
==== Front
Heart Rhythm O2
Heart Rhythm O2
Heart Rhythm O2
2666-5018
Elsevier

S2666-5018(24)00225-3
10.1016/j.hroo.2024.07.006
Topics in Review
From genes to clinical management: A comprehensive review of long QT syndrome pathogenesis and treatment
Zhu Wenjing BS ∗
Bian Xueyan BS †
Lv Jianli PhD drjllv@gmail.com
‡∗
∗ Department of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
† Department of Pediatrics, Lixia District People’s Hospital, Jinan, Shandong, China
‡ Department of Pediatric Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
∗ Address reprint requests and correspondence: Dr Jianli Lv, Department of Pediatric Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China. drjllv@gmail.com
15 7 2024
8 2024
15 7 2024
5 8 573586
© 2024 Heart Rhythm Society. Published by Elsevier Inc.
2024
Heart Rhythm Society
https://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Background

Long QT syndrome (LQTS) is a rare cardiac disorder characterized by prolonged ventricular repolarization and increased risk of ventricular arrhythmias. This review summarizes current knowledge of LQTS pathogenesis and treatment strategies.

Objectives

The purpose of this study was to provide an in-depth understanding of LQTS genetic and molecular mechanisms, discuss clinical presentation and diagnosis, evaluate treatment options, and highlight future research directions.

Methods

A systematic search of PubMed, Embase, and Cochrane Library databases was conducted to identify relevant studies published up to April 2024.

Results

LQTS involves mutations in ion channel–related genes encoding cardiac ion channels, regulatory proteins, and other associated factors, leading to altered cellular electrophysiology. Acquired causes can also contribute. Diagnosis relies on clinical history, electrocardiographic findings, and genetic testing. Treatment strategies include lifestyle modifications, β-blockers, potassium channel openers, device therapy, and surgical interventions.

Conclusion

Advances in understanding LQTS have improved diagnosis and personalized treatment approaches. Challenges remain in risk stratification and management of certain patient subgroups. Future research should focus on developing novel pharmacological agents, refining device technologies, and conducting large-scale clinical trials. Increased awareness and education are crucial for early detection and appropriate management of LQTS.

Keywords

Long QT syndrome
Ventricular arrhythmias
Ion channelopathies
Diagnosis
Treatment strategies
==== Body
pmc Key Findings

1. Pathogenesis▪ Long QT syndrome (LQTS) involves mutations in ion channel–related genes, leading to altered cellular electrophysiology and prolonged ventricular repolarization.

▪ Both congenital and acquired forms of LQTS exist, with the former being genetically heterogeneous and the latter often drug induced or due to electrolyte imbalances.

2. Diagnosis▪ Diagnosis of LQTS relies on a combination of clinical history, electrocardiographic findings, and genetic testing.

▪ The Schwartz score and genetic testing are critical tools for assessing the probability of LQTS and identifying specific subtypes.

3. Epidemiology and clinical importance▪ The prevalence of congenital LQTS is estimated to be 1:2000 to 1:2500, but the actual prevalence may be higher because of silent mutation carriers.

▪ LQTS is a significant cause of sudden cardiac death in young, apparently healthy individuals.

4. Historical perspective▪ LQTS has been recognized since the 1950s, with significant advancements in understanding its genetic basis and clinical management over the decades.

▪ The identification of key genes (KCNQ1, KCNH2, and SCN5A) in the 1990s was a major breakthrough in understanding the disorder.

5. Treatment strategies▪ Treatment includes lifestyle modifications, β-blockers, potassium channel openers, device therapy, and surgical interventions.

▪ Advances in understanding LQTS have led to personalized treatment approaches, improving patient care and outcomes.

6. Future directions▪ Future research should focus on developing novel pharmacological agents, refining device technologies, and conducting large-scale clinical trials.

▪ Increased awareness and education are crucial for early detection and appropriate management of LQTS.

Introduction

Definition of long QT syndrome

Long QT syndrome (LQTS) is a genetically heterogeneous cardiac channelopathy characterized by prolonged ventricular repolarization, which manifests as a prolonged QT interval on the surface electrocardiogram (ECG).1 The prolonged QT interval results from delayed inactivation of inward sodium (INa) or calcium (ICa) currents or a loss of function in outward potassium (slow delayed rectifier potassium channel [IKs], rapid delayed rectifier potassium channel [IKr], or inward rectifier potassium current [IK1]) currents, leading to an extended action potential duration (APD) in cardiac myocytes.2,3 This prolonged repolarization predisposes individuals to ventricular arrhythmias, particularly torsades de pointes (TdP), a polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation and cause sudden cardiac death (SCD).4

LQTS can be classified into 2 main categories: congenital and acquired. Congenital LQTS is caused by genetic mutations in genes encoding cardiac ion channels or their regulatory proteins, resulting in altered channel function and prolonged repolarization.5 Mutations in at least 17 genes have been associated with LQTS, with LQTS type 1 (LQT1) (KCNQ1 gene), LQTS type 2 (LQT2) (KCNH2 gene), and LQTS type 3 (LQT3) (SCN5A gene) accounting for ∼80%–90% of genotype-positive cases.6,7 Conversely, acquired LQTS (aLQTS) results from various environmental factors, including certain medications (eg, antiarrhythmic drugs, antibiotics, and antipsychotics), electrolyte imbalances (eg, hypokalemia and hypomagnesemia), and medical conditions (eg, bradycardia and hypothyroidism).8,9

Diagnosis of LQTS relies on a comprehensive evaluation of clinical history, family history, ECG findings, and genetic testing. The Schwartz score, which incorporates these factors, is widely used to assess the probability of LQTS, with a score of ≥3.5 indicating a high likelihood of the disorder.10 Genetic testing has emerged as a crucial tool for confirming the diagnosis and identifying specific LQTS subtypes, which informs risk stratification and management strategies.11

Epidemiology and clinical importance

The prevalence of congenital LQTS is estimated to be ∼1:2000 to 1:2500 in the general population.3,12,13 However, the actual prevalence may be higher because of variable penetrance and expressivity as well as the presence of silent mutation carriers.14 The prevalence of aLQTS is more challenging to determine, as it depends on exposure to various environmental triggers.15

LQTS is clinically significant because of its potential to cause life-threatening ventricular arrhythmias, particularly TdP, which can lead to syncope, seizures, and SCD.4 It is a leading cause of SCD in young, apparently healthy individuals, accounting for ∼54% of sudden unexplained deaths in those younger than 35 years.16 Clinical presentation varies widely, from asymptomatic individuals to those experiencing recurrent syncope or cardiac arrest.17 The risk of life-threatening arrhythmias is influenced by factors such as age, sex, genotype, QT interval, and exposure to triggers.18

The importance of LQTS extends to family members. Given the autosomal dominant inheritance pattern of the most common subtypes (LQT1, LQT2, and LQT3), first-degree relatives of an affected individual have a 50% chance of carrying the pathogenic variant.19 Cascade genetic screening is crucial for identifying asymptomatic carriers who may benefit from preventive measures and close monitoring.20

Furthermore, LQTS serves as a paradigm for understanding the complex interplay between genetic predisposition and environmental factors in cardiac arrhythmias.21 Insights gained from studying LQTS have improved our understanding of the disorder and contributed to the development of targeted therapies and risk stratification strategies for other cardiac channelopathies and arrhythmogenic disorders.22

Historical perspective

The first description of LQTS dates back to 1957 when Jervell and Lange-Nielsen reported a family with congenital deafness, prolonged QT interval, and sudden death.23 This autosomal recessive form, now known as Jervell and Lange-Nielsen syndrome (JLNS), was later found to be caused by homozygous or compound heterozygous mutations in the KCNQ1 or KCNE1 genes, encoding subunits of the IKs.24

In 1963 and 1964, Romano25 and Ward26 independently described families with a prolonged QT interval and syncope without deafness, which became known as Romano-Ward syndrome. Romano-Ward syndrome, an autosomal dominant form of LQTS, is more common than JLNS. Studies in the 1970s and 1980s further characterized the clinical features and familial nature of LQTS, leading to the recognition of its genetic heterogeneity.27

A major breakthrough occurred in the 1990s with the identification of the first 3 LQTS-associated genes: KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3).28 These discoveries improved understanding of LQTS pathophysiology and paved the way for genotype-specific management strategies.29

Since then, numerous other genes have been implicated in LQTS, with at least 17 genes currently associated with the disorder.30 These genes encode various ion channels, channel subunits, and regulatory proteins involved in cardiac repolarization. The expanding genetic knowledge has led to more comprehensive testing panels and facilitated genotype-phenotype correlations.31

Advancements in clinical management have paralleled genetic discoveries. β-Blockers, established as the mainstay of LQTS therapy in the 1970s, remain a cornerstone of treatment.32 Implantable cardioverter-defibrillators (ICDs) have been increasingly used since the 1990s for high-risk patients or those with recurrent events despite medical therapy.33 More recently, left cardiac sympathetic denervation (LCSD) has emerged as an effective adjunctive therapy for patients with refractory symptoms or β-blocker intolerance.34

The historical journey of LQTS, from its initial description to the current understanding of its genetic basis and clinical management, has been marked by significant advancements in molecular genetics, electrophysiology, and clinical cardiology. These advancements have improved patient care and provided valuable insights into the complex mechanisms underlying cardiac arrhythmogenesis.

Methods

Literature search and study selection

This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive literature search was performed using databases such as PubMed, EMBASE, and Cochrane Library to identify relevant studies on LQTS. Keywords and MeSH terms related to LQTS were used to ensure an extensive search. Studies discussing the pathogenesis, diagnosis, treatment, or epidemiology of LQTS were included.

Pathogenesis of LQTS

Genetic basis and molecular mechanisms of LQTS

LQTS is a genetically heterogeneous disorder, with at least 17 genes implicated in its pathogenesis.35 These genes primarily encode cardiac ion channels or their regulatory proteins, leading to altered ion channel function, prolonged ventricular repolarization, and increased arrhythmia risk.36

The 3 most common LQTS subtypes are LQT1, LQT2, and LQT3, accounting for ∼80%–90% of genotype-positive cases.35 LQT1, the most prevalent subtype, is caused by loss-of-function mutations in the KCNQ1 gene, encoding the α subunit of the IKs.37 LQT2 results from loss-of-function mutations in the KCNH2 gene (also known as human Ether-à-go-go-related gene), encoding the α subunit of the IKr.38 LQT3 is caused by gain-of-function mutations in the SCN5A gene, encoding the α subunit of the cardiac sodium channel (Nav1.5).39

Other less common LQTS subtypes include mutations in genes such as ANKB, KCNE1, KCNE2, KCNJ2, and CACNA1C,40, 41, 42, 43, 44, 45 which encode various ion channels and their regulatory proteins. Mutations in these genes lead to similar mechanisms of prolonged repolarization and increased arrhythmia risk.

