Long QT Syndrome Type Research Articles

Modeling incomplete penetrance in long QT syndrome type 3 (LQT3) through ion channel heterogeneity: An in silico population study.

Many cardiac diseases are characterized by an increased late sodium current, including heart failure, hypertrophic cardiomyopathy, and inherited long QT syndrome type 3 (LQT3). The late sodium current in LQT3 is caused by a gain-of-function mutation in the voltage-gated sodium channel Nav1.5. Despite a well-defined genetic cause of LQT3, treatment remains inconsistent due to incomplete penetrance of the mutation and variability of anti-arrhythmic efficacy. Here, we investigate the relationship between LQT3-associated mutation incomplete penetrance and variability in ion channel expression, simulating a population of 1,000 single-cell “individuals” using the O’Hara-Rudy model of the human ventricular myocyte. We first simulate healthy electrical activity (i.e., in the absence of a mutation), then incorporate heterozygous expression for three LQT3-associated mutations (Y1795C, I1768V, and ∆KPQ), to directly compare the effects of each mutation on individuals across a diverse population. For all mutations, we find that susceptibility, defined either by the presence of an early after depolarization (EAD) or prolonged action potential duration (APD), primarily depends on the balance between the conductance of IKr and INa, for which individuals with a higher IKr-INa ratio are less susceptible. Further, we find distinct differences across the population, observing individuals susceptible to zero, one, two, or all three mutations. Individuals tend to be less susceptible with an appropriate balance of repolarizing currents, typically via increased IKs or IK1. Interestingly, the more critical repolarizing current is mutation specific. We conclude that balance between key currents plays a significant role in mutant-specific presentation of the disease phenotype in LQT3.

Determining the role of the unique N-terminal 1b domain in the gating of heterotetrameric hERG1a/hERG1b potassium channels.

Two isoforms of hERG (human Ether-a-go-go-Related Gene) potassium channel, hERG1a and hERG1b, associate in the heart to form the rapid delayed rectifier current (IKr), which is primarily responsible for repolarizing cardiac action potentials. Inherited mutations in both hERG1a and hERG1b cause Long QT Syndrome type 2 (LQT2), marked by prolonged cardiac repolarization and sudden death arrhythmia. The assembly of hERG1a subunits with hERG1b subunits increases the number of hERG1b subunits at the plasma membrane, but the mechanism by which hERG1a enhances hERG1b is not completely understood. Recently, it was reported that when expressed in trans, the hERG1a N-terminal region markedly increased hERG1b currents and increased biotin-labelled hERG1b protein at the plasma membrane surface. A direct structural interaction between the hERG1a N-terminal residues 216-220 and the hERG1b N-terminal region was characterized and proposed to be necessary for the upregulation of hERG1b (Johnson, Crawford, and Trudeau, 2022). However, hERG1b channels with a deletion of the unique N-terminal 1b domain did not have a measurable increase in current density or in biotinylated protein when co-expressed with hERG1a N-terminal region pieces. This indicates that the 1b domain is required for the increase in hERG1b by hERG1a. Interestingly, the 1b domain-deleted hERG1b channels displayed a large leftward shift in the voltage dependence of activation when co-expressed with the full hERG1a N-terminal region. This is unexpected, as the 1b domain was not previously considered as a determinant of hERG gating. Here, we will investigate the mechanism of this large leftward shift and determine the role of the 1b domain in the gating properties of hERG1a/hERG1b heterotetrameric channels.

Structural insights for the modulation of KCNQ1 channel by ML277.

