DOI: 10.1161/CIRCULATIONAHA.114.013698
Cardiac Electrophysiologic Substrate Underlying the ECG Phenotype and Electrogram Abnormalities in Brugada Syndrome Patients
Running title: Zhang et al.; Cardiac EP Substrate in Brugada Syndrome Patients Junjie Zhang, BS1,2; Frédéric Sacher, MD3; Kurt Hoffmayer, MD4; Thomas O’Hara, PhD5; Maria Strom, PhD6; Phillip Cuculich, MD1,7; Jennifer Silva, MD1,7; Daniel Cooper, MD1,7; Mitchell Faddis, MD1,7; Mélèze Hocini, MD3; Michel Haïssaguerre, MD MD3; Melvin Scheinman, MD8; Yoram Rudy, PhD1,2,7 1
Cardiac Ca ard rdia iaac Bi Bioe Bioelectricity o leect oe ctri r ci ri c ty and Arrhythmia Center, Wa Washington Universi University, ity ty,, St. Louis, MO; 2Dept of
Biomedical MO; Bi iom med edical al Engineering, Eng ngin inee eeri ring ngg, Washington W sh Wa shin ingt g on University, gt Uni nive vers rsit ity, y, St. St. Louis, Lou ouis is,, MO O; 3Bo Bordeaux Bord rdea eauxx U University nive ni vers rsit ityy Hospital, Hosp Ho sppit i al LIRYC LIIRYC instit institute, itut utee, Pessac, Pes essaac, France; Fra ranc nce;; 4Sc School Scho ho ool ooff Medi Medicine, diccine nee, Un Univ University verssitty off W Wisconsin, isc scconsi sin, n M Madison, ad disson on, W WI; I; 5 6
Institute In nsttit itut utee fo for or C Computational om mputtat mput a io iona nall Me na Med Medicine, diciine, dici ne, Jo John Johns hnss Ho hn Hopk Hopkins pkiins pk ins Un Univ University, iv ver e siity y, Ba Balt Baltimore, ltim lt imor oree, M or MD; D; D;
CardioInsight Card Ca rdio rd ioIn io Insi In sigh si ghtt Te gh Tech Technologies, chno ch nolo no logi lo gies gi es,, Cl es Clev Cleveland, evel ev elan el andd, an d, O OH; H; 7Sc School Scho hool ho ol ooff Me Medi Medicine, dici di cine ci ne,, Wa ne Wash Washington shin sh ingt in gton gt on U University, nive ni vers ve rsit rs ityy, it y, St. St Louis, Loui Lo uis is, M MO; O; 8Sc School Scho hool ol ooff Me Medi Medicine, dici cine ne, Th Thee Un Univ University iver ersi sity ty of California, Cal alif ifor orni niaa, S San an F Francisco, ranc ra ncis isco co, CA
Address for Correspondence: Yoram Rudy, PhD Director, Cardiac Bioelectricity and Arrhythmia Center Campus Box 1097, One Brookings Drive Washington University in St. Louis St. Louis, MO 63130 Tel:314-935-8160 Fax: 314-935-8168 E-mail: [email protected] Journal Subject Code:Diagnostic testing:[171] Electrocardiology 1 Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on March 25, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013698
Abstract
Background—Brugada syndrome (BrS) is a highly arrhythmogenic cardiac disorder, associated with an increased incidence of sudden death. Its arrhythmogenic substrate in the intact human heart remains ill-defined. Methods and Results—Using noninvasive ECG imaging (ECGI), we studied 25 BrS patients to characterize the electrophysiologic substrate, and 6 patients with right bundle branch block (RBBB) for comparison. Seven normal subjects provided control data. Abnormal substrate was observed exclusively in the right ventricular outflow tract (RVOT) with the following properties (compared compared to normal controls; p120ms were studied for comparison. All BrS and RBBB patients had no evidence of structural heart disease on echocardiography or MRI. Data from seven normal subjects12 provided normal control. Subject characteristics are provided in Supplemental Table 2. Protocols were approvedd by the the Institutional nstitutional Review Boards at the three centers; written informed consent was obtained from all pa patients. atiien ents ts. ts N Noninvasive on ni ninvasive Map Ma Mapping ppin ing in 9-14 4 ECGI methodology was EC CGI m etho et hoddolo ho dolo ogyy w ass ddescribed e crib es crib bed ppreviously revi re v ou vi oussly sly9-1 ((Supplemental Supp pple lem le ment ntal nt all F Figure igur ig uree 1A). 1A A). ) B Briefly, riief efly ly,, to torso ors rsoo
