Risk stratification of patients with primary arrhythmia syndrome

Among primary arrhythmia syndromes, the follows are frequently seen: long QT syndrome(LQTS), ST elevation in the right precordium, right bundle branch block(RBBB), sudden cardiac death(SCD) and catecholaminergic polymorphic ventricular tachycardia(CPVT)/ventricular fibrillation(VF).

LQTS is autosomal dominant, rarely autosomal recessive and is usually associated with deafness. It has been found by testing gene-specific features of LQTS that 17 genes of over 60% genotypes are involved in genetic heterogeneity.

Established risk factors of LQTS are aborted sudden death and syncope event. Family history of SCD is not a risk factor in LQTS which has been proved by many studies. Other risk factors include the presence of Torsades de pointes(TdP) and T-wave alternans(TWA) on ECG, and the prolongation of QT interval. The longer the QT, the higher the risk. And deafness inherited in the autosomal recessive mode, that is congenital deafness, is also a risk factor of LQTS. Among the above risk factors, TdP, TWA and the prolongation of QT interval can be identified on ECG.

The QT prolongation over 500 ms on ECG indicates the patient being at risk. T-wave morphology is an important indicator, particularly TWA. In the following example, we’re not sure about the existence of QT-dispersion, however, reduced heart rate suggests the possibility of conduction block. In addition, TdP is also a risk factor of LQTS.

As shown in Fig.1, the patient is a 26-year-old female with congenital deafness and life-long “seizure disorder” (probably wrongly diagnosed). She was presented with recurrent syncope one week after the birth of her 3rd child. ECG abnormalities were recognized by the computer and physicians, particularly extremely abnormal T-waves. A patient like this should be considered as being at high risk for syncope events and that is echo arrhythmias.

Fig.1 ECG of a patient at high risk for syncope events

1 Risk stratification of long QT syndrome

QT interval has already been proved to be an important risk factor of LQTS[1]. The quartile of QTc is ≤446 ms, 447-468 ms, 469-498 ms and ≥499 ms, respectively. As shown in Fig.2, the cumulative cardiac-event-free survival is plotted along the vertical axis and age on the horizontal axis. The longer the QTc, the more likely the patient is becoming symptomatic. But importantly, the patient in the first quartile with normal QTc is not cardiac-event-free.

Fig.2 The cumulative cardiac-event-free survival with age

In a 500-case group at high risk of cardiac events, symptomatic individuals account for about 70%, with an annual incidence of cardiac events of 2%. For the cases falling in the normal QTc interval range, the proportion and rate are separately about 20% and 0.5% per year.

Based on QT interval and genetic theories, Silvia G Priori came up with the “pyramid” of risk stratification of LQTS. The high-risk patient is identified by QTc≥500 ms with genotype of LQT1 or LQT2, but LQT3 is found in males only. For the females with LQT3 and long QT interval, the risk is apparently lower, that is,intermediate risk. Males with LQT2, or patients with LQT1 and QTc<500 ms have low risk of LQTS.

Fig.3 shows another patient at high risk, and it is the first ECG of a neonate shortly after birth. Prenatal bradycardia had already been recognized. The patient has syndactyly which is a sign that he/she may suffer from LQTS with genotype of LQT8. Marked alternans can be clearly observed on ECG(as pointed by black arrow in Fig.3), which are determinants of high risk for adverse event in near future. Fig.4 is from the same patient and the risk of LQTS appears to be much lower if compared with Fig.3. There are two P waves, one functional atrioventricular block and one QRS complex. These P waves can’t conduct downward because the repolarization of the ventricle has not been completed yet. And the functional atrioventricular block is also a risk indicator of abnormally prolonged QT interval.

Fig.3 The first ECG of a neonate shortly after birth

Fig.4 ECG of the same patient as Fig.3

Fig.5 shows an elderly individual treated with Sotalol also under indicator of risk. Once again, there are marked prolonged QT intervals and bradycardia. And then the alternans on top of the U wave or T wave can be observed twice. In the occurrence of alternans, it is almost be sure that the next ECG in the next minute will be like Fig.6. The patient should be monitored accurately.

