Lesson Ninety-one Drug-induced fatal arrhythmias:Acquired Brugada syndromes

Current concept of Brugada syndrome

Brugada syndrome（BrS）is recognized by the characteristic coved-type ST elevations（denoted as type 1）in right precordial leads in the absence of structural heart disease.Fig.1 depicts typical ECG features induced by pilsicainide tolerance test.According to the J-Wave Syndromes Expert Consensus Report published in 2016,BrS is diagnosed by the following criteria:

1.In patients with spontaneous type 1 ST-segment elevation of 2 mm or more in at least one lead among leads V1-V3,positioned in the 2nd,3rd or 4th intercostal space;or,

2.In patientswith drug-induced type 1 ST-segment elevation of 2 mm or more in at least one lead among leads V1-V3,positioned in the 2nd,3rd or 4th intercostal space and at least one of the following:（i） unexplained sudden cardiac death （SCD） or documented ventricular fibrillation（VF）/polymorphic ventricular tachycardia （VT）, （ii） nocturnal agonal respirations,（iii）syncope of probable arrhythmic cause,（iv）first or second degree relative with definite BrS.

In 1992,BrS was presented as a genetic disorder showing familial aggregation that was associated with a characteristic ECG pattern and sudden cardiac death secondary to polymorphic VT or VF.Mechanisms behind creation of macroscopic arrhythmias by cellular currentchangesremain controversial.Mainly two hypotheses,based on repolarization or depolarization changes,have been proposed and might be acting alone orin conjunction.The firsthypothesis proposes amplification of the inherent differences in repolarization patterns ofthe differentlayers of myocardium which is commonly referred to as the spatial dispersion of repolarization（SDR）.Transient outward current（Ito） is the most important current ascribed to SDR.It is present in the epicardial cells and M cells,but not in the innermost of the three myocardial layers,the endocardium （Fig.2A）.Moreover,in the right ventricle,Ito is of nearly three fold magnitude compared to the left ventricle which is behind the arrhythmogenesis of right ventricular origin in BrS.

Fig.1 Pilsicainide-induced Brugada pattern ECG changes:the left panel shows baseline precordial leads and the right panel shows the same after intravenous injection of pilsicainide（0.8mg/kg）

Transmuralvoltage difference in phase 1 repolarization caused by heterogeneous expression ofIto between endocardium and epicardium explains the abnormal J point elevation seen in BrS（Fig.2B）.Ito prominence subjects cells to all-or-none repolarization once the nadir of action potentials（AP）phase 1 reaches below the activation threshold of L-type calcium channels resulting in loss of the AP dome and shortening of the AP duration （Fig.2C）.This is contributed by certain pathophysiologic conditions and drug interventions that decrease depolarizing currents.Heterogeneous loss of the AP dome in the epicardium results in epicardial dispersion of repolarization and contributes more to the inherent transmural heterogeneity.When the dome of AP is lost in epicardial cells,but not in endocardial cells,a transmural voltage gradient between endocardium and epicardium occurs,showing itselfas the characteristic ST segment elevations inscribed on the ECG.

Progression of currents,within the epicardium or transmurally,from areas where phase 2 is preserved to those where it is lost,cause short coupled re-excitations named phase 2 re-entry which provides the trigger for VT and VF seen in BrS（Fig.2D）.This hypothesis is also supported by the ECG response of BrS patients to autonomic changes,i.e.parasympathetic activation induced increase inIto and/or decrease inICa attenuate the spike and dome pattern of the AP increasing the dispersion of repolarization and accentuating the ST elevation seen on ECG.

A second hypothesis for development of arrhythmias in BrS proposes slowing of depolarization and conduction by fibrosis and decreasedINa in right ventricular outflow tract（RVOT） as the primary mechanism.Relatively delayed depolarization in RVOT with respect to other sites of RV creates regional potential differences that ascribe itself as the ST-segment elevation seen on the right precordial leads.

