부정맥질환을유발하는것이보고되었다. 3,4 LQTS는 600개이상의다양한유전적이상뿐만아니라다양한임상양상으로진단이쉽지않다. 5 최근들어유전적이상에대한정보제공이급격하게발전하여임상정보와함께다양한유전정보를정확하게해석하고 LQTS의진단과치료에적절하게이용할수있도록하는것이중요하다.

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Download "부정맥질환을유발하는것이보고되었다. 3,4 LQTS는 600개이상의다양한유전적이상뿐만아니라다양한임상양상으로진단이쉽지않다. 5 최근들어유전적이상에대한정보제공이급격하게발전하여임상정보와함께다양한유전정보를정확하게해석하고 LQTS의진단과치료에적절하게이용할수있도록하는것이중요하다."

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MAIN TOPIC REVIEWS Congenital Long QT Syndrome 성균관대학교의과대학소아과학교실허준 June Huh, MD, PhD Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

1 MAIN TOPIC REVIEWS Congenital Long QT Syndrome 성균관대학교의과대학소아과학교실허준 June Huh, MD, PhD Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Congenital long QT syndrome ABSTRACT Long QT syndrome (LQTS) is a well-known inheritable channelopathy that causes fatal ventricular arrhythmias. With the advancement of genetic science, the treatment of LQTS has become a paradigm for the use of genetic information in clinical practice. LQTS can present with incomplete penetrance and variable expressivity. Ten percent of silent carriers of a disease-causing mutation usually experienced symptoms when they were treated with QT-prolonging drugs. Patients with LQTS and multiple mutations have a greater risk for life-threatening cardiac events than do patients with a single mutation. LQTS tends to be easily overdiagnosed because of overlapping of a corrected QT interval (QTc), the range between normal values and LQTS, and lack of complete diagnostic criteria. The first line of treatment for all patients is β-blocker therapy. Left cardiothoracic sympathetic denervation (LCSD) may be a therapeutic adjunct for young patients with LQTS who are not fully protected by β blocker therapy. In patients with recurrent symptoms during therapy or in those at high risk for arrhythmias, an implantable cardioverter-defibrillator (ICD) should be considered. The most important aspect of the treatment of LQTS is to determine whether the patient is at high or low risk for life-threatening arrhythmias, so that treatment can be tailored accordingly on an individual basis, more or less aggressively. Key words: adrenergic beta-antagonists defibrillators genetic diseases implantable inborn left cardiothoracic sympathetic denervation long QT syndrome 서론 Received: September 23, 2013 Revision Received: December 9, 2013 Accepted: December 27, 2013 Correspondence: June Huh, MD, PhD, Department of Pediatrics, Samsung Medical Center, Cardiac and Vascular Center, Sungkyunkwan University School of Medicine, #50, Irwon-dong, Gangnam-gu, Seoul, Korea ( ) Tel: (Office) Fax: herzhuh@skku.edu, herzhuh@gmail.com Congenital long QT syndrome (LQTS) 은 1990년대초유전적결함으로인해심근세포의이온통로기능이상으로인한심근재분극장애기전으로발생하는것이알려졌고, 이후많은유전자이상이보고되고있다. 1,2 초기에는주로 α-subunit 이상이보고되었고, 점차 β-subunit 그리고 cytoskeleton 단백과세포막단백의유전적결함도유전성 6 The Official Journal of Korean Heart Rhythm Society

