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Background: An electrocardiogram (ECG)-based artificial intelligence (AI) algorithm has shown good performance in detecting hypertrophic cardiomyopathy (HCM). However, its application in routine clinical practice may be challenging owing to the low disease prevalence and potentially high false-positive rates., Objective: Identify clinical characteristics associated with true- and false-positive HCM AI-ECG results to improve its clinical application., Methods: We reviewed the records of the 200 patients with highest HCM AI-ECG scores in January 2021 at our institution. Logistic regression was used to create a clinical variable-based "Candidacy for HCM Detection (HCM-DETECT)" score, differentiating true-positive from false-positive AI-ECG results. We validated the HCM-DETECT score in an independent cohort of 200 patients with the highest AI-ECG scores from January 2022., Results: In the 2021 cohort (median age 71 [interquartile range 58-80] years, 48% female), the rates of true-positive, false-positive, and indeterminate AI-ECG results for HCM detection were 36%, 48%, and 16%, respectively. In the 2022 cohort, the rates were 26%, 47%, and 27%, respectively. The HCM-DETECT score included age, coronary artery disease, prior pacemaker, and prior cardiac valve surgery, and had an area under the receiver operating characteristic curve of 0.81 (95% confidence interval 0.73-0.87) for differentiating true- vs false-positive AI results. When the 2022 cohort was limited to HCM detection candidates identified with the HCM-DETECT score, the false-positive AI-ECG rate was reduced from 47% to 13.5%., Conclusion: Application of a clinical score (HCM-DETECT) in tandem with an AI-ECG model improved HCM detection yield, reducing the false-positive rate of AI-ECG more than 3-fold., (© 2022 Published by Elsevier Inc. on behalf of Heart Rhythm Society.)

Background: Cardiac magnetic resonance (CMR) imaging is important for diagnosis and risk stratification of hypertrophic cardiomyopathy (HCM) patients. However, collection of information from large numbers of CMR reports by manual review is time-consuming, error-prone and costly. Natural language processing (NLP) is an artificial intelligence method for automated extraction of information from narrative text including text in CMR reports in electronic health records (EHR). Our objective was to assess whether NLP can accurately extract diagnosis of HCM from CMR reports., Methods: An NLP system with two tiers was developed for information extraction from narrative text in CMR reports; the first tier extracted information regarding HCM diagnosis while the second extracted categorical and numeric concepts for HCM classification. We randomly allocated 200 HCM patients with CMR reports from 2004 to 2018 into training (100 patients with 185 CMR reports) and testing sets (100 patients with 206 reports)., Results: NLP algorithms demonstrated very high performance compared to manual annotation. The algorithm to extract HCM diagnosis had accuracy of 0.99. The accuracy for categorical concepts included HCM morphologic subtype 0.99, systolic anterior motion of the mitral valve 0.96, mitral regurgitation 0.93, left ventricular (LV) obstruction 0.94, location of obstruction 0.92, apical pouch 0.98, LV delayed enhancement 0.93, left atrial enlargement 0.99 and right atrial enlargement 0.98. Accuracy for numeric concepts included maximal LV wall thickness 0.96, LV mass 0.99, LV mass index 0.98, LV ejection fraction 0.98 and right ventricular ejection fraction 0.99., Conclusions: NLP identified and classified HCM from CMR narrative text reports with very high performance., (© 2022. The Author(s).)

Background: The transient outward current (Ito) that mediates early (phase 1) repolarization is conducted by the KCND3 -encoded Kv4.3 pore-forming α-subunit. KCND3 gain-of-function mutations have been reported previously as a pathogenic substrate for J wave syndromes (JWS), including the Brugada syndrome and early repolarization syndrome, as well as autopsy-negative sudden unexplained death (SUD). Acacetin, a natural flavone, is a potent Ito current blocker. Acacetin may be a novel therapeutic for KCND3 -mediated J wave syndrome., Methods: KCND3-V392I was identified in an 18-year-old male with J wave syndrome/early repolarization syndrome, and a history of cardiac arrest including ventricular tachycardia/ventricular fibrillation and atrial fibrillation/atrial flutter. Pathogenic KCND3 mutation was engineered by site-directed mutagenesis and co-expressed with wild-type KChIP2 in TSA201 cells. Gene-edited/variant-corrected isogenic control and patient-specific pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from the p. Val392Ile-KCND3-positive patient were generated. I to currents and action potentials were recorded before and after treatment with Acacetin using the whole cell patch-clamp and multielectrode array technique. Western blot and immunocytochemistry were performed to investigate KCND3 expression., Results: KCND3-V392I demonstrated a marked gain-of-function phenotype, increasing peak I to current density by 92.2% ( P <0.05 versus KCND3-WT). KCND3 expression was significantly increased in KCND3-V392I-derived iPSC-CMs ( P <0.05 versus isogenic control). While KCND3-WT revealed an IC50 of 7.2±1.0 µmol/L for acacetin effect, 30 µmol/L acacetin dramatically inhibited KCND3-V392I peak Ito current density by 96.2% ( P <0.05 versus before Acacetin). Ito was also increased by 60.9% in Kv4.3-V392I iPSC-CM ( P <0.05 versus isogenic control iPSC-CM). Ten micromoles per liter acacetin, a concentration approaching its IC50 value, inhibited Ito by ≈50% in patient-derived iPSC-CMs and reduced the accentuated action potential notch displayed in KCND3-V392I-derived iPSC-CMs., Conclusions: This preclinical study provides pharmacological and functional evidence to suggest that Acacetin may be a novel therapeutic for patients with KCND3 gain-of-function-associated J wave syndrome by inhibiting I to and abolishing the accentuated action potential notch in patient-derived iPSC-CMs.

Background: β-Blockers (BBs), sodium channel blockers (SCBs), left cardiac sympathetic denervation (LCSD), and implantable cardioverter-defibrillators (ICDs) are used to prevent or counter long QT syndrome (LQTS)-triggered syncope, seizures, and sudden cardiac death. The spectrum and extent of side effects/complications associated with these guideline-directed therapies (GDTs) remain unknown., Objective: The purpose of this study was to identify the types/prevalence of treatment-associated side effects/complications for patients with the most common LQTS subtypes after GDT., Methods: Retrospective analysis was performed on 1310 patients with type 1, 2, or 3 LQTS evaluated in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic (average age at the time of diagnosis 22 ± 18 years; average length of follow-up 5 ± 5 years) and treated with ≥1 of the common GDTs for LQTS., Results: BBs were used in 1102 (84%), SCBs in 104 (8%), LCSD in 197 (15%), and an ICD was used in 251 (19%) patients. Overall, 727 (55%) patients reported at least 1 treatment-associated side effect/complication. A total of 490 of 1102 patients treated with BBs (44%) reported side effects, with fatigue (381 [35%]) being the most common; 28 of 104 SCB-treated patients (27%) reported side effects, most common being gastrointestinal distress/vomiting (18 [17%]); 80 of 197 patients (41%) reported side effects after LCSD, most reporting neuropathic pain (57 [29%]); and 129 of 251 patients (51%) experienced ≥1 complication after ICD implantation, including inappropriate shocks (46 [18%])., Conclusion: Although LQTS-triggered sudden cardiac death is uncommon in the properly treated patient, this study demonstrates that contemporary GDTs for LQTS are not innocuous. Their treatment-related side effects are not trivial and should compel an ongoing quest for new LQTS therapies., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a cardiac channelopathy causing ventricular tachycardia following adrenergic stimulation. Pathogenic variants in RYR2-encoded ryanodine receptor 2 (RYR2) cause CPVT1 and cluster into domains I-IV, with the most N-terminal domain involving residues 77-466. Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated for RYR2-F13L, -L14P, -R15P, and -R176Q variants. Isogenic control iPSCs were generated using CRISPR-Cas9/PiggyBac. Fluo-4 Ca 2+ imaging assessed Ca 2+ handling with/without isoproterenol (ISO), nadolol (Nad), and flecainide (Flec) treatment. CPVT1 iPSC-CMs displayed increased Ca 2+ sparking and Ca 2+ transient amplitude following ISO compared with control. Combined Nad treatment/ISO stimulation reduced Ca 2+ amplitude and sparking in variant iPSC-CMs. Molecular dynamic simulations visualized the structural role of these variants. We provide the first functional evidence that these most proximal N-terminal localizing variants alter calcium handling similar to CPVT1. These variants are located at the N-terminal domain and the central domain interface and could destabilize the RYR2 channel promoting Ca 2+ leak-triggered arrhythmias., Competing Interests: Conflict of interests M.J.A. is a consultant for Abbott, ARMGO Pharma, Boston Scientific, Daiichi Sankyo, Invitae, LQT Therapeutics, and Medtronic. M.J.A. and/or Mayo Clinic are involved in an equity/royalty relationship with AliveCor, Anumana, Pfizer, and UpToDate. However, none of these entities were involved in this study in any manner. A.R.M. and Columbia University own shares in ARMGO Pharma, a biotech company developing RyR-targeted therapeutics., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of interest: none declared.