Genetic mutations associated with LQTS lead to ion channelopathies, disorders characterized by abnormal ion channel function at the molecular level. These channelopathies disrupt the delicate balance of ionic currents responsible for proper cardiac myocyte repolarization, resulting in prolonged APD and increased arrhythmia risk.46LQT1: Loss-of-function mutations in KCNQ1 reduce IKs, a key repolarizing current that activates slowly and contributes to action potential termination. Reduced IKs leads to prolonged APD and QT interval.47

LQT2: Loss-of-function mutations in KCNH2 reduce IKr, another critical repolarizing current that activates rapidly and helps terminate the action potential.38,48

LQT3: Gain-of-function mutations in SCN5A increase the late sodium current (INaL), leading to a persistent INa during the plateau phase, prolonging APD and QT interval.49

Understanding these mechanisms provides insight into the pathophysiology of LQTS and guides the development of targeted therapies and risk stratification strategies.

Acquired causes of LQTS

Drugs and substances that can prolong the QT interval

aLQTS occurs when the QT interval is prolonged because of external factors such as medications, illicit substances, or toxins without a genetic predisposition. The most common cause of aLQTS is drug-induced QT prolongation, which is a significant reason for drug withdrawal or relabeling.50

Various medications across multiple therapeutic classes have been linked to QT prolongation and an increased risk of TdP. Notable examples include the following:Antiarrhythmic drugs: class IA (eg, quinidine, procainamide, and disopyramide) and class III (eg, sotalol, dofetilide, and ibutilide)51

Antibiotics: Macrolides (eg, erythromycin, clarithromycin, and azithromycin) and fluoroquinolones (eg, levofloxacin and moxifloxacin)15

Antipsychotics: Typical (eg, haloperidol and thioridazine) and atypical (eg, risperidone, quetiapine, and ziprasidone)52,53

Antidepressants: Tricyclic antidepressants (eg, amitriptyline and imipramine) and selective serotonin reuptake inhibitors (eg, citalopram and fluoxetine)54

Antihistamines: Nonsedating antihistamines, such as terfenadine and astemizole (both withdrawn)55

Antimalarials: Chloroquine and hydroxychloroquine, particularly with azithromycin56

Antifungals: Azole antifungals (eg, ketoconazole and fluconazole)57

Antiemetics: 5-hydroxytryptamine type 3 receptor antagonists (eg, ondansetron and granisetron)58

Opioids: Methadone, used for opioid addiction treatment and chronic pain management59

In addition to medications, illicit substances such as cocaine and methamphetamine have been associated with QT prolongation and increased risk of SCD.60,61

The risk of drug-induced LQTS depends on several factors, including the drug’s inherent proarrhythmic potential, dosage, route of administration, pharmacokinetic properties, and individual patient characteristics (eg, age, sex, comorbidities, electrolyte abnormalities, and genetic predisposition).62,63 Careful evaluation of the risk-benefit ratio, consideration of alternative therapies, and close monitoring are essential when prescribing QT-prolonging medications.

Electrolyte imbalances

Electrolyte imbalances, particularly hypokalemia and hypomagnesemia, are well-recognized risk factors for aLQTS and can exacerbate the effects of QT-prolonging drugs.64

Hypokalemia, defined as serum potassium below 3.5 mEq/L, can lead to prolonged repolarization and increased risk of TdP.65 Low extracellular potassium reduces the conductance of the IK1, essential for maintaining resting membrane potential and terminal repolarization of cardiac myocytes. It also enhances Na+/Ca2+ exchanger activity, increasing intracellular calcium levels and prolonging APD.66

Hypomagnesemia, defined as serum magnesium below 1.7 mg/dL, is another important risk factor for aLQTS.67 Magnesium is a critical cofactor for various ion channels and transporters involved in cardiac repolarization. Low magnesium levels can impair the function of IKr, IKs, and Na+/K+-ATPase, leading to prolonged APD and increased arrhythmia risk.68

The combination of hypokalemia and hypomagnesemia can have a synergistic effect on aLQTS and TdP risk.69 This is particularly relevant in patients treated with diuretics, which can cause both potassium and magnesium depletion. Other conditions leading to electrolyte imbalances include gastrointestinal disorders, renal disorders, and endocrine disorders.70

Hypocalcemia has also been associated with QT prolongation, although the mechanisms are less well understood.71 Calcium plays a crucial role in cardiac electrophysiology, and low extracellular calcium levels can alter the function of various ion channels and transporters involved in repolarization.

Identifying and correcting electrolyte imbalances is essential in managing patients with aLQTS or those at risk. Monitoring serum electrolyte levels, particularly in patients treated with QT-prolonging medications or those with predisposing conditions, can help prevent life-threatening arrhythmias.72

Other medical conditions contributing to aLQTS

Several medical conditions can contribute to the development of aLQTS by directly affecting cardiac repolarization or indirectly influencing the risk of QT prolongation through altered pharmacokinetics or pharmacodynamics of QT-prolonging medications.Cardiac conditions

Bradycardia: Slow heart rates can prolong the QT interval and increase TdP risk.73,74

Heart failure: Associated with an increased risk of QT prolongation and TdP because of altered ion channel expression, neurohumoral activation, and electrolyte disturbances.75

Myocardial ischemia and infarction: Can lead to QT prolongation by altering ion channel function and increasing repolarization dispersion.76

Endocrine disorders

Hypothyroidism: Can prolong the QT interval by altering cardiac ion channel expression and function.77

Pheochromocytoma: Catecholamine excess can lead to QT prolongation and increased ventricular arrhythmia risk.78

Neurological conditions

Subarachnoid hemorrhage: Increased risk of QT prolongation and TdP because of autonomic dysfunction, electrolyte disturbances, and QT-prolonging medications.79

Stroke: Acute stroke, particularly involving the insular cortex, can lead to QT prolongation and increased ventricular arrhythmia risk.80

Liver disease: Hepatic dysfunction can alter QT-prolonging drug metabolism, leading to increased plasma levels and higher aLQTS risk.81

Renal disease: Chronic kidney disease and end-stage renal disease are associated with increased QT prolongation and TdP risk.82

Eating disorders: Anorexia nervosa and bulimia nervosa can lead to QT prolongation and increased SCD risk.83

Autoimmune disorders: Systemic lupus erythematosus and other autoimmune disorders have been associated with QT prolongation.84, 85, 86

Recognizing and managing these underlying medical conditions is crucial for minimizing aLQTS risk. Patients with these conditions should be closely monitored for QT prolongation, especially when treated with QT-prolonging medications, and appropriate interventions should be implemented to correct modifiable risk factors.

Pathophysiological mechanisms

Cellular and cardiac electrophysiology

Cellular and cardiac electrophysiology are crucial for understanding LQTS pathophysiology. The prolonged QT interval results from alterations in the delicate balance of ionic currents governing cardiac APD.63 Action potentials are generated by coordinated opening and closing of voltage-gated sodium, calcium, and potassium channels.87

The cardiac action potential consists of the following:1. Phase 0 (Initial depolarization): Rapid sodium influx (INa)

2. Phase 1 (Early repolarization): Transient outward potassium current

3. Phase 2 (Plateau): Balance between inward L-type calcium current (ICaL) and outward delayed rectifier potassium currents (IKr and IKs)

4. Phase 3 (Final repolarization): IK1

In LQTS, mutations lead to reduced outward potassium currents or increased INa/ICa, prolonging APD and QT interval.88 This delayed repolarization increases the risk of early afterdepolarizations (EADs), which can trigger ventricular arrhythmias, particularly TdP.63,89,90

EAD formation mechanisms involve L-type calcium channel reactivation during prolonged APD91 and intracellular calcium overload activating the sodium-calcium exchanger.92

Arrhythmogenic substrate in LQTS is modulated by the following:1. Adrenergic stimulation: Enhances ICaL and promotes calcium overload93

2. Bradycardia: Exacerbates QT prolongation and increases TdP risk94

3. Electrolyte imbalances: Alter potassium channel and ion transporter function95

Understanding LQTS cellular and cardiac electrophysiology has important clinical implications for risk stratification and management. Genotype-specific triggers and QT interval dynamics assessment guide preventive strategies and optimize treatment.96 Insights into molecular mechanisms have led to targeted therapies, such as INaL inhibitors and potassium channel openers, aiming to correct electrophysiological abnormalities and reduce life-threatening arrhythmia risk.97

Clinical implications of altered repolarization

Altered repolarization in LQTS has profound clinical implications, creating a substrate highly susceptible to life-threatening ventricular arrhythmias.98 The delayed repolarization in LQTS, resulting from the altered function of cardiac ion channels, leads to a prolonged APD and an increased dispersion of repolarization across the ventricular myocardium.99 This spatial heterogeneity of repolarization creates a favorable milieu for the generation and propagation of EADs and triggered activity.100 EADs, secondary depolarizations during the plateau or repolarization phases, are a hallmark of LQTS and the primary triggering mechanism for TdP.38

The risk of EADs and TdP is modulated by genetic, environmental, and physiological factors.88 Genotype-specific differences contribute to variable clinical expressivity and arrhythmogenic risk. For example, patients with LQT1, are particularly susceptible to arrhythmias during exercise or emotional stress, as the impaired IKs function limits the ability to shorten the QT interval during adrenergic activation.101

Additional clinical implications include T-wave alternans (TWA) and impaired QT interval rate adaptation. TWA is a marker of electrical instability and predictor of arrhythmic risk.102,103 The impaired QT adaptation, quantified by the QT/RR slope, has been associated with an increased risk of cardiac events.18,104

Clinical presentation and diagnosis

Clinical manifestations of LQTS

The clinical manifestations of LQTS are diverse and can vary significantly among affected individuals, even those with the same genetic subtype.105 The hallmark feature is QT interval prolongation on the ECG, reflecting delayed ventricular repolarization.106 However, clinical presentation extends beyond ECG findings and includes symptoms related to increased ventricular arrhythmia risk.107

Common clinical manifestations are as follows:Syncope: Occurs in ∼60% of untreated patients.108 Triggers vary by genetic subtype:

1. LQT1 (KCNQ1 mutations): Exercise or swimming, particularly in younger patients109

2. LQT2 (KCNH2 mutations): Rest or sleep, often in response to auditory triggers110

3. LQT3 (SCN5A mutations): Sleep or rest, more pronounced at slower heart rates.110

Aborted cardiac arrest or SCD: SCD can be the presenting symptom in up to 10% of untreated patients.111 Risk factors include the following111, 112, 113, 114:

1. History of syncope

2. Corrected QT (QTc) interval > 500 ms

3. Family history of SCD

4. History of aborted cardiac arrest

5. Syncope during the first year of life

Seizures or seizure-like activity: LQTS can be misdiagnosed as epilepsy.115, 116, 117 Distinction is crucial because of different treatment strategies and prognoses.118,119

Extracardiac manifestations: JLNS presenting as congenital bilateral sensorineural deafness in addition to prolonged QT interval.120,121

Age-specific presentations: Functional 2:1 atrioventricular block (pseudo-atrioventricular block) due to extreme QT prolongation in neonates and infants.122,123

Risk factors for arrhythmia in patients with LQTS

The risk of arrhythmic events in patients with LQTS is influenced by a complex interplay of genetic, clinical, and environmental factors.124 Major risk factors include the following:Genetic subtype:

1. LQT2 and LQT3: Higher risk of syncope and SCD compared to LQT1125

2. LQT1: High risk during exercise, especially swimming126

3. LQT2: Prone to events during rest or sleep127

4. LQT3: Higher risk during sleep or at rest.110

QTc interval: QTc interval > 500 ms is associated with a significantly increased risk of SCD, particularly in patients with LQT1 and LQT2.105 In addition, the presence of QTc interval > 500 ms in the first year of life is a major risk factor for SCD in infants with LQTS.114

Sex: In childhood, males have a higher risk of SCD than do females, particularly in LQT1.128 However, after puberty, the risk of SCD is higher in females, especially in LQT2.129, 130, 131

History of syncope: A history of syncope is a major risk factor for SCD in patients with LQTS, particularly if the syncope is recurrent or occurs in the absence of a trigger.132 In patients with a history of syncope, the risk of SCD is highest in the first year after the syncopal event and decreases thereafter.132 The presence of syncope in the first year of life is also a strong predictor of SCD in infants with LQTS.133

Family history of SCD: Significant risk factor, especially in young relatives (<40 years) or multiple family members.134

Genotype-specific triggers: The risk of arrhythmic events in patients with LQTS is influenced by genotype-specific triggers, which can precipitate syncope or SCD in susceptible individuals.135

Electrolyte imbalances: Electrolyte imbalances, particularly hypokalemia and hypomagnesemia, can prolong the QT interval and increase the risk of arrhythmic events.136

Medications: QT-prolonging drugs increase the arrhythmic risk.69,137

Comorbidities: Hypothyroidism, eating disorders, diabetes, obesity, and obstructive sleep apnea.83,138

Genotype-phenotype modifiers: In addition to the primary genetic defect, other genetic factors (such as single nucleotide polymorphisms or modifier genes) can influence the clinical manifestations and arrhythmic risk in patients with LQTS. For example, the presence of certain polymorphisms in the NOS1AP gene (which encodes a nitric oxide synthase adaptor protein) has been associated with an increased risk of SCD in patients with LQTS, particularly those with LQT1.139,140

Diagnostic criteria and tools

ECG findings

The hallmark ECG feature of LQTS is a prolonged QT interval, reflecting delayed ventricular repolarization.141 QTc interval > 460 ms in females and QTc interval > 450 ms in males are considered prolonged.142 However, up to 25% of patients with genetically confirmed LQTS may have normal QTc intervals.143,144 Additional ECG findings suggestive of LQTS include TWA, T-wave notching, and bradycardia.145

Schwartz score

The Schwartz score assigns points to clinical and ECG features to estimate LQTS probability.10 Scores range from 0 to 9, with ≥3.5 indicating high LQTS probability. The clinical features included in the Schwartz score are syncope (1–2 points), congenital deafness (0.5 points), and a family history of LQTS or unexplained sudden death (0.5–1 points). The ECG features included are QTc interval ≥ 480 ms (3 points), 460–479 ms (2 points), or 450–459 ms (1 point); TWA (1 point); notched T waves in 3 leads (1 point); and bradycardia (0.5 points).

Genetic testing

Genetic testing is essential for confirming LQTS diagnosis and identifying specific subtypes.146 Commercial panels screen for mutations in up to 17 LQTS-associated genes, with a 50%–80% diagnostic yield.147,148 KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3) account for 75% of genetically confirmed cases.149 Genetic testing aids in identifying asymptomatic family members at risk and guiding genotype-specific management.150

Provocative testing

Provocative tests can unmask LQTS in patients with borderline QTc intervals or normal ECGs151:1. Exercise stress testing: Useful for diagnosing LQT1152,153

2. Epinephrine infusion: Helps distinguish between LQT1 and LQT2154

3. Mental stress testing: Potential method for unmasking concealed LQTS155

Holter monitoring and event recorders

Ambulatory ECG monitoring can capture transient QT prolongation or T-wave abnormalities.156,157 Implantable loop recorders may be used for long-term monitoring or risk stratification.158

Family screening

Family screening is essential because of the autosomal dominant inheritance of most LQTS subtypes.159 First-degree relatives have a 50% chance of carrying the same mutation and should undergo clinical evaluation, ECG screening, and genetic testing.160 Cascade screening helps identify asymptomatic carriers who may benefit from preventive measures and regular follow-up.161

Treatment options for LQTS

Risk stratification and lifestyle modifications

Effective LQTS management relies on accurate risk stratification and appropriate lifestyle modifications to minimize life-threatening arrhythmic events.124 Risk stratification integrates clinical, ECG, and genetic factors to identify patients at highest risk of SCD who may benefit from more aggressive interventions.125

Identification of high-risk patients

Key risk factors for SCD in patients with LQTS include the following:1. QTc interval: QTc interval ≥ 500 ms is a major risk factor, particularly in LQT1 and LQT2.162

2. Genetic subtype: Patients with LQT2 have a higher SCD risk compared to other subtypes.163

3. Sex and age: Males have higher risk in childhood and females after puberty.130,164

4. History of syncope: Particularly if recurrent or without trigger.134

5. Family history of SCD: Especially in young first-degree relatives.113

Counseling on lifestyle changes and avoidance of triggers

Lifestyle modifications are crucial in LQTS management and should be tailored to the patient’s specific genetic subtype and risk profile.165 Key recommendations include the following:1. Avoidance of QT-prolonging medications:

Avoid certain antibiotics, antipsychotics, and antiarrhythmic drugs161

Consult with physicians or pharmacists before initiating new medications

2. Electrolyte balance:

Maintain normal potassium and magnesium levels64

Avoid diuretics and medications causing electrolyte disturbances

3. Exercise restrictions:

Recommendations vary by genetic subtype and risk profile166

LQT1: Avoid competitive sports and strenuous exercise, especially swimming167

LQT2 and LQT3: Low-intensity exercise under medical supervision may be allowed168

4. Stress management:

Emotional stress can trigger arrhythmic events, particularly in LQT1 and LQT2169,170

Implement stress management techniques (eg, relaxation therapy and cognitive-behavioral therapy)171

5. Trigger avoidance:

Educate patients about genotype-specific triggers

LQT2: Avoid sudden loud noises and use gradual wake-up alarms113

6. Compliance with medical therapy:

Emphasize importance of adhering to prescribed therapy (eg, β-blockers)111

Patients should undergo regular follow-up to monitor the QTc interval, assess therapy response, and adjust management plans. They should also be educated about arrhythmic event signs and symptoms, with instructions to seek prompt medical attention for syncope, palpitations, or other concerning symptoms.

Pharmacological interventions

β-Blockers

β-Blockers are the mainstay of LQTS pharmacological therapy, recommended for all patients with a confirmed diagnosis.13,172 They attenuate sympathetic stimulation effects on the heart, reducing cardiac event risk by up to 60%.173 Commonly used β-blockers include propranolol and nadolol, with nadolol showing significant risk reduction in patients with LQT2.174 The choice and dosing should be individualized on the basis of genotype, age, weight, and tolerance.175, 176, 177 Patients should be monitored for side effects such as nightmares, coldness of extremities, tiredness, dizziness, and impaired physical condition.162

Potassium channel openers

Potassium channel openers such as nicorandil and pinacidil have been proposed for LQTS, particularly LQT2.178,179 They enhance outward potassium current (IKr) and shorten APD. However, their use is limited by lack of clinical trial data and side effect concerns.180

Other antiarrhythmic drugs

Mexiletine and ranolazine have been used in select patients with LQTS intolerant or unresponsive to β-blockers.74,181 Mexiletine, a class IB antiarrhythmic, shortens QT interval and reduces arrhythmic events in LQT3.182 Ranolazine, an INaL inhibitor, shows benefits in LQT3 and aLQTS.13,183,184 These medications are currently off-label and reserved for patients failing first-line therapies.185

Role of magnesium and potassium supplements

Magnesium and potassium supplements are used as adjunctive therapies in LQTS, particularly for recurrent arrhythmic events despite β-blocker therapy.63,186 Magnesium does not shorten QT interval but can reduce TdP risk in aLQTS.187 Potassium supplements help maintain normal serum levels, preventing QT prolongation and arrhythmic events.13,188 Routine use is not currently recommended; their use should be individualized on the basis of electrolyte status and clinical response.

Device therapy

ICDs

ICDs are recommended for patients with LQTS who have survived a cardiac arrest or have recurrent syncope despite optimal medical therapy.129 They detect and terminate ventricular arrhythmias, such as TdP and ventricular fibrillation, by delivering an electric shock. The decision to implant an ICD should be based on a careful assessment of the patient’s SCD risk and the potential benefits and risks of the device.189 Patients with ICDs require regular follow-up to monitor device function, assess shock appropriateness, and adjust programming as needed.190

Pacemakers

Pacemakers may be considered for patients with LQTS with bradycardia-induced QT prolongation or recurrent syncope despite β-blocker therapy.191 They maintain a stable heart rate and prevent bradycardia, which can trigger arrhythmic events in patients with LQTS.192 The decision to implant a pacemaker should be individualized on the basis of the patient’s clinical presentation, ECG findings, and response to medical therapy. In some cases, a dual-chamber pacemaker may be preferred to optimize atrioventricular synchrony and prevent pacemaker-induced QT prolongation.193

Surgical and other interventions

LCSD

LCSD is a surgical procedure involving the removal of the left stellate ganglion and the first 3–4 thoracic ganglia, responsible for sympathetic innervation of the heart.194 It has been shown to reduce arrhythmic events and SCD risk in patients with LQTS intolerant or unresponsive to β-blockers.195 LCSD works by decreasing sympathetic tone and attenuating adrenergic stimulation effects on the heart. It is typically reserved for high-risk patients or those with recurrent events despite optimal medical therapy.196 Complications include Horner syndrome, hemothorax, and pneumothorax, but these are generally rare and self-limited.197

Catheter ablation

Catheter ablation has been proposed as a potential therapy for patients with LQTS with recurrent arrhythmic events despite optimal medical and device therapy.198 The procedure involves identifying and ablating focal triggers or substrates responsible for initiating or maintaining ventricular arrhythmias.199 However, its role in LQTS is currently limited by lack of clinical trial data and concerns about procedural risks, such as heart block and perforation. Catheter ablation should be considered only in highly selected patients and performed by experienced operators in specialized centers.

