The Best ECG Lead for Predicting the Risk of Drug-Induced Torsade De Pointes Using Corrected QT Interval: A Comparative Prognostic Study.

Introduction: Torsade de pointes (TdP) is a deadly complication from drug-induced QT prolongation. Each of the 12 lead of an electrocardiogram (ECG) has a different length of QT interval, and thus might have a different performance in TdP prediction. This study aimed to determine the best ECG lead or set of leads in this regard. Methods: This is a comparative prognostic accuracy study using a two-gate data gathering design. The population in this study was from two sources, a case group (Patients who had drug-induced TdP, which were identified through a systematic Medline search) and a control group (those who overdosed on QT-prolonging drugs, which included patients who were under the consultation of Medical Toxicology Services). The areas under the receiver operating characteristic curve (AUROC) of heart rate-corrected QT (QTc) in each single ECG lead and of a mean/median QTc from a set of ECG leads (17 index test) in predicting the risk of TdP were calculated and compared with each other, trying to find the best lead for this propose. QTc Interval measurements were done by four investigators (Interrater reliabilities 0.95). Results: Finally, we included 136 and 148 ECGs from TdP cases and controls, respectively. V3 lead had the highest frequency of longest QTc interval, among the leads. The lead having the longest QTc yielded the greatest AUROC in predicting TdP regardless of QT correction formulas (QTcFRA=0.9915, QTcRTH=0.9893, QTcBZT=0.9904). The mean QTc of 3 leads (lead II, plus any two of leads V2-V4), and a median QTc of 6 leads (I, II, aVF, V2, V4, V6) provided similar overall performance for TdP prediction (regardless of the type of QTc formula). Conclusion: The longest QTc provided the greatest AUROC in predicting drug-induced TdP, however, the longest QTc is not located in a fixed individual lead in any patient. A less time-consuming method with comparable performance to that of the longest QTc was to use a mean QTc from 3 leads (lead II, plus any two of leads V2-V4). The potential clinical impact of this finding needs to be verified in a prospective cohort study.

Opportunities and challenges for identifying undiagnosed Rare Disease patients through analysis of primary care records: long QT syndrome as a test case.

BACKGROUND: Patients with rare genetic diseases frequently experience significant diagnostic delays. Routinely collected data in the electronic health record (EHR) may be used to help identify patients at risk of undiagnosed conditions. Long QT syndrome (LQTS) is a rare inherited cardiac condition associated with significant morbidity and premature mortality. In this study, we examine LQTS as an exemplar disease to assess if clinical features recorded in the primary care EHR can be used to develop and validate a predictive model to aid earlier detection. METHODS: 1495 patients with an LQTS diagnostic code and 7475 propensity-score matched controls were identified from 10.5 million patients' electronic primary care records in the UK's Clinical Practice Research Datalink (CPRD). Associated clinical features recorded before diagnosis (with p < 0.05) were incorporated into a multivariable logistic regression model, the final model was determined by backwards regression and validated by bootstrapping to determine model optimism. RESULTS: The mean age at LQTS diagnosis was 58.4 (SD 19.41). 18 features were included in the final model. Discriminative accuracy, assessed by area under the curve (AUC), was 0.74, (95% CI 0.73, 0.75) (optimism 6%). Features occurring at significantly greater frequency before diagnosis included: epilepsy, palpitations, syncope, collapse, mitral valve disease and irritable bowel syndrome. CONCLUSION: This study demonstrates the potential to develop primary care prediction models for rare conditions, like LQTS, in routine primary care records and highlights key considerations including disease suitability, finding an appropriate linked dataset, the need for accurate case ascertainment and utilising an approach to modelling suitable for rare events.

[Andersen-Tawil Syndrome, a differential of bidirectional ventricular tachycardia: a case report]. / Síndrome de Andersen-Tawil, un diferencial de taquicardia ventricular bidireccional: reporte de un caso.

