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Brugada phenocopy: emergence of a new clinical entity

ByronHGottschalk,DanielDAnselm,AdrianBaranchuk

[Abstract]Brugada phenocopies (BrP) are clinical entities that present with ECG patterns identical to true Brugada syndrome (BrS) but are induced by various clinical conditions. They are characterized by type 1 or type 2 Brugada ECG patterns in precordial leads (V1-V3) that present during an associated underlying condition. Upon resolution of the underlying condition, these ECG patterns normalize. In this study, we reviewed the classification of BrP, methods for differentiating BrP from BrS, and recently discussed etiologies of BrP. In addition, we provided an update on the international online registry for BrP and discussed future directions in BrP research.

[Key words]Brugada ECG pattern; Brugada phenocopy; Brugada syndrome

1Introduction

Brugada syndrome (BrS) is an inherited sudden cardiac death syndrome with autosomal dominant inheri-tance and variable penetrance. Over 70 mutations have been linked to the condition, most of which are found in cardiac sodium channels[1]. About 20-30 percent of patients affected by true BrS will have an identifiable SCN5A mutation[2].The condition is characterized on ECG by ST-segment changes in the right precordial leads (V1-V3) resulting in two defining patterns. The Type 1 (“coved”) Brugada ECG pattern is defined by a high take-off ST-segment elevation(≥2 mm), followed by a slow down-sloping concave or rectilinear ST-segment and a negative symmetric T wave (Fig.1)[1]. The Type 2 (“saddleback”) Brugada ECG pattern presents with a high take-off r′≥2 mm from the isoelectric baseline, followed by a convex ST-segment elevation of ≥0.05 mV with a variable T wave in lead V1and a positive or flat T-wave in lead V2(Fig.2)[1].While these patterns serve as the hallmark of BrS, it is important to note that the changes seen on ECG may be dynamic and are often concealed. In some patients, the typical ECG findings are “unmasked” by certain drugs or febrile states[3-4]. A personal or family history of syncope or aborted sudden cardiac death(SCD) provide additional clues to the BrS diagnosis. In cases where the diagnosis is not clear based on history and ECG changes alone, a positive provocative challenge with a potent sodium channel blocking agent such as ajmaline, procainamide, or flecainide suggests sodium channel dysfunction. BrS is important to identify as it is associated with a high risk for sudden cardiac death in young, otherwise healthy adults[5]. Upon diagnosis, patients should undergo risk stratification to determine their likelihood of malignant ventricular arrhythmias and high-risk patients are often referred for implantable cardiac defibrillator (ICD) therapy to reduce the morbidity and mortality associated with BrS.

(A) True congenital type 1 Brugada syndrome electrocardiogram shown in comparison to (B) congenital hypokalemic periodic paralysis

(A) True congenital type 2 Brugada syndrome shown in comparison to (B) congenital pectus excavatum causing mechanical mediastinal

Brugada phenocopies (BrP) are clinical entities with ECG findings identical to either the type 1 or type 2 Brugada ECG patterns yet differ etiologically from true congenital BrS[6-8]. These patient’s ECG findings are associated with an identifiable condition and upon resolution of that condition, the ECG pattern normalizes. Importantly, these patients have a negative sodium channel blocker provocative challenge suggesting a pathophysiological basis other than sodium channel dysfunction[7]. Alternatively, the sodium channel dysfunction may be transient occurring only during the inciting clinical event such as metabolic abnormality or ischemia, although this remains speculative. While the arrhythmogenic properties of BrS are well known along with the risk of sudden cardiac death, not much is known about the natural history of BrP. In an effort to facilitate research into the various etiologies, pathophysiology, and prognosis of the condition, we have developed an online educational portal and international registry for BrP (see www.brugadaphenocopy.com)[8]. This paper reviews previous cases of BrP, the various etiologies that have been identified in BrP, and future directions in research on this relatively new clinical entity.

2Classification of BrP

BrP may be induced under a multitude of clinical circumstances that have been characterized in six distinct etiological groups: (i) metabolic conditions, (ii) mechanical compression, (iii) ischemia, (iv) myocardial and pericardial disease, (v) ECG modulation, and (vi) miscellaneous(Tab.1)[7, 9]. In addition, they are further classified according to the presenting ECG morphology: type 1 BrP if the patient presents with a type 1 Brugada ECG pattern; or type 2 BrP if the patient presents with a type 2 Brugada ECG pattern. Cases of BrP are further sub-classified as A, B, and C(Tab.1). Class A includes true BrP in which all mandatory diagnostic criteria have been including negative provocative challenge with a sodium channel blocking agent. Class B includes cases highly suspected to be BrP; however, the mandatory diagnostic criteria are incomplete. These are cases where a provocative challenge is not possible due to factors such as the patient being deceased or lost to follow-up. Class C includes highly suspected cases of BrP; however, provocative testing was not justified such as in cases with recent surgical right ventricular outflow tract(RVOT) manipulation[10].