2 부정맥질환을유발하는것이보고되었다. 3,4 LQTS는 600개이상의다양한유전적이상뿐만아니라다양한임상양상으로진단이쉽지않다. 5 최근들어유전적이상에대한정보제공이급격하게발전하여임상정보와함께다양한유전정보를정확하게해석하고 LQTS의진단과치료에적절하게이용할수있도록하는것이중요하다. 임상적특징 LQTS의임상양상으로실신과심정지가발생하는데, 잘알려져있는대로아드레날린유발자극과관련이있지만 10~15% 정도에서는안정시혹은수면중에도발생한다. 6 실신은매년약 5% 정도에서발생하고, 돌연사는매년 1.9% 정도발생한다. 7 실제로부검에서특이소견을발견하지못한청소년기돌연사의첫번째사인으로 LQTS가보고되고있으며, 8 영아돌연사증후군의한원인으로도알려져있다. 9 LQTS에서심장문제는 torsade de pointes (TdP) 라는특이한형태의심실빈맥으로, 결국심실세동으로이행하여심정지가발생한다. 하지만종종저절로중단되기도해서실신처럼보이기도한다. 저절로수초만에돌아오는경우와아닌경우의차이는아직모른다. 진단은 corrected QT interval (QTc) 을기준으로다른소견을종합해서내린다 (Table 1). QTc 간격과함께심전도상재분극이상소견인 T파의이상소견 (biphasic T, notched T, low amplitude, very slow onset T) 을고려한다. QTc 간격을정확하게측정하는것이진단에중요하기때문에적어도 10~20박동정도는 RR interval의안정된상태를확인하고 QT 간격을측정하는것이좋다. 10 예후관련인자도 QT 간격이가장중요한데, 500 msec를초과하는경우돌연사의위험이매우높다. 11 하지만유전적이상이있어도 10~35% 의환자에서는정상 QTc 간격을보인다. 12 유전자이상이있던환자에서 10% 정도가 QT 연장유발약제로인해처음심부정맥증상을 경험하기도한다. 13 이런환자군을고려한다면진단시증상이없더라도증상발현이전에베타차단제치료를조기에고려해야한다. 정상인중 5~10% 에서도 QTc 간격연장소견이관찰된다. 14,15 QTc 간격의중복은 LQTS 진단을어렵게만들고, 결국과잉진단에이르게된다. 다른예후관련인자로 T파 alternans, notched T 파등이제시되고있지만, 역시 QTc 500 msec에서주로관찰된다. 16 LQTS에서진단에운동검사가이용되는데, 실제로운동검사에서부정맥이발생하는것은대부분 LQT1 이나, 실제병원에서하는운동검사시에는실제상황과다르게심한경쟁과스트레스가없는운동상태이므로부정맥이잘유발되지않는다. 운동검사시 QTc 간격의변화측정도 LQT1, LQT2를구별하는데도움이될수는있으나, 부정맥예측과는관련성이낮다. 17 갑작스런기립자세 (abrupt standing) 를취하면 QTc 간격이 LQTS의각유형마다다르게변화하며, 18 LQT1 환자에서부정맥발생위험도가높은경우운동검사후 baroreflex sensitivity에대한평가로운동최대치후회복기 1분에심박수에서더많은변화를보여예후예측과관련이있다고한다. 19 하지만 LQT2, LQT3에서는유의한관련성을보이지않는데, 이는 IKs current 결함이 LQT1에서주로발생하는것과관련이있다. 실신은치명적부정맥발생과관련성이높은데특히베타차단제사용후에발생한경우가장위험하고, 베타차단제사용이전에는실신이다수발생한경우에서도중간위험도로평가된다. 20 LQTS 환자에서실신증상에대한베타차단제의치료효과는 14세이전에는남녀에서차이가없으나, 14세이후에는남성에서의실신발생이여성보다더많이줄어든다. 20 LQTS와관련하여임상에서접하는중요한문제는과잉진단인데, 이는몇가지주의하여줄이는노력을할수있다. 21 첫째로 LQTS 진단이안된가족에서검사전 LQTS 가능성은 1:2000이지만, LQTS로진단된가족에서는 50% 정도로매우높아진다. 두번째로실신에대한정확한병력청취가필요한데, 부정맥관련실신인지신경매개성실신인지구분하는것이중요하다. 특히 QTc 간격이경계수치인경우과잉 MAIN TOPIC REVIEWS VOL.14 NO.4 7