Background: Mitral annular disjunction (MAD) has recently been recognized as an arrhythmogenic entity. Data on the electrophysiological substrate as well as the outcomes of catheter ablation of ventricular arrhythmias in patients with MAD is limited., Methods: Forty patients with MAD (mean age 47±15 years; 70% female) underwent catheter ablation for ventricular arrhythmias. Detailed clinical, electrocardiographic, cardiac imaging, and procedural data were collected. Clinical outcomes were compared between patients who had substrate modification in the MAD area and those who did not., Results: Twenty-three (57.5%) patients had ablation for premature ventricular contractions, 10 (25%) patients for sustained ventricular tachycardia, and 7 (17.5%) patients for premature ventricular contraction-triggered ventricular fibrillation. Mean end-systolic MAD length was 10.58±3.49 mm on transthoracic echocardiography. Seventeen (42.5%) patients had preprocedural cardiac magnetic resonance imaging, and 5 (29%) patients had late gadolinium enhancement. Among the 18 (45%) patients who had abnormal local electrograms (low voltage, long-duration, fractionated, isolated mid-diastolic potentials) during electroanatomical mapping, 10 (25%) patients had abnormal electrograms in the anterolateral mitral annulus and/or MAD area. Substrate modification was performed in 10 (25%) patients. Catheter ablation was acutely successful in 36 (90%) patients (elimination of premature ventricular contraction or noninducibility of ventricular tachycardia). After a median follow-up duration of 54.08 (interquartile range, 10.67-89.79) months, premature ventricular contraction burden decreased from a median of 9.75% (interquartile range, 3.25-14) before the ablation to a median of 4% (interquartile range, 1-7.75) after the ablation ( P =0.03 [95% CI, 0.055-6.5]). Eight (20.5%) patients had repeat ablation for ventricular arrhythmias. Substrate modification of the MAD was associated with a trend toward lower rates of repeat ablation (0% versus 26.7%; P =0.16)., Conclusions: Patients with MAD have a complex arrhythmogenic substrate, and catheter ablation is effective in reducing recurrence of ventricular arrhythmias. Substrate mapping and ablation may be considered in these patients.

Background: Women with congenital long QT syndrome (LQTS) experience increased cardiac event risk after the onset of adolescence, perhaps stemming from the known modulating effects of sex hormones on the cardiac potassium channels., Objective: We hypothesized that the effect of sex hormones on cardiac ion channel function may modify electrocardiographic (ECG) parameters associated with the propensity for ventricular tachyarrhythmias during the menstrual cycle in women with LQTS., Methods: We prospectively enrolled 65 women with congenital LQTS (type 1 LQTS [LQT1], n = 24 [36.9%]; type 2 LQTS [LQT2], n = 20 [30.8%]) and unaffected female relatives (n = 21 [32.3%]). Patients underwent three 7-day ECG recordings during their menstrual cycles. Simultaneous saliva testing of sex hormone levels was conducted on the first day of each 7-day ECG recording cycle., Results: The mean age was 35 ± 8 years, without a significant difference among the groups. In women with LQT2, linear mixed effects models showed significant inverse correlations of the corrected QT interval with progesterone levels (P < .001) and with the progesterone to estradiol ratio (P < .001). Inverse relationships of the R-R interval with estradiol levels (P = .003) and of the T-wave duration with testosterone levels (P = .014) were also observed in women with LQT2. In contrast, no significant associations were observed between ECG parameters and sex hormone levels in women with LQT1 or unaffected relatives., Conclusion: This is the first study to prospectively assess correlations between repolarization dynamics and sex hormone levels during the menstrual cycle in women with congenital LQTS. Our findings show genotype-specific unique corrected QT dynamics during the menstrual cycle that may affect the propensity for ventricular tachyarrhythmia in women with LQTS, particularly women with LQT2., (Copyright © 2022. Published by Elsevier Inc.)

An abundance of literature describes physiological and pathological determinants of cardiac performance, building on the principles of excitation-contraction coupling. However, the mutual influencing of excitation-contraction and mechano-electrical feedback in the beating heart, here designated 'electromechanical reciprocity', remains poorly recognized clinically, despite the awareness that external and cardiac-internal mechanical stimuli can trigger electrical responses and arrhythmia. This review focuses on electromechanical reciprocity in the long-QT syndrome (LQTS), historically considered a purely electrical disease, but now appreciated as paradigmatic for the understanding of mechano-electrical contributions to arrhythmogenesis in this and other cardiac conditions. Electromechanical dispersion in LQTS is characterized by heterogeneously prolonged ventricular repolarization, besides altered contraction duration and relaxation. Mechanical alterations may deviate from what would be expected from global and regional repolarization abnormalities. Pathological repolarization prolongation outlasts mechanical systole in patients with LQTS, yielding a negative electromechanical window (EMW), which is most pronounced in symptomatic patients. The electromechanical window is a superior and independent arrhythmia-risk predictor compared with the heart rate-corrected QT. A negative EMW implies that the ventricle is deformed-by volume loading during the rapid filling phase-when repolarization is still ongoing. This creates a 'sensitized' electromechanical substrate, in which inadvertent electrical or mechanical stimuli such as local after-depolarizations, after-contractions, or dyssynchrony can trigger abnormal impulses. Increased sympathetic-nerve activity and pause-dependent potentiation further exaggerate electromechanical heterogeneities, promoting arrhythmogenesis. Unraveling electromechanical reciprocity advances the understanding of arrhythmia formation in various conditions. Real-time image integration of cardiac electrophysiology and mechanics offers new opportunities to address challenges in arrhythmia management., Competing Interests: Conflicts of interest: K.E.O, H.J.v.d.L, P.G.A.V., and R.M.A.t.B declare no conflict of interest. M.J.A. declares royalties from AliveCor, Anumana, Pfizer; consulting fees from Abbott, ARMGO Pharma, Boston Scientific, Bristol Myers Squipp, Daiichi Sankyo, Invitae, Medtronic, UpToDate; and a leadership role (President of Board) at the Sudden Arrhythmia Death Syndromes (SADS) Foundation., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Proper management of patients affected by genetic disorders causing life-threatening arrhythmias is important for several reasons, including even societal ones, given the predominantly young age of those affected. Incorrect management often has dire consequences, ranging from unnecessary psychologic damage for the patients whose life becomes too limited by the fear of sudden death to equally avoidable tragedies when the entire armamentarium of effective therapies is not fully utilized. In this review, we focus primarily on long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) and deal specifically with the clinical impact of the most commonly used cardiac sympathetic denervation (CSD), namely left cardiac sympathetic denervation (LCSD). The two of us have used LCSD in the management of our patients with either LQTS or CPVT for a very long time and have been involved in ∼500 such interventions. It is on the basis of this personal and direct experience that we wish to share our views with clinical cardiologists and electrophysiologists, adult and paediatric, and with genetic cardiologists. We will begin by reviewing the history and rationale underlying sympathetic denervation therapy and will continue with a disease-specific intensification of therapy, and then with a discussion on how the impressive efficacy of LCSD should translate into guideline-directed therapy in both current and future guidelines, in order to upgrade the quality of care in the era of precision medicine., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To assess whether right ventricular enlargement (RVE) and right ventricular dysfunction (RVD) adversely affect prognosis in hypertrophic cardiomyopathy (HCM)., Patients and Methods: Data were retrieved from Mayo Clinic's prospectively collected HCM registry between January 1, 2000, and September 30, 2012. Right ventricle (RV) size and function were semiquantitatively categorized via echocardiography as normal (RV-Norm) versus abnormal (RV-Abn) (RVE or RVD). All-cause mortality was the primary endpoint., Results: Of 1878 HCM patients studied (mean age 53±15 years; 41.6% female), only 71 (3.8%) had RV-Abn (24 RVE, 28 RVD, 19 combined RVE and RVD). Compared with HCM patients with RV-Norm, RV-Abn patients were older (57±14 vs 53±15 years, P=.02), more symptomatic (New York Heart Association functional class III-IV in 62.0% vs 48.6%, P=.03), had more atrial fibrillation (53.5% vs 17.3%, P<.001), and more prior implantable cardioverter-defibrillator implantation (23.9% vs 11.3%, P=.02). Median follow-up was 9.4 years with 311 deaths. Patients who were RV-Abn had higher all-cause mortality compared with RV-Norm (log-rank P<.001); 24.1% (95% CI, 15.5% to 35.3%) vs 6.1% (95% CI, 5.1% to 7.3%) at 5 years. In multivariable Cox modeling, RV-Abn (hazard ratio, 1.89; 95% CI, 1.18 to 3.03; P=.008) was associated independently with all-cause mortality after adjusting for age, female sex, New York Heart Association functional class, atrial fibrillation, hypertension, coronary artery disease, implantable cardioverter-defibrillator implantation, beta blocker use, prior septal reduction therapy, resting LV outflow tract gradient, maximal LV wall thickness, and moderate or greater tricuspid regurgitation., Conclusion: Although perturbations in RV size and function were observed in fewer than 5% of patients with HCM, they were associated with nearly two-fold higher all-cause mortality at long-term follow-up., (Copyright © 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Long QT syndrome (LQTS) is an autosomal dominant disorder characterized by a prolonged QT interval. Electrocardiographic (ECG) screening in the first 48 hours of life may be misleading, even in newborns with a genotype-positive LQTS parent., Objective: The purpose of this study was to determine the ECG's diagnostic accuracy in the first 48 hours of life for neonates born to a parent with LQTS., Methods: We conducted a retrospective review of all neonates born at Mayo Clinic to a parent with ≥1 pathogenic variant in a LQTS-causative gene who had least 1 ECG in the first 48 hours and genetic test results were available. The sensitivity and specificity of the diagnostic ECG were calculated using Bazett's heart rate-corrected QT (QTc) thresholds of 440, 450, 460, and 470 ms., Results: Overall, 74 newborns (36 females [49%]) were included (mean QTc interval on the first ECG 489 ± 54 ms; 50 [68%] LQTS genotype-positive). The mean QTc interval in the first 48 hours for neonates that ultimately were genotype-positive was greater (506 ± 52 ms) than that for genotype-negative neonates (455 ± 41 ms) (P = .0004). When using a recommended threshold QTc interval of ≥440 ms, 6 of 50 genotype-positive neonates (12%) were missed (underdiagnosed) and 17 of 24 genotype-negative neonates (71%) were overdiagnosed (sensitivity 88%; specificity 29%)., Conclusion: The newborn ECG should not be used in isolation to make the diagnosis of LQTS since it will result in many misclassifications. Genetic testing must be initiated before discharge, and proper anticipatory guidance is vital while awaiting test results., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Most of the long QT syndrome (LQTS) stems from pathogenic variants in KCNQ1, KCNH2, or SCN5A. However, ∼10%-20% of LQTS index cases remain genotype-negative., Objective: The purpose of this study was to identify and characterize functionally a novel LQTS genetic substrate in a multigenerational, "genotype-negative" LQTS pedigree., Methods: The patient was a 40-year-old woman with a history of syncope, seizures, ventricular fibrillation, and a family history of LQTS and sudden death. Commercial genetic testing of all LQTS-causative genes was negative. Genome sequencing was performed on 6 affected family members. Patient-specific and CRISPR/Cas9 "gene-corrected" isogenic control induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated., Results: No ultrarare, nonsynonymous heterozygous variants cosegregated among the 6 LQTS phenotype-positive individuals. Instead, a deep intronic KCNH2 variant (c.3331-316G>T) was present in all affected individuals. Reverse transcription polymerase chain reaction analysis of patient-specific iPSC-CM-derived RNA revealed that c.3331-316G>T creates a novel 89 base-pair exon that results in a frameshift variant (p.S1112Pfs∗171). Action potential duration (APD 90 ) was significantly longer in p.S1112Pfs∗171-iPSC-CMs (602.4 ± 12.2 ms; n =70) compared to isogenic control iPSC-CMs (425.7 ± 9.3 ms; n = 61; P <.0001). Further, field potential duration was significantly longer in p.S1112Pfs∗171-iPSC-CMs (358.9 ± 7.7 ms; n = 65) compared to isogenic control iPSC-CMs (282.2 ± 10.8 ms; n = 51; P <.0001)., Conclusion: A novel deep intronic KCNH2 variant was identified in a multigenerational, genetically elusive LQTS pedigree. The iPSC-CMs establish that the variant is the monogenetic cause for this family's LQTS. Deep intronic variants within the 2 most common LQTS-susceptibility genes should be considered in patients with seemingly genetically elusive LQTS., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The analysis and interpretation of cardiac magnetic resonance (CMR) images are often time-consuming. The automated segmentation of cardiac structures can reduce the time required for image analysis. Spatial similarities between different CMR image types were leveraged to jointly segment multiple sequences using a segmentation model termed a multi-image type UNet (MI-UNet). This model was developed from 72 exams (46% female, mean age 63 ± 11 years) performed on patients with hypertrophic cardiomyopathy. The MI-UNet for steady-state free precession (SSFP) images achieved a superior Dice similarity coefficient (DSC) of 0.92 ± 0.06 compared to 0.87 ± 0.08 for a single-image type UNet (p < 0.001). The MI-UNet for late gadolinium enhancement (LGE) images also had a superior DSC of 0.86 ± 0.11 compared to 0.78 ± 0.11 for a single-image type UNet (p = 0.001). The difference across image types was most evident for the left ventricular myocardium in SSFP images and for both the left ventricular cavity and the left ventricular myocardium in LGE images. For the right ventricle, there were no differences in DCS when comparing the MI-UNet with single-image type UNets. The joint segmentation of multiple image types increases segmentation accuracy for CMR images of the left ventricle compared to single-image models. In clinical practice, the MI-UNet model may expedite the analysis and interpretation of CMR images of multiple types.

