GL_大江班.indd

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1 QT QT LQT LQT LQT LQTLQTLQTLQT Jervell-Lange Nielsen QT QT QT QT QT QT T QTQTTdP QTQTTdP Brugada Brugada Brugada Brugada 1205

2 Brugada Brugada Brugada QT QT QT sudden infant death syndrome QTQTc Torsade de pointes T-wave alternans Notched T wave in leads low heart rate for age T-wave alternans T-wave alternans TdP QT Na + ICD QT QT QT QT QT QT QT QT QT Brugada Na + T-wave alternans QT Brugada Brugada Brugada electrical storm 1206

3 QTBrugada QTSchwartz QT QTQT QT QT Brugada consensus conferencetype coved type Brugada type type type QTBrugada QTBrugada QTBrugada QT QTQT Brugada Brugada A BC AHAACC QTLQTSQT 1207

4 torsade de pointestdp QT BazzetQTQTcQTc msec mseclqts msec msec LQTS LQTSQT TULQTS LQTSRomano- WardJervell-Lange Nielsen LQTS1 LQTS1 LQTS,,. LQTS Moss LQTS Romano-Ward Romano WardLQTS Romano-Ward Romano-Ward Jervell-Lange Nielsen JervellLange- NielsenLQTS LQTS Romano-Ward LQTLQT QTJervell- Lange Nielsen QT QT Romano-Ward Jervell-Lange Nielsen QT QT H2 K + Mg 2+ Ca

5 JNLJLN Keating p.harvey ras- WangLQTS K + KCNQ KvLQT KCNQ K + minkk + I K I Ks I Ks I K I Ks I Ks QTKCNQ LQT Ca + LQT T prolonged T wave duration CurranQT q-k + HERG HERG Human ether-a-go-go related gene KCNQ K + mink-related peptide MiRP K + I Kr I Kr K + I Kr I Ks HERG I Kr QT HERG LQT TT small or notched T wave WangLQTS p-na + SCNA Na + QT LQTQT LQTLQT T STdelayed onset of T wave LQT Ankyrin-B Na + /K + ATPaseNa + Ca + I NaCa LQT QT TUlong pause T LQTKCNQ mink KCNE I Ks LQT LQTHERG MiRP QT TdP LQT Andersen KCNJ U Jervell-Lange Nielsen 1209

6 KCNQ JLN KCNE JLN KCNQ KCNQ minkapical membrane K + K + Jervell-Lange Nielsen K + QT../ QTc msec ½ LQT LQTLQT LQTLQTLQT LQT LQTLQT Schwartz QT QTTdP QTQT QT TdP.. QT QT/ QTTdP QTQT QTTdP K + anorexia nervosa Liquide diet QTTdP QTQTU T QT TdP msecqt TdP QTQT I kr I Kr QT QTEAD TdP QT SNP QT RR QT QT 1210

7 QTLQTSLQTS QTTorsade de PointesTdP LQTS QT LQTS Romano-Ward K + LQTNa + LQTCa + LQTAPD QT LQTSQTTdP monophasic action potentialmap MAP MAP Vmax MAP APD LQTS QTTTdP Epi APD mid-myocardialm Endo late-appearingt LQTS EpiEndo T MAP QT MAP MAPD 1 early afterdepolarizationeadhump1 TdPEAD MAPD spacial dispersion of repolarization SDRTdPSDR LQTS LQTSTdP LQTLQTLQT TdP2AB TdPAPD Epi TdP 2CTdP QRS M Endo EAD LQTS M APD transmural dispersion of repolarizationtdr TdPSDR TDR 3 LQTSQT TdP LQTSLQTLQTLQT broad-basedt low-amplitudenotchedtst LQTSIA I Kr K

8 QTLQTSg/MAP V RVantRVsepMAP msec QTQTQTcmsec / MAP EADMAP MAPD msec EAD QTcMAPD LQTSLQTLQTLQT I Kr LQTS TQTTdP I Ks K + I Kr LQTS I Ks Chromanol BQT TDRI Kr E- EpiAPD MEndo APD QT TDRLQTSTdP T EpiEAD TdP LQTS QTTAPD TdP TdPEAD TdP 1212

9 BrugadaV V covedsaddle back ST VF Brugada VF Na + SCNA Brugada Brugada MEpiECG AB LQTLQTTorsade de PointesTdPCLQT Brugada TdPTdP QRS J.mV S M covedsaddle backst AB BrugadaQRS M APD APD / EpiTdP TdP C Epi-M-Endo KCNQ1KCNH2SCN5AANKB KCNE1KCNE2KCNJ2CACNA1CCAV3SCN4B I Ks I Kr I K1 latei Na Ca 2 II Ca LQT15 APD LQT263 M APD LQT1-10 EAD QT QT Torsade de Pointes 1213

10 Miyasaka.mVST.. Funahashi.mVST. Matsuo.mV ST. STcoved Atarashi.mVcovedST. Miyasaka.. Funahashi. Hermida.mV covedst. STJ.mVSakabe covedsaddle backst.covedst..mv covedst. Yamakawa.mVcoved saddle backst. Brugada.... coved..mvcovedsttype. Oe type. type Brugada. type... Matsuo Brugada. Brugada Brugada Matsuo Sakabe saddle back Miyasaka.saddle back Atarashicoved VF.HermidaOe 2 Brugada* Priori** /5 251/17 120/24 135/55 152/ / / VFEPS 7187/ / VF/VTEPS SAECG 7066/ /141 VSA 2215/67 187/38 VFVTEPSSAECGVSA *** 1214

11 VF VF AF AF AF Na + STT ST Ca + K + ST type ST ST EPS VF VT VF vs VF/ VT vs VF vs VF/./././ type ST./ type Brugada saddle back STmm ST Brugada VF ICD VF/ VF ICD VF/. VF/..... type ST ST. type ST.. Brugada V-V STVF ST ST covedsaddle back covedvf Brugada ST Na+ covedst VF covedst 1215

12 VF Brugada ST saddle back coved STBrugada Brugada Na + SCNA SCNABrugada SCNA QT Lev-Lenegre SCNA SCNA Na + Na + Na + trafficking defect Na + loss of function Na + loss of functionbrugada VF Antzelevitch Brugada 4 APD notch notchnotch notch 1216

13 K + I to I to notch Na + notchdome LCa + I to K + K + I k ATP K + Na + Ca + notch dome ST 4A Na + loss of functioni to notch spike and dome STJ APD APD saddle backst 4B Ca + notch STT 4C Brugada covedstnotchca + domeloss of domedome dome 4Dphase reentry4e ST Na + Ca + ST Na + mg/kg Ca + ST I to ST VF Brugada Antzelevitch Aiba Antzelevitch VF dome AP phase reentry VF Brugada QRS HV SCNA VF Brugada ST BrugadaVF Brugada QTQT Jervel and Lange-Nielsen syndrome 1217

14 Romano-Ward syndrome genotypephenotype QT QT QT QT Wenckebach 5AV blockqt LQTLQT LQT LQT LQT rd trimester QT SCNA QT,./, birth QTQTc. sec / QTc.QTc. QTc Odds... QT KCNQ SCNA KCNH QT compound heterozygous digenic inheritance QT,, QTTorsade de pointes 1218

15 QTSchwartz socre3 QT. risk factorp. P. SchwartzLQTS score. QT QT QT Schwartz 3 pointsqtc torsade de pointestdp5 TT-wave alternans6notched T wave7 TdP TTdP notched T wave QT dispersion LQTS QTQT points 1 ABazettQT 0.48sec 1/ sec 1/ sec 1/2 1 Btorsade de pointes* 2 CT 1 D3 notched T 1 E A* 2 1 B Adefinite LQTS 1 B high probabilityor definite intermediate probability low probability *torsade de pointes eqtc Fridericia T anotched T waveb VV 1219

