EBM Presentation: Brugada Syndrome and

LQTS27 Feb 2015

Koh Choong HouSupervisor: Colin Yeo

Scope• Brugada Syndrome

• Diagnosis

• Risk Stratification

• Management

• Long QT Syndrome

• Diagnosis

• Risk Stratification

• Management

Brugada Syndrome

Brugada P, Brugada J. A distinct clinical and electrocardiographic syndrome: right bundle branch block, persistent ST segment elevation with normal QT interval and sudden cardiac death (abstr) PACE. 1991;14:746.

• Type 1 is diagnostic of Brugada syndrome and is characterized by a coved ST-segment elevation >/=2 mm (0.2 mV) followed by a negative T wave. Brugada syndrome is definitively diagnosed when a type 1 ST-segment elevation is observed in 1 right precordial lead (V1 to V3) in the presence or absence of a sodium channel– blocking agent, and in conjunction with one of the following: documented ventricular fibrillation (VF), polymorphic ventricular tachycardia (VT), a family history of sudden cardiac death at <45 years old, coved-type ECGs in family members, inducibility of VT with programmed electrical stimulation, syncope, or nocturnal agonal respiration.

• Confounding factors for ECG abnormality or syncope should be excluded:

1. Atypical RBBB, LVH, early repolarization, acute pericarditis, AMI, pulmonary embolism, Prinzmetal angina, dissecting aortic aneurysm, various central and autonomic nervous system abnormalities, Duchenne muscular dystrophy, thiamin deficiency, hyperkalemia, hypercalcemia, ARVC, pectus excavatum, hypothermia, and mechanical compression of RVOT as occurs in mediastinal tumor or hemopericardium

Diagnosis of BrS

Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference. Heart Rhythm 2005;2:429–440.

BrS Supporting Features

• Attenuation of ST-segment elevation at peak of exercise stress test followed by its appearance during recovery phase.

• Presence of AF

• Fragmented QRS

• ST-T alternans, spontaneous LBBB VPBs during prolonged ECG monitoring

• V-ERP < 200ms during EPS, and HV interval > 60ms

• Signal average ECG: late potentials

• 1st degree AVB, left axis deviation

• Absence of structural heart disease including myocardial ischaemia

Morita H, Kusano KF, Miura D, et al. Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome. Circulation 2008;118:1697–1704.

Date of download: 2/7/2015

Copyright © The American College of Cardiology. All rights reserved.

From: Augmented ST-Segment Elevation During Recovery From Exercise Predicts Cardiac Events in Patients With Brugada Syndrome

J Am Coll Cardiol. 2010;56(19):1576-1584. doi:10.1016/j.jacc.2010.06.033

Typical Responses of ST-Segment Amplitude in Leads V1, V2, V3, and V5 During Exercise Testing in Brugada Syndrome Patients (A) In the group 1 Brugada patient showing saddle-back type ST-segment (lead V2) at baseline, ST-segment amplitude slightly decreased at peak exercise, but reascended at early recovery (3 min), resulting in typical coved-type ST-segment elevation. (B, C) In the group 2 Brugada patient and (D) in the control subject, ST-segment amplitude decreased at peak exercise and gradually recovered to the baseline at recovery. It is noteworthy that the peak J-point amplitude in lead V2 was augmented despite not showing ST-segment augmentation in A and C. The ST-segment amplitudes are shown as numeric values expressed in millivolts (mV). The red vertical line indicates the line from the end point of the QRS interval at electrocardiography lead V5.

Figure Legend:

Risk stratification: Augmented ST-Elevation During Recovery From Exercise

Makimoto H, Nakagawa E, Takaki H, et al. Augmented ST-segment elevation during recovery from exercise predicts cardiac events in patients with Brugada syndrome. J Am Coll Cardiol 2010;56:1576–1584.

Date of download: 2/7/2015

Copyright © The American College of Cardiology. All rights reserved.

