JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 67, NO. 1, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2015.10.020

REVIEW TOPIC OF THE WEEK

A Tale of 2 Diseases The History of Long-QT Syndrome and

Ofer Havakuk, MD, Sami Viskin, MD

ABSTRACT

The Brugada syndrome (BrS) and long-QT syndrome (LQTS) present as congenital or acquired disorders with diagnostic electrocardiograms (ST-segment elevation and prolonged QT interval, respectively) and increased risk for malignant . Our understanding of the 2 disease forms (congenital vs. acquired) differs. A female patient on quinidine for atrial fibrillation who develops ventricular fibrillation is diagnosed with “acquired LQTS” and is discharged with no therapy other than instructions to avoid QT-prolonging medications. In contrast, an asymptomatic male patient who develops a Brugada electrocardiogram on flecainide is diagnosed with “asymptomatic BrS” and could be referred for an electrophysiological evaluation that could result in defibrillator implantation. The typical patient undergoing defibrillator implantation for BrS is asymptomatic but has a Brugada electrocardiogram provoked by a drug. The authors describe how the histories of LQTS and BrS went through the same stages, but in different sequences, leading to different conclusions. (J Am Coll Cardiol 2016;67:100–8) © 2016 by the American College of Cardiology Foundation.

“History is nothing whatever but a record of congenital or acquired (mainly drug-induced) ar- what living persons have done in the past.” rhythmogenic disorders; both have diagnostic elec- —Rose Wilder Lane (1) trocardiograms (ECGs), with a prolonged QT interval in the former (Figure 1) and coved ST-segment his observation is exemplified by the elevation >2mminthelatter(Figure 2); and both T nonparallel pathways that led to different may lead to polymorphic ventricular tachyarrhyth- approaches for the management of 2 com- mias (Figures 1 and 2). However, our understanding of mon arrhythmic syndromes: long-QT syndrome the interplay between these 2 forms (congenital and (LQTS) and Brugada syndrome (BrS). acquired) of disease differs. The 2013 Heart Rhythm Society, European Heart Take, for example, the following patients: 1) a Rhythm Association, and Asia PacificHeartRhythm woman on quinidine for atrial fibrillation who de- Society consensus report states that congenital LQTS velops (TdP) and ventricular (cLQTS) is diagnosed “in the presence of [corrected] fibrillation (VF) requiring resuscitation; and 2) an QT interval >500 ms.when a secondary cause for asymptomatic man who develops a type I Brugada QT-prolongation is absent.” In contrast, BrS is diag- ECG after receiving intravenous flecainide. After car- nosed “in patients with ST-segment elevation with diac arrest from quinidine, the female patient is likely type 1 morphology.either spontaneously or after to receive a diagnosis of drug-induced LQTS (diLQTS) provocative drug test with a Class I antiarrhythmic and will be discharged with no therapy, other than drug” (2). instructions to avoid QT-prolonging medications. This fundamental discrepancy in diagnostic In contrast, the asymptomatic male patient with Listen to this manuscript’s approach is intriguing. After all, both LQTS and flecainide-induced ST-segment elevation is likely to audio summary by BrS share important characteristics: both present as bediagnosedwithasymptomaticBrSandcouldbe JACC Editor-in-Chief Dr. Valentin Fuster.

From the Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Manuscript received July 21, 2015; revised manuscript received September 18, 2015, accepted October 6, 2015. JACC VOL. 67, NO. 1, 2016 Havakuk and Viskin 101 JANUARY 5/12, 2016:100– 8 History of Long-QT and Brugada Syndromes

