Provocation Testing and Therapeutic Response in a Newly Described Channelopathy: RyR2 Calcium Release Deficiency Syndrome
Provocation Testing and Therapeutic Response in a Newly Described Channelopathy: RyR2 Calcium Release Deficiency Syndrome
复制标题
DOI：
10.1161/circgen.121.003589
复制
发表时间：
2022-02-01
影响因子：
7.4
通讯作者：
Watkins, Hugh
中科院分区：
文献类型：
--
作者：
Ormerod, Julian O. M.;Ormondroyd, Elizabeth;Watkins, Hugh
背景：最近描述了一种新型家族性心律失常综合征，即心脏兰尼碱受体（RyR2）钙释放缺乏综合征（CRDS）。我们评估了一个大型且特征明确的家庭，以评估 CRDS 的激发试验、危险因素分层和治疗反应。方法：我们提出了一个家庭，该家庭有多起未预见的心脏性猝死和心脏骤停，主要是儿童和年轻人，标准临床测试没有明确的表型。结果：包括全基因组测序在内的遗传分析明确证实，RYR2 中的错义突变 Ala4142Thr 是该家族疾病的根本原因。细胞模型中该变体的功能研究显示 RyR2 功能丧失，表明该家族受到 CRDS 的影响。 EPS（电生理学研究）在 9 名已知携带该突变的受试者中进行，其中包括心源性猝死流产的幸存者，并测试了单独使用氟卡尼以及与美托洛尔联合使用的效果。 EPS 受试者之间非持续性和持续性室性心律失常的诱发性存在明显的分级，中止心源性猝死的幸存者是最容易诱发的受试者。给予氟卡尼显着降低了该受试者的心律失常诱发性，并消除了所有其他受试者的心律失常。最后，测试了额外的美托洛尔的效果；它增加了 4/9 受试者的诱导能力。结论：RYR2 的 Ala4142Thr 突变导致新型遗传性心律失常综合征 CRDS，其特征是在没有既往症状或动态监测或运动负荷测试可识别表型的情况下发生家族性猝死。我们增加了人类受试者中特定 EPS 方案的经验，并表明它有助于确定基因携带者的临床状态，并具有风险分层的潜在用途。我们的数据证明氟卡尼对患有 CRDS 的人类受试者具有保护作用，与之前在小鼠模型中显示的效果一致。
Background: A novel familial arrhythmia syndrome, cardiac ryanodine receptor (RyR2) calcium release deficiency syndrome (CRDS), has recently been described. We evaluated a large and well characterized family to assess provocation testing, risk factor stratification and response to therapy in CRDS. Methods: We present a family with multiple unheralded sudden cardiac deaths and aborted cardiac arrests, primarily in children and young adults, with no clear phenotype on standard clinical testing. Results: Genetic analysis, including whole genome sequencing, firmly established that a missense mutation in RYR2, Ala4142Thr, was the underlying cause of disease in the family. Functional study of the variant in a cell model showed RyR2 loss-of-function, indicating that the family was affected by CRDS. EPS (Electrophysiological Study) was undertaken in 9 subjects known to carry the mutation, including a survivor of aborted sudden cardiac death, and the effects of flecainide alone and in combination with metoprolol were tested. There was a clear gradation in inducibility of nonsustained and sustained ventricular arrhythmia between subjects at EPS, with the survivor of aborted sudden cardiac death being the most inducible subject. Administration of flecainide substantially reduced arrhythmia inducibility in this subject and abolished arrhythmia in all others. Finally, the effects of additional metoprolol were tested; it increased inducibility in 4/9 subjects. Conclusions: The Ala4142Thr mutation of RYR2 causes the novel heritable arrhythmia syndrome CRDS, which is characterized by familial sudden death in the absence of prior symptoms or a recognizable phenotype on ambulatory monitoring or exercise stress testing. We increase the experience of a specific EPS protocol in human subjects and show that it is helpful in establishing the clinical status of gene carriers, with potential utility for risk stratification. Our data provide evidence that flecainide is protective in human subjects with CRDS, consistent with the effect previously shown in a mouse model.