1 69 2 70 3 71 4 The many faces of early repolarization syndrome: A 72 5 73 6 Q1 single-center case series 74 7 75 8 76 Q23 Aleksandr Voskoboinik, MBBS, PhD,* Henry Hsia, MD,* Joshua Moss, MD,* 9 † † 77 10 Vasanth Vedantham, MD, PhD,* Ronn E. Tanel, MD,* Akash Patel, MD,* 78 11 Q2 Julianne Wojciak, MS,* Natalie Downs, MS,* Melvin M. Scheinman, MD* 79 12 80 13 From the *Cardiology Division, University of California, San Francisco, San Francisco, California, and 81 14 † 82 Q3 15 Pediatric Cardiology Division, University of California, San Francisco, San Francisco, California. 83 16 84 17 85 fi 18 BACKGROUND Early repolarization syndrome (ERS) is a rare but of 10 patients had variants of uncertain signi cance on genetic 86 19 increasingly recognized cause of malignant ventricular arrhythmias. testing. Quinidine effectively suppressed arrhythmias in 5 of 5 pa- 87 20 tients but required dose escalation to .1 g/d in 3 of 5 patients. 88 21 OBJECTIVE The purpose of this study was to characterize the pre- Abnormal epicardial electrograms were recorded over the inferolat- 89 22 sentations and treatments of ERS at our institution. eral left ventricle in 2 patients who underwent mapping and were 90 23 91 METHODS We performed a retrospective chart review of all patients successfully ablated. Premature ventricular contraction triggers 24 were also targeted for ablation in 3 patients. 92 25 presenting to our institution between 2008 and 2019 with ERS. 93 26 Exclusion criteria included Brugada syndrome, positive provocative CONCLUSION ERS is a heterogeneous condition and may be asso- 94 27 testing with class I antiarrhythmic drugs, metabolic disturbances, ciated with both atrial and ventricular arrhythmias, atrioventricular 95 28 or structural heart disease. block, dynamic electrocardiographic changes, and variable triggers. 96 29 97 fi In addition to targeting premature ventricular contraction triggers, 30 Q5 RESULTS Of 10 patients identi ed with ERS, 8 were men with a 98 mapping and ablation of abnormal epicardial electrograms may be a 31 mean age of 30 6 17 years at diagnosis. Documented arrhythmias 99 32 included ventricular fibrillation in 7 of 10, polymorphic ventricular potential future treatment strategy. 100 33 tachycardia in 3 of 10, and monomorphic ventricular tachycardia in 101 34 3 of 10 patients. Atrial fibrillation was diagnosed in 3 of 10, and KEYWORDS Early repolarization syndrome; J wave; Ventricular 102 35 atrioventricular block was seen in 2 of 10. J waves and/or electro- fibrillation; Cardiac arrest; Catheter ablation 103 36 cardiographic early repolarization patterns were dynamic in 7 of 104 37 10. Arrhythmias occurred at rest in 8 of 10 and with exertion in 2 (Heart Rhythm 2019;-:1–9) 2019 Heart Rhythm Society. 105 38 © 106 of 10. Only 1 patient had a family history of sudden death, and 4 All rights reserved. 39 107 40 108 41 109 42 Introduction specifying the electrocardiographic (ECG) pattern 110 43 Our understanding of early repolarization syndrome (ERS) observed.3 111 44 has dramatically evolved over the past decade. The early 112 45 113 46 repolarization (ER) pattern, once thought to be a benign Methods 114 fi 47 nding, is now known to be associated with sudden death. We searched our institution’s Genetic Arrhythmia Registry to 115 1 48 The initial description of ERS by Haissaguerre et al of identify all patients between 2008 and 2019 with a diagnosis 116 49 Q6 QRS–ST-segment elevation in the inferior or lateral leads fi 117 50 of ERS. Patients also had to ful ll a diagnosis of at least 118 and a propensity for ventricular fibrillation (VF) has been 4 51 “possible” ERS with a Shanghai ERS score of 3. We 119 52 broadened. Moreover, debate exists as to whether ERS excluded Brugada syndrome (BrS), positive provocative 120 2 53 represents a repolarization or depolarization abnormality. testing with class I antiarrhythmic drugs, metabolic distur- 121 54 Putative genes, electrophysiological manifestations, and bances (eg, hypothermia), and ischemia (including coronary 122 55 fi 123 potential targets for ablation require further clari cation. spasm) as the primary causes of ECG changes. All patients 56 We sought to review all cases of ERS from our institution 124 57 underwent echocardiography to exclude structural heart dis- 125 58 with the aim of describing its range of presentations. We ease. Records were reviewed retrospectively to obtain demo- 126 59 follow the recent American Heart Association statement graphic data, clinical course, ECG changes, arrhythmias, 127 60 outcomes of electrophysiology studies, and events at 128 61 129 62 follow-up (Table 1). Supplemental Table 1 provides a sum- 130 63 Address reprint requests and correspondence: Dr. Aleksandr Voskoboi- mary of cardiac and genetic testing, and Supplemental 131 64 nik, Cardiology Division, University of California, San Francisco, San Fran- Figure 1 shows each patient’s ECG. The study was approved 132 65 Q4 cisco, CA. E-mail address: [email protected]. by our institutional review board. 133 66 134 67 135 68 1547-5271/$-see front matter © 2019 Heart Rhythm Society. All rights reserved. https://doi.org/10.1016/j.hrthm.2019.09.013 136