Experimental therapies and future directions

Several experimental therapies are being investigated for LQTS treatment17,200, 201, 202: Gene therapy aims to correct the underlying genetic defect by delivering normal copies of the affected gene to cardiac cells using viral vectors. Stem cell therapy involves using pluripotent stem cells to regenerate or replace dysfunctional cardiac tissue.203 Novel pharmacological agents, such as allosteric modulators of ion channels and gene-specific therapies, are being developed to target specific LQTS subtypes and improve the specificity and efficacy of treatment.204

In addition to these experimental therapies, future directions in LQTS research include the development of more accurate risk stratification tools, such as genotype-specific risk scores and machine learning algorithms.205,206 These tools may help identify patients at the highest risk of SCD and guide personalized management strategies.207 Other areas of active research include the identification of novel genetic and epigenetic modifiers of LQTS, the elucidation of genotype-phenotype correlations, and the development of more sensitive and specific diagnostic tests.208

Future directions in LQTS research

The field of LQTS research has made significant strides in recent years, with advancements in genetic testing, risk stratification, and personalized therapies. However, there are still many unanswered questions and areas for future investigation.

Advances in genetic testing and personalized medicine

Next-generation sequencing technologies have revolutionized the field of genetic testing, allowing for the rapid and cost-effective analysis of multiple genes simultaneously.209 The use of next-generation sequencing in LQTS has led to the identification of novel disease-causing variants and the expansion of the genetic spectrum of the disorder.210 Future research should focus on the clinical validation and interpretation of these variants as well as the development of standardized guidelines for the reporting of genetic test results.211

The integration of genetic information with clinical and electrophysiological data has the potential to improve risk stratification and guide personalized treatment strategies.212 For example, the use of induced pluripotent stem cell–derived cardiomyocytes from patients with LQTS has emerged as a promising tool for drug screening and precision medicine.213 Future studies should explore the utility of induced pluripotent stem cell–derived cardiomyocytes in predicting patient-specific responses to therapies and identifying novel drug targets.214

Novel pharmacological agents

While β-blockers remain the mainstay of therapy for LQTS, they are not effective in all patients and may have significant side effects.215 Therefore, there is a need for novel pharmacological agents that can specifically target the underlying molecular defects in LQTS.216,217 Some promising candidates include INaL inhibitors (eg, ranolazine and eleclazine), potassium channel openers (eg, nicorandil and retigabine), and calcium channel blockers (eg, verapamil).218, 219, 220 Future research should focus on the preclinical and clinical evaluation of these agents as well as the identification of new therapeutic targets on the basis of the expanding knowledge of LQTS pathophysiology.221

Innovative device technologies

ICDs have been shown to be effective in preventing SCD in patients with high-risk LQTS.189 However, ICDs are associated with significant morbidity and may not be suitable for all patients, particularly children and young adults. Future research should focus on the development of less invasive and more patient-friendly device technologies, such as subcutaneous ICDs,222 leadless pacemakers, and wearable defibrillators.

The use of mobile health technologies, such as smartphone apps and wearable sensors, has the potential to improve the monitoring and management of patients with LQTS.223 These technologies can help track patient symptoms, medication adherence, and QT interval changes, enabling early detection of arrhythmias and timely interventions. However, further validation and integration of these technologies into clinical practice are needed.

Another promising area of research is the development of gene therapy approaches for LQTS. Preclinical studies have demonstrated the feasibility of using viral vectors to deliver wild-type copies of LQTS-associated genes or to silence mutant alleles in animal models.224,225 While these approaches are still in the early stages of development, they hold promise for providing a curative therapy for LQTS in the future.

Clinical trials and registries

Clinical trials are essential for evaluating the safety and efficacy of novel therapies for LQTS. Currently, several trials are underway to assess the efficacy of new pharmacological agents, such as the INaL inhibitor eleclazine (GS-6615)226 and the IKs activator ML277227, in the treatment of LQTS. These trials may provide additional therapeutic options for patients who do not respond adequately to conventional therapies or who experience intolerable side effects.

Registries play a crucial role in advancing the understanding of LQTS by providing valuable data on the natural history, genotype-phenotype correlations, and treatment outcomes in large cohorts of patients. The International LQTS Registry, established in 1979, has been instrumental in defining the clinical characteristics and risk factors for cardiac events in patients with LQTS.228 Ongoing efforts to expand and harmonize LQTS registries worldwide will facilitate the identification of novel risk factors, the validation of risk stratification models, and the evaluation of long-term treatment outcomes.

Public health strategies and education

Public health strategies and education are crucial for improving the diagnosis, management, and outcomes of LQTS. These strategies may include the following:Increasing awareness among physicians, nurses, and other relevant medical professionals, educating patients and families, promoting genetic counseling, and implementing school-based screening programs are key components.142,229

Collaborating with patient advocacy groups and community organizations is essential to raise awareness, provide support, and advance research and education efforts.

Conclusion

Implementation of these strategies and initiatives aims to improve LQTS recognition, management, and outcomes, ultimately reducing the burden of SCD associated with this disorder.

LQTS remains a complex and potentially life-threatening cardiac channelopathy that presents significant challenges in diagnosis, risk stratification, and management. This comprehensive review has highlighted the multifaceted nature of LQTS, encompassing its genetic basis, pathophysiological mechanisms, clinical presentation, and current treatment strategies.

The expanding knowledge of LQTS genetics has led to improved diagnostic capabilities and a better understanding of genotype-phenotype correlations. However, the variable expressivity and incomplete penetrance of LQTS-associated mutations underscore the need for a comprehensive approach to diagnosis and risk assessment that integrates clinical, ECG, and genetic data.

Management of LQTS has evolved significantly, with β-blockers remaining the cornerstone of therapy for most patients. The role of more aggressive interventions, such as LCSD and ICDs, has been further defined for high-risk individuals.

Despite these advances, several challenges persist. The development of more effective and targeted therapies, improvement of risk stratification models, and optimization of management strategies for genotype-specific LQTS subtypes remain active areas of research. The emergence of novel technologies, including gene therapy and personalized medicine approaches, holds promise for future breakthroughs in LQTS treatment.

As we move forward, continued collaborative efforts in research, clinical practice, and public health initiatives will be crucial in improving outcomes for individuals with LQTS. By advancing our understanding of the disorder’s underlying mechanisms and refining our approach to patient care, we can work toward reducing the burden of SCD and improving the quality of life for those affected by LQTS.

Funding Sources

The authors have no funding sources to disclose.

Disclosures

We declare that there are no conflicts of interest related to the research, authorship, and/or publication of this manuscript.

Authorship

All authors attest they meet the current ICMJE criteria for authorship.
==== Refs
References