16 dispersiont QT QTRR BazettQT/RR / QTBazett 8 / QTQT av F V V QT notched T wavev V / QT notched T wave.qt/rr. exponential correction of the QT intervaleqtc 9 Fridericia QT/RR / 4 QTFridericia QTQTc QRS QT TdP TdP T T-wave alternans T-wave alternans QT Bifid T wavet T T T Notched T wave Romano- Ward Rijnbeek 1220

17 5 LQT LQT LQTQT LQT QT QTc QTc msec ½ * 122* * 1 QT QTc 440msecQT 2 QT 3 a 1 2 LQT1LQT2 b QT QT V V V QTmsec/HRbpm.QT QT QT QT TT-wave alternans T-wave alternans QTQT msec QTT QT dispersion T peak-endqt T QT LQTLQT b 1 QT QTc 440msecQT 2 QT 1221

18 QT torsade de pointestdp LQTLQT RR HRV TdP QT QT T QT TT-wave alternanstwa TWA TWA TdP TWA QT TWA QT TWA TWA TdP TdP monophasic action potentialmap QT MAP EAD short-long-short EAD QT PESTdP APD R-Rshortlong-shortPES QTPES MAP QT EAD EAD 8 TdP EAD APDM LQTI Ks LQTI Kr LQTlate I Na ATX-QT a 1 QT b 1 C 2Torsade de pointestdp B 3 TdP QT C 1 QT QT C 1222

19 LQT LQTLQT KCNJCACNAC QTLQTS Romano-Ward 9 loss of functiongain of functionapd QT LQTLQTKCNQ KCNE LQTLQTKCNH KCNE K + I K I Ks I Kr I Ks I Kr LQTSCNANa + late Na + I Na LQT Na + /K + ATPaseNa + Ca + I NaCa IP Ca + QT LQTAndersen-Tawil K + I K LCa + I Ca L LQTLQT CAV SCNBI Na Jervell- Lange Nielsen KCNQ KCNE JLN JLN KCNQ KCNE QT Romano-Ward QT QT LQTS Romano-Ward LQTS LQTLQTLQT KCNQKCNHSCNA 9 LQTS LQTS Romano-Ward LQTLQT QT Romano-Ward LQT1 1111p15.5 KCNQ1 I Ks LQT2 77q35-36 KCNH2 I Kr LQT3 33p21-23 SCN5A I Na LQT4 44q25-27 ANK2 Na + K + ATPaseI NaCa LQT5 2121q KCNE1 I Ks LQT6 2121q KCNE2 I Kr LQT7 1717q23 KCNJ2 I K1 LQT8 1212p13.3 CACNA1C I CaL LQT9 33p25 CAV3 I Na LQT q233 SCN4B I Na Jervell-Lange Nielsen JLN1 1111p15.5 KCNQ1homozygous I Ks JLN2 2121q KCNE1homozygous I Ks QT 1111p15.5 KCNQ1 I Ks 77q35-36 KCNH2 I Kr 33p21-23 SCN5A I Na 1223

20 - LQT LQTLQTLQT LQTLQTLQT T Torsade de Pointes LQTS LQTLQT KCNQKCNH QT QTQT Torsade de pointestdp TdP TdP TdP TdP QT TdP QT TdP TdPK + TdP TdP QT QTc msec ½ QTJervell-Lange Nielsen / LQT LQT LQT Moss. QT Priori LQTLQTLQT QT QTc 10 QT T QT LQTQT KCNH KT QT QT ICD.. ICD. ICD 1224

21 High Risk 50% QTc500 msec LQT1 LQT2 Male sex, LQT3 Intermediate Risk 3049% QTc500 msec Female sex, LQT2 Female sex, LQT3 Male sex, LQT3 QTc500 msec Female sex, LQT3 Low Risk 30% QTc500 msec Male sex, LQT2 LQT1 ICD ICD 10 LQT TdP LQTLQTLQT TdP LQTNa + QT LQTK + K + K + QT QT LQT Brugada QTTdP LQT LQT LQT LQTLQT QT a K + Mg + QT LQT

22 Ca + LQT TimothyEAD QTI Ks I Kr K + K + QT LQTK K SCNALQT 11 Torsade de PointesTdP QT ICD QT QT LQT1LQT2 a QT b a 1LQT3QT 2QT 12 ICD TdP torsade de pointes ICD ICD 13 A Torsade de pointestdp 3 ab TdP a a a a b b TdP ab QT LQT b b 1 ICD 2 torsade de pointes B 1226

23 QTQT QT QTQT Torsade de pointestdp TdP Early Afterdepolarization EAD TdPQT QT QT QTTdP QTQTQT TdP TdP TdP.. QT TdP K + I Kr K + I Ks QT QTTdP TdP QT QT QT/ QTI Kr QT QTEAD TdP QT TdPEAD humpmap QT SNP subclinical QT QT RR QTTdP QTQT TdP QT TdP TdPQT QTEAD K + QT QT K + QTc msec ½ msec ½ TdPTdPT long-short sequence TdP QT msec 1227

24 RR IA TdP TdP QT QT QT QT QT QT QT QT QT QT QT 1 QT TdPQT QTK + BazettQTQTc.sec ½ QT QT 114 QTTdP QT A g mg/b / B / B. mmol/l C mg QTQT TdP Na /K + K + QTEAD TdPTdP QT TdP A K + QT QT Mg 2+ QT 1228

25 TdP QTc msec ½ TdP TdPT long-shortsequence EAD QT QT / QT TdP/ QT TdP QT QT QT QT QT msec msec QT QTc msec ½ QT QT QT QTc msec QTc msec ½ QT I to I K QT IDDM QT QT TdP anorexia nervosa QT K + QTT K + QTTdP QTU T QT TdP msec QT TdP TdP QT g 1229

26 Brugada PBrugada J V VST QT Brugada Brugada Brugada implantable cardiovertor defibrillatoricd ST.mV.mV coved ST coved ST covedstna + ST Brugada V V coved ST Brugada Brugada Brugada ST coved ST covedstbrugada 11 coved J mm.mvt type Brugada 15 coved type type Na + type covedtype type type STBrugada covedst ST.mV BrugadacovedSTPR HV ST PR.... type 1 type 2 type 3 J 2mm 2mm 2mm T or ST-T Coved Saddle back Saddle back* ST 1mm 1mm * consensus conferencesaddle backcoved 1230

27 Na + Brugada Na +.mg/kg/ ST T-wave alternanstwa TWA Brugada coved Brugada 1231

28 msec Chen Q Brugada SCNABrugada SCNA SCNAQT LQTBrugada Brugada ST QT QTc msec ½ CACNACCACNB L-type Ca channelloss of function Brugada BrugadaSCNA Brugada V VST Brugada ST ST ST QRS STJ Wilde consensus report V V JmmST type STcoved type type saddle backst mmmm type covedst ST gradually descending consensus conferencetype STcovedsaddle back Brugadatype type type type Brugada Brugada type type Brugada Brugada BrugadaST ST covedst J mm J mmcovedst BrugadaV V ST-T AcovedST J.mVBsaddle backst J.mV CcovedST.mVJ.mV Brugada ABrugada J.mV R R.mvR R R BJ.mV 1232

