Clinical Advances in Congenital Long QT Syndrome

Abstract

Long QT syndrome is an inherited arrhythmia characterized by a prolonged QT interval and increased risk of life-threatening cardiac events, including arrhythmogenic syncope, seizures, and sudden cardiac death with a structurally normal heart. Since its first description in the 1950s, extensive researches allowed a better understanding of the cause and mechanisms of this disease, which improved our ability of early diagnosis, risk stratification, and precise therapy of these patients. This article provides an updated review of the clinical and molecular profiles of this potentially lethal inherited disorder and summarizes current knowledge regarding diagnosis, risk stratification, and therapy.

Introduction

Congenital long QT syndrome (LQTS) is one of the most common cardiac channelopathies characterized by impaired repolarization properties of cardiomyocytes with a tendency to cause life-threatening cardiac events, including arrhythmogenic syncope, seizures, and sudden cardiac death (SCD).^[1–4] The estimated prevalence of LQTS is approximately 1: 2500 in America,^[5] the figure which has not been reported in China.

In the past few decades, extensive researches allowed a better understanding of the underlying molecular mechanisms and improving the early diagnosis, risk stratification and precise therapy of these patients.^[6–9] This review will focus on the clinical and molecular profiles of this potentially lethal inherited disorder, summarizing current knowledge regarding diagnosis, risk stratification and therapy, taking into account novel and more targeted approaches such as gene-specific therapy.

Diagnosis

LQTS is a clinical diagnosis based on symptoms, family history and electrocardiogram (ECG) findings [Table 1]. According to the latest diagnostic scoring system (updated in 2015), patients with a Schwartz score ≥3 points in the absence of a secondary cause for QT prolongation are of a high probability of LQTS.^[3] Typical LQTS cases present no diagnostic difficulty for physicians aware of the disease, whereas latent patients with normal QTc at rest are more complex and require the evaluation of multiple variables besides clinical history and ECG. In suspected cases, serial ECGs, 24-hour Holter recordings, and an exercise or epinephrine test are recommended to reveal subclinical QT prolongation.

Table 1 - LQTS diagnostic criteria (updated in 2015)

Criteria	Points
Electrocardiographic findings∗
A. QTc interval†
≥ 480 ms	3
460–479 ms	2
450–459 ms (men)	1
B. QTc ≥ 480 ms during 2nd–4th min of recovery from exercise stress test	1
C. Documented Torsade de-Pointes (TdP)‡	2
D. T-wave alternans	1
E. Notched T wave in three leads	1
F. Resting heart rate below second percentile for age	0.5
Clinical history
A. Syncope‡
With stress	2
Without stress	1
B. Congenital deafness	0.5
Family history
A. Relatives with clinically definitive LQTS§	1
B. Unexplained sudden cardiac death in immediate relative <30 years of age§	0.5

Total score indicates the probability of LQTS: ≤1 point (low), 2–3 points (intermediate), and ≥3.5 points (high).

^∗In the absence of medication, electrolyte abnormalities, or disorders known to influence these electrocardiographic parameters.

^†QTc calculated using Bazett formula.

^‡Mutually exclusive.

^§Same family member cannot be counted twice.LQTS: Long QT syndrome.

Besides, the importance of a correct diagnosis has assumed a new dimension in the molecular era. A previous study by Taggart et al^[10] showed that in a group of 176 consecutive patients diagnosed as affected by LQTS, genetic testing verified 41% of them as unaffected, 32% as probably affected, and only 27% as definite cases of LQTS. Thus, it highlights the physician's responsibility to identify the most logical candidates for molecular screening. The appropriate approach consists of using the Schwartz score for the selection of patients who should undergo genetic testing and using “cascade screening” for the identification of all affected family members, including the silent mutation carriers.^[11]

At present, LQTS is reported linking to mutations in 16 different genes [Table 2], which could prolong the QT interval by decreasing potassium current (loss-of-function) or increasing sodium or calcium current (gain-of-function).^[12] And approximately 75% of patients possess a pathogenic mutation in one of the three major LQTS-causing genes (KCNQ1, 35%; KCNH2, 30%; and SCN5A, 10%).