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Table 1 Summary of the clinical characteristics of patients in case series Q21 Age at diagnosis Presenting Case Sex (y) symptoms ECG changes Arrhythmias Treatment Ablation Follow-up 1 F 20 VF arrest Global J waves with VF, AF Quinidine (required higher Nil 6 mo

L .. DTD 5.6.0 FLA augmentation at longer doses), ICD coupling intervals 2 F 17 VF arrest Global ST-segment VF, AF, atrial flutter, Isoproterenol suppressed Nil 8 y elevation with J waves multifocal PVCs, third- PVCs, quinidine, and augmentation at degree AV block cilostazol, ICD longer coupling RH84_ro 2Otbr21 :7p ce pm 8:47 2019 October 12 HRTHM8145_proof intervals 3 M 18 Syncope Terminal QRS notching in PMVT, VF, unifocal PVCs Failed b-blockers, sotalol, Targeted PVC trigger and 2y the inferior leads flecainide, ICD abnormal substrate inferolateral epicardium 4 M 27 VF arrest Terminal QRS notching in VF, PMVT, MMVT, unifocal ICD Targeted PVC trigger, 18 mo Previous syncope the inferior leads PVCs abnormal substrate, mid-diastolic potentials during VT in the inferolateral epicardium 5 M 55 Bradycardic arrest Transient inferior ST- MMVT/organized fascicular Quinidine (required higher Nil 2 y segment elevation arrhythmias, VF doses), ICD 6 M 46 Presyncope Intermittent J waves MMVT, PMVT, third-degree Quinidine (breakthrough Right ventricular outflow 2y inferiorly and anteriorly, AV block, PVCs VT at ,1 g/d), ICD tract PVCs targeted transient inferior ST- segment elevation 7 M 22 Polymorphic VT arrest Transient inferior ST- PMVT ICD, failed metoprolol, Nil 7 y segment elevation, quinidine successful terminal QRS notching Vol Rhythm, Heart in the inferior leads 8 M 61 VF arrest Prominent J waves in the VF ICD Nil 10 y inferior leads 9 M 18 Syncope Terminal QRS notching in Nil ICD Nil 18 mo the inferior leads 10 M 15 VF arrest Global ST-segment VF, PMVT, AF Metoprolol, ICD Nil 11 y

elevation -

AF 5 atrial fibrillation; AV 5 atrioventricular; ECG 5 electrocardiographic; F 5 female; ICD 5 implantable cardioverter-defibrillator; M 5 male; MMVT 5 monomorphic ventricular tachycardia; PMVT 5 polymorphic ,No ventricular tachycardia; PVC 5 premature ventricular contraction; VF 5 ventricular fibrillation; VT 5 ventricular tachycardia. - , - 2019 272 271 270 269 268 267 266 265 264 263 262 261 260 259 258 257 256 255 254 253 252 251 250 249 248 247 246 245 244 243 242 241 240 239 238 237 236 235 234 233 232 231 230 229 228 227 226 225 224 223 222 221 220 219 218 217 216 215 214 213 212 211 210 209 208 207 206 205 Voskoboinik et al Early Repolarization Syndrome 3

273 Results and inferolateral J waves, more prominent at slower rates 341 274 (Figure 1B). She received amiodarone but continued to 342 275 Atrial fibrillation and ERS 343 276 have frequent multifocal premature ventricular contractions 344 277 Case 1 (PVCs) and developed further VF in the setting of brady- 345 278 cardia and pauses triggered by short-coupled PVCs. Isopro- 346 A 20-year-old woman was admitted following resuscitated 279 terenol infusion markedly decreased PVCs. A dual- 347 VF after collapsing in her kitchen. Her brother had died sud- 280 chamber ICD was implanted, and ibutilide was administered 348 281 denly at the age of 15. Postdefibrillation, the ECG showed 349 for persistent AF. During ibutilide infusion, the QRS width 282 atrial fibrillation (AF) with slow ventricular response and 350 and corrected QT interval prolonged, resulting in torsades 283 global J waves despite euthermia. These persisted beyond 351 284 de pointes. Its discontinuation combined with ventricular 352 her index presentation. Notably, J waves were apparent 285 pacing at higher rates facilitated hospital discharge. Three 353 only at slower rates and longer coupling intervals 286 months later, she presented following numerous shocks for 354 287 (Figure 1A) and were not accentuated with procainamide. 355 VF, with esmolol and theophylline failing to suppress com- 288 She received quinidine 325 mg thrice daily and an implant- 356 plex ventricular ectopy. Isoproterenol reduced PVCs but re- 289 able cardioverter-defibrillator (ICD). Genetic testing 357 290 sulted in rapid AF with inappropriate shocks. She was 358 (Supplemental Table 1) revealed variants of uncertain signif- 291 stabilized on quinidine 648 mg thrice daily and cilostazol 359 Q7 icance (VUSs). Cardioversion for AF briefly restored sinus 292 200 mg thrice daily and has been well for the past 8 years 360 293 rhythm; however, AF recurred later that day and she received 361 other than an isolated VF recurrence 4 years ago because of 294 inappropriate shocks for AF during follow-up. Quinidine was 362 noncompliance. In the interim, she has also developed com- 295 increased to 650 mg thrice daily, and she spontaneously con- 363 296 plete heart block and is 100% AV paced. 364 297 verted to sinus rhythm. On review 6 months later, she is 365 298 asymptomatic without further arrhythmias. 366 299 Epicardial ablation for ERS 367 300 Case 2 368 301 Case 3 369 302 A 17-year-old adolescent girl presented following resusci- 370 303 tated VF arrest while at school. Three weeks previously, An 18-year-old man presented with recurrent syncope trig- 371 304 she had undergone cardioversion for atrial flutter. Postarrest, gered by exertion and anxiety. The ECG demonstrated an 372 305 the ECG demonstrated AF with slow ventricular response ER pattern with intermittent inferior J waves, becoming 373 306 374 307 375 308 376 309 377 310 378 311 379 312 380 313 381 314 382 315 383 316 384 317 385 318 386 319 387 320 388 321 389 322 390 323 391 324 392 325 393 326 394 327 395 328 396 329 397 330 398