29 J STTST C.mVJ.mVA R R R.mvR R.mv Brugada covedsaddle back Brugada ST ST Vaughan-Williams IA IC Na + ST covedstj.mv mg/kg mg/kg mg/kg ST saddle backst Brugada ICD Brugada STsaddle back ST Brugada Brugada saddle backst Brugada ST covedsaddle back ST STSTsaddle back coved STcoved Brugada Brugada SAECG LP LP SAECG QRS f-qrsqrs msec 1233

30 RMS QRS V LAS Brugada RMS LAS LP LPBrugada LP LP Brugada Brugada TWA Brugada QTT peak-end T peak-end dispersionbrugada QT dispersion BrugadaSTVF Antzelevitch VF HRV HRV HF Brugada Brugada HF HF Brugada TT-wave alternanstwa TWA Brugada BrugadaTWA Brugada Brugada Heart rhythm type type type Brugada Brugada Brugada programmed electrical stimulation PESVF VF K + I to Brugada PES Brugada PES VF PES Brugada 1234

31 HV msec PES VF VF HV SCNAHV HV PES VTVF Brugada 16 BrugadaST ST K + I to Brugada Na + SCNA SCNAQT LQT PCCD Na + BrugadaSCNA Brugada Brugada SCNA SCNA I to K + I K LCa + WeissBrugada BrSp- glycerol- phosphate dehydrogenase like GPD-LAV Na + QTBrugadaCa + CACNAC CACNBb QT SCNAGPD-L CACNACCACNBbBrugada BrSBrSBrSBrS PCR 1 coved Brugada 2 coved Brugada a 1 saddle backbrugada 2 saddle backbrugada 3 Brugada coved saddle back B b 1 Brugada coved saddle back 2 Brugada covedsaddle back 1235

32 SSCP DHPLC SCNA Na + Brugada loss-offunction SCNA Bezzina SNP SNP SNP HapA HapBHapB SCNA Brugada HapB K + QT KCNQ BrugadaSCNA SCNA GPD-LCACNBb BrugadaSCNA PR HV Brugada.. BrugadaBrugada Brugada SCNA SCNA Brugada PVT/VF ICDBrugada ICD Brugada ICD ICD ICD ICD QOL BrugadaICD ICD PVT/VF ICD PVT/VF 1236

33 Brugada BrugadaICD Brugada.. PrioriEckardt PrioriBrugada Eckardt Priori Kanda Eckardt PVT/VF PVT/VF Brugada type ST PVT/VF SCNANa + type ST covedsttype saddle backstvf ST covedst Na + S Brugada PVT/VF 1237

34 ProriPVT/VF ACC/AHA Gehi Na + SCNA Ajiro RMS V Brugada I to ST phase reentryvf I to Na + Ca + ATPK + I Ks I Kr PVT/VF ICD PVT/VF I to phospkodiesterasepdecamp Ca ++ I to Brugadaelectrical storm g bolus.g/min ICD HRS/EHR type STICD PVT/VF PVD/VF a ACC/AHA Brugada Brugada Brugada ICD type ST PVT/VF a b a Brugada ICDBrugada ICD ICD.g/Kg/min C BrugadaPVT/VF 1238

35 mg/ mg/ C I Ca I to mg/ Ca ++ I to K + mg/ Brugada ICD Brugada ICD ICD 17ICD 1 2 Brugada coved 3 a b VF a a a a b b b a b Brugada Brugadasaddle back 1239

36 . Schwartz. P.J., Priori SG. The long QT Syndrome: Genotype-phenotype correlation Cardiac Electrophysiology. From Cell to Bedside. Forth edition. : -.. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Ortiz-Lopez R, Wang Z, Antzelevitch C, O Brien RE, Schulze-Bahr E, Keating MT, Towbin JA, Wang Q. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. ; (): -.. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation. ; (): -.. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. ; (): -.. Yoshida H, Horie M, Otani H, Kawashima T, Onishi Y, Sasayama S. Bradycardia-induced long QT syndrome caused by a de novo missense mutation in the S-S inner loop of HERG. Am J Med Genet. ; (): -.. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation. ; (): -.. Miyamoto K, Yokokawa M, Tanaka K, Nagai T, Okamura H, Noda T, Satomi K, Suyama K, Kurita T, Aihara N, Kamakura S, Shimizu W. Diagnostic and prognostic value of a type Brugada electrocardiogram at higher (third or second) V to V recording in men with Brugada syndrome. Am J Cardiol. ; (): -.. Gregoratos G, Abrams J, Epstein AE, Freedman RA, Hayes DL, Hlatky MA, Kerber RE, Naccarelli GV, Schoenfeld MH, Silka MJ, Winters SL, Gibbons RJ, Antman EM, Alpert JS, Gregoratos G, Hiratzka LF, Faxon DP, Jacobs AK, Fuster V, Smith SC, Jr. ACC/AHA/NASPE guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the Pacemaker Guidelines). Circulation. ; (): -.. Jpn Cir J. ; (suppl V): -.. : Circ J ; (suppl IV): -.. Jpn Circ J ; (suppl V).. Hashiba K. Sex differences in phenotypic manifestation and gene transmission in the Romano-Ward syndrome. Ann N Y Acad Sci. ; : -.. Jackman WM, Friday KJ, Anderson JL, Aliot EM, Clark M, Lazzara R. The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis. ; (): -.. Moss AJ, Schwartz PJ, Crampton RS, Tzivoni D, Locati EH, MacCluer J, Hall WJ, Weitkamp L, Vincent GM, Garson A, Jr., et al. The long QT syndrome. Prospective longitudinal study of families. Circulation. ; (): -.. Romano C, Gemme G, Pongiglione R. [Rare Cardiac Arrythmias of the Pediatric Age. Ii. Syncopal Attacks Due to Paroxysmal Ventricular Fibrillation. (Presentation of st Case in Italian Pediatric Literature)]. Clin Pediatr (Bologna). ; : -.. Romano C. Congenital Cardiac Arrhythmia. Lancet. ; : -.. Ward OC. A New Familial Cardiac Syndrome in Children. J Ir Med Assoc. ; : -.. Hashiba K. Some genetic analysis of the Romano-Ward syndrome : With special reference to the incidence of manifestations and its sex difference Proceedings of International Symposium on Cardiac Arrhythmias : Recent progressive in investigation and mangement... Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J. ; (): -.. Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras- gene. Science. ; (): -.. Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, Shen J, Timothy KW, Vincent GM, de Jager T, Schwartz PJ, Toubin JA, Moss AJ, Atkinson DL, Landes GM, Connors TD, Keating MT. Positional cloning of a novel potassium channel gene: KVLQT mutations cause cardiac arrhythmias. Nat Genet. ; (): -.. Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G. K(V)LQT and lsk (mink) proteins associate to form the I(Ks) cardiac potassium current. Nature. ; (): -.. Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL, Keating MT. Coassembly of K(V)LQT and mink (IsK) proteins to form cardiac I(Ks) potassium channel. Nature. ; (): -.. Schwartz P, Moss A, Priori S, et al. Gene-specific influence on the triggers for cardiac arrest in the long QT syndrome(abstruct). Circulation. ; : -.. Chiang CE, Roden DM. The long QT syndromes: genetic 1240