3 MAIN TOPIC REVIEWS 진단이될수있으므로중요하다. 세번째로가족력을자세히확인하는것이중요하다. 돌연사뿐만아니라의문의사고나익사혹은간질에대한가족력을확인하도록한다. QTc 간격의측정과해석도쉽지않은데, 심전도측정기계조차도 80~90% 정도의정확성을보이며, 심박수가빠르거나느릴경우차이를보일수있다. 따라서심전도를가지고실제로직접수동으로측정해보는것이중요하다. AHA/ACC/HRS 가이드라인에서남자 450 msec, 여자 460 msec 초과수치를기준으로제시했기때문에과잉진단하는쪽으로더강화됐다고볼수있다. QTc 간격연장이반드시 LQTS를의미하지는않는다는것을잊지말아야한다. 심전도상재분극시변화도중요한데, 특히 U파를포함한경우 QTc 간격측정오류가생기므로주의해야한다. 재분극변화로 notched T파, T파 alternans의동반유무를잘 관찰해야한다. LQTS 진단에이용되는 Schwartz 진단점수도 3.5점이상인경우 LQTS 가능성이매우높다고되어있는데, QTc 간격이 480 msec 정도만되어도가족중 LQTS가있으면 3.5점이상으로평가되므로진단점수표상가능성이높다고해서반드시 LQTS 진단을의미하지는않는다 (Table 1). 임상적으로환자진료후 Schwartz 진단점수를적용한후추가검사를하게되는데, 24시간심전도, 운동검사, epinephrine 부하 QT 검사, 갑작스런기립자세검사, 유전자검사등을한다. 24시간심전도의경우수면중 QTc 간격의변화로 LQTS 진단을하기보다는재분극양상의변화를관찰하는데도움이된다. 유전학검사에서양성을보이는경우가전체 LQTS 환자의 80% 정도이고, 20% 는유전자이상이확인되지않아도임상적으로분명한경우에는유전자이상여부와상관없이진단을할수있다. Table 1. Diagnostic criteria for long QT syndrome Points Electrocardiographic findings a A QTc 480 ms 460~479 ms 450~459 (male) ms B QTc b 4 th minute of recovery from exercise stress test 480 ms 1 C Torsade de pointes c 2 D T-wave alternans 1 E Notched T-wave in three leads 1 F Low heart rate for age d 0.5 Clinical history A Syncope with stress 2 Without stress 1 B Congenital deafness 0.5 Family history A Family members with definite LQTS e 1 B Unexplained sudden cardiac death below age 30 among immediate family members e 0.5 SCORE: 1 point: low probability of LQTS; 1.5 to 3 points: intermediate probability of LQTS; 3.5 points: high probability. a In the absence of medications or disorders known to affect these electrocardiographic features. b QTc calculated by Bazett s formula. c Mutually exclusive. d Resting heart rate below the second percentile for age. e The same family member cannot be counted in A and B The Official Journal of Korean Heart Rhythm Society

4 유전형과표현형의관련성 LQTS는유전적으로상염색체양성이가장흔하고, 열성유전은신경감각성청력소실을동반하며드물다. LQTS와관련되어 16개의유전자가알려져있다. 22 하지만 3가지유전자인 KCNQ1 (LQT1), KCNH2 (LQT2), 그리고 SCN5A (LQT3) 가임상적으로확진된 LQTS 전체의 75% 정도를차지하고, 20% 정도는유전적으로규명되지않았고, 나머지유전자들이 5% 를차지한다 (Table 2). 유전형과임상표현형의상관관계에대한연구중초기연구에서 T파의양상이유전형에따라다르다고보고되었다 (Table 3). 23 3가지유형에서심장증상발생유발인자가다르다고알려졌는데, LQT1은주로운동중에발생하고, LQT2 는강한흥분감정, 큰소리, 놀람에서, LQT3는안정시혹은수면중에발생하지만, 6 서로중첩된소견을보일 수있다. LQT2가있는여성및 LQT3의남성환자에서심장증상발생위험이더높고, QTc 간격이 500 msec 를초과할경우위험도가더높다. 13 진단에서유전자검사의중요성이높아졌는데, 명확한 QTc 간격의연장소견이있는경우유전자검사를통하여유전자이상을확인하여유형을분류하고효과적인치료를결정할수있다. 또한유전자검사를통해가족중무증상유전자이상보유자와정상을진단할수있다. 하지만경계선상의환자에서유전자검사로확인되는것은전체의 75~80% 정도로보인다. 24 흔한 3가지유형뿐만아니라다른보고되지않은새로운유전자변이와표현형의관계를정확히해석하는것이주요한문제로부각되고있다. LQT1에서는유전자이상은양성이나임상적으로 QTc 간격이 440 msec 미만인음성환자가 36% 이며, 이는침투도 (penetrance) 차이와관련된다. 같은 MAIN TOPIC REVIEWS Table 2. Gene mutation relevant to long QT syndrome Gene Locus Protein LONG QT SYNDROME KCNQ1 (LQT1) 11p15.5 IKs potassium channel alpha subunit (KVLQT1, KV7.1) KCNH2 (LQT2) 7q35-36 IKr potassium channel alpha subunit (HERG, KV11.1) SCN5A (LQT3) p21-p24 Cardiac sodium channel alpha subunit (NaV1.5) AKAP9 7q21-q22 Yotiao CACNA1C 12p13.3 Voltage gated L-type calcium channel (CaV 1.2) CALM1 14q32.11 Calmodulin 1 CALM2 2p21.3-p21.1 Calmodulin 2 CAV3 3p25 Caveolin-3 KCNE1 21q22.1 Potassium channel beta subunit (MinK) KCNE2 21q22.1 Potassium channel beta subunit (MiRP1) KCNJ5 11q24.3 Kir3.4 subunit of IKAch channel SCN4B 11q23.3 Sodium channel beta 4 subunit SNTA1 20q11.2 Syntrophin-alpha 1 ANDERSEN-TAWIL SYNDROME KCNJ2 (ATS1) 17q23 IK1 potassium channel (Kir2.1) ANKYRIN-B SYNDROME ANKB 4q25-q27 Ankyrin B TIMOTHY SYNDROME CACNA1C (TS) 12p13.3 Voltage gated L-type calcium channel (CaV 1.2) VOL.14 NO.4 9

