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(nèi)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(zhì)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(fā)作后狀態(tài)”，通常指癲癇發(fā)作過后的一種狀態(tài)，時間是從癲癇發(fā)作結(jié)束到恢復(fù)基礎(chǔ)（發(fā)作前）狀態(tài)期間，表現(xiàn)為意識混亂、昏睡、精神異常、昏迷，也可出現(xiàn)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(fā)的致命性心律失常-獲得性Brugada綜合征

Brugada綜合征的現(xiàn)代概念

Brugada綜合征（BrS）特征表現(xiàn)為右胸導(dǎo)聯(lián)穹形ST段抬高（1型）而無結(jié)構(gòu)性心臟疾病。圖1顯示吡西卡尼耐力試驗誘發(fā)的典型心電圖特征。根據(jù)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(dǎo)聯(lián)上出現(xiàn)自發(fā)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(dǎo)聯(lián)上出現(xiàn)藥物誘發(fā)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(xiàn)和繼發(fā)于多形性室性心動過速（VT）或心室顫動（VF）的心源性猝死。產(chǎn)生這種明顯心律失常的細胞電流變化機制仍存爭議?；趶?fù)極和除極變化，主要提出兩種假說，單一或聯(lián)合起作用。第一種假說推測不同心肌層之間的內(nèi)在復(fù)極差異得到放大，通常稱作復(fù)極空間離散（SDR）。短暫外向電流（Ito）是SDR中最重要的電流。出現(xiàn)于心外膜細胞和M細胞，而不出現(xiàn)于三層心肌中的最內(nèi)層心內(nèi)膜（圖2A）。此外，右心室Ito量是左心室的近3倍，這是BrS右心室致心律失常的原因。

心內(nèi)膜與心外膜之間Ito表達不均一導(dǎo)致的復(fù)極1相透壁電位差解釋了BrS的異常J點抬高（圖2B）。Ito明顯而致細胞面臨全-或-無復(fù)極（現(xiàn)象），一旦動作電位1相谷值到達L-型鈣通道激動閾值以下時即導(dǎo)致動作電位穹頂消失和動作電位時程縮短（圖2C）。某些降低復(fù)極電流的病理狀態(tài)或藥物干預(yù)促進這一現(xiàn)象。心外膜動作電位穹頂?shù)牟痪粊G失導(dǎo)致心外膜復(fù)極離散而進一步加劇內(nèi)在的透壁不均一性。當心外膜細胞丟失動作電位穹頂而心內(nèi)膜不丟失時，心內(nèi)膜與心外膜之間即發(fā)生透壁電壓梯度，表現(xiàn)為心電圖上的特征性ST段抬高。

心外膜內(nèi)或透壁電流擴布，從保留動作電位2相的部位流向動作電位2相缺失的部位，引發(fā)短偶聯(lián)間期的再興奮，稱作2相折返，這成為BrS VT和VF發(fā)作的觸發(fā)機制（圖2D）。這一假說得到BrS患者因自主神經(jīng)張力改變而發(fā)生ECG變化的支持，即迷走神經(jīng)激動引發(fā)的Ito增加和（或）ICa減少降低了動作電位的尖峰和穹頂圖形，從而加劇復(fù)極離散和ECG ST段抬高。

第二種關(guān)于BrS心律失常的假說推測纖維化引起除極與傳導(dǎo)延緩，右心室流出道（RVOT）INa減少是主要機制。相對于右心室其他部位，RVOT的相對延緩除極導(dǎo)致局部電位差，這在右胸導(dǎo)聯(lián)上表現(xiàn)為ST段抬高。

藥物誘發(fā)的Brugada綜合征

對于生物學上易感患者，環(huán)境因素將改變觀察到的表型。自主神經(jīng)變化、激素變化、飲酒、發(fā)熱和藥物可以使正常心電圖轉(zhuǎn)變成BrS心電圖。多個研究報道，運動、阿托品和異丙腎上腺素滴注可使BrS心電圖正?；?，而毒蕈堿和選擇性α-腎上腺受體刺激，通過反射性迷走激活，可以加劇ST段抬高。這也解釋了BrS患者傾向于夜間發(fā)生VT/VF。同樣，雖然以交感神經(jīng)激動為目標的左側(cè)心臟神經(jīng)離斷術(shù)是廣為接受的頑固性長QT間期綜合征治療方法，卻增加BrS的心律失常。多個研究報道，應(yīng)用磷酸二酯酶抑制劑米力農(nóng)和西洛他唑能成功預(yù)防BrS的頑固性VF發(fā)作。這些藥物提高細胞內(nèi)環(huán)AMP水平，增加L-型鈣電流（ICa），從而恢復(fù)心外膜動作電位穹頂。

一直認為發(fā)熱是BrS心律失常的危險因素。有些SCN5A突變只能在高溫下改變鈉通道動力。其他研究提示對熱的敏感性并非歸因于突變，而是野型SCN5A或Ito的熱依賴特性，以及發(fā)熱助長了RVOT和浦肯野纖維的自發(fā)活動。

基于上述討論總結(jié)，任何可降低INa或ICa或增加Ito的藥物，均可引發(fā)BrS心律失常。根據(jù)它們的作用機制，這些藥物可以分成三大組：

鈉通道阻斷劑

INa的幅度決定達到動作電位0相頂端的最大正向膜電位。如INa減少，動作電位1相起始膜電位較低，結(jié)束時負向電位更明顯。1相結(jié)束時的內(nèi)外電流平衡決定ICa能否克服外向電流而形成動作電位穹頂。因為心內(nèi)膜與心外膜對INa阻斷劑的反應(yīng)不同，它們可以導(dǎo)致動作電位穹頂形成過程中的透壁不一致性。因此，IA和IC抗心律失常制劑用于揭示BrS表型。