1 Viskin S. Long QT syndromes and torsade de pointes Lancet 354 1999 1625 1633 10560690
2 Eggeling T. Höher M. Osterhues H.H. Kochs M. Weismüller P. Hombach V. The arrhythmogenic substrate of the long QT syndrome: genetic basis, pathology, and pathophysiologic mechanisms Eur Heart J 14 1993 73 79
3 Krahn A.D. Laksman Z. Sy R.W. Congenital long QT syndrome JACC Clin Electrophysiol 8 2022 687 706 35589186
4 Schwartz P.J. Ackerman M.J. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy Eur Heart J 34 2013 3109 3116 23509228
5 Shimizu W. The long QT syndrome: therapeutic implications of a genetic diagnosis Cardiovasc Res 67 2005 347 356 15979599
6 Wilde A.A.M. Amin A.S. Postema P.G. Diagnosis, management and therapeutic strategies for congenital long QT syndrome Heart 108 2022 332 338 34039680
7 Neves R. Bains S. Bos J.M. MacIntyre C. Giudicessi J.R. Ackerman M.J. Precision therapy in congenital long QT syndrome Trends Cardiovasc Med 34 2024 39 47 35772688
8 Itoh H. Crotti L. Aiba T. The genetics underlying acquired long QT syndrome: impact for genetic screening Eur Heart J 37 2016 1456 1464 26715165
9 El-Sherif N. Turitto G. Boutjdir M. Acquired long QT syndrome and torsade de pointes Pacing Clin Electrophysiol 41 2018 414 421 29405316
10 Schwartz P.J. Moss A.J. Vincent G.M. Crampton R.S. Diagnostic criteria for the long QT syndrome: an update Circulation 88 1993 782 784 8339437
11 Kapa S. Tester D.J. Salisbury B.A. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants Circulation 120 2009 1752 1760 19841300
12 Schwartz P.J. Stramba-Badiale M. Crotti L. Prevalence of the congenital long-QT syndrome Circulation 120 2009 1761 1767 19841298
13 Barsheshet A. Dotsenko O. Goldenberg I. Congenital long QT syndromes: prevalence, pathophysiology and management Paediatr Drugs 16 2014 447 456 25288402
14 Ackerman M.J. Tester D.J. Jones G.S. Will M.L. Burrow C.R. Curran M.E. Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome Mayo Clin Proc 78 2003 1479 1487 14661677
15 Schwartz P.J. Woosley R.L. Predicting the unpredictable: drug-induced QT prolongation and torsades de pointes J Am Coll Cardiol 67 2016 1639 1650 27150690
16 Badura K. Bulawska D. Dabek B. Primary electrical heart disease—principles of pathophysiology and genetics Int J Mol Sci 25 2024 1826 38339103
17 Chai S. Wan X. Ramirez-Navarro A. Physiological genomics identifies genetic modifiers of long QT syndrome type 2 severity J Clin Invest 128 2018 1043 1056 29431731
18 Barsheshet A. Peterson D.R. Moss A.J. Genotype-specific QT correction for heart rate and the risk of life-threatening cardiac events in adolescents with congenital long-QT syndrome Heart Rhythm 8 2011 1207 1213 21397043
19 Kauferstein S. Kiehne N. Neumann T. Pitschner H.F. Bratzke H. Cardiac gene defects can cause sudden cardiac death in young people Dtsch Arztebl Int 106 2009 41 47 19564966
20 Al-Hassnan Z.N. Al-Fayyadh M. Al-Ghamdi B. Clinical profile and mutation spectrum of long QT syndrome in Saudi Arabia: the impact of consanguinity Heart Rhythm 14 2017 1191 1199 28438721
21 Amin A.S. Pinto Y.M. Wilde A.A. Long QT syndrome: beyond the causal mutation J Physiol 591 2013 4125 4139 23753525
22 Ackerman M.J. The long QT syndrome: ion channel diseases of the heart Mayo Clin Proc 73 1998 250 269 9511785
23 Jervell A. Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death Am Heart J 54 1957 59 68 13435203
24 Huang L. Bitner-Glindzicz M. Tranebjaerg L. Tinker A. A spectrum of functional effects for disease causing mutations in the Jervell and Lange-Nielsen syndrome Cardiovasc Res 51 2001 670 680 11530100
25 Romano C. Gemme G. Pongiglione R. [Rare cardiac arrythmias of the pediatric age. II. Syncopal attacks due to paroxysmal ventricular fibrillation. (Presentation of 1st case in Italian pediatric literature)] Clin Pediatr (Bologna) 45 1963 656 683 14158288
26 Ward O.C. A new familial cardiac syndrome in children J Ir Med Assoc 54 1964 103 106 14136838
27 Abriel H. Zaklyazminskaya E.V. Cardiac channelopathies: genetic and molecular mechanisms Gene 517 2013 1 11 23266818
28 Chiang C.E. Roden D.M. The long QT syndromes: genetic basis and clinical implications J Am Coll Cardiol 36 2000 1 12 10898405
29 Alameh M. Oliveira-Mendes B.R. Kyndt F. A need for exhaustive and standardized characterization of ion channels activity: the case of KV11.1 Front Physiol 14 2023 1132533
30 Adler A. Novelli V. Amin A.S. An international, multicentered, evidence-based reappraisal of genes reported to cause congenital long QT syndrome Circulation 141 2020 418 428 31983240
31 Ackerman JP, Bartos DC, Kapplinger JD, Tester DJ, Delisle BP, Ackerman MJ. The promise and peril of precision medicine: phenotyping still matters most [published online ahead of print October 8, 2016]. Mayo Clin Proc. https://doi.org/10.1016/j.mayocp.2016.08.008.
32 Goldenberg I. Moss A.J. Long QT syndrome J Am Coll Cardiol 51 2008 2291 2300 18549912
33 Moss A.J. Zareba W. Hall W.J. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction N Engl J Med 346 2002 877 883 11907286
34 Anderson H.N. Bos J.M. Rohatgi R.K. Ackerman M.J. The effect of left cardiac sympathetic denervation on exercise in patients with long QT syndrome JACC Clin Electrophysiol 5 2019 1084 1090 31537339
35 Nakano Y. Shimizu W. Genetics of long-QT syndrome J Hum Genet 61 2016 51 55 26108145
36 Albesa M. Grilo L.S. Gavillet B. Abriel H. Nedd4-2-dependent ubiquitylation and regulation of the cardiac potassium channel hERG1 J Mol Cell Cardiol 51 2011 90 98 21463633
37 Eldstrom J. Xu H. Werry D. Mechanistic basis for LQT1 caused by S3 mutations in the KCNQ1 subunit of IKs J Gen Physiol 135 2010 433 448 20421371
38 Bellin M. Casini S. Davis R.P. Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome EMBO J 32 2013 3161 3175 24213244
39 Abriel H. Cabo C. Wehrens X.H. Novel arrhythmogenic mechanism revealed by a long-QT syndrome mutation in the cardiac Na+ channel Circ Res 88 2001 740 745 11304498
40 Hsiao P.Y. Tien H.C. Lo C.P. Juang J.M. Wang Y.H. Sung R.J. Gene mutations in cardiac arrhythmias: a review of recent evidence in ion channelopathies Appl Clin Genet 6 2013 1 13 23837003
41 Garmany R. Giudicessi J.R. Ye D. Zhou W. Tester D.J. Ackerman M.J. Clinical and functional reappraisal of alleged type 5 long QT syndrome: causative genetic variants in the KCNE1-encoded minK β-subunit Heart Rhythm 17 2020 937 944 32058015
42 Fodstad H. Swan H. Auberson M. Loss-of-function mutations of the K+ channel gene KCNJ2 constitute a rare cause of long QT syndrome J Mol Cell Cardiol 37 2004 593 602 15276028
43 Hedley P.L. Jorgensen P. Schlamowitz S. The genetic basis of long QT and short QT syndromes: a mutation update Hum Mutat 30 2009 1486 1511 19862833
44 Abbott G.W. KCNE genetics and pharmacogenomics in cardiac arrhythmias: much ado about nothing? Expert Rev Clin Pharmacol 6 2013 49 60 23272793
45 Chavali N.V. Kryshtal D.O. Parikh S.S. Patient-independent human induced pluripotent stem cell model: a new tool for rapid determination of genetic variant pathogenicity in long QT syndrome Heart Rhythm 16 2019 1686 1695 31004778
46 Antzelevitch C. Fish J. Electrical heterogeneity within the ventricular wall Basic Res Cardiol 96 2001 517 527 11770069
47 Boulet I.R. Raes A.L. Ottschytsch N. Snyders D.J. Functional effects of a KCNQ1 mutation associated with the long QT syndrome Cardiovasc Res 70 2006 466 474 16564513
48 Liu G.X. Choi B.R. Ziv O. Differential conditions for early after-depolarizations and triggered activity in cardiomyocytes derived from transgenic LQT1 and LQT2 rabbits J Physiol 590 2012 1171 1180 22183728
49 Comollo T.W. Zou X. Zhang C. Exploring mutation specific beta blocker pharmacology of the pathogenic late sodium channel current from patient-specific pluripotent stem cell myocytes derived from long QT syndrome mutation carriers Channels (Austin) 16 2022 173 184 35949058
50 Choi J.I. Wang C. Thomas M.J. Pitt G.S. α1-Syntrophin variant identified in drug-induced long QT syndrome increases late sodium current PLoS One 11 2016 e0152355
51 Lehtonen A. Fodstad H. Laitinen-Forsblom P. Toivonen L. Kontula K. Swan H. Further evidence of inherited long QT syndrome gene mutations in antiarrhythmic drug-associated torsades de pointes Heart Rhythm 4 2007 603 607 17467628
52 Killeen M.J. Antipsychotic-induced sudden cardiac death: examination of an atypical reaction Expert Opin Drug Saf 8 2009 249 252 19505259
53 Fernandes F.M. Silva E.P. Martins R.R. Oliveira A.G. QTc interval prolongation in critically ill patients: prevalence, risk factors and associated medications PLoS One 13 2018 e0199028
54 Letinier L. Pujade I. Duthoit P. Emergency department admissions induced by drug-drug interactions in the elderly: a cross-sectional study Clin Transl Sci 15 2022 1472 1481 35244984
55 Cavero I. Mestre M. Guillon J.M. Heuillet E. Roach A.G. Preclinical in vitro cardiac electrophysiology: a method of predicting arrhythmogenic potential of antihistamines in humans? Drug Saf 21 1999 19 31 discussion 81–87 10597865
56 Giudicessi J.R. Noseworthy P.A. Friedman P.A. Ackerman M.J. Urgent guidance for navigating and circumventing the QTc-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 19 (COVID-19) Mayo Clin Proc 95 2020 1213 1221 32359771
57 Han S. Zhang Y. Chen Q. Fluconazole inhibits hERG K+ channel by direct block and disruption of protein trafficking Eur J Pharmacol 650 2011 138 144 20951697
58 Hafermann M.J. Namdar R. Seibold G.E. Page R.L. Effect of intravenous ondansetron on QT interval prolongation in patients with cardiovascular disease and additional risk factors for torsades: a prospective, observational study Drug Healthc Patient Saf 3 2011 53 58 22046106
59 Anchersen K. Hansteen V. Gossop M. Clausen T. Waal H. Opioid maintenance patients with QTc prolongation: congenital long QT syndrome mutation may be a contributing risk factor Drug Alcohol Depend 112 2010 216 219 20702049