urface ECG G po pote teent ntia i ls ia l , re eco cord r ed ssimultaneously im mul ulta tane ta neou ne oussly ffrom ou rom ro m 25 2500 el eelectrodes, ectr ec troddes tr es,, we were re ccombined ombi om bine bi nedd ne surface potentials, recorded mathematically with patient-specific heart-torso geometry from ECG-gated computed tomography (CT) to construct epicardial potentials, unipolar EGMs, and maps of epicardial activation and repolarization. Bipolar EGMs were constructed for fractionation analysis. The method was validated extensively for reconstruction of EGMs,9-10 activation11-12 and repolarization.10, 12 Additional validation references are provided in Supplemental References. Spatial properties of the EP substrate were determined by dividing the epicardium into 6 segments based on CT images (Supplemental Table 3; the RVOT is depicted in Supplemental Figure 1B). EGMs from valvular regions were excluded. On average, 1154 EGMs/patient were
5 Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on March 25, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013698
used for analysis. EGMs were evaluated for morphology, magnitude and fractionation. EGM Brugada morphology was defined as STE followed by T-wave inversion. EGM magnitude (EMM) was measured peak-to-peak during the EGM QRS; for fractionated EGMs, the measurement was confined to the fractionated segment. Fractionation was expressed as number of low-amplitude deflections per EGM and displayed on epicardial EGM deflection maps (EDMs).13 For the fractionation analysis, bipolar EGMs were approximated by time derivatives of unipolar EGMs. Local activation time (AT, referenced to beginning of QRS in ECG lead II) was determined by the maximal negative slope of the EGM during QRS inscription (Supplemental low w cconduction ondu on duct du c io ct ion Figure 1C). From the ATs, epicardial activation isochrone maps were created. Sl Slow iss represented by crowded isochrones. Regional activation duration (AD) was defined as the nteerv rval al bbetween etw et we n tthe ween he earliest and latest AT in a re he regi gioon, considerin ng alll EG EGMs in that region. interval region, considering reccovvery re very y ttime imee (R im (RT) T) w as determined determ mi d ffrom mined rom m tthe he m axiimal ax imal ppositive osiitiv iv ve sl slop oppe of tthe hee E GM Local recovery was maximal slope EGM T-wa Twave wa ve ((Supplemental Su upp pple leme ment ntal al Figure Fig i ure ure 1C); 1C)); 1C ); it it reflects reefl fleects tss tthe he ssum he um m ooff loca llocal oca call ac aactivation tiva ti v tioon ttime va imee an im nd lo loc cal ac cal act tioon T-wave and local action dura raati t on o (APD). (AP APD) D . For D) For a given give gi veen activation acti ac tiva ti vati va tiion sequence, seq eque u nc ue nce, e, RT RT de dete erm rmin ines in es sspatial paati tial a vvoltage al olta ol t ge potential duration determines gradients during repolarization, and underlies ST-T deflections. RT dispersion provides substrate for unidirectional block and reentry. Activation-recovery interval (ARI) was defined as the difference between RT and AT. ARI is independent of AT and a surrogate for local APD.16 Epicardial RT and ARI gradients were computed as the difference between neighboring epicardial nodes, divided by the distance between them. ECGI was conducted in 6 patients during increased heart rate (HR; 3 with exercise and 3 with isoprenaline). ECGI maps at baseline and during the faster HR were compared.