Fig.5 ECG of an elderly individual

Fig.6 ECG of a patient with ventricular tachycardia

Hence, the risk of LQTS depends on genic phenotype, gender(female gender), QTc (≥500 ms, female gender) and age(male gender at very young age). Specific ECG features such as alternans and serum inhibition factor suggest functional atrioventricular block. However, as mentioned earlier, genotype is also important. Specific genic mutations usually indicate high malignancy. For example,A34 1Vis one of the best-known malignant genic mutations.The chances of high malignancy are higher in the appearance of pore mutations, autosomal dominant variant mutations and C-loop mutations. It has been revealed that LQT2 belongs to pore mutation while we are not very clear about LQT3.Specific genic mutations can be used to screen out the high risk population for LQTS.

2 Risk stratification of Brugada syndrome

Fig.7 is the ECG of typical type 1 Brugada syndrome acquired from a 40-year-old male with a family history of nocturnal sudden death. It is unknown whether he has undergone drug therapy or not, and the ECG might be acquired from the 4th intercostal space, or higher in the 2nd, 3rd or intercostal space. His ECG may vary from day to day and sudden death events may occur at rest or at exercise. Fever can increase the rate of sudden death but rarely are children reported.

The ECG of type 1 Brugada syndrome can be easily discriminated from type 2 and 3, however, the ECG of type 2 and 3 can be transformed into type 1 by taking class Ⅰ anti-arrhythmia drugs.

The risk stratification of Brugada syndrome is somewhat disputative. It’s widely agreed that the patients with cardiac arrest or VF are high-risky. Patients with symptoms like syncope are at high risk. EPS inducibility could probably be utilized in predicting Brugada syndrome although it’s still controversial. However, in my personal opinion, its predictive value is limited. Spontaneous alterations have been enrolled in the list of risk factors by different studies, like fragmented QRS complex(fQRS). Recently, Japanese study found thatSCN5Amutations may add some extra risk of Brugada syndrome.

The fQRS and spontaneous alteration are obvious on ECG[2-3]. If a patient comes in with usually normal ECGs and the above abnormal ECGs at onset, it seems that the patient is high risky of Brugada syndrome. Fig.8 shows spontaneous variation of ST elevation in the same patient at different ages—55, 56, 57 and 58 years old[2]. Sometimes the ECG is normal although this might be influenced by different locations of electrodes. However, most of the time the ECG is abnormal， and on the ECG with marked variation there are a lot of fractionations which indicate high risk for ventricular arrhythmias.

Fig.7 ECG of a 39-year-old male

Fig.8 Spontaneous variations of fragmented QRS complex

Fig.9 is another example of fQRS in Brugada syndrome[2]. There is marked fQRS here on this QRS complexes and it’s omnipresent. Morita et al[2]illustrated that the presence of fQRS predicted sudden death in the future.

Fig.9 Example of fQRS in Brugada syndrome

3 Risk stratification of catecholaminergic polymorphic ventricular tachycardia

As shown in Fig.10, this is a patient with exercise-induced arrhythmias and the ECG has very typical features of CPVT. However, it manifests as alternating morphology of bidirectional VT and QRS complex, which is referred to as “bidirectional”. When clinically confronting with this ECG, we can strongly doubt the diagnosis of CPVT.

CPVT is autosomal dominant. Its initial clinical manifestations are syncope or aborted sudden cardiac death during exercise or under emotional stress, and usually appear during the first or second decade of life. At present, 6 subtypes of CPVT have been reported. It usually starts at young age and importantly, the baseline of ECG is normal.

The patients at high risk of CPVT are in accordance with at least one of the following conditions: (ⅰ) a medical history of cardiac arrest; (ⅱ) initial presentation at young age; (ⅲ) occurrence of complex arrhythmias during exercise test, as shown in Fig.10; (ⅳ) patients not using beta blocker are definitely at higher risk. In addition, it has been prove by our research that CPVT is related to some mental retardation. The result has not been published yet but has been submitted recently.

