Genetic factors predisposing to arrhythmic events and QTc prolongation during follow-up in long QT patients with unaffected QTc at initial presentation: Swedish experience
Authors: Dahlberg P , Roijer R , Svensson A , Markljung M , Ringborn M , Platonov P 
Published: November 2023

Abstract

Background
Patients carrying genetic variants associated with long QT syndrome (LQTS) who initially present with normal QTc (concealed LQTS) is a large and growing group of patients. Long-term progression of QTc interval and risk factors associated with arrhythmic events in this patient group remain poorly described.

Purpose
1) To assess the prevalence of concealed LQTS among patients with genetically verified LQTS; 2) To explore genetic factors associated with QTc prolongation and arrhythmic events in patients with concealed LQTS.

Methods
Adult LQTS patients (LQT1-3) from three cardiogenetic clinics in Sweden were included in a prospective register. Digital ECGs recorded for any reason both in-hospital and in outpatient settings, were retrieved from ECG archives. Concealed LQTS was defined as QTcB &lt; 460 ms in men or &lt;470 ms in women at initial presentation. The proportion of patients exhibiting QTcB above 480, 490 and 500 ms thresholds at any time during follow-up (FU) was assessed. Ventricular arrhythmias (VA) were defined as torsades de pointes, appropriate ICD shock, aborted cardiac arrest or sudden cardiac death. Cardiac events (CE) were defined as VA or syncope. The risk of CE and VA by the age of 60 years associated with LQTS genotype, KCNH2 pore region mutations and KCNQ1 membrane-spanning mutations was assessed using Kaplan Meier survival curve analysis and Cox regression analysis adjusted for sex, proband status and beta blocker use.

Results
1). Out of 211 LQTS patients, 89 (42%) had concealed LQTS (52 (58%) women, 22 (25%) probands, 16 (18%) had CE by the time of diagnosis). Median age at diagnosis was 39 [IQR 22-55] years, age at the end of FU 47 [31-62] years. Concealed LQTS prevalence did not differ between genotypes: LQT1 – 59/141 (42%), LQT2 – 25/57 (44%), LQT3 – 5/13 (39%). 2). LQT1 patients were least and LQT3 patients were most prone to develop QTc prolongation during FU (Table). 3). VA were reported in 3 (3.5%) patients and in all cases preceded by syncope. None of the LQT1 patients experienced VA during FU. Both VA events among LQT2 patients were reported in carriers of KCNH2 pore region mutations (log rank p=0.023). 4). Patients with LQT2 were at higher risk to develop CE than LQT1 patients (HRadj=3.04 95%CI 1.22-7.55). Among LQT1 patients, carriers of mutations affecting membrane-spanning KCNQ1 channel region tended to have higher risk of CE (log rank p=0.018, HRadj=3.99 95%CI 0.80-19.89).

Conclusions
Concealed LQTS patients represent a significant proportion of the LQTS population and are similarly distributed between the most common LQTS genotypes. These patients have low risk of VA, which is confined to LQT3 patients and LQT2 patients carrying KCNH2 pore region mutations. Concealed LQT1 patients are at the lowest risk of CE and VA and have the lowest risk of experiencing QTc prolongation during FU. Carriers of mutations affecting KCNQ1 membrane-spanning region represent the high-risk LQT1 group with regard to CE.Concealed LQTS patients characteristicsRisk of VA in concealed LQTS by genotype