37 basis and clinical implications. J Am Coll Cardiol. ; (): -.. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. ; (): -.. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA. MiRP forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell. ; (): -.. Wilde AA, Jongbloed RJ, Doevendans PA, Duren DR, Hauer RN, van Langen IM, van Tintelen JP, Smeets HJ, Meyer H, Geelen JL. Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS) patients from KVLQT-related patients (LQTS). J Am Coll Cardiol. ; (): -.. Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA, Keating MT. SCNA mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell. ; (): -.. Bennett PB, Yazawa K, Makita N, George AL, Jr. Molecular mechanism for an inherited cardiac arrhythmia. Nature. ; (): -.. Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, Guatimosim S, dubell WH, Song LS, Haurogne K, Kyndt F, Ali ME, Rogers TB, Lederer WJ, Escande D, Le Marec H, Bennett V. Ankyrin-B mutation causes type long-qt cardiac arrhythmia and sudden cardiac death. Nature. ; (): -.. Splawski I, Tristani-Firouzi M, Lehmann MH, Sanguinetti MC, Keating MT. Mutations in the hmink gene cause long QT syndrome and suppress IKs function. Nat Genet. ; (): -.. Andersen ED, Krasilnikoff PA, Overvad H. Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies. A new syndrome? Acta Paediatr Scand. ; (): -.. Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL, Jr., Fish FA, Hahn A, Nitu A, Ozdemir C, Serdaroglu P, Subramony SH, Wolfe G, Fu YH, Ptacek LJ. Mutations in Kir. cause the developmental and episodic electrical phenotypes of Andersen s syndrome. Cell. ; (): -.. Neyroud N, Tesson F, Denjoy I, Leibovici M, Donger C, Barhanin J, Faure S, Gary F, Coumel P, Petit C, Schwartz K, Guicheney P. A novel mutation in the potassium channel gene KVLQT causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet. ; (): -.. Schulze-Bahr E, Wang Q, Wedekind H, Haverkamp W, Chen Q, Sun Y, Rubie C, Hordt M, Towbin JA, Borggrefe M, Assmann G, Qu X, Somberg JC, Breithardt G, Oberti C, Funke H. KCNE mutations cause jervell and Lange-Nielsen syndrome. Nat Genet. ; (): -.. Sakagami M, Fukazawa K, Matsunaga T, Fujita H, Mori N, Takumi T, Ohkubo H, Nakanishi S. Cellular localization of rat Isk protein in the stria vascularis by immunohistochemical observation. Hear Res. ; (-): -.. Vetter DE, Mann JR, Wangemann P, Liu J, McLaughlin KJ, Lesage F, Marcus DC, Lazdunski M, Heinemann SF, Barhanin J. Inner ear defects induced by null mutation of the isk gene. Neuron. ; (): -.. Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Robinson JL, Priori SG, Benhorin J, Locati EH, Towbin JA, Keating MT, Lehmann MH, Hall WJ. Influence of genotype on the clinical course of the long-qt syndrome. International Long- QT Syndrome Registry Research Group. N Engl J Med. ; (): -.. Locati EH, Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Lehmann MH, Towbin JA, Priori SG, Napolitano C, Robinson JL, Andrews M, Timothy K, Hall WJ. Age- and sex-related differences in clinical manifestations in patients with congenital long-qt syndrome: findings from the International LQTS Registry. Circulation. ; (): -.. Moss AJ, Zareba W, Hall WJ, Schwartz PJ, Crampton RS, Benhorin J, Vincent GM, Locati EH, Priori SG, Napolitano C, Medina A, Zhang L, Robinson JL, Timothy K, Towbin JA, Andrews ML. Effectiveness and limitations of beta-blocker therapy in congenital long-qt syndrome. Circulation. ; (): -.. Schwartz PJ ea. The long QT syndrome. Cardiac Electrophysiology. :.. Morganroth J, Horowitz LN. Incidence of proarrhythmic effects from quinidine in the outpatient treatment of benign or potentially lethal ventricular arrhythmias. Am J Cardiol. ; (): -.. Soyka LF, Wirtz C, Spangenberg RB. Clinical safety profile of sotalol in patients with arrhythmias. Am J Cardiol. ; (): A-A; discussion A-A.. Fowler NO, McCall D, Chou TC, Holmes JC, Hanenson IB. Electrocardiographic changes and cardiac arrhythmias in patients receiving psychotropic drugs. Am J Cardiol. ; (): -.. McComb JM, Campbell NP, Cleland J. Recurrent ventricular tachycardia associated with QT prolongation after mitral valve replacement and its association with intravenous administration of erythromycin. Am J Cardiol. ; (): -.. Reinoehl J, Frankovich D, Machado C, Kawasaki R, Baga JJ, Pires LA, Steinman RT, Fromm BS, Lehmann MH. Probucol-associated tachyarrhythmic events and QT prolongation: importance of gender. Am Heart J. ; (): -.. Lee KW, Kayser SR, Hongo RH, Tseng ZH, Scheinman MM. Famotidine and long QT syndrome. Am J Cardiol. ; (): -.. Chen CY, Wang FL, Lin CC. Chronic hydroxychloroquine use associated with QT prolongation and refractory 1241

38 ventricular arrhythmia. Clin Toxicol (Phila). ; (): -.. Haverkamp W, Breithardt G, Camm AJ, Janse MJ, Rosen MR, Antzelevitch C, Escande D, Franz M, Malik M, Moss A, Shah R. The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: clinical and regulatory implications. Report on a Policy Conference of the European Society of Cardiology. Cardiovasc Res. ; (): -.. Ohe T, Kurita T, Aihara N, Kamakura S, Matsuhisa M, Shimomura K. Electrocardiographic and electrophysiologic studies in patients with torsades de pointe--role of monophasic action potentials. Jpn Circ J. ; (): -.. Kurita T, Ohe T, Marui N, Aihara N, Takaki H, Kamakura S, Matsuhisa M, Shimomura K. Bradycardia-induced abnormal QT prolongation in patients with complete atrioventricular block with torsades de pointes. Am J Cardiol. ; (): -.. Gladman G, Davis AM, Fogelman R, Hamilton RM, Gow RM. Torsade de pointes, acquired complete heart block and inappropriately long QT in childhood. Can J Cardiol. ; (): -.. Takahashi N, Ito M, Inoue T, Koumatsu K, Takeshita Y, Tsumabuki S, Tamura M, Inoue K, Maeda T, Saikawa T. Torsades de pointes associated with acquired long QT syndrome: observation of cases. J Cardiol. ; (): -.. Isner JM, Roberts WC, Heymsfield SB, Yager J. Anorexia nervosa and sudden death. Ann Intern Med. ; (): -.. Isner JM, Sours HE, Paris AL, Ferrans VJ, Roberts WC. Sudden, unexpected death in avid dieters using the liquidprotein-modified-fast diet. Observations in patients and the role of the prolonged QT interval. Circulation. ; (): -.. Izumi C, Inoko M, Kitaguchi S, Himura Y, Iga K, Gen H, Konishi T. Polymorphic ventricular tachycardia in a patient with adrenal insufficiency and hypothyroidism. Jpn Circ J. ; (): -.. Kukla P, Szczuka K, Slowiak-Lewinska T, Bromblik A, Hajduk B, Kluczewski M, Lenard B, Przewor M. [Acquired long QT syndrome with torsade de pointes in a patient with primary hypothyroidism]. Kardiol Pol. ; (): -.. Perron AD, Brady WJ. Electrocardiographic manifestations of CNS events. Am J Emerg Med. ; (): -.. Andreoli A, di Pasquale G, Pinelli G, Grazi P, Tognetti F, Testa C. Subarachnoid hemorrhage: frequency and severity of cardiac arrhythmias. A survey of cases studied in the acute phase. Stroke. ; (): -.. Chao CL, Chen WJ, Wu CC, Lee YT. Torsade de pointes and T-wave alternans in a patient with brainstem hemorrhage. Int J Cardiol. ; (): -.. Nattel S, Ranger S, Talajic M, Lemery R, Roy D. Erythromycin-induced long QT syndrome: concordance with quinidine and underlying cellular electrophysiologic mechanism. Am J Med. ; (): -.. Alexandrou AJ, Duncan RS, Sullivan A, Hancox JC, Leishman DJ, Witchel HJ, Leaney JL. Mechanism of herg K+ channel blockade by the fluoroquinolone antibiotic moxifloxacin. Br J Pharmacol. ; (): -.. Mok NS, Lo YK, Tsui PT, Lam CW. Ketoconazole induced torsades de pointes without concomitant use of QT intervalprolonging drug. J Cardiovasc Electrophysiol. ; (): -.. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. ; (): -.. Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC, Hohnloser SH, Shimizu W, Schwartz PJ, Stanton M, Murray KT, Norris K, George AL, Jr., Roden DM. Allelic variants in long-qt disease genes in patients with drugassociated torsades de pointes. Circulation. ; (): -.. Ackerman MJ, Tester DJ, Jones GS, Will ML, Burrow CR, Curran ME. Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome. Mayo Clin Proc. ; (): -.. Makita N, Horie M, Nakamura T, Ai T, Sasaki K, Yokoi H, Sakurai M, Sakuma I, Otani H, Sawa H, Kitabatake A. Druginduced long-qt syndrome associated with a subclinical SCNA mutation. Circulation. ; (): -.. Roden DM, Viswanathan PC. Genetics of acquired long QT syndrome. J Clin Invest. ; (): -.. Carlson AM, Morris LS. Coprescription of terfenadine and erythromycin or ketaconazole: an assessment of potential harm. J Am Pharm Assoc (Wash). ; NS(): -.. Antzelevitch C, Sicouri S. Clinical relevance of cardiac arrhythmias generated by afterdepolarizations. Role of M cells in the generation of U waves, triggered activity and torsade de pointes. J Am Coll Cardiol. ; (): -.. Kawasaki R, Machado C, Reinoehl J, Fromm B, Baga JJ, Steinman RT, Lehmann MH. Increased propensity of women to develop torsades de pointes during complete heart block. J Cardiovasc Electrophysiol. ; (): -.. Shimizu W. The long QT syndrome: therapeutic implications of a genetic diagnosis. Cardiovasc Res. ; (): -.. Shimizu W, Ohe T, Kurita T, Takaki H, Aihara N, Kamakura S, Matsuhisa M, Shimomura K. Early afterdepolarizations induced by isoproterenol in patients with congenital long QT syndrome. Circulation. ; (): -.. Shimizu W, Ohe T, Kurita T, Kawade M, Arakaki Y, Aihara N, Kamakura S, Kamiya T, Shimomura K. Effects of verapamil and propranolol on early afterdepolarizations and ventricular arrhythmias induced by epinephrine in congenital long QT syndrome. J Am Coll Cardiol. ; (): -.. Shimizu W, Kurita T, Matsuo K, Suyama K, Aihara N, 1242