This paper gives a flavor of Dr. Donald A.B. Lindberg's view of the expanding role of libraries, his curiosity, and his tolerance for taking educated risks, through the creation and nurturing of National Library of Medicine's Visible Human Project. That project produced the Visible Man and Visible Woman datasets and a suite of tools for presenting and analyzing those and similar datasets. The results are used in teaching anatomy and other medical school courses and in software from the open-source Insight Tool Kit (ITK) that is included in many if not most volume-reconstructing systems. This story is a bit personal. From the beginning we recognized and understood each other since we were both "boys from Brooklyn"., (© 2022 – The authors. Published by IOS Press.)

From 1992 to 1995 Donald A.B. Lindberg M.D. served concurrently as the founding director of the National Coordination Office (NCO) for High Performance Computing and Communications (HPCC) and NLM director. The NCO and its successors coordinate the Presidential-level multi-agency HPCC research and development (R&D) program called for in the High-Performance Computing Act of 1991. All large Federal science and technology R&D and applications agencies, including those involved in medical research and health care, participate in the now-30-year-old program. Lindberg's HPCC efforts built on his pioneering work in developing and applying advances in computing and networking to meet the needs of the medical research and health care communities. As part of NLM's participation in HPCC, Lindberg promoted R&D and demonstrations in telemedicine, including testbeds, medical data privacy, medical decision-making, and health education. That telemedicine technologies were ready to meet demand during the COVID-19 pandemic is testament to Lindberg's visionary leadership., (© 2022 – The authors. Published by IOS Press.)

Background: During the early stages of the coronavirus disease 2019 (COVID-19) pandemic, a marked increase in sudden cardiac death (SCD) was observed. The p.S1103Y-SCN5A common variant, which is present in ∼8% of individuals of African descent, may be a circumstance-dependent, SCD-predisposing, proarrhythmic polymorphism in the setting of hypoxia-induced acidosis or QT-prolonging drug use., Objective: The purpose of this study was to ascertain the effects of acidosis and hydroxychloroquine (HCQ) on the action potential duration (APD) in a patient-specific induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model of p.S1103Y-SCN5A., Methods: iPSC-CMs were generated from a 14-year-old p.S1103Y-SCN5A-positive African American male. The patient's variant-corrected iPSC-CMs (isogenic control [IC]) were generated using CRISPR/Cas9 technology. FluoVolt voltage-sensitive dye was used to assess APD 90 values in p.S1103Y-SCN5A iPSC-CMs compared to IC before and after an acidotic state (pH 6.9) or 24 hours of treatment with 10 μM HCQ., Results: Under baseline conditions (pH 7.4), there was no difference in APD 90 values of p.S1103Y-SCN5A vs IC iPSC-CMs (P = NS). In the setting of acidosis (pH 6.9), there was a significant increase in fold-change of APD 90 in p.S1103Y-SCN5A iPSC-CMs compared to IC iPSC-CMs (P <.0001). Similarly, with 24-hour 10 μM HCQ treatment, the fold-change of APD 90 was significantly higher in p.S1103Y-SCN5A iPSC-CMs compared to IC iPSC-CMs (P <.0001)., Conclusion: Although the African-specific p.S1103Y-SCN5A common variant had no effect on APD 90 under baseline conditions, the physiological stress of either acidosis or HCQ treatment significantly prolonged APD 90 in patient-specific, re-engineered heart cells., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Congenital long QT syndrome (LQTS) encompasses a group of heritable conditions that are associated with cardiac repolarization dysfunction. Since its initial description in 1957, our understanding of LQTS has increased dramatically. The prevalence of LQTS is estimated to be ∼1:2,000, with a slight female predominance. The diagnosis of LQTS is based on clinical, electrocardiogram, and genetic factors. Risk stratification of patients with LQTS aims to identify those who are at increased risk of cardiac arrest or sudden cardiac death. Factors including age, sex, QTc interval, and genetic background all contribute to current risk stratification paradigms. The management of LQTS involves conservative measures such as the avoidance of QT-prolonging drugs, pharmacologic measures with nonselective β-blockers, and interventional approaches such as device therapy or left cardiac sympathetic denervation. In general, most forms of exercise are considered safe in adequately treated patients, and implantable cardioverter-defibrillator therapy is reserved for those at the highest risk. This review summarizes our current understanding of LQTS and provides clinicians with a practical approach to diagnosis and management., Competing Interests: Funding Support and Author Disclosures The study was supported by the Heart in Rhythm Organization (Dr Krahn, Principal Investigator), which receives support from the Canadian Institute of Health Research (RN380020-406814). Dr Krahn has received support from the Sauder Family and Heart and Stroke Foundation Chair in Cardiology (Vancouver, BC), the Paul Brunes Chair in Heart Rhythm Disorders (Vancouver, BC), and the Paul Albrechtson Foundation (Winnipeg, MB). Dr Laksman has received support from The University of British Columbia, Department of Medicine and the School of Biomedical Engineering, The University of British Columbia Cardiology Academic Practice Plan. Dr Ackerman receives support from The Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. Dr Wilde has received support from the Netherlands CardioVascular Research Initiative”: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences (PREDICT2). Dr Han is supported by a Robert and Elizabeth Albert Travel Grant from the RACP Foundation, Australia. Dr Laksman is a consultant for Abbott, Medtronic, and Boston Scientific. Dr Ackerman is a consultant for Abbott, ARMGO Pharma, Boston Scientific, Daiichi-Sankyo, Invitae, LQT Therapeutics, Medtronic, and UpToDate; and holds equity in Alivecor and Anumana. Dr Wilde is a member of the scientific advisory board for LQT therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Study Objective: The primary objective of this retrospective safety study was to determine the incidence of torsades de pointes (TdP) or death following perioperative administration of low-dose, 4 mg, ondansetron for postoperative nausea and vomiting., Design and Setting: This is a single-center retrospective clinical trial., Patients: The authors identified 32,737 patients who received 37,589 doses of ondansetron during a 2-year time frame between March 2009 and February 2011 for surgical nausea prophylaxis or treatment of nausea., Measurements and Main Results: Patients were cross-matched with an electrocardiogram and adverse outcome database; this identified 4759 patients with documentation of a QTc >450 milliseconds (ms), all ventricular tachycardias including TdP within 48 hours of receiving ondansetron, or death within 7 days of receiving ondansetron. No patients developed TdP or died as a direct result of ondansetron administration (n = 0; event rate = 0.0 per 10,000, 95% CI 0.0 to 1.1 per 10,000). Forty-six of 32,737 surgical patients had documented monomorphic ventricular tachycardia (VT) (n = 14; event rate = 4.3 per 10,000, 95% CI 2.3 to 7.2 per 10,000) or died (n = 32; event rate = 9.8 per 10,000, 95% CI 6.7 to 13.8 per 10,000) within 48 h of ondansetron administration. All monomorphic VT episodes were precipitated by existing cardiovascular disease; and 7 of 14 patients had documented monomorphic VT prior to receiving ondansetron. Of the 32 surgical patients who died, all deaths were precipitated by pre-existing disease., Conclusion: No episodes of TdP were identified in patients receiving ondansetron perioperatively. This suggests that low-dose ondansetron does not contribute to the development of TdP., (© 2022 Pharmacotherapy Publications, Inc.)

