In the current issue of the Circulation Research, Karmouch et al¹ present a provocative study attributing a pivotal role in the pathogenesis of arrhythmogenic cardiomyopathy (ACM) to the loss of DSP (desmoplakin) gene in a subpopulation of the cells of the conduction system. This hypothesis is in sharp departure from the current view on the disease, and it opens the question on whether the data reported in mice with a selective expression of the genetic defects in the specialized cells of the conduction system replicate the clinical phenotype found in patients.

Article, see p 1346

ACM is a genetic disease of the heart muscle caused, in most instances, by mutations in genes encoding for desmosomal proteins that is predominantly inherited as an autosomal dominant trait.¹ Two syndromic recessive forms of the disease have been described and both present abnormalities in skin² and heart. Carvajal Syndrome³ presents a striate type of keratoderma, is associated with a cardiomyopathy with preferred involvement of the left ventricle, and is associated with DSP mutations. Occasionally, Carvajal is inherited as a dominant disease that also presents hypodontia.⁴ Naxos disease⁵ is associated with mutations in the plakoglobin gene and manifests diffuse keratoderma and right ventricular cardiomyopathy. Occasionally, Naxos disease with dominant inheritance has been reported.

Karmouch et al¹ investigate the recessive form of ACM caused by mutations in the DSP gene that manifests with palmo-plantar keratosis, wooly hair, and dilatation of both ventricular chambers with fibro-fatty infiltration and life-threatening arrhythmias.³ There is general consensus that cardiac manifestations of the disease are the consequence of DSP mutations that alter the function of cardiac myocytes (CMs). The assumption that mutations in cardiac genes affect CMs is not unique to ACM; rather, it is the paradigm in the study of most …

在最新一期的《循环研究》中，Karmouch等人¹提出了一项具有启发性的研究，该研究将致心律失常性心肌病（ACM）的发病机理中的关键作用归因于传导系统细胞亚群中DSP（去粘斑素）基因的丢失。这一假设与当前对这种疾病的看法大相径庭，它提出了一个问题，即在传导系统的特殊细胞中选择性表达遗传缺陷的小鼠中报道的数据是否能复制患者体内的临床表型。

文章，请参阅第1346页

在大多数情况下，ACM是一种心肌遗传病，是由编码桥粒蛋白的基因突变引起的，而桥粒蛋白主要是作为常染色体显性遗传而遗传的。¹已经描述了该疾病的两种症状性隐性形式，并且都在皮肤²和心脏中均表现出异常。Carvajal综合征³呈条纹状角化病，与心肌病相关，优选累及左心室，并与DSP突变相关。有时，Carvajal被遗传为占主导地位的疾病，也表现出牙髓不足。⁴纳克索斯病⁵与plakoglobin基因突变有关，并表现为弥漫性角化病和右心室心肌病。偶尔，已经报道了具有显性遗传的纳克索斯病。

Karmouch等人¹研究了由DSP基因突变引起的ACM隐性形式，其表现为掌-角化病，羊毛状毛发以及两个室腔的扩张伴有纤维脂肪浸润和危及生命的心律不齐。³人们普遍认为，该疾病的心脏表现是DSP突变的结果，而DSP突变会改变心肌细胞（CMs）的功能。心脏基因突变影响CM的假设并非ACM独有。相反，它是大多数……研究的范式。