331 FPO 399 = 332 400 333 401 334 402 335 403 336 print & web 4C 404 Figure 1 A: Case 1: Atrial fibrillation with the early repolarization pattern demonstrating A. Augmentation of J waves (arrow) at slower ventricular rates and Q22 337 405 beat-to-beat variability with presence of J waves (circled) only at longer coupling intervals. Note is made of taller and narrower QRS complexes in beats without J 338 406 waves. Lead V shows minor right ventricular conduction delay, but not a true Brugada pattern. B: Case 2 with more prominent J waves at longer coupling in- 339 1 407 tervals (left) and ibutilide causing QRS and corrected QT interval prolongation with early premature ventricular contraction triggering torsades de pointes (right). 340 408

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409 more prominent at slower heart rates. A loop recorder was in- tion (Figure 3A) despite flecainide and metoprolol. Repeat 477 410 serted, and this documented multiple self-terminating episodes electrophysiology study demonstrated spontaneous PVCs 478 411 479 412 of polymorphic ventricular tachycardia (VT)/VF. An ICD was (Figure 3B; right bundle branch pattern, superior axis) and 480 413 implanted, and the patient received several appropriate shocks inducible rapid monomorphic VT. A multipolar catheter 481 414 for PVC-triggered VF despite b-blockers, sotalol, and flecai- advanced into a lateral coronary sinus branch over the infero- 482 415 nide. He was referred for ablation to target the triggering lateral LV epicardium demonstrated early presystolic local 483 416 PVC (Figure 2A). Endocardial mapping of the left ventricle recordings (276 ms) during VT compared to those recorded 484 417 2 485 418 (LV) demonstrated normal endocardial voltages, and activa- directly opposite on the endocardial surface ( 34 ms) 486 419 tion mapping of occasional PVCs identified the earliest endo- (Figure 3C). Epicardial access was undertaken, and a small 487 420 cardial site in the inferolateral LV “on time” with QRS onset. patchy abnormal low-voltage region was found over the in- 488 421 Epicardial access was performed, and mapping in sinus rhythm ferolateral LV with extreme delayed activation into the re- 489 422 490 identified local abnormal ventricular activities coincident with gion during sinus rhythm (Figure 3D, not visible on CMR). Q9 423 491 424 the J wave, together with late potentials and fragmented elec- Discrete fractionated late potentials were recorded in the 492 425 trograms in the inferolateral epicardial region (Figures 2B– abnormal epicardial LV that corresponded in timing with 493 426 2E). Early PVC activation and good pace maps from this ECG J waves during sinus rhythm. Although sustained VT 494 427 area were also demonstrated, and ablation in this region was no longer inducible under general anesthesia, early pre- 495 428 rendered the patient arrhythmia-free over 3 years follow-up. systolic potentials (Figure 3B) were recorded during the cor- 496 429 497 430 responding PVCs of the same morphology. Epicardial 498 431 Case 4 ablation in this region eliminated the PVCs, and the patient 499 432 A 27-year-old man presented with resuscitated VF on the has remained asymptomatic in spite of resumption of 500 433 vigorous activities for 18 months. 501 434 background of recurrent syncope while playing basketball. 502 435 The ECG showed terminal QRS notching in the inferior 503 436 leads. Genetic testing identified a VUS in the SCN5A sodium Dynamic inferior ST-segment elevation 504 437 channel gene. VF was induced during electrophysiology 505 438 study following aggressive stimulation (400/250/200/200 Case 5 506 439 507 440 Q8 ms). A subcutaneous ICD was implanted, but the patient A 55-year-old man with previous bradycardic arrest and 508 441 continued to receive shocks for pleomorophic VT with exer- dual-chamber pacemaker was transferred following recurrent 509 442 510 443 511 444 512 445 513 446 514 447 515 448 516 449 517 450 518 451 519 452 520 453 521 454 522 455 523 456 524 457 525 458 526 459 527 460 528 461 529 462 530 463 531 464 532 465 533 466 534

467 FPO 535 = 468 536 469 537 470 538 471 539 472 print & web 4C 540 Figure 2 Case 3: A: Early-coupled premature ventricular contractions (PVCs) triggering polymorphic ventricular tachycardia. B: J waves more prominent at 473 541 longer cycle lengths (right beat). C: Pace mapping from the inferolateral epicardium (right beat) demonstrated right bundle branch morphology with right superior 474 542 axis similar to the triggering PVC (left beat). D: Activation mapping of triggering PVCs with the earliest site 50 ms ahead of QRS in the inferolateral epicardium 475 543 with the corresponding endocardial site on time with QRS onset. E: Abnormal local signals in the inferolateral epicardium with late potentials and fragmented 476 544 electrograms.