Tab.1　Brugada phenocopy etiological categories and morphological classification system

Adapted from Gottschalk et al[10]

3Differentiating BrP from BrS

Establishing a clear diagnostic distinction between BrP and BrS is of the utmost importance[11-12]. The fact that BrS may occur spontaneously, with no personal or family history of suggestive of the condition and in the absence of known genetic abnormalities makes differentiating between the two conditions challenging[1-2]. Current recommendations for diagnosis and risk stratification of BrS rely on a combination of clinical factors, presenting ECG morphologies, and positive provocative testing with a sodium channel blocking agent. It is this combination of factors that guides the clinical decision of whether to implant an ICD or not[1]. Similarly, the clinical diagnosis of BrP requires clinical factors(an identifiable underlying condition that triggers the ECG pattern in the absence of personal or family history suggestive of BrS), presenting ECG morphologies identical to BrS that normalizes upon resolution of the underlying condition, and a negative provocative test with sodium channel blocking agents[7]. Tab.2 depicts the current recommended systematic diagnostic criteria for BrP.

The importance of this distinction is highlighted by the natural history of the two conditions; while for patients with high risk of BrS who are candidates for treatment with an ICD, the clinical implications of BrP remain unknown. Therefore, current recommendations for treatment of BrP focus on resolving the underlying condition.

3.1Methods

Using Ovid MEDLINE(R) and Ovid OLDMEDLINE(R) from 1947 to May Week 1 2015, EMBASE from 1980 to May Week 1 2015, and PubMed we performed a search using “Brugada Syndrome”MeSH heading combined with keyword searches for “Brugada Phenocopy”“mimicking Brugada”“induced Brugada syndrome”“acquired Brugada”“Brugada-like”“Brugada type”, and “Brugada pattern”. The results were reviewed and case reports were selected according to the following inclusion criteria: (i) the case report was published; (ii) the case report includes a legible ECG showing a Brugada ECG pattern; (iii) the patient in the case does not have true BrS determined by a low clinical probability, absence of a positive provocative test, and/or absence of a positive genetic test for BrS. Case reports were excluded if they reported an example of confirmed (or suspected) underlying BrS being unmasked by drug, fever, or other clinical circumstances.

Tab.2　Brugada phenocopy diagnostic criteria

Adapted from Anselm et al[13]. Abbreviation: ECG, electrocardiogram; RVOT, right ventricular outflow tract; SCN5A, sodium channel voltage-gated type V alpha subunit

3.2Results

Fifty-eight case reports, reporting 71 individual cases of BrP met our inclusion criteria. These cases were classified according to the updated classification of BrP[9]. Tab.3 depicts an updated summary of BrP as of May, 2015. Since the first literature review on BrP published by our group in 2012, 37 cases have been added to the database[7]. These include BrP in the context of myocardial infarction, pulmonary embolism, and intracranial hemorrhage.

Tab.3　Summary of Brugada Phenocopy Registry

Continued

Quoted from Gottschalk et al[8]

3.2.1BrP：myocardial infarctionAt this time,there are 5 cases of BrP in the context of myocardial ische-mia[14-18]. Of the reports demonstrating BrP in the context of myocardial infarction, 3 were the result of a right coronary artery occlusion and 2 were the result of a left coronary artery occlusion. All 5 of the cases presented without a family history or personal history suggestive of BrS, thus making BrP very likely. Two of the 5 cases was a confirmed type 1A BrP in that all the diagnostic criteria were met[14, 18].

Is ischemia eliciting BrP or unmasking BrS?

Interestingly, ischemia may either induce BrP as previously discussed, or it may result in unmasking of true BrS through modulation of myocardial sodium channels[19-20]. Two interesting case reports demonstrate this phenomenon and illustrate the importance of proper diagnostic investigations in this patient population[18, 21]. Jiang et al[18]described a patient who presented with a type 1 Brugada ECG pattern and elevated troponin Ⅰ levels shortly after radiofrequency catheter ablation as treatment of atrial fibrillation. The patient underwent coronary angiography that revealed a sub-total occlusion in the first diagonal. In this case, we hypothesized that the ST-segment elevations produced after this procedure were likely the result of ischemia[20]. This patient underwent a diagnostic provocative test using a sodium channel blocker for BrS. The result was negative,which coupled with the patient’s lack of personal or family history suggestive of BrS, which was diagnostic for a type 1A BrP due to myocardial ischemia. This case is the second confirmed BrP reported in the context of myocardial ischemia in the international registry.