Background: Refractory epilepsy confers a considerable lifetime risk of sudden unexplained death in epilepsy (SUDEP). Mechanisms may overlap with sudden cardiac death (SCD), particularly regarding QTc prolongation. Guidelines in the United States do not mandate the use of electrocardiography (ECG) in diagnostic evaluation of seizures or epilepsy., Objective: The purpose of this study was to determine the frequency of ECG use and of QT prolongation, and whether QT prolongation predicts mortality in patients with seizures., Methods: We performed a retrospective cohort study including all patients seen at Mayo Clinic in Rochester, Minnesota, from January 1, 2000, to July 31, 2015, with index evaluation for seizure or epilepsy. Patients with an ECG were categorized by the presence of a prolonged QT interval with a primary endpoint of all-cause mortality after the 15-year observation period., Results: Optimal cutoff QT intervals most predictive of mortality were identified. Median age was 40.0 years. An ECG was obtained in 18,222 patients (57.4%). After patients with confounding ECG findings were excluded, primary prolonged QT intervals were seen in 223 cases (1.4%), similar to the general population. Kaplan-Meier analysis demonstrated a significant increase in mortality (Cox hazard ratio [HR] 1.90; 95% confidence interval [CI] 1.76-2.05) for prolonged optimal cutoff QT, maintained after adjustments for age, Charlson comorbidity index, and sex (HR 1.48; 95% CI 1.37-1.59)., Conclusion: Use of ECG in diagnostic workup of patients with seizures is poor. A prolonged optimal cutoff QTc interval predicts all-cause mortality in patients evaluated for seizure and those diagnosed with epilepsy. We advocate the routine use of a 12-lead ECG at index evaluation in patients with seizure or epilepsy., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Pathogenic/likely pathogenic (P/LP) variants in the KCNQ1-encoded Kv7.1 potassium channel cause type 1 long QT syndrome (LQT1). Despite the revamped 2015 American College of Medical Genetics (ACMG) variant interpretation guidelines, the burden of KCNQ1 variants of uncertain significance (VUS) in patients with LQTS remains ∼30%., Objective: The purpose of this study was to determine whether a phenotype-enhanced (PE) variant classification approach could reduce the VUS burden in LQTS genetic testing., Methods: Retrospective analysis was performed on 79 KCNQ1 missense variants in 356 patients from Mayo Clinic and an independent cohort of 42 variants in 225 patients from Amsterdam University Medical Center (UMC). Each variant was classified initially using the ACMG guidelines and then readjudicated using a PE-ACMG framework that incorporated the LQTS clinical diagnostic Schwartz score plus 4 "LQT1-defining features": broad-based/slow upstroke T waves, syncope/seizure during exertion, swimming-associated events, and a maladaptive LQT1 treadmill stress test., Results: According to the ACMG guidelines, Mayo Clinic variants were classified as follows: 17 of 79 P variants (22%), 34 of 79 LP variants (43%), and 28 of 79 VUS (35%). Similarly, for Amsterdam UMC, the variant distribution was 9 of 42 P variants (22%), 14 of 42 LP variants (33%), and 19 of 42 variants VUS (45%). After PE-ACMG readjudication, the total VUS burden decreased significantly from 28 (35%) to 13 (16%) (P = .0007) for Mayo Clinic and from 19 (45%) to 12 (29%) (P = .02) for Amsterdam UMC., Conclusion: Phenotype-guided variant adjudication decreased significantly the VUS burden of LQT1 case-derived KCNQ1 missense variants in 2 independent cohorts. This study demonstrates the value of incorporating LQT1-specific phenotype/clinical data to aid in the interpretation of KCNQ1 missense variants identified during genetic testing for LQTS., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Sudden cardiac arrest (SCA) and sudden unexplained death (SUD) are feared sequelae of many genetic heart diseases. In rare circumstances, pathogenic variants in cardiomyopathy-susceptibility genes may result in electrical instability leading to SCA/SUD before any structural manifestations of underlying cardiomyopathy are evident., Methods: Collectively, 38 unexplained SCA survivors (21 males; mean age at SCA 26.4±13.1 years), 68 autopsy-inconclusive SUD cases (46 males; mean age at death 20.4±9.0 years) without disease-causative variants in the channelopathy genes, and 973 ostensibly healthy controls were included. Following exome sequencing, ultrarare (minor allele frequency ≤0.00005 in any ethnic group within Genome Aggregation Database [gnomAD, N=141 456 individuals]) nonsynonymous variants identified in 24 Clinical Genome Resource adjudicated definitive/strong evidence cardiomyopathy-susceptibility genes were analyzed. Eligible variants were adjudicated as pathogenic, likely pathogenic, or variant of uncertain significance in accordance with current American College of Medical Genetics and Genomics guidelines., Results: Overall, 7 out of 38 (18.4%) SCA survivors and 14 out of 68 (20.5%) autopsy-inconclusive, channelopathic-negative SUD cases had at least one pathogenic/likely pathogenic or a variant of uncertain significance nonsynonymous variant within a strong evidence, cardiomyopathy-susceptibility gene. Following American College of Medical Genetics and Genomics criterion variant adjudication, a pathogenic or likely pathogenic variant was identified in 3 out of 38 (7.9%; P =0.05) SCA survivors and 8 out of 68 (11.8%; P =0.0002) autopsy-inconclusive SUD cases compared to 20 out of 973 (2.1%) European controls. Interestingly, the yield of pathogenic/likely pathogenic variants was significantly greater in autopsy-inconclusive SUD cases with documented interstitial fibrosis (4/11, 36%) compared with only 4 out of 57 (7%, P <0.02) SUD cases without ventricular fibrosis., Conclusions: Our data further supports the inclusion of strong evidence cardiomyopathy-susceptibility genes on the genetic testing panels used to evaluate unexplained SCA survivors and autopsy-inconclusive/negative SUD decedents. However, to avoid diagnostic miscues, the careful interpretation of genetic test results in patients without overt phenotypes is vital.

Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk, but studies comparing individual β-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of β-blocker in a large cohort of symptomatic children with CPVT., Methods: From 2 international registries of patients with CPVT, RYR2 variant-carrying symptomatic children (defined as syncope or sudden cardiac arrest before β-blocker initiation and age at start of β-blocker therapy <18 years), treated with a β-blocker were included. Cox regression analyses with time-dependent covariates for β-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope., Results: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7-15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8-12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective β-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective β-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial β-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for β1-selective compared with nonselective β-blockers (HR, 2.04 [95% CI, 1.31-3.17]; and HR, 1.99 [95% CI, 1.20-3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44-4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47-7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08-4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30-5.55])., Conclusions: β1-selective β-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective β-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred β-blocker for treating symptomatic children with CPVT.

