Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Circulation. 2012 Apr 24;125(16):1988-96. doi: 10.1161/CIRCULATIONAHA.111.048041. Epub 2012 Mar 28.
β-Adrenergic stimulation is the main trigger for cardiac events in type 1 long-QT syndrome (LQT1). We evaluated a possible association between ion channel response to β-adrenergic stimulation and clinical response to β-blocker therapy according to mutation location.
The study sample comprised 860 patients with genetically confirmed mutations in the KCNQ1 channel. Patients were categorized into carriers of missense mutations located in the cytoplasmic loops (C loops), membrane-spanning domain, C/N terminus, and nonmissense mutations. There were 27 aborted cardiac arrest and 78 sudden cardiac death events from birth through 40 years of age. After multivariable adjustment for clinical factors, the presence of C-loop mutations was associated with the highest risk for aborted cardiac arrest or sudden cardiac death (hazard ratio versus nonmissense mutations=2.75; 95% confidence interval, 1.29-5.86; P=0.009). β-Blocker therapy was associated with a significantly greater reduction in the risk of aborted cardiac arrest or sudden cardiac death among patients with C-loop mutations than among all other patients (hazard ratio=0.12; 95% confidence interval, 0.02-0.73; P=0.02; and hazard ratio=0.82; 95% confidence interval, 0.31-2.13; P=0.68, respectively; P for interaction=0.04). Cellular expression studies showed that membrane spanning and C-loop mutations produced a similar decrease in current, but only C-loop mutations showed a pronounced reduction in channel activation in response to β-adrenergic stimulation.
Patients with C-loop missense mutations in the KCNQ1 channel exhibit a high risk for life-threatening events and derive a pronounced benefit from treatment with β-blockers. Reduced channel activation after sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations.
β-肾上腺素能刺激是 1 型长 QT 综合征（LQT1）心脏事件的主要触发因素。我们根据突变位置评估了离子通道对β-肾上腺素能刺激的反应与β-受体阻滞剂治疗临床反应之间的可能关联。
研究样本包括 860 名经基因证实存在 KCNQ1 通道基因突变的患者。患者分为位于细胞质环（C 环）、跨膜域、C/N 末端的错义突变携带者和非错义突变携带者。从出生到 40 岁，有 27 例心搏骤停中止和 78 例心源性猝死。对临床因素进行多变量调整后，C 环突变的存在与心搏骤停中止或心源性猝死的最高风险相关（与非错义突变相比，危险比=2.75；95%置信区间，1.29-5.86；P=0.009）。β-受体阻滞剂治疗与 C 环突变患者心搏骤停中止或心源性猝死风险显著降低相关，而非所有其他患者（危险比=0.12；95%置信区间，0.02-0.73；P=0.02；危险比=0.82；95%置信区间，0.31-2.13；P=0.68；交互作用 P=0.04）。细胞表达研究表明，跨膜和 C 环突变导致电流相似减少，但只有 C 环突变显示出对β-肾上腺素能刺激的通道激活明显减少。
KCNQ1 通道 C 环错义突变患者发生危及生命事件的风险较高，β-受体阻滞剂治疗获益显著。交感神经激活后通道激活减少可解释 C 环突变患者的临床风险增加和对治疗的反应。
