Importance Truncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia.

Objective To determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv).

Design, Setting, and Participants This cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020.

Main Outcomes and Measures The primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only.

Results In total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (≥500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [HR] per 10%, 1.83 [95% CI, 1.30-2.57]; P < .001) and proband status (HR, 3.18 [95% CI, 1.12-9.04]; P = .03) remained independent risk factors on multivariable analysis (excluding myocardial fibrosis and ventricular ectopy owing to case censoring). There was no difference in freedom from MVA between FLNCtv carriers with mild to moderate or severe (LVEF ≤35%) LVSD (HR, 1.29 [95% CI, 0.45-3.72]; P = .64). Carriers of FLNCtv with impaired LVEF at baseline evaluation (n = 69) had reduced freedom from MVA compared with 244 TTNtv carriers with similar baseline LVEF (for mild to moderate LVSD: HR, 16.41 [95% CI, 3.45-78.11]; P < .001; for severe LVSD: HR, 2.47 [95% CI, 1.04-5.87]; P = .03).

Conclusions and Relevance The high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCtv carriers.

重要性 编码细丝蛋白 C (FLNCtv) 的基因中的截短变异与致心律失常和扩张型心肌病相关，据报道，这些心肌病具有室性心律失常的高风险。

目的确定 FLNCtv 携带者与 TTN截短变体 (TTNtv)携带者相比发生不良事件的频率和危险因素。

设计、设置和参与者 该队列研究招募了 1990 年至 2018 年间来自 19 个欧洲心肌病转诊单位的 167 名连续 FLNCtv 携带者和 244 名与左心室射血分数 (LVEF) 相匹配的 TTNtv 患者组成的对照队列。数据分析于 6 月至 2018 年间进行。 2020 年 10 月。

主要结局和措施 主要终点是恶性室性心律失常（MVA）（心源性猝死、心源性猝死、适当的植入式心脏复律除颤器电击和持续性室性心动过速）和终末期心力衰竭（心脏移植或心脏骤停）的复合终点。与终末期心力衰竭相关的死亡率）。次要终点仅包括 MVA 事件。

结果 总共对 167 名 FLNCtv 患者进行了研究（55 名先证者 [33%]；89 名男性 [53%]；基线评估时的平均 [SD] 年龄为 43 [18] 岁）。中位随访时间为 20 个月（四分位距，7-60 个月），29 名患者 (17.4%) 达到主要终点（19 名 MVA 患者和 10 名终末期心力衰竭患者）。基线轻度至中度左心室收缩功能障碍 (LVSD) (LVEF = 36%-49%) 的个体中发生了 8 例 (44%) 心律失常事件。与主要终点相关的单变量危险因素包括先证者状态、每 10% 的 LVEF 减少、心室异位（24 小时内≥500）以及心脏磁共振成像检测到的心肌纤维化。LVEF 减量（每 10% 的风险比 [HR]，1.83 [95% CI，1.30-2.57]；P  < .001）和先证者状态（HR，3.18 [95% CI，1.12-9.04]；P  = .03 ）在多变量分析中仍然是独立的危险因素（排除由于病例审查导致的心肌纤维化和心室异位）。轻度至中度或重度 (LVEF ≤ 35%) LVSD 的 FLNCtv 携带者之间的 MVA 自由度没有差异（HR，1.29 [95% CI，0.45-3.72]；P  = .64）。与 244 名基线 LVEF 相似的 TTNtv 携带者相比，基线评估时 LVEF 受损的 FLNCtv 携带者 (n = 69) 的 MVA 自由度降低（轻度至中度 LVSD：HR，16.41 [95% CI，3.45-78.11]；P  < .001；对于严重 LVSD：HR，2.47 [95% CI，1.04-5.87]；P  = .03）。

结论和相关性 轻度至中度 LVSD 的 FLNCtv 患者中 MVA 发生率较高，这表明对于 FLNCtv 携带者，应考虑采用比目前推荐值更高的 LVEF 值进行预防性植入式心脏复律除颤器治疗。