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545 episodes of monomorphic VT with right bundle branch outflow tract (RVOT) with a closely matched pace map. 613 546 morphology and right inferior axis, suggesting origin in the Transient periods of asymptomatic inferior ST-segment 614 547 615 548 left anterior fascicle. VT onset was preceded by marked infe- elevation occurred throughout the procedure (Supplemental 616 549 Q10 rior ST-segment elevation without chest pain that was unre- Figure 1). Catheter ablation was performed but sustained 617 550 sponsive to nitrates, and arrhythmias terminated with VT recurred, and quinidine 324 mg thrice daily was initiated. 618 551 resolution of these changes (Figure 4A or 4B), as reported The patient remains well 2 years later with an isolated 619 552 previously.5 The coronary angiogram included a negative episode of VT that was successfully treated with antitachy- 620 553 621 554 acetylcholine challenge for vasospasm. He was upgraded to cardia pacing. 622 555 an ICD and received appropriate therapies for VF at 623 556 follow-up (Figure 4C). Quinidine 325 mg thrice daily was Case 7 624 557 initiated, resulting in marked reduction in VT episodes. Quin- A 22-year-old man with a history of recurrent “seizures” was 625 558 idine was then increased to 650 mg thrice daily, which abol- 626 559 resuscitated from polymorphic VT occurring at rest. There 627 560 ished ST-segment elevation, and he has not had further VT was no family history of sudden death. The initial ECG 628 561 over 2 years follow-up. demonstrated marked inferior ST-segment elevation 629 562 (Figure 5A). An ICD was implanted, and he was commenced 630 563 Case 6 on metoprolol 50 mg thrice daily but continued to receive 631 564 632 565 A 46-year-old man developed presyncope without prodrome. appropriate shocks for polymorphic VT during sleep. Ge- 633 566 A troponin elevation prompted coronary angiography, which netic testing was unremarkable. He was switched to quini- 634 567 was normal, although he had an episode of monomorphic VT dine 300 mg twice daily and has remained arrhythmia-free 635 568 during the procedure. On his first night in the hospital, he for 7 years. 636 569 637 570 collapsed after getting out of bed and required cardiopulmo- 638 571 nary resuscitation for complete heart block and pause- Stable ER pattern 639 572 dependent VT. A dual-chamber pacemaker was implanted. 640 573 The ECG at follow-up demonstrated a subtle ER pattern Case 8 641 574 642 with intermittent terminal QRS notching in leads V3 through A 61-year-old man developed agonal breathing during sleep, 575 fi 643 576 V5 and II. Genetic testing identi ed a ryanodine-receptor and his wife performed cardiopulmonary resuscitation until 644 577 RYR2 VUS. He subsequently developed episodes of mono- he was defibrillated for VF. The ECG demonstrated J waves 645 578 morphic and polymorphic VT triggered by late-coupled in the inferior leads. The coronary angiogram revealed a diag- 646 579 PVCs and was upgraded to an ICD. Infrequent spontaneous onal branch stenosis, which was stented; however, this was not 647 580 PVCs were mapped to the low anteroseptal right ventricular felt to be the cause of VF because of its small caliber. VF was 648 581 649 582 650 583 651 584 652 585 653 586 654 587 655 588 656 589 657 590 658 591 659 592 660 593 661 594 662 595 663 596 664 597 665 598 666 599 667 600 668 601 669 602 670 603 671

604 FPO 672 = 605 673 606 674 607 675 608 676 609 print & web 4C 677 Figure 3 Case 4: A: Late-coupled premature ventricular contractions (PVCs) triggering polymorphic ventricular tachycardia (VT). B: ST-segment elevation 610 678 with notching in the inferior leads and lead V and fractionated potentials during the sinus beat (left) and an early local electrogram seen in the inferolateral epicar- 611 1 679 dium 60 ms pre-PVC (right). C: Presystolic potentials during monomorphic VT with simultaneous mapping in the inferolateral left ventricular endo- and epicar- 612 680 dium. D: Voltage map in sinus rhythm with the isolated region of abnormal electrograms within the inferolateral epicardium. CS 5 coronary sinus.

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681 749 682 750 683 751 684 752 685 753 686 754 687 755 688 756 689 757 690 758 691 759 692 760 693 761 694 762 695 763 696 764 697 765 698 766 699 767

700 FPO 768 = 701 769 702 770 703 771 704 772 705 print & web 4C 773 Figure 4 Case 5: A: Resting electrocardiogram without abnormalities. B: Marked inferior ST-segment elevation before monomorphic ventricular tachycardia 706 774 (VT) onset. C: Degeneration of VT to ventricular fibrillation requiring implantable cardioverter-defibrillator therapy. 707 775 708 776 709 777 710 inducible with double extrastimuli during electrophysiology Case 9 778 711 study, and an ICD was implanted. Both his son and daughter An 18-year-old man with a history of recurrent syncope was 779 712 were found to have ER in the lateral leads but have been admitted for a syncopal event without prodrome, resulting in 780 713 781 714 asymptomatic. Genetic testing showed a VUS in the MYH7 a car accident and associated traumatic brain injury. No sig- 782 715 gene. The patient has not had any further sustained ventricular nificant family history was reported. ECGs intermittently 783 716 arrhythmias over 10 years without antiarrhythmic drugs. demonstrated ER with terminal QRS notching in the 784 717 785 718 786 719 787 720 788 721 789 722 790 723 791 724 792 725 793 726 794 727 795 728 796 729 797 730 798 731 799 732 800 733 801 734 802 735 803 736 804 737 805 738 806 739 807 740 808

