Short QT Research Articles

Novel electrocardiographic criteria for short QT syndrome in children and adolescents.

Although shortening of the corrected QT interval (QTc) is a key finding in the diagnosis of short QT syndrome (SQTS), there may be overlap of the QTc between SQTS patients and normal subjects in childhood and adolescence. We aimed to investigate electrocardiographic findings for differentiation of SQTS patients. The SQTS group comprised 34 SQTS patients <20 years old, including 9 from our institutions and 25 from previous reports. The control group comprised 61 apparently healthy subjects with an QTc of <360 ms who were selected from 13 314 participants in a school-based screening programme. We compared electrocardiographic findings, including QT and Jpoint-Tpeak intervals (QT and J-Tpeak, respectively), those corrected by using the Bazett's and Fridericia's formulae (cB and cF, respectively) and early repolarization (ER) between the groups. QT, QTc by using Bazett's formula (QTcB), QTc by using Fridericia's formula (QTcF), J-Tpeak, J-Tpeak cB, and J-Tpeak cF were significantly shorter in the SQTS group than in the control group. On receiver operating characteristic curve analysis, the area under the curve (AUC) was largest for QTcB (0.888) among QT, QTcB, and QTcF, with a cut-off value of 316 ms (sensitivity: 79.4% and specificity: 96.7%). The AUC was largest for J-Tpeak cB (0.848) among J-Tpeak, J-Tpeak cB, and J-Tpeak cF, with a cut-off value of 181 ms (sensitivity: 80.8% and specificity: 91.8%). Early repolarization was found more frequently in the SQTS group than in the control group (67% vs. 23%, P = 0.001). A QTcB <316 ms, J-Tpeak cB < 181 ms, and the presence of ER may indicate SQTS patients in childhood and adolescence.

Optogenetic modulation of cardiac action potential properties may prevent arrhythmogenesis in short and long QT syndromes.

Abnormal action potential (AP) properties, as occurs in long or short QT syndromes (LQTS and SQTS, respectively), can cause life-threatening arrhythmias. Optogenetics strategies, utilizing light-sensitive proteins, have emerged as experimental platforms for cardiac pacing, resynchronization, and defibrillation. We tested the hypothesis that similar optogenetic tools can modulate the cardiomyocyte’s AP properties, as a potentially novel antiarrhythmic strategy. Healthy control and LQTS/SQTS patient–specific human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) were transduced to express the light-sensitive cationic channel channelrhodopsin-2 (ChR2) or the anionic-selective opsin, ACR2. Detailed patch-clamp, confocal-microscopy, and optical mapping studies evaluated the ability of spatiotemporally defined optogenetic protocols to modulate AP properties and prevent arrhythmogenesis in the hiPSC-CMs cell/tissue models. Depending on illumination timing, light-induced ChR2 activation induced robust prolongation or mild shortening of AP duration (APD), while ACR2 activation allowed effective APD shortening. Fine-tuning these approaches allowed for the normalization of pathological AP properties and suppression of arrhythmogenicity in the LQTS/SQTS hiPSC-CM cellular models. We next established a SQTS–hiPSC-CMs–based tissue model of reentrant-arrhythmias using optogenetic cross-field stimulation. An APD-modulating optogenetic protocol was then designed to dynamically prolong APD of the propagating wavefront, completely preventing arrhythmogenesis in this model. This work highlights the potential of optogenetics in studying repolarization abnormalities and in developing novel antiarrhythmic therapies.

Functional characterization of drug responses in induced pluripotent stem cell-derived cardiomyocytes from a short QT syndrome type 5 patient

