Long QT Research Articles

Clinical presentation and genetic characterization of early-onset atrial fibrillation in patients affected by long QT syndrome: A single-center experience.

Early-onset atrial fibrillation (AF) has already been observed in approximately 2% of patients with genetically proven long QT syndrome (LQTS). This frequency is higher than population-based estimates of early-onset AF. However, the concomitant expression of AF in LQTS is likely underestimated. The purpose of this study was to examine the clinical presentation, genetic background, and outcomes of a cohort of patients with LQTS and early-onset AF referred to a single tertiary center. Twenty-seven patients diagnosed with congenital LQTS were included in the study based on the documentation of early-onset (age ≤50 years) clinical or subclinical AF episodes in all available medical records, including standard electrocardiograms, wearable monitor or cardiac implantable electronic devices. Seventeen patients experienced clinical AF during the follow-up period. Subclinical AF was detected in 10 patients through insertable or wearable cardiac monitors. In our series, the mean heart rate during AF episodes was found to be relatively low despite the patients' young age and the low or minimal effective doses of beta-blockers used for QTc interval control. All patients exhibiting LQTS and early-onset AF were genotype positive, carrying mutations in the KCNQ1 (66%), KCNH2, KCNE1, and SCN5A genes. Notably, most of these patients carried the same p.(R231C) mutation in the KCNQ1 gene (59%) and were from the same families, suggesting concurrent expression of familial AF and LQTS. LQTS patients are prone to developing clinical and subclinical AF, even at a younger age. The occurrence of early-onset AF in the LQTS population could be more frequent than previously assumed. AF should be considered as a potential dysrhythmia related to LQTS. Our study emphasizes the importance of carefully researching clinical and/or subclinical episodes of AF through strict heart rhythm monitoring in the LQTS population.

Electrocardiographic Findings in Children Treated with Leuprolide Acetate for Precocious Puberty: Does it Cause Prolonged QT?

Central precocious puberty is treated with long-acting GnRH analogues. Some adult patients undergoing GnRHa treatment experienced prolonged QT syndrome, which is associated with an increased risk of serious cardiac events such as myocardial infarction, stroke, arrhythmias, and sudden cardiac death. Seventy-four patients, aged between 5 and 11 years and diagnosed with central precocious puberty but with no other concomitant disease or medication use, underwent electrocardiogram assessment. They had been receiving 3.75 mg leuprolide acetate (Lucrin® Depot) injections every 28 days for at least three months. The electrocardiograms of all patients showed a QTc interval within normal limits, consistent with the data of healthy Turkish children of the same age and gender. No other pathological physical examination or ECG findings were observed. Furthermore, there was no significant difference in QTc interval in relation to age, anthropometric data, or the duration or cumulative dose of the treatment. The study found no correlation between QTc interval values and age, treatment duration, total cumulative dose, and anthropometric data. The findings suggest that cardiovascular adverse events associated with GnRHa may be related to age and other underlying physiopathological conditions rather than the drug.

Prevalence and predictors of false positive QTc prolongation by the automated measurement.

Corrected QT (QTc) is an important electrocardiographic (ECG) interval. Physicians rely on automated QTc provided by ECG machines while the manual method is the recommended method. We sought to assess the prevalence and predictors of false positive QTc prolongation by the automated measurement. Consecutive ECGs were retrieved from the ECG