741 FPO 809 = 742 810 743 811 744 812 745 813 746 print & web 4C 814 Figure 5 A: Case 7: Initial electrocardiogram (ECG) following resuscitation from polymorphic ventricular tachycardia (VT) demonstrating marked inferior 747 815 ST-segment elevation (top) with improvement 15 minutes later (bottom). B: Case 10: ECG demonstrating global ST-segment elevation (top); tight-coupled pre- 748 816 mature ventricular contractions (PVCs) seen following a short-long sequence triggering polymorphic VT (bottom).

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817 inferolateral leads. The decision was made to implant a dual- augmentation of epicardial action potential notch amplitude 885 818 chamber ICD on the basis of history and potentially malig- and J wave at longer cycle lengths8 and using cholinergic ag- 886 819 9 “ – ” 887 820 nant J-wave pattern. The patient remains well 18 months later onists. In a series of J-wave associated VF, 15 of 27 dis- 888 821 without device therapy. played significant pause-dependent J-wave augmentation— 889 822 not seen in matched controls without previous VF.10 In a 890 823 Case 10 study of 4 families with ERS, the Valsalva maneuver 891 824 892 A 15-year-old adolescent boy with a history of a “seizure dis- augmented the J-wave amplitude in 17 of 20 probands and 825 11 893 826 order” presented with resuscitated VF occurring at rest. The unmasked ER in 17 relatives. 894 827 ECG demonstrated global ST-segment elevation 895 828 (Figure 5B), and no structural heart disease or genetic abnor- 896 829 897 mality was found. Electrophysiology study demonstrated Role of catheter ablation 830 While ablation of VF-triggering PVCs in ERS is an attractive 898 831 dual atrioventricular (AV) nodal physiology, and he under- 899 832 went slow pathway modification. A single-chamber ICD option, their sporadic nature makes mapping challenging. In 900 833 was implanted but was upgraded to a dual-chamber ICD 17 a study of patients identified with ERS undergoing body sur- 901 834 months later for AF. He has remained on metoprolol 50 face mapping, 2 of 29 had PVC triggers originating from the 902 835 apical and the inferior LV, respectively, corresponding to the 903 836 mg/d for 11 years, with brief self-limiting episodes of poly- 904 morphic VT only but no ICD therapy. epicardial region with J waves, short activation recovery in- 837 12 905 838 terval, and steep activation recovery interval gradients. 906 839 These findings suggest that reactivation of early repolarizing 907 840 Discussion cells from local currents could produce ectopy,13 as was seen 908 841 This case series of 10 patients highlights the heterogeneous in 2 of 10 patients in the present study whereby the inferolat- 909 842 nature of ERS on the basis of current diagnostic criteria. In eral region corresponded to the site of abnormal epicardial 910 843 contrast to the original report by Haissaguerre et al,1 3of 911 844 signals, ECG changes, and PVCs. However, like in related 912 845 10 patients presented with monomorphic VT. We also BrS, VF-triggering PVCs have also been identified outside 913 846 emphasize the presence of AF and AV block, as well as the the region of epicardial abnormalities.14 One patient demon- 914 847 role of bradycardia in arrhythmia initiation. Two patients strated organized fascicular rhythms before VF onset (likely 915 848 had successful epicardial catheter ablation of PVC triggers left anterior fascicular origin) and another an RVOT trigger. 916 849 and epicardial substrate modification. Finally, although the 917 850 Previous case reports of ERS have focused on targeting VF- 918 fi 2,15 851 therapeutic ef cacy of quinidine is accepted, there is no triggering PVC originating in the septal Purkinje systems, 919 852 consensus on dose. In this report, we used graded doses left posterior fascicle,16 and RVOT.17 920 . 853 and found that 1 g/d may be required. “Substrate”-based ablation targeting abnormal potentials 921 854 in the epicardial RVOT is increasingly used in BrS. It has 922 855 923 856 Dynamic nature of ECG changes been postulated that the main difference between BrS and 924 18 857 This study highlights the dynamic nature of ECG changes in ERS is the region of the heart affected. The inferior wall 925 858 ERS. Three patients had escalating ST-segment elevation has been proposed as a “hot spot” for epicardial abnormalities 926 859 9 927 before arrhythmia initiation; 3 patients had consistent J in ERS owing to higher intrinsic Ito levels, and the J wave Q13 860 waves with augmentation during long cycle lengths; and 2 may either be intermittent, buried in the QRS complex, or 928 861 19 929 862 showed intermittent and subtle terminal QRS notching. not necessary. Epicardial mapping has rarely been reported 930 863 One patient exhibited “narrow and tall” QRS complexes on in ERS despite increasing evidence that repolarization abnor- 931 864 beats without J waves, postulated to represent either malities are primarily seen on the epicardial surface. This was 932 865 enhanced sodium channel function, enhanced gap junctional first identified by Yan and Antzelevitch,8 who demonstrated 933 866 conductance and density, or abnormal Purkinje fiber network using perfused canine wedge preparations that the J wave 934 867 6 935 868 predisposing to triggered arrhythmias. Development of ar- represented an exaggeration of the transmural gradient in 936 869 rhythmias at rest in 8 of 10 and J-wave prominence at longer the amplitude of the Ito-mediated transient repolarizing cur- 937 870 coupling intervals argues in favor of a repolarization abnor- rent, with a prominent action potential notch seen in the 938 871 mality in ERS, perhaps related to slow reactivation kinetics epicardium but not in the endocardium. Ablation of the cor- 939 872 940 Q11 of I and greater contribution of potassium channels I and responding epicardial fractionated low-voltage electrical ac- 873 to to 941 874 Q12 IK-ATP to the action potential spike and dome slope. The pres- tivity and late potentials in similar canine wedge 942 875 ence of fragmented electrograms and late potentials can also preparations reduced J-wave amplitude and VF inducibility 943 876 occur because of abnormal repolarization,7 as demonstrated owing to the destruction of cells with the most prominent ac- 944 877 by Szel and Antzelevitch in an isolated arterially perfused tion potential notch.20 Two recent human studies using body 945 878 canine ventricular wedge preparation model. Fractionated surface mapping in ERS demonstrated abnormal epicardial 946 879 947 880 electrograms were seen in the epicardium but not in the endo- repolarization characterized by areas with short activation re- 948 881 cardium because of heterogeneities in the appearance of the covery intervals, heterogeneous shortening of action poten- 949 882 second epicardial action potential upstroke with high- tial duration, and abnormal sinus rhythm epicardial 950 883 frequency spikes developing because of concealed phase 2 electrograms, while ventricular depolarization appeared 951 884 reentry. Similar in vitro models have demonstrated an normal.12,19 952