KCNQ1 is a voltage-gated potassium ion channel protein which co-assembles with its accessory regulatory KCNE subunits, KCNE1-5, in order to fulfill its diverse physiological roles in various tissues. In the heart, KCNQ1 helps maintain a normal QT interval in the electrocardiogram, and loss of function mutations can lead to long QT syndrome type 1 (LQT1), seizures, and sudden death. Activators of KCNQ1 may be a promising strategy to oppose the effect of LQT mutations. In this work, we determined the cryo-EM structure of Xenopus KCNQ1 bound to Ca2+/calmodulin with or without the KCNQ1 activator, ML277. Our results showed that a binding site for ML277 lies in the transmembrane domain of the channel which is lined by residues of the S4-S5 linker, and the S5 and S6 helices of two adjacent subunits. MD simulations, along with point mutations, support the binding site location and showed that ML277 binds almost identically in open and closed channels. Comparative structural analyses highlighted important residues for the selectivity of ML277 towards KCNQ1, among other KCNQ subfamily members, and provided an explanation for the limited efficacy of ML277 in the presence of KCNE3. This work paves the way for a better understanding of KCNQ1 regulation by small molecules and may lead to the development of novel and potent activators of KCNQ1, providing a framework for therapeutic intervention targeting KCNQ1 loss of function pathologies.

Human-induced pluripotent stem cell-derived cardiomyocytes to study PUFA analogues as a potential treatment of long QT syndrome.

Long QT syndrome (LQTS) is an inheritable ventricular arrhythmia that predisposes patients to torsades de pointes and sudden cardiac death. Mutations in voltage-gated ion channels (VGC) and their regulatory β subunits involved in the cardiac action potential (AP) generate LQTS by prolonging the QT interval of the electrocardiogram. 15 types of LQTS has been described depending on the underlying gene mutated. LQT1 and LQT5 are described as loss-of-function mutations in genes that encode Kv7.1 (alpha pore-forming subunit) and its β-regulatory subunit KCNE1, respectively. Kv7.1/KCNE1 channels elicit one of the main repolarization currents (IKs) involved in the cardiac AP. Therefore, Kv7.1/KCNE1 channel-specific activators might be a potential treatment for LQTS. Polyunsaturated fatty acid (PUFA) analogues can broadly modulate cardiac VGC when applied on isolated channels in a heterologous system. In the present study, we measured the effects of these four compounds, Linoleoyl-taurine (LIN-Tau), docosahexaenoyl-Tau (DHA-Tau), Linoleoyl-Glycine (LIN-Gly), and DHA-Gly, on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). DHA-analogues shortened the hiPSC-CMs AP duration (APD), while LIN-analogues prolonged hiPSC-CMs APD. DHA-analogues were also tested in isogenic hiPSC-CMs lines for two KCNQ1 (Kv7.1 gene) mutations that cause LQT1, R190Q, and G269S. R190Q is an autosomal dominant missense mutation characterized by a 70-80 % reduction of IKs because of a dominant negative traffic defect. Moreover, we also analyzed DHA-analogues in a heterozygous missense KCNQ1 mutation, G269S. G269S mutation shows a net effect of less than 50% reduction of IKs current (haploinsufficiency). We here use a combination of hiPSC-CM monolayers with a high-resolution, all-optical electrophysiology system for screening the anti-arrhythmic properties of diverse PUFA analogues. Moreover, the well-characterized hiPSC-CMs mutants show us whether PUFA analogues might be a potential treatment approach for more than one type of LQT1.

Precision medicine for long QT syndrome: patient-specific iPSCs take the lead.

Long QT syndrome (LQTS) is a detrimental arrhythmia syndrome mainly caused by dysregulated expression or aberrant function of ion channels. The major clinical symptoms of ventricular arrhythmia, palpitations and syncope vary among LQTS subtypes. Susceptibility to malignant arrhythmia is a result of delayed repolarisation of the cardiomyocyte action potential (AP). There are 17 distinct subtypes of LQTS linked to 15 autosomal dominant genes with monogenic mutations. However, due to the presence of modifier genes, the identical mutation may result in completely different clinical manifestations in different carriers. In this review, we describe the roles of various ion channels in orchestrating APs and discuss molecular aetiologies of various types of LQTS. We highlight the usage of patient-specific induced pluripotent stem cell (iPSC) models in characterising fundamental mechanisms associated with LQTS. To mitigate the outcomes of LQTS, treatment strategies are initially focused on small molecules targeting ion channel activities. Next-generation treatments will reap the benefits from development of LQTS patient-specific iPSC platform, which is bolstered by the state-of-the-art technologies including whole-genome sequencing, CRISPR genome editing and machine learning. Deep phenotyping and high-throughput drug testing using LQTS patient-specific cardiomyocytes herald the upcoming precision medicine in LQTS.