referred for an electrophysiological study (EPS) that, shock” from toxic effects on the nervous ABBREVIATIONS if the findings are positive, will result in the implan- system (11) were the prevailing explanations. AND ACRONYMS tation of an implantable cardioverter-defibrillator Dessertenne (12) not only described in detail BrS = Brugada syndrome (ICD). the same in patients with atrio- cLQTS = congenital long-QT We explore the possibility that the divergent ventricular block but also coined the term syndrome course of events during the description of these 2 eventually used to denote the unique ar- diLQTS = drug-induced long- diseases led to the paradigms behind their different rhythmia of LQTS: torsades de pointes. QT syndrome modes of treatment. In other words, the histories of Strange as it may sound today, neither ECG = electrocardiogram LQTS and BrS went through the same stages, Dessertenne (12) nor Selzer and Wray (8) EPS = electrophysiological including: 1) description of the congenital and ac- considered QT prolongation as the cause of study quired forms of each disease; 2) understanding of the TdP, instead blaming the arrhythmia on ICD = implantable pathophysiology of each disease type; and 3) under- widening of the QRS complex. The lack of cardioverter-defibrillator standing of the interaction between the 2 disease understanding of the interplay between the LQTS = long-QT syndrome variants, with the eventual development of diag- drug effects, the QT prolongation, and the TdP = torsades de pointes nostic tests. However, the sequence of these stages arrhythmia is best illustrated by the use of VF = ventricular fibrillation differed for LQTS and BrS (Central Illustration). quinidine at that time to treat the arrhyth- mias caused by congenital (3) and atrioventricular ACT I: HISTORY OF LQTS block–related (13) LQTS. Only during the following years was QT prolongation by quinidine linked to RECOGNITION OF THE CONGENITAL FORM OF arrhythmia causation (14–16). LQTS. The recognition that QT prolongation might be Other drugs were soon found to display compara- responsible for sudden death emerged in the late ble effects on the QT segment, with similar conse- 1950s, as Jervell and Lange-Nielsen (3) and Levine and quences, making diLQTS a recognized entity. This Woodworth (4) described sudden deaths in children phenomenon became even more intriguing as medi- with congenital deafness. In the affected children, cations with noncardiac indications (naturally as- ECGs showing prolonged QT intervals were docu- sumed to have no cardiac effects) were recognized to mented, although no malignant tachyarrhythmias display proarrhythmic effects. The first was the anti- were captured (3,4). Shortly thereafter, Romano et al. psychotic drug thioridazine (17).Ironically,as (5) and Ward (6) reported additional families with long described earlier, quinidine was used at some point to QT intervals and sudden death but without deafness. treat this new form of diLQTS (17).Themedical None of the original publications included recordings community would have to wait until the 1990s before ’ of the arrhythmias onset, although some in- the mechanism of QT prolongation by noncardiac vestigators had them (Figure 1). Consequently, the drugs would finally be understood. cause-and-effect association between QT prolonga- tion and the risk for sudden death remained unex- UNDERSTANDING QT PROLONGATION. The mecha- ’ plained for years. Although Levine and Woodworth s nism responsible for QT prolongation remained (4) contribution was never acknowledged, the elusive for decades. The observation that syncope Jervell-Lange-Nielsen and Romano-Ward syndromes and in patients with cLQTS are often became recognized as cLQTS with and without deaf- triggered by stress (18) led researchers to believe that ness, respectively. It would take 40 years to explain sympathetic imbalance is responsible for the disease. the deafness component of the syndrome (7).More Animal experiments showing that stimulation of the important, the story of an acquired form of LQTS was left sympathetic ganglion produced QT prolongation developing in parallel, and it would take the same (19) provided credible proof for the “sympathetic amount of time before physicians grasped the inter- imbalance” theory, to the point that in 1971, Moss and play between the congenital and the acquired forms of McDonald (20) performed left sympathectomy in a the disease. woman with severe cLQTS, demonstrating not only diLQTS. In 1964, Selzer and Wray (8) documented dramatic shortening of her QT interval but antiar- polymorphic ventricular tachyarrhythmia as the rhythmic effects as well. We now understand that cause of “quinidine syncope.” Tales of patients inhibition of sympathetic tone prevents arrhythmia treated with quinidine suddenly collapsing, some- triggers in patients with the arrhythmogenic sub- times even dying suddenly, had been around since strate of LQTS. It turned out that left cardiac sympa- the early 1920s (9,10), but the connection between thetic denervation, a procedure conceived for the quinidine and long QT intervals had not been recog- wrong reasons, proved an effective therapeutic mea- nized. Instead, “systemic embolism” or “quinidine sure for LQTS patients refractory or intolerant to 102 Havakuk and Viskin JACC VOL. 67, NO. 1, 2016 History of Long-QT and Brugada Syndromes JANUARY 5/12, 2016:100– 8

FIGURE 1 Initial Reports of the Congenital Long-QT Syndrome

(A) The first electrocardiogram of autosomal-recessive congenital long-QT syndrome (cLQTS) with deafness, published in 1957 by Jervell and Lange-Nielsen (3), and reprinted with permission. (B) The first publication of cLQTS without deafness by Ward (6) in 1964, reprinted with permission. (C) Onset of spontaneous torsades de pointes in the first patient described by Ward. Conor Ward sent us this unpublished trace in 1999 (together with the business card shown here and permission to publish), which is presented here for the first time.

beta-blockers (21). Nevertheless, in those days, the 1 gene. Ironically, this proved to be “the wrong therapeutic effects of sympathectomy reinforced the gene” (25),asHarvey-ras1simplyhappenedtobe misconception of “unbalanced sympathetic in- near the true culprit gene, KCNQ1, which encodes the

nervations.” main component of the IKs potassium channel. As with other familial diseases, the assumption Nevertheless, this formidable work shifted the that a genetic etiology lies at the heart of LQTS was attention of scientists to genes encoding car- held for years (22), although proper technological diomyocyte membrane ion channels. Four years methods were unavailable. Genetic research at the later, 2 reports, appearing only a few pages apart in end of the 1980s focused on the candidate gene thesameissueofCell, established HERG (26) and approach, which relies on physiology-based mecha- SCN5A (27) (encoding a potassium and a sodium nistic hypotheses. In 1988, calcium-channel dys- channel, respectively) as the causes of the second function was proposed as possible etiology for LQTS and third recognized forms of cLQTS. This finally but was also ruled out (23).Then,in1991,afteryears clarified that patients with LQTS have arrhythmo- of meticulous research on 3 large families with LQTS genic prolongation of their action potential (and thus residing in Utah, Keating et al. (24) published a their QT intervals) because of faulty repolarizing probable link between LQTS and a region in chro- currents caused by mutations in genes encoding mosome 11, ultimately pointing to the Harvey-ras specific ion channels located at the myocyte JACC VOL. 67, NO. 1, 2016 Havakuk and Viskin 103 JANUARY 5/12, 2016:100– 8 History of Long-QT and Brugada Syndromes