6 Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on March 25, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013698
Simulation The O'Hara-Rudy (ORd) model of a human ventricular myocyte17 was used in the simulations. Fast/late INa and Ito were replaced by formulations used previously to represent the prominent phase-1 repolarization notch characteristic of RVOT APs.18 The model was paced to steady state at normal and slow rates (1,000 beats at 1 and 0.5 Hz, respectively) with various combinations of reduced INa and enhanced Ito conductances (GNa and Gto). Combinations were selected to span a virtual Brugada severity space. APD was measured at 90% repolarization (APD90 in ms). Statistical Analysis For every subject, the mean values for EGM variables within each epicardial segment were computed. All statistical tests were performed at the level of epicardial segment ts.. D iffe if fere fe renc enc nces e in es segments. Differences variables among epicardial segments were compared by one-way repeated measures ANOVA. Wh hen the the assumption ass ssum umpt ptio pt ion of sphericity was violated, d G d, reenhouse-Geeis i serr co cor rrection was performed. When Greenhouse-Geisser correction U sin in ng the Bonferroni Bonf nfferro onii method, met etho hod, ho d, pairwise paiirw rwis isee comparisons com mpaarison ons bbetween on etwe tween RV VOT OT aand nd d oother theer th er rregions egio eg ions io nss w eree er Using RVOT were co ond nduc ucte uc tedd (5 tests tes estts in in total). totaal) tota l). Continuous Cont Cont ntin inuo in uouus variables var ariiabl iabl bles e att baseline es baaseeli linne ne and and increased inc ncre nc r aseed re ed HR HR were weere compared com ompa parredd conducted by paired t-te est st.. Co Cont n in nt nuo u us va vvariables riab ri able ab lees be betw twee tw eenn Br ee BrS S an aand d co cont ntro nt rol, ro l, aand ndd bbetween etwe et ween we e B en rS aand nd RBBB t-test. Continuous between control, BrS were compared by unpaired t-test. The Satterthwaite modified t-test was used for variables with unequal variances. All tests with P
Cardiac Electrophysiologic Substrate Underlying the ECG Phenotype and Electrogram Abnormalities in Brugada Syndrome Patients
Running title: Zhang et al.; Cardiac EP Substrate in Brugada Syndrome Patients Junjie Zhang, BS1,2; Frédéric Sacher, MD3; Kurt Hoffmayer, MD4; Thomas O’Hara, PhD5; Maria Strom, PhD6; Phillip Cuculich, MD1,7; Jennifer Silva, MD1,7; Daniel Cooper, MD1,7; Mitchell Faddis, MD1,7; Mélèze Hocini, MD3; Michel Haïssaguerre, MD MD3; Melvin Scheinman, MD8; Yoram Rudy, PhD1,2,7 1
Cardiac Ca ard rdia iaac Bi Bioe Bioelectricity o leect oe ctri r ci ri c ty and Arrhythmia Center, Wa Washington Universi University, ity ty,, St. Louis, MO; 2Dept of
Biomedical MO; Bi iom med edical al Engineering, Eng ngin inee eeri ring ngg, Washington W sh Wa shin ingt g on University, gt Uni nive vers rsit ity, y, St. St. Louis, Lou ouis is,, MO O; 3Bo Bordeaux Bord rdea eauxx U University nive ni vers rsit ityy Hospital, Hosp Ho sppit i al LIRYC LIIRYC instit institute, itut utee, Pessac, Pes essaac, France; Fra ranc nce;; 4Sc School Scho ho ool ooff Medi Medicine, diccine nee, Un Univ University verssitty off W Wisconsin, isc scconsi sin, n M Madison, ad disson on, W WI; I; 5 6
Institute In nsttit itut utee fo for or C Computational om mputtat mput a io iona nall Me na Med Medicine, diciine, dici ne, Jo John Johns hnss Ho hn Hopk Hopkins pkiins pk ins Un Univ University, iv ver e siity y, Ba Balt Baltimore, ltim lt imor oree, M or MD; D; D;
CardioInsight Card Ca rdio rd ioIn io Insi In sigh si ghtt Te gh Tech Technologies, chno ch nolo no logi lo gies gi es,, Cl es Clev Cleveland, evel ev elan el andd, an d, O OH; H; 7Sc School Scho hool ho ol ooff Me Medi Medicine, dici di cine ci ne,, Wa ne Wash Washington shin sh ingt in gton gt on U University, nive ni vers ve rsit rs ityy, it y, St. St Louis, Loui Lo uis is, M MO; O; 8Sc School Scho hool ol ooff Me Medi Medicine, dici cine ne, Th Thee Un Univ University iver ersi sity ty of California, Cal alif ifor orni niaa, S San an F Francisco, ranc ra ncis isco co, CA