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953 In the first study using epicardial mapping via a lateral cor- harmful. In this report, we used escalating quinidine doses 1021 954 onary sinus branch in ERS, similar to our observations in and found that .1 g/d was required to suppress arrhythmias 1022 955 21 1023 956 cases 3 and 4, Nakagawa et al observed that prominent po- in 3 of 5 patients. However, both underdosing and compli- 1024 957 tentials were seen corresponding with the surface J wave on ance may be potential limitations in patient management. A 1025 958 the unipolar recording and immediately after the QRS com- study of 37 patients on quinidine found that 73% had subther- 1026 959 plex on the bipolar recording. These potentials were not re- apeutic levels,31 highlighting the challenges related to its 1027 960 corded within the opposing endocardium and were short half-life, frequent dosing intervals, and side-effect pro- 1028 961 fi 1029 962 accentuated with class Ic antiarrhythmic drugs and dimin- le. Routine monitoring of quinidine levels may be useful in 1030 963 ished with isoproterenol in concert with the surface ECG J patients with life-threatening arrhythmias on chronic therapy. 1031 964 wave; however, no ablation was performed. Haissaguerre 1032 965 et al2 argued that in some patients with J wave syndromes, Diagnostic challenges 1033 966 abnormal electrograms may indeed represent delayed depo- 1034 967 Seemingly atypical presentations of ERS (including AF, AV 1035 968 larization owing to microstructural abnormalities not block, monomorphic VT, sympathetic triggers, and apparent 1036 969 apparent on noninvasive imaging. Many cases of idiopathic epicardial “substrate”) may delay diagnosis, and in our series 1037 970 VF may also represent “undiagnosed” J wave syndromes, the diagnosis was often not made during the index presenta- 1038 971 with abnormal epicardial electrograms reported during inva- tion. These additional features have not been observed in 1039 972 1040 Q14 sive mapping in 15 of 24 IVF survivors, which were colo- 973 larger registries of patients with aborted sudden death (J. Q16 1041 32 974 cated with VF drivers on noninvasive mapping. In our Roberts, personal communication, July 18, 2019). Q17 1042 975 study, an approach targeting triggers and substrate facilitated Although standardized criteria for description of the ER pat- 1043 976 arrhythmia control in 2 patients and may obviate the need for tern(s) have been developed,33 the high prevalence of ER 1044 977 continued drug or ICD therapy. pattern in healthy adults and lack of confirmatory tests create 1045 978 1046 979 diagnostic challenges. Fleeting ECG changes highlight the 1047 980 Association with AF and AV block importance of prolonged observation and close inspection, 1048 fi 981 The early onset of atrial arrhythmias in 3 of 10 patients in the particularly at longer coupling intervals. Signi cant ER 1049 982 1050 absence of an identifiable mutation suggests a common un- was observed in 23% of patients with idiopathic VF from 983 the Cardiac Arrest Survivors With Preserved Ejection Frac- 1051 984 derlying ventricular and atrial proarrhythmic mechanism un- 1052 985 related to previously reported mutations in potassium tion Registry; however, the pattern was variable in 58%. 1053 986 channels KCNJ8 and KCNA5.22 In observational studies, Those with idiopathic VF and ER had greater J-point eleva- 1054 987 – tion and wider distribution of changes than those with an es- 1055 the inferolateral ER pattern is 2 3 times more common in 32 988 23 tablished cause of VF. In a series of 35 idiopathic VF 1056 989Q15 AF than in controls and has been associated with AF recur- 1057 24 survivors, an ER pattern was the strongest predictor of 990 rence following ablation. In those with ERS and previous 34 1058 991 VF, AF has been reported in 23% of cases and may relate frequent and earlier ICD therapies. These data suggest 1059 992 that ERS may be a more common cause of VF than previ- 1060 to prominence of Ito-mediated transient repolarizing currents 993 in the atria with short-coupled atrial premature beats trig- ously appreciated, and its exquisite response to quinidine 1061 994 1062 gering phase 2 reentry,25 a postulated mechanism for VF and potential ablation targets underscore the importance of 995 making the diagnosis. 1063 996 initiation. Inappropriate shocks for AF have been reported 1064 997 in 20% of patients identified with ERS,26 suggesting that 1065 998 the association between AF and J wave syndromes is not Conclusion 1066 999 27 1067 restricted to BrS. ERS fi Q18 1000 was initially de ned as a clinical syndrome character- 1068 1001 The association between ERS and heart block, as was pre- ized by J waves in 2 contiguous inferior and/or lateral leads 1069 1002 sent in 2 patients in our series, has not been described previ- or slurring of the terminal QRS associated with aborted sud- Q19 1070 1003 ously. In a series of 50 patients with idiopathic VF and the ER den death. Our experience suggests an expanded definition 1071 1004 pattern, Watanabe et al28 reported longer PR intervals in that encompasses monomorphic VT, AF, and AV block. 1072 1005 cases compared with age-matched controls. Three patients The importance of prompt recognition rests on providing 1073 1006 1074 1007 in this series had an SCN5A sodium channel mutation, which an effective treatment regimen including quinidine therapy 1075 1008 has also been described in J wave syndromes, early-onset AF, and/or catheter ablation. 1076 1009 and heart block.29 Mutations in L-type calcium channels have 1077 1010 30 1078 also been described in ERS, and these mutations in sodium Appendix 1011 and calcium channels suggest potential depolarization abnor- 1079 1012 Supplementary data 1080 malities in some patients identified with ERS.2 1013 Supplementary data associated with this article can be found 1081 1014 in the online version at https://doi.org/10.1016/j.hrthm.2019. 1082 1015 1083 1016 Pharmacological therapy for ERS 09.013. 1084 1017 The class Ia antiarrhythmic drug quinidine has emerged as an 1085 1018 important therapy in J wave syndromes because of its unique 1086 1019 References 1087 inhibition of Ito channels, while b-blockers, amiodarone, fle- 1020 1. Haissaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with 1088 cainide, ibutilide, and dofetilide appear to be unhelpful or early repolarization. N Engl J Med 2008;358:2016–2023.