Fig.10 The ECG of catecholaminergic polymorphic ventricular tachycardia

4 Relationship between lamin A/C cardiomyo-pathy and primary arrhythmia syndrome

Cardiomyopathy induced by lamin A/C genic mutation is not primary arrhythmia syndrome, but its first manifestations are atrioventricular block and atrial fibrillation. Obvious cardiomyopathy fails to appear at an early phase while left ventricular dysfunction emerges in later period. So initially these patients may present with symptoms similar to primary arrhythmia syndrome. In the neurologic phenotype, a known clinical manifestation is limb girdle muscular dystrophy, for instance, progressive muscular dystrophy and elevation of creatine kinase. The cardiac phenotype has the initial manifestation of first degree atrioventricular block and atrial fibrillation, followed by left ventricular dysfunction. ECG is typical recognized by P-waves with low amplitude, first degree atrioventricular block, and narrow or normal QRS.

Fig.11 is the ECG of a 32-year-old male with strong family history of sudden death. His father died of heart failure at age 42 and uncle died at age 38 implanted with pacemaker from age 35. The ECG shows P-wave with very low amplitude and marked first degree atrioventricular block, but the QRS complex and repolarization is completely normal. This is very typical of lamin A/C cardiomyopathy and the ECG indicates high risk of sudden death.

van Rijsingen et al[4]carried out a multicenter study involving 275 patients, and proposed that risk factor is left ventricular ejection fraction(LVEF) <50%, not the usual 35% in other academic hypothesis. Non-sustained VTs on the Holter, male gender and LVEF<50% are three risk factors, which enormously increased the risk for ventricular arrhythmias. During a follow-up 20 months , over 30% of the individuals have developed VT/VF. So these patients should be considered as high-risk cases.

Fig.11 The ECG with prolonged PR, normal QRS and low amplitude P-wave

5 Conclusion

The risk assessment of primary arrhythmia syndrome is as follows, (ⅰ) long QT syndrome: QTc≥500 ms, T-wave alternans and genetic abnormality; (ⅱ) Brugada syndrome: spontaneous ST-segment elevation, variable ECG morphology and fQRS, and the symptom is like long QT syndrome; (ⅲ) CPVT: all patients need to be treated. In addition, other patients especially those with complex arrhythmias during exercise are also at high risk. The specificity of ECG in dilated cardiomyopathy conduction disease is not that high, but in the presence of LMNA as a virulence gene, high risk for dilated cardiomyopathy conduction disease is strongly indicated.

[1] Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome[J]. N Engl J Med, 2003,348(19)：1866-1874.

[2] Morita H, Kusano KF, Miura D, et al. Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome[J]. Circulation, 2008,118(17)：1697-1704.

[3] Take Y, Morita H, Wu J, et al. Spontaneous electrocardiogram alterations predict ventricular fibrillation in Brugada syndrome[J]. Heart Rhythm, 2011,8(7)：1014-1021.

[4] van Rijsingen IA, Arbustini E, Elliott PM, et al. Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study[J]. J Am Coll Cardiol, 2012, 59(5)：493-500.

[摘要] 遺傳性原發(fā)性心律失常綜合征主要包括長QT綜合征、Brugada綜合征及兒茶酚胺敏感性心動過速(catecholaminergic polymorphic ventricular tachycardia，CPVT)等。由于該類疾病猝死風險極高，因此及早診斷并進行危險分層極其重要。確定極高?；虻臀€體相對容易，但對多數(shù)中危患者進行分層較困難，基因分析和臨床評估對危險分層有一定的臨床價值。本文結(jié)合病例分析，主要探討對長QT綜合征、Brugada綜合征及CPVT危險分層的相關(guān)因素。其中，長QT綜合征危險分層與QTc、明顯的T波改變及基因變異有關(guān)；Brugada綜合征危險分層因素包括基因變異及碎裂QRS波；CPVT危險分層因素包含心臟驟停病史、發(fā)病年齡及是否應用β受體阻滯劑。此外，文章還闡述了核纖層蛋白A/C基因突變致心肌病與遺傳性原發(fā)性心律失常綜合征的關(guān)系。