Background: Recommendations for return to play (RTP) for athletes with genetic (or congenital) heart diseases (GHD) predisposing to sudden cardiac death (SCD) have evolved from an initially paternalistic and conservative approach, to supporting a more flexible approach to decision-making. The experiences of athletes and their families during the RTP process are unknown., Objective: To understand current RTP processes., Methods: We administered a mixed-methods telephone interview combining quantitative and qualitative components to 30 athletes with a GHD who had RTP, and 23 parents. Participants were identified from the Yale ICD Sports registry and Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic. Qualitative data were analyzed using a grounded theory approach to identify common themes., Results: Most common diagnoses were long QT syndrome and hypertrophic cardiomyopathy and most common sports, soccer, basketball, and football. Twenty-three athletes encountered ≥1 perceived barrier(s) to RTP: 17 were restricted by their first cardiologist; 6 were required to meet with school administrators, 4 signed waivers, and 3 hired lawyers. Common themes expressed by athletes and their parents were frustration with poor communication, perceived lack of physician knowledge of their diagnosis, and unilateral, paternalistic decision-making, as well as cynicism that physicians and schools were primarily concerned with liability. After RTP, 26 athletes had some form of emergency action plan, although responsibility was often left to the family., Conclusion: Many perceived barriers exist for athletes with GHD who wish to RTP after their diagnoses. Shared decision-making from the onset is critical for RTP., (© 2022 Heart Rhythm Society. Published by Elsevier Inc.)

Background: Type 3 long QT syndrome (LQT3) is caused by pathogenic, gain-of-function variants in SCN5A leading to a prolonged action potential, ventricular ectopy, and torsades de pointes. Treatment options include pharmacotherapy, cardiac denervation, and/or device therapy. Rarely, patients with malignant LQT3 require cardiac transplantation., Objective: The purpose of this study was to evaluate the role of chronic continuous intravenous (IV) lidocaine as a therapeutic option for select patients with LQT3 refractory to standard therapy., Methods: We performed a retrospective review of patients evaluated and treated at Mayo Clinic and identified 4 of 161 patients with LQT3 (2.5%) who were refractory to standard therapies and therefore treated with IV lidocaine., Results: There were 4 patients (2 female [50%]). The median age at first IV lidocaine infusion was 2 months (interquartile range 1.5-4.8 months), and the median cumulative duration on IV lidocaine was 11.5 months (interquartile range 8.7-17.8 months). The main indication for IV lidocaine in all patients was persistent ventricular arrhythmias. Before IV lidocaine, all patients received an implantable cardioverter-defibrillator, and while on intermittent IV lidocaine, all patients underwent bilateral cardiac sympathetic denervation. Additionally, 2 (50%) patients had cardiac ablation for premature ventricular complexes. In all patients, lidocaine infusion resulted in a significant reduction of LQT3-triggered cardiac events. The main side effects of IV lidocaine observed were dizziness (n = 2, 50%) and seizures (n = 2, 50%). During follow-up, 3 of 4 (75%) patients underwent orthotopic cardiac transplantation. The remaining patient continues to receive IV lidocaine bolus for rescue as needed., Conclusion: For patients with LQT3 who are refractory to standard treatment, chronic IV lidocaine infusion can be used as a potential "bridge to transplant.", (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Sudden unexplained death in childhood (SUDC) is an understudied problem. Whole-exome sequence data from 124 "trios" (decedent child, living parents) was used to test for excessive de novo mutations (DNMs) in genes involved in cardiac arrhythmias, epilepsy, and other disorders. Among decedents, nonsynonymous DNMs were enriched in genes associated with cardiac and seizure disorders relative to controls (odds ratio = 9.76, P = 2.15 × 10 -4 ). We also found evidence for overtransmission of loss-of-function (LoF) or previously reported pathogenic variants in these same genes from heterozygous carrier parents (11 of 14 transmitted, P = 0.03). We identified a total of 11 SUDC proband genotypes (7 de novo, 1 transmitted parental mosaic, 2 transmitted parental heterozygous, and 1 compound heterozygous) as pathogenic and likely contributory to death, a genetic finding in 8.9% of our cohort. Two genes had recurrent missense DNMs, RYR2 and CACNA1C Both RYR2 mutations are pathogenic ( P = 1.7 × 10 -7 ) and were previously studied in mouse models. Both CACNA1C mutations lie within a 104-nt exon ( P = 1.0 × 10 -7 ) and result in slowed L-type calcium channel inactivation and lower current density. In total, six pathogenic DNMs can alter calcium-related regulation of cardiomyocyte and neuronal excitability at a submembrane junction, suggesting a pathway conferring susceptibility to sudden death. There was a trend for excess LoF mutations in LoF intolerant genes, where ≥1 nonhealthy sample in denovo-db has a similar variant (odds ratio = 6.73, P = 0.02); additional uncharacterized genetic causes of sudden death in children might be discovered with larger cohorts., Competing Interests: Competing interest statement: M.J.A. is a consultant for Abbott, ARMGO Pharma, Boston Scientific, Daiichi Sankyo, Invitae, LQT Therapeutics, Medtronic, and UpToDate. M.J.A. and the Mayo Clinic have an equity/royalty relationship with AliveCor and Anumana. However, none of these entities are related to study. D.B.G. reports he is cofounder and holds equity in Q State–Pairnomix and Praxis Therapeutics, and equity in Apostle Inc. He receives personal fees from AstraZeneca, outside the submitted work. R.W.T. reports his participation on the Scientific Advisory boards of HHMI, the Institute of Neuroscience (Shanghai), and the Institute of Science and Technology (Vienna). R.W.T. also reports his participation in the Actelion Scientific Advisory Board (Basel) with no compensation during 3-y span. O.D. reports equity interest in Empatica and receives funding from National Institute of Neurological Disorders and Stroke on sudden unexplained death in epilepsy research. M.J.A., P.T.L., and O.D. are members of the Sudden Unexplained Death in Children (SUDC) Foundation’s scientific advisory board. L.G. is President of the SUDC Foundation. L.G., M.J.A., P.T.L., and O.D. do not participate in grant funding decisions or negotiations by the SUDC Foundation to New York University Langone Health., (Copyright © 2021 the Author(s). Published by PNAS.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has challenged researchers performing clinical trials to develop innovative approaches to mitigate infectious risk while maintaining rigorous safety monitoring., Methods: In this report we describe the implementation of a novel exclusively remote randomized clinical trial (ClinicalTrials.gov NCT04354428) of hydroxychloroquine and azithromycin for the treatment of the SARS-CoV-2-mediated COVID-19 disease which included cardiovascular safety monitoring. All study activities were conducted remotely. Self-collected vital signs (temperature, respiratory rate, heart rate, and oxygen saturation) and electrocardiographic (ECG) measurements were transmitted digitally to investigators while mid-nasal swabs for SARS-CoV-2 testing were shipped. ECG collection relied on a consumer device (KardiaMobile 6L, AliveCor Inc.) that recorded and transmitted six-lead ECGs via participants' internet-enabled devices to a central core laboratory, which measured and reported QTc intervals that were then used to monitor safety., Results: Two hundred and thirty-one participants uploaded 3245 ECGs. Mean daily adherence to the ECG protocol was 85.2% and was similar to the survey and mid-nasal swab elements of the study. Adherence rates did not differ by age or sex assigned at birth and were high across all reported race and ethnicities. QTc prolongation meeting criteria for an adverse event occurred in 28 (12.1%) participants, with 2 occurring in the placebo group, 19 in the hydroxychloroquine group, and 7 in the hydroxychloroquine + azithromycin group., Conclusions: Our report demonstrates that digital health technologies can be leveraged to conduct rigorous, safe, and entirely remote clinical trials., Competing Interests: Competing interestsThe Mayo Clinic and P.A.N., M.J.A., and P.A.F. have a potential equity/royalty relationship with AliveCor® regarding its QTc solution, which was developed in partnership between the Mayo Clinic and AliveCor®. The rest of the authors declare no competing interests., (© The Author(s) 2021.)