39 Kamakura S, Towbin JA, Shimomura K. Improvement of repolarization abnormalities by a K+ channel opener in the LQT form of congenital long-qt syndrome. Circulation. ; (): -.. Kurita T, Ohe T, Shimizu W, Suyama K, Aihara N, Takaki H, Kamakura S, Shimomura K. Early afterdepolarizationlike activity in patients with class IA induced long QT syndrome and torsades de pointes. Pacing Clin Electrophysiol. ; ( Pt ): -.. Franz MR. Long-term recording of monophasic action potentials from human endocardium. Am J Cardiol. ; (): -.. Shimizu W, Antzelevitch C. Sodium channel block with mexiletine is effective in reducing dispersion of repolarization and preventing torsade des pointes in LQT and LQT models of the long-qt syndrome. Circulation. ; (): -.. Shimizu W, Antzelevitch C. Cellular basis for the ECG features of the LQT form of the long-qt syndrome: effects of beta-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation. ; (): -.. Shimizu W, Antzelevitch C. Effects of a K(+) channel opener to reduce transmural dispersion of repolarization and prevent torsade de pointes in LQT, LQT, and LQT models of the long-qt syndrome. Circulation. ; (): -.. Moss AJ, Zareba W, Benhorin J, Locati EH, Hall WJ, Robinson JL, Schwartz PJ, Towbin JA, Vincent GM, Lehmann MH. ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation. ; (): -.. Donger C, Denjoy I, Berthet M, Neyroud N, Cruaud C, Bennaceur M, Chivoret G, Schwartz K, Coumel P, Guicheney P. KVLQT C-terminal missense mutation causes a forme fruste long-qt syndrome. Circulation. ; (): -.. K u b o t a T, S h i m i z u W, K a m a k u r a S, H o r i e M. Hypokalemia-induced long QT syndrome with an underlying novel missense mutation in S-S linker of KCNQ. J Cardiovasc Electrophysiol. ; (): -.. Aiba T, Shimizu W, Inagaki M, Noda T, Miyoshi S, Ding WG, Zankov DP, Toyoda F, Matsuura H, Horie M, Sunagawa K. Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil. J Am Coll Cardiol. ; (): -.. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol. ; (): -.. Nademanee K, Veerakul G, Nimmannit S, Chaowakul V, Bhuripanyo K, Likittanasombat K, Tunsanga K, Kuasirikul S, M alasit P, Tansupasawadikul S, Tatsanavivat P. Arrhythmogenic marker for the sudden unexplained death syndrome in Thai men. Circulation. ; (): -.. ; : -.. Miyasaka Y, Tsuji H, Yamada K, Tokunaga S, Saito D, Imuro Y, Matsumoto N, Iwasaka T. Prevalence and mortality of the Brugada-type electrocardiogram in one city in Japan. J Am Coll Cardiol. ; (): -.. Furuhashi M, Uno K, Tsuchihashi K, Nagahara D, Hyakukoku M, Ohtomo T, Satoh S, Nishimiya T, Shimamoto K. Prevalence of asymptomatic ST segment elevation in right precordial leads with right bundle branch block (Brugadatype ST shift) among the general Japanese population. Heart. ; (): -.. Matsuo K, Akahoshi M, Nakashima E, Suyama A, Seto S, Hayano M, Yano K. The prevalence, incidence and prognostic value of the Brugada-type electrocardiogram: a populationbased study of four decades. J Am Coll Cardiol. ; (): -.. Atarashi H, Ogawa S, Harumi K, Sugimoto T, Inoue H, Murayama M, Toyama J, Hayakawa H. Three-year follow-up of patients with right bundle branch block and ST segment elevation in the right precordial leads: Japanese Registry of Brugada Syndrome. Idiopathic Ventricular Fibrillation Investigators. J Am Coll Cardiol. ; (): -.. ST ; : -.. Hermida JS, Lemoine JL, Aoun FB, Jarry G, Rey JL, Quiret JC. Prevalence of the brugada syndrome in an apparently healthy population. Am J Cardiol. ; (): -.. Sakabe M, Fujiki A, Tani M, Nishida K, Mizumaki K, Inoue H. Proportion and prognosis of healthy people with coved or saddle-back type ST segment elevation in the right precordial leads during years follow-up. Eur Heart J. ; (): -.. Yamakawa Y, Ishikawa T, Uchino K, Mochida Y, Ebina T, Sumita S, Kobayashi T, Matsushita K, Matsumoto K, Ohkusu Y, Nishizawa T, Takigiku K, Iwamoto M, Kimura K, Umemura S. Prevalence of right bundle-branch block and right precordial ST-segment elevation (Brugada-type electrocardiogram) in Japanese children. Circ J. ; (): -.. Oe H, Takagi M, Tanaka A, Namba M, Nishibori Y, Nishida Y, Kawarabayashi T, Yoshiyama M, Nishimoto M, Tanaka K, Yoshikawa J. Prevalence and clinical course of the juveniles with Brugada-type ECG in Japanese population. Pacing Clin Electrophysiol. ; (): -.. Kanda M, Shimizu W, Matsuo K, Nagaya N, Taguchi A, S u y a m a K, K u r i t a T, A i h a r a N, K a m a k u r a S. Electrophysiologic characteristics and implications of induced ventricular fibrillation in symptomatic patients with Brugada syndrome. J Am Coll Cardiol. ; (): -.. Brugada J, Brugada R, Antzelevitch C, Towbin J, 1243