60 Havakuk O. Rezkalla S.H. Kloner R.A. The cardiovascular effects of cocaine J Am Coll Cardiol 70 2017 101 113 28662796
61 Schürer S. Klingel K. Sandri M. Clinical characteristics, histopathological features, and clinical outcome of methamphetamine-associated cardiomyopathy JACC Heart Fail 5 2017 435 445 28571597
62 Fitzgerald P.T. Ackerman M.J. Drug-induced torsades de pointes: the evolving role of pharmacogenetics Heart Rhythm 2 2005 S30 S37 16253929
63 El-Sherif N. Turitto G. Boutjdir M. Acquired long QT syndrome and electrophysiology of torsade de pointes Arrhythm Electrophysiol Rev 8 2019 122 130 31114687
64 El-Sherif N. Turitto G. Electrolyte disorders and arrhythmogenesis Cardiol J 18 2011 233 245 21660912
65 Weiss J.N. Qu Z. Shivkumar K. Electrophysiology of hypokalemia and hyperkalemia Circ Arrhythm Electrophysiol 10 2017 e004667
66 Antzelevitch C. Burashnikov A. Overview of basic mechanisms of cardiac arrhythmia Card Electrophysiol Clin 3 2011 23 45 21892379
67 Gupta A. Lawrence A.T. Krishnan K. Kavinsky C.J. Trohman R.G. Current concepts in the mechanisms and management of drug-induced QT prolongation and torsade de pointes Am Heart J 153 2007 891 899 17540188
68 Mubagwa K. Gwanyanya A. Zakharov S. Macianskiene R. Regulation of cation channels in cardiac and smooth muscle cells by intracellular magnesium Arch Biochem Biophys 458 2007 73 89 17123458
69 Roden D.M. Drug-induced prolongation of the QT interval N Engl J Med 350 2004 1013 1022 14999113
70 Kardalas E. Paschou S.A. Anagnostis P. Muscogiuri G. Siasos G. Vryonidou A. Hypokalemia: a clinical update Endocr Connect 7 2018 R135 R146 29540487
71 Eryol N.K. Colak R. Ozdoğru I. Effects of calcium treatment on QT interval and QT dispersion in hypocalcemia Am J Cardiol 91 2003 750 752 12633817
72 Etchegoyen C.V. Keller G.A. Mrad S. Cheng S. Di Girolamo G. Drug-induced QT interval prolongation in the intensive care unit Curr Clin Pharmacol 12 2017 210 222 29473523
73 Chevalier P. Bellocq C. Millat G. Torsades de pointes complicating atrioventricular block: evidence for a genetic predisposition Heart Rhythm 4 2007 170 174 17275752
74 Li G. Zhang L. The role of mexiletine in the management of long QT syndrome J Electrocardiol 51 2018 1061 1065 30497731
75 Tomaselli G.F. Marbán E. Electrophysiological remodeling in hypertrophy and heart failure Cardiovasc Res 42 1999 270 283 10533566
76 Kenigsberg D.N. Khanal S. Kowalski M. Krishnan S.C. Prolongation of the QTc interval is seen uniformly during early transmural ischemia J Am Coll Cardiol 49 2007 1299 1305 17394962
77 Colzani R.M. Emdin M. Conforti F. Passino C. Scarlattini M. Iervasi G. Hyperthyroidism is associated with lengthening of ventricular repolarization Clin Endocrinol (Oxf) 55 2001 27 32 11453949
78 Choi S.Y. Cho K.I. Han Y.J. Impact of pheochromocytoma on left ventricular hypertrophy and QTc prolongation: comparison with Takotsubo cardiomyopathy Korean Circ J 44 2014 89 96 24653738
79 van der Bilt I.A.C. Hasan D. Vandertop W.P. Impact of cardiac complications on outcome after aneurysmal subarachnoid hemorrhage: a meta-analysis Neurology 72 2009 635 642 19221297
80 Koppikar S. Baranchuk A. Guzmán J.C. Morillo C.A. Stroke and ventricular arrhythmias Int J Cardiol 168 2013 653 659 23602297
81 Lee W. Vandenberk B. Raj S.R. Lee S.S. Prolonged QT interval in cirrhosis: twisting time? Gut Liver 16 2022 849 860 35864808
82 Liu P. Wang L. Han D. Sun C. Xue X. Li G. Acquired long QT syndrome in chronic kidney disease patients Ren Fail 42 2020 54 65 31878817
83 Sachs K.V. Harnke B. Mehler P.S. Krantz M.J. Cardiovascular complications of anorexia nervosa: a systematic review Int J Eat Disord 49 2016 238 248 26710932
84 Lazzerini P.E. Laghi-Pasini F. Bertolozzi I. Systemic inflammation as a novel QT-prolonging risk factor in patients with torsades de pointes Heart 103 2017 1821 1829 28490617
85 Aromolaran A.S. Srivastava U. Ali A. Interleukin-6 inhibition of hERG underlies risk for acquired long QT in cardiac and systemic inflammation PLoS One 13 2018 e0208321
86 Lazzerini P.E. Laghi-Pasini F. Boutjdir M. Capecchi P.L. Anti-Ro/SSA antibodies and the autoimmune long-QT syndrome Front Med (Lausanne) 8 2021 730161
87 Killeen M.J. Sabir I.N. Grace A.A. Huang C.L. Dispersions of repolarization and ventricular arrhythmogenesis: lessons from animal models Prog Biophys Mol Biol 98 2008 219 229 19027779
88 Schwartz P.J. Crotti L. Insolia R. Long-QT syndrome: from genetics to management Circ Arrhythm Electrophysiol 5 2012 868 877 22895603
89 Antzelevitch C. Sicouri S. Clinical relevance of cardiac arrhythmias generated by afterdepolarizations: role of M cells in the generation of U waves, triggered activity and torsade de pointes J Am Coll Cardiol 23 1994 259 277 8277090
90 Kirchhof P. Franz M.R. Bardai A. Wilde A.M. Giant T-U waves precede torsades de pointes in long QT syndrome: a systematic electrocardiographic analysis in patients with acquired and congenital QT prolongation J Am Coll Cardiol 54 2009 143 149 19573731
91 Alexander C. Bishop M.J. Gilchrist R.J. Burton F.L. Smith G.L. Myles R.C. Initiation of ventricular arrhythmia in the acquired long QT syndrome Cardiovasc Res 119 2023 465 476 35727943
92 Du Y. Demillard L.J. Ren J. Sarcoplasmic reticulum Ca2+ dysregulation in the pathophysiology of inherited arrhythmia: an update Biochem Pharmacol 200 2022 115059
93 Antzelevitch C. Ionic, molecular, and cellular bases of QT-interval prolongation and torsade de pointes Europace 9 2007 iv4 iv15 17766323
94 Bhattad P.B. Jha A. Wholey R. Bradycardia-induced torsades de pointes in atrioventricular block Cureus 15 2023 e37507
95 Guo J. Massaeli H. Xu J. Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines J Clin Invest 119 2009 2745 2757 19726881
96 Hammond-Haley M. Patel R.S. Providencia R. Lambiase P.D. Exercise restrictions for patients with inherited cardiac conditions: current guidelines, challenges and limitations Int J Cardiol 209 2016 234 241 26897076
97 Anson B.D. Ackerman M.J. Tester D.J. Molecular and functional characterization of common polymorphisms in HERG (KCNH2) potassium channels Am J Physiol Heart Circ Physiol 286 2004 H2434 H2441 14975928
98 Cheng J.H. Kodama I. Two components of delayed rectifier K+ current in heart: molecular basis, functional diversity, and contribution to repolarization Acta Pharmacol Sin 25 2004 137 145 14769199
99 Bohannon B.M. de la Cruz A. Wu X. Polyunsaturated fatty acid analogues differentially affect cardiac NaV, CaV, and KV channels through unique mechanisms Elife 9 2020 e51453
100 Brado J. Dechant M.J. Menza M. Phase-contrast magnet resonance imaging reveals regional, transmural, and base-to-apex dispersion of mechanical dysfunction in patients with long QT syndrome Heart Rhythm 14 2017 1388 1397 28479515
101 Kapetanopoulos A. Kluger J. Maron B.J. Thompson P.D. The congenital long QT syndrome and implications for young athletes Med Sci Sports Exerc 38 2006 816 825 16672832
102 Chinushi M. Restivo M. Caref E.B. El-Sherif N. Electrophysiological basis of arrhythmogenicity of QT/T alternans in the long-QT syndrome: tridimensional analysis of the kinetics of cardiac repolarization Circ Res 83 1998 614 628 9742057
103 Narayan S.M. T-wave alternans and the susceptibility to ventricular arrhythmias J Am Coll Cardiol 47 2006 269 281 16412847
104 Viskin S. Postema P.G. Bhuiyan Z.A. The response of the QT interval to the brief tachycardia provoked by standing: a bedside test for diagnosing long QT syndrome J Am Coll Cardiol 55 2010 1955 1961 20116193
105 Brink P.A. Crotti L. Corfield V. Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population Circulation 112 2005 2602 2610 16246960
106 Goldenberg I. Moss A.J. Zareba W. QT interval: how to measure it and what is “normal.” J Cardiovasc Electrophysiol 17 2006 333 336 16643414
107 Dalal A. Czosek R.J. Kovach J. Clinical presentation of pediatric patients at risk for sudden cardiac arrest J Pediatr 177 2016 191 196 27502104
108 Colman N. Bakker A. Linzer M. Reitsma J.B. Wieling W. Wilde A.A. Value of history-taking in syncope patients: in whom to suspect long QT syndrome? Europace 11 2009 937 943 19482852
109 Herbert E. Trusz-Gluza M. Moric E. Smiłowska-Dzielicka E. Mazurek U. Wilczok T. KCNQ1 gene mutations and the respective genotype-phenotype correlations in the long QT syndrome Med Sci Monit 8 2002 RA240 RA248 12388934
110 Schwartz P.J. Priori S.G. Spazzolini C. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias Circulation 103 2001 89 95 11136691
111 Goldenberg I. Moss A.J. Peterson D.R. Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome Circulation 117 2008 2184 2191 18427136
112 Brink P.A. Schwartz P.J. Of founder populations, long QT syndrome, and destiny Heart Rhythm 6 2009 S25 S33 19880070
113 Goldenberg I. Horr S. Moss A.J. Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals J Am Coll Cardiol 57 2011 51 59 21185501
114 Spazzolini C. Mullally J. Moss A.J. Clinical implications for patients with long QT syndrome who experience a cardiac event during infancy J Am Coll Cardiol 54 2009 832 837 19695463
115 Eddy C.A. MacCormick J.M. Chung S.K. Identification of large gene deletions and duplications in KCNQ1 and KCNH2 in patients with long QT syndrome Heart Rhythm 5 2008 1275 1281 18774102
116 Anderson J.H. Bos J.M. Cascino G.D. Ackerman M.J. Prevalence and spectrum of electroencephalogram-identified epileptiform activity among patients with long QT syndrome Heart Rhythm 11 2014 53 57 24103226
117 Gonzalez A. Aurlien D. Larsson P.G. Seizure-like episodes and EEG abnormalities in patients with long QT syndrome Seizure 61 2018 214 220 30218808
118 Auerbach D.S. McNitt S. Gross R.A. Zareba W. Dirksen R.T. Moss A.J. Genetic biomarkers for the risk of seizures in long QT syndrome Neurology 87 2016 1660 1668 27466471