FIGURE 2 Initial Reports of Brugada Syndrome

(A) First presentation of electrocardiograms nowadays defined as type I Brugada syndrome in 3 ostensibly healthy men with a pattern “resembling ,” followed for years by Osher and published in 1953 (49). (B) Presentation of 6 patients with idiopathic ventricular fibrillation, including 1 with “type-I Brugada-like pattern,” by Martini et al. (50). (C) Description of 8 patients with “right , persistent ST-segment elevation and sudden death” by Pedro and Josep Brugada in 1992 (48), an entity soon to become recognized as Brugada syndrome.

membrane. Research on diLQTS was also influenced by quinidine was due to blockade of the IKr channel. dramatically by these great leaps forward. Thesameyear,Jackmanetal.(31) demonstrated that UNDERSTANDING diLQTS. During the first decades patients with drug-induced TdP were at higher risk after its recognition, diLQTS was considered “idio- for recurrence when exposed to a second offending syncratic,” simply unpredictable, although high-risk drug and that their QT intervals tended to be at the characteristics (older women, patients with heart upper end of the normal range, even before drug failure) had been recognized (28).In1981(11years exposure. This led them to propose an “inborn pre- before the discovery of the genes responsible for disposition” as the etiology for diLQTS (31).The cLQTS), Colatsky (29) demonstrated,inananimal unraveled mechanism of cLQTS (as described earlier) model, that quinidine prolongs the action potential, now served to establish IKr blockade as the cause of even suggesting that suppression of the potassium diLQTS (32).Yetthequestionofwhoisproneto delayed-rectifier current (IKr) was the probable etiol- diLQTS remained unanswered. ogy. In 1988, Roden et al. (30) proved this hypothesis In 1998, Roden (33) wrote a brief editorial, “Taking correct, showing that action potential prolongation the ‘Idio’ out of ‘Idiosyncratic’:PredictingTorsades 104 Havakuk and Viskin JACC VOL. 67, NO. 1, 2016 History of Long-QT and Brugada Syndromes JANUARY 5/12, 2016:100– 8

CENTRAL ILLUSTRATION The History of Long-QT Syndrome and Brugada Syndrome Discovery

1957 1964 1971 Late 1980s 1988 Implantable Long QT Families with Left sympathectomy Genetic Calcium-channel dysfunction proposed as cardioverter reported to be long QT and performed in LQTS research possible etiology for cLQTS, then ruled out defibrillator (ICD) responsible for sudden death, patient showed focused on for patients sudden death but without shortening of QT candidate with recurrent in congenitally deafness, are interval and anti- gene 1991 arrhythmias deaf children reported arrhythmic effects Link between LQTS and gene or high-risk region in chromosome 11 proposed characteristics Beta-blockers

1995 Culprit gene identified as KCNQ1, which encodes for IKs potassium-channel Congenital Long QT syndrome (cLQTS) syndrome QT Congenital Long 1950 1960 1970 1980 1990 2000 Therapies 1988 Action prolongation by quinidine due to IKr channel blockade is documented 1998 No therapy 1981 An "inborn T-wave patterns 1964 1966 Quinidine predisposition" for similar to LQT1, LQT2 Instructions Arrhythmias Similar arrhythmias prolonging diLQTS, unmasked only and LQT3,reproduced to avoid QT- caused by in patients with the action after in lab model subjected prolonging quinidine are atrioventricular potential is challenge exposure, to IKs , IKr and Sodium medications documented block are described documented is proposed (Na)-channel blockers Drug-induced (diLQTS) Drug-induced

1991 1998 Na-channel blockers applied on canine myocardium, 3 mutations in SCN5A ICD produced ST-segment elevation and increased gene (which encodes the dispersion of ventricular repolarization for cardiac Na-channel) Quinidine are identified, pinpointing 1992 Na-channel mutations as the underlying Discovery of inherited form cause of Brs disease of Brugada syndrome Brugada syndrome (BrS) Brugada syndrome 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 Therapies

1996 2000 Referred Mid 1990s Antiarrhythmic is used to block for evaluation First reports drug modulation the Na-channel, creating with ajmaline connecting of ST-segment “a positive ajmaline test” test, that could cocaine use with elevation is to expose typical findings result in ICD BrS with normal documented in of ST elevations in patients Quinidine patients with BrS suspected of having BrS Drug-induced (”unmasked” Brs) (”unmasked” Drug-induced

Havakuk, O. et al. J Am Coll Cardiol. 2016; 67(1):100–8.