From: Augmented ST-Segment Elevation During Recovery From Exercise Predicts Cardiac Events in Patients With Brugada Syndrome

J Am Coll Cardiol. 2010;56(19):1576-1584. doi:10.1016/j.jacc.2010.06.033

Kaplan-Meier Analysis of Cardiac Events During Follow-Up Kaplan-Meier analysis of (A) cardiac events during follow-up, depending on patterns in response to ST-segment elevation during exercise test (groups 1 and 2), (B) incidence of previous episode of ventricular fibrillation (VF), (C)SCN5A mutation, and (D) spontaneous coved-type ST-segment elevation. Group 1 Brugada patients had a significantly higher cardiac event rate than did group 2 Brugada patients (log-rank, p = 0.0029). Brugada patients with previous episodes of VF or with SCN5A mutation had significantly greater values for occurrence of subsequent cardiac events than did patients without VF episodes or SCN5A mutation (p = 0.0013, p = 0.028, respectively), whereas spontaneous coved-type ST-segment elevation in Brugada patients did not predict cardiac events compared with patients not having such ST-segment elevation (p = 0.068).

Figure Legend:

Augmented ST-Elevation During Recovery From Exercise

Risk stratification: SAECG late potentials

Ikeda T, Sakurada H, Sakabe K, et al. Assessment of noninvasive markers in identifying patients at risk in the Brugada syndrome: insight into risk stratification. J Am Coll Cardiol 2001;37:1628–1634.

Risk Stratification: spont type 1 ECG +/- syncope

Priori SG, Napolitano C, Gasparini M, et al. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation 2002;105: 1342–1347.

Risk stratification: QRS-fragmentation vs VT/VF inducibility

Priori SG, Gasparini M, Napolitano C, et al. Risk stratification in Brugada syndrome: results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) registry. J Am Coll Cardiol 2012;59:37–45.

Management of BrS

• Pharmacological Options

1. Quinidine

2. Isoprenaline

• RFA

ICDs not indicated in asymptomatic low risk group

Mizusawa Y, Wilde AA. Brugada syndrome. Circ Arrhythm Electrophysiol 2012;5:606–616.

Kaplan–Meier curve of inappropriate shock depending on the period of implantation.

Sacher F et al. Circulation. 2013;128:1739-1747

Copyright © American Heart Association, Inc. All rights reserved.

BrS Pharmacological Rx

• BrS pathophysiological basis: gain of function of Ito or Ik , or loss of function of INa or ICa

• Isoprenaline, which increases the L-type calcium current, has proven to be useful for treatment of electrical storm in BrS (but controlled data on its therapeutic role is not available)

• Quinidine, a class IA anti arrhythmic with Ito or IKr blocking effects, shown to prevent VF induction and suppress spontaneous ventricular arrhythmias in a clinical setting. Currently used for:

1. Pts with ICD and multiple shocks

2. ICD contraindicated

3. Rx of supra ventricular arrhythmias

Maury P, Hocini M, Haissaguerre M. Electrical storms in Brugada syndrome: review of pharmacologic and ablative therapeutic options. Indian Pacing Electro- physiol J 2005;5:25–34.

Marquez MF, Bonny A, Hernandez-Castillo E, et al. Long-term efficacy of low doses of quinidine on malignant arrhythmias in Brugada syndrome with an implantable cardioverter-defibrillator: a case series and literature review. Heart Rhythm 2012;9:1995–2000.

RFA in BrS

Nademanee K, Veerakul G, Chandanamattha P, et al. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation 2011;123:1270–1279.

A delayed effect of epicardial ablation on the ECG pattern.

Left lateral view of the right ventricular outflow tract (RVOT) displays the

difference in ventricular electrograms between the endocardial (ENDO) and

epicardial (EPI) site of the anterior RVOT.

Long QT Syndrome

Curran ME, Splawski I, Timothy KW, et al. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995;80:795–803. Wang Q, Shen J, Splawski I, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805–811.