We present the case of a patient with Andersen-Tawil syndrome (ATS), a rare genetic disorder characterized by the presence of ventricular arrhythmias, skeletal dysmorphic features, and periodic muscle paralysis. The diagnosis was delayed due to the non-simultaneity of symptom presentation. The report highlights the importance of investigating neurological symptoms in the presence of ventricular arrhythmias of unclear origin or cardiac symptoms in patients with periodic paralysis. The diagnosis was confirmed by the identification of a mutation in the KCNJ2 gene (c.224C>T(p.Thr75Met)); this specific mutation has not been reported in the gnomAD database, suggesting a minor allele frequency (MAF) of less than 1%. The patient is currently managed pharmacologically with a beta-blocker and remains free of arrhythmias.

Frequency of and outcomes associated with nonadherence to guideline-based recommendations for an implantable cardioverter-defibrillator in patients with congenital long QT syndrome.

BACKGROUND: Guideline-directed device therapy for long QT syndrome (LQTS) has evolved during the years, and indications for an implantable cardioverter-defibrillator (ICD) vary between professional cardiac societies. OBJECTIVE: We aimed to identify the subset of patients with LQTS who satisfied a class I or class II 2022 European Society of Cardiology guideline-based recommendation for an ICD and to determine the outcomes of those patients who received an ICD compared with those treated without an ICD. METHODS: Retrospective analysis was conducted of 2861 patients with LQT1, LQT2, or LQT3 to identify patients meeting contemporary recommendations for guideline-directed device therapy. Basic demographics, clinical characteristics, and frequency/type of breakthrough cardiac events (BCEs) were extracted, and outcomes/complications were compared between patients treated with an ICD and those treated without one. RESULTS: Of the 290 patients (approximately 10%) who met a guideline-based recommendation, 53 (18%) satisfied a class I/level B indication for an ICD; 56 (19%), a class I/level C indication; 19 (7%), a class IIa/level C indication; and 162 (56%), a class IIb/level B indication. However, most patients (156/290 [54%]) did not receive an ICD. Of those who received an ICD, 55 of 134 (41%) experienced ≥1 appropriate ventricular fibrillation-terminating ICD therapy, whereas ICD-related complications occurred in 13 patients (10%). Of those who were treated without an ICD, only 6 of 156 patients (4%) had nonlethal BCEs, which was significantly lower compared with the ICD group (P < .001). CONCLUSION: With >1200 years of combined follow-up, the experience and evidence from our 2 LQTS specialty centers suggest that many patients who satisfy a recommendation for an ICD based on the latest 2022 European Society of Cardiology guidelines may not need one. This is particularly true when the indication stemmed from a BCE while receiving beta blocker therapy or in asymptomatic patients with an increased 1-2-3-LQTS-Risk score.

Torsades de Pointes electrical storm in children with KCNH2 mutations.

Congenital long QT syndrome (LQTS) is a genetic heart disorder, which may lead to life-threatening arrhythmias, especially in children. Here, we reported two children who were initially misdiagnosed with epilepsy and experienced Torsades de Pointes (TdP) cardiac electrical storm (ES). Through whole exome sequencing (WES), we identified two Potassium voltage-gated channel subfamily H member 2 (KCHN2) mutations (c.1841 C > T and c.1838 C > T) respectively in a 6-year-old boy and a 13-year-old girl. Clinical data indicated that the QT interval was significantly prolonged, the T-wave pattern of chest V5-V6 leads and limb leads were inverted. Our study suggests that patients with epilepsy, especially those refractory epilepsy with atypical features, need comprehensive evaluation of cardiovascular function. KCNH2 mutation in pore region, QT interval prolongation and T wave inversion are high risk factors for ES. For LQT2 patients with ES, Nadolol and left cardiac sympathetic denervation are indicated, sometimes with an ICD.

Defining Cardiomyocyte Repolarization Response to Pharmacotherapy in Long-QT Syndrome Type 3.