Landmark events in the discovery of long QT syndrome and Brugada syndrome. BrS ¼ Brugada syndrome; cLQTS ¼ congenital long-QT syndrome; diLQTS ¼ drug- induced long-QT syndrome; ICD ¼ implantable cardioverter defibrillator; LQT ¼ long QT; LQTS ¼ long-QT syndrome; Na ¼ sodium.

de Pointes,” as a comment on a paper describing diLQTS. According to the principle of reduced repo- electrocardiographic predictors of TdP after almoka- larization reserve, some patients were more prone to lant treatment for atrial fibrillation (34).Thatoriginal drug-induced TdP than others because of additional report on almokalant is no longer remembered, but a factors (including genetic background) that impair term coined in Roden’s accompanying editorial, the repolarization current. Genetic support for this “reduced repolarization reserve,” was soon to be model came from studies showing incomplete pene- quoted in practically all future publications on trance of long-QT genes among members of families JACC VOL. 67, NO. 1, 2016 Havakuk and Viskin 105 JANUARY 5/12, 2016:100– 8 History of Long-QT and Brugada Syndromes

carrying the mutant gene, resulting in seemingly arrhythmias in cLQTS. Treatment of cLQTS was never normal QT intervals that were unmasked only after on the basis of randomized studies. Instead, as early exposure to a repolarization challenge (35,36).The as 1975, Schwartz et al. (18) reviewed all published overlap between congenital and acquired LQTS was cases of cLQTS reported by then, including the finally understood to some extent. empirical treatment they had received. In contrast to EVOLUTION OF DIAGNOSTIC PRINCIPLES AND digoxin (proposed for its QT-shortening effect), INTERPRETATIONS OF CHALLENGE TESTS. Adirect phenobarbital, or hydantoin, beta-blockers effec- result of the identification of genes causing cLQTS tively prevented recurrent arrhythmias (18).Bythe was the realization that some carriers of genetic mu- time the ICD became clinically available, the medical tations had QT intervals within the normal range (37), community knew that the vast majority of patients such that a significant overlap exists between the with cLQTS do well on beta-blockers. It so happened QT intervals of the healthy and the affected pop- that ICD implantation became indicated only for pa- ulations. Consequently, diagnostic tests to distin- tients with LQTS with recurrent arrhythmias while on guish the former from the latter group became beta-blockers, or for a small minority of asymptom- fi imperative. In 1998, Yan and Antzelevitch (38) atic patients with identi able high-risk characteristics reproduced T-wave patterns similar to the proto- (2). Here, too, the evolution of therapeutic ap- typic LQT1, LQT2, and LQT3 in a laboratory model proaches in BrS was different. of canine myocardium subjected to IKs,IKr,and ACTII:HISTORYOFBrS sodium-channel blockers, respectively. Yet the administration of potassium-channel blockers as a BrS: DISCOVERY OF THE INHERITED FORM. In 1992, diagnostic test for cLQTS was scarcely used in clinical Pedro and Josep Brugada (48) described “adistinct practice, because other tests, including the use of clinical and electrocardiographic syndrome of right epinephrine (39,40) and, less commonly, adenosine bundle branch block, persistent ST-elevation and (41), to expose the abnormal response of the QT in- sudden cardiac death” (Figure 2). Similar electrocar- terval to drug-induced changes in heart rate were diographic patterns had been reported decades earlier used. Together with the use of exercise (42) and but considered benign (Figure 2A) (49). In 1989, “ ” quick standing (43) tests, this achieved excellent Martini et al. (50) described comparable ECGs in pa- diagnostic accuracy, limiting the need for drug chal- tients with otherwise “idiopathic VF” (Figure 2B)and lenge tests directly interfering with repolarization. concluded that these patients probably had some Use of IKr blockers to challenge repolarization was form of right ventricular . used primarily to identify patients prone to devel- Yan and Antzelevitch (51) coined the eponym oping diLQTS. For example, Kääb et al. (44) demon- “Brugada syndrome” in a report describing the strated that patients with histories of drug-induced cellular basis of the J waves on the ECG. That the TdP had excessive QT prolongation when challenged Brugada brothers were the only authors of the orig- with intravenous sotalol. Similarly, Kannankeril et al. inal report, combined with the interesting phonetics (45) showed that relatives of patients with diLQTS of “Brugada” and the long title of this newly had excessive QT prolongation after exposure to described entity, probably contributed to its quick quinidine. It was only in 2008 that erythromycin was adoption. In contrast to LQTS, for which it took >30 used to unmask genetically positive long-QT patients years from its first description to identification of the fi with normal QT intervals, marking the rst use of an responsible gene, this process took only 6 years for IKr blocker to diagnose cLQTS (46).TheuseofIKr BrS. In 1998, Chen et al. (52) identified 3 mutations blockers never became common practice for diag- in the SCN5A gene, encoding the alpha subunit of nosing cLQTS. This aspect of history was very the cardiac sodium channel, pointing out sodium- different from the sequence of events leading to the channel mutations as the underlying cause of the use of sodium-channel blockers to diagnose congen- disease. ital BrS. DRUG CHALLENGE TO UNRAVEL BrS. Soon after the EVOLUTION OF THERAPEUTIC APPROACHES. It was initial description of BrS, it became clear that the mainly through the multicenter cooperation gener- distinctive coved ST-segment elevation was not pre- ated by the International Long QT Syndrome Registry sent in affected patients at all times, obviating the (22,47), initiated by Schwartz and Moss, that need for a diagnostic test to expose “concealed BrS” adequate data could be generated for better under- (53,54). A fascinating sequence of events set the standing of the clinical and electrocardiographic background for the use of sodium-channel blockers for (and ultimately genetic) risk factors for malignant unraveling congenital BrS. One year before the first 106 Havakuk and Viskin JACC VOL. 67, NO. 1, 2016 History of Long-QT and Brugada Syndromes JANUARY 5/12, 2016:100– 8

