●心電學(xué)英語

Catecholaminergic Polymorphic Ventricular Tachycardia

The primary electric disorders responsible for polymorphic ventricular tachycardia(VT)or ventricular fibrillation are long-QT syndrome,Brugada syndrome, the short-coupled variant of torsades de pointes, short-QT syndrome,and catecholaminergic polymorphic VT(CPVT).CPVT is a rare arrhythmogenic disorder characterized by adrenergic-induced bidirectional and polymorphic VT.The prevalence of the disease is estimated to be 1:10 000 in Europe.The first case was reported in 1975.Key features include polymorphic VT reproducibly induced during exercise tests,isoproterenol infusion,or emotion and exercise.CPVT occurs in children and adolescents and causes syncope and sudden cardiac death at a young age,in the absence of structural heart disease.The resting ECG,including the QTc interval,is normal.The mortality of CPVT is extremely high,reaching 31%by the age of 30 years when untreated.The estimated 4-and 8-year cardiac event rates were 33%and 58%,respectively,in our series of patients without β-blockers.There is a clear correlation between the age of the first syncope and the severity of the disease,with a worse prognosis in the case of early occurrence.β-blockers without sympathomimetic activity are clinically effective in reducing syncope.However,arrhythmic event rate with β-blocker therapy remains significant,suggesting the need for alternate pharmacological and nonpharmacological therapies.

With the advancements of molecular genetics and the identification of mutations in the genes encoding the cardiac ryanodine receptor and cardiac calsequestrin 21in patients with CPVT,the central role of the intracellular calcium dysregulation in myocardial cells is progressively better understood through expression studies and murine models.

Genetic Background

Priori et al and Laitinen et al identified the first mutations in the cardiac ryanodine receptor gene (RYR2)in families suffering of this type of CPVT,now known as CPVT1.Lahat et al.identified a homozygous missense mutation in the cardiac calsequestrin gene (CASQ2)as the cause of this recessive form,now known as CPVT2.RYR2 mutations are frequent, whereas CASQ2 mutations are rare;altogether,mutations are only found in 50%to 60%of patients with CPVT,which suggests that other genes are involved.

Ryanodine Receptor

The cardiac ryanodine receptors(RyR2)are calcium(Ca2+)release channels present in the sarcoplamic reticulum(SR),an intracellular vesicular network playing a major role in the regulation of Ca2+homeostasis in the heart.The mechanism of their activation is called calcium-induced calcium release because it requires that Ca2+provided by the activated L-type Ca2+channel (Cav1.2).Calcium binds to RyR2 and triggers opening of a high-conductance channel,allowing rapid Ca2+efflux from the SR.The consecutive high cytoplasmic Ca2+induces myocardial contraction,then Ca2+is reuptaken in the SR,where it is stored at high concentrations.

RYR2 Mutations

The 4967-amino acid RyR2 channel is encoded by one of the largest genes in the human genome,containing 105 exons.To date,＞50 mutations have been reported,most of them for CPVT1 and unexplained or exercise-induced sudden death.Most of the RYR2 mutations are missense mutations,occurring in 3 hot-spotregions:the N-terminal region,the central region where the calstabin-21binding domain is localized,and the C-terminal domain,including the channel region.These 3 regions are well conserved among the RyR gene family and are involved in the regulation of RyR channels.

High variability of the phenotypic expression among subjects of the same family or unrelated families was demonstrated and estimates of the penetrance range from 25%to 100%.It is noteworthy that there are asymptomatic RyR2 mutation carriers with normal exercise stress tests.Some of them can further present with exercise-induced arrhythmia during a subsequent stress test,but more importantly may die suddenly as the first manifestation of the disease.