40 Nademanee K, Brugada P. Long-term follow-up of individuals with the electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V to V. Circulation. ; (): -.. Brugada J, Brugada R, Brugada P. Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest. Circulation. ; (): -.. Priori SG, Napolitano C, Gasparini M, Pappone C, Della Bella P, Giordano U, Bloise R, Giustetto C, De Nardis R, Grillo M, Ronchetti E, Faggiano G, Nastoli J. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation. ; (): -.. Eckardt L, Probst V, Smits JP, Bahr ES, Wolpert C, Schimpf R, Wichter T, Boisseau P, Heinecke A, Breithardt G, Borggrefe M, LeMarec H, Bocker D, Wilde AA. Long-term prognosis of individuals with right precordial ST-segmentelevation Brugada syndrome. Circulation. ; (): -.. Brugada. : -.. Brugada R, Brugada J, Antzelevitch C, Kirsch GE, Potenza D, Towbin JA, Brugada P. Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. Circulation. ; (): -.. Morita H, Morita ST, Nagase S, Banba K, Nishii N, Tani Y, Watanabe A, Nakamura K, Kusano KF, Emori T, Matsubara H, Hina K, Kita T, Ohe T. Ventricular arrhythmia induced by sodium channel blocker in patients with Brugada syndrome. J Am Coll Cardiol. ; (): -.. Morita H, Takenaka-Morita S, Fukushima-Kusano K, Kobayashi M, Nagase S, Kakishita M, Nakamura K, Emori T, Matsubara H, Ohe T. Risk stratification for asymptomatic patients with Brugada syndrome. Circ J. ; (): -.. Ikeda T, Sakurada H, Sakabe K, Sakata T, Takami M, Tezuka N, Nakae T, Noro M, Enjoji Y, Tejima T, Sugi K, Yamaguchi T. Assessment of noninvasive markers in identifying patients at risk in the Brugada syndrome: insight into risk stratification. J Am Coll Cardiol. ; (): -.. Takami M, Ikeda T, Enjoji Y, Sugi K. Relationship between ST-segment morphology and conduction disturbances detected by signal-averaged electrocardiography in Brugada syndrome. Ann Noninvasive Electrocardiol. ; (): -.. Wilde AA, Antzelevitch C, Borggrefe M, Brugada J, Brugada R, Brugada P, Corrado D, Hauer RN, Kass RS, Nademanee K, Priori SG, Towbin JA. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation. ; (): -.. Bezzina CR, Rook MB, Wilde AA. Cardiac sodium channel and inherited arrhythmia syndromes. Cardiovasc Res. ; (): -.. Grant AO, Carboni MP, Neplioueva V, Starmer CF, Memmi M, Napolitano C, Priori S. Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation. J Clin Invest. ; (): -.. Balser JR. The cardiac sodium channel: gating function and molecular pharmacology. J Mol Cell Cardiol. ; (): -.. Antzelevitch C. The Brugada syndrome: ionic basis and arrhythmia mechanisms. J Cardiovasc Electrophysiol. ; (): -.. Yan GX, Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation. ; (): -.. Miyazaki T, Mitamura H, Miyoshi S, Soejima K, Aizawa Y, Ogawa S. Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome. J Am Coll Cardiol. ; (): -.. Hermida JS, Denjoy I, Clerc J, Extramiana F, Jarry G, Milliez P, Guicheney P, Di Fusco S, Rey JL, Cauchemez B, Leenhardt A. Hydroquinidine therapy in Brugada syndrome. J Am Coll Cardiol. ; (): -.. Mizusawa Y, Sakurada H, Nishizaki M, Hiraoka M. Effects of low-dose quinidine on ventricular tachyarrhythmias in patients with Brugada syndrome: low-dose quinidine therapy as an adjunctive treatment. J Cardiovasc Pharmacol. ; (): -.. Kurita T, Shimizu W, Inagaki M, Suyama K, Taguchi A, Satomi K, Aihara N, Kamakura S, Kobayashi J, Kosakai Y. The electrophysiologic mechanism of ST-segment elevation in Brugada syndrome. J Am Coll Cardiol. ; (): -.. Aiba T, Shimizu W, Hidaka I, Uemura K, Noda T, Zheng C, Kamiya A, Inagaki M, Sugimachi M, Sunagawa K. Cellular basis for trigger and maintenance of ventricular fibrillation in the Brugada syndrome model: high-resolution optical mapping study. J Am Coll Cardiol. ; (): -.. Nagase S, Kusano KF, Morita H, Fujimoto Y, Kakishita M, Nakamura K, Emori T, Matsubara H, Ohe T. Epicardial electrogram of the right ventricular outflow tract in patients with the Brugada syndrome: using the epicardial lead. J Am Coll Cardiol. ; (): -.. Tukkie R, Sogaard P, Vleugels J, de Groot IK, Wilde AA, Tan HL. Delay in right ventricular activation contributes to Brugada syndrome. Circulation. ; (): -.. Meregalli PG, Wilde AA, Tan HL. Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more? Cardiovasc Res. ; (): -.. Corrado D, Basso C, Thiene G. Sudden cardiac death in young people with apparently normal heart. Cardiovasc Res. 1244