Fig.2 Dispersion ofrepolarization and phase2 reentry hypothesis in Brugada syndrome:A）Ito is themain current responsible for the phase 1 of the AP and is absent in endocardial cells.B）Transmural voltage difference in phase 1 repolarization caused by heterogeneous expression of Ito between endocardium and epicardium explains the abnormalJ point elevation seen in J wave syndromes. C）Ito prominence and/or decrease in inward sodium or calcium currents in BrS subject cells to all-or-none repolarization once the nadir of AP phase 1 reaches belowthe activation threshold ofL-type calcium channels thereby resulting in loss of the AP dome and shortening of the AP duration.D）Progression of currents,within the epicardiumor transmurally,from areas where phase 2 is preserved to those where it is lost cause short coupled re-excitations named phase 2 re-entry which provides the trigger for VT and VF seen in BrS.

Drug-induced Brugada syndrome

In biologically predisposed patients,environmental factors could modulate the observed phenotype.Autonomic changes,hormonal changes,alcohol,fever,and medications can turn a normal ECG to a BrS ECG.Several studies reported that exercise,atropine and isoproterenol infusion could normalize a BrS ECG,whereas muscarinic and selective α-adrenoceptor stimulation,through reflexvagalactivation,could augment the ST elevation.This also explains the propensity of VT/VF episodes during night time in BrS.Similarly,while targeting sympathetic activity via left cardiac sympathetic denervation is a widely accepted therapy for intractable long QT syndrome,it may increase arrhythmias in BrS.Several studies reported successful prevention of intractable episodes of VF in BrS using phosphodiesterase inhibitors,milrinone and cilostazol.These drugs elevate cyclic AMP levels in the cell and increase L-type calcium current（ICa）,thereby restoring the epicardial AP dome.

Fever has long been recognized as a risk factor for arrhythmias seen in BrS.Some SCN5A mutations cause alteration in sodium channel kinetics only at high temperatures.Other studies have suggested that sensibility to fever may not be due to mutations,but due to temperature-dependent properties of the wild-type SCN5A orIto,as well as fever induced facilitation of spontaneous activity in RVOT and Purkinje fibers.

As can be summarized from above discussions,any drug that would decreaseINa orICa or increaseIto would be arrhythmogenic in BrS.According to their mechanism of action,these drugs can be classified into three major groups:

Sodium channel blockers

The amplitude ofINa underlies the maximum positive membrane potential reached at the end of AP phase 0.IfINa is diminished,then AP phase 1 starts at lower membrane potential and ends at more negative potentials.The balance of inward and outward currents at the end of phase 1 determines whether or notICa can overcome the outward currents and induce formation of the AP dome.Since endocardium and epicardium have different responses toINa blocking agents,they cause transmural heterogeneity in the formation of the AP dome.Class IA and IC antiarrhythmic agents are therefore utilized in unmasking the BrS phenotype.

Tricyclic antidepressants（amitriptyline,desimipramine,nortriptyline,clomipramine,imipramine）and tetracyclicantidepressants（maprotiline）,viatheirsodium channel blocking effects,are known to precipitate Brugada type ECG by diminishing the net inward current at the end of phase 1 AP.

Neuroleptic drug class phenothiazines（chlorpromazine,trifluoperazine,cyamemazine,perphenazine）,haloperidol and loxapine can induce BrS type ECG via sodium channel blocking properties.

SSRIs,particularly fluoxetine,have sodium and calcium channel blocking properties in mammalian ventricular myocytes and have been shown to induce BrS type ECG.Another SSRI,citalopram,has been found to inhibit activation ofINa as well.Other SSRIs,fluvoxamine and paroxetine are also reported to unmask BrS ECG.

Antihistaminic drug,terfenadine,which has bothINa andICa blocking properties was shown to be more effective in provoking VT thanINa blockers alone in canine models of ventricular wedge preparations.Among sodium channel blocking agents those with potentIto blocking effects are less likely（flecainide and disopyramide）or even not likely（quinidine）to induce arrhythmogenesis.Lithium,cocaine,cannabis,alcohol and anesthetic agents（propofol,bupivacaine,ketamine）also unmask BrS phenotype by decreasingINa.Even though methadone is better known for its association with drug-induced long QT Syndrome,it has also been reported to induce BrS ECG.Another synthetic opioid tramadol which blocks neuronal sodium channels is also reported to unmask BrS type ECG.Many antiepileptic medications assert their affect via blockage of the neuronal sodium channels.Some of these have also been shown to alter cardiac sodium channel kinetics,while some are yet to be shown to do so.