Reengineering Mexiletine by chemical synthesis to decrease toxicity and improve pharmacological properties with patient-derived iPSC cardiomyocytes.

Heart disease is one of the top causes of healthcare expenses in the United States. Lethal ventricular cardiac arrhythmia can arise in acquired or congenital heart disease. Long QT syndrome type 3 (LQT3) is a congenital form of ventricular arrhythmia caused by mutations in the cardiac sodium channel SCN5A.

Modeling long QT syndrome type 2 on-a-chip via in-depth assessment of isogenic gene-edited 3D cardiac tissues.

Long QT syndrome (LQTS) is a cardiovascular disease characterized by QT interval prolongation that can lead to sudden cardiac death. Many mutations with heterogeneous mechanisms have been identified in KCNH2, the gene that encodes for hERG (Kv11.1), which lead to onset of LQTS type 2 (LQTS2). In this work, we developed a LQTS2-diseased tissue-on-a-chip model, using 3D coculture of isogenic stem cell-derived cardiomyocytes (CMs) and cardiac fibroblasts (CFs) within an organotypic microfluidic chip technology. Primarily, we created a hiPSC line with R531W mutation in KCNH2 using CRISPR-Cas9 gene-editing technique and characterized the resultant differentiated CMs and CFs. A deficiency in hERG trafficking was identified in KCNH2-edited hiPSC-CMs, revealing a possible mechanism of R531W mutation in LQTS2 pathophysiology. Following creation of a 3D LQTS2 tissue-on-a-chip, the tissues were extensively characterized, through analysis of calcium handling and response to β-agonist. Furthermore, attempted phenotypic rescue via pharmacological intervention of LQTS2 on a chip was investigated.

A Possible Explanation for the Low Penetrance of Pathogenic KCNE1 Variants in Long QT Syndrome Type 5.

Long QT syndrome (LQTS) is an inherited cardiac rhythm disorder associated with increased incidence of cardiac arrhythmias and sudden death. LQTS type 5 (LQT5) is caused by dominant mutant variants of KCNE1, a regulatory subunit of the voltage-gated ion channels generating the cardiac potassium current IKs. While mutant LQT5 KCNE1 variants are known to inhibit IKs amplitudes in heterologous expression systems, cardiomyocytes from a transgenic rabbit LQT5 model displayed unchanged IKs amplitudes, pointing towards the critical role of additional factors in the development of the LQT5 phenotype in vivo. In this study, we demonstrate that KCNE3, a candidate regulatory subunit of IKs channels minimizes the inhibitory effects of LQT5 KCNE1 variants on IKs amplitudes, while current deactivation is accelerated. Such changes recapitulate IKs properties observed in LQT5 transgenic rabbits. We show that KCNE3 accomplishes this by displacing the KCNE1 subunit within the IKs ion channel complex, as evidenced by a dedicated biophysical assay. These findings depict KCNE3 as an integral part of the IKs channel complex that regulates IKs function in cardiomyocytes and modifies the development of the LQT5 phenotype.

Modeling incomplete penetrance in long QT syndrome type 3 through ion channel heterogeneity: an in silico population study.

