Importance Calcium-release deficiency syndrome (CRDS), which is caused by loss-of-function variants in cardiac ryanodine receptor 2 (RyR2), is an emerging cause of ventricular fibrillation. However, the lack of complex polymorphic/bidirectional ventricular tachyarrhythmias during exercise stress testing (EST) may distinguish it from catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, in the first clinical series describing the condition, mouse and human studies showed that the long-burst, long-pause, short-coupled ventricular extra stimulus (LBLPS) electrophysiology protocol reliably induced CRDS ventricular arrhythmias. Data from larger populations with CRDS and its associated spectrum of disease are lacking.

Objective To further insight into CRDS through international collaboration.

Design, Setting, and Participants In this multicenter observational cohort study, probands with unexplained life-threatening arrhythmic events and an ultrarare RyR2 variant were identified. Variants were expressed in HEK293 cells and subjected to caffeine stimulation to determine their functional impact. Data were collected from September 1, 2012, to March 6, 2021, and analyzed from August 9, 2015, to March 6, 2021.

Main Outcomes and Measures The functional association of RyR2 variants found in putative cases of CRDS and the associated clinical phenotype(s).

Results Of 10 RyR2 variants found in 10 probands, 6 were loss-of-function, consistent with CRDS (p.E4451del, p.F4499C, p.V4606E, p.R4608Q, p.R4608W, and p.Q2275H) (in 4 [67%] male and 2 [33%] female probands; median age at presentation, 22 [IQR, 8-34] years). In 5 probands with a documented trigger, 3 were catecholamine driven. During EST, 3 probands with CRDS had no arrhythmias, 1 had a monomorphic couplet, and 2 could not undergo EST (deceased). Relatives of the decedents carrying the RyR2 variant did not have EST results consistent with CPVT. After screening 3 families, 13 relatives were diagnosed with CRDS, including 3 with previous arrhythmic events (23%). None had complex ventricular tachyarrhythmias during EST. Among the 19 confirmed cases with CRDS, 10 had at least 1 life-threatening event at presentation and/or during a median follow-up of 7 (IQR, 6-18) years. Two of the 3 device-detected ventricular fibrillation episodes were induced by a spontaneous LBLPS-like sequence. β-Blockers were used in 16 of 17 surviving patients (94%). Three of 16 individuals who were reportedly adherent to β-blocker therapy (19%) had breakthrough events.

Conclusions and Relevance The results of this study suggest that calcium-release deficiency syndrome due to RyR2 loss-of-function variants mechanistically and phenotypically differs from CPVT. Ventricular fibrillation may be precipitated by a spontaneous LBLPS-like sequence of ectopy; however, CRDS remains difficult to recognize clinically. These data highlight the need for better diagnostic tools and treatments for this emerging condition.

钙释放缺乏综合征 ( CRDS ) 是由心脏兰尼碱受体 2 (RyR2) 功能丧失变异引起的，是心室颤动的一个新兴原因。然而，在运动负荷试验 (EST) 期间缺乏复杂的多形性/双向室性心动过速可将其与儿茶酚胺能多形性室性心动过速 (CPVT) 区分开来。最近，在描述该病症的第一个临床系列中，小鼠和人类研究表明，长爆发、长暂停、短耦合心室额外刺激 (LBLPS) 电生理协议可靠地诱导 CRDS 室性心律失常。缺乏来自更多 CRDS 人群及其相关疾病谱的数据。

目标 通过国际合作进一步深入了解 CRDS。

设计、设置和参与者 在这项多中心观察性队列研究中，确定了具有无法解释的危及生命的心律失常事件和极其罕见的 RyR2 变异的先证者。变体在 HEK293 细胞中表达并受到咖啡因刺激以确定它们的功能影响。数据收集时间为 2012 年 9 月 1 日至 2021 年 3 月 6 日，分析时间为 2015 年 8 月 9 日至 2021 年 3 月 6 日。

主要结果和测量 在推定的 CRDS 病例中发现的 RyR2 变体的功能关联和相关的临床表型。

结果 在 10 个先证者中发现的 10 个 RyR2 变体中，6 个功能丧失，与 CRDS（p.E4451del、p.F4499C、p.V4606E、p.R4608Q、p.R4608W 和 p.Q2275H）一致（在 4 [ 67%] 男性和 2 [33%] 女性先证者；出现时的中位年龄，22 [IQR，8-34] 岁）。在 5 名有记录的触发因素的先证者中，3 名是儿茶酚胺驱动的。EST期间，3名CRDS先证者无心律失常，1名有单态性对联，2名不能进行EST（已故）。携带 RyR2 变体的死者的亲属没有与 CPVT 一致的 EST 结果。筛查 3 个家庭后，13 名亲属被诊断为 CRDS，其中 3 名有既往心律失常事件（23%）。没有人在 EST 期间出现复杂的室性快速性心律失常。在 19 例 CRDS 确诊病例中，10 例在就诊时和/或中位随访 7 例期间至少发生 1 次危及生命的事件（IQR，6-18) 岁。3 个设备检测到的心室颤动发作中有两个是由自发的 LBLPS 样序列诱导的。17 名幸存患者中有 16 名（94%）使用了 β 受体阻滞剂。据报道，16 名依从 β 受体阻滞剂治疗的人中有 3 名（19%）发生了突破性事件。

结论和相关性 本研究结果表明，由 RyR2 功能丧失变异引起的钙释放缺乏综合征在机制和表型上与 CPVT 不同。自发性 LBLPS 样异位序列可诱发心室颤动；然而，CRDS 在临床上仍然难以识别。这些数据强调了对这种新兴疾病的更好诊断工具和治疗方法的需求。