report of BrS (48), Krishnan and Antzelevitch (55) also applied to asymptomatic patients who had their demonstrated that sodium-channel blockers applied BrS “unraveled” by sodium-channel-blocker tests. on canine myocardium produced ST-segment eleva- The DEBUT (Defibrillator Versus b-Blockers for Un- tion by abbreviating action potentials in the epicar- explained Death in Thailand) randomized study, dium more than in the , thus increasing conducted in the 1990s, comparing drug therapy with the dispersion of ventricular repolarization. Miyazaki ICD therapy for BrS with cardiac arrest or malignant et al. (56) astutely noticed that 1 patient with BrS syncope (65), was prematurely stopped because of demonstrated augmented ST-segment elevation when the unacceptably high mortality rate in the medica- treated with disopyramide (a sodium-channel blocker) tion arm. Regrettably, the medication used in the for atrial fibrillation. After discussing this observation “drug arm” of this trial (propranolol) was the with Antzelevitch (T. Miyazaki, personal communi- wrong drug to test. In fact, this beta-blocker with cation, May 2015), Miyazaki challenged 3 patients with sodium-channel-blocker properties is now listed BrS and intermittent ST-segment elevation with dis- among the “drugs to preferably avoid” in BrS (62).By opyramide or procainamide (another sodium-channel the time the DEBUT trial was designed, quinidine had blocker). Aggravation of the Brugada electrocardio- already been successfully used to prevent recurrent graphic pattern immediately occurred in all 3 patients, arrhythmias in idiopathic VF (67,68),andshortlyafter and the observations were published as “Antiar- publication of the DEBUT trial, quinidine was also rhythmic Drug Modulation of ST-Segment Elevation in found to be effective in BrS (69,70). By now, however, Patients With Brugada Syndrome” (56).Thus,when the ICD was already “the only acceptable therapy” for Chen et al. (52) described that SCN5A mutations were BrS (58). As the years passed, accumulating data behindthecongenitalBrS,thestagewassettotest showed that the rates of sudden deaths in patients sodium-channel blockers as a means to unravel with BrS were much lower for the subgroup that was congenital BrS. In 2000, Brugada et al. (57),bynow asymptomatic at the time of diagnosis (71),andthe using ajmaline to block the sodium channel, found therapeutic approach was challenged. Nevertheless, 100% concordance between positive results on an these patients were (and still are) referred for EPS and ajmaline test and the presence of SCN5A mutations may undergo ICD implantation (72). in family members with BrS. Consensus papers embraced the sodium-channel blockers drug chal- ACT III: LOOKING BACK TO UNDERSTAND lenge as a diagnostic criterion for congenital BrS in HOW WE GOT HERE proper clinical context (58). “ DRUG-INDUCED BrS. Suddendeathsincocaineusers History never looks like history when you are ” had been reported for years, but the mechanism was living through it. — poorly understood (59,60) given the drug’smyriad John W. Gardner (73) effects, including vasoactive effects, in addition to The therapeutic approach to asymptomatic patients fi sodium-channel-blocking activity. The rst reports radically differs between BrS and LQTS. This is due in connecting cocaine use with BrS arrived in the part to the less forgiving course of BrS; only a mi- mid-1990s, describing coved ST-segment elevation in nority of patients with BrS will develop arrhythmias, young patients with normal coronary arteries, now but for those who do, cardiac arrest is often the pre- “ ” interpreted as unmasked BrS (61).Othercardiac senting symptom (74). In contrast, in LQTS, patients and noncardiac drugs were soon found to display a with cardiac arrest often have warning symptoms in similar drug-induced BrS (62). the form of syncope, or identifiable high-risk charac- THERAPEUTIC APPROACH FOR BrS. The first reports teristics, such as a very long QT interval (75).Also,the on BrS portrayed an alarming picture for asymptom- safety profile in terms of adverse events is better for atic patients recognized because of their ECGs. beta-blockers than for quinidine. Young, ostensibly healthy men with this peculiar However, history also appears to have influenced electrocardiographic pattern were considered at risk the way these patients are treated. By 2006, one-half for impending doom, as cardiac arrest rates for of the ICD implantations performed in Europe for BrS initially asymptomatic patients appeared to be as were in completely asymptomatic patients. More- high as 10% per year (63). Given the contemporary over, the most common indication for ICD implanta- availability of ICDs, it seemed logical to advise such tion in the asymptomatic group was a “positive asymptomatic patients (if they had inducible VF ajmaline test with positive EPS” (76). Sure enough, at during EPS) to undergo ICD implantation (64,65).As 3 years of follow-up, only 1.6% of the initially discussed in detail (66), these recommendations were asymptomatic patients who had type I Brugada ECGs JACC VOL. 67, NO. 1, 2016 Havakuk and Viskin 107 JANUARY 5/12, 2016:100– 8 History of Long-QT and Brugada Syndromes

revealed by the ajmaline test had experienced spon- unthinkable to most of us. To understand how we taneous VF, whereas 31% had serious ICD-related ended up with so many ICDs in asymptomatic pa- complications (76). Publication of these numbers tients with drug-exposed Brugada ECGs, we ought to eventually led to a more conservative approach, and look back at how the understanding of LQTS and BrS nowadays, the proportion of ICD implantations for evolved over the years. asymptomatic BrS, particularly that “revealed by drugs,” is decreasing, at least in academic institutions REPRINT REQUESTS AND CORRESPONDENCE: Dr. (72).Prophylacticdefibrillator implantation for Sami Viskin, Tel Aviv Medical Center, Department of asymptomatic patients who develop long QT in- Cardiology, Weizman 16, Tel Aviv 64239, Israel. tervals when challenged by medications would be E-mail: [email protected].