Many cardiac diseases are characterized by an increased late sodium current, including heart failure, hypertrophic cardiomyopathy, and inherited long QT syndrome type 3 (LQT3). The late sodium current in LQT3 is caused by a gain-of-function mutation in the voltage-gated sodium channel Nav1.5. Despite a well-defined genetic cause of LQT3, treatment remains inconsistent because of incomplete penetrance of the mutation and variability of antiarrhythmic efficacy. Here, we investigate the relationship between LQT3-associated mutation incomplete penetrance and variability in ion channel expression, simulating a population of 1,000 individuals with the O'Hara-Rudy model of the human ventricular myocyte. We first simulate healthy electrical activity (i.e., in the absence of a mutation) and then incorporate heterozygous expression for three LQT3-associated mutations (Y1795C, I1768V, and ΔKPQ), to directly compare the effects of each mutation on individuals across a diverse population. For all mutations, we find that susceptibility, defined by either the presence of an early afterdepolarization (EAD) or prolonged action potential duration (APD), primarily depends on the balance between the conductance of IKr and INa, for which individuals with a higher IKr-to-INa ratio are less susceptible. Furthermore, we find distinct differences across the population, observing individuals susceptible to zero, one, two, or all three mutations. Individuals tend to be less susceptible with an appropriate balance of repolarizing currents, typically via increased IKs or IK1. Interestingly, the more critical repolarizing current is mutation specific. We conclude that the balance between key currents plays a significant role in mutant-specific presentation of the disease phenotype in LQT3.NEW & NOTEWORTHY An in silico population approach investigates the relationship between variability in ion channel expression and gain-of-function mutations in the voltage-gated sodium channel associated with the congenital disorder long QT syndrome type 3 (LQT3). We find that ion channel variability can contribute to incomplete penetrance of the mutation, with mutant-specific differences in ion channel conductances leading to susceptibility to proarrhythmic action potential duration prolongation or early afterdepolarizations.

When the Gates Swing Open Only: Arrhythmia Mutations That Target the Fast Inactivation Gate of Nav1.5

Nav1.5 is the main voltage-gated sodium channel found in cardiac muscle, where it facilitates the fast influx of Na+ ions across the cell membrane, resulting in the fast depolarization phase-phase 0 of the cardiac action potential. As a result, it plays a major role in determining the amplitude and the upstroke velocity of the cardiac impulse. Quantitively, cardiac sodium channel activates in less than a millisecond to trigger the cardiac action potential and inactivates within 2-3 ms to facilitate repolarization and return to the resting state in preparation for firing the next action potential. Missense mutations in the gene that encodes Nav1.5 (SCN5A), change these time constants which leads to a wide spectrum of cardiac diseases ranging from long QT syndrome type 3 (LQT3) to sudden cardiac death. In this mini-review I will focus on the missense mutations in the inactivation gate of Nav1.5 that results in arrhythmia, attempting to correlate the location of the missense mutation to their specific phenotype.

Beckwith-Wiedemann syndrome with long QT caused by a deletion involving KCNQ1 but not KCNQ1OT1:TSS-DMR

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder with characteristic features, such as overgrowth, macroglossia, and exomphalos. Hypomethylation of the KCNQ1OT1:TSS-differentially methylated region (DMR) on the 11p15.5 imprinted region is the most common etiology of BWS. KCNQ1 on 11p15.5 is expressed from the maternally inherited allele in most tissues, but is biparentally expressed in the heart, and maternal KCNQ1 transcription is required to establish the maternal DNA imprint in the KCNQ1OT1:TSS-DMR. Loss of function variants in KCNQ1 result in long QT syndrome type 1 (LQT1). To date, eight patients with BWS due to KCNQ1 splice variants or structural abnormalities involving KCNQ1 but not the KCNQ1OT1:TSS-DMR have been reported (KCNQ1-BWS), and four of them had LQT1. We report a Japanese boy with BWS and LQT1 presenting with extreme hypomethylation of the KCNQ1OT1:TSS-DMR caused by a de novo 215-kb deletion including KCNQ1 but not the KCNQ1OT1:TSS-DMR on the maternal allele. He was born by emergency cesarean section due to suspicion of placental abruption at 30 weeks of gestation. His birth weight and length were +1.6 SD and +1.0 SD, respectively. His placental weight was +3.9 SD, and histological examination of his placenta was consistent with mesenchymal dysplasia. He had BWS clinical features, including macroglossia, ear creases and pits, body asymmetry, and rectus abdominis muscle dehiscence, and BWS was therefore diagnosed. LQT1 was first noticed at three months in a preoperative examination for lingual frenectomy. The summarized data of our patient and the previously reported eight patients in KCNQ1-BWS showed more frequent and earlier preterm births and smaller sized birth weight in KCNQ1-BWS cases than those with BWS caused by epimutation of the KCNQ1OT1:TSS-DMR. In addition, in five of nine patients with KCNQ1-BWS, LQT1 was detected, and two of them were identified at school age. In our patient and in another single case with LQT1, the LQT1 was not detected early despite neonatal ECG monitoring. For BWS patients with extreme hypomethylation of the KCNQ1OT1:TSS-DMR, searching for CNVs involving KCNQ1 and mutation screening for KCNQ1 should be considered together with periodic ECG monitoring. (338/500 words)