Background Sudden cardiac arrest is the leading mode of death in the United States. Epilepsy affects 1% of Americans; yet epidemiological data show a prevalence of 4% in cases of sudden cardiac arrest. Sudden unexpected death in epilepsy (SUDEP) may share features with sudden cardiac arrest. The objective of this study was to report autopsy and genomic findings in a large cohort of SUDEP cases. Methods and Results Mayo Clinic Sudden Death Registry containing cases (ages 0-90 years) of sudden unexpected and unexplained deaths 1960 to present was queried. Exome sequencing performed on decedent cases. From 13 687 cases of sudden death, 656 (4.8%) had a history of seizures, including 368 confirmed by electroencephalography, 96 classified as SUDEP, 58 as non-SUDEP, and 214 as unknown (insufficient records). Mean age of death in SUDEP was 37 (±19.7) years; 56 (58.3%) were male; 65% of deaths occurred at night; 54% were found in bed; and 80.6% were prone. Autopsies were obtained in 83 cases; bystander coronary artery disease was frequently reported as cause of death; nonspecific fibrosis was seen in 32.6% of cases, in structurally normal hearts. There were 4 cases of Dravet syndrome with pathogenic variants in SCN1A gene. Using whole exome sequencing in 11 cases, 18 ultrarare nonsynonymous variants were identified in 6 cases including CACNB2, RYR2, CLNB, CACNA1H, and CLCN2 . Conclusions This study examined one of the largest single-center US series of SUDEP cases. Several cases were reclassified as SUDEP, 15% had an ECG when alive, and 11 (11.4%) had blood for whole exome sequencing analysis. The most frequent antemortem genetic finding was pathogenic variants in SCN1A ; postmortem whole exome sequencing identified 18 ultrarare variants.

The Sorbin and SH3 domain-containing protein 2 (Sorbs2) is an important component of cardiomyocyte sarcomere. It has been recently reported that loss of Sorbs2 is causally associated with arrhythmogenic cardiomyopathy in human. However, the ionic mechanisms leading to cardiac arrhythmogenesis by Sorbs2 deficiency are unknown. In this study, we hypothesized that Sorbs2 plays an important role in regulating cardiac ion channel expression and function. Using electrophysiological and molecular biological approaches, we found that the Sorbs2 knockout (KO) mice progressively developed cardiac structural and electrical remodeling as early as 1 to 2 months of age and died prematurely at 5 to 7 months of age. Electrocardiographic recordings showed that Sorbs2 KO mice had conduction delays, spontaneous ventricular extrasystoles and polymorphic ventricular tachyarrhythmia. Intracellular recordings revealed abnormal action potentials with depolarized resting potential, reduced upstroke velocity, prolonged repolarization, and effective refractory period in the ventricular preparations of Sorbs2 KO mice. Patch clamp experiments demonstrated that Sorbs2 KO mice displayed distinct abnormalities in the expression and function of cardiac ion channels, including those of the voltage-gated Na + channels, L-type Ca 2+ channels, the voltage-gated K + channels and the inward-rectifier K + channels. Moreover, Sorbs2 physically interacted with the RNAs and/or proteins of important cardiac ion channels and directly regulated their expression in vitro. Our results indicate that Sorbs2 plays a pivotal role in the regulation of cardiac channel physiology. Loss of Sorbs2 promotes cardiac ion channelopathies and life-threatening arrhythmias., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background : Mutations in SCN5A that decrease Na current underlie arrhythmia syndromes such as the Brugada syndrome (BrS). SCN5A in humans has two splice variants, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077. We investigated the effect of splice variant background on loss-of-function and rescue for R1512W, a mutation reported to cause BrS. Methods and results : We made the mutation in both variants and expressed them in HEK-293 cells for voltage-clamp study. After 24 hours of transfection, the current expression level of R1512W was reduced by ~50% in both Q1077del and Q1077 compared to the wild-type (WT) channel, respectively. The activation and inactivation midpoint were not different between WT and mutant channels in both splice variant backgrounds. However, slower time constants of recovery and enhanced intermediate inactivation were observed for R1512W/Q1077 compared with WT-Q1077, while the recovery and intermediate inactivation parameters of R1512W/Q1077del were similar to WT-Q1077del. Furthermore, both mexiletine and the common polymorphism H558R restored peak sodium current ( I Na ) amplitude of the mutant channel by increasing the cell surface expression of SCN5A. Conclusion : These findings provide further evidence that the splice variant affects the molecular phenotype with implications for the clinical phenotype, and they provide insight into the expression defect mechanisms and potential treatment in BrS.

A genetic risk of sudden cardiac arrest and sudden death due to an arrhythmic cause, known as sudden cardiac death (SCD), has become apparent from epidemiological studies in the general population and in patients with ischaemic heart disease. However, genetic susceptibility to sudden death is greatest in young people and is associated with uncommon, monogenic forms of heart disease. Despite comprehensive pathology and genetic evaluations, SCD remains unexplained in a proportion of young people and is termed sudden arrhythmic death syndrome, which poses challenges to the identification of relatives from affected families who might be at risk of SCD. In this Review, we assess the current understanding of the epidemiology and causes of SCD and evaluate both the monogenic and the polygenic contributions to the risk of SCD in the young and SCD associated with drug therapy. Finally, we analyse the potential clinical role of genomic testing in the prevention of SCD in the general population., (© 2021. Springer Nature Limited.)

Calreticulin (CALR) is a highly conserved multifunctional chaperone protein primarily present in the endoplasmic reticulum, where it regulates Ca 2+ homeostasis. Recently, CALR has gained special interest for its diverse functions outside the endoplasmic reticulum, including the cell surface and extracellular space. Although high-resolution structures of CALR exist, it has not yet been established how different regions and individual amino acid residues contribute to structural stability of the protein. In the present study, we have identified key residues determining the structural stability of CALR. We used a Saccharomyces cerevisiae expression system to express and purify 50 human CALR mutants, which were analysed for several parameters including secretion titer, melting temperature (T m ), stability and oligomeric state. Our results revealed the importance of a previously identified small patch of conserved surface residues, amino acids 166-187 ("cluster 2") for structural stability of the human CALR protein. Two residues, Tyr172 and Asp187, were critical for maintaining the native structure of the protein. Mutant D187A revealed a severe drop in secretion titer, it was thermally unstable, prone to degradation, and oligomer formation. Tyr172 was critical for thermal stability of CALR and interacted with the third free Cys163 residue. This illustrates an unusual thermal stability of CALR dominated by Asp187, Tyr172 and Cys163, which may interact as part of a conserved structural unit. Besides structural clusters, we found a correlation of some measured parameter values in groups of CALR mutants that cause myeloproliferative neoplasms (MPN) and in mutants that may be associated with sudden unexpected death (SUD)., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Interval duration measurements (IDMs) were compared between standard 12-lead electrocardiograms (ECGs) and 6-lead ECGs recorded with AliveCor's KardiaMobile 6L, a hand-held mobile device designed for use by patients at home., Methods: Electrocardiograms were recorded within, on average, 15 min from 705 patients in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic. Interpretable 12-lead and 6-lead recordings were available for 685 out of 705 (97%) eligible patients. The most common diagnosis was congenital long QT syndrome (LQTS, 343/685 [50%]), followed by unaffected relatives and patients (146/685 [21%]), and patients with other genetic heart diseases, including hypertrophic cardiomyopathy (36 [5.2%]), arrhythmogenic cardiomyopathy (23 [3.4%]), and idiopathic ventricular fibrillation (14 [2.0%]). IDMs were performed by a central ECG laboratory using lead II with a semi-automated technique., Results: Despite differences in patient position (supine for 12-lead ECGs and sitting for 6-lead ECGs), mean IDMs were comparable, with mean values for the 12-lead and 6-lead ECGs for QTcF, heart rate, PR, and QRS differing by 2.6 ms, -5.5 beats per minute, 1.0 and 1.2 ms, respectively. Despite a modest difference in heart rate, intervals were close enough to allow a detection of clinically meaningful abnormalities., Conclusions: The 6-lead hand-held device is potentially useful for a clinical follow-up of remote patients, and for a safety follow-up of patients participating in clinical trials who cannot visit the investigational site. This technology may extend the use of 12-lead ECG recordings during the current COVID-19 pandemic as remote patient monitoring becomes more common in virtual or hybrid-design clinical studies., (© 2021 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC.)

Background: There is no established screening approach for hypertrophic cardiomyopathy (HCM). We recently developed an artificial intelligence (AI) model for the detection of HCM based on the 12‑lead electrocardiogram (AI-ECG) in adults. Here, we aimed to validate this approach of ECG-based HCM detection in pediatric patients (age ≤ 18 years)., Methods: We identified a cohort of 300 children and adolescents with HCM (mean age 12.5 ± 4.6 years, male 68%) who had an ECG and echocardiogram at our institution. Patients were age- and sex-matched to 18,439 non-HCM controls. Diagnostic performance of the AI-ECG model for the detection of HCM was estimated using the previously identified optimal diagnostic threshold of 11% (the probability output derived by the model above which an ECG is considered to belong to an HCM patient)., Results: Mean AI-ECG probabilities of HCM were 92% and 5% in the case and control groups, respectively. The area under the receiver operating characteristic curve (AUC) of the AI-ECG model for HCM detection was 0.98 (95% CI 0.98-0.99) with corresponding sensitivity 92% and specificity 95%. The positive and negative predictive values were 22% and 99%, respectively. The model performed similarly in males and females and in genotype-positive and genotype-negative HCM patients. Performance tended to be superior with increasing age. In the age subgroup <5 years, the test's AUC was 0.93. In comparison, the AUC was 0.99 in the age subgroup 15-18 years., Conclusions: A deep-learning, AI model can detect pediatric HCM with high accuracy from the standard 12‑lead ECG., (Copyright © 2021. Published by Elsevier B.V.)