BACKGROUND: Long-QT syndrome is a primary cardiac ion channelopathy predisposing a patient to ventricular arrhythmia through delayed repolarization on the resting ECG. We aimed to establish a patient-specific, human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes model of long-QT syndrome type 3 (LQT3) using clustered regularly interspaced palindromic repeats (CRISPR/Cas9), for disease modeling and drug challenge. METHODS AND RESULTS: HiPSCs were generated from a patient with LQT3 harboring an SCN5A pathogenic variant (c.1231G>A; p.Val411Met), and an unrelated healthy control. The same SCN5A pathogenic variant was engineered into the background healthy control hiPSCs via CRISPR/Cas9 gene editing to generate a second disease model of LQT3 for comparison with an isogenic control. All 3 hiPSC lines were differentiated into cardiomyocytes. Both the patient-derived LQT3 (SCN5A+/-) and genetically engineered LQT3 (SCN5A+/-) hiPSC-derived cardiomyocytes showed significantly prolonged cardiomyocyte repolarization compared with the healthy control. Mexiletine, a cardiac voltage-gated sodium channel (NaV1.5) blocker, shortened repolarization in both patient-derived LQT3 and genetically engineered LQT3 hiPSC-derived cardiomyocytes, but had no effect in the control. Notably, calcium channel blockers nifedipine and verapamil showed a dose-dependent shortening of repolarization, rescuing the phenotype. Additionally, therapeutic drugs known to prolong the corrected QT in humans (ondansetron, clarithromycin, and sotalol) demonstrated this effect in vitro, but the LQT3 clones were not more disproportionately affected compared with the control. CONCLUSIONS: We demonstrated that patient-derived and genetically engineered LQT3 hiPSC-derived cardiomyocytes faithfully recapitulate pathologic characteristics of LQT3. The clinical significance of such an in vitro model is in the exploration of novel therapeutic strategies, stratifying drug adverse reaction risk and potentially facilitating a more targeted, patient-specific approach in high-risk patients with LQT3.

The fully activated open state of KCNQ1 controls the cardiac "fight-or-flight" response.

The cardiac KCNQ1 + KCNE1 (IKs) channel regulates heart rhythm under both normal and stress conditions. Under stress, the ß-adrenergic stimulation elevates the intracellular cyclic adenosine monophosphate (cAMP) level, leading to KCNQ1 phosphorylation by protein kinase A and increased IKs, which shortens action potentials to adapt to accelerated heart rate. An impaired response to the ß-adrenergic stimulation due to KCNQ1 mutations is associated with the occurrence of a lethal congenital long QT syndrome (type 1, also known as LQT1). However, the underlying mechanism of ß-adrenergic stimulation of IKs remains unclear, impeding the development of new therapeutics. Here, we find that the unique properties of KCNQ1 channel gating with two distinct open states are key to this mechanism. KCNQ1's fully activated open (AO) state is more sensitive to cAMP than its intermediate open state. By enhancing the AO state occupancy, the small molecules ML277 and C28 are found to effectively enhance the cAMP sensitivity of the KCNQ1 channel, independent of KCNE1 association. This finding of enhancing AO state occupancy leads to a potential novel strategy to rescue the response of IKs to ß-adrenergic stimulation in LQT1 mutants. The success of this approach is demonstrated in cardiac myocytes and also in a high-risk LQT1 mutation. In conclusion, the present study not only uncovers the key role of the AO state in IKs channel phosphorylation, but also provides a target for antiarrhythmic strategy.

Mechanisms underlying the spontaneous termination of torsades de pointes in an experimental model of long QT syndrome.