Case report of antiseizure medicine-induced long QT syndrome and a literature review

BackgroundTo realize the clinical characteristics of long QT syndrome (LQTS) caused by antiseizure medicines (ASMs), and to improve the prevention and management of ASM-acquired QT syndrome.Case presentationA case of ASM-acquired QT syndrome was diagnosed and relevant literature was reviewed. The case was a 7-year-old boy who presented with a sudden onset of panic followed by changes in consciousness, with or without convulsions, lasting from tens of seconds to 3 min. The patient then received antiepileptic treatment with valproic acid, levetiracetam and oxcarbazepine and was seizure free for about a year. However, on August 12, 2021, his illness flared up again. Electroencephalogram (EEG) showed the background activity was slow, and no obvious epileptic discharge was detected. But electrocardiogram (ECG) showed a surprisingly prolonged QT interval (770 ms). Torsades de Pointes was found during Holter monitoring, while electrolyte levels were normal. The ECG recordings gradually returned to normal after stopping ASMs. For literature search, only 21 related papers were obtained after reading titles and full-texts of 105 English-language papers retrieved using keywords "acquired QT interstitial syndrome/acquired Long QT Syndrome (aLQTS)" and "anti-epileptic seizure drugs/ASMs", in the databases of Wanfang, CNKI, Pubmed, and other databases, from publication year 1965 to October 26, 2021. There are 12 types of drug-acquired LQTS caused by ASMs, most of which are Na+ blockers, but LQTS caused by oxcarbazepine had not been reported previously.ConclusionsASMs such as oxcarbazepine can cause acquired LQTS. When Na+ or K+ channel blockers are used clinically, ECG should be reviewed regularly and abnormal ECG should be intervened in time to reduce iatrogenic accidents in patients with epilepsy.

Abstract 11929: Rare Presentation of Fetal Long QT Syndrome With 2:1 Atrioventricular Conduction

Case Presentation: A 34 year-old G2P1 mother with Long QT syndrome Type 2 (LQTS2), history of sympathetic denervation, implantable defibrillator, and strong family history of LQTS2 including sudden death, presented to fetal cardiology at 29+3 weeks gestation with fetal 2:1 atrioventricular (AV) conduction and a ventricular rate of ≈60 bpm on fetal echocardiogram without hydrops. Findings persisted at 30+5 weeks by echo. The patient’s KCNH2 p.Met645Ile variant was previously classified as a Variant of Uncertain Significance, but segregation analysis of the family by a genetic counselor upgraded the variant to Likely Pathogenic. Prior to pregnancy, the patient was taking nadolol, then started on 2000 IU of vitamin D at 30+6 weeks due to borderline vitamin D level. Within 24 hours of initiating vitamin D, fetal magnetocardiography (fMCG) demonstrated predominant sinus rhythm with 1:1 conduction at ≈120 bpm and occasional 2:1 AV conduction. The QTc measured ≈550 msec during 1:1 conduction, and ≈720 msec during 2:1 conduction. Following the multidisciplinary diagnosis of fetal LQTS, several decisions were made. The patient declined amniocentesis, as the risk outweighed the benefit of additional genetic information. Daily home fetal heart monitoring, with goal heart rate 70-170 bpm, allowed for fewer fetal echos. Maternal vitamin D intake was liberalized to 4000 IU/day. Follow-up fMCG was recommended to exclude late-onset Torsade de Pointes, which would require transplacental treatment and complex perinatal management. Discussion with electrophysiology outlined longitudinal outcomes for the family, including potential need for neonatal pacing wires. Discussion: LQTS affects ~1/2,500 live births, with even fewer presenting with fetal AV conduction abnormalities. Optimized maternal vitamin D level may be associated with improved conduction. A multidisciplinary approach is crucial in diagnosis and management of these high-risk fetuses.