41 ; (): -.. Coronel R, Casini S, Koopmann TT, Wilms-Schopman FJ, Verkerk AO, de Groot JR, Bhuiyan Z, Bezzina CR, Veldkamp MW, Linnenbank AC, van der Wal AC, Tan HL, Brugada P, Wilde AA, de Bakker JM. Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic, and computational study. Circulation. ; (): -.. ; : -.. Hamada H, Horigome H, Asaka M, Shigemitsu S, Mitsui T, Kubo T, Kandori A, Tsukada K. Prenatal diagnosis of long QT syndrome using fetal magnetocardiography. Prenat Diagn. ; (): -.. Hoorntje T, Alders M, van Tintelen P, van der Lip K, Sreeram N, van der Wal A, Mannens M, Wilde A. Homozygous premature truncation of the HERG protein : the human HERG knockout. Circulation. ; (): -.. Miura M, Yamagishi H, Morikawa Y, Matsuoka R. Congenital long QT syndrome and : atrioventricular block with a mutation of the SCNA gene. Pediatr Cardiol. ; (): -.. Gorgels AP, Al Fadley F, Zaman L, Kantoch MJ, Al Halees Z. The long QT syndrome with impaired atrioventricular conduction: a malignant variant in infants. J Cardiovasc Electrophysiol. ; (): -.. Schmitz L, Burghoff M. Images in cardiovascular medicine. Magnetocardiography in a fetus with long-qt syndrome. Circulation. ; (): e-.. Miller TE, Estrella E, Myerburg RJ, Garcia de Viera J, Moreno N, Rusconi P, Ahearn ME, Baumbach L, Kurlansky P, Wolff G, Bishopric NH. Recurrent third-trimester fetal loss and maternal mosaicism for long-qt syndrome. Circulation. ; (): -.. Schwartz PJ, Stramba-Badiale M, Segantini A, Austoni P, Bosi G, Giorgetti R, Grancini F, Marni ED, Perticone F, Rosti D, Salice P. Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med. ; (): -.. Schwartz PJ, Priori SG, Bloise R, Napolitano C, Ronchetti E, Piccinini A, Goj C, Breithardt G, Schulze-Bahr E, Wedekind H, Nastoli J. Molecular diagnosis in a child with sudden infant death syndrome. Lancet. ; (): -.. Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC, Towbin JA. Postmortem molecular analysis of SCNA defects in sudden infant death syndrome. Jama. ; (): -.. Christiansen M, Tonder N, Larsen LA, Andersen PS, Simonsen H, Oyen N, Kanters JK, Jacobsen JR, Fosdal I, Wettrell G, Kjeldsen K. Mutations in the HERG K+-ion channel: a novel link between long QT syndrome and sudden infant death syndrome. Am J Cardiol. ; (): -.. Shim SH, Ito M, Maher T, Milunsky A. Gene sequencing in neonates and infants with the long QT syndrome. Genet Test. ; (): -.. Tanaka Y, Yoshinaga M, Anan R, Tanaka Y, Nomura Y, Oku S, Nishi S, Kawano Y, Tei C, Arima K. Usefulness and cost effectiveness of cardiovascular screening of young adolescents. Med Sci Sports Exerc. ; (): -.. Zupancic JA, Triedman JK, Alexander M, Walsh EP, Richardson DK, Berul CI. Cost-effectiveness and implications of newborn screening for prolongation of QT interval for the prevention of sudden infant death syndrome. J Pediatr. ; (): -.. Fukushige T, Yoshinaga M, Shimago A, Nishi J, Kono Y, Nomura Y, Miyata K, Imamura M, Shibata T, Nagashima M, Niimura I. Effect of age and overweight on the QT interval and the prevalence of long QT syndrome in children. Am J Cardiol. ; (): -.. Yoshinaga M, Nagashima M, Shibata T, Niimura I, Kitada M, Yasuda T, Iwamoto M, Kamimura J, Iino M, Horigome H, Seguchi M, Aiba S, Izumida N, Kimura T, Ushinohama H, Nishi J, Kono Y, Nomura Y, Miyata K. Who is at risk for cardiac events in young patients with long QT syndrome? Circ J. ; (): -.. QT ; : -.. Moss AJ. Long QT Syndrome. Jama. ; (): -.. Tan HL, Hofman N, van Langen IM, van der Wal AC, Wilde AA. Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination in surviving relatives. Circulation. ; (): -.. Novotny T, Sisakova M, Kadlecova J, Florianova A, Semrad B, Gaillyova R, Vlasinova J, Chroust K, Toman O. Occurrence of notched T wave in healthy family members with the long QT interval syndrome. Am J Cardiol. ; (): -.. Kaltman JR, Ro PS, Stephens P, McBride MG, Cohen MI, Tanel RE, Vetter VL, Rhodes LA. Effects of beta-adrenergic antagonists on the QT measurements from exercise stress tests in pediatric patients with long QT syndrome. Pediatr Cardiol. ; (): -.. Takenaka K, Ai T, Shimizu W, Kobori A, Ninomiya T, Otani H, Kubota T, Takaki H, Kamakura S, Horie M. Exercise stress test amplifies genotype-phenotype correlation in the LQT and LQT forms of the long-qt syndrome. Circulation. ; (): -.. Extramiana F, Denjoy I, Badilini F, Chabani I, Neyroud N, Berthet M, Fressard V, Guicheney P, Beaufils P, Leenhardt A, Coumel P, Maison-Blanche P. Heart rate influences on repolarization duration and morphology in symptomatic versus asymptomatic KCNQ mutation carriers. Am J Cardiol. ; ():

42 . Bilchick K, Viitasalo M, Oikarinen L, Fetics B, Tomaselli G, Swan H, Laitinen PJ, Vaananen H, Kontula K, Berger RD. Temporal repolarization lability differences among genotyped patients with the long QT syndrome. Am J Cardiol. ; (): -.. Nemec J, Buncova M, Bulkova V, Hejlik J, Winter B, Shen WK, Ackerman MJ. Heart rate dependence of the QT interval duration: differences among congenital long QT syndrome subtypes. J Cardiovasc Electrophysiol. ; (): -.. Viitasalo M, Oikarinen L, Swan H, Vaananen H, Glatter K, Laitinen PJ, Kontula K, Barron HV, Toivonen L, Scheinman MM. Ambulatory electrocardiographic evidence of transmural dispersion of repolarization in patients with long-qt syndrome type and. Circulation. ; (): -.. Viitasalo M, Oikarinen L, Vaananen H, Swan H, Piippo K, Kontula K, Barron HV, Toivonen L, Scheinman MM. Differentiation between LQT and LQT patients and unaffected subjects using -hour electrocardiographic recordings. Am J Cardiol. ; (): -.. Shimizu W, Tanabe Y, Aiba T, Inagaki M, Kurita T, Suyama K, Nagaya N, Taguchi A, Aihara N, Sunagawa K, Nakamura K, Ohe T, Towbin JA, Priori SG, Kamakura S. Differential effects of beta-blockade on dispersion of repolarization in the absence and presence of sympathetic stimulation between the LQT and LQT forms of congenital long QT syndrome. J Am Coll Cardiol. ; (): -.. Noda T, Takaki H, Kurita T, Suyama K, Nagaya N, Taguchi A, Aihara N, Kamakura S, Sunagawa K, Nakamura K, Ohe T, Horie M, Napolitano C, Towbin JA, Priori SG, Shimizu W. Gene-specific response of dynamic ventricular repolarization to sympathetic stimulation in LQT, LQT and LQT forms of congenital long QT syndrome. Eur Heart J. ; (): -.. Shimizu W, Noda T, Takaki H, Kurita T, Nagaya N, Satomi K, Suyama K, Aihara N, Kamakura S, Sunagawa K, Echigo S, Nakamura K, Ohe T, Towbin JA, Napolitano C, Priori SG. Epinephrine unmasks latent mutation carriers with LQT form of congenital long-qt syndrome. J Am Coll Cardiol. ; (): -.. Fabritz L, Kirchhof P, Franz MR, Nuyens D, Rossenbacker T, Ottenhof A, Haverkamp W, Breithardt G, Carmeliet E, Carmeliet P. Effect of pacing and mexiletine on dispersion of repolarisation and arrhythmias in DeltaKPQ SCNA (long QT) mice. Cardiovasc Res. ; (): -.. Shimizu W, Horie M, Ohno S, Takenaka K, Yamaguchi M, Shimizu M, Washizuka T, Aizawa Y, Nakamura K, Ohe T, Aiba T, Miyamoto Y, Yoshimasa Y, Towbin JA, Priori SG, Kamakura S. Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT form of congenital long QT syndrome: multicenter study in Japan. J Am Coll Cardiol. ; (): -.. Vyas H, Hejlik J, Ackerman MJ. Epinephrine QT stress testing in the evaluation of congenital long-qt syndrome: diagnostic accuracy of the paradoxical QT response. Circulation. ; (): -.. Nakagawa M, Ooie T, Ou B, Ichinose M, Takahashi N, Hara M, Yonemochi H, Saikawa T. Gender differences in autonomic modulation of ventricular repolarization in humans. J Cardiovasc Electrophysiol. ; (): -.. Viskin S. Drug challenge with epinephrine or isoproterenol for diagnosing a long QT syndrome: should we try this at home? J Cardiovasc Electrophysiol. ; (): -.. Yoshinaga M, Tomari T, Aihoshi S, Kawashita T, Nishi J, Tanaka Y, Takezaki T, Kono Y, Yuasa Y, Nakamura M, et al. Exponential correction of QT interval to minimize the effect of the heart rate in children. Jpn Circ J. ; (): -.. Aihoshi S, Yoshinaga M, Nakamura M, Oku S, Haraguchi T, Nishibatake M. Screening for QT prolongation using a new exponential formula. Jpn Circ J. ; (): -.. Aihoshi S, Yoshinaga M, Tomari T, Nakamura M, Nomura Y, Oku S, Haraguchi T, Osawa N, Miyata K. Correction of the QT interval in children. Jpn Circ J. ; (): -.. ; (): -.. Vincent GM. The long-qt syndrome--bedside to bench to bedside. N Engl J Med. ; (): -.. Shusterman V, Goldberg A, London B. Upsurge in T-wave alternans and nonalternating repolarization instability p r e c e d e s s p o n t a n e o u s i n i t i a t i o n o f v e n t r i c u l a r tachyarrhythmias in humans. Circulation. ; (): -.. Narayan SM, Smith JM, Lindsay BD, Cain ME, Davila- Roman VG. Relation of T-wave alternans to regional left ventricular dysfunction and eccentric hypertrophy secondary to coronary heart disease. Am J Cardiol. ; (): -.. Lupoglazoff JM, Denjoy I, Berthet M, Neyroud N, Demay L, Richard P, Hainque B, Vaksmann G, Klug D, Leenhardt A, Maillard G, Coumel P, Guicheney P. Notched T waves on Holter recordings enhance detection of patients with LQt (HERG) mutations. Circulation. ; (): -.. Malfatto G, Beria G, Sala S, Bonazzi O, Schwartz PJ. Quantitative analysis of T wave abnormalities and their prognostic implications in the idiopathic long QT syndrome. J Am Coll Cardiol. ; (): -.. Vincent GM. The heart rate of Romano-Ward syndrome patients. Am Heart J. ; (): -.. Rijnbeek PR, Witsenburg M, Schrama E, Hess J, Kors JA. New normal limits for the paediatric electrocardiogram. Eur Heart J. ; (): -.. QT 1246