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): ETH Zurich Personalized Health and Related Technologies; German Centre for Cardiovascular Research Introduction Short QT syndrome (SQTS) and Brugada syndrome (BrS) are rare channelopathies causing sudden cardiac death (SCD). There are only few investigations of effective therapies of SQTS and BrS linked to CACNB2 variants. Since treatment data of SQTS are sparse, we studied drug responses of induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) 2D cultures carrying a mutation in the CACNB2 gene from a SQTS type 5 (SQT5) patient with an established phenotype. We used high-density microelectrode arrays (HD-MEAs), patch clamp, and calcium-transient imaging. Purpose To investigate the electrophysiological responses of SQT5 patient-derived iPSC-CMs upon exposure to antiarrhythmic drugs. Methods Human iPSCs, derived from a SQT5 patient and a healthy donor, were cultured and differentiated into cardiomyocytes by temporal modulation of the Wnt signaling. For electrophysiological measurements, spontaneously beating cardiomyocytes at day 40-60 were dissociated and plated a) on petri dishes for patch clamp and calcium-transient measurements and b) directly on HD-MEAs. Antiarrhythmic drugs, including sotalol, quinidine, and flecainide, were dosed to the cells after plating as soon as stable activity levels were measured. After baseline measurements, drug doses were sequentially increased from low to high concentrations. Results We observed spontaneous and synchronous beating of SQT5 patient- and healthy donor-derived iPSC-CMs. Quinidine, which is known to be effective for treatment of SQTS with possible differences for subtypes, prolonged field-potential duration (FPD) and action-potential duration in SQT5 patient-derived iPSC-CMs. Sotalol slightly increased FPD at 30µM as measured with HD-MEAs, whereas action-potential duration (APD) measured through patch clamp did not exhibit a notable effect at 30 µM. APD became shorter at higher concentrations, which is in line with clinical data of SQTS patients. HD-MEA measurements showed that flecainide shortened the FPD of SQT5 patient-derived CMs at 20µM. For healthy donor-derived iPSC-CMs, quinidine, sotalol, and flecainide prolonged FPDs in HD-MEA measurements. Using calcium-transient imaging, quinidine showed a slight antiarrhythmic effect, whereas sotalol did not have antiarrhythmic effects. Conclusion We used HD-MEAs, patch clamp, and calcium-transient imaging to analyze electrophysiological responses of SQT5 patient-derived iPSC-CMs upon dosage of antiarrhythmic drugs. Our preliminary results show that quinidine - but not flecainide - could prolong the repolarization duration in SQT5 patient-derived iPSC-CMs.

A novel variant in the SLC4A3 gene with high penetrance in a family with short QT Syndrome

Abstract Funding Acknowledgements Type of funding sources: None. Background Short QT syndrome (SQTS) is a rare, autosomal dominant disease causing sudden cardiac death (SCD). Current guidelines recommend genetic testing. Associated variants in KCNQ1, KCNH2, KCNJ2 and SLC4A3 genes have been reported. Purpose We report a family with a variant in the SLC4A3 gene with several presentations of SCD and high clinical penetrance of SQTS. Methods We performed a post-mortem genetic testing in the index patient in whom prior ECG was available. Subsequently, clinical and electrophysiological work-up and cascade screening (CS) of the detected suspected variant was carried out in available relatives. Results The index patient had suffered a SCD at the age of 17 (figure, upper panel, arrow). A previously registered ECG showed a shortened QTc of 340ms (figure, lower panel). Autopsy revealed no structural heart disease. Post-mortem genetic testing revealed variants in the LDB3, MYH7 and a novel heterozygous missense variant, p.(Ser1039Arg) also in the SLC4A3 gene. Although predictive bioinformatic algorithms (AlignGVGD, SIFT, MutationTaster, Polyphen2) showed conflicting classifications, family history was notable for SCD without post-mortem genetic work-up in three second degree relatives (figure, upper panel, patients 207, 208 and 305, age of death 33, 25 and 33 years respectively). CS was performed in first and second degree relatives of the index patient and was highly suggestive for disease association of the variant in the SLC4A3 gene with co-segregation in all clinically affected family members. Only one patient with the variant had a normal QTc (figure, upper panel, patient 202) of 407ms, however this patient was on regular QT-prolonging medication (risperidone and loperamide). Conclusion Genetic testing revealed a novel in the SLC4A3 gene, which was recently implicated in the pathogenesis of the SQTS. Although predictive bioinformatic algorithms yielded conflicting results, CS of family members suggests a likely pathogenicity (class IV) of the variant. Further CS or functional tests are necessary to establish causality. Abstract Figure. ECG of index patient and family tree

Pharmacology of Cenobamate: Mechanism of Action, Pharmacokinetics, Drug-Drug Interactions and Tolerability.