BACKGROUND: Torsades de pointes (TdP) represent a complex polymorphic ventricular tachycardia. While the triggering mechanisms of early afterdepolarization and increased dispersion of repolarization are well investigated, the sudden self-limiting termination remains poorly understood. OBJECTIVE: The purpose of this study was to perform analysis of TdP to investigate factors causing spontaneous termination. METHODS: We used a large data set from Langendorff experiments in isolated rabbit hearts in which drug-induced QT prolongation, bradycardia, and hypokalemia provoke TdP. We included 427 episodes with typical TdP characteristics of polymorphic self-terminating beats and twisting QRS complexes occurring in the presence of abnormal QT prolongation due to various different QT-prolonging drugs. The use of 8 monophasic action potential catheters allowed the characterization of action potential duration, configuration, and dispersion of repolarization beyond the capabilities of the surface electrocardiogram. To identify possible mechanisms of arrhythmia termination, the initial, midpoint, and terminal 3 ventricular complexes were analyzed for each episode. RESULTS: An abrupt decrease in spatial dispersion over the course of a TdP episode was identified as a precursor for termination of TdP. Within the last 3 beats, a sudden significant decrease in the dispersion of repolarization was observed as a predictor of termination. In parallel, there was a decrease in action potential duration (action potential duration at 90% repolarization) before termination. Also, a change in action potential configuration (action potential duration at 90% repolarization/action potential duration at 50% repolarization ratio) in terms of the loss of action potential dome with a restitution of action potential triangulation was observed. CONCLUSION: In >400 TdP episodes, homogenization of myocardial repolarization with the recovery of an action potential configuration determines the termination of TdP episodes.

Rapid Return to Play After Extravascular Implantable Cardioverter-Defibrillator Implantation in a Competitive Runner.

We present a case of long QT syndrome type 2 in a competitive runner who underwent implantation of a primary prevention extravascular implantable cardioverter defibrillator with a rapid return to partial activity within 2 weeks and a return to full activity within 4 weeks of implantation without affecting wound healing or device function.

Quercetin is a foe in the heart by targeting the hERG potassium channel.

Objectives: Quercetin is a plant flavonoid known for its pharmacological activities, such as antioxidant, anti-inflammatory, and anti-cancer properties. However, there is limited information available regarding its potential toxicities. A previous study showed that quercetin can inhibit human ether-a-go-related gene (hERG, also named KCNH2) currents, which may lead to long QT syndrome, torsade de pointes (TdP), and even sudden cardiac death. This study aimed to investigate the effects of quercetin on hERG and its potential mechanism. Materials and Methods: hERG currents and action potential duration (APD) were assessed using the patch clamp technique. Molecular docking was employed to elucidate the binding sites between quercetin and hERG. Transfection of wild-type or mutant plasmids was used to verify the results of molecular docking. Western blot was performed to determine the expression levels of hERG, transcription factor SP1, molecular chaperones HSP70 and HSP90, phosphorylated E3 ubiquitin ligase p-Nedd4-2, serum- and glucocorticoid-inducible kinase (SGK1), and phosphatidylinositol 3-kinase (PI3K). Immunoprecipitation was conducted to evaluate hERG ubiquitination. Results: Quercetin acutely blocked hERG current by binding to F656 amino acid residue, subsequently accelerating channel inactivation. Long-term incubation of quercetin accelerates Nedd4-2-mediated ubiquitination degradation of hERG channels by inhibiting the PI3K/SGK1 signaling pathway. Moreover, the APD of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) is significantly prolonged by 30 µM quercetin. Conclusion: Quercetin has a potential risk of proarrhythmia, which provided useful information for the usage and development of quercetin as a medication.

The Perfect Storm: Abnormal Baseline QT With Chronic Methadone Use and Serious Hypokalemia.

Methadone, a well-known drug used for pain control and as a treatment for opioid addiction, can cause arrhythmias, including torsades de pointes (TdP), which may progress to ventricular fibrillation and sudden death. We present a case of a middle-aged woman with a long history of methadone use who presented to the emergency department after experiencing cardiac arrest at home. During her hospitalization, she experienced multiple episodes of TdP that improved with isoproterenol and potassium correction. The initial diagnosis was methadone-induced prolonged QT. However, even with discontinuation of methadone, her QTc remained prolonged. Congenital long QT syndrome was suspected, and genetic testing was instructed to test in the outpatient setting. She was discharged on nadolol and a LifeVest.

Clinical Features, Long-Term Prognosis, and Clinical Management of Genotype-Negative Long QT Syndrome Patients.