In contrast to the previously discussed case, Garg et al[21]discussed a particularly interesting case of a patient presenting with a Brugada ECG pattern during an acute coronary event. This patient subsequently underwent a provocative test with ajmaline, which proved to be positive, thereby diagnosing BrS in this patient that was unmasked by ischemia.

These cases highlight the need to investigate the cause of a Brugada ECG pattern. Indeed, the patient described by Garg et al would require risk stratification in order to determine his risk for SCD.

3.2.2BrP：pulmonary embolismTo date, there have been 4 reported cases of BrP in the context of acute pulmonary embolism[22-24]. Three of these cases presented with a type 1 Brugada ECG pattern while the final case presented with a type 2 Brugada ECG pattern. The phenomenon of right precordial ST-elevations caused by moderate to severe pulmonary emboli has been previously reported in the literature[25-28]. In all 4 reported cases of BrP in the context of acute pulmonary embolism, the responsible embolism was either large or massive. A speculated mechanism behind these ECG manifestations is the idea that large emboli results in significant right ventricular strain leading to transient sodium channel dysfunction[13].Zhan et al[24]further postulated that the right ventricular strain results in transmural ischemia of the right ventricle leading to the ST-elevations through a similar mechanism that is found during BrP in the context of right ventricular myocardial infarctions.

3.2.3BrP：neurological diseaseOur group published the first documented case of a confirmed BrP caused by a neurological condition in 2014[29].Briefly, an 85-year-old man was admitted to ICU after syncope complicated by traumatic head injury. A CT scan demonstrated temporo-parietal subarachnoid hemorrhage and 12 hours after the patient was admitted, he developed a type 2 Brugada ECG pattern that resolved within 9 hours. This patient underwent a subsequent CT scan demonstrating an insular hematoma with intraventricular hemorrhage.The patient underwent sodium channel provocation with flecainide that failed to induce a Brugada ECG pattern.He was therefore diagnosed with a type 2A BrP.There are various reports in the literature of cardiac manifestations of neurologic disease[30-32].These complications include ST-segment elevation on ECG in cases of subarachnoid hemorrhage. Indeed, there are multiple reports[30, 33-35]of the relationship between the insular region and ECG abnormalities(including ST-segment elevation).We postulated that our patient’s Brugada ECG manifestations were a result of neurological dysfunction caused by hematoma formation in the insular region of the brain[29].It is likely that resolution of the pressure effect of the hematoma resulted in normalization of the ECG pattern in this patient.To our knowledge,this is the only published case of BrP due to a neurologic disease to date and the only case of its kind registered in our international database.

3.3Future directions

Most reported cases of BrP discussed a single inciting event such as metabolic derangement or myocardial ischemia during which the Brugada ECG pattern was observed. Recently, we advanced the concept of clinical reproduction in BrP where resolution of an underlying condition resulted in normalization of the ECG[36]. The pattern subsequently reappeared when the same underlying condition reoccurred. In short, a young patient with diarrhea was admitted to the hospital following the development of severe hypokalemia(K+1.5 mEq/L). An ECG was performed and demonstrated a type 1 Brugada ECG pattern. After correction of the patient’s metabolic abnormalities, an ECG showed resolution of the Brugada ECG pattern. During the same admission, the patient again became hypokalemic(K+2.6 mEq/L) due to ongoing gastrointestinal losses. The corresponding ECG demonstrated recurrence of the type 1 Brugada ECG pattern that subsequently normalized after correction of the metabolic derangement. This patient had no personal or family history suggestive of BrS and underwent a negative provocative challenge. This is the first case that demonstrated clinical reproducibility of BrP.

Future investigations of BrP must focus on the development of experimental models designed to fully understand the mechanisms behind BrP. Through experimentation, we will begin to understand whether BrP are the result of transient sodium channel dysfunction that is not reproduced by sodium channel blocking agents, or whether the key to the ECG manifestations lies in malfunction of other ion channels. We may find that BrP and BrS are indeed entities along a continuous spectrum of ion channel dysfunction.

3.4Conclusions

The BrP international registry is aimed at furthering knowledge on the etiology, pathophysiology, and natural history of these phenomena. At this point, it is unknown whether BrP is a risk factor for malignant arrhythmias since there have been no studies examining the long-term prognosis of these patients. The question of clinical reproducibility of BrP has been demonstrated through one report thus far; however, we will be looking for more such examples in the future. Questions that remain unanswered include whether development of BrP predisposes patients to malignant arrhythmias under certain clinical conditions, or whether a patient that develops BrP in the context of one etiology is at risk of developing BrP in another etiology. The international database will aid in answering these questions through collating patients, identification of patterns, and assessing the long-term morbidity and mortality of these patients with longitudinal follow-up. Within the first year of the website being operational, it has generated over 2 000 unique visitors resulting in the submission of a number of potential BrP cases. With further awareness of the concept and more widespread use of the term “Brugada phenocopy” in the literature, we expect this number to grow more rapidly. In order to facilitate research on this phenomenon, we encourage other investigators to use the term “Brugada phenocopy” when reporting such cases. In addition, we invite the submission of cases to our online international registry at www.brugadaphenocopy.com.