Accelerated QT adaptation following atropine-induced heart rate increase in LQT1 patients versus healthy controls: A sign of disturbed hysteresis.

Hysteresis, a ubiquitous regulatory phenomenon, is a salient feature of the adaptation of ventricular repolarization duration to heart rate (HR) change. We therefore compared the QT interval adaptation to rapid HR increase in patients with the long QT syndrome type 1 (LQT1) versus healthy controls because LQT1 is caused by loss-of-function mutations affecting the repolarizing potassium channel current IKs , presumably an important player in QT hysteresis. The study was performed in an outpatient hospital setting. HR was increased in LQT1 patients and controls by administering an intravenous bolus of atropine (0.04 mg/kg body weight) for 30 s. RR and QT intervals were recorded by continuous Frank vectorcardiography. Atropine induced transient expected side effects but no adverse arrhythmias. There was no difference in HR response (RR intervals) to atropine between the groups. Although atropine-induced ΔQT was 48% greater in 18 LQT1 patients than in 28 controls (p < 0.001), QT adaptation was on average 25% faster in LQT1 patients (measured as the time constant τ for the mono-exponential function and the time for 90% of ΔQT; p < 0.01); however, there was some overlap between the groups, possibly a beta-blocker effect. The shorter QT adaptation time to atropine-induced HR increase in LQT1 patients on the group level corroborates the importance of IKs in QT adaptation hysteresis in humans and shows that LQT1 patients have a disturbed ultra-rapid cardiac memory. On the individual level, the QT adaptation time possibly reflects the effect-size of the loss-of-function mutation, but its clinical implications need to be shown.

Association of the P441L KCNQ1 variant with severity of long QT syndrome and risk of cardiac events.

Dysfunction of potassium voltage-gated channel subfamily Q member 1 (KCNQ1) is a primary cause of long QT syndrome type 1 (LQT1). Here, we report a missense mutation P441L in KCNQ1 C-terminus of a 37-year-old woman with severe LQT1 phenotype. Variant P441L transporting to the plasma membrane and interacting with KCNE1 were both markedly decreased, leading to potassium efflux disorder and eventually LQT1. Mutations between the C-terminal helix A and helix B of KCNQ1 have linked with low cardiac event risk, however, we firstly find variant P441L causing a severe LQT1 phenotype with a high risk of cardiac events.

Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance.

Variants in KCNH2, encoding the human ether a-go-go (hERG) channel that is responsible for the rapid component of the cardiac delayed rectifier K+ current (IKr), are causal to long QT syndrome type 2 (LQTS2). We identified eight index patients with a new variant of unknown significance (VUS), KCNH2:c.2717C > T:p.(Ser906Leu). We aimed to elucidate the biophysiological effect of this variant, to enable reclassification and consequent clinical decision-making. A genotype-phenotype overview of the patients and relatives was created. The biophysiological effects were assessed independently by manual-, and automated calibrated patch clamp. HEK293a cells expressing (i) wild-type (WT) KCNH2, (ii) KCNH2-p.S906L alone (homozygous, Hm) or (iii) KCNH2-p.S906L in combination with WT (1:1) (heterozygous, Hz) were used for manual patching. Automated patch clamp measured the variants function against known benign and pathogenic variants, using Flp-In T-rex HEK293 KCNH2-variant cell lines. Incomplete penetrance of LQTS2 in KCNH2:p.(Ser906Leu) carriers was observed. In addition, some patients were heterozygous for other VUSs in CACNA1C, PKP2, RYR2 or AKAP9. The phenotype of carriers of KCNH2:p.(Ser906Leu) ranged from asymptomatic to life-threatening arrhythmic events. Manual patch clamp showed a reduced current density by 69.8 and 60.4% in KCNH2-p.S906L-Hm and KCNH2-p.S906L-Hz, respectively. The time constant of activation was significantly increased with 80.1% in KCNH2-p.S906L-Hm compared with KCNH2-WT. Assessment of KCNH2-p.S906L-Hz by calibrated automatic patch clamp assay showed a reduction in current density by 35.6%. The reduced current density in the KCNH2-p.S906L-Hz indicates a moderate loss-of-function. Combined with the reduced penetrance and variable phenotype, we conclude that KCNH2:p.(Ser906Leu) is a low penetrant likely pathogenic variant for LQTS2.