BACKGROUND: Approximately 15% to 20% of patients clinically diagnosed with long QT syndrome (LQTS) are genotype-negative (GEN-). Whether they have a different arrhythmic risk or should be managed differently remains unclear, often leading to incomplete treatment. OBJECTIVES: The purpose of this study was to compare clinical aspects of GEN- and genotype-positive (GEN+) LQTS patients. METHODS: We retrospectively evaluated 832 LQTS patients genetically screened in Japan (n = 347) and Italy (n = 485), including 698 with a disease-causing variant in the KCNQ1, KCNH2, and SCN5A genes (GEN+), and 134 without variants in these LQTS-related genes (GEN-). RESULTS: At diagnosis, the Japanese patients were more often probands (86% vs 60%), symptomatic (39% vs 18%), and of younger age than the Italian patients; conversely, they used less ß-blockers (65% vs 95%), more rarely had a family history (FH) of LQTS (42% vs 73%), and had more cardiac events during follow-up (13% vs 4%) (P < 0.001 for all comparisons). Within the Japanese cohort, the GEN- had more cardiac arrests, used less ß-blockers, and had much less FH for LQTS compared their GEN+ counterpart. The Italian cohort was more homogeneous, with just more LQTS FH among the GEN+. QTc shortening (close to 30 ms in all groups) during follow-up was similar between Japanese and Italian patients, irrespective of their being GEN+ or GEN-. In both cohorts, during an average follow-up of 6 and 7 years, respectively, GEN+ and GEN- patients showed a comparable clinical outcome. CONCLUSIONS: Arrhythmic risk is similar between GEN+ and GEN- LQTS patients; they should be managed and treated in the same way.

Implantable loop recorder via subscapular approach in 2.7 kg neonate.

Implantable loop records allow continuous heart rhythm monitoring with the ability to be stored and viewed remotely. The limited use in the pediatric population stems from the unknown indications of use and feasibility of implantation. We describe the case of a 2.7kg female with Long QT3. A loop recorder helped identify breakthrough tachycardia and helped her transition to the next stage of care. Placement was at the left subscapular region with no complications. Implantable loop recorder placement is achievable in a 2.7 kg patient at corrected gestational age 38 weeks for LQT3 syndrome monitoring and management.

[Box: see text].

Frequency and Genotype-Dependence of intrinsic chronotropic insufficiency among patients with congenital long QT syndrome.

INTRODUCTION: Long QT syndrome (LQTS) is a cardiac channelopathy characterized by QT prolongation and a potential for arrhythmic syncope, sudden cardiac arrest or deaths (SCA/SCD). It has been speculated that patients with LQTS might have a primary sinoatrial node (SAN) phenotype of chronotropic insufficiency (CI). This has not been demonstrated convincingly before because of the potentially confounding effects of beta blocker (BB) therapy. Herein, we set out to determine whether untreated patients with LQTS demonstrate intrinsic CI. METHODS AND RESULTS: A retrospective review of all treadmill exercise stress tests (TEST) was performed on patients with one of the three most common LQTS genotypes: LQT1, LQT2, and LQT3. For each patient, the first TEST completed while off BB was analyzed. Patients with prior left cardiac sympathetic denervation (LCSD) therapy were excluded. CI was defined as having an age- and gender-predicted peak heart rate (HR) < 85% and/or a predicted HR reserve (HRR) < 80%. Overall, 463 LQTS patients (245 LQT1, 125 LQT2, and 93 LQT3) were included (267 female [58%]; mean age at time of TEST [29 ± 17 years]). Mean % predicted peak HR for all LQTS patients was 87.6% (range 42.9% - 119.1%) and mean % predicted HRR was 80% (range 19.1% - 153%). Overall, half of all LQTS patients (n = 234; 51%) displayed CI; 64% of patients with LQT1 (n = 157), 37% with LQT2 (n = 46), and 33% with LQT3 (n = 31). Patients with LQT1 were most likely to exhibit CI compared to patients with LQT2 (p < .0001) and LQT3 (p < .0001). CI was significantly more common in LQT1 compared to controls (p < .0001), while there was no difference between LQT2 (p = .5) or LQT3 and controls (p > .9). Presence of CI was not a predictor of LQTS-associated symptoms, BB side effects or likelihood of future breakthrough cardiac events (BCE). CONCLUSIONS: Patients with LQTS, particularly LQT1, demonstrate a SAN phenotype of CI. If assessing BB therapy effect by impact on peak HR, the patient's pretreatment peak HR, rather than an age- and gender-predicted maximum HR, should be used.