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Brugada擬表型：一個(gè)新的臨床實(shí)體

ByronHGottschalk,DanielDAnselm,AdrianBaranchuk蔣祖勛 譯并審校

[摘要]Brugada擬表型(Brugada phenocopy, BrP)是臨床實(shí)體,它與真正的Brugada綜合征(Brugada syndrome, BrS)具有相同的心電圖波形,但前者是由各種臨床狀況誘發(fā)的。在某種相關(guān)的潛隱狀況下,BrP的特征表現(xiàn)為心前區(qū)導(dǎo)聯(lián)V1～V3呈1型或2型Brugada心電圖波形。隨著潛隱狀況的糾正,這些心電圖波形恢復(fù)正常。本研究中,我們回顧了BrP的分類、與BrS鑒別的方法及有關(guān)BrP病因的最新研究結(jié)果。此外,我們提供了BrP國際在線注冊的更新數(shù)據(jù),并討論了BrP未來的研究方向。 表3Brugada擬表型注冊的類別個(gè)體數(shù)量(病例報(bào)道的數(shù)量)平均年齡(范圍)男性:女性BrP類型代謝狀況33(26)49±16(19~89)23:82例未知Type1A:8Type2A:1Type1B:17Type2B:7Type1C:0Type2C:0機(jī)械壓迫11(10)42±23(1~71)6:5Type1A:8Type2A:1Type1B:5Type2B:1Type1C:2Type2C:0缺血和肺動(dòng)脈栓塞8(7)54±9(43~70)3:5Type1A:1Type2A:0Type1B:5Type2B:2Type1C:0Type2C:0心肌和心包疾病10(7)48±12(28~72)7:3Type1A:2Type2A:1Type1B:5Type2B:2Type1C:0Type2C:0心電圖調(diào)制3(3)34±19(20~55)2:1Type1A:0Type2A:1Type1B:0Type2B:0Type1C:0Type2C:2其他6(5)33±30(7~85)3:3Type1A:0Type2A:2Type1B:1Type2B:1Type1C:2Type2C:0

[關(guān)鍵詞]Brugada心電圖波形; Brugada擬表型; Brugada綜合征

1引言

Brugada綜合征(Brugada syndrome, BrS)是一種遺傳心源性猝死綜合征,具有常染色體顯性遺傳和可變的外顯率。超過70種基因突變與這種狀況有關(guān),大多數(shù)突變發(fā)現(xiàn)在心臟鈉通道中[1]。在真正的BrS患者中,約20%～30%可檢測出SCN5A基因突變[2]。這種狀況的特征性心電圖表現(xiàn)為在右心前區(qū)導(dǎo)聯(lián)V1～V3上出現(xiàn)ST段改變,產(chǎn)生兩個(gè)典型的波形。1型(穹窿型)Brugada心電圖波形定義為迅速上升的ST段抬高(≥2 mm),緊接著一個(gè)較慢的下斜凹面或直線ST段,以及負(fù)性對稱T波[圖1：各種1型Brugada擬表型(Brugada phenocopy, BrP)的比較；(A) 真正的先天性1型BrS心電圖；(B) 先天性低鉀周期性癱瘓(1B型BrP)；(C) 急性下壁ST段抬高型心肌梗死伴右室受累(1A型BrP)；(D) 并行高鉀、低鈉及酸中毒(1A型BrP)；(E) 急性肺動(dòng)脈栓塞(1B型BrP)。圖下數(shù)字是BrP國際注冊的身份編號。][1]。2型(馬鞍型)Brugada心電圖波形表現(xiàn)為從等電位基線出現(xiàn)一個(gè)迅速上升的r′≥2 mm,緊接著一個(gè)凸面ST抬高(≥0.05 mV),伴V1導(dǎo)聯(lián)變化的T波和V2導(dǎo)聯(lián)正向或扁平的T波[圖2：各種2型BrP的比較；(A) 真正的先天性2型BrS；(B) 先天性漏斗胸引起機(jī)械縱隔壓迫(2A型BrP)；(C) 急性心包炎(2A型BrP)；(D) 意外觸電損害后(2A型BrP)；(E) 采用不恰當(dāng)?shù)母咄ㄐ碾妶D濾波的結(jié)果(2C型BrP)。圖下數(shù)字是BrP國際注冊的身份編號。][1]。當(dāng)把這些波形作為BrS的標(biāo)志時(shí),需要特別注意的是,心電圖上看到的改變可以是動(dòng)態(tài)的并且常常是不易被發(fā)現(xiàn)的。對一些患者而言,某種藥物或發(fā)熱狀態(tài)可使典型的心電圖表現(xiàn)暴露出來[3-4]。暈厥或心源性猝死(SCD)中止的個(gè)人或家族病史提供了BrS診斷的另一線索。對于單純基于病史和心電圖改變難以確診的患者,采用強(qiáng)力鈉通道阻滯劑(如阿馬林、普魯卡因胺或氟卡尼)進(jìn)行的陽性激發(fā)試驗(yàn)可提示鈉通道功能失常。由于與年輕人及健康成人的心源性猝死高危分層相關(guān),因此BrS的識別是很重要的[5]。依據(jù)診斷,應(yīng)對患者進(jìn)行危險(xiǎn)分層以決定其發(fā)生惡性心律失常的可能性,并且高?；颊叱１灰罂紤]植入心臟除顫器(ICD),以降低BrS相關(guān)的發(fā)病率和死亡率。