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1089 2. Haissaguerre M, Nademanee K, Hocini M, et al. Depolarization versus repolari- 18. Di Diego JM, Antzelevitch C. Inferolateral J-wave syndromes: a reflection of 1157 1090 zation abnormality underlying inferolateral J-wave syndromes: new concepts in abnormal repolarization, depolarization, or both? Heart Rhythm 2019; 1158 1091 sudden cardiac death with apparently normal hearts. Heart Rhythm 2019; 16:791–792. 1159 1092 16:781–790. 19. Ghosh S, Cooper DH, Vijayakumar R, et al. Early repolarization associated with 1160 1093 3. Patton KK, Ellinor PT, Ezekowitz M, et al. Electrocardiographic early repolariza- sudden death: insights from noninvasive electrocardiographic imaging. Heart 1161 fi – 1094 tion: a scienti c statement from the American Heart Association. Circulation Rhythm 2010;7:534 537. 1162 2016;133:1520–1529. 20. Patocskai B, Yoon N, Antzelevitch C. Mechanisms underlying epicardial radio- 1095 1163 4. Antzelevitch C, Yan GX, Ackerman MJ, et al. J-wave syndromes expert frequency ablation to suppress arrhythmogenesis in experimental models of Bru- 1096 consensus conference report: emerging concepts and gaps in knowledge. J Ar- gada syndrome. JACC Clin Electrophysiol 2017;3:353–363. 1164 1097 rhythm 2016;32:315–339. 21. Nakagawa K, Nagase S, Morita H, Ito H. Left ventricular epicardial electrogram 1165 1098 5. Cardona-Guarache R, Vedantham V, Scheinman MM. Ischemia with marked ST recordings in idiopathic ventricular fibrillation with inferior and lateral early repo- 1166 1099 elevation or J-wave syndrome? J Electrocardiol 2019;55:26–27. larization. Heart Rhythm 2014;11:314–317. 1167 1100 6. Wolpert C, Veltmann C, Schimpf R, Antzelevitch C, Gussak I, Borggrefe M. Is a 22. Delaney JT, Muhammad R, Blair MA, et al. A KCNJ8 mutation associated with 1168 1101 narrow and tall QRS complex an ECG marker for sudden death? Heart Rhythm early repolarization and atrial fibrillation. Europace 2012;14:1428–1432. 1169 1102 2008;5:1339–1345. 23. Hasegawa Y, Watanabe H, Ikami Y, et al. Early repolarization and risk of lone 1170 fi – 1103 7. Szel T, Antzelevitch C. Abnormal repolarization as the basis for late potentials atrial brillation. J Cardiovasc Electrophysiol 2019;30:565 568. 1171 and fractionated electrograms recorded from epicardium in experimental models 24. Hunuk B, de Asmundis C, Mugnai G, et al. Early repolarization pattern as a pre- 1104 1172 of Brugada syndrome. J Am Coll Cardiol 2014;63:2037–2045. dictor of atrial fibrillation recurrence following radiofrequency pulmonary vein 1105 8. Yan GX, Antzelevitch C. Cellular basis for the electrocardiographic J wave. Cir- isolation. Ann Noninvasive Electrocardiol 2019;24:e12627. 1173 1106 culation 1996;93:372–379. 25. Francis J, Antzelevitch C. Atrial fibrillation and Brugada syndrome. J Am Coll 1174 1107 9. Koncz I, Gurabi Z, Patocskai B, et al. Mechanisms underlying the development of Cardiol 2008;51:1149–1153. 1175 1108 the electrocardiographic and arrhythmic manifestations of early repolarization 26. Hwang KW, Nam GB, Han J, et al. Incidence of atrial tachyarrhythmias in pa- 1176 1109 syndrome. J Mol Cell Cardiol 2014;68:20–28. tients with early repolarization syndrome. Int Heart J 2017;58:43–49. 1177 1110 10. Aizawa Y, Sato A, Watanabe H, et al. Dynamicity of the J-wave in idiopathic ven- 27. Morita H, Kusano-Fukushima K, Nagase S, et al. Atrial fibrillation and atrial 1178 1111 tricular fibrillation with a special reference to pause-dependent augmentation of vulnerability in patients with Brugada syndrome. J Am Coll Cardiol 2002; 1179 – – 1112 the J-wave. J Am Coll Cardiol 2012;59:1948 1953. 