已知三環(huán)類抗抑郁制劑（阿米替林，去甲丙咪嗪，去甲阿米替林，氯丙米嗪，丙咪嗪）和四環(huán)類抗抑郁制劑（馬普替林），通過鈉通道阻斷作用，減少動作電位1相結(jié)束時凈內(nèi)向電流而促發(fā)Brugada心電圖。

抑制神經(jīng)藥物吩噻嗪類（氯丙嗪，三氟拉嗪，氰美馬嗪，奮乃靜），氟哌丁苯和洛沙平可通過鈉通道阻斷特性而誘發(fā)BrS心電圖。

選擇性血清素重攝取抑制劑（SSRIs），特別是氟西汀具有哺乳類動物心室細胞的鈉和鈣通道阻斷特性，已顯示能誘發(fā)BrS心電圖。另一SSRI西酞普蘭也能抑制INa激活。其他SSRIs氟伏沙明和帕羅西汀也能揭示BrS心電圖。

抗組胺類藥物丁苯哌丁醇具有INa和ICa阻斷特性，在犬契形標本上顯示其激發(fā)VT的作用超過單一的INa阻斷劑。在鈉通道阻斷劑中，那些具有明顯Ito阻斷作用的少有可能（氟卡尼和丙吡胺）或甚至不可能（奎尼?。┱T發(fā)心律失常。鋰、可卡因、大麻、酒精和麻醉劑（丙泊酚，布比卡因，氯胺酮）也可通過減少INa而揭示BrS表型。盡管眾所周知美沙酮與藥物誘發(fā)長QT綜合征相關(guān)，也有報道其可誘發(fā)BrS心電圖。另一合成麻醉制劑曲馬多阻斷神經(jīng)元鈉通道，也有報道可揭示BrS心電圖。許多抗癲癇藥物通過阻斷神經(jīng)元鈉通道而起作用。其中有些也改變心臟鈉通道動力，雖然有些尚需證實。

發(fā)生暈厥并處于“發(fā)作后狀態(tài)”的患者可能有心律失常發(fā)作，并出現(xiàn)腦低灌注引起的混亂狀態(tài)，這可誤判為發(fā)作后狀態(tài)。對這些患者采用鈉通道阻斷劑抗癲癇藥物（苯妥英，卡馬西平，撲癇酮，拉莫三嗪，和托吡酯等）的定向治療措施可誘發(fā)BrS和導(dǎo)致不良后果。因此，癲癇診斷只能在仔細排除BrS后才能得以確立。

鉀通道開通劑

動作電位1相結(jié)束時內(nèi)外向電流的平衡決定復(fù)極是否發(fā)生全-或-無形式，因此，任何外向電流（IKATP，Ito和IKr）的增加可引起動作電位穹頂?shù)膩G失，并導(dǎo)致電流表達不同區(qū)域之間電壓梯度上的易損窗口。IKATP激動劑匹那地爾和尼可地爾已顯示能導(dǎo)致實驗?zāi)Ｐ蜕螴to為主導(dǎo)而引起2相折返區(qū)域的動作電位穹頂丟失。葡萄糖和胰島素通過減少血清鉀濃度和增加Ito而揭示BrS。利尿劑和遠端腎小管酸中毒通過減少血清鉀濃度而起到類似作用。

鈣通道阻斷劑

ICa是形成動作電位穹頂?shù)闹饕娏?。如在動作電?相結(jié)束時ICa降低并且不能克服外向電流的平衡，穹頂就消失。已顯示形成動作電位1相的主要電流在心肌的不同層之間表達不一致，因此，在Ito增加區(qū)域強ICa是動作電位穹頂?shù)耐炀日?。鈣通道阻斷劑激發(fā)BrS的基礎(chǔ)，部分源于難以達到所需的電位閾值來挽救Ito強大區(qū)域（RVOT）的動作電位穹頂。鈣通道阻斷劑和β-阻斷劑通過降低L-型鈣電流而揭示BrS。乙酰膽堿通過抑制ICa導(dǎo)致動作電位穹頂?shù)膩G失并促發(fā)心律失常。同樣，硝酸鹽具有L-型鈣通道阻斷特性，能引發(fā)BrS表型。在上述所列的INa阻斷劑中，三氟拉嗪，氰美馬嗪，氟西汀，丁苯哌丁醇，氯胺酮，酒精等也能阻斷ICa而增加這些藥物揭示BrS表型的效應(yīng)。

圖1吡西卡尼誘發(fā)的Brugada心電圖變化：左圖為基礎(chǔ)狀態(tài)胸導(dǎo)聯(lián)心電圖，右圖為靜脈注射吡西卡尼（0.8mg/kg）后胸導(dǎo)聯(lián)心電圖。

圖2Brugada綜合征復(fù)極離散和2相折返假說：A：Ito是動作電位1相的主要電流，心內(nèi)膜細胞缺乏此電流；B：心內(nèi)膜與心外膜之間不一致的Ito表達導(dǎo)致復(fù)極1相透壁電位差，是J波綜合征中J點抬高的原因；C：BrSIto明顯和（或）內(nèi)向鈉或鈣電流減少致使細胞面臨全-或-無現(xiàn)象，一旦動作電位1相谷值達到L-型鈣通道激動閾值以下時即導(dǎo)致動作電位穹頂丟失和動作電位時程縮短；D：心外膜內(nèi)或透壁電流擴布，從保留動作電位2相的部位流向動作電位2相缺失的部位，引發(fā)短偶聯(lián)間期的再興奮，稱作2相折返，這成為BrS VT和VF發(fā)作的觸發(fā)機制。