Lesson Sixty Arrhythmogenicrightventricular dysplasia/cardiomyopathyand cardiac sarcoidosis distinguishing features when the diagnosis is unclear

●思考與分析

●心電學(xué)英語

Lesson Sixty Arrhythmogenicrightventricular dysplasia/cardiomyopathyand cardiac sarcoidosis distinguishing features when the diagnosis is unclear

Arrhythmogenic right ventricular dysplasia/cardiomyopathy（ARVD/C）is an inherited desmosomal cardiomyopathy characterized by fibrofatty replacement of the right ventricular（RV）myocardium.Disease expression is variable and the spectrum of structural changes range from subtle basal RV involvement to diffuse biventricular involvement.The broad spectrum of phenotypic manifestations makes the clinical diagnosis challenging.In the absence of histological evidence of myocardial fibrofatty replacement，the diagnosis is often established based on fulfilling various clinical criteria proposed by an International Task Force.Unfortunately，other infiltrative myocardial diseases，such as cardiac sarcoidosis（CS）1，may show overlap in clinical presentation and meet the 2010 Task Force Criteria as well. Being able to distinguish between the 2 is clinically important as the diagnostic and treatment strategies vary significantly and may involve genetic testing of family members or use of systemic immunosuppression.These reports suggest that there may be distinguishing features.

Patient Registry and Diagnostic Evaluation

Among 1140 patients enrolled，15 patients who were initially diagnosed with definite ARVD/C before referral were ultimately diagnosed as having CS.The control group consisted of probands who were selected based on（1）harboring a pathogenic ARVD/C-associated desmosomal mutation2，（2）fulfilling definite 2010 diagnostic criteria for ARVD/C，and（3）the availability of a comprehensive set of data for analysis.

The 2010 diagnostic criteria were used to establish a diagnosis of ARVD/C.Definite ARVD/C was characterized by the presence of≥2 major criteria，1 major and 2 minor criteria or 4 minor criteria.2

The diagnosis of CS was based on the Japanese guidelines revised in 2006 by the Japan Society of Sarcoidosis and Other Granulomatous Disorders.7

Patient Characteristics

Among 1140 patients enrolled in the Johns Hopkins ARVD/C registry，15 patients were subsequently diagnosed with CS.Forty-two probands harboring pathogenic ARVD/C-associated desmosomal mutations and fulfilling definite 2010 Diagnostic criteria for ARVD/C served as a control group（Table 1）.

Demographic Features and Clinical History

The predominant presenting symptom for both groups was palpitations and≈30%had syncope.The majority of patients in both groups presented initially with ventricular arrhythmias and among these patients，the morphology was predominantly left bundle branch block for both groups.Twenty-nine percent of patients with ARVD/C had a history of ventricular tachycardia（VT）storm，defined as≥3 episodes of VT within a 24-hour period at any point in the patient's history，as compared with 33%with CS（P=0.75）.Although therewas no statistical difference in ventricular premature beats between the 2 groups，there was a trend toward more ventricular premature beats in the group with ARVD/C（2375[971-7369]versus 596[400-785]；P=0.05）.

Patients with CS were older at the age of symptom onset（45[40-47]versus 23[18-29]years；P＜0.001）and more likely to have comorbidities including hypertension，coronary artery disease，and atrial arrhythmias. Heart failure symptoms were present only in patients with CS.Family history of disease（39.5%versus 0%；P=0.003）and premature sudden cardiac death（19% versus 0%；P=0.10）were present only in ARVD/C patients.

Electrocardiographic Characteristics

The electrocardiographic characteristics of the study population are shown in Table 2.

With respect to atrioventricular conduction，firstdegree atrioventricular block（Figure 1）was exclusively seen among patients with CS（53%versus 0%in ARVD/C；P＜0.001）.The median PR interval in patients with CS was 211（198-260）ms versus 159（140-177）ms for ARVD/C（P＜0.001）.Third degree atrioventricular block was also exclusively seen among subjects with CS as compared with ARVD/C patients（33%versus 0%；P≤0.001）.In this cohort，the sensitivity and specificity of having any atrioventricular block for the diagnosis of sarcoidosis were 66.7%and 100%，respectively.Interventricular conduction delay was observed more commonly in patients with CS as compared with those with ARVD/C.Nine of 15 patients with CS demonstrated a QRS duration＞120 ms including 5 with a right bundle branch block（RBBB）pattern and 4 with nonspecific interventricular conduction delay.Seven of 42 patients with ARVD/C demonstrated a QRS duration＞120 ms and all 7 had a RBBBpattern.The median QRS duration in patients with CS was significantly greater than in ARVD/C patients（132[100-142]ms versus 89[85-102]ms；P＜0.001）.

