachycardia remodeling. Figure 4. Modulating factors of atrial fibrillation. Figure 3.

3 - Boyoung Joung. Mechanism of atrial fibrillation - Figure 2. Pathophysiology of AF promotion by atrial tachycardia remodeling. Figure 4. Modulating factors of atrial fibrillation. Figure 3. Illustration of the potential interplay of electrical, contractile and structural feedback loops of atrial remodeling on AF. 는박동이매우규칙적이었으며, 주변부로는 complex fragmented atrial electrogram (CFAE) 이관찰되었다 [5]. 하지만아직까지 rotors의존재유무와위치는논란의여지가있다. 최근에는 rotor의위치가고정되지않고, 움직인다는 drifting rotor [6] 개념이제시되었다 심방세동에서발생하는재구도화 (remodeling) 심방세동이오래되면심방세동이쉽게발생하고, 유지될수있게재구도화되는 atrial fibrillation begets atrial fibrillation 현상이발생한다 [7]. 심방세동이나빠른심방빈맥이있으면각각의활동전위때마다 inward L-type Ca 2+ current (I CaL) 을통하여칼슘이세포내로들어가게되어세포의칼슘이증가하게된다 [8]. 증가된세포내칼슘은세포생존에치명적이므로칼슘을감소시키기위한적응기전으로 I CaL 가억제되고, I K1 과 I KAch 가증가하여, 활동전위기간 (APD) 이짧아지게 된다 (Fig. 2) [9]. 이와같은현상을전기적재구도화 (electrical remodeling) 라고하며, 심방세동이지속되고, 쉽게재발되는조건을만들게된다 [10]. 심방세동은또한심방의수축력재구도화 (contractile remodeling) 를유발한다. 전기적재구도화에의한 L-type Ca 2+ channels의저하는수축력재구도화의일차적원인이라고생각한다. 이로인하여심방의수축력은감소하고, compliance 는증가하게되며, 근육세포들이늘어나게된다. 또한심방섬유화를증가시키고, connexin의숫자감소및위치가외측화 (lateralization) 되어서, 조직간의이질성을증가시키는구조적재구도화를유발한다. 이러한현상은다시악순환을이루어서전도속도를늦추고, 심방의불응기에도영향을주어서심방세동을더욱오래지속시킬수있는섬유화등의전기-해부학적기질을만들수있다 (Fig. 3) [11]. 전기적리모델링및수축력저하는심방세동이종료되면가역적으로호전이되는데구조적재구도화는완전하게호전되지는않는것으로알려져있다 [11]. 세포내칼슘대사변화와심방세동세포내칼슘대사의변화는심방세동의기전과연관됨이최근에밝혀졌다. Honjo 등 [12] 은소량의 ryanodine을이용하여 sarcoplasmic reticulum (SR) 의자발적인칼슘분비를증가시키면폐정맥에서빠른빈맥이나옴을보고하였다. 또한지속적인심방세동환자에서정상인에비하여심방세포의 Ca 2+ spark 및 wave가증가함이밝혀졌다 [13]. 이러한현상의

4 - 대한내과학회지 : 제 81 권제 4 호통권제 614 호 원인으로는 SR ryanodine receptor type 2 [14] 혹은 phospholamban 의과인산화 [15] 가제시되고있다. 이와같이증가된 SR 칼슘분비는심방세동이재발하는기전으로제시되는 late-phase 3 EAD 와도밀접한연관이있다 [16]. 흥미롭게도심방조직은이와같이 SR 칼슘의분비가증가된상태를보였지만, 동결절은오히려칼슘의분비가저하되는소견을보였다 [17]. 심방세동이발생을조절하는인자 심방세동의발생을조절하는인자로는교정가능혹은불가능한인자로분류할수있다. 교정불가능한인자로는유전적요인, 고령등을들수있다. 교정가능한인자로는염증, 내분비계이상, 심방및폐정맥의 stretch, 자율신경계이상등이있다 (Fig. 4). Figure 5. Illustration of the possible role of oxidative stress and inflammation contributing to electrical remodeling in AF. Pulmonary veins and atrial function 폐정맥은 trigger 로작용하여심방세동을발생시킬수있으며 [2], 회귀를조장하고, 심방세동을지속시키는심방의재구도화를유발시킬수있다 [18]. 폐정맥에서는동결절과유사하게 P cells, transitional cells, Purkinje cells 등이관찰되었다 [19]. 또한심방의압력이증가하고, 늘어나면폐정맥에서부정맥의유발됨이관찰되었다 [20]. 이와같은현상은아직까지논란이있으나 stretch-receptor의항진과연관되며, stretchreceptor 를억제하는 tarantula peptide 는심방세동발생을억제함이보고되었다 [21]. 또한폐정맥으로는여러층으로구성된좌심방심근섬유들은다양한배열로분포되어복잡한 3차원섬유배열을보여서, 회귀가조장되는것으로알려져있다 [22]. 자율신경계심방세포의전기생리학적성상은부교감및교감신경의영향에따라서다르게조절된다. 예를들어미주신경의영향은활동전위기간과불응기를줄여서심방의이질성을유발하고, 회귀기전을조장한다. 교감신경은비정상적인자동능및 triggered activity를조장한다. 미주신경성 (vagally mediated) 심방세동은주로젊은남성, 기저질환이없는사람에서발생하고, 심방조동도같이보이는경우가흔하다. 운동선수에서발견되는심방세동의경우도항진된미주신경의톤에영향을받는것으로알려져있다. 최근연구에의하면운동선 수의심방세동도전극도자절제술이좋은결과를보였다 [23]. 이에반하여교감신경성심방세동은주로심장질환을가진경우에발생하며, vagal withdrawal 와연관된다. Framingham Heart Study 에따르면 heart rate variability 로측정된자율신경계의이상이심방세동과연관됨을보여주었다 [24]. 염증염증을반영하는 C-reactive protein (CRP) 는심방세동의초기 24시간이내에증가하고 [25], 지속성심방세동에서발작성심방세동보다높은수준을보였다 [26]. 또한오래된심방세동에서는염증세포침윤, 섬유화, 세포괴사등이관찰되었다 [27]. 이러한점은염증이심방세동과연관됨을시사한다. 하지만심방세동이염증을활성화시키는지, 아니면기존에있던전신의염증상태가심방세동을조장하는지는아직은불분명하다. 관동맥및심장염증에의한심방세동의발생기전은그림 5와같다. 수술을하는환자에서 corticosteroid 투여로도움을심방세동을억제하였다는보고가있으며, 최근에는심방세동도관절제술후 steroid를투여하여심방세동을억제하였다는보고가있다 [28]. HMG-CoA reductase 억제제의다양한효과도심방세동의발생에영향을주는지연구가되고있다. 섬유화및염증은심방의해부학적전기생리학적기질의변화를초래하는것으로알려져있다. Statin 등을이용한치료는심방세동의염증및섬유화를조절하여도움이될수있