Prevalence and associated factors of ECG abnormality patterns indicative of cardiac channelopathies among adult general population of Tehran, Iran: a report from the Tehran Cohort Study (TeCS).

BACKGROUND: The characteristics of electrocardiogram (ECG) abnormalities related to cardiac channelopathies potentially linked to sudden cardiac death (SCD) are not widely recognized in Iran. We examined the prevalence of such ECG patterns and their related factors among adult residents of Tehran, Iran. METHODS: The clinical characteristics and 12-lead ECGs of Tehran Cohort Study participants were examined. Long QT intervals, short QT intervals, Brugada syndrome (BrS) patterns, and early repolarization (ER) were evaluated using computer-based assessment software validated by cardiologists. Logistic regression models were employed to identify the factors associated with the prevalence of different ECG patterns. RESULTS: Out of 7678 available ECGs, 7350 were included in this analysis. Long QT interval, ER pattern, BrS patterns, and short QT interval were found in 3.08%, 1.43%, 0.31%, and 0.03% of participants, respectively. The prevalence of long QT interval increased with age, opium consumption, and presence of hypertension. Younger age, lower body mass index (BMI), alcohol use and male sex were independently linked to an elevated prevalence of ER pattern. Most individuals with BrS patterns were men (95%) and had lower BMI, high- and low-density lipoprotein, and total cholesterol compared to those without the BrS pattern. At a mean follow-up of 30.2 ± 5.5 months, all-cause mortality in the group exhibiting abnormal ECG patterns (6.3%) was approximately twice as high as that in the group without such patterns (2.96%). CONCLUSION: Abnormal ECG patterns corresponding to channelopathies were relatively rare among adult residents of the Tehran population, and their prevalence was influenced by various factors. CLINICAL TRIAL NUMBER: Not applicable.

Comprehensive characterization of long QT syndrome-associated genes in cancer and development of a robust prognosis model.

Cancer is the leading public health problem worldwide. However, the side effects accompanying anti-cancer therapies, particularly those pertaining to cardiotoxicity and adverse cardiac events, have been the hindrances to treatment progress. Long QT syndrome (LQTS) is one of the major clinic manifestations of the anti-cancer drug associated cardiac dysfunction. Therefore, elucidating the relationship between the LQTS and cancer is urgently needed. Transcriptomic sequencing data and clinic information of 10,531 patients diagnosed with 33 types of cancer was acquired from TCGA database. A pan-cancer applicative gene prognostic model was constructed based on the LQTS gene signatures. Meanwhile, transcriptome data and clinical information from various cancer types were collected from the GEO database to validate the robustness of the prognostic model. Furthermore, the expression level of transcriptomes and multiple clinical features were integrated to construct a Nomo chart to optimize the prognosis model. The ssGSEA analysis was employed to analysis the correlation between the LQTS gene signatures, clinic features and cancer associated signalling pathways. Our findings revealed that patients with lower LQTS gene signatures enrichment levels exhibit a poorer prognosis. The correlation of enrichment levels with the typical pathways was observed in multiple cancers. Then, based on the 17 LQTS gene signatures, we construct a prognostic model through the machine-learning approaches. The results obtained from the validation datasets and training datasets indicated that our prognostic model can effectively predict patient outcomes across diverse cancer types. Finally, we integrated this model with clinical features into a nomogram, demonstrating its potential as a valuable prognostic tool for cancer patients. Our study sheds light on the intricate relationship between LQTS and cancer pathways. A LQTS feature based clinic decision tool was developed aiming to enhance precision treatment of cancer.

Low foetal heart rate, a potentially ominous finding: case report.