Cenobamate is one of the latest antiseizure medications (ASMs) developed for the treatment of focal onset seizures in adult patients. The recommended starting dose is 12.5mg/day, titrated gradually to the target daily dose of 200 mg, which may be increased to a maximum of 400 mg/day based on clinical response. Although the high rate of seizure freedom observed in randomized, placebo-controlled clinical trials has resulted in exciting expectations, further clinical studies are needed to better define its clinical profile. Cenobamate is characterized by a peculiar pharmacology regarding both pharmacodynamics and pharmacokinetics. The mechanism of action has only partly been described, with the drug acting on voltage-gated sodium channels through a pronounced action on persistent rather than transient currents. Cenobamate also acts as a positive allosteric modulator of GABAA receptors independently from the benzodiazepine binding site. The bioavailability of cenobamate is not influenced by other drugs, except phenytoin; it can inhibit cytochrome P450 (CYP)2C19 and induce CYP3A4 and 2B6, and hence can potentially interact with many drugs (e.g. dose adjustments may be required for lamotrigine, carbamazepine and clobazam). The pharmacokinetics of cenobamate are not linear and dosage increases imply a disproportional increase in plasma levels, particularly at doses higher than 300mg. The most common and dose-related adverse effects associated with cenobamate include central nervous system-related symptoms, mainly somnolence, dizziness, diplopia, and disturbances in gait and coordination. A somewhat higher incidence of adverse events has been observed in patients concomitantly treated with sodium channel blockers. The most relevant safety issues are currently represented by the risk of severe skin reactions (apparently avoidable by a slow titration) and QT shortening (the drug is contraindicated in patients with familial short QT syndrome or taking QT-shortening drugs). Overall, cenobamate is a promising ASM with an intriguing and not fully understood mechanism of action; pharmacokinetic issues need to be considered in clinical practice.

Transgenic rabbit models for cardiac disease research.

To study the pathophysiology of human cardiac diseases and to develop novel treatment strategies, complex interactions of cardiac cells on cellular, tissue and on level of the whole heart need to be considered. As in vitro cell-based models do not depict the complexity of the human heart, animal models are used to obtain insights that can be translated to human diseases. Mice are the most commonly used animals in cardiac research. However, differences in electrophysiological and mechanical cardiac function and a different composition of electrical and contractile proteins limit the transferability of the knowledge gained. Moreover, the small heart size and fast heart rate are major disadvantages. In contrast to rodents, electrophysiological, mechanical and structural cardiac characteristics of rabbits resemble the human heart more closely, making them particularly suitable as an animal model for cardiac disease research. In this review, various methodological approaches for the generation of transgenic rabbits for cardiac disease research, such as pronuclear microinjection, the sleeping beauty transposon system and novel genome-editing methods (ZFN and CRISPR/Cas9)will be discussed. In the second section, we will introduce the different currently available transgenic rabbit models for monogenic cardiac diseases (such as long QT syndrome, short-QT syndrome and hypertrophic cardiomyopathy) in detail, especially in regard to their utility to increase the understanding of pathophysiological disease mechanisms and novel treatment options. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.

Electrophysiologic Changes and Their Effects on Ventricular Arrhythmias in Patients with Continuous-Flow Left Ventricular Assist Devices.