REFERENCES

1. Lane RW. Give Me Liberty. Caldwell, IA: Caxton established atrioventricular dissociation. Am Heart mutations cause long QT syndrome. Cell 1995;80: Printers, 1954:48. J 1953;45:404–15. 795–803.

2. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/ 14. Motte G, Coumel P, Abitbol G, et al. The long 27. Wang Q, Shen J, Splawski I, et al. SCN5A APHRS expert consensus statement on the diagnosis QT syndrome and syncope caused by spike tor- mutations associated with an inherited cardiac and management of patients with inherited primary sades [in French]. Arch Mal Coeur Vaiss 1970;63: arrhythmia, long QT syndrome. Cell 1995;80: arrhythmia syndromes: document endorsed by HRS, 831–53. 805–11. EHRA, and APHRS in May 2013 and by ACCF, AHA, 15. Raynaud R, Brochier M, Néel JL, et al. Ven- 28. Kay GN, Plumb VJ, Arciniegas JG, et al. PACES, and AEPC in June 2013. Heart Rhythm 2013; tricular with variable focus and dys- Torsade de pointes: the long-short initiating 10:1932–63. kaliemia [in French]. Arch Mal Coeur Vaiss 1969; sequence and other clinical features: observations 3. Jervell A, Lange-Nielsen F. Congenital deaf- 62:1578–98. in 32 patients. J Am Coll Cardiol 1983;2:806–17. mutism, functional heart disease with prolonga- 16. Krikler DM, Curry PV. Torsade de pointes, an 29. Colatsky TJ. Mechanisms of action of lidocaine tion of the Q-T interval and sudden death. Am atypical . Br Heart J 1976; and quinidine on action potential duration in rabbit Heart J 1957;54:59–68. 38:117–20. cardiac Purkinje fibers. An effect on steady state – 4. Levine SA, Woodworth CR. Congenital deaf- 17. Schoonmaker FW, Osteen RT, Greenfield JC Jr. sodium currents? Circ Res 1982;50:17 27. mutism, prolonged QT interval, syncopal attacks Thioridazine (mellaril)-induced ventricular tachy- 30. Roden DM, Bennett PB, Snyders DJ, et al. and sudden death. N Engl J Med 1958;259:412–7. cardia controlled with an artificial pacemaker. Ann Quinidine delays IK activation in guinea pig ven- 5. Romano C, Gemme G, Pongiglione R. Rare car- Intern Med 1966;65:1076–8. tricular myocytes. Circ Res 1988;62:1055–8. diac arrhythmias of the pediatric age. II. Syncopal 18. Schwartz PJ, Periti M, Malliani A. The long Q-T 31. Jackman WM, Friday KJ, Anderson JL, et al. attacks due to paroxysmal ventricular fibrillation. syndrome. Am Heart J 1975;89:378–90. The long QT syndromes: a critical review, new (Presentation of 1st case in Italian pediatric liter- 19. Yanowitz F, Preston JB, Abildskov JA. Func- clinical observations and a unifying hypothesis. ature) [in Italian]. Clin Pediatr (Bologna) 1963;45: – tional distribution of right and left stellate inner- Prog Cardiovasc Dis 1988;31:115 72. 656–83. vation to the ventricles. Production of neurogenic 32. Sanguinetti MC, Jiang C, Curran ME, et al. 6. Ward OC. A new familial cardiac syndrome in electrocardiographic changes by alteration of A mechanistic link between an inherited and an – children. J Ir Med Assoc 1964;54:103 6. sympathetic tone. Circ Res 1966;18:416–28. acquired cardiac arrhythmia: HERG encodes the IKr – 7. Neyroud N, Tesson F, Denjoy I, et al. A novel 20. Moss AJ, McDonald J. Unilateral cervico- potassium channel. Cell 1995;81:299 307. mutation in the potassium channel gene KVLQT1 thoracic sympathetic ganglionectomy for the 33. Roden DM. Taking the “idio” out of “idiosyn- causes the Jervell and Lange-Nielsen car- treatment of long QT interval syndrome. N Engl J cratic”: predicting torsades de pointes. Pacing Clin dioauditory syndrome. Nat Genet 1997;15:186–9. – Med 1971;285:903 4. Electrophysiol 1998;21:1029–34. 8. Selzer A, Wray HW. Quinidine syncope. Parox- 21. Schwartz PJ, Locati EH, Moss A, et al. Left 34. Houltz B, Darpö B, Edvardsson N, et al. Elec- ysmal ventricular fibrillation occurring during cardiac sympathetic denervation in the therapy of trocardiographic and clinical predictors of torsades treatment of chronic atrial arrhythmias. Circulation congenital long QT syndrome. A worldwide report. de pointes induced by almokalant infusion in pa- 1964;30:17–26. – Circulation 1991;84:503 11. tients with chronic atrial fibrillation or flutter: a 9. Levy RL. Clinical studies of quinidine. IV. The 22. Moss AJ, Schwartz PJ, Crampton RS, et al. The prospective study. Pacing Clin Electrophysiol clinical toxicology of quinidine. JAMA 1922;79: long QT syndrome: a prospective international 1998;21:1044–57. 1108–13. – study. Circulation 1985;71:17 21. 35. Abbott GW, Sesti F, Splawski I, et al. MiRP1