CASQ2 Mutations

The399-amino acid CASQ2 protein is encoded by a gene containing 11 exons.Twenty-one distinct CASQ2 mutations have been reported,either homozygous or compound heterozygous mutations transmitted under a recessive mode of inheritance.Half of them are missense mutations localized in different exons.The others lead to truncated proteins by various mechanisms,nonsense codon, small deletion,and abnormal splicing leading to premature stop codon.Interestingly,a synonymous c.381C＞T variation in exon 3,recently identified in a family with CPVT2,was shown to induce abnormal splicing and a premature stop codon using a splicing minigene assay.

The phenotype is similar among the patients with 2 CASQ2 mutations and the patients with an RyR2 mutation.Most of the carriers of a single CASQ2 mutation are healthy.Nevertheless,several clinical investigations suggested that a single CASQ2 mutation could represent a potential susceptibility for ventricular arrhythmias in some subjects.The origin of the variability among subjects of a same family is still unknown.

Clinical Presentation

CVPT is extremely uncommon before the age of 2 years.The first episode of syncope usually occurs during the first or second decade of life.The symptoms are always triggered by exercise or emotional stress.Often,epilepsy is diagnosed and children are inappropriately treated with long-term antiepileptic therapy.A mean delay in diagnosis of≥2 years is usually reported in patients with syncope initially attributed to vasovagal or neurological causes.A family history of exercise-related syncope,seizure,or sudden death is reported in 30% of the patients.

Diagnosis

A history of exercise-induced or emotional stress-induced syncope with polymorphic ventricular arrhythmia in a child is highly suggestive of CPVT. The heart is structurally normal.The arrhythmia is reproducibly induced during an exercise test as well as during isoproterenol infusion.Holter monitoring or an exercise test can document CPVT by showing the ventricular arrhythmia progressively appearing after a heart rate threshold(around 120-130 beats per minute).Polymorphic VT is usually not inducible by programmed ventricular stimulation.Implantable loop recorders can be useful to record CPVT in children with adrenergically triggered,unexplained syncope.

Electrocardiographic key features in CVPT

The resting ECG is usually normal,and there is progressive ventricular ectopy as heart rate increases during exercise or isoproterenol infusion.Frequency and complexity increase as heart rate increases,first monomorphic ventricular premature beats(VPBs)followed by bidirectional VT(Figure 1).VPBs usually have a right bundle branch block pattern with alternating right and left axis deviation,suggesting a left ventricular origin.If the exercise is continued,salvos of polymorphic VT may appear and become more sustained and rapid,leading to syncope.Usually,the arrhythmia is self-terminating,but in some cases it can degenerate into ventricular fibrillation and sudden death(Figure 2). The arrhythmia disappears with the discontinuation of the exercise or after cessation of the isoproterenol infusion. The reverse heart rate-dependent sequence is usually observed during recovery.Some individuals expressing bidirectional VT during exercise may not have CPVT.Instead,clinical consideration of either Andersen-Tawil syndrome2or long-QT syndrome and appropriate genetic testing may be warranted for individuals without a RyR2 mutation but considered as patients with CPVT,particu-larly women.Careful inspection of the TU-wave morphology may assist in distinguishing between CPVT and Andersen-Tawil syndrome in a patient exhibiting exercise-induced bidirectional VT.Atrial arrhythmias,including atrial fibrillation,are not uncommon during exercise tests and have been described in some adult patients.

Current Management

β-Blockers

The first-line therapeutic option for patients with CPVT is β-blockers without sympathomimetic activity, in accordance with the arrhythmia's catecholaminergic mechanism,combined with exercise restriction.Nadolol, a long-acting drug,is preferred for prophylactic therapy and has been found to be effective clinically.In our experience,the dosage used to provide adequate prevention of CVPT and syncope is usually high(1.8 mg/kg).We reported in 2009 the long-term follow-up results of 101 patients with CPVT with an estimated 8-year cardiac event rate of 27%,even in those taking β-blockers.