119 Auerbach D.S. Biton Y. Polonsky B. Risk of cardiac events in long QT syndrome patients when taking antiseizure medications Transl Res 191 2018 81 92.e87 29121487
120 Chang R.K. Lan Y.T. Silka M.J. Genetic variants for long QT syndrome among infants and children from a statewide newborn hearing screening program cohort J Pediatr 164 2014 590 595 e591–e593 24388587
121 Neyroud N. Tesson F. Denjoy I. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome Nat Genet 15 1997 186 189 9020846
122 Chang C.C. Acharfi S. Wu M.H. A novel SCN5A mutation manifests as a malignant form of long QT syndrome with perinatal onset of tachycardia/bradycardia Cardiovasc Res 64 2004 268 278 15485686
123 Aziz P.F. Tanel R.E. Zelster I.J. Congenital long QT syndrome and 2:1 atrioventricular block: an optimistic outcome in the current era Heart Rhythm 7 2010 781 785 20197117
124 Giudicessi J.R. Ackerman M.J. Genotype- and phenotype-guided management of congenital long QT syndrome Curr Probl Cardiol 38 2013 417 455 24093767
125 Priori S.G. Schwartz P.J. Napolitano C. Risk stratification in the long-QT syndrome N Engl J Med 348 2003 1866 1874 12736279
126 Lanfranchi P.A. Ackerman M.J. Kara T. Gene-specific paradoxical QT responses during rapid eye movement sleep in women with congenital long QT syndrome Heart Rhythm 7 2010 1067 1074 20470906
127 Dahlberg P. Axelsson K.J. Rydberg A. Lundahl G. Gransberg L. Bergfeldt L. Spatiotemporal repolarization dispersion before and after exercise in patients with long QT syndrome type 1 versus controls: probing into the arrhythmia substrate Am J Physiol Heart Circ Physiol 325 2023 H1279 H1289 37773058
128 Locati E.H. Zareba W. Moss A.J. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry Circulation 97 1998 2237 2244 9631873
129 Daubert J.P. Zareba W. Rosero S.Z. Budzikowski A. Robinson J.L. Moss A.J. Role of implantable cardioverter defibrillator therapy in patients with long QT syndrome Am Heart J 153 2007 53 58 17394903
130 Furukawa T. Kurokawa J. Regulation of cardiac ion channels via non-genomic action of sex steroid hormones: implication for the gender difference in cardiac arrhythmias Pharmacol Ther 115 2007 106 115 17583354
131 Bjelic M. Zareba W. Peterson D.R. Sex hormones and repolarization dynamics during the menstrual cycle in women with congenital long QT syndrome Heart Rhythm 19 2022 1532 1540 35525425
132 Hobbs J.B. Peterson D.R. Moss A.J. Risk of aborted cardiac arrest or sudden cardiac death during adolescence in the long-QT syndrome JAMA 296 2006 1249 1254 16968849
133 Kelle A.M. Bos J.M. Etheridge S.P. Cardiac transplantation in children and adolescents with long QT syndrome Heart Rhythm 14 2017 1182 1188 28416468
134 Kaufman E.S. McNitt S. Moss A.J. Risk of death in the long QT syndrome when a sibling has died Heart Rhythm 5 2008 831 836 18534367
135 Keller D.I. Grenier J. Christe G. Characterization of novel KCNH2 mutations in type 2 long QT syndrome manifesting as seizures Can J Cardiol 25 2009 455 462 19668779
136 Roden D.M. Clinical practice: long-QT syndrome N Engl J Med 358 2008 169 176 18184962
137 Barra S. Agarwal S. Begley D. Providencia R. Post-acute management of the acquired long QT syndrome Postgrad Med J 90 2014 348 358 24696523
138 Lubberding A.F. Zhang J. Lundh M. Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V Sci Rep 11 2021 12253
139 Crotti L. Monti M.C. Insolia R. NOS1AP is a genetic modifier of the long-QT syndrome Circulation 120 2009 1657 1663 19822806
140 Earle N. Yeo Han D. Pilbrow A. Single nucleotide polymorphisms in arrhythmia genes modify the risk of cardiac events and sudden death in long QT syndrome Heart Rhythm 11 2014 76 82 24096169
141 Moss A.J. Kass R.S. Long QT syndrome: from channels to cardiac arrhythmias J Clin Invest 115 2005 2018 2024 16075042
142 Fukuyama M. Horie M. Aoki H. School-based routine screenings of electrocardiograms for the diagnosis of long QT syndrome Europace 24 2022 1496 1503 35060598
143 Immanuel S.A. Sadrieh A. Baumert M. T-wave morphology can distinguish healthy controls from LQTS patients Physiol Meas 37 2016 1456 1473 27510854
144 Doldi F. Plagwitz L. Hoffmann L.P. Detection of patients with congenital and often concealed long-QT syndrome by novel deep learning models J Pers Med 12 2022 1135 35887632
145 Lane C.M. Bos J.M. Rohatgi R.K. Ackerman M.J. Beyond the length and look of repolarization: defining the non-QTc electrocardiographic profiles of patients with congenital long QT syndrome Heart Rhythm 15 2018 1413 1419 29723683
146 Ackerman M.J. Priori S.G. Willems S. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA) Europace 13 2011 1077 1109 21810866
147 Chung S.K. MacCormick J.M. McCulley C.H. Long QT and Brugada syndrome gene mutations in New Zealand Heart Rhythm 4 2007 1306 1314 17905336
148 Horigome H. Nagashima M. Sumitomo N. Clinical characteristics and genetic background of congenital long-QT syndrome diagnosed in fetal, neonatal, and infantile life: a nationwide questionnaire survey in Japan Circ Arrhythm Electrophysiol 3 2010 10 17 19996378
149 Barsheshet A. Goldenberg I. Cardiovascular syncope: diagnostic approach and risk assessment Minerva Med 102 2011 223 238 21593723
150 Hofman N. Wilde A.A. Kaab S. Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: do we need a scoring system? Eur Heart J 28 2007 575 580 17090615
151 Abrahams T. Davies B. Laksman Z. Provocation testing in congenital long QT syndrome: a practical guide Heart Rhythm 20 2023 1570 1582 37481219
152 Chattha I.S. Sy R.W. Yee R. Utility of the recovery electrocardiogram after exercise: a novel indicator for the diagnosis and genotyping of long QT syndrome? Heart Rhythm 7 2010 906 911 20226272
153 Horner J.M. Horner M.M. Ackerman M.J. The diagnostic utility of recovery phase QTc during treadmill exercise stress testing in the evaluation of long QT syndrome Heart Rhythm 8 2011 1698 1704 21699858
154 Ackerman M.J. Khositseth A. Tester D.J. Hejlik J.B. Shen W.K. Porter C.B. Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome Mayo Clin Proc 77 2002 413 421 12004990
155 Etienne P. Huchet F. Gaborit N. Mental stress test: a rapid, simple, and efficient test to unmask long QT syndrome Europace 20 2018 2014 2020 29688407
156 Katritsis D.G. Siontis G.C. Camm A.J. Prognostic significance of ambulatory ECG monitoring for ventricular arrhythmias Prog Cardiovasc Dis 56 2013 133 142 24215745
157 Anys S. Arnaud M. Minois D. Dose response to nadolol in congenital long QT syndrome Heart Rhythm 18 2021 1377 1383 33905813
158 Solbiati M. Casazza G. Dipaola F. The diagnostic yield of implantable loop recorders in unexplained syncope: a systematic review and meta-analysis Int J Cardiol 231 2017 170 176 28052814
159 Baruteau A.E. Baruteau J. Joomye R. Role of congenital long-QT syndrome in unexplained sudden infant death: proposal for an electrocardiographic screening in relatives Eur J Pediatr 168 2009 771 777 19266217
160 Bokil N.J. Baisden J.M. Radford D.J. Summers K.M. Molecular genetics of long QT syndrome Mol Genet Metab 101 2010 1 8 20594883
161 Hofman N. Tan H.L. Alders M. van Langen I.M. Wilde A.A. Active cascade screening in primary inherited arrhythmia syndromes: does it lead to prophylactic treatment? J Am Coll Cardiol 55 2010 2570 2576 20513597
162 Koponen M. Marjamaa A. Hiippala A. Follow-up of 316 molecularly defined pediatric long-QT syndrome patients: clinical course, treatments, and side effects Circ Arrhythm Electrophysiol 8 2015 815 823 26063740
163 Wedekind H. Burde D. Zumhagen S. QT interval prolongation and risk for cardiac events in genotyped LQTS-index children Eur J Pediatr 168 2009 1107 1115 19101729
164 Diez-Escute N. Arbelo E. Martinez-Barrios E. Sex differences in long QT syndrome Front Cardiovasc Med 10 2023 1164028
165 Priori S.G. Wilde A.A. Horie M. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013 Heart Rhythm 10 2013 1932 1963 24011539
166 Behere S.P. Shubkin C.D. Weindling S.N. Recent advances in the understanding and management of long QT syndrome Curr Opin Pediatr 26 2014 727 733 25313972
167 Choi G. Kopplin L.J. Tester D.J. Will M.L. Haglund C.M. Ackerman M.J. Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes Circulation 110 2004 2119 2124 15466642
168 Furst M.L. Aziz P.F. The evolution of sports participation guidelines and the influence of genotype-phenotype correlation in long QT syndrome Trends Cardiovasc Med 26 2016 690 697 27260221
169 Hintsa T. Puttonen S. Toivonen L. Kontula K. Swan H. Keltikangas-Jarvinen L. A history of stressful life events, prolonged mental stress and arrhythmic events in inherited long QT syndrome Heart 96 2010 1281 1286 20659946
170 Hintsa T. Maattanen I. Hintsanen M. Work stress and the long QT syndrome: high job strain and effort-reward imbalance at work associated with arrhythmic risk in the long QT syndrome J Occup Environ Med 55 2013 1387 1393 24270299
171 Ingles J. Yeates L. Hunt L. Health status of cardiac genetic disease patients and their at-risk relatives Int J Cardiol 165 2013 448 453 21930314
172 Zipes D.P. Camm A.J. Borggrefe M. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J Am Coll Cardiol 48 2006 e247 e346 16949478
173 Sauer A.J. Moss A.J. McNitt S. Long QT syndrome in adults J Am Coll Cardiol 49 2007 329 337 17239714
174 Abu-Zeitone A. Peterson D.R. Polonsky B. McNitt S. Moss A.J. Efficacy of different beta-blockers in the treatment of long QT syndrome J Am Coll Cardiol 64 2014 1352 1358 25257637
175 Chockalingam P. Crotti L. Girardengo G. Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: higher recurrence of events under metoprolol J Am Coll Cardiol 60 2012 2092 2099 23083782
176 Ahn J. Kim H.J. Choi J.I. Effectiveness of beta-blockers depending on the genotype of congenital long-QT syndrome: a meta-analysis PLoS One 12 2017 e0185680
177 Han L. Liu F. Li Q. The efficacy of beta-blockers in patients with long QT syndrome 1-3 according to individuals’ gender, age, and QTc intervals: a network meta-analysis Front Pharmacol 11 2020 579525