10. Kerr WJ, Bender WL. Paroxysmal ventricular 23. Weinstein LS, Spiegel AM, Carter AD. Cloning forms IKr potassium channels with HERG and is fibrillation with cardiac recovery in a case of atrial and characterization of the human gene for the associated with cardiac arrhythmia. Cell 1999;97: fibrillation with complete heart-block while under a-subunit of Gi2, a GTP-binding signal trans- 175–87. quinidine sulphate therapy. Heart 1922;9:269–81. – duction protein. FEBS Lett 1988;232:333 40. 36. Donger C, Denjoy I, Berthet M, et al. KVLQT1 11. Thomson GW. Quinidine as a cause of sudden 24. Keating M, Atkinson D, Dunn C, et al. Linkage C-terminal missense mutation causes a forme death. Circulation 1956;14:757–65. of a cardiac arrhythmia, the long QT syndrome, fruste long-QT syndrome. Circulation 1997;96: and the Harvey ras-1 gene. Science 1991;252: 2778–81. 12. Dessertenne F. Ventricular tachycardia with 2 704–6. variable opposing foci [in French]. Arch Mal Coeur 37. Vincent GM, Timothy KW, Leppert M, et al. The Vaiss 1966;59:263–72. 25. Curran M, Atkinson D, Timothy K, et al. Locus spectrum of symptoms and QT intervals in carriers heterogeneity of autosomal dominant long QT of the gene for the long-QT syndrome. N Engl J 13. Schwartz SP, Margolies MP, Firenze A. Tran- syndrome. J Clin Invest 1993;92:799–803. Med 1992;327:846–52. sient ventricular fibrillation. V. The effects of the oral administration of quinidine sulphate on pa- 26. Curran ME, Splawski I, Timothy KW, et al. 38. Yan GX, Antzelevitch C. Cellular basis for tients with transient ventricular fibrillation during A molecular basis for cardiac arrhythmia: HERG the normal and the electrocardiographic 108 Havakuk and Viskin JACC VOL. 67, NO. 1, 2016 History of Long-QT and Brugada Syndromes JANUARY 5/12, 2016:100– 8