The apparent discrepancy in the efficacy of β-blocker treatment between the various studies probably reflects differences in genetic background and in β-blocker dosages or a poor drug compliance.This discrepancy in β-blocker efficacy may also be because of the presence of polymorphisms influencing their metabolism.

Meanwhile,the maximal well-tolerated dosages of β-blockers should be prescribed and Holter recordings and exercise tests should be repeated periodically to ensure that the degree of sinus tachycardia that precedes the onset of arrhythmias is never reached.Furthermore, once the diagnosis is established,it is crucial to make the patients aware of the necessity of faultless compliance with the β-blocker therapy,given the number ofnoncompliance-related sudden cardiac deaths.It is strongly suggested that genetically positive family members should receive β-blockers even after a negative exercise test.

Figure 2 Holter tracings showing pleiomorphic and polymorphic ventricular tachycardia preceding the occurrence of ventricular fibrillation in a patient with catecholaminergic polymorphic ventricular tachycardia.

Implantable Cardioverter Defibrillator

An implantable cardioverter defibrillator(ICD)implantation is recommended in patients with CPVT and syncope or documented sustained VT,despite β-blocker therapy.Nevertheless,ICDs can potentially have proarrhythmic effects in patients with CPVT because stress caused by appropriate or inappropriate discharges could prove disastrous by evoking a self-induced vicious circle.However,a combination therapy involving both an ICD and an optimized dosage of β-blocker should safeguard against any such adverse effects and provide ultimate protection in nonresponsive patients.

Left Cardiac Sympathetic Denervation

The first publication reported the efficacy of LCSD in 3 young patients with CPVT,with a long follow-up in 2(aged 20 and 10 years)in whom ventricular arrhythmias were not controlled by β-blocker therapy.The following series reported results of LCSD in patients with resistant and symptomatic ventricular arrhythmias, despite optimal pharmacological therapy.Although the short-term results seem encouraging,more data from a long-term follow-up are needed.LCSD is not available in many centers worldwide because it requires well-trained surgeons and dedicated techniques.

詞匯

Murine n.&adj.鼠；鼠的

Calsequestrin n.集鈣蛋白

Salvo n.&v.一陣，一片，爆發(fā)，齊射；齊射

Exon n.外顯子

Truncate v.截去，刪節(jié)

Codon n.密碼子

Faultless adj.無錯(cuò)誤的,完美的

Disastrous adj.災(zāi)難性的,災(zāi)難性,極壞的

注釋

1.Calstabin-2是一種小的調(diào)節(jié)蛋白即FKBP12.6，能與RyR2結(jié)合并穩(wěn)定其，阻止這種結(jié)合會(huì)增加室性心律失常危險(xiǎn)。

2.Andersen-Tawil syndrome又稱長QT綜合征7，是一種罕見的常染色體顯性遺傳疾病，60%與KCNJ2基因有關(guān)，除長Q-T間期，室性心律失常外，合并存在發(fā)作性或持續(xù)性肌無力及軀體異常，如小下頜、低耳位、指彎曲等。

參考譯文

第59課兒茶酚胺源性多形性室性心動(dòng)過速

與多形性室性心動(dòng)過速（VT）或心室顫動(dòng)相關(guān)的原發(fā)性電子病有長QT綜合征、Brugada綜合征、短偶聯(lián)間期尖端扭轉(zhuǎn)型室性心動(dòng)過速、短QT綜合征和兒茶酚胺源性多形性室性心動(dòng)過速（CPVT）。CPVT是一種罕見的致心律失常疾病，特征表現(xiàn)為腎上腺素誘發(fā)的雙向性和多形性VT。在歐洲該疾病發(fā)病率估計(jì)為1:10 000。1975年首次報(bào)道。關(guān)鍵特征包括運(yùn)動(dòng)試驗(yàn)、滴注異丙腎上腺素、情緒激動(dòng)和運(yùn)動(dòng)能重復(fù)誘發(fā)多形性VT。CPVT發(fā)生于兒童和青少年，導(dǎo)致無結(jié)構(gòu)性心臟病的少年暈厥和心臟性猝死。靜息心電圖包括Q-TC間期正常。CPVT死亡率極高，如不治療，到30歲時(shí)可達(dá)31%。本文作者報(bào)道系列患者非β受體阻滯劑治療下4年和8年的心臟事件發(fā)生率分別達(dá)33%和58%。首次暈厥發(fā)作的年齡與疾病嚴(yán)重性之間存在明確的相關(guān)性，早發(fā)者預(yù)后差。臨床上，無擬交感活性的β受體阻滯劑能有效減少暈厥發(fā)生。然而，β受體阻滯劑治療下心律失常事件仍然明顯，提示需要更換藥物和非藥物治療。

