Diagnosis, management and therapeutic strategies for congenital long QT syndrome

Abstract

Congenital long QT syndrome (LQTS) is characterised by heart rate corrected QT interval prolongation and life-threatening arrhythmias, leading to syncope and sudden death. Variations in genes encoding for cardiac ion channels, accessory ion channel subunits or proteins modulating the function of the ion channel have been identified as disease-causing mutations in up to 75% of all LQTS cases. Based on the underlying genetic defect, LQTS has been subdivided into different subtypes. Growing insights into the genetic background and pathophysiology of LQTS has led to the identification of genotype-phenotype relationships for the most common genetic subtypes, the recognition of genetic and non-genetic modifiers of phenotype, optimisation of risk stratification algorithms and the discovery of gene-specific therapies in LQTS. Nevertheless, despite these great advancements in the LQTS field, large gaps in knowledge still exist. For example, up to 25% of LQTS cases still remain genotype elusive, which hampers proper identification of family members at risk, and it is still largely unknown what determines the large variability in disease severity, where even within one family an identical mutation causes malignant arrhythmias in some carriers, while in other carriers, the disease is clinically silent. In this review, we summarise the current evidence available on the diagnosis, clinical management and therapeutic strategies in LQTS. We also discuss new scientific developments and areas of research, which are expected to increase our understanding of the complex genetic architecture in genotype-negative patients, lead to improved risk stratification in asymptomatic mutation carriers and more targeted (gene-specific and even mutation-specific) therapies.

Keywords: genetic services; tachycardia; ventricular; ventricular fibrillation.

Figure 1

Diagnostic criteria for long QT syndrome (LQTS) (the ‘Schwartz-score’). Definite LQTS is defined by an LQTS score ≥3.5 points, intermediate probability of LQTS by an LQTS score of <3.5 and >1 and a low probability of LQTS by ≤1 point. In the family history rows, the same family member cannot be counted in both categories.

Figure 2

Schematic flow chart for the diagnosis LQTS. Flow chart for the diagnosis of LQTS following the Heart Rhythm Society/European Heart Rhythm Association/Asian Pacific Heart Rhythm Society consensus document from 2013. The LQTS risk score (ie, the ‘Schwartz score’) is presented in figure 1. *QTc calculated by Bazett formula (QTc=QT/√RR). LQTS, long QT syndrome; QTc, corrected QT interval.

Figure 3

Genotype–phenotype relationship for the three most important subtypes, types 1, 2 and 3. See text for further explanation. I _Kr, rapidly activating delayed rectifier potassium current; I _Kr, rapidly activating delayed rectifier potassium current; I _{Na, L}, late sodium current; LQTS, long QT syndrome; ↓, decrease; ↑, increase; +, therapeutic effect size of β-blocker therapy.

Figure 4

Pathophysiological mechanisms underlying LQTS and associated arrhythmia. Figure parts A–C show the illustrations of (A) an ECG with a normal P-QRS-TU complex, (B) a corresponding ventricular action potential with the different cardiac ion currents (I) and (C) a cardiomyocyte with different ion channels, subunits and their currents. In long QT syndrome, the phase 2 late sodium inward current (I _Na) the slow calcium inward current (I _Ca-L), or the potassium rectifier currents during phase 3 and phase 4 (I _Kr, I _Ks, I _K1) are involved. (D and E) In these illustrations, the action potential prolongation caused by a decrease in net repolarising current (I _repol) by changes in one of the repolarising currents in blue is shown. (D) If any of the currents in repolarisation is altered (eg, by a LQT3 SCN5A mutation with more net I _Na or a LQT1 KCNQ1 mutation with less net I _Ks), the ventricular action potential (and the corresponding QT interval) will lengthen. (E) When a second hit on net repolarising current is introduced, for example, by (further) decrease of I _Kr current due to the use of certain drugs, the ventricular action potentials and the QT interval will further lengthen. It can be appreciated that a loss of function of I _K1 only has a minor effect on the action potential duration (purple). (F) In this illustration, the prolonged ventricular action potential durations correspond with prolonged QT intervals, which are further challenged by changes in heart rate and proceed to early after depolarisation (EAD). These EADs finally result in a triggered beat and the onset of malignant ventricular arrhythmia (Torsades de Pointes). LQTS, long QT syndrome.

Figure 5

Schematic flow chart for the therapeutic choices in LQTS. Flow chart for therapeutic choices in LQTS following the HRS/EHRA/APHRS consensus document from 2013. See text for further discussion. ICD, internal cardioverter defibrillator; LQTS, long QT syndrome.

Figure 6

Schematic representation of the effects of genetic and environmental factors in LQTS. (A) LQTS-associated mutation causes prolongation of the QT interval on the ECG. (B) Environmental factors such as certain drugs (which decrease repolarisation reserve) or hypokalaemia, or genetic factors (ie, deleterious alleles) act in a conjoint manner with the LQTS-associated mutation to further prolong the QT interval. (C) Protective alleles counteract the effects of the mutation and reduce the extent of QT prolongation. The presence of deleterious and/or protective alleles may underlie, at least partially, the variable expressivity in LQTS. LQTS, long QT syndrome.