Barsheshet Alon, Moss Arthur J, McNitt Scott, Polonsky Slava, Lopes Coeli M, Zareba Wojciech, Robinson Jennifer L, Ackerman Michael J, Benhorin Jesaia, Kaufman Elizabeth S, Towbin Jeffrey A, Vincent G Michael, Qi Ming, Goldenberg Ilan
Cardiology Division, University of Rochester Medical Center, Rochester, NY 14642, USA.
Circ Cardiovasc Genet. 2011 Oct;4(5):491-9. doi: 10.1161/CIRCGENETICS.111.960179. Epub 2011 Aug 10.
Current clinical diagnosis of long-QT syndrome (LQTS) includes genetic testing of family members of mutation-positive patients. The present study was designed to assess the clinical course of individuals who are found negative for the LQTS-causing mutation in their families.
Multivariate Cox proportional hazards model was used to assess the risk for cardiac events (comprising syncope, aborted cardiac arrest [ACA], or sudden cardiac death [SCD]) from birth through age 40 years among 1828 subjects from the LQTS Registry who were found negative for their family LQTS-causing mutation. The median QTc of study subjects was 423 ms (interquartile range, 402-442 ms). The cumulative probability of a first syncope through age 40 years was 15%. However, only 2 patients (0.1%) had ACA, and none died suddenly during follow-up. Independent risk factors for syncope in genotype-negative subjects included female sex (hazard ratio [HR], 1.60; P=0.002), prolonged QTc (HR=1.63 per 100 ms increment, P=0.02), family history of ACA or SCD (HR=1.89, P=0.002), and LQT2 versus LQT1 family mutation (HR=1.41, P=0.03). Subgroup analysis showed that the presence of the K897T polymorphism in the LQT2 gene in an affected family was associated with an 11-fold (P=0.001) increase in the risk of recurrent syncope in genotype-negative subjects.
Our findings suggest that cardiac events among genotype-negative family members of LQTS patients are dominated by nonfatal syncopal episodes without occurrence of sudden cardiac death. The risk for nonfatal events in this population may be mediated by the presence of common polymorphisms in LQTS genes.
长QT综合征（LQTS）目前的临床诊断包括对突变阳性患者的家庭成员进行基因检测。本研究旨在评估那些在其家族中被发现未携带导致LQTS突变的个体的临床病程。
采用多变量Cox比例风险模型，对长QT综合征注册中心的1828名受试者进行评估，这些受试者在其家族中被发现未携带导致LQTS的突变，评估从出生到40岁发生心脏事件（包括晕厥、心脏骤停未遂[ACA]或心源性猝死[SCD]）的风险。研究对象的QTc中位数为423毫秒（四分位间距，402 - 442毫秒）。到40岁时首次晕厥的累积概率为15%。然而，只有2例患者（0.1%）发生了心脏骤停未遂，且在随访期间无一人猝死。基因型阴性受试者发生晕厥的独立危险因素包括女性（风险比[HR]，1.60；P = 0.002）、QTc延长（每增加100毫秒，HR = 1.63，P = 0.02）、心脏骤停未遂或心源性猝死家族史（HR = 1.89，P = 0.002）以及LQT2与LQT1家族突变（HR = 1.41，P = 0.03）。亚组分析显示，在受影响家族中LQT2基因存在K897T多态性与基因型阴性受试者复发性晕厥风险增加11倍（P = 0.001）相关。
我们的研究结果表明，LQTS患者基因型阴性的家庭成员中的心脏事件以非致命性晕厥发作为主，未发生心源性猝死。该人群中非致命事件的风险可能由LQTS基因中常见多态性的存在介导。