隨著分子遺傳學(xué)的進(jìn)展和CPVT患者編碼ryanodine受體和心臟集鈣蛋白2（calsequestrin 2）基因突變的發(fā)現(xiàn)，通過表達(dá)研究和小鼠模型，更進(jìn)一步了解了心肌細(xì)胞胞內(nèi)鈣調(diào)節(jié)異常的中心作用。

遺傳性背景

Priori和Laitinen等在罹患CPVT的家族首次發(fā)現(xiàn)心臟ryanodine受體基因（RYR2）突變，現(xiàn)稱作CPVT1。Lahat等發(fā)現(xiàn)心臟集鈣蛋白基因（CASQ2）的純合子錯(cuò)義突變?yōu)殡[性形式的原因，現(xiàn)稱作CPVT2。RYR2突變常見，而CASQ2突變罕見；合計(jì)只有50%～60%的CPVT患者發(fā)現(xiàn)突變,提示其他基因受累。

Ryanodine受體

心臟ryanodine受體（RyR2）是肌質(zhì)網(wǎng)上的鈣釋放通道，這是一種細(xì)胞內(nèi)囊狀網(wǎng)絡(luò)，在心臟的鈣離子穩(wěn)態(tài)調(diào)節(jié)中起重要作用。激活機(jī)制需要活化的L型鈣離子通道（Cav1.2）提供鈣離子，因此稱為鈣誘導(dǎo)鈣釋放。鈣結(jié)合到RyR2并促發(fā)開放高通量通道，使得鈣離子快速從肌質(zhì)網(wǎng)流出。連續(xù)的胞漿內(nèi)高鈣離子誘發(fā)心肌收縮，隨后，鈣離子被重新攝回到肌質(zhì)網(wǎng)中以高濃度存儲其中。

RYR2突變

有4 967個(gè)氨基酸的RyR2通道由人體基因組中最大基因之一編碼，該基因包含105個(gè)外顯子。至今，已報(bào)道＞50個(gè)突變，其中多數(shù)與CPVT1和不明原因或運(yùn)動(dòng)誘發(fā)的猝死有關(guān)。多數(shù)RYR2突變?yōu)殄e(cuò)義突變，發(fā)生在3個(gè)熱點(diǎn)區(qū)域：N-端區(qū)域；中心區(qū)域，鈣活動(dòng)調(diào)節(jié)蛋白2（calstabin-2）結(jié)合域位于此區(qū)域；C-端區(qū)域，包含通道區(qū)域。這3個(gè)區(qū)域在RyR基因家族中是極保守的，涉及RyR通道的調(diào)節(jié)。

已證實(shí)同一家族或不同家族個(gè)體之間的表型表達(dá)高度易變，估計(jì)外顯率為25%～100%。值得注意的是存在運(yùn)動(dòng)試驗(yàn)正常的無癥狀RyR2突變攜帶者。他們中的一些人在隨后的負(fù)荷試驗(yàn)中進(jìn)一步表現(xiàn)出運(yùn)動(dòng)誘發(fā)的心律失常，但更重要的是首次表現(xiàn)可為猝死。