Address for Correspondence: Yoram Rudy, PhD Director, Cardiac Bioelectricity and Arrhythmia Center Campus Box 1097, One Brookings Drive Washington University in St. Louis St. Louis, MO 63130 Tel:314-935-8160 Fax: 314-935-8168 E-mail: [email protected] Journal Subject Code:Diagnostic testing:[171] Electrocardiology 1 Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on March 25, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013698
Abstract
Background—Brugada syndrome (BrS) is a highly arrhythmogenic cardiac disorder, associated with an increased incidence of sudden death. Its arrhythmogenic substrate in the intact human heart remains ill-defined. Methods and Results—Using noninvasive ECG imaging (ECGI), we studied 25 BrS patients to characterize the electrophysiologic substrate, and 6 patients with right bundle branch block (RBBB) for comparison. Seven normal subjects provided control data. Abnormal substrate was observed exclusively in the right ventricular outflow tract (RVOT) with the following properties (compared compared to normal controls; p120ms were studied for comparison. All BrS and RBBB patients had no evidence of structural heart disease on echocardiography or MRI. Data from seven normal subjects12 provided normal control. Subject characteristics are provided in Supplemental Table 2. Protocols were approvedd by the the Institutional nstitutional Review Boards at the three centers; written informed consent was obtained from all pa patients. atiien ents ts. ts N Noninvasive on ni ninvasive Map Ma Mapping ppin ing in 9-14 4 ECGI methodology was EC CGI m etho et hoddolo ho dolo ogyy w ass ddescribed e crib es crib bed ppreviously revi re v ou vi oussly sly9-1 ((Supplemental Supp pple lem le ment ntal nt all F Figure igur ig uree 1A). 1A A). ) B Briefly, riief efly ly,, to torso ors rsoo
urface ECG G po pote teent ntia i ls ia l , re eco cord r ed ssimultaneously im mul ulta tane ta neou ne oussly ffrom ou rom ro m 25 2500 el eelectrodes, ectr ec troddes tr es,, we were re ccombined ombi om bine bi nedd ne surface potentials, recorded mathematically with patient-specific heart-torso geometry from ECG-gated computed tomography (CT) to construct epicardial potentials, unipolar EGMs, and maps of epicardial activation and repolarization. Bipolar EGMs were constructed for fractionation analysis. The method was validated extensively for reconstruction of EGMs,9-10 activation11-12 and repolarization.10, 12 Additional validation references are provided in Supplemental References. Spatial properties of the EP substrate were determined by dividing the epicardium into 6 segments based on CT images (Supplemental Table 3; the RVOT is depicted in Supplemental Figure 1B). EGMs from valvular regions were excluded. On average, 1154 EGMs/patient were
5 Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on March 25, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013698
used for analysis. EGMs were evaluated for morphology, magnitude and fractionation. EGM Brugada morphology was defined as STE followed by T-wave inversion. EGM magnitude (EMM) was measured peak-to-peak during the EGM QRS; for fractionated EGMs, the measurement was confined to the fractionated segment. Fractionation was expressed as number of low-amplitude deflections per EGM and displayed on epicardial EGM deflection maps (EDMs).13 For the fractionation analysis, bipolar EGMs were approximated by time derivatives of unipolar EGMs. Local activation time (AT, referenced to beginning of QRS in ECG lead II) was determined by the maximal negative slope of the EGM during