Table 2 - Summary of LQTS types

Type	Gene	Protein	Function	Inheritance pattern
LQT1	KCNQ1	KvLQT1	↓I Ks	Autosomal dominant/recessive
LQT2	KCNH2	HERG	↓I Kr	Autosomal dominant
LQT3	SCN5A	Hav1.5	↑I Na	Autosomal dominant
LQT4	ANK2	Ankyrin B	Multichannel interactions	Autosomal dominant
LQT5	KCNE1	MinK	↓I Ks	Autosomal dominant
LQT6	KCNE2	MIRP	↓I Kr	Autosomal dominant
LQT7, Andersen-Tawil syndrome	KCNJ2	Kir2.1	↓I K1	Autosomal dominant
LQT8, Timothy syndrome	CACNA1c	Cav1.2	↑I CaL	Sporadic
LQT9	CAV3	caveolin 3	↑I Na	Autosomal dominant
LQT10	SCN4B	Nav1.5 β4	↑I Na	Autosomal dominant
LQT11	AKAP9	Yotiao	↓I Ks	Autosomal dominant
LQT12	SNTA1	Syntrophin	↑I Na	Autosomal dominant
LQT13	KCNJ5	Kir3.4/GIRK4	↓I KACh	Autosomal dominant
LQT14	CALM1	Calmodulin 1	↑I CaL	Sporadic
LQT15	CALM2	Calmodulin 2	↑I CaL	Sporadic
LQT16	CALM3	Calmodulin 3	↑I CaL	Sporadic

I_CaL: L-type Ca²⁺ current; I_K1: Inward rectifier K⁺ current; I_KACh: Acetylcholine-sensitive K⁺ current; I_Kr: Rapid delayed rectifier K⁺ current; I_Ks: Slow delayed rectifier K⁺ current; I_Na: Voltage-dependent Na⁺ current; LQTS: Long QT syndrome.

General clinical presentation

The typical ECG features of LQTS are prolonged QT interval, abnormal T wave, often accompanied by T wave alternation (TWA), and even Torsades de-Pointes (TdP), a serious, mostly self-limiting type of ventricular tachycardiathat can produce transient syncope but can also degenerate into ventricular fibrillation and cause SCD. T wave morphology may help differentiate LQT1 to 3. Typically, a broad T wave is observed in LQT1 [Figure 1A], a biphasic T wave in LQT2 [Figure 1B], and a late-appearing T wave in LQT3, which has a narrow and tall shape and appears at the very end of the QT interval [Figure 1C].^[13]

Figure 1: ECG patterns of LQTS patients. (A) Broad-based T-wave pattern and late-onset T-wave pattern of a 9-year old female LQT1 patient. (B) Bifid T waves of a 29-year old LQT2 patient. (C) Late-onset biphasic T wave of a 22-year old female LQTS patient. ECG: Electrocardiogram; LQTS: Long QT syndrome.

LQTS can have numerous clinical manifestations, ranging from no symptoms to sudden cardiac death, which reflects the heterogeneity in channel dysfunction. Mutation type, location, and even a patient's ethnic background, age, and gender are critical factors that affect the pathophysiology of the disease.^[11]

Clinical characteristic of major LQTS subtype

Those with mutation in each of these particular genes have different clinical manifestations and are associated with distinct triggers for cardiac events and response to treatment.

LQT1 is more frequently experience cardiac events triggered by adrenergic stimuli (eg, physical exertion or emotional stress) compared with other LQTS subtype, particularly by diving and swimming.^[14] Under normal physiological conditions, slow delayed rectifier K⁺ current (I_Ks) could be physiologically increased by sympathetic activation, which is essential for QT adaptation when heart rate increases.^[15] When I_Ks is defective, the QT interval fails to shorten appropriately during tachycardia, thus creating a highly arrhythmogenic condition.^[11,16] Heterozygous KCNQ1 mutations cause the dominant Romano-Ward LQT1 syndrome, while homozygous or compound heterozygous mutations cause the recessive Jervell and Lange-Nielsen syndrome (JLNS) variant, characterized by deafness due to the reduced I_Ks in the inner ear.