CASQ2突變

有399個(gè)氨基酸的CASQ2蛋白由包含11個(gè)外顯子的基因編碼。已報(bào)道21個(gè)明確的CASQ2突變，系純合子突變或隱性遺傳的復(fù)合雜合子突變。其中半數(shù)為位于不同外顯子的錯(cuò)義突變。其他的通過各種機(jī)制，無義密碼子，小缺失，異常剪接致提前中止密碼子，導(dǎo)致截短蛋白。令人感興趣的是，使用剪接小基因檢測顯示，最近在一CPVT2家族中發(fā)現(xiàn)的外顯子3上的同義c.381C＞T變異誘發(fā)出異常剪接和提前中止密碼子。

兩種CASQ2突變的患者與RyR2突變的患者的表型是相類似的。多數(shù)單一CASQ2突變攜帶者是健康的。然而，數(shù)個(gè)臨床研究表明某些單一CASQ2突變患者表現(xiàn)出發(fā)生室性心律失常的潛在易感性。同一家族不同個(gè)體之間變異的根源尚不清楚。

臨床表現(xiàn)

CVPT 2歲前極少發(fā)生。首次暈厥通常發(fā)生在10歲前或20歲前。癥狀總是由運(yùn)動(dòng)或情緒壓力所觸發(fā)。兒童常被診斷癲癇發(fā)作，而長期不適當(dāng)?shù)亟邮芸拱d癇治療。對于最初將暈厥歸因于血管迷走或神經(jīng)源性的患者，診斷上通常平均延后2年或以上。據(jù)報(bào)道，30%患者有運(yùn)動(dòng)相關(guān)暈厥、癲癇發(fā)作或猝死的家族史。

診斷

兒童有運(yùn)動(dòng)誘發(fā)或情緒壓力誘發(fā)暈厥伴多形性室性心律失常病史高度提示CVPT。心臟結(jié)構(gòu)正常。運(yùn)動(dòng)試驗(yàn)及異丙腎上腺素滴注可重復(fù)誘發(fā)這種心律失常。動(dòng)態(tài)心電記錄或運(yùn)動(dòng)試驗(yàn)通過顯示當(dāng)心率達(dá)到臨界值（約120～130次/min）后室性心律失常逐漸出現(xiàn)而印證CVPT。程序心室刺激通常不能誘發(fā)多形性VT。對于腎上腺素觸發(fā)、不明原因暈厥的兒童植入型記錄器是有用的。

CPVT心電圖關(guān)鍵特征

靜息心電圖通常正常，運(yùn)動(dòng)或異丙腎上腺素滴注過程隨著心率增加室性異位搏動(dòng)逐漸增加。隨著心率增加，頻率及復(fù)雜性增加，首先為單形性室性期前收縮，接著為雙向性VT（圖1）。室性期前搏動(dòng)通常呈右束支傳導(dǎo)阻滯圖形伴心電軸右偏和左偏交替，提示為左心室起源。如果運(yùn)動(dòng)持續(xù)，可出現(xiàn)陣發(fā)多形VT，并變得更持久更快，導(dǎo)致暈厥。通常，心律失常呈自限性，但有時(shí)蛻化為心室顫動(dòng)和猝死（圖2）。心律失常隨著運(yùn)動(dòng)的中止或異丙腎上腺素滴注結(jié)束而消失?；謴?fù)期可見到反向心率依賴變化過程。某些個(gè)體運(yùn)動(dòng)中表現(xiàn)為雙向性VT而不發(fā)生CPVT。反之，臨床應(yīng)考慮Andersen-Tawil綜合癥或長QT綜合征，對于無RyR2突變但認(rèn)為是CPVT患者，特別是女性，應(yīng)做恰當(dāng)?shù)幕驕y試。對于運(yùn)動(dòng)誘發(fā)雙向性VT的患者，仔細(xì)檢查TU波形態(tài)有助于鑒別CPVT和Andersen-Tawil綜合征。運(yùn)動(dòng)中房性心律失常，包括心房顫動(dòng)并非少見，已報(bào)道見于某些成年患者。