Electrophysiological Characteristics

During electrophysiology study，VT inducibility was observed in both groups（80%sarcoidosis versus 64%ARVD/C；P=0.34）.There were no significant differences in the mean cycle lengths or the morphology/axis of the induced VTs.The HV interval was significantly longer in patients with CS（50[50-55]ms versus 44[40-45]ms；P≤0.001）.The median number of VTs induced per patient was significantly greater among patients with CS（2.0[1-4]versus 1.0[1-2]；P=0.007）.

Imaging Characteristics

The RV ejection fraction was moderately reduced for both groups with no significant difference in the RV end-diastolic volume.The presence of major RV structural abnormality was present in 45%of ARVD/C patients and 33%of patients with CS（P=0.55）.Among 37 ARVD/C patients and 12 patients with CS who underwent cardiac MRI and had adequate image quality，49% of patients with ARVD/C had evidence of delayed enhancement，whereas 58%of patients with CS had delayed myocardial enhancement（P=0.74）.

Patients with CS had lower left ventricular（LV）ejection fractions（57[35-60]%versus 63[55-65]%；P＜0.001）.Furthermore，intramyocardial fat was significantly more common in ARVD/C patients（67% versus 8%；P＜0.001）.Septal involvement of gadolinium delayed enhancement（Figure 2）was more commonly associated with CS（42%versus 11%；P=0.004）. Mediastinal lymphadenopathy noted on standard chest roentgenogram，computed tomography，and MRI images was also seen more often in patients with CS（27% versus 0%；P=0.004）.

Among the 42 control patients，each patient had a pathogenic ARVD/C-associated desmosomal mutation and met diagnostic criteria for definite ARVD/C.The vast majority（76%）had a pathogenic mutation affecting the PKP2 gene.Application of the diagnostic criteria for CS to this group revealed that only 1 patient met criteria for CS.Among this group，15 patients（36%）underwent endomyocardial biopsies and 3 patients had fibrofatty infiltration meeting major tissue criteria based on the 1994 diagnostic criteria.

This study identified several important observations.First，ARVD/C patients present with symptoms at a younger age often are without cardiovascular comorbidities and more commonly have a family history of disease.Second，atrioventricular conduction abnormalities were seen exclusively in patients with CS.Third，LV dysfunction and heart failure symptoms were more commonly observed in patients with CS.Finally，MRI delayed enhancement of the septum was more commonlyassociated with CS along with extracardiac abnormalities such as mediastinal lymphadenopathy.

詞匯

sarcoidosis n.肉樣瘤病

immunosuppression n.免疫抑制

distinguish v.分別，區(qū)分，辨別出，看清

harbor n.&v.港口；藏匿

granulomatous adj.屬于肉芽腫的

Desmosomal adj.橋粒的

demographic adj.人口的

Comorbidity n.伴隨疾病，共患病

exclusively adv.專門，僅僅

gadolinium n.釓

mediastinal adj.中隔的

lymphadenopathy n.淋巴結(jié)病

roentgenogram n.倫琴射線照相

biopsy n.活組織切除

注釋

1.cardiac sarcoidosis是指“心臟結(jié)節(jié)病”，歸類于限制性心肌病，與心肌間質(zhì)炎癥有關(guān)，伴心室舒張功能異常，發(fā)病率不確定，多于老年發(fā)病，半數(shù)患者有心電圖異常表現(xiàn)，心性猝死是最常見的死亡原因，與完全性房室傳導(dǎo)阻滯或惡性快速心律失常有關(guān)。

2.desmosomal mutation指“橋粒突變”，橋粒（desmosome）是一種細(xì)胞間的連接結(jié)構(gòu)，促進(jìn)細(xì)胞與細(xì)胞的粘連、信號(hào)傳遞、各種組織發(fā)育和分化，已報(bào)道有10種不同的橋?；虺手虏⌒猿Ｈ旧w顯性或隱性突變，引起的系列表型累及皮膚、毛發(fā)和心臟。