43 Torsade de pointes ; : -.. RT W. ; : -.. Walker BD, Krahn AD, Klein GJ, Skanes AC, Yee R. Burst bicycle exercise facilitates diagnosis of latent long QT syndrome. Am Heart J. ; (): -.. Shimizu W, Ohe T, Kurita T, Shimomura K. Differential response of QTU interval to exercise, isoproterenol, and atrial pacing in patients with congenital long QT syndrome. Pacing Clin Electrophysiol. ; ( Pt ): -.. Walker BD, Krahn AD, Klein GJ, Skanes AC, Yee R, Wang J, Hegele RA. Effect of change in posture and exercise on repolarization in patients with long QT syndrome with HERG channel mutations. Can J Cardiol. ; (): -.. Chauhan VS, Krahn AD, Mitoff P, Klein GJ, Skanes AC, Yee R. Sudden intense exercise increases QT heart rate slope and T wave complexity in long QT syndrome and normal subjects. Pacing Clin Electrophysiol. ; (): -.. Kaufman ES, Gorodeski EZ, Dettmer MM, Dikshteyn M. Use of autonomic maneuvers to probe phenotype/genotype discordance in congenital long QT syndrome. Am J Cardiol. ; (): -.. Shimizu W, Noda T, Takaki H, Nagaya N, Satomi K, Kurita T, Suyama K, Aihara N, Sunagawa K, Echigo S, Miyamoto Y, Yoshimasa Y, Nakamura K, Ohe T, Towbin JA, Priori SG, Kamakura S. Diagnostic value of epinephrine test for genotyping LQT, LQT, and LQT forms of congenital long QT syndrome. Heart Rhythm. ; (): -.. Yoshinaga M, Kamimura J, Fukushige T, Kusubae R, Shimago A, Nishi J, Kono Y, Nomura Y, Miyata K. Face immersion in cold water induces prolongation of the QT interval and T-wave changes in children with nonfamilial long QT syndrome. Am J Cardiol. ; (): -, A.. QT QT/HRQT ; : -(level ).. Nishizaki M, Ashikaga T, Yamawake N, Fujii H, Arita M, Sumitomo N, Sakurada H, Hiraoka M. Effects of glucoseinduced insulin secretion on ventricular repolarization in patients with congenital long QT syndrome. Circ J. ; (): -.. Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, Cappelletti D. Risk stratification in the long-qt syndrome. N Engl J Med. ; (): -.. Eggeling T, Osterhues HH, Hoeher M, Gabrielsen FG, Weismueller P, Hombach V. Value of Holter monitoring in patients with the long QT syndrome. Cardiology. ; (-): -.. Merri M, Moss AJ, Benhorin J, Locati EH, Alberti M, Badilini F. Relation between ventricular repolarization duration and cardiac cycle length during -hour Holter recordings. Findings in normal patients and patients with long QT syndrome. Circulation. ; (): -.. Eggeling T, Hoeher M, Osterhues HH, Weismueller P, Hombach V. Significance of noninvasive diagnostic techniques in patients with long QT syndrome. Am J Cardiol. ; (): -.. Emori T, Ohe T, Aihara N, Kurita T, Shimizu W, Kamakura S, Shimomura K. Dynamic relationship between the Q-aT interval and heart rate in patients with long QT syndrome during -hour Holter ECG monitoring. Pacing Clin Electrophysiol. ; (): -.. Neyroud N, Maison-Blanche P, Denjoy I, Chevret S, Donger C, Dausse E, Fayn J, Badilini F, Menhabi N, Schwartz K, Guicheney P, Coumel P. Diagnostic performance of QT interval variables from -h electrocardiography in the long QT syndrome. Eur Heart J. ; (): -.. Sugao M, Fujiki A, Sakabe M, Nishida K, Tsuneda T, Iwamoto J, Mizumaki K, Inoue H. New quantitative methods for evaluation of dynamic changes in QT interval on hour Holter ECG recordings: QT interval in idiopathic ventricular fibrillation and long QT syndrome. Heart. ; (): -.. Lubinski A, Lewicka-Nowak E, Kempa M, Baczynska AM, Romanowska I, Swiatecka G. New insight into repolarization abnormalities in patients with congenital long QT syndrome: the increased transmural dispersion of repolarization. Pacing Clin Electrophysiol. ; ( Pt ): -.. Morita H, Yamanari H, Ohe T. Evaluation of autonomic nervous activity in patients with congenital long QT syndrome by an analysis of RR variability. Jpn Circ J. ; (): -.. Fujiki A, Nishida K, Mizumaki K, Nagasawa H, Shimono M, Inoue H. Spontaneous onset of torsade de pointes in long- QT syndrome and the role of sympathovagal imbalance. Jpn Circ J. ; (): -.. Kaufman ES, Priori SG, Napolitano C, Schwartz PJ, Iyengar S, Elston RC, Schnell AH, Gorodeski EZ, Rammohan G, Bahhur NO, Connuck D, Verrilli L, Rosenbaum DS, Brown AM. Electrocardiographic prediction of abnormal genotype in congenital long QT syndrome: experience in related family members. J Cardiovasc Electrophysiol. ; (): -.. Shimizu W, Kamakura S, Arakaki Y, Kamiya T, Shimomura K. T wave alternans in idiopathic long-qt syndrome: insight from body surface mapping. Pacing Clin Electrophysiol. ; (): -.. Rosenbaum MB, Acunzo RS. Pseudo : atrioventricular block and T wave alternans in the long QT syndromes. J Am Coll Cardiol. ; (): -.. Zareba W, Moss AJ, le Cessie S, Hall WJ. T wave alternans in idiopathic long QT syndrome. J Am Coll Cardiol. ; 1247