Ventricular arrhythmias (VAs) continue even after left ventricular assist device (LVAD) implantation. The effect of LVAD on VAs is controversial. We investigated electrophysiologic changes after LVAD and its effects on VAs development. A total of 107 implantable cardioverter-defibrillator (ICD) patients, with LVAD, were included in this study. Electrocardiographic parameters including QRS duration (between the beginning of the QRS complex and the end of the S wave), QT duration (between the first deflection of the QRS complex and the end of the T wave) corrected QT (QTc), QTc dispersion, fragmented QRS (F-QRS), and ICD recordings before, and post-LVAD first year were analyzed. All sustained VAs were classified as polymorphic ventricular tachycardia (PVT) or monomorphic VT (MVT). The QRS, QT, QTc durations, and QTc dispersion had decreased significantly after LVAD implantation (p < 0.001 for all). Also MVT increased significantly from 28.9% to 49.5% (p = 0.019) whereas PVT decreased from 27.1% to 4.67% (p = 0.04) compared to pre-LVAD period. A strong correlation was found between QT shortening and the decrease in PVT occurrence. Besides, the increase in the F-QRS after LVAD was associated with post-LVAD de nova MVT development. Finally, F-QRS before LVAD was found as an independent predictor of post-LVAD late VAs in multivariate analysis. Pre-existing or newly developed F-QRS was associated with post-LVAD late VAs, and it may be used to determine the risk of VAs after LVAD implantation.

Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1.

Aims: The short QT syndrome type 1 (SQT1) is linked to hERG channel mutations (e.g., N588K). Drug effects on hERG channel gating kinetics in SQT1-cells have not been investigated. Methods: This study used hiPSC-CMs of a healthy donor and a SQT1-patient carrying the N588K mutation and patch clamp to examine the drug effects on hERG channel gating kinetics. Results: Ajmaline, amiodarone, ivabradine, flecainide, quinidine, mexiletine and ranolazine inhibited the hERG channel current (IKr) less strongly in hiPSC-CMs from the SQTS1-patient (SQT1-hiPSC-CMs) comparing with cells from the healthy donor (donor-hiPSC-CMs). Quinidine and mexiletine reduced, but ajmaline, amiodarone, ivabradine and ranolazine increased the time to peak of IKr similarly in SQT1-hiPSC-CMs and donor-hiPSC-CMs. Although regarding the shift of activation and inactivation curves, tested drugs showed differential effects in donor- and SQT1-hiPSC-CMs, quinidine, ajmaline, ivabradine and mexiletine but not amiodarone, flecainide and ranolazine reduced the window current in SQT1-hiPSC-CMs. Quinidine, ajmaline, ivabradine and mexiletine differentially changed the time constant of recovery from inactivation, but all of them increased the time constant of deactivation in SQT1-hiPSC-CMs. Conclusion: The window current-reducing and deactivation-slowing effects may be important for the antiarrhythmic effect of ajmaline, ivabradine, quinidine and mexiletine in SQT1-cells. This information may be helpful for selecting drugs for treating SQT1-patients with hERG channel mutation.

Patients With Primary Hyperparathyroidism Have Shorter QT/QTc Intervals

Background: Previous studies suggest that patients with primary hyperparathyroidism (PHPT) have subclinical cardiovascular disease, but data regarding cardiac conduction abnormalities are limited. The aim of this study was to assess cardiac conduction abnormalities in patients with PHPT compared to controls with thyroid disease (TD). Method: We conducted a retrospective analysis of patients over 40 years of age who underwent parathyroidectomy or thyroidectomy at a single tertiary institution between 2013 and 2018. Demographics and EKG parameters from pre-operative EKG reports were compared using the Mann-Whitney U and Chi Square tests. Regression was used to compare EKG differences between the PHPT and control groups adjusted for sex, age, and other variables found to be significant on univariate analysis. Results: A total of 1181 patients were analyzed, 51% in the PHPT group (n=602) and 49% in the TD group (n=579). The median age was 60.5 years (IQR 53.5–67.9) and there was no difference in sex between the cohorts. PHPT patients had a higher prevalence of hyperlipidemia (HLD, 49% vs 36%, p<0.001) and hypertension (HTN, 50.7% vs 42.1%, p<0.01), but had no differences in EKG rhythm patterns or prevalence of arrhythmia compared to TD patients. As expected, mean serum calcium levels were higher for the PHPT group, 10.74 (0.66) vs 9.53 (0.44). However, the PHPT group included both normocalcemic and hypercalcemic patients. The PHPT group had a lower median QT interval compared to the TD group, 386ms (IQR 368–406) vs 398ms (IQR 376–418), p<0.001 and a higher median PR value, 158ms (IQR 144–174.5) vs 156ms (IQR 143.5–171), p<0.05. More PHPT patients (n=21, 3.5%) had a short QTc interval (<360ms males/<370ms females), compared to TD controls (n=1, 0.2%). Among PHPT patients with a short QT interval, the proportion of patients with hypercalcemia (95%) was higher than that of the PHPT group overall (75%). On multivariable analysis, PHPT patients had a shorter QT interval than TD controls after controlling for sex, age, HLD, HTN. There was no difference between PHPT and TD when serum calcium was included in the model, suggesting that calcium mediates the relationship between QT interval and disease status. Conclusion: PHPT patients have shorter QT/QTc intervals compared to TD controls, but no increased prevalence of arrythmia at baseline. While the QT interval was associated with degree of serum calcium elevation, these findings in a large cohort suggest that PHPT is not associated with arrythmia at baseline among those undergoing parathyroidectomy.