appearance LQT3 INa 5-10% 90% Long isoelectric segment with a normal symmetrical T wave 유전자이상의경우에서도불완전침투도와변이성의발현도 (variable expressivity) 를보이는것은복수의유전자결함과관련된다.

22,25 증상이없는유전자결함보인자의경우추적관찰시심전도상 QTc variance (standard deviation of the mean QTc [QTcSD]) 를분석해보면유전자변이에특이적인예후예측의의미가있고, 특히 LQT1에서더뚜렷하다고한다. 26 치료 베타차단제로 propranolol (2~4 mg/kg/day 2~3회 ) 과 nadolol (0.

5 MAIN TOPIC REVIEWS Table 3. ECG patterns according to the subtypes of LQTS Type Current Functional effect Frequency ECG Penetrance LQT1 IKs 30-35% 62% A broad T wave LQT2 IKr 25-30% 75% A notched T wave with an asymmetrical appearance LQT3 INa 5-10% 90% Long isoelectric segment with a normal symmetrical T wave 유전자이상의경우에서도불완전침투도와변이성의발현도 (variable expressivity) 를보이는것은복수의유전자결함과관련된다. 복수유전자결함은 8~11% 의이환율로혈연관계가없는환자들에서단일유전자결함보다심장문제발생위험이더높고증상이청장년기에일찍발생하며, 특히단일유전자의중복돌연변이가여러다른유전의중복변이보다더위험하다. 22,25 증상이없는유전자결함보인자의경우추적관찰시심전도상 QTc variance (standard deviation of the mean QTc [QTcSD]) 를분석해보면유전자변이에특이적인예후예측의의미가있고, 특히 LQT1에서더뚜렷하다고한다. 26 치료 베타차단제로 propranolol (2~4 mg/kg/day 2~3회 ) 과 nadolol (0.75~1.5 mg/kg/day 1일 1회 ) 이주로 사용된다. Metoprolol 사용시에는잘재발하고, atenolol의경우덜효과적인것같지만보고자료가적다. 27 LQT3가다른유형에비해예후가나쁜것으로알려져있고, LQT1은베타차단제사용후부정맥발생이더적다. 11 LQT2에서도베타차단제가효과적이지만, 여성의경우효과가떨어진다. LQT 유형과더불어 QTc 간격은위험예측시반드시같이고려하는것이필요하다. 베타차단제를사용하던환자에서발생한돌연사는약물을제대로복용하지않았거나 QT 연장유발약제와관련이있다. 28 LQT2는혈중칼륨농도에매우예민하므로칼륨농도저하를유발하는체중감량에주의해야하고, 필요시칼륨보충약제혹은 spironolactone 같은칼륨보존이뇨제를고려할수있다. 갑작스런소음이증상을유발할수있으므로전화나자명종등은침실에두지말고, 환자를깨울때소리지르지말고부드럽게대해야한다. LQT2 여성은출산후위험도가증가하므로주의해야한다. 특히 10 The Official Journal of Korean Heart Rhythm Society