40:1437 1444. 1180 11. Gourraud JB, Le Scouarnec S, Sacher F, et al. Identification of large families in 28. Watanabe H, Nogami A, Ohkubo K, et al. Electrocardiographic characteristics 1113 1181 early repolarization syndrome. J Am Coll Cardiol 2013;61:164–172. and SCN5A mutations in idiopathic ventricular fibrillation associated with early 1114 12. Zhang J, Hocini M, Strom M, et al. The electrophysiological substrate of early repolarization. Circ Arrhythm Electrophysiol 2011;4:874–881. 1182 1115 repolarization syndrome: noninvasive mapping in patients. JACC Clin Electro- 29. Wang DW, Viswanathan PC, Balser JR, George AL Jr, Benson DW. Clinical, ge- 1183 1116 physiol 2017;3:894–904. netic, and biophysical characterization of SCN5A mutations associated with atrio- 1184 1117 13. Benito B, Guasch E, Rivard L, Nattel S. Clinical and mechanistic issues in early ventricular conduction block. Circulation 2002;105:341–346. 1185 1118 repolarization of normal variants and lethal arrhythmia syndromes. J Am Coll 30. Burashnikov E, Pfeiffer R, Barajas-Martinez H, et al. Mutations in the cardiac L- 1186 1119 Cardiol 2010;56:1177–1186. type calcium channel associated with inherited J-wave syndromes and sudden car- 1187 1120 14. Fernandes GC, Fernandes A, Cardoso R, et al. Ablation strategies for the manage- diac death. Heart Rhythm 2010;7:1872–1882. 1188 1121 ment of symptomatic Brugada syndrome: a systematic review. Heart Rhythm 31. Squire A, Goldman ME, Kupersmith J, Stern EH, Fuster V, Schweitzer P. Long- 1189 2018;15:1140–1147. term antiarrhythmic therapy: problem of low drug levels and patient noncompli- 1122 1190 15. Voskoboinik A, McLellan AJ, Kistler PM. Ventricular fibrillation storm in a ance. Am J Med 1984;77:1035–1038. 1123 young man with early repolarisation abnormality: the role of isoprenaline and 32. Derval N, Simpson CS, Birnie DH, et al. Prevalence and characteristics of early 1191 1124 quinidine. Intern Med J 2014;44:309–311. repolarization in the CASPER registry: Cardiac Arrest Survivors With Preserved 1192 1125 16. Latcu DG, Bun SS, Zarqane N, Saoudi N. Ablation of left ventricular substrate Ejection Fraction Registry. J Am Coll Cardiol 2011;58:722–728. 1193 1126 in early repolarization syndrome. J Cardiovasc Electrophysiol 2016; 33. Macfarlane PW, Antzelevitch C, Haissaguerre M, et al. The early repolarization 1194 1127 27:490–491. pattern: a consensus paper. J Am Coll Cardiol 2015;66:470–477. Q20 1195 1128 17. Kakihara J, Takagi M, Hayashi Y, Tatsumi H, Doi A, Yoshiyama M. Radiofre- 34. Siebermair J, Sinner MF, Beckmann BM, et al. Early repolarization pattern is the 1196 1129 quency catheter ablation for treatment of premature ventricular contractions trig- strongest predictor of arrhythmia recurrence in patients with idiopathic ventricular 1197 fi fl fi 1130 gering ventricular brillation from the right ventricular out ow tract in a patient brillation: results from a single centre long-term follow-up over 20 years. Euro- 1198 with early repolarization syndrome. HeartRhythm Case Rep 2016;2:342–346. pace 2016;18:718–725. 1131 1199 1132 1200 1133 1201 1134 1202 1135 1203 1136 1204 1137 1205 1138 1206 1139 1207 1140 1208 1141 1209 1142 1210 1143 1211 1144 1212 1145 1213 1146 1214 1147 1215 1148 1216 1149 1217 1150 1218 1151 1219 1152 1220 1153 1221 1154 1222 1155 1223 1156 1224

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