參考譯文

第60課致心律失常右心室發(fā)育不全/心肌病與心臟結(jié)節(jié)病——診斷不明時(shí)的鑒別特征

致心律失常右心室發(fā)育不全/心肌?。ˋRVD/C）是一種遺傳性橋粒（突變）心肌病，特征為纖維脂肪取代右心室心肌。疾病表現(xiàn)多變，結(jié)構(gòu)變化從右心室基底部輕微受累到雙心室彌漫性受累。廣泛的表型表現(xiàn)使得臨床診斷具有挑戰(zhàn)性。當(dāng)缺乏心肌纖維脂肪取代的組織學(xué)依據(jù)時(shí)，?；跐M足國際特別工作組建議的不同臨床標(biāo)準(zhǔn)而做出診斷。遺憾的是其他浸潤性心肌疾病，如心臟結(jié)節(jié)?。–S），可有重疊的臨床表現(xiàn)，并且也符合2010特別工作組標(biāo)準(zhǔn)。能夠區(qū)別這兩種疾病具有臨床意義，因?yàn)樵\斷和治療方案明顯不同，并涉及家庭成員的基因檢測或使用全身性的免疫抑制劑。本報(bào)道提示有可鑒別的特征。

患者注冊和診斷評(píng)估

在入選的1 140例患者中，15例最初診斷為明確ARVD/C的患者最后診斷為CS。對(duì)照組由先征者組成，入選依據(jù)：（1）含有與致病性ARVD/C相關(guān)的橋粒突變；（2）滿足2010ARVD/C診斷標(biāo)準(zhǔn)；（3）具有一整套完整資料可供分析使用。

2010診斷標(biāo)準(zhǔn)用于診斷ARVD/C。明確的ARVD/C特征表現(xiàn)為≥2個(gè)主要標(biāo)準(zhǔn)，或1個(gè)主要標(biāo)準(zhǔn)加兩個(gè)次要標(biāo)準(zhǔn)，或4個(gè)次要標(biāo)準(zhǔn)。

CS診斷參照2006日本結(jié)節(jié)病和其他肉芽腫病學(xué)會(huì)修訂的指南。

患者特征

1140例入選JohnsHopkinsARVD/C注冊的患者中，15例隨后診斷為CS。42例先征者含有致病性ARVD/C相關(guān)的橋粒突變，并且滿足2010ARVD/C診斷標(biāo)準(zhǔn)而列為對(duì)照組（表1）。

人群特征與臨床病史

兩組患者共同的主要癥狀是心悸，30%有暈厥。兩組中多數(shù)患者的初診為室性心律失常，在這些患者中，以左束支傳導(dǎo)阻滯圖形居多。29%的ARVD/C患者病史中有過室性心動(dòng)過速風(fēng)暴，定義為24h內(nèi)室性心動(dòng)過速發(fā)作≥3次，相比之下，CS患者占33%（P=0.75）。雖然兩組間室性期前搏動(dòng)未達(dá)到統(tǒng)計(jì)學(xué)差異，但ARVD/C組室性期前搏動(dòng)趨向更多[2375（971～7369）比596（400～785）；P=0.05].

CS患者癥狀發(fā)作時(shí)的年齡較大[45（40～47）比23（18～29）歲；P＜0.001]，有更多合并癥，包括原發(fā)性高血壓、冠狀動(dòng)脈疾病和心律失常。心力衰竭只見于CS患者。家族史（39.5%比0%；P=0.003）和早發(fā)心性猝死（19%比0%；P=0.10）僅見于ARVD/C患者。

心電圖特征

研究人群心電圖特征見表2。

關(guān)于房室傳導(dǎo)阻滯，一度房室傳導(dǎo)阻滯（圖1）無例外地出現(xiàn)于CS患者（53%比0%在ARVD/C患者中；P＜0.001）。P-R間期中位數(shù)CS患者與ARVD/C患者相比為211（198～260）ms比159（140～177）ms（P＜0.001）。三度房室傳導(dǎo)阻滯也無例外地見于CS患者（33%比0%；P≤0.001）。在本組中，具備任一類型的房室傳導(dǎo)阻滯診斷心臟結(jié)節(jié)病，其敏感度和特異度分別為66.7%和100%。心室間傳導(dǎo)延遲CS患者較ARVD/C患者更常見。15例CS患者中，9例QRS時(shí)間＞120 ms，包括5例右束支傳導(dǎo)阻滯和4例非特異性心室間傳導(dǎo)延遲。42例ARVD/C患者中7例QRS時(shí)間＞120 ms，均為右束支傳導(dǎo)阻滯圖形。QRS間期中位數(shù)CS患者顯著大于ARVD/C患者[132（100～142）ms比89（85～102）ms；P＜0.001]。