BrP是臨床實(shí)體,其心電圖表現(xiàn)與1型或2型BrS心電圖波形相同,然而在病因?qū)W上又不同于真正的先天性BrS[6-8]。這些患者的心電圖表現(xiàn)與某種可辨識的狀況相關(guān)聯(lián),且隨著這種狀況的糾正,心電圖波形恢復(fù)正常。重要的是,這些患者的鈉通道阻滯劑激發(fā)試驗(yàn)結(jié)果呈陰性,提示除鈉通道功能失常以外還存在病理生理基礎(chǔ)[7]。或者,鈉通道功能失?？赡軆H僅一過性地出現(xiàn)在刺激性臨床事件中,如代謝異?；蛉毖?盡管這仍然是推測性的。人們能夠清楚地認(rèn)識BrS的致心律失常特性與心源性猝死風(fēng)險(xiǎn),然而關(guān)于BrP的自然病史卻所知不多。為了推進(jìn)病因?qū)W、病理生理學(xué)和疾病預(yù)后等各層面的研究,我們開發(fā)了一個(gè)在線教育入口和BrP國際注冊系統(tǒng)(見www.brugadaphenocopy.com)[8]。本文回顧了之前的BrP病例、已識別的BrP病因以及這種相對較新的臨床實(shí)體的未來研究方向。

2BrP的分類

BrP可在許多臨床環(huán)境下被誘發(fā),依特征分為6個(gè)病因組：① 代謝狀況；② 機(jī)械壓迫；③ 缺血；④ 心肌和心包疾?。虎?心電圖調(diào)制；⑥ 其他(表1)[7, 9]。此外,依據(jù)表現(xiàn)出來的心電圖形態(tài),BrP可被進(jìn)一步分類：1型BrP,如果患者表現(xiàn)為1型Brugada心電圖波形；或2型BrP,如果患者表現(xiàn)為2型Brugada心電圖波形。BrP的病例還能進(jìn)一步亞分為A、B和C類(表1)。A類包括真正的BrP,所有的強(qiáng)制診斷標(biāo)準(zhǔn)是完整的,包括鈉通道阻滯劑的激發(fā)試驗(yàn)結(jié)果呈陰性。B類包括高度懷疑BrP的病例,然而強(qiáng)制診斷標(biāo)準(zhǔn)是不完備的。由于患者死亡或無法進(jìn)行隨訪等因素,對上述病例不可能進(jìn)行激發(fā)試驗(yàn)。C類包括高度懷疑BrP的病例,然而激發(fā)試驗(yàn)不適用,例如近期行右心室流出道外科手術(shù)的病例[10]。

表1　Brugada擬表型病因類別和形態(tài)分類系統(tǒng)病因類別

改編自Gottschalk等[10]

3BrP與BrS的鑒別

建立BrS和BrP之間清晰的鑒別診斷標(biāo)準(zhǔn)至關(guān)重要[11-12]。BrS可在無相關(guān)個(gè)人或家族病史,且缺乏已知的基因異常的情形下自發(fā)出現(xiàn),這就使二者的鑒別具有挑戰(zhàn)性[1-2]。對于BrS的診斷和危險(xiǎn)分層,目前推薦綜合臨床因素、表現(xiàn)出的ECG形態(tài)和鈉通道阻滯劑的陽性激發(fā)試驗(yàn)加以考量。正是這些因素的結(jié)合指導(dǎo)臨床決定是否植入ICD[1]。類似地,BrP的診斷要求臨床因素(即某種可識別的潛隱狀況,在無BrS相關(guān)個(gè)人或家族病史的情況下引發(fā)相應(yīng)的ECG波形),表現(xiàn)出與BrS相同的、隨潛隱狀況糾正而正?；腅CG形態(tài),以及鈉通道阻滯劑激發(fā)試驗(yàn)陰性[7]。表2為目前推薦的BrP的診斷標(biāo)準(zhǔn)。