Long QT syndrome: long story short.

The first report of long QT syndrome (LQTS) dates back to 1856 when Friedrich Ludwig Meissner, a German obstetrician and pediatrician, described a child with deafness, who died while being publicly reprimanded by the schoolteacher.1 It took nearly a century to document the very first electrocardiogram (ECG) of a prolonged QT interval coinciding with deafness and syncope.2 The association between sudden deaths in children with congenital deafness and QT prolongation was brought up by two concurrent publications authored by Anton Jervell with Fred Lange-Nielsen and Samuel A. Levine with Clyde R. Woodworth.3 Following closely, Cesarino Romano et al. and Owen C. Ward described analogous cases in the absence of the auditory component.3 Although Levine and Woodworth’s contribution was never acknowledged, two eponyms, Jervell-Lange-Nielsen and Romano-Ward syndromes, were coined with reference to the congenital form of LQTS with or without deafness, respectively.3 Because syncope and cardiac arrest mainly occurred in stressful situation, sympathetic imbalance was long believed to underlie LQTS.3 It would take 40 years to find the fault in the genes. With the biological Rosetta stone deciphered, research has become ever more crucial to translate gene expression into clinical care for LQTS. While the spectrum of mutations initially encompassed 17 genes reported to be linked to LQTS, 7 are now classified as having disputed evidence.4 Mutations in three genes (KCNQ1, KCNH2, and SCN5A) encoding for cardiac voltage-gated K+ (Kv7.1 or KCNQ1, Kv11.1 or hERG) and Na+ channels (Nav1.5) causing a delay in cardiac repolarization account for the majority of LQTS forms (types 1, 2, and 3, respectively).4 LQTS types 1 and 2 are based on a loss-of-function in Kv7.1 and Kv11.1 channels, respectively, reducing repolarizing outward K+ currents (IKs and IKr). In contrast, LQTS type 3 relates to an increased late Na+ inward current (INa, late) resulting from gain-of-function in Nav1.5 channels.4 While LQTS type 1 typically manifests during childhood, LQTS types 2 and 3 patients become symptomatic after the onset of puberty. Because of the decreased Kv11.1 channel density compared to male as well as the direct inhibitory effect of estrogen, female LQTS type 2 patients are at particular risk for arrhythmias.4 Such cardiac events predominantly occur at rest in LQTS type 3. In contrast, exercise and acoustic/emotional stimuli may trigger malignant arrhythmias in patients with LQTS type 1 and type 2, respectively. Mechanistically, the LQTS heart fails to adapt (impaired repolarization reserve) in response to the excess Ca2+ inflow resulting from sustained adrenergic tone (exercise) or an adrenergic surge (sudden arousal).4 Given the crucial role of sympathetic activity, it is no surprise that beta-blockers are advocated for LQTS patients. Late Na+ channel blockers present a viable adjunct in the pharmacological treatment of LQTS type 3. Left cardiac sympathetic denervation is a surgical antiadrenergic intervention mainly reserved to patients refractory to standard of care. An implantable cardioverter-defibrillator is considered in high-risk and resuscitated patients for the prevention of sudden cardiac death.4 Collectively, none of these treatment modalities addresses the cause of LQTS. In addition, some LQTS patients continue to experience breakthrough cardiac events despite maximal therapy, sparking research efforts in developing new treatment strategies.

DETECTION OF CONGENITAL LONG QT SYNDROME WITH ARTIFICIAL INTELLIGENCE

DETECTION OF CONGENITAL LONG QT SYNDROME WITH ARTIFICIAL INTELLIGENCE

ARumenamides: A novel class of potential antiarrhythmic compounds.