The development of cardiac events in LQT2 patients is associated with emotional stress and sudden exposure to auditory stimuli, such as noise from telephones, alarm clocks, and crying babies; hence, these sounds should be avoided. Besides, for female patients, the risk of cardiac events is increased during the postpartum period and menstrual period.^[17,18] In LQT3, about 65% of cardiac events occur during sleep or rest (bradycardia-triggered arrhythmias). And a clear causative role of this sinus bradycardia in cardiac events seems reserved to SCN5A mutations. Besides, sinus pauses, unrelated to sinus arrhythmia, are additional warning signals in LQT3 patients. Slow heart rate induced excessive action potential duration could predispose individuals with LQT3 to fatal arrhythmias, typically at rest or during sleep without emotional arousal.

Risk stratification

Clinical features and genetic substrate could influence the risk stratification in individuals with LQTS, with several patterns and groups associated with differential risk.

Prior syncope

Cardiac events would continue to occur in symptomatic patients, even patients are taking the prescribed β-blockers. 32% of symptomatic patients will have a cardiac event over 5 years, and 14% of patients with a prior cardiac arrest will have a recurrence within 5 years.^[19]

Age

Koponen et al^[7] reported the risk was distinctly higher in patients who were symptomatic before the age of 18 years (cumulative rate 52% vs. 9%, P < 0.001; HR = 5.93, P < 0.001). Kutyifa et al^[8] confirmed that males <14 years and females >14 years as predictors of cardiac events in LQT1 and LQT2.

Sex

Several studies have verified a modulating effect of gender on the clinical course of the disease. Koponen et al^[7] reported that both LQT1 and LQT2 females were more often symptomatic than males (cumulative rate 16% vs. 3%, P < 0.001, for LQT1; and 23% vs. 8%, P = 0.010, for LQT2), with a hazard ratio of 3.2 for the female versus male comparison (P < 0.001). Wilde et al^[9] confirmed that female LQT3 patients had a higher probability of a first cardiac event than males, especially during the 30 to 40-year age range.

Pregnancy and postpartum period

Various researches have indicated that cardiac events during the postpartum period are more common in patients with LQTS, especially for LQT2 patients.^[20–23]

ECG characteristics

Various studies have verified that ECG characteristics are important factors for the prognosis of LQTS patients.^[24] High risk is present whenever QTc > 500 ms and becomes an extremely high risk when QTc > 600 ms. A recent registry study including 1923 LQTS patients identified that QTc > 500 ms as predictors of cardiac events in the most common genotypes (LQT1, LQT2 and LQT3).^[8] Koponen et al^[7] reported for LQT1 and LQT2 patients, QTc duration ≥500 ms increased the risk 2.7-fold compared to QTc < 470 ms (P = 0.001). Wilde et al^[25] reported prolonged QTc also predisposed patients with LQT3 to life-threatening cardiac events, at least between the age of 16 to 26 years. Each 10 ms increase in QTc duration up to 500 ms was associated with a 19% increase in cardiac events. Besides, LQTS patients with a broader variation in QTc duration are associated with an increased risk of cardiac events, especially for LQT1 patients.^[26] On the other hand, Zhang et al^[27] revealed that low-risk LQTS patients (LQT1 and LQT2) identified by QTc < 500 ms and no cardiac events before age 20 had a 45-year mortality rate of about 4% between age 20 and 65, and this low mortality rate was similar to that of unaffected genotype-negative family members. Besides, the risk of cardiac events in LQT2 carriers with normal QTc (QTc < 460 ms in men and <470 ms in women) is associated with abnormal T-wave morphology (“broad”, “flat”, “notched”, “negative” or “biphasic”).^[28]

As a marker of major electrical instability, TWA is defined as a beat-to-beat alternation in the morphology and amplitude of the ST segment or T wave and could identify patients at particularly high risk. Its presence in a patient already on treatment should alert the physician to persistent high risk and warrants an immediate reassessment of therapy.^[11]

Genetic background

Intragenic risk evaluation has been realized for LQTS patients based on mutation type, location, and cellular function.^[29] LQT1 patients with transmembrane-spanning are at greater risk of an LQT1-triggered cardiac event than patients with C-terminal region mutations.^[30] Previous study reported that the hot spot KCNQ1-A341V and KCNQ1-D317N patients were more likely to have cardiac events.^[31]