Patients who develop a syncopal episode and found in a"postictal state"1could have had an arrhythmic episode and found in a state of confusion due to cerebral hypoperfusion which could be mistaken for postictal status.In these patients well-intended therapeutic maneuvers with sodium channel blocking antiepileptic medications（phenytoin,carbamazepine,primidone,lamotrigine,and topiramate etc.）could induce BrS and have deleterious consequences.Therefore,diagnosis of seizure disorder should only be made after careful exclusion of the possibility of BrS.

Potassium channel openers

The balance of inward and outward currents at the end ofAP phase1 determineswhetherornot repolarization will occur in an all-or-none fashion;therefore,any increase in outward currents（IKATP,Ito,andIKr）can cause loss of the AP dome and result in a vulnerable window in voltage gradients between areas where these currentsare differentially expressed.IKATP activators,pinacidil and nicorandil,have been shown to cause loss of the AP dome in areas whereIto is prominent with resultant phase-2 reentry in experimental models.Glucose and insulin could unmask the BrS phenotype by decreasing serum potassium concentrations and accentuatingIto.Diuretics and distal renal tubular acidosis can act in a similar manner by decreasing serum potassium levels.

Calcium channel blockers

ICa is the main current to form the AP dome.If it is diminished and cannot overcome the outward balance of currents at the end of phase 1 AP,the dome disappears.It has been shown thatIto which is the main current responsible for formation of phase 1 is heterogeneously expressed in between different layers of the myocardium,therefore a strongICa acts as the rescuer of the AP dome whereIto is increased.The basis of provocation of BrS phenotype with calcium channel blockers,in part,is due to failing to reach the potential threshold needed to rescue the AP dome in areas whereIto is strong（RVOT）.Calcium channel blockers and β-blockers unmask BrS by decreasing L-type calcium currents.Acetylcholine,by inhibition ofICa,can result in loss of the AP dome and trigger arrhythmias.Nitrates,similarly,have L-type Ca channel blocking properties and could induce BrS phenotype. Of theINa blockers listed above,trifluoperazine,cyamemazine,fluoxetine,terfenadine,ketamine,alcohol etc.also blockICa increasing the effects of these drugs in uncovering the BrS phenotype.

詞 匯

agonal adj.痛苦的，瀕死痛苦的，呻吟待斃的，臨死前的

aggregation n.聚集，聚集體，聚合作用

macroscopic adj.肉眼可見的，宏觀的

spatial adj.空間的

ascribe v.把…歸因于，把…歸咎于，認為是…的特點

innermost n.&adj.最深處；內心深處的，最靠近中心的，最深處的

heterogeneous adj.各種各樣的，由很多種類組成的，不均質的

propensity n.傾向，癖好，習性

intractable adj.難駕馭的，難加工的，難治療的

arrhythmogenesis n.致心律失常，心律失常

注 釋

1.postictal state“發作后狀態”，通常指癲癇發作過后的一種狀態，時間是從癲癇發作結束到恢復基礎（發作前）狀態期間，表現為意識混亂、昏睡、精神異常、昏迷，也可出現暴力行為，記憶缺失等，確切的機制未完全明了。

參考譯文

第91課 藥物誘發的致命性心律失常-獲得性Brugada綜合征

Brugada綜合征的現代概念

Brugada綜合征（BrS）特征表現為右胸導聯穹形ST段抬高（1型）而無結構性心臟疾病。圖1顯示吡西卡尼耐力試驗誘發的典型心電圖特征。根據2016 J-波綜合征專家共識報告，BrS診斷標準如下：

1.電極位于第2，第3或第4肋間的V1～V3上，至少有一個導聯上出現自發性1型ST段抬高2mm或以上；或

2.電極位于第2，第3或第4肋間的V1～V3上，至少有一個導聯上出現藥物誘發的1型ST段抬高2mm或以上，同時具備下列條件之一：（i）不能解釋的心源性猝死或記錄到心室顫動/多形性室性心動過速，（ii）夜間瀕死樣呼吸，（iii）暈厥可能由心律失常引起，（iv）一級或二級親屬中有明確的BrS。

1992年，BrS以遺傳性家族聚集性疾病加以報道，伴隨特征心電圖表現和繼發于多形性室性心動過速（VT）或心室顫動（VF）的心源性猝死。產生這種明顯心律失常的細胞電流變化機制仍存爭議?！?br>