這兩種狀況的自然病史使BrP與BrS鑒別的重要性更為突出；而對BrS高危且預(yù)備進(jìn)行ICD治療的患者而言,臨床上是否預(yù)示著發(fā)生BrP尚不明確。因此目前對BrP的治療,我們推薦先集中精力改善潛隱狀況。

表2　Brugada擬表型診斷標(biāo)準(zhǔn)

改編自Anselm等[13]?？s寫：RVOT,右心室流出道；SCN5A,鈉通道電壓門控V型a亞單位

3.1方法

我們以“Brugada綜合征”為MeSH主題詞,以“Brugada擬表型”“擬Brugada”“誘發(fā)的Brugada綜合征”“獲得性Brugada”“Brugada樣”“Brugada型”和“Brugada波形”為關(guān)鍵詞,應(yīng)用Ovid MEDLINE(R)和Ovid OLDMEDLINE(R)搜索從1947年至2015年5月第一周、EMBASE搜索從1980年至2015年5月第一周及PubMed搜索相關(guān)文獻(xiàn)。我們對結(jié)果進(jìn)行了回顧分析,且依據(jù)下列納入標(biāo)準(zhǔn)選取病例報(bào)告：① 該病例報(bào)告已發(fā)表；② 該病例報(bào)告中至少有一張顯示Brugada心電圖波形的清晰的心電圖；③ 由于較低的臨床可能性、未做陽性激發(fā)試驗(yàn)和/或未做BrS的陽性基因測試,判斷病例中的患者未患有真正的BrS。排除標(biāo)準(zhǔn)：由于藥物、發(fā)熱或其他臨床環(huán)境,而被揭示出來的確認(rèn)(或疑似)的潛在BrS。

3.2結(jié)果

我們共選出58份病例報(bào)告,報(bào)道了71例BrP個(gè)案病例,其均滿足事先設(shè)定的納入標(biāo)準(zhǔn)。依據(jù)更新的BrP分類標(biāo)準(zhǔn)[10]對這些病例進(jìn)行分類。表3為2015年5月更新的BrP國際注冊的統(tǒng)計(jì)數(shù)據(jù)。自從2012年我們團(tuán)隊(duì)發(fā)表了第一篇關(guān)于BrP的文獻(xiàn)綜述,已有37個(gè)病例加入到了這一數(shù)據(jù)庫中[7]。這些病例包括心肌梗死、肺動(dòng)脈栓塞和顱內(nèi)出血合并的BrP。

續(xù)表

引自Gottschalk等[8]

3.2.1BrP： 心肌梗死此時(shí),在心肌梗死的情況下有5例BrP[14-18]。在心肌梗死背景下顯示BrP的報(bào)道中,3例是由右冠狀動(dòng)脈阻塞導(dǎo)致的,2例是由左冠狀動(dòng)脈阻塞導(dǎo)致的。上述所有5例患者并沒有BrS相關(guān)的個(gè)人或家族病史,由此患有BrP的可能性很大。5例中的2例被確認(rèn)為1A型BrP,滿足所有的診斷標(biāo)準(zhǔn)[14, 18]。

缺血將會(huì)激發(fā)BrP,還是會(huì)暴露BrS？

有趣的是, 缺血既可以誘發(fā)BrP(正如先前討論的),也可以通過心肌鈉通道的調(diào)制使真正的BrS暴露出來[19-20]。兩例有趣的病例報(bào)道證實(shí)了這一現(xiàn)象并且闡明了對該類患者群進(jìn)行適當(dāng)?shù)脑\斷性調(diào)查的重要性[18, 21]。Jiang等[18]報(bào)道了一例患者,行心房顫動(dòng)射頻消融術(shù)后短時(shí)間內(nèi)表現(xiàn)為1型Brugada心電圖和肌鈣蛋白Ⅰ水平升高。冠脈造影顯示該患者第一對角支幾乎完全阻塞。在這一病例中,我們假定消融術(shù)后產(chǎn)生的ST段抬高可能是缺血造成的[20]。該患者因BrS接受了鈉通道阻滯劑的診斷性激發(fā)試驗(yàn)。激發(fā)試驗(yàn)呈陰性,加之缺乏BrS相關(guān)的個(gè)人或家族病史,患者診斷為心肌缺血引起的1A型BrP。在BrP國際注冊中,上述病例是心肌缺血背景下第二例確診的BrP。