178 Shimizu W. Antzelevitch C. Effects of a K+ channel opener to reduce transmural dispersion of repolarization and prevent torsade de pointes in LQT1, LQT2, and LQT3 models of the long-QT syndrome Circulation 102 2000 706 712 10931813
179 Limprasutr V. Saengklub N. Meedech P. Kijtawornrat A. Hamlin R.L. Characteristics of electromechanical window in anesthetized rabbit models of short QT and long QT syndromes J Toxicol Sci 42 2017 579 587 28904293
180 Rapoport A.M. Lipton R.B. Potassium channel openers—novel triggers of aura and migraine Nat Rev Neurol 17 2021 397 398 34040232
181 Badri M. Patel A. Patel C. Mexiletine prevents recurrent torsades de pointes in acquired long QT syndrome refractory to conventional measures JACC Clin Electrophysiol 1 2015 315 322 29759319
182 Alhourani N. Wolfes J. Konemann H. Relevance of mexiletine in the era of evolving antiarrhythmic therapy of ventricular arrhythmias Clin Res Cardiol 113 2024 791 800 38353682
183 Huang H. Priori S.G. Napolitano C. O’Leary M.E. Chahine M. Y1767C, a novel SCN5A mutation, induces a persistent Na+ current and potentiates ranolazine inhibition of Nav1.5 channels Am J Physiol Heart Circ Physiol 300 2011 H288 H299 21076026
184 Cano J. Zorio E. Mazzanti A. Ranolazine as an alternative therapy to flecainide for SCN5A V411M long QT syndrome type 3 patients Front Pharmacol 11 2020 580481
185 Yu S. Li G. Huang C.L. Lei M. Wu L. Late sodium current associated cardiac electrophysiological and mechanical dysfunction Pflugers Arch 470 2018 461 469 29127493
186 Hoshino K. Ogawa K. Hishitani T. Isobe T. Eto Y. Optimal administration dosage of magnesium sulfate for torsades de pointes in children with long QT syndrome J Am Coll Nutr 23 2004 497S 500S 15466950
187 Hoshino K. Ogawa K. Hishitani T. Isobe T. Etoh Y. Successful uses of magnesium sulfate for torsades de pointes in children with long QT syndrome Pediatr Int 48 2006 112 117 16635167
188 Etheridge S.P. Compton S.J. Tristani-Firouzi M. Mason J.W. A new oral therapy for long QT syndrome: long-term oral potassium improves repolarization in patients with HERG mutations J Am Coll Cardiol 42 2003 1777 1782 14642687
189 Horner J.M. Kinoshita M. Webster T.L. Haglund C.M. Friedman P.A. Ackerman M.J. Implantable cardioverter defibrillator therapy for congenital long QT syndrome: a single-center experience Heart Rhythm 7 2010 1616 1622 20816872
190 Biton Y. Rosero S. Moss A.J. Primary prevention with the implantable cardioverter-defibrillator in high-risk long-QT syndrome patients Europace 21 2019 339 346 29947754
191 Moss A.J. Liu J.E. Gottlieb S. Locati E.H. Schwartz P.J. Robinson J.L. Efficacy of permanent pacing in the management of high-risk patients with long QT syndrome Circulation 84 1991 1524 1529 1914094
192 Bauer A. Donahue J.K. Voss F. Pro- and antiarrhythmic effects of fast cardiac pacing in a canine model of acquired long QT syndrome Naunyn Schmiedebergs Arch Pharmacol 369 2004 447 454 14985939
193 Chu S.-Y. Sheng Q.-H. Shi Q.-P. Qiu L. Wu L. Zhou J. Case report: torsade de pointes induced by the bigeminy result from retrograde ventriculoatrial activation in VVI pacing and resolved by intentional atrial pacing Front Cardiovasc Med 10 2023 1156658
194 Collura C.A. Johnson J.N. Moir C. Ackerman M.J. Left cardiac sympathetic denervation for the treatment of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia using video-assisted thoracic surgery Heart Rhythm 6 2009 752 759 19467503
195 Bos J.M. Bos K.M. Johnson J.N. Moir C. Ackerman M.J. Left cardiac sympathetic denervation in long QT syndrome: analysis of therapeutic nonresponders Circ Arrhythm Electrophysiol 6 2013 705 711 23728945
196 Dusi V. Pugliese L. De Ferrari G.M. Left cardiac sympathetic denervation for long QT syndrome: 50 years’ experience provides guidance for management JACC Clin Electrophysiol 8 2022 281 294 35331422
197 Dubey N. Ubhadiya T.J. Garg V.S. Unlocking the potential of left cardiac sympathetic denervation: a scoping review of a promising approach for long QT syndrome Cureus 15 2023 e47306
198 Pappone C. Ciconte G. Anastasia L. Right ventricular epicardial arrhythmogenic substrate in long-QT syndrome patients at risk of sudden death Europace 25 2023 948 955 36610790
199 Birati E.Y. Belhassen B. Bardai A. Wilde A.A. Viskin S. The site of origin of torsade de pointes Heart 97 2011 1650 1654 21561894
200 Brunner M. Kodirov S.A. Mitchell G.F. In vivo gene transfer of Kv1.5 normalizes action potential duration and shortens QT interval in mice with long QT phenotype Am J Physiol Heart Circ Physiol 285 2003 H194 H203 12793978
201 Castiglione A. Hornyik T. Wulfers E.M. Docosahexaenoic acid normalizes QT interval in long QT type 2 transgenic rabbit models in a genotype-specific fashion Europace 24 2022 511 522 34601592
202 Ge N. Liu M. Li R. Using ribonucleoprotein-based CRISPR/Cas9 to edit single nucleotide on human induced pluripotent stem cells to model type 3 long QT syndrome (SCN5A+/−) Stem Cell Rev Rep 19 2023 2774 2789 37653182
203 Dainis A.M. Ashley E.A. Cardiovascular precision medicine in the genomics era JACC Basic Transl Sci 3 2018 313 326 30062216
204 Sala L. Yu Z. Ward-van Oostwaard D. A new hERG allosteric modulator rescues genetic and drug-induced long-QT syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cells EMBO Mol Med 8 2016 1065 1081 27470144
205 Crotti L. Spazzolini C. Porretta A.P. Vagal reflexes following an exercise stress test: a simple clinical tool for gene-specific risk stratification in the long QT syndrome J Am Coll Cardiol 60 2012 2515 2524 23158531
206 Kekenes-Huskey P.M. Burgess D.E. Sun B. Mutation-specific differences in Kv7.1 (KCNQ1) and Kv11.1 (KCNH2) channel dysfunction and long QT syndrome phenotypes Int J Mol Sci 23 2022 7389 35806392
207 MacIntyre C.J. Rohatgi R.K. Sugrue A.M. Bos J.M. Ackerman M.J. Intentional nontherapy in long QT syndrome Heart Rhythm 17 2020 1147 1150 32105774
208 Jiang R. Cheung C.C. Garcia-Montero M. Deep learning-augmented ECG analysis for screening and genotype prediction of congenital long QT syndrome JAMA Cardiol 9 2024 377 384 38446445
209 Chae H. Kim J. Lee G.D. Considerations when using next-generation sequencing for genetic diagnosis of long-QT syndrome in the clinical testing laboratory Clin Chim Acta 464 2017 128 135 27871843
210 Dell'Edera D. Allegretti A. Forte F. 7q35q36.3 deletion and concomitant 20q13.2q13.33 duplication in a newborn: familiar case Eur Rev Med Pharmacol Sci 25 2021 2949 2957 33877658
211 Ghouse J. Have C.T. Weeke P. Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval Eur Heart J 36 2015 2523 2529 26159999
212 Giudicessi J.R. Ackerman M.J. Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes Transl Res 161 2013 1 14 22995932
213 Giacomelli E. Sala L. Oostwaard D.W. Bellin M. Cardiac microtissues from human pluripotent stem cells recapitulate the phenotype of long-QT syndrome Biochem Biophys Res Commun 572 2021 118 124 34364290
214 Egashira T. Yuasa S. Suzuki T. Disease characterization using LQTS-specific induced pluripotent stem cells Cardiovasc Res 95 2012 419 429 22739119
215 Martinez K. Bains S. Giudicessi J.R. Bos J.M. Neves R. Ackerman M.J. Spectrum and prevalence of side effects and complications with guideline-directed therapies for congenital long QT syndrome Heart Rhythm 19 2022 1666 1672 35710045
216 Duncan G. Firth K. George V. Drug-mediated shortening of action potentials in LQTS2 human induced pluripotent stem cell-derived cardiomyocytes Stem Cells Dev 26 2017 1695 1705 28992755
217 Giannetti F. Barbieri M. Shiti A. Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2 Europace 25 2023 euad094
218 Horváth B. Hézső T. Kiss D. Late sodium current inhibitors as potential antiarrhythmic agents Front Pharmacol 11 2020 413 32372952
219 Lawson K. Potassium channel openers as potential therapeutic weapons in ion channel disease Kidney Int 57 2000 838 845 10720937
220 Sakata S. Kurata Y. Li P. Instability of KCNE1-D85N that causes long QT syndrome: stabilization by verapamil Pacing Clin Electrophysiol 37 2014 853 863 24499369
221 De Waard S. Montnach J. Ribeiro B. Functional impact of BeKm-1, a high-affinity hERG blocker, on cardiomyocytes derived from human-induced pluripotent stem cells Int J Mol Sci 21 2020 7167 32998413
222 Conte G. Kawabata M. de Asmundis C. High rate of subcutaneous implantable cardioverter-defibrillator sensing screening failure in patients with Brugada syndrome: a comparison with other inherited primary arrhythmia syndromes Europace 20 2018 1188 1193 28340026
223 Castelletti S. Dagradi F. Goulene K. A wearable remote monitoring system for the identification of subjects with a prolonged QT interval or at risk for drug-induced long QT syndrome Int J Cardiol 266 2018 89 94 29887480
224 Koren G. Electrical remodeling and arrhythmias in long-QT syndrome: lessons from genetic models in mice Ann Med 36 2004 22 27 15176420
225 Wallace E. Howard L. Liu M. Long QT syndrome: genetics and future perspective Pediatr Cardiol 40 2019 1419 1430 31440766
226 Rajamani S. Liu G. El-Bizri N. The novel late Na+ current inhibitor, GS-6615 (eleclazine) and its anti-arrhythmic effects in rabbit isolated heart preparations Br J Pharmacol 173 2016 3088 3098 27449698
227 De la Cruz A. Wu X. Rainer Q.C. Pharmacological screening of Kv7.1 and Kv7.1/KCNE1 activators as potential antiarrhythmic drugs in the zebrafish heart Int J Mol Sci 24 2023
228 Lowengrub K.M. Moss D.R. Moss D.A. Moss A.J. Long QT syndrome: how effective therapy in a single patient favorably influenced the long-term clinical course and genetic understanding of this hereditary disorder Prog Cardiovasc Dis 58 2015 221 226 26247496
229 Earle N. Crawford J. Smith W. Community detection of long QT syndrome with a clinical registry: an alternative to ECG screening programs? Heart Rhythm 10 2013 233 238 23123674