電生理特征

電生理檢查中，兩組均觀察到室性心動(dòng)過速的高誘發(fā)性（80%CS比64%ARVD/C；P=0.34）。平均周長或所誘發(fā)的室性心動(dòng)過速的形態(tài)/電軸無顯著差異。HV間期CS患者較長[50（50～55）ms比44（40～45）ms；P≤0.001]。每例患者誘發(fā)出的室性心動(dòng)過速次數(shù)中位數(shù)CS患者顯著大于ARVD/C患者[2.0（1～4）比1.0（1～2）；P=0.007]。

影像學(xué)特征

兩組患者的右心室射血分?jǐn)?shù)中度降低，右心室舒張末期容積無顯著差異。明顯的右心室結(jié)構(gòu)異常見于45%的ARVD/ C患者和33%的CS患者（P=0.55）。在行心臟MRI檢查的37例ARVD/C患者和12例CS患者中，49%的ARVD/C患者和58%的CS患者存在心肌延遲強(qiáng)化（P=0.74）。

CS患者左心室射血分?jǐn)?shù)較低[57（35～60）%比63（55～ 65）%；P＜0.001]。另外，ARVD/C患者心肌內(nèi)脂肪顯著增多（67%比8%；P＜0.001）。涉及室間隔的釓延遲強(qiáng)化（圖2）多見于CS患者（42%比11%；P=0.004）。CS患者常于標(biāo)準(zhǔn)X線胸片、CT和MRI圖像上見到縱膈淋巴結(jié)腫大（27%比0%；P=0.004）。

在42例對(duì)照患者中，每例患者均有致病性ARVD/C相關(guān)的橋粒突變，并且符合ARVD/C的診斷標(biāo)準(zhǔn)。大多數(shù)（76%）有影響PKP2基因的致病性突變。CS診斷標(biāo)準(zhǔn)用于本組，只有1例患者符合CS標(biāo)準(zhǔn)。在本組中，15例患者（36%）進(jìn)行心內(nèi)膜活檢，3例存在纖維脂肪浸潤，符合1994診斷標(biāo)準(zhǔn)中的主要組織標(biāo)準(zhǔn)。

本研究獲得多個(gè)重要的觀察結(jié)果。第一，較年輕時(shí)出現(xiàn)癥狀的ARVD/C患者常不伴心血管合并癥，而更常有疾病家族史。其次，房室傳導(dǎo)阻滯只見于CS患者。第三，左心室功能不全和心力衰竭癥狀更常見于CS患者。最后，室間隔MRI延遲強(qiáng)化更常與CS相關(guān)聯(lián)，伴隨心外異常如縱膈淋巴結(jié)腫大。

圖1初始誤診為ARVD/C的心臟結(jié)節(jié)病患者的12導(dǎo)聯(lián)心電圖。心電圖V1～V5顯示與ARVD/C相關(guān)的特征性T波倒置，同時(shí)顯示P-R間期延長，這并不見于ARVD/C患者。

圖2CS和ARVD/C患者延遲強(qiáng)化的MRI。A.CS患者的短軸延遲強(qiáng)化圖像。B.CS患者的軸向延遲強(qiáng)化圖像。箭頭示右心室心肌強(qiáng)化，包含室間隔的強(qiáng)化。值得注意的是該患者經(jīng)支氣管左上肺葉針穿顯示肺實(shí)質(zhì)非干酪樣肉芽腫炎癥。C.ARVD/C患者短軸延遲強(qiáng)化圖像。D.ARVD/C患者軸向延遲強(qiáng)化圖像。箭頭示右心室心肌強(qiáng)化。無室間隔心肌強(qiáng)化。

[1]Philips B，Madhavan S，James C A，et al.Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and Cardiac Sarcoidosis -Distinguishing Features When the Diagnosis Is Unclear[J].Circ Arrhythm Electrophysiol，2014，7：230-236.

（童鴻）

●思考與分析