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

●思考与分析

●心电学英语

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.

词汇

sarcoidosis n.肉样瘤病

immunosuppression n.免疫抑制

distinguish v.分别，区分，辨别出，看清

harbor n.&v.港口；藏匿

granulomatous adj.属于肉芽肿的

Desmosomal adj.桥粒的

demographic adj.人口的

Comorbidity n.伴随疾病，共患病

exclusively adv.专门，仅仅

gadolinium n.钆

mediastinal adj.中隔的

lymphadenopathy n.淋巴结病

roentgenogram n.伦琴射线照相

biopsy n.活组织切除

注释

1.cardiac sarcoidosis是指“心脏结节病”，归类于限制性心肌病，与心肌间质炎症有关，伴心室舒张功能异常，发病率不确定，多于老年发病，半数患者有心电图异常表现，心性猝死是最常见的死亡原因，与完全性房室传导阻滞或恶性快速心律失常有关。

2.desmosomal mutation指“桥粒突变”，桥粒（desmosome）是一种细胞间的连接结构，促进细胞与细胞的粘连、信号传递、各种组织发育和分化，已报道有10种不同的桥粒基因呈致病性常染色体显性或隐性突变，引起的系列表型累及皮肤、毛发和心脏。

参考译文

第60课致心律失常右心室发育不全/心肌病与心脏结节病——诊断不明时的鉴别特征

致心律失常右心室发育不全/心肌病（ARVD/C）是一种遗传性桥粒（突变）心肌病，特征为纤维脂肪取代右心室心肌。疾病表现多变，结构变化从右心室基底部轻微受累到双心室弥漫性受累。广泛的表型表现使得临床诊断具有挑战性。当缺乏心肌纤维脂肪取代的组织学依据时，常基于满足国际特别工作组建议的不同临床标准而做出诊断。遗憾的是其他浸润性心肌疾病，如心脏结节病（CS），可有重叠的临床表现，并且也符合2010特别工作组标准。能够区别这两种疾病具有临床意义，因为诊断和治疗方案明显不同，并涉及家庭成员的基因检测或使用全身性的免疫抑制剂。本报道提示有可鉴别的特征。

患者注册和诊断评估

在入选的1 140例患者中，15例最初诊断为明确ARVD/C的患者最后诊断为CS。对照组由先征者组成，入选依据：（1）含有与致病性ARVD/C相关的桥粒突变；（2）满足2010ARVD/C诊断标准；（3）具有一整套完整资料可供分析使用。

2010诊断标准用于诊断ARVD/C。明确的ARVD/C特征表现为≥2个主要标准，或1个主要标准加两个次要标准，或4个次要标准。

CS诊断参照2006日本结节病和其他肉芽肿病学会修订的指南。

患者特征

1140例入选JohnsHopkinsARVD/C注册的患者中，15例随后诊断为CS。42例先征者含有致病性ARVD/C相关的桥粒突变，并且满足2010ARVD/C诊断标准而列为对照组（表1）。

人群特征与临床病史

两组患者共同的主要症状是心悸，30%有晕厥。两组中多数患者的初诊为室性心律失常，在这些患者中，以左束支传导阻滞图形居多。29%的ARVD/C患者病史中有过室性心动过速风暴，定义为24h内室性心动过速发作≥3次，相比之下，CS患者占33%（P=0.75）。虽然两组间室性期前搏动未达到统计学差异，但ARVD/C组室性期前搏动趋向更多[2375（971～7369）比596（400～785）；P=0.05].

CS患者症状发作时的年龄较大[45（40～47）比23（18～29）岁；P＜0.001]，有更多合并症，包括原发性高血压、冠状动脉疾病和心律失常。心力衰竭只见于CS患者。家族史（39.5%比0%；P=0.003）和早发心性猝死（19%比0%；P=0.10）仅见于ARVD/C患者。

心电图特征

研究人群心电图特征见表2。

关于房室传导阻滞，一度房室传导阻滞（图1）无例外地出现于CS患者（53%比0%在ARVD/C患者中；P＜0.001）。P-R间期中位数CS患者与ARVD/C患者相比为211（198～260）ms比159（140～177）ms（P＜0.001）。三度房室传导阻滞也无例外地见于CS患者（33%比0%；P≤0.001）。在本组中，具备任一类型的房室传导阻滞诊断心脏结节病，其敏感度和特异度分别为66.7%和100%。心室间传导延迟CS患者较ARVD/C患者更常见。15例CS患者中，9例QRS时间＞120 ms，包括5例右束支传导阻滞和4例非特异性心室间传导延迟。42例ARVD/C患者中7例QRS时间＞120 ms，均为右束支传导阻滞图形。QRS间期中位数CS患者显著大于ARVD/C患者[132（100～142）ms比89（85～102）ms；P＜0.001]。

电生理特征

电生理检查中，两组均观察到室性心动过速的高诱发性（80%CS比64%ARVD/C；P=0.34）。平均周长或所诱发的室性心动过速的形态/电轴无显著差异。HV间期CS患者较长[50（50～55）ms比44（40～45）ms；P≤0.001]。每例患者诱发出的室性心动过速次数中位数CS患者显著大于ARVD/C患者[2.0（1～4）比1.0（1～2）；P=0.007]。

影像学特征

两组患者的右心室射血分数中度降低，右心室舒张末期容积无显著差异。明显的右心室结构异常见于45%的ARVD/ C患者和33%的CS患者（P=0.55）。在行心脏MRI检查的37例ARVD/C患者和12例CS患者中，49%的ARVD/C患者和58%的CS患者存在心肌延迟强化（P=0.74）。

CS患者左心室射血分数较低[57（35～60）%比63（55～ 65）%；P＜0.001]。另外，ARVD/C患者心肌内脂肪显著增多（67%比8%；P＜0.001）。涉及室间隔的钆延迟强化（图2）多见于CS患者（42%比11%；P=0.004）。CS患者常于标准X线胸片、CT和MRI图像上见到纵膈淋巴结肿大（27%比0%；P=0.004）。

在42例对照患者中，每例患者均有致病性ARVD/C相关的桥粒突变，并且符合ARVD/C的诊断标准。大多数（76%）有影响PKP2基因的致病性突变。CS诊断标准用于本组，只有1例患者符合CS标准。在本组中，15例患者（36%）进行心内膜活检，3例存在纤维脂肪浸润，符合1994诊断标准中的主要组织标准。

本研究获得多个重要的观察结果。第一，较年轻时出现症状的ARVD/C患者常不伴心血管合并症，而更常有疾病家族史。其次，房室传导阻滞只见于CS患者。第三，左心室功能不全和心力衰竭症状更常见于CS患者。最后，室间隔MRI延迟强化更常与CS相关联，伴随心外异常如纵膈淋巴结肿大。

图1初始误诊为ARVD/C的心脏结节病患者的12导联心电图。心电图V1～V5显示与ARVD/C相关的特征性T波倒置，同时显示P-R间期延长，这并不见于ARVD/C患者。

图2CS和ARVD/C患者延迟强化的MRI。A.CS患者的短轴延迟强化图像。B.CS患者的轴向延迟强化图像。箭头示右心室心肌强化，包含室间隔的强化。值得注意的是该患者经支气管左上肺叶针穿显示肺实质非干酪样肉芽肿炎症。C.ARVD/C患者短轴延迟强化图像。D.ARVD/C患者轴向延迟强化图像。箭头示右心室心肌强化。无室间隔心肌强化。

[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.

（童鸿）

●思考与分析