[關(guān)鍵詞] 遺傳性原發(fā)性心律失常綜合征；長QT綜合征；Brugada綜合征；兒茶酚胺敏感性心動過速；危險分層

[中圖分類號] R540.4 [文獻標志碼] A [文章編號] 2095-9354(2018)03-0169-09

DOI：10.13308/j.issn.2095-9354.2018.03.004

作者單位： 1100DE 荷蘭 阿姆斯特丹，阿姆斯特丹大學心內(nèi)科,學術(shù)醫(yī)學中心
作者簡介： Arthur AM Wilde，醫(yī)學教授，主要從事心血管疾病遺傳學的相關(guān)研究，E-mail：a.a.wilde@amc.uva.nl

就目前的認識，常見的遺傳性原發(fā)性心律失常綜合征包括：長QT綜合征(LQTS)、右心前區(qū)ST段抬高、右束支阻滯(RBBB)、心源性猝死(SCD)和兒茶酚胺敏感性多形性室性心動過速(CPVT)/心室顫動(VF)。

LQTS通過常染色體顯性遺傳，很少發(fā)生隱性遺傳，且通常與耳聾有關(guān)。通過測試LQTS的基因特異性特征后發(fā)現(xiàn)，其遺傳異質(zhì)性主要涉及17個基因，超過60%的基因型。

目前已知的LQTS的危險因素包括猝死和暈厥事件。許多研究已證實，SCD家族史并不是LQTS的危險因素。其他危險因素包括心電圖證實的尖端扭轉(zhuǎn)型室性心動過速(TdP)和T波電交替(TWA)以及QT間期延長，并且，QT間期越長，風險越高。通過常染色體隱性遺傳導致的耳聾，即先天性耳聾亦為LQTS的危險因素。在這些危險因素中，TdP、TWA以及QT間期延長均可通過心電圖識別出來。

當心電圖提示QT間期延長超過500 ms時，預示著患者可能處于危險之中。T波形態(tài)是提示LQTS的重要危險因素，特別是TWA。對于下面這個病例，我們并不確定是否有QT間期離散，但減慢的心率提示可能存在傳導阻滯。此外，TdP也是LQTS的一個危險因素。

如圖1所示，患者女，26歲，患有先天性耳聾和終生“癲癇癥”(可能被誤診)。在她的第三個孩子出生后一周，患者開始出現(xiàn)反復暈厥。計算機和人工均識別到心電圖異常，尤其是T波極度異常。像這樣的患者應該被歸為暈厥事件的高危人群，也就是回聲障礙。

1 長QT綜合征的危險分層

既往已證明QT間期是LQTS的重要危險因素[1]。QTc數(shù)值被劃分為四層：≤446 ms、447～468 ms、469～498 ms和≥499 ms。如圖2所示，以無心臟事件的累積生存率為縱軸、以年齡為橫軸作圖。QTc越長，患者越有可能出現(xiàn)癥狀。然而需要注意的是，QTc正?；颊?QTc≤446 ms)也可能發(fā)生心臟事件。

在QTc>500 ms的高危組中，心臟事件的年發(fā)生率為2%,其中，70%的個體有臨床癥狀。而在QTc正常者中，20%的個體有臨床癥狀，心臟事件的年發(fā)生率為0.5%。

根據(jù)QT間期和遺傳學理論，Silvia G Priori提出了LQTS風險分層的“金字塔”。高風險患者的QTc>500 ms，基因型為LQT1或LQT2，但只有男性有LQT3。對于長QT間期且基因型為LQT3的女性，其風險明顯較低，屬于中風險。基因型為LQT2的男性，或基因型為LQT1且QTc<500 ms的患者，其LQTS風險較低。

再舉一例 LQTS風險較高的病例。圖3為一名新生兒出生后不久的第一份心電圖，其已診斷出產(chǎn)前心動過緩。該病例患有并指，提示其可能患有LQT8型LQTS。從心電圖中可清楚地觀察到明顯的交替現(xiàn)象(箭頭所指處)，這是近期不良事件高風險的決定性因素。圖4來自同一患者，從心電圖來看，其LQTS風險較圖3明顯降低。心電圖顯示有兩個P波、一個功能性的房室阻滯和一個QRS波群，其中，這些P波不能下傳，因為心室復極尚未完成;該房室阻滯同時也是QT間期異常延長的風險指標，預示著高風險。

圖5為一例接受索他洛爾治療的老年患者心電圖，亦提示存在LQTS風險因素。與之前的病例類似，該患者心電圖上可明顯觀察到QT間期延長和心動過緩。此外，兩次出現(xiàn)了U波或T波的頂部交替現(xiàn)象。當出現(xiàn)這一現(xiàn)象時，我們幾乎可以肯定下一分鐘的下一個心電圖就類似于圖6。如果患者有這樣的心電圖，就意味著需要對其進行心電監(jiān)護。

因此，LQTS風險高低取決于基因表型、性別(女性)、QTc(≥500 ms，女性)和年齡(年輕男性)。特定的心電圖特征，如交替現(xiàn)象和血清抑制因子則提示功能性房室阻滯。但正如前文所述，基因型也很重要。當出現(xiàn)特定基因突變時，通常提示高度惡性：A34 1V就是人們熟知的惡性突變之一；當出現(xiàn)細胞孔蛋白突變、常染色體顯性變異突變或C-環(huán)突變時，高度惡性的風險似乎更高。研究表明，LQT2屬于孔蛋白突變，LQT3則尚不清楚。特定的基因突可用于鑒別診斷LQTS的高風險人群。

2 Brugada綜合征的危險分層

圖7為一例典型的1型Brugada綜合征患者心電圖。患者男，40歲，有夜間猝死家族史。我們不清楚該患者是否采取藥物治療，心電圖可能采集自第四肋間間隙，或者在第二、第三或肋間間隙較高的位置。他的心電圖可能每天都不同，猝死事件可能在休息時發(fā)生，也可能在運動時發(fā)生。發(fā)燒可能會使猝死發(fā)生率升高，但兒童少見這方面的報道。

1型Brugada綜合征心電圖較2型和3型更易識別，但通過應用Ⅰ類抗心律失常藥物，2型和3型心電圖也可以轉(zhuǎn)化為1型心電圖特征。

目前，Brugada綜合征的危險分層仍存在爭議，普遍接受的觀點是心臟驟?；騐F的患者發(fā)生事件的風險非常高。表現(xiàn)為暈厥等癥狀的患者有較高的危險性。電生理檢查(EPS)誘導性或許可用于預測Brugada綜合征，盡管該指標尚存在爭議，但筆者認為價值有限。自發(fā)交替現(xiàn)象在不同的研究中均被列為危險因素，正如碎裂QRS波。最近，日本的研究表明SCN5A突變可能會使Brugada綜合征的患病風險升高。

碎裂QRS波和自發(fā)性交替現(xiàn)象在心電圖上表現(xiàn)得較為明顯[2-3]。如果一例平時心電圖正常的患者在發(fā)病時出現(xiàn)上述異常心電圖，則提示該患者屬于Brugada綜合征的高危人群。圖8顯示同一患者在不同年齡(55、56、57和58歲)發(fā)生ST段抬高的情況[2]。由圖8可見，有時心電圖是正常的(盡管這可能受到不同電極位置的影響)，但大多數(shù)時間都是異常的，且這種明顯變異的心電圖中存在很多的碎裂波，即室性心律失常的高危因素。

圖9是Brugada綜合征中碎裂QRS波的另一個例子[2]。圖中可見明顯的碎裂QRS，并且它無處不在。Morita等[2]的研究表明，碎裂QRS波提示未來可能發(fā)生猝死事件。

3 兒茶酚胺敏感性多形性室速的危險分層

某病例患有運動性心律失常，如圖10所示，其心電圖具有非常典型的CPVT的特征，但表現(xiàn)為雙向VT和QRS波群交替的形態(tài)。這就是所謂的“雙向性”。臨床上面對這份心電圖時，我們可以強烈質(zhì)疑CPVT的診斷。

CPVT為常染色體顯性遺傳。CPVT最初的臨床表現(xiàn)是在運動或情緒激動時，發(fā)生暈厥或心臟性猝死事件，通常在10歲或20歲以前發(fā)病。目前，已知CPVT有6種亞型。CPVT一般好發(fā)于年輕人，且心電圖基線正常。

CPVT高?；颊唔毞舷铝袟l件中至少一項：① 既往發(fā)生過心臟驟停；② 在年輕時首次出現(xiàn)CPVT；③ 在運動試驗中出現(xiàn)復雜心律失常(圖10)；④ 未使用β受體阻滯劑的患者必定有更高的風險。此外，我們經(jīng)研究得出，CPVT與(某些)智力低下存在相關(guān)性，具體研究結(jié)果尚未公布，但近期已向相關(guān)期刊投稿。

4 核纖層蛋白A/C基因突變致心肌病與遺傳性原發(fā)性心律失常綜合征的關(guān)系

核纖層蛋白A/C基因突變致心肌病不屬于遺傳性原發(fā)性心律失常綜合征，卻以房室阻滯和心房顫動為首發(fā)表現(xiàn)，且早期并沒有明顯的心肌病發(fā)作，到病程晚期才會出現(xiàn)左室功能不全。因此，這類患者起初可能會出現(xiàn)類似原發(fā)性心律失常綜合征的癥狀。該病在神經(jīng)系統(tǒng)的臨床表現(xiàn)包括已知的肢帶肌營養(yǎng)不良，如進行性肌營養(yǎng)不良和肌酸激酶升高；在心臟方面則以一度房室阻滯和心房顫動為最初臨床表現(xiàn)，之后會發(fā)生左室功能不全。心電圖的典型表現(xiàn)為低振幅P波、一度房室阻滯和正常的窄QRS波。

圖11是一位32歲男性患者的心電圖。該患者有猝死家族史，他的父親42歲時死于心力衰竭，他的叔叔在35歲時接受心臟起搏器植入術(shù)，38歲離世。該患者的心電圖表現(xiàn)為極小振幅的P波且有明顯的一度房室阻滯，而QRS波群和復極波完全正常。這是典型的核纖層蛋白A/C基因突變致心肌病，其心電圖提示猝死的高風險。

van Rijsingen等[4]開展的一項多中心研究納入275例患者，研究指出危險因素為左室射血分數(shù)(LVEF)<50%，而非其他理論假設中提出的“LVEF<35%”。24 h動態(tài)心電圖記錄到的非持續(xù)性室速、男性和LVEF<50%，三者均為危險因素，大大增加了發(fā)生室性心律失常的風險。在20個月的隨訪期間，超過30%的患者最終發(fā)展為室速/室顫，故這類患者應該被視為高風險人群。

5 結(jié)語

遺傳性心律失常綜合征的風險評估可總結(jié)如下，① 長QT綜合征：QTc≥500 ms，T波交替和遺傳學異常；② Brugada綜合征：自發(fā)性ST段抬高、多變的心電圖圖形形態(tài)和碎裂QRS波，且臨床癥狀類似于長QT綜合征；③ CPVT：所有患者均需要治療。此外，其他患者，特別是在運動過程中出現(xiàn)復雜心律失常的患者亦處于高危狀態(tài)。對于擴張型心肌病傳導障礙，心電圖的特異性有限，但如果同時存在LMNA作為致病基因，那么通常高度提示擴張型心肌病傳導障礙的風險較高。