QRS inscription (Supplemental low w cconduction ondu on duct du c io ct ion Figure 1C). From the ATs, epicardial activation isochrone maps were created. Sl Slow iss represented by crowded isochrones. Regional activation duration (AD) was defined as the nteerv rval al bbetween etw et we n tthe ween he earliest and latest AT in a re he regi gioon, considerin ng alll EG EGMs in that region. interval region, considering reccovvery re very y ttime imee (R im (RT) T) w as determined determ mi d ffrom mined rom m tthe he m axiimal ax imal ppositive osiitiv iv ve sl slop oppe of tthe hee E GM Local recovery was maximal slope EGM T-wa Twave wa ve ((Supplemental Su upp pple leme ment ntal al Figure Fig i ure ure 1C); 1C)); 1C ); it it reflects reefl fleects tss tthe he ssum he um m ooff loca llocal oca call ac aactivation tiva ti v tioon ttime va imee an im nd lo loc cal ac cal act tioon T-wave and local action dura raati t on o (APD). (AP APD) D . For D) For a given give gi veen activation acti ac tiva ti vati va tiion sequence, seq eque u nc ue nce, e, RT RT de dete erm rmin ines in es sspatial paati tial a vvoltage al olta ol t ge potential duration determines gradients during repolarization, and underlies ST-T deflections. RT dispersion provides substrate for unidirectional block and reentry. Activation-recovery interval (ARI) was defined as the difference between RT and AT. ARI is independent of AT and a surrogate for local APD.16 Epicardial RT and ARI gradients were computed as the difference between neighboring epicardial nodes, divided by the distance between them. ECGI was conducted in 6 patients during increased heart rate (HR; 3 with exercise and 3 with isoprenaline). ECGI maps at baseline and during the faster HR were compared.
6 Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on March 25, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013698
Simulation The O'Hara-Rudy (ORd) model of a human ventricular myocyte17 was used in the simulations. Fast/late INa and Ito were replaced by formulations used previously to represent the prominent phase-1 repolarization notch characteristic of RVOT APs.18 The model was paced to steady state at normal and slow rates (1,000 beats at 1 and 0.5 Hz, respectively) with various combinations of reduced INa and enhanced Ito conductances (GNa and Gto). Combinations were selected to span a virtual Brugada severity space. APD was measured at 90% repolarization (APD90 in ms). Statistical Analysis For every subject, the mean values for EGM variables within each epicardial segment were computed. All statistical tests were performed at the level of epicardial segment ts.. D iffe if fere fe renc enc nces e in es segments. Differences variables among epicardial segments were compared by one-way repeated measures ANOVA. Wh hen the the assumption ass ssum umpt ptio pt ion of sphericity was violated, d G d, reenhouse-Geeis i serr co cor rrection was performed. When Greenhouse-Geisser correction U sin in ng the Bonferroni Bonf nfferro onii method, met etho hod, ho d, pairwise paiirw rwis isee comparisons com mpaarison ons bbetween on etwe tween RV VOT OT aand nd d oother theer th er rregions egio eg ions io nss w eree er Using RVOT were co ond nduc ucte uc tedd (5 tests tes estts in in total). totaal) tota l). Continuous Cont Cont ntin inuo in uouus variables var ariiabl iabl bles e att baseline es baaseeli linne ne and and increased inc ncre nc r aseed re ed HR HR were weere compared com ompa parredd conducted by paired t-te est st.. Co Cont n in nt nuo u us va vvariables riab ri able ab lees be betw twee tw eenn Br ee BrS S an aand d co cont ntro nt rol, ro l, aand ndd bbetween etwe et ween we e B en rS aand nd RBBB t-test. Continuous between control, BrS were compared by unpaired t-test. The Satterthwaite modified t-test was used for variables with unequal variances. All tests with P