現(xiàn)行治療方法

β受體阻滯劑

基于該心律失常的兒茶酚胺源性機(jī)制，CPVT患者一線治療應(yīng)選擇無擬交感活性的β受體阻滯劑，結(jié)合運(yùn)動(dòng)限制。納多洛爾（Nadolol）,一種長效制劑，適合預(yù)防治療，并證實(shí)臨床有效。根據(jù)本文作者經(jīng)驗(yàn)，為保證充分預(yù)防CPVT和暈厥的發(fā)生，通常需給大劑量（1.8 mg/kg）。2009年本文作者報(bào)道101例CPVT患者長期隨訪結(jié)果，即使那些服用β受體阻滯劑者，8年心臟事件為27%。

不同研究之間β受體阻滯劑治療療效的明顯不一致可能反映遺傳背景或β受體阻滯劑劑量不同或服藥依從性差。β受體阻滯劑療效明顯不一也可因存在影響其代謝的多態(tài)性。

同時(shí)，應(yīng)予以最大良好耐受劑量的β受體阻滯劑，并定期重復(fù)動(dòng)態(tài)心電圖和運(yùn)動(dòng)試驗(yàn)檢查，以確保絕不達(dá)到（室性）心律失常發(fā)作前竇性心動(dòng)過速的速率。此外，鑒于一些因缺乏依從性而導(dǎo)致的心臟性猝死，一旦診斷明確，至關(guān)重要的是讓患者意識到完全遵醫(yī)囑服用β受體阻滯劑治療的必要性。強(qiáng)烈建議基因陽性家族成員接受β受體阻滯劑治療，即使運(yùn)動(dòng)試驗(yàn)陰性。

植入性心律轉(zhuǎn)復(fù)除顫器

CPVT和暈厥或記錄到持續(xù)性VT患者，除了β受體阻滯劑治療外，建議植入心律轉(zhuǎn)復(fù)除顫器（ICD）。不過，ICD對CPVT患者有致心律失常作用，因?yàn)榍‘?dāng)或不恰當(dāng)放電所致的壓力可引起自-誘發(fā)惡性循環(huán)而導(dǎo)致災(zāi)難性后果。然而，聯(lián)合ICD和最佳劑量β受體阻滯劑治療應(yīng)能防范任何這類不良反應(yīng)，并能對無反應(yīng)者提供根本保護(hù)。

心臟左交感神經(jīng)去除術(shù)

首篇文章報(bào)道了3例年輕CPVT患者心臟左交感神經(jīng)去除術(shù)（LCSD）的療效，長期隨訪的2例（年齡分別為20歲和10歲）為β受體阻滯劑不能控制室性心律失常的患者。其后系列報(bào)道了優(yōu)化藥物治療下頑固性癥狀性室性心律失?；颊叩腖CSD結(jié)果。雖然短期結(jié)果令人鼓舞，但需更多的長期隨訪資料。LCSD在世界上許多中心無法實(shí)行，因其需要良好訓(xùn)練的外科醫(yī)生和專用的技術(shù)。

圖1負(fù)荷試驗(yàn)中12導(dǎo)聯(lián)心電圖顯示典型的雙向性VT，特征為QRS電軸每搏呈180°交替，伴隨右束支傳導(dǎo)阻滯圖形提示左心室起源。

圖2動(dòng)態(tài)心電圖記錄顯示一例兒茶酚胺源性室性心動(dòng)過速患者心室顫動(dòng)發(fā)生前多種形態(tài)的VT。

[1]Leenhardt A,Denjoy I,Guicheney P.Catecholaminergic Polymorphic Ventricular Tachycardia[J].Circ Arrhythm Electrophysiol,2012,5：1044-1052.

（童鴻）