Schwartz PJ, Periti M, Malliani A. The long Q-T syndrome. Am Heart J 1975;89: 378-90.Moss AJ, Schwartz PJ, Crampton RS, Locati E, Carleen E. The long QT syn- drome: a prospective international study. Circulation 1985;71:17-21.

Diagnosis of LQTS

Diagnosis of LQTS is still based on measurement of QT internal corrected for HR (QTc) using Bazett’s formula. Need to exclude secondary causes of QTc prolongation (drugs, electrolyte imbalances etc)

Schwartz Score

Text

QTc calculated by Bazett’s formula. Resting HR < 2nd percentile for age. Definite LQTS if score more than 3.

Schwartz PJ, Moss AJ, Vincent GM, et al. Diagnostic criteria for the long QT syndrome. An update. Circulation 1993;88:782–784.

Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: do we need a scoring system? Nynke Hofman , Arthur A.M. Wilde , Stefan Kääb , Irene M. van Langen , Michael W.T. Tanck , Marcel M.A.M. Mannens , Martin Hinterseer , Britt-Maria Beckmann , Hanno L. Tan. Eur Heart Journal Nov 2006.

Risk stratification

• Specific genetic variants: Jervell Lange-Nielsen syndrome, Timothy syndrome (LQT8)

• Mutations in loops of LQT1

• LQT1 mutations with dominant negative ion current effects

• Mutations in pore region of LQT2

Schwartz PJ, Spazzolini C, Crotti L, et al. The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome. Circulation 2006;113:783–790.

Splawski I, Timothy KW, Sharpe LM, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004;119:19–31.

Barsheshet A, Goldenberg I, O-Uchi J, et al. Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to beta-blocker therapy in type 1 long-QT syndrome. Circulation 2012;125:1988–1996.

Migdalovich D, Moss AJ, Lopes CM, et al. Mutation and gender-specific risk in type 2 long QT syndrome: implications for risk stratification for life-threatening cardiac events in patients with long QT syndrome. Heart Rhythm 2011;8: 1537–1543.

Moss AJ, Zareba W, Kaufman ES, et al. Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go- related gene potassium channel. Circulation 2002;105:794–799.

Risk stratification: QTc duration > 500ms

Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003;348:1866–1874.

Risk stratification: Syncope / childhood SCA

Priori SG, Napolitano C, Schwartz PJ, et al. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA 2004;292:1341–1344.

Management of LQTS

• Lifestyle modifications: avoidance of strenuous exercise, esp swimming, without supervision in LQT1 puts

• Reduction in exposure to abrupt loud noises in LQT2

• Avoidance of all QT-prolonging drugs

• Beta blockers

• ICD implantation

• Left cardiac sympathetic denervation

• Class I antiarrhythmics (mexiletine, flecainide)1. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the

Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114: e385–e484.

Beta blockers in LQTS

Priori SG, Napolitano C, Schwartz PJ, et al. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA 2004;292:1341–1344.

Schwartz PJ, Spazzolini C, Crotti L. All LQT3 patients need an ICD: true or false? Heart Rhythm 2009;6:113–120. J Am Coll Cardiol. 2014;64(13):1352-1358. doi:10.1016/j.jacc.2014.05.068

ICD therapy in LQTS: arrhythmic events despite BBs

Jons C, Moss AJ, Goldenberg I, et al. Risk of fatal arrhythmic events in long QT syndrome patients after syncope. J Am Coll Cardiol 2010;55:783–788.

Schwartz PJ, Spazzolini C, Priori SG, et al. Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them?: data from the European Long-QT Syndrome Implantable Cardioverter- Defibrillator (LQTS ICD) Registry. Circulation 2010;122:1272–1282.

Schwartz PJ, Priori SG, Cerrone M, et al. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation 2004;109:1826–1833.

A word on ICDs and an “incurable” disease