對比先前討論過的病例,Garg等[21]討論了一例在急性冠脈事件中表現(xiàn)出Brugada心電圖波形的特別有趣的病例。該患者隨后做了一次阿馬林激發(fā)試驗(yàn),結(jié)果呈陽性,由此診斷為缺血所暴露的BrS。

這些病例說明探討B(tài)rugada心電圖波形的成因很有必要。實(shí)際上,應(yīng)對Garg描述的這些患者進(jìn)行危險(xiǎn)分層,以判斷其心源性猝死的風(fēng)險(xiǎn)。

3.2.2BrP： 肺動(dòng)脈栓塞迄今為止,在急性肺動(dòng)脈栓塞的背景下,我們已有4例BrP的報(bào)道[22-24],其中3例表現(xiàn)為1型Brugada心電圖波形,1例表現(xiàn)為2型Brugada心電圖波形。由中度至嚴(yán)重肺動(dòng)脈栓塞引起的右心前區(qū)導(dǎo)聯(lián)ST段抬高的現(xiàn)象,之前已經(jīng)相關(guān)文獻(xiàn)[25-28]報(bào)道。在所有報(bào)道的4例急性肺動(dòng)脈栓塞背景下的BrP病例中,起重要影響的栓塞要么是大塊,要么是巨大塊。據(jù)猜測,出現(xiàn)這些心電圖表現(xiàn)的機(jī)制是大栓塞產(chǎn)生明顯的右室牽張,從而導(dǎo)致一過性鈉通道功能失常[13]。Zhan等[24]進(jìn)一步推測：右室牽張產(chǎn)生右室透壁性缺血,繼而導(dǎo)致ST段抬高,其發(fā)生機(jī)制就類似于右室心肌梗死背景下發(fā)生BrP的機(jī)制。

3.2.3BrP：神經(jīng)系統(tǒng)疾病我們研究團(tuán)隊(duì)在2014年公開發(fā)表了第一例確診的BrP病例[29],其是由神經(jīng)系統(tǒng)狀況引起的。簡述如下：患者男,85歲,因暈厥合并頭部外傷收入ICU。CT掃描示顱頂部蛛網(wǎng)膜下腔出血；入院12 h后,該患者出現(xiàn)2型Brugada心電圖波形,9 h內(nèi)消失。隨后再行CT掃描,顯示存在一個(gè)孤立的血腫伴腦室內(nèi)出血。對該患者用氟卡尼進(jìn)行鈉通道激發(fā)試驗(yàn),未能誘發(fā)Brugada心電圖波形。由此該患者被診斷為2A型BrP。在反映神經(jīng)系統(tǒng)疾病心臟表現(xiàn)的相關(guān)文獻(xiàn)中,已有多篇報(bào)道[30-32]。在蛛網(wǎng)膜下腔出血的病例中,這些并發(fā)癥包括心電圖ST段抬高。實(shí)際上,已有多篇報(bào)道[30, 33-35]涉及孤立區(qū)域和心電圖異常(包括ST段抬高)之間的關(guān)系。 現(xiàn)在我們假定患者的Brugada心電圖表現(xiàn)是腦部孤立區(qū)域血腫形成、引起神經(jīng)功能失常所致[29]。血腫壓力效應(yīng)的消退有可能使該患者的心電圖波形恢復(fù)正常。據(jù)我們所知,這是迄今為止報(bào)道的唯一一例神經(jīng)系統(tǒng)疾病所致的BrP病例,并且這類病例在我們的BrP國際數(shù)據(jù)庫中也僅注冊了一例。

3.3未來研究方向

大多數(shù)BrP病例報(bào)道討論的是在一個(gè)單獨(dú)的激發(fā)事件(如代謝失常或心肌缺血)過程中所觀察到Brugada心電圖波形。近年來,我們發(fā)展了BrP臨床再現(xiàn)的概念,某種潛隱狀況的糾正將導(dǎo)致心電圖正?；痆36]。當(dāng)同樣的潛隱狀況再次發(fā)生時(shí),這種心電圖波形隨后再次出現(xiàn)。下面簡要介紹一例。一位年輕患者因腹瀉入院,繼而發(fā)展為嚴(yán)重的低鉀(K+1.5 mEq/L)。心電圖顯示為1型Brugada波形?；颊叩拇x異常糾正后,心電圖示Brugada波形消失。住院期間,患者因持續(xù)的胃腸道損失而再次出現(xiàn)低鉀狀況(K+2.6 mEq/L)。相應(yīng)的心電圖顯示再次出現(xiàn)1型Brugada心電圖波形,代謝失常糾正后波形恢復(fù)正常。該患者無BrS相關(guān)的個(gè)人或