6 신생아수유는모유수유가아니라면가능한한아빠가수유를담당하는것이필요하다. LQT3의치료에는아드레날린스트레스의영향이적어베타차단제의효과가제한적이므로 Na + 이온통로차단제인 mexiletine이나 flecainide가치료제로제안되었다. Mexiletine의사용은경구투여효과검사후고려할수있다. 하루용량의반을한번에투여하고 2시간후심전도상 QTc가 40 msec 이상줄어들고 PR간격연장이없는경우사용을고려한다. 29 Na + 이온통로차단제사용시에는다른심장전도이상여부를잘관찰해야한다. LQT3의경우 mexiletine과 propranolol이상호보완적효과를볼수있다. 30 Flecainide는 IKr 차단효과로 Brugada 증후군을노출시킬수있어 LQTS에서추천되지는않는다. 31 최근 Ranolazine이도움이된다고보고되었는데, Na + 이온통로차단제로특히 late sodium current에효과적이다. 32 Left cardiothoracic sympathetic denervation (LCSD) 은약물에잘반응하지않는환자에사용되어좋은결과를보이는데, 개흉술이나영상보조개흉술 (video-assisted thoracoscopy) 을택한다. 33,34 LCSD는특히 LQT3 환자에서좋은결과를보이는데, 35 항심실세동효과가있고 36 norepinephrine 분비가감소하며 37 심박수저하가없기때문이다. 38 LCSD는 implantable cardioverter-defibrillator (ICD) 환자에서적절한 shock 발생시, 적절한약제사용에도증상이발생하는경우, 베타차단제사용시부작용이나천식으로실패한경우, 고위험청소년에서약제사용만으로충분히예방을할수없는경우등에적용을고려해야한다. 심장증상이빈발하거나위험군인경우당연히삽입형제세동기가필요하다. 11 제세동기삽입은 QTc 간격 500 msec 초과, 심정지병력, 시술나이가 20세이하경우, 약물투여시에도증상이발생하는경우모두에서양성인경우 70% 의환자에서적절한 shock이발생한다. 39 따라서약제사용시심정지발생, 진단이안된경우혹은치료하지않았던 LQT1에서심정지후소생한경우, 약제사용시에도 LQT 유발실신이 발생한경우로 LCSD 가어렵거나원하지않을때, 사춘기이후여성에서 QTc 550 ms 및고위험소견 (T 파 alternans, 비정상 T 파 morphology) 을동반한경우, Jervell and Lange-Nielsen 증후군이나 Timothy 증후군은약제로예방이잘되지않으므로베타차단제, LCSD, ICD 를모두고려하는것이좋다. 결론 LQTS 는아직진단이쉽지않은질환으로유전자 이상에대한많은연구결과가진단과치료방향의 결정에임상적으로중요하게이용되고있다. 하지만 임상에서과잉진단의문제가지속되고있으므로많은 정보에대한정확한해석을통하여이를줄이는노력이 필요하다. 치료시에도베타차단제, LCSD, ICD 등모든 LQTS 치료를근간으로하여환자별, 유전형별로 적절한치료를찾아야한다. References 1. Zipes DP. The long QT interval syndrome: a Rosetta stone for sympathetic related ventricular tachyarrhythmias. Circulation. 1991;84: Morita H, Wu J, Zipes DP. The QT syndromes: long and short. Lancet. 2008;372: Schulze-Bahr E, Wang Q, Wedekind H, Haverkamp W, Chen Q, Sun Y, Rubie C, Hördt M, Towbin JA, Borggrefe M, Assmann G, Qu X, Somberg JC, Breithardt G, Oberti C, Funke H. KCNE1 mutations cause Jervell and Lange-Nielsen syndrome. Nat Genet. 1997;17: Ackerman MJ, Mohler PJ. Defining a new paradigm for human arrhythmia syndromes: phenotypic manifestations of gene mutations in ion channel- and transporter-associated proteins. Circ Res. 2010;107: Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol. 2008; 51: Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, Denjoy I, Guicheney P, Breithardt G, Keating MT, Towbin JA, Beggs AH, Brink P, Wilde AA, Toivonen L, Zareba W, Robinson JL, Timothy KW, Corfield V, Wattanasirichaigoon D, Corbett C, Haverkamp W, Schulze-Bahr E, Lehmann MH, Schwartz K, Coumel P, Bloise R. Genotype-phenotype correlation MAIN TOPIC REVIEWS VOL.14 NO.4 11

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서론 - 대상및방법 결과 임상적특성 Table 1. Clinical characteristics of the study patients No Sexage FHx Provocating factor Structural heart ds Clinical manifestatio

서론 - 대상및방법 결과 임상적특성 Table 1. Clinical characteristics of the study patients No Sexage FHx Provocating factor Structural heart ds Clinical manifestatio Original Articles Korean Circulation J 2002;329:798-806 선천성 QT 연장증후군의임상적특성에대한고찰 김정호 1 남기병 1 김현국 1 이경석 1 한기훈 1 최기준 1 고재곤 2 박인숙 2 김유호 1 Clinical and Electrocardiographic Features of Patients with Congenital