Background: The follow-up of implantable cardioverter-defibrillators (ICDs) generates large amounts of valuable structured and unstructured data embedded in device interrogation reports., Objective: We aimed to build a natural language processing (NLP) model for automated capture of ICD-recorded events from device interrogation reports using a single-center cohort of patients with hypertrophic cardiomyopathy (HCM)., Methods: A total of 687 ICD interrogation reports from 247 HCM patients were included. Using a derivation set of 480 reports, we developed a rule-based NLP algorithm based on unstructured (free-text) data from the interpretation field of the ICD reports to identify sustained atrial and ventricular arrhythmias, and ICD therapies. A separate model based on structured numerical tabulated data was also developed. Both models were tested in a separate set of the 207 remaining ICD reports. Diagnostic performance was determined in reference to arrhythmia and ICD therapy annotations generated by expert manual review of the same reports., Results: The NLP system achieved sensitivity 0.98 and 0.99, and F1-scores 0.98 and 0.92 for arrhythmia and ICD therapy events, respectively. In contrast, the performance of the structured data model was significantly lower with sensitivity 0.33 and 0.76, and F1-scores 0.45 and 0.78, for arrhythmia and ICD therapy events, respectively., Conclusion: An automated NLP system can capture arrhythmia events and ICD therapies from unstructured device interrogation reports with high accuracy in HCM. These findings demonstrate the feasibility of an NLP paradigm for the extraction of data for clinical care and research from ICD reports embedded in the electronic health record.

Background: Within the last 5 years, cardiac society guidelines have begun to acknowledge shared decision making (SDM) for the athlete with sudden cardiac death-predisposing genetic heart diseases (GHDs), such as long QT syndrome (LQTS), and the possibility for that athlete's return to play. Previously, international guidelines embraced a de facto disqualification for all such athletes including athletes with solely a positive genetic test in Europe., Objectives: This study sought to examine the prevalence and outcomes of athletes with sudden cardiac death-predisposing GHDs, particularly LQTS, after their return to play., Methods: A retrospective review of the electronic medical record was performed on all athletes with GHD, with a primary analysis for those with LQTS, who were evaluated, risk stratified, and treated in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic by a single genetic cardiologist between July 1, 2000, and July 31, 2020., Results: There were 672 athletes with GHD overall including 494 athletes with LQTS (231 female athletes [46.8%]; mean age at diagnosis 14.8 ± 10.5 years; mean follow-up 4.2 ± 4.8 years) who were given return-to-play approval. Overall, 79 of 494 athletes with LQTS (16.0%) were symptomatic before diagnosis, and 58 (11.7%) had an implantable cardioverter-defibrillator. In 2,056 combined years of follow-up, there was no GHD-sports associated mortality. Instead, 29 patients (5.9%) had ≥1 nonlethal, LQTS-associated breakthrough cardiac event. Of those, 15 (3.0%) were athletes at the time of the breakthrough cardiac event, with 3 (0.6%) experiencing a sports-related breakthrough cardiac event, and 12 (2.4%) a non-sports-related event. Overall, the event rate was 1.16 nonlethal events per 100 athlete-years of follow-up., Conclusions: This 20-year single center experience challenges the status quo of disqualification for all athletes with LQTS and provides additional observational evidence, albeit from a single center, in support of the more contemporary SDM approaches to this complex issue., Competing Interests: Funding Support and Author Disclosures This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program and Mayo Clinic Center for Clinical and Translational Science through grant UL1TR002377 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health. Dr. Ackerman has served as a consultant for Abbott, ARMGO Pharma Inc., Audentes Therapeutics, Biotronik, Boston Scientific, Daiichi-Sankyo, Invitae, LQT Therapeutics, Medtronic, MyoKardia, and UpToDate. Dr. Ackerman and Mayo Clinic have a potential equity and/or royalty relationship with AliveCor Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Mitral valve prolapse (MVP) is largely considered a benign condition. However, MVP is over-represented consistently in sudden unexplained death in the young (SUDY) cohorts., Objective: To determine the prevalence and potential genetic underpinnings of suspected arrhythmogenic MVP in a referral cohort of SUDY cases., Methods: In this retrospective study, medical records/autopsy reports and whole exome molecular autopsy (WEMA) results for 77 SUDY victims (27 female; average age at death 20.6 ± 8.9 years) were reviewed for evidence of myxomatous MVP and left ventricle (LV) fibrosis. Variants detected in the prespecified 147 WEMA gene panel with a minor allele frequency ≤ 0.001 in public exomes/genomes were classified using the 2015 American College of Medical Genetics (ACMG) guidelines., Results: Overall, 6 of 77 (7.8%; 2 female; average age at death 20.7 ± 6.9 years) SUDY cases had MVP as the lone abnormal postmortem finding. The majority had bileaflet involvement (5/6; 83%) and microscopic LV fibrosis (5/6; 83%). In 2 SUDY cases (33%), subjects were diagnosed with MVP by echocardiography prior to death. Unexpectedly, an ACMG pathogenic/likely pathogenic (P/LP) was more likely to be detected in SUDY cases with MVP than those without (3/6 [50%] vs 9/71 [13%]; P < .05). Interestingly, the 3 variants identified in MVP-positive SUDY cases localized to genes associated previously with a cardiomyopathy/channelopathy predisposition (p.E1518fsX25-DMD, p.S285N-RYR2, and p.R109X-TTN)., Conclusion: This WEMA series provides additional evidence that the combination of MVP and LV fibrosis underlies an unexpected number of SUDY cases. Whether P/LP variants in cardiomyopathy/channelopathy-susceptibility genes contribute to the pathogenesis of arrhythmogenic MVP requires further investigation., (© 2021 Published by Elsevier Inc. on behalf of Heart Rhythm Society.)

While published guidelines are useful in the care of patients with long-QT syndrome, it can be difficult to decide how to apply the guidelines to individual patients, particularly those with intermediate risk. We explored the diversity of opinion among 24 clinicians with expertise in long-QT syndrome. Experts from various regions and institutions were presented with 4 challenging clinical scenarios and asked to provide commentary emphasizing why they would make their treatment recommendations. All 24 authors were asked to vote on case-specific questions so as to demonstrate the degree of consensus or divergence of opinion. Of 24 authors, 23 voted and 1 abstained. Details of voting results with commentary are presented. There was consensus on several key points, particularly on the importance of the diagnostic evaluation and of β-blocker use. There was diversity of opinion about the appropriate use of other therapeutic measures in intermediate-risk individuals. Significant gaps in knowledge were identified.

Background: Prior epidemiological studies demonstrated that the p.D85N-Potassium voltage-gated channel subfamily E member 1 (KCNE1) common variant reduces repolarization reserve and predisposes to drug-induced QT prolongation/torsades de pointes. We sought to develop a cellular model for drug-induced long QT syndrome using a patient-specific induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM)., Methods: p.D85N-KCNE1 iPSCs were generated from a 23-year-old female with an exaggerated heart rate-corrected QT interval response to metoclopramide (ΔQTc of 160 ms). Clustered regularly interspaced short palindromic repeats-associated 9 technology was used to generate gene-corrected isogenic iPSCs. Field potential duration and action potential duration (APD) were measured from iPSC-CMs., Results: At baseline, p.D85N-KCNE1 iPSC-CMs displayed significantly longer field potential duration (281±15 ms, n=13 versus 223±8.6 ms, n=14, P <0.01) and action potential duration at 90% repolarization (APD90; 579±22 ms, n=24 versus 465±33 ms, n=26, P <0.01) than isogenic-control iPSC-CMs. Dofetilide at a concentration of 2 nM increased significantly field potential duration (379±20 ms, n=13, P <0.01) and APD90 (666±11 ms, n=46, P <0.01) in p.D85N-KCNE1 iPSC-CMs but not in isogenic-control. The effect of dofetilide on APD90 (616±54 ms, n=7 versus 526±54 ms, n=10, P <0.05) was confirmed by Patch-clamp. Interestingly, treatment of p.D85N-KCNE1 iPSC-CMs with estrogen at a concentration of 1 nM exaggerated further dofetilide-induced APD90 prolongation (696±9 ms, n=81, P <0.01) and caused more early afterdepolarizations (11.7%) compared with isogenic control (APD90: 618±8 ms, n=115 and early afterdepolarizations: 2.6%, P <0.05)., Conclusions: This iPSC-CM study provides further evidence that the p.D85N-KCNE1 common variant in combination with environmental factors such as QT prolonging drugs and female sex is proarrhythmic.