manifestations of the long-QT syndrome. Circula- description of six cases. Am Heart J 1989;118: leads V1 through V3: a marker for sudden death in tion 1998;98:1928–36. 1203–9. patients without demonstrable structural heart disease. Circulation 1998;97:457–60. 39. Shimizu W, Noda T, Takaki H, et al. Epineph- 51. Yan GX, Antzelevitch C. Cellular basis for the rine unmasks latent mutation carriers with LQT1 electrocardiographic J wave. Circulation 1996;93: 64. Brugada J, Brugada R, Brugada P. Pharmaco- form of congenital long-QT syndrome. J Am Coll 372–9. logical and device approach to therapy of inheri- Cardiol 2003;41:633–42. ted cardiac diseases associated with cardiac 52. Chen Q, Kirsch GE, Zhang D, et al. Genetic arrhythmias and sudden death. J Electrocardiol 40. Ackerman MJ, Khositseth A, Tester DJ, et al. basis and molecular mechanism for idiopathic 2000;33 Suppl:41–7. Epinephrine-induced QT interval prolongation: a ventricular fibrillation. Nature 1998;392:293–6. fi 65. Nademanee K, Veerakul G, Mower M, et al. gene-speci c paradoxical response in congenital 53. Sumiyoshi M, Nakata Y, Hisaoka T, et al. A case Defibrillator Versus b-Blockers for Unexplained long QT syndrome. Mayo Clin Proc 2002;77: of idiopathic ventricular fibrillation with incom- – Death in Thailand (DEBUT): a randomized clinical 413 21. plete right bundle branch block and persistent ST trial. Circulation 2003;107:2221–6. 41. Viskin S, Rosso R, Rogowski O, et al. Provo- segment elevation. Jpn Heart J 1993;34:661–6. 66. Viskin S, Rosso R, Friedensohn L, et al. cation of sudden heart rate oscillation with aden- 54. Bjerregaard P, Gussak I, Kotar SL, et al. Everybody has Brugada syndrome until proven osine exposes abnormal QT responses in patients Recurrent syncope in a patient with prominent J otherwise? Heart Rhythm 2015;12:1595–8. with long QT syndrome: a bedside test for diag- wave. Am Heart J 1994;127:1426–30. nosing long QT syndrome. Eur Heart J 2006;27: 67. Belhassen B, Shapira I, Shoshani D, et al. – 55. Krishnan SC, Antzelevitch C. Sodium channel 469 75. Idiopathic ventricular fibrillation: inducibility and block produces opposite electrophysiological ef- beneficial effects of class I antiarrhythmic agents. 42. Krahn AD, Klein GJ, Yee R. Hysteresis of the RT fects in canine ventricular epicardium and endo- Circulation 1987;75:809–16. interval with exercise: a new marker for the long- cardium. Circ Res 1991;69:277–91. – QT syndrome? Circulation 1997;96:1551 6. 68. Viskin S, Belhassen B. Idiopathic ventricular 56. Miyazaki T, Mitamura H, Miyoshi S, et al. fibrillation. Am Heart J 1990;120:661–71. 43. Viskin S, Postema PG, Bhuiyan ZA, et al. The Autonomic and antiarrhythmic drug modulation of response of the QT interval to the brief tachy- ST segment elevation in patients with Brugada 69. Belhassen B, Glick A, Viskin S. Efficacy of cardia provoked by standing: a bedside test for syndrome. J Am Coll Cardiol 1996;27:1061–70. quinidine in high-risk patients with Brugada syn- diagnosing long QT syndrome. J Am Coll Cardiol drome. Circulation 2004;110:1731–7. 57. Brugada R, Brugada J, Antzelevitch C, et al. 2010;55:1955–61. Sodium channel blockers identify risk for sudden 70. Hermida JS, Denjoy I, Clerc J, et al. Hydro- 44. Kääb S, Hinterseer M, Näbauer M, et al. death in patients with ST-segment elevation and quinidine therapy in Brugada syndrome. J Am Coll Sotalol testing unmasks altered repolarization in right bundle branch block but structurally normal Cardiol 2004;43:1853–60. patients with suspected acquired long-QT- hearts. Circulation 2000;101:510–5. 71. Viskin S, Rogowski O. Asymptomatic Brugada syndrome—a case-control pilot study using i.v. 58. Antzelevitch C, Brugada P, Borggrefe M, et al. syndrome: a cardiac ticking time-bomb? Europace sotalol. Eur Heart J 2003;24:649–57. Brugada syndrome: report of the second consensus 2007;9:707–10. 45. Kannankeril PJ, Roden DM, Norris KJ, et al. conference. Heart Rhythm 2005;2:429–40. 72. Sacher F, Probst V, Maury P, et al. Outcome Genetic susceptibility to acquired long QT syn- 59. Brody SL, Slovis CM, Wrenn KD. Cocaine- after implantation of a cardioverter-defibrillator in drome: pharmacologic challenge in first-degree related medical problems: consecutive series of patients with Brugada syndrome: a multicenter relatives. Heart Rhythm 2005;2:134–40. 233 patients. Am J Med 1990;88:325–31. study-part 2. Circulation 2013;128:1739–47. 46. Jeyaraj D, Abernethy DP, Natarajan RN, et al. 60. Escobedo LG, Ruttenber AJ, Agocs MM, et al. 73. Priori SG, Napolitano C, Gasparini M, et al. I channel blockade to unmask occult congenital Kr Emerging patterns of cocaine use and the Natural history of Brugada syndrome: insights for long QT syndrome. Heart Rhythm 2008;5:2–7. epidemic of cocaine overdose deaths in Dade risk stratification and management. Circulation 47. Schwartz PJ. The idiopathic long QT syn- County, Florida. Arch Pathol Lab Med 1991;115: 2002;105:1342–7. drome: the need for a prospective registry. Eur 900–5. 74. Goldenberg I, Moss AJ. Long QT syndrome. Heart J 1983;4:529–31. 61. Bauman JL, Grawe JJ, Winecoff AP, et al. J Am Coll Cardiol 2008;51:2291–300. 48. Brugada P, Brugada J. Right bundle branch Cocaine-related sudden cardiac death: a hypoth- 75. Sacher F, Probst V, Iesaka Y, et al. Outcome block, persistent ST segment elevation and sud- esis correlating basic science and clinical obser- after implantation of a cardioverter-defibrillator in den cardiac death: a distinct clinical and electro- vations. J Clin Pharmacol 1994;34:902–11. patients with Brugada syndrome: a multicenter cardiographic syndrome. A multicenter report. 62. Postema PG, Wolpert C, Amin AS, et al. Drugs study. Circulation 2006;114:2317–24. J Am Coll Cardiol 1992;20:1391–6. and Brugada syndrome patients: review of the 76. Tripp RT. The International Thesaurus of 49. Osher HL, Wolff L. Electrocardiographic literature, recommendations, and an up-to-date Quotations. New York, NY: Crowell, 1970:280. pattern simulating acute myocardial injury. Am J website (http://www.brugadadrugs.org). Heart Med Sci 1953;226:541–5. Rhythm 2009;6:1335–41.

50. Martini B, Nava A, Thiene G, et al. Ven- 63. Brugada J, Brugada R, Brugada P. Right KEY WORDS electrocardiogram, history, tricular fibrillation without apparent heart disease: bundle-branch block and ST-segment elevation in ventricular fibrillation