Background: Most therapeutics targeting cardiac voltage-gated sodium channels (Nav1.5) attenuate the sodium current (INa) conducted through the pore of the protein. Whereas these drugs may be beneficial for disease states associated with gain-of-function (GoF) in Nav1.5, few attempts have been made to therapeutically treat loss-of-function (LoF) conditions. The primary impediment to designing efficacious therapies for LoF is a tendency for drugs to occlude the Nav1.5 central pore. We hypothesized that molecular candidates with a high affinity for the fenestrations would potentially reduce pore block. Methods and Results: Virtual docking was performed on 21 compounds, selected based on their affinity for the fenestrations in Nav1.5, which included a class of sulfonamides and carboxamides we identify as ARumenamide (AR). Six ARs, AR-051, AR-189, AR-674, AR-802, AR-807 and AR-811, were further docked against Nav1.5 built on NavAb and rNav1.5. Based on the virtual docking results, these particular ARs have a high affinity for Domain III-IV and Domain VI-I fenestrations. Upon functional characterization, a trend was observed in the effects of the six ARs on INa. An inverse correlation was established between the aromaticity of the AR’s functional moieties and compound block. Due to its aromaticity, AR-811 blocked INa the least compared with other aromatic ARs, which also decelerated fast inactivation onset. AR-674, with its aliphatic functional group, significantly suppresses INa and enhances use-dependence in Nav1.5. AR-802 and AR-811, in particular, decelerated fast inactivation kinetics in the most common Brugada Syndrome Type 1 and Long-QT Syndrome Type 3 mutant, E1784K, without affecting peak or persistent INa. Conclusion: Our hypothesis that LoF in Nav1.5 may be therapeutically treated was supported by the discovery of ARs, which appear to preferentially block the fenestrations. ARs with aromatic functional groups as opposed to aliphatic groups efficaciously maintained Nav1.5 availability. We predict that these bulkier side groups may have a higher affinity for the hydrophobic milieu of the fenestrations, remaining there rather than in the central pore of the channel. Future refinements of AR compound structures and additional validation by molecular dynamic simulations and screening against more Brugada variants will further support their potential benefits in treating certain LoF cardiac arrhythmias.

To Modify or Not to Modify: Allele-Specific Effects of 3'UTR-KCNQ1 Single Nucleotide Polymorphisms on Clinical Phenotype in a Long QT 1 Founder Population Segregating a Dominant-Negative Mutation.

Background There are conflicting reports with regard to the allele-specific gene suppression effects of single nucleotide polymorphisms (SNPs) in the 3'untranslated region (3'UTR) of the KCNQ1 gene in long QT syndrome type 1 (LQT1) populations. Here we assess the allele-specific effects of 3 previously published 3'UTR-KCNQ1's SNPs in a LQT1 founder population segregating a dominant-negative mutation. Methods and Results Bidirectional sequencing of the KCNQ1's 3'UTR was performed in the p.Y111C founder population (n=232, 147 genotype positive), with a minor allele frequency of 0.1 for SNP1 (rs2519184) and 0.6 for linked SNP2 (rs8234) and SNP3 (rs107980). Allelic phase was assessed in trios aided by haplotype data, revealing a high prevalence of derived SNP2/3 in cis with p.Y111C (89%). Allele-specific association analyses, corrected using a relatedness matrix, were performed between 3'UTR-KCNQ1 SNP genotypes and clinical phenotypes. SNP1 in trans was associated with a significantly higher proportion of symptomatic phenotype compared with no derived SNP1 allele in trans (58% versus 32%, corrected P=0.027). SNP2/3 in cis was associated with a significantly lower proportion of symptomatic phenotype compared with no derived SNP2/3 allele in cis (32% versus 69%, corrected P=0.010). Conclusions Allele-specific modifying effects on symptomatic phenotype of 3'UTR-KCNQ1 SNPs rs2519184, rs8234, and rs107980 were seen in a LQT1 founder population segregating a dominant-negative mutation. The high prevalence of suppressive 3'UTR-KCNQ1 SNPs segregating with the founder mutation could contribute to the previously documented low incidence of cardiac events in heterozygous carriers of the p.Y111C KCNQ1 mutation.