In the initial 3 papers in this Focus Seminar series, the fundamentals and key concepts of precision medicine were reviewed, followed by a focus on precision medicine in the context of vascular disease and cardiomyopathy. For the remaining 2 papers, we focus on precision medicine in the context of arrhythmias. Specifically, in this fourth paper we focus on long QT syndrome, Brugada syndrome, and atrial fibrillation. The final (fifth) paper will deal with catecholaminergic polymorphic ventricular tachycardia. These arrhythmias represent a spectrum of disease ranging from common to relatively rare, with very different genetic and environmental causative factors, and with differing clinical manifestations that range from almost no consequences to lethality in childhood or adolescence if untreated. Accordingly, the emerging precision medicine approaches to these arrhythmias vary significantly, but several common themes include increased use of genetic testing, avoidance of triggers, and personalized risk stratification to guide the use of arrhythmia-specific therapies., Competing Interests: Funding Support and Author Disclosures This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. Dr. Fatkin has received support from the Victor Chang Cardiac Research Institute, Estate of the Late R.T. Hall, New South Wales Health, Australian Genomics, National Health and Medical Research Council of Australia. Dr. Kovacic has received research support from the National Institutes of Health (R01HL130423, R01HL135093, R01HL148167–01A1) and New South Wales Health (RG194194). Dr. Giudicessi has modest equity interest in 3M, GlaxoSmithKline, Medtronic, MyoKardia, and Pfizer. Dr. Ackerman is a consultant for Abbott, ARMGO Pharma, Audentes Therapeutics, Boston Scientific, Daiichi-Sankyo, Invitae, LQT Therapeutics, Medtronic, MyoKardia, and UpToDate; and he and the Mayo Clinic are involved in an equity/royalty relationship with AliveCor (AliveCor was not involved in this study)., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Hypertrophic cardiomyopathy (HCM) is characterized by multiple pathological features including myocyte hypertrophy, myocyte disarray, and interstitial fibrosis., Objectives: This study sought to correlate myocardial histopathology with clinical characteristics of patients with obstructive HCM and post-operative outcomes following septal myectomy., Methods: The authors reviewed the pathological findings of the myocardial specimens from 1,836 patients with obstructive HCM who underwent septal myectomy from 2000 to 2016. Myocyte hypertrophy, myocyte disarray, interstitial fibrosis, and endocardial thickening were graded and analyzed., Results: The median age at operation was 54.2 years (43.5 to 64.3 years), and 1,067 (58.1%) were men. A weak negative correlation between myocyte disarray and age at surgery was identified (ρ = -0.22; p < 0.001). Myocyte hypertrophy (p < 0.001), myocyte disarray (p < 0.001), and interstitial fibrosis (p < 0.001) were positively associated with implantable cardioverter-defibrillator implantation. Interstitial fibrosis (p < 0.001) and endocardial thickening (p < 0.001) were associated with atrial fibrillation pre-operatively. In the Cox survival model, older age (p < 0.001), lower degree of myocyte hypertrophy (severe vs. mild hazard ratio: 0.41; 95% confidence interval: 0.19 to 0.86; p = 0.040), and lower degree of endocardial thickening (moderate vs. mild hazard ratio: 0.75; 95% confidence interval: 0.58 to 0.97; p = 0.019) were independently associated with worse post-myectomy survival. Among 256 patients who had genotype analysis, patients with pathogenic or likely pathogenic variants (n = 62) had a greater degree of myocyte disarray (42% vs. 15% vs. 20%; p = 0.022). Notably, 13 patients with pathogenic or likely pathogenic genetic variants of HCM had no myocyte disarray., Conclusions: Histopathology was associated with clinical manifestations including the age of disease onset and arrhythmias. Myocyte hypertrophy and endocardial thickening were negatively associated with post-myectomy mortality., Competing Interests: Funding Support and Author Disclosures This study was supported by the Paul and Ruby Tsai and Family to Dr. Schaff. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: Long QT syndrome (LQTS) is characterized by prolongation of the QT interval and is associated with an increased risk of sudden cardiac death. However, although QT interval prolongation is the hallmark feature of LQTS, approximately 40% of patients with genetically confirmed LQTS have a normal corrected QT (QTc) at rest. Distinguishing patients with LQTS from those with a normal QTc is important to correctly diagnose disease, implement simple LQTS preventive measures, and initiate prophylactic therapy if necessary., Objective: To determine whether artificial intelligence (AI) using deep neural networks is better than the QTc alone in distinguishing patients with concealed LQTS from those with a normal QTc using a 12-lead electrocardiogram (ECG)., Design, Setting, and Participants: A diagnostic case-control study was performed using all available 12-lead ECGs from 2059 patients presenting to a specialized genetic heart rhythm clinic. Patients were included if they had a definitive clinical and/or genetic diagnosis of type 1, 2, or 3 LQTS (LQT1, 2, or 3) or were seen because of an initial suspicion for LQTS but were discharged without this diagnosis. A multilayer convolutional neural network was used to classify patients based on a 10-second, 12-lead ECG, AI-enhanced ECG (AI-ECG). The convolutional neural network was trained using 60% of the patients, validated in 10% of the patients, and tested on the remaining patients (30%). The study was conducted from January 1, 1999, to December 31, 2018., Main Outcomes and Measures: The goal of the study was to test the ability of the convolutional neural network to distinguish patients with LQTS from those who were evaluated for LQTS but discharged without this diagnosis, especially among patients with genetically confirmed LQTS but a normal QTc value at rest (referred to as genotype positive/phenotype negative LQTS, normal QT interval LQTS, or concealed LQTS)., Results: Of the 2059 patients included, 1180 were men (57%); mean (SD) age at first ECG was 21.6 (15.6) years. All 12-lead ECGs from 967 patients with LQTS and 1092 who were evaluated for LQTS but discharged without this diagnosis were included for AI-ECG analysis. Based on the ECG-derived QTc alone, patients were classified with an area under the curve (AUC) value of 0.824 (95% CI, 0.79-0.858); using AI-ECG, the AUC was 0.900 (95% CI, 0.876-0.925). Furthermore, in the subset of patients who had a normal resting QTc (<450 milliseconds), the QTc alone distinguished those with LQTS from those without LQTS with an AUC of 0.741 (95% CI, 0.689-0.794), whereas the AI-ECG increased this discrimination to an AUC of 0.863 (95% CI, 0.824-0.903). In addition, the AI-ECG was able to distinguish the 3 main genotypic subgroups (LQT1, LQT2, and LQT3) with an AUC of 0.921 (95% CI, 0.890-0.951) for LQT1 compared with LQT2 and 3, 0.944 (95% CI, 0.918-0.970) for LQT2 compared with LQT1 and 3, and 0.863 (95% CI, 0.792-0.934) for LQT3 compared with LQT1 and 2., Conclusions and Relevance: In this study, the AI-ECG was found to distinguish patients with electrocardiographically concealed LQTS from those discharged without a diagnosis of LQTS and provide a nearly 80% accurate pregenetic test anticipation of LQTS genotype status. This model may aid in the detection of LQTS in patients presenting to an arrhythmia clinic and, with validation, may be the stepping stone to similar tools to be developed for use in the general population.

This international multidisciplinary document intends to provide clinicians with evidence-based practical patient-centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families., (© 2021 The Asia Pacific Heart Rhythm Society and the Heart Rhythm Society. Published by John Wiley and Sons Australia, Ltd / Elsevier Inc. This article is published under the Creative Commons CC‐BY license.)

Background: Type 1 long QT syndrome (LQT1) is caused by loss-of-function variants in the KCNQ1 -encoded K v 7.1 potassium channel α-subunit that is essential for cardiac repolarization, providing the slow delayed rectifier current. No current therapies target the molecular cause of LQT1., Methods: A dual-component suppression-and-replacement (SupRep) KCNQ1 gene therapy was created by cloning a KCNQ1 short hairpin RNA and a short hairpin RNA-immune KCNQ1 cDNA modified with synonymous variants in the short hairpin RNA target site, into a single construct. The ability of KCNQ1-SupRep gene therapy to suppress and replace LQT1-causative variants in KCNQ1 was evaluated by means of heterologous expression in TSA201 cells. For a human in vitro cardiac model, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated from 4 patients with LQT1 (KCNQ1-Y171X, -V254M, -I567S, and -A344A/spl) and an unrelated healthy control. CRISPR-Cas9 corrected isogenic control iPSC-CMs were made for 2 LQT1 lines (correction of KCNQ1-V254M and KCNQ1-A344A/spl). FluoVolt voltage dye was used to measure the cardiac action potential duration (APD) in iPSC-CMs treated with KCNQ1-SupRep., Results: In TSA201 cells, KCNQ1-SupRep achieved mutation-independent suppression of wild-type KCNQ1 and 3 LQT1-causative variants (KCNQ1-Y171X, -V254M, and -I567S) with simultaneous replacement of short hairpin RNA-immune KCNQ1 as measured by allele-specific quantitative reverse transcription polymerase chain reaction and Western blot. Using FluoVolt voltage dye to measure the cardiac APD in the 4 LQT1 patient-derived iPSC-CMs, treatment with KCNQ1-SupRep resulted in shortening of the pathologically prolonged APD at both 90% and 50% repolarization, resulting in APD values similar to those of the 2 isogenic controls., Conclusions: This study provides the first proof-of-principle gene therapy for complete correction of long QT syndrome. As a dual-component gene therapy vector, KCNQ1-SupRep successfully suppressed and replaced KCNQ1 to normal wild-type levels. In TSA201 cells, cotransfection of LQT1-causative variants and KCNQ1-SupRep caused mutation-independent suppression and replacement of KCNQ1 . In LQT1 iPSC-CMs, KCNQ1-SupRep gene therapy shortened the APD, thereby eliminating the pathognomonic feature of LQT1.