Background: Congenital long QT syndrome (LQTS) type 1 is characterized by abnormally prolonged ventricular repolarization caused by inherited defects in cardiac potassium channels. Patients are predisposed to ventricular arrhythmias and even sudden cardiac death. In some cases, foetal sinus bradycardia is the only sign, making prenatal diagnosis challenging. Physicians should be aware of this subtle presentation of LQTS. Early diagnosis and proactive treatment are crucial for preventing unexpected cardiac events. Case summary: A healthy and asymptomatic 25-year-old pregnant woman was referred to our institute for cardiac evaluation after persistent foetal sinus bradycardia was detected during repeated ultrasounds, despite the absence of any foetal morphological or functional cardiac anomalies. After a thorough assessment, the mother was diagnosed with LQTS type 1, as confirmed by molecular genetic testing. Appropriate management, including maternal medication and increased surveillance, was initiated. The infant was delivered safely, and his electrocardiogram revealed a significantly prolonged QTc interval. Genetic testing confirmed the maternally inherited variant in KCNQ1 gene, and beta-blocker therapy was started. No arrhythmic events were noted. Discussion: Detection and careful stratification of foetal heart rate (FHR) is crucial in every pregnancy. Foetal bradycardia can be caused by both maternal and foetal factors. Persistent low FHR should raise a high suspicion for LQTS. The condition may also present with atrioventricular blocks, torsades de pointes, or sudden intrauterine foetal demise. Accurate and early diagnosis of LQTS is essential for implementing appropriate management strategies, which include vigilant monitoring, effective medical treatment, careful planning of delivery, and post-natal care.

Idiopathic Ventricular Fibrillation - Just How Much Idiopathic is it?

Idiopathic ventricular fibrillation is diagnosed in survivors of sudden cardiac death that has been caused by ventricular fibrillation without known structural or electrical abnormalities, even after extensive investigation. It is a common cause of sudden death in young adults. Although idiopathic ventricular fibrillation is a diagnosis of exclusion, in many cases only a partial investigation algorithm is performed. The aim of this review is to present a comprehensive diagnostic evaluation algorithm with a focus on diagnostic assessment of inherited arrhythmic syndromes and genetic background.

Inhibition of hERG K channels by verapamil at physiological temperature: Implications for the CiPA initiative.

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative reassesses using the inhibition of hERG potassium channels by drugs as the major determinant for the potential to cause drug-induced Torsades de Pointes (TdP) cardiac arrhythmias. Here we report our findings on the next phase of CiPA: Determination of hERG inhibitory properties using the standard CiPA-defined data acquisition protocol, here called the standard protocol, at physiological temperature (37 degrees Celsius). To do this, we measured inhibition of hERG1a potassium channels stably expressed in HEK293 cells by the small molecule verapamil, using manual whole-cell patch-clamp electrophysiology recordings with the standard protocol, which is characterized, in part, by a series of 10 s duration voltage steps to 0 mV, ultimately leading to a cumulative recording time of approximately 30 min. Using the standard protocol, we measured an IC50 for verapamil of 225 nM, a Hill coefficient of 1, and time constant of inhibition at 0 mV of 0.64 s. But, using the standard protocol resulted in a very low (5 %) experimental success rate per cell, which had low practicality for future experiments. To address the 5 % success rate, we generated a revised protocol characterized, in part, by a series of 3 s duration voltage steps to 0 mV, leading to a cumulative recording time of approximately 10 min. Using the revised protocol, we found an IC50 for verapamil of 252 nM, a Hill coefficient of 0.8, and time constant of inhibition at 0 mV of 0.67 s. The values measured with the revised protocol were similar to those measured using the standard protocol and, furthermore, our success rate using the revised protocol rose to 25 %, an increase of 5-fold over the standard protocol, and more in line with the success rate for biophysical studies. In summary, we captured key pharmacological data for subsequent analysis in CiPA using a revised protocol with an increased success rate and an overall enhanced feasibility and practicality. We propose that the revised protocol may be more pragmatic for generation of some hERG channel drug inhibition data for CiPA and other regulatory sciences.