Fast Track hERG phenotyping to evaluate the pathogenicity of KCNH2 genetic variants

Mutations in KCNH2 (coding for hERG) cause long or short QT syndromes (LQTS or SQTS), predisposing to life-threatening arrhythmias. More than 1000 variations in hERG sequences have been described, most of them are to be characterized. The objective is to standardize and accelerate the entire process necessary to phenotype hERG variants. An in silico evaluation was also included to characterize the structural impact of the variants. We selected 12 variants from patients with LQTS, and 1 with SQTS. We optimized the protocol to efficiently introduce mutations in hERG cDNA despite GC-rich sequences, using the Gibson assembly strategy. A pH-sensitive fluorescent tag was fused to hERG for fast-track evaluation of hERG cell trafficking. An optimized patch-clamp protocol of 35 sec was developed to evaluate hERG channel activity in transfected cells. R software was used to speed up analyses. In the present work, we observed a good correlation between cell surface expression, assessed by the pH-sensitive tag, and current densities. Also, we showed that the new biophysical protocol allows a significant gain of time in recording ion channel properties and provides extensive information on WT and variant channel biophycical parameters, that can all be recapitulated in a single parameter defined herein as the repolarization power. The impact of the variants on channel structure were also reported where structural information was available. These three readouts (trafficking, repolarization power and structural impact) define 3 pathogenicity indexes that may help clinical diagnosis. Fast track characterization of KCNH2 genetic variants shows its relevance to discriminate mutants that affect hERG channel activity from variants with undetectable effects. This information is meant to fill a patient database, as a basis for personalized medicine. The next steps will be to further accelerate the process using an automated patch-clamp system.

Computational prediction of drug response in short QT syndrome type 1 based on measurements of compound effect in stem cell-derived cardiomyocytes.

Short QT (SQT) syndrome is a genetic cardiac disorder characterized by an abbreviated QT interval of the patient’s electrocardiogram. The syndrome is associated with increased risk of arrhythmia and sudden cardiac death and can arise from a number of ion channel mutations. Cardiomyocytes derived from induced pluripotent stem cells generated from SQT patients (SQT hiPSC-CMs) provide promising platforms for testing pharmacological treatments directly in human cardiac cells exhibiting mutations specific for the syndrome. However, a difficulty is posed by the relative immaturity of hiPSC-CMs, with the possibility that drug effects observed in SQT hiPSC-CMs could be very different from the corresponding drug effect in vivo. In this paper, we apply a multistep computational procedure for translating measured drug effects from these cells to human QT response. This process first detects drug effects on individual ion channels based on measurements of SQT hiPSC-CMs and then uses these results to estimate the drug effects on ventricular action potentials and QT intervals of adult SQT patients. We find that the procedure is able to identify IC50 values in line with measured values for the four drugs quinidine, ivabradine, ajmaline and mexiletine. In addition, the predicted effect of quinidine on the adult QT interval is in good agreement with measured effects of quinidine for adult patients. Consequently, the computational procedure appears to be a useful tool for helping predicting adult drug responses from pure in vitro measurements of patient derived cell lines.

MicroRNA Biophysically Modulates Cardiac Action Potential by Direct Binding to Ion Channel.

MicroRNAs (miRs) play critical roles in regulation of numerous biological events, including cardiac electrophysiology and arrhythmia, through a canonical RNA interference mechanism. It remains unknown whether endogenous miRs modulate physiologic homeostasis of the heart through noncanonical mechanisms. We focused on the predominant miR of the heart (miR1) and investigated whether miR1 could physically bind with ion channels in cardiomyocytes by electrophoretic mobility shift assay, in situ proximity ligation assay, RNA pull down, and RNA immunoprecipitation assays. The functional modulations of cellular electrophysiology were evaluated by inside-out and whole-cell patch clamp. Mutagenesis of miR1 and the ion channel was used to understand the underlying mechanism. The effect on the heart ex vivo was demonstrated through investigating arrhythmia-associated human single nucleotide polymorphisms with miR1-deficient mice. We found that endogenous miR1 could physically bind with cardiac membrane proteins, including an inward-rectifier potassium channel Kir2.1. The miR1-Kir2.1 physical interaction was observed in mouse, guinea pig, canine, and human cardiomyocytes. miR1 quickly and significantly suppressed IK1 at sub-pmol/L concentration, which is close to endogenous miR expression level. Acute presence of miR1 depolarized resting membrane potential and prolonged final repolarization of the action potential in cardiomyocytes. We identified 3 miR1-binding residues on the C-terminus of Kir2.1. Mechanistically, miR1 binds to the pore-facing G-loop of Kir2.1 through the core sequence AAGAAG, which is outside its RNA interference seed region. This biophysical modulation is involved in the dysregulation of gain-of-function Kir2.1-M301K mutation in short QT or atrial fibrillation. We found that an arrhythmia-associated human single nucleotide polymorphism of miR1 (hSNP14A/G) specifically disrupts the biophysical modulation while retaining the RNA interference function. It is remarkable that miR1 but not hSNP14A/G relieved the hyperpolarized resting membrane potential in miR1-deficient cardiomyocytes, improved the conduction velocity, and eliminated the high inducibility of arrhythmia in miR1-deficient hearts ex vivo. Our study reveals a novel evolutionarily conserved biophysical action of endogenous miRs in modulating cardiac electrophysiology. Our discovery of miRs' biophysical modulation provides a more comprehensive understanding of ion channel dysregulation and may provide new insights into the pathogenesis of cardiac arrhythmias.

Cardiac channelopathies: diagnosis and contemporary management

### Learning objectives The inherited arrhythmia (IA) syndromes are a group of disorders characterised by an increased risk of sudden cardiac death (SCD), abnormal cardiac electrical function and typically, a...

Computational analysis of the effect of KCNH2 L532P mutation on ventricular electromechanical behaviors

The KCNH2 L532P mutation is an alteration in the IKr channel that is associated with short QT syndrome and atrial fibrillation in zebrafish. In preliminary studies, the electrophysiological effects of the hERG L532P mutation were investigated using a mathematical model in a single-cell and 2D sheet medium. The objective of this study was to quantify the effects of the KCNH2 L532P mutation on the 3D ventricular electrophysiological behavior and the mechanical pumping responses. We used a realistic three-dimensional ventricular electrophysiological–mechanical model, which was adjusted into two conditions: the wild-type (WT) condition, i.e., the original case of the Tusscher et al. model, and the L532P mutation condition, with modification of the original IKr equation. The action potential duration (APD) in the mutant ventricle was reduced by 73% owing to the significant increase of the IKr current density. In the 3D simulation, the L532P mutation maintained the sustainability of reentrant waves; however, the reentry was terminated in the WT condition. The contractility of the ventricle with L532P mutation was significantly reduced compared with that in WT which results in sustain shivering heart during reentry condition. The reduction of the contractility was associated with the shortening APD which simultaneously shortened the duration of the Ca2+ channel opening. In conclusion, the ventricle with KCNH2 L532P mutation is prone to reentry generation with a sustained chaotic condition, and the mutation significantly reduced the pumping performance of the ventricles.

Long-term prognosis of short QT interval in Korean patients: a multicenter retrospective cohort study

BackgroundShort QT syndrome is a rare, inherited channelopathy associated with sudden cardiac arrest (SCA) but the characteristics and prognosis of short QT interval (SQTI) in Korean patients remain unclear. This study aimed to determine the clinical characteristics and outcomes of SQTI in a Korean population.MethodsConsecutive patients with SQTI from January 1999 to March 2019 in three university hospitals in South Korea were recruited. SQTI was defined as a Bazett’s formula-corrected QT interval (QTc) ≤ 340 ms in serial electrocardiograms. Age- and sex-matched patients with a normal QTc and without overt cardiovascular disease were included in a 1:4 ratio. Clinical and ECG features and outcomes were compared between patients with and without SQTI.Results34 patients with SQTI [age, 23.5 (21–30.5) years; 31 male] were followed up for 4.8 (2.0–7.8) years. Early repolarization, tall T wave, and U wave were significantly more frequent in patients with SQTI than in those without SQTI. QT dispersion [44.0 (28.0–73.0) vs. 20.0 (12.0–35.0) ms, P < 0.001] was significantly wider and heart rate [52.0 (47.0–58.0) vs. 70.0 (62.3–84.0)/min, P < 0.001] was significantly slower in patients with SQTI than in those without. Atrial fibrillation (AF, 11.8% vs. 2.2%, P = 0.030) and ventricular arrhythmia (VA)/SCA (8.7% vs. 0%, P = 0.007) were significantly more frequent in patients with SQTI than in those without. SQTI was significantly associated with AF [odds ratio, 5.911; 95% confidence interval, 1.257–27.808; P = 0.025] and VA/SCA.ConclusionsIn this subset of Korean population, SQTI was associated with AF and VA/SCA.

In Silico Investigation of CACNA2D1 S755T Mutation Associated With Short QT Syndrome

Short QT syndrome (SQTS) is a genetic disease characterized by constantly short QT intervals and high risks of sudden death. SQTS6 is one of the identified SQTS genotype variants associated with the CACNA2D1 S755T mutation. However, the pathogenesis of SQTS induced arrhythmias remains unclear. To identify the underlying mechanisms of SQTS6 induced arrhythmias, a multi-scale human ventricle model comprising cell to organ levels was built. Cellular data was fitted at the cell level to reproduce the electrophysiological alterations reported in experiments. The influences were further explored at tissue and organ levels using idealized strand or tissue sheet models, and realistic ventricular slice and three-dimensional organ models. Simulation results suggested that, at the cellular level, the action potential duration (APD) and the effective refractory period (ERP) of myocytes were significantly abbreviated in the mutation condition. The unevenly changed APD and ERP led to transmural heterogeneity remodeling, and resulted in decreased temporal vulnerability. In addition, the S755T mutation shortened the critical length for initiating reentrant spiral waves, which enhanced the spatial vulnerability and provided substrates for reentry arrhythmias. Regarding the sustainability of arrhythmias, the evoked spiral waves or scroll waves persisted in the mutation condition but did not persist in the wild-type condition. The present study clearly suggested that the CACNA1DC S755T mutation can facilitate the initiation and maintenance of ventricular arrhythmias, and therefore contributes to higher risks of ventricular arrhythmias in SQTS6 patients.

Physiological Functions, Biophysical Properties, and Regulation of KCNQ1 (KV7.1) Potassium Channels.

KCNQ1 (KV7.1) K+ channels are expressed in multiple tissues, including the heart, pancreas, colon, and inner ear. The gene encoding the KCNQ1 protein was discovered by a positional cloning effort to determine the genetic basis of long QT syndrome, an inherited ventricular arrhythmia that can cause sudden death. Mutations in KCNQ1 can also cause other types of arrhythmia (i.e., short QT syndrome, atrial fibrillation) and the gene may also have a role in diabetes and certain cancers. KCNQ1 α-subunits can partner with accessory β-subunits (KCNE1-KCNE5) to form K+-selective channels that have divergent biophysical properties. In the heart, KCNQ1 α-subunits coassemble with KCNE1 β-subunits to form channels that conduct IKs, a very slowly activating delayed rectifier K+ current. KV7.1 channels are highly regulated by PIP2, calmodulin, and phosphorylation, and rich pharmacology includes blockers and gating modulators. Recent biophysical studies and a cryo-EM structure of the KCNQ1-calmodulin complex have provided new insights into KV7.1 channel function, and how interactions between KCNQ1 and KCNE subunits alter the gating properties of heteromultimeric channels.

The Postmortem Interpretation of Cardiac Genetic Variants of Unknown Significance in Sudden Death in the Young: A Case Report and Review of the Literature.

Sudden cardiac death (SCD) in adolescents and young adults is a major traumatic event for families and communities. In these cases, it is not uncommon to have a negative autopsy with structurally and histologically normal heart. Such SCD cases are generally attributed to channelopathies, which include long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. Our understanding of the causes for SCDs has changed significantly with the advancements in molecular and genetic studies, where many mutations are now known to be associated with certain channelopathies. Postmortem analysis provides great value in informing decision-making with regard to screening tests and prophylactic measures that should be taken to prevent sudden death in first degree relatives of the decedent. As this is a rapidly advancing field, our ability to identify genetic mutations has surpassed our ability to interpret them. This led to a unique challenge in genetic testing called variants of unknown significance (VUS). VUSs present a diagnostic dilemma and uncertainty for clinicians and patients with regard to next steps. Caution should be exercised when interpreting VUSs since misinterpretation can result in mismanagement of patients and their families. A case of a young adult man with drowning as his proximate cause of death is presented in circumstances where cardiac genetic testing was indicated and undertaken. Eight VUSs in genes implicated in inheritable cardiac dysfunction were identified and the interpretation of VUSs in this scenario is discussed.

Antiepileptic rufinamide and QTc interval shortening in a patient with long QT syndrome: case report.

BackgroundThere is limited pharmacologic therapy to reduce the QT interval in hereditary long QT syndrome (LQTS).Case summaryWe describe a child with Allan–Herndon–Dudley syndrome, Lennox–Gastaut epileptic syndrome (LGS), and LQTS Type 1 (LQTS1). Rufinamide was added to his antiepileptic medications to improve seizure control and was noted to be associated with a marked improvement in electrocardiogram QT interval. To the best of our knowledge, this is the first reported case of successful pharmacologic shortening of the QT interval in LQTS1.DiscussionThis case report highlights the potential benefits of rufinamide, a drug associated with mild QT shortening in normal individuals, to markedly reduce and normalize QT duration in a subject with LQTS1.

Human-induced pluripotent stem cells as models for rare cardiovascular diseases: from evidence-based medicine to precision medicine.

Rare cardiovascular diseases (RCDs) refer to those cardiovascular diseases that display a low prevalence as well as morbidity. Due to the vast variety of underlying genetic mutations and the relatively low patient population, RCDs present additional challenges for diagnosis. Precision medicine may offer opportunities for designing patient-specific therapies in particular for carriers of variants with undetermined significance. Moreover, precision medicine strategies provide benefit to patients with "common" symptoms but carry in rare genetic variants. Induced pluripotent stem cells (iPSCs) present a state-of-the-art precision medicine approach which recently made contributions to the study of RCDs via patient-specific iPSC-derived cardiomyocytes (iPSC-CMs). Human iPSC-CMs are derived from a patient's somatic cells and thus recapitulate a personalized genomics background, serving as patient-specific disease models. In light of these advantages, iPSC-CMs evolved as an effective tool for modeling cardiac disease phenotypes and accurately evaluating the toxicity of potential therapeutic compounds. This review covers approaches for studying RCDs and iPSC-CM models generated so far for different RCDs, such as long QT syndrome (LQT), short QT syndrome (SQT), Brugada syndrome (BrS), arrhythmogenic right ventricular cardiomyopathy (ARVC), and other rare diseases accomplished by cardiac-related syndromes like Fabry disease (FD) and Marfan syndrome (MFS). This overview aims to aid better understanding of the utility of iPSC-CM models, their various features, and future prospects.