家族病史,且激發(fā)試驗(yàn)呈陰性。這是證實(shí)BrP臨床再現(xiàn)性的第一例。

未來的BrP研究應(yīng)當(dāng)聚焦于設(shè)計(jì)和發(fā)展實(shí)驗(yàn)?zāi)Ｐ?以便完全理解BrP的發(fā)生機(jī)制。借助實(shí)驗(yàn),我們將逐步了解BrP是否是一過性的鈉通道功能失常(利用鈉通道阻滯劑無法重現(xiàn))造成的,或者心電圖表現(xiàn)的發(fā)生機(jī)制是否在于其他離子通道功能失常。我們可能發(fā)現(xiàn)：BrP和BrS實(shí)際上是沿著離子通道功能失常連續(xù)譜系存在著的臨床實(shí)體。

3.4結(jié)論

BrP國際注冊旨在增進(jìn)人們對上述現(xiàn)象在病因?qū)W、病理生理學(xué)及自然病史方面的了解。就這一點(diǎn)而言,BrP是否是惡性心律失常的危險(xiǎn)因素尚不明確,原因是目前還沒有關(guān)于這些患者長期預(yù)后的研究。迄今為止,BrP臨床再現(xiàn)性的問題已被一份病例報(bào)告所證實(shí),然而將來我們會(huì)尋找更多這樣的例子。仍有待回答的問題包括：BrP的進(jìn)展是否易使患者在某種臨床狀況下發(fā)生惡性心律失常；或由于某一病因發(fā)生BrP的患者在另一病因下是否有發(fā)生BrP的風(fēng)險(xiǎn)。通過整理患者資料、鑒別心電圖波形,以及在縱向隨訪中評價(jià)這些患者的長期發(fā)病率和死亡率,我們所開發(fā)的國際數(shù)據(jù)庫將有助于回答上述問題。在網(wǎng)站開放的第一年內(nèi),它吸引了超過2 000位獨(dú)立訪問者,并提交了大量潛在的BrP病例。隨著對這一概念認(rèn)識的加深以及在文獻(xiàn)中越來越普遍地使用“Brugada擬表型”這一術(shù)語,我們期待著它的使用頻次增長得更為迅速。為了方便對該現(xiàn)象的研究,我們鼓勵(lì)其他研究者在報(bào)道這樣的病例時(shí)運(yùn)用術(shù)語“Brugada擬表型”。此外,我們誠邀研究者們將相關(guān)病例提交到我們的BrP在線國際注冊系統(tǒng),見www.brugadaphenocopy.com。

參考文獻(xiàn)(圖和請查閱前面的英文原文)

【致謝】衷心感謝廣東省人民醫(yī)院心功能科的蔣祖勛主任在百忙中承擔(dān)了本文的翻譯和審校工作。

(本文編輯：顧艷)

作者單位： 050031 河北 石家莊,河北醫(yī)科大學(xué)第一醫(yī)院急診科(蘇冠麗,李斌),心血管內(nèi)科(劉剛,鄭明奇)

作者單位： 050051 河北 石家莊,河北醫(yī)科大學(xué)附屬石家莊市第三醫(yī)院心血管內(nèi)科(劉紅彬,張曉華,劉志紅)；050041 河北 石家莊,石家莊市建北社區(qū)衛(wèi)生服務(wù)中心心血管內(nèi)科(張志剛)

專題主持/劉剛

Author Unit： K7L 2V7 Kingston, Ontario, Canada, Department of Cardiology, Kingston General Hospital, Queen’s University(Byron H Gottschalk, Adrian Baranchuk); T2N 2T9 Calgary, Alberta, Canada, Libin Cardiovascular Institute of Alberta, Foothills Medical Centre, University of Calgary(Daniel D Anselm

Author Brief Introduction：Byron H Gottschalk,BMSc,medical student at Queen’s University;research interests:Brugada phenocopy,Brugada ECG pattern.

Correspondence Author:Adrian Baranchuk, E-mail: barancha@kgh.kari.net

通信作者：劉剛,E-mail：cardio2004@163.com

作者簡介：蘇冠麗,主治醫(yī)師,主要從事心血管內(nèi)科研究。 劉紅彬,主任醫(yī)師、教授,主要從事冠心病及其介入治療研究,E-mail：lhbyxr@126.com

基金項(xiàng)目：河北省科技計(jì)劃項(xiàng)目(13277720D)；河北省重大醫(yī)學(xué)科研課題資助項(xiàng)目(zd2013081,ZL201320,ZL20140141) 河北省科技計(jì)劃項(xiàng)目(13277720D)

收稿日期：(2015-06-19)

[中圖分類號]R541; R540.4

[文獻(xiàn)標(biāo)志碼]A

[文章編號]2095-9354(2015)04-0245-11

DOI：10.13308/j.issn.2095-9354.2015.04.002 10.13308/j.issn.2095-9354.2015.04.002