Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals

Abstract

Objectives: This study was designed to assess the clinical course and to identify risk factors for life-threatening events in patients with long-QT syndrome (LQTS) with normal corrected QT (QTc) intervals.

Background: Current data regarding the outcome of patients with concealed LQTS are limited.

Methods: Clinical and genetic risk factors for aborted cardiac arrest (ACA) or sudden cardiac death (SCD) from birth through age 40 years were examined in 3,386 genotyped subjects from 7 multinational LQTS registries, categorized as LQTS with normal-range QTc (≤ 440 ms [n = 469]), LQTS with prolonged QTc interval (> 440 ms [n = 1,392]), and unaffected family members (genotyped negative with ≤ 440 ms [n = 1,525]).

Results: The cumulative probability of ACA or SCD in patients with LQTS with normal-range QTc intervals (4%) was significantly lower than in those with prolonged QTc intervals (15%) (p < 0.001) but higher than in unaffected family members (0.4%) (p < 0.001). Risk factors ACA or SCD in patients with normal-range QTc intervals included mutation characteristics (transmembrane-missense vs. nontransmembrane or nonmissense mutations: hazard ratio: 6.32; p = 0.006) and the LQTS genotypes (LQTS type 1:LQTS type 2, hazard ratio: 9.88; p = 0.03; LQTS type 3:LQTS type 2, hazard ratio: 8.04; p = 0.07), whereas clinical factors, including sex and QTc duration, were associated with a significant increase in the risk for ACA or SCD only in patients with prolonged QTc intervals (female age > 13 years, hazard ratio: 1.90; p = 0.002; QTc duration, 8% risk increase per 10-ms increment; p = 0.002).

Conclusions: Genotype-confirmed patients with concealed LQTS make up about 25% of the at-risk LQTS population. Genetic data, including information regarding mutation characteristics and the LQTS genotype, identify increased risk for ACA or SCD in this overall lower risk LQTS subgroup.

Figure 1. Distribution of QTc Interval Duration in Genotype-Positive Patients With LQTS

Distribution of corrected QT (QTc) interval durations in genotype-positive study patients. LQTS = long-QT syndrome.

Figure 2. Rate of ACA or SCD by Genotype and QTc Category

Kaplan-Meier cumulative probabilities of aborted cardiac arrest (ACA) and sudden cardiac death (SCD) by genotype and corrected QT (QTc) subgroup. LQTS = long-QT syndrome.

Figure 3. Rate of ACA or SCD in Patients With Normal-Range and Prolonged QTc Intervals by Mutation Location and Type

Kaplan-Meier cumulative probabilities of aborted cardiac arrest (ACA) and sudden cardiac death (SCD) by mutation location and type in patients with long-QT syndrome (LQTS) with (A) corrected QT (QTc) intervals ≤440 ms and (B) QTc intervals >440 ms.

Figure 4. Polymorphic Ventricular Tachycardia in a Patient With a Normal-Range QTc Interval

Spontaneous generation of polymorphic ventricular tachycardia in a patient with long-QT syndrome type 1 with a normal-range corrected QT (QTc) interval. (A) The patient had a QTc duration of 410 ms on baseline electrocardiography. (B) Electrocardiographic tracing at the time of arrhythmic event demonstrates sinus rate with an RR interval of 1,000 ms without significant QT prolongation before the arrhythmia. (C) The patient was treated with nadolol and received an implantable cardioverter-defibrillator but continued to exhibit arrhythmic episodes that were recorded on implantable cardioverter-defibrillator interrogation.