5 - 정보영. 심방세동의기전 - 을것으로예측되고있다. 내분비계이상 갑상선호르몬의농도변화는심방세동의시작과억제에영향을준다 [29]. Renin-angiotensin system (RAS) 또한심방세동과연관되어있는데, RAS 를억제하는 captopril 및 candesartan 은심방빈맥을감소시킨다. RAS 억제제는섬유화를억제하여서, structural remodeling 을예방하는것과연관되어있다 [30]. Framingham Heart Study에따르면당뇨병이있으면심방세동의빈도가남성에서 1.4배, 여성에서 1.6배로증가되었다 [31]. 당뇨병이심방세동의발생을증가시키는기전도심방의섬유화와연관된것으로추정되고있다. 결 다른상심성빈맥에비하여심방세동의기전은매우복잡하다. 그이유는심방세동이다양한스펙트럼을가진질환이기때문이다. 심방세동은다양한질병및조건과연관되어발생한다. 지금까지많은동물실험및실험모델에서밝혀진기전의경우도실제사람에서심방세동의발생과지속됨을설명하는데부족한점이많다. 결론적으로한개의기전으로심방세동의다양성을설명하기는부족하며, 여러가지기전이심방세동의발생과지속에연관되어있음을알아야한다. 따라서심방세동의예방및치료에있어서도이러한다양성을인정하는접근방법이필요하다고할수있다. 중심단어 : 심방세동 ; 심방세동기전 ; 재구도화 ; 위험인자 론 REFERENCES 1. Moe GK, Abildskov JA. Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge. Am Heart J 1959; 58: Haïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339: Mandapati R, Skanes A, Chen J, Berenfeld O, Jalife J. Stable microreentrant sources as a mechanism of atrial fibrillation in the isolated sheep heart. Circulation 2000;101: Mansour M, Mandapati R, Berenfeld O, Chen J, Samie FH, Jalife J. Left-to-right gradient of atrial frequencies during acute atrial fibrillation in the isolated sheep heart. Circulation 2001;103: Kalifa J, Tanaka K, Zaitsev AV, et al. Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation. Circulation 2006;113: Yamazaki M, Vaquero LM, Hou L, et al. Mechanisms of stretch-induced atrial fibrillation in the presence and the absence of adrenocholinergic stimulation: interplay between rotors and focal discharges. Heart Rhythm 2009;6: Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation: astudy in awake chronically instrumented goats. Circulation 1995;92: Sun H, Chartier D, Leblanc N, Nattel S. Intracellular calcium changes and tachycardia-induced contractile dysfunction in canine atrial myocytes. Cardiovasc Res 2001;49: Nattel S, Maguy A, Le Bouter S, Yeh YH. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev 2007;87: Nattel S. New ideas about atrial fibrillation 50 years on. Nature 2002;415: Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 2002;54: Honjo H, Boyett MR, Niwa R, et al. Pacing-induced spontaneous activity in myocardial sleeves of pulmonary veins after treatment with ryanodine. Circulation 2003;107: Hove-Madsen L, Llach A, Bayes-Genís A, et al. Atrial fibrillation is associated with increased spontaneous calcium release from the sarcoplasmic reticulum in human atrial myocytes. Circulation 2004;110: Vest JA, Wehrens XH, Reiken SR, et al. Defective cardiac ryanodine receptor regulation during atrial fibrillation. Circulation 2005;111: El-Armouche A, Boknik P, Eschenhagen T, et al. Molecular determinants of altered Ca2+ handling in human chronic atrial fibrillation. Circulation 2006;114: Burashnikov A, Antzelevitch C. Reinduction of atrial fibrillation immediately after termination of the arrhythmia is mediated by late phase 3 early afterdepolarization-induced triggered activity. Circulation 2003;107: Joung B, Lin SF, Chen Z, et al. Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation. Heart Rhythm 2010;7: Arora R, Verheule S, Scott L, et al. Arrhythmogenic substrate of the pulmonary veins assessed by high-resolution optical mapping. Circulation 2003;107: Perez-Lugones A, McMahon JT, Ratliff NB, et al. Evidence of specialized conduction cells in human pulmonary veins of patients with atrial fibrillation. J Cardiovasc Electrophysiol 2003;14:

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ºÎÁ¤¸ÆÃÖÁ¾ MAIN TOPIC REVIEWS Young-Keun On, MD, PhD Division of Cardiology, Department of Medicine Cardiac & Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Catheter