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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 Brugada Syndrome 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 arrhythmias. 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 torsades de pointes (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 arrhythmia 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 arrhythmias 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 prolongation 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 cardiac arrest 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

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