Overall, LQT2 genotype was associated with a higher risk of cardiac events in comparison to LQT1 (cumulative probability 18% vs. 11%, P = 0.010; HR = 2.1, P = 0.002). LQT2 patients with pore region KCNH2 mutations have a longer QTc, a more severe clinical manifestation of the disorder, and more arrhythmia-related cardiac events occurring at a younger age than those LQT2 patients with non-pore mutations.^[30] Besides, Koponen et al^[7] revealed KCNH2 c.453delC, L552S and R176W associated with a lower risk of cardiac events in comparison to other KCNH2 mutations (HR = 0.11–0.23, P < 0.001). In addition, recent studies showed that patients with LQT3 and patients with multiple gene mutations are at the highest risk of breakthrough cardiac events when compared with LQT1 and LQT2 patients.^[32,33] And the Jervell and Lange-Nielsen syndrome^[34] and the Timothy syndrome (LQT8)^[35] have a significantly higher cardiac event risk.

Therapy

Lifestyle modifications

Lifestyle change is an essential part of LQTS management, which include avoidance of competitive sports, especially swimming or water sports in LQT1 patients, reduction in exposure to abrupt loud noises (alarm clock, phone ringing, etc) in LQT2 patients, and avoidance of QT-prolonging drugs and identification and correction of electrolyte abnormalities caused by vomiting, diarrhea, metabolic conditions or imbalanced diets for weight loss.^[4,14,36]

Antiadrenergic therapy

Life-threatening ventricular arrhythmias in LQTS patients are usually triggered by increased sympathetic activity, like physical exercise and emotional stress. Beta-blocker therapy is considered a milestone in all high and intermediate-risk patients with LQTS since the mid-1970s. They are recommended in all symptomatic patients and in asymptomatic patients with a resting QTc greater than 470 ms. However, their use is also reasonable in asymptomatic patients with a resting QTc less than 470 ms.^[37] A previous study showed that beta-blockers were associated with a significant reduction in cardiac events in LQTS probands and in the affected family members (0.97 ± 1.42 to 0.31 ± 0.86 and 0.26 ± 0.84 to 0.15 ± 0.69 events per year, respectively).^[19] However, despite a significant reduction in mortality, about 3% of LQTS patients treated with beta-blockers still experience recurrent cardiac event.^[19,38] Furthermore, the protective effect of beta-blockers is not uniform in LQTS patients, and they are thought to be more beneficial in patients with LQT1.^[39] Beta-blockers are considered reasonably safe during pregnancy and should be continued or initiated in patients with LQTS to reduce the risk of cardiac events.^[22,40,41] A recent study focused on LQT3 revealed that time-dependent beta-blocker therapy was associated with an 83% reduction in cardiac events in females (P = 0.015) but not in males (who had much fewer events).^[9]

Nevertheless, certain patients still experience cardiac events despite high doses of beta-blockers or fail to tolerate high dose beta-blockers. Left cardiac sympathetic denervation (LCSD) involves surgical resection of the lower half of the stellate ganglion and the left-sided sympathetic chain from T1 to T4 [Figure 2A], which reduces sympathetic activation by preventing norepinephrine release in the heart and then increasing the threshold for fatal ventricular arrhythmias. Nowadays, LCSD is usually used in very-high risk patients to bridge the therapeutic and comorbidity gap between pharmacological and implantable cardioverter defibrillator (ICD) therapy. In a research of 147 LQTS patients, there was a >90% reduction in cardiac events post denervation.^[42] Besides, video-assisted thoracoscopic left cardiac sympathetic denervation (VATS-LCSD) is a less invasive surgical procedure [Figure 2B], without serious complications, including Horner syndrome.^[43] A previous study demonstrated that VATS-LCSD is a low-morbidity procedure that achieves a marked response in Chinese LQTS patients [Figure 2C and D].^[44]

Figure 2: LCSD treatment for LQTS patients. (A) Surgical resection of the lower half of the stellate ganglion and the left-sided sympathetic chain from T1 to T4. (B) Small scar after VATS-LCSD (Arrow). (C) Body surface ECG showed the QTc was shortened after LCSD in a 22-year-old female patient. (D) Comparison of cardiac events before and after LSCD. ECG: Electrocardiogram; LCSD: Left cardiac sympathetic denervation; LQTS: Long QT syndrome; VATS-LCSD: Video-assisted thoracoscopic left cardiac sympathetic denervation.

Gene-specific therapies

LQT2 patients are extremely sensitive to serum potassium levels, which should be maintained at an appropriate level. When reasonable levels are not maintained by Potassium supplementation, a combination with K⁺ sparing agents should be considered. Besides, a recent study showed that mexiletine could significantly shorten the QT interval in patients with potassium channel-mediated LQT2.^[45] However, ECG response may not correlate with clinical efficacy and long-term data are necessary.

LQT3 is caused by SCN5A mutations that have a “gain-of-function” effect. Sodium channel blockers such as mexiletine, flecainide, and ranolazine have been used as adjuvant therapy in high-risk LQT3 patients with a QTc > 500 ms.^[3,46] Mazzanti et al^[47] reported that mexiletine can not only shorten the QTc interval, but also significantly reduce life-threatening arrhythmic events in LQT3 patients, thus representing an efficacious therapeutic strategy. Windle et al^[48] reported that low-dose, oral flecainide consistently shortened the QTc interval and normalized the repolarization T-wave pattern, indicating that low-dose flecainide is a promising therapeutic agent. However, flecainide may induce ST-segment elevation in LQT3 patients, raising concerns about the safety of flecainide therapy.^[49] Ranolazine is a drug that exerted a concentration-dependent block of the late Na⁺ currents (I_Na-L) without reducing peak voltage-dependent Na⁺ current (I_Na-P) significantly. In a previous study, among 8 LQT3 patients with D1790G mutation, ranolazine had no effects on the sinus rate or QRS width but shortened the QTc from (509 ± 41) ms to (451 ± 26) ms (P = 0.012) and the QT-shortening effect remained effective throughout the entire study period of (22.8 ± 12.8) months.^[50]

ICD implantation

The recommended indications of ICD implantation are patients with previous cardiac arrest, patients who experienced syncope and/or ventricular tachycardia while receiving an adequate dose of beta-blockers (and LCSD).^[3] However, international guidelines are not always followed, and risk stratification may be based on genotype rather than individual risk profile. A previous research revealed that 30% of Swedish LQTS patients with ICD received the treatment without a strong indication based on international guidelines. LQT3 patients were over-represented among asymptomatic patients, and many LQT1 patients received ICD despite the known effect of beta-blockers.^[51] Another recent study with 157 patients showed a trend that most patients had Class II and Class III indications for ICD implantation.^[52] Therefore, prudent consideration is needed before deciding to recommend an ICD implantation, and more detailed data regarding the role of ICD for the primary prevention of sudden cardiac death in patients with LQTS is needed. In 2018, Biton et al^[53] built a risk score based on Rochester LQTS-ICD registry and each risk variable was assigned for a score roughly reflecting the relative parameter estimate in the model (2 points for QTc ≥ 550 ms and 1 point for each of the other variables: QTc 500–550 ms, syncope while on β-blockers treatment, LQT2 genotype, and multiple mutations). And the results revealed that for patients with a score of 0, 1, 2, and ≥3, the cumulative probabilities of the first appropriate shock were 0%, 15%, 23%, and 50%, respectively after 10 years, (P < 0.001) which provided genetic and clinical criteria to identify high-risk patients for whom ICD provides appropriate and necessary shocks.

Besides, ICD is usually not recommended for asymptomatic LQTS patients, especially for those who have not been tried on beta-blocker therapy.^[4] However, prophylactic ICD therapy may be considered, on an individual basis, in high-risk patients such as women with LQT2 and QTc > 500 ms, patients with QTc > 500 ms and signs of electrical instability and patients with high-risk genetic profiles (carriers of 2 mutations, including Jervell and Lange-Nielsen syndrome or Timothy syndrome).^[3]

Funding

This work was funded by The Capital Health Research and Development of Special (NO. Z191100006619007), Beijing Municipal Administration of Hospitals Clinical medicine Development of special funding support (NO. ZYLX201831) and Beijing Municipal Administration of Hospitals’ Ascent Plan (NO. DFL20190902).

Conflicts of interest

None.

Editor note: Ping Zhang is an Editorial Board Member of Cardiology Discovery. The article was subject to the journal's standard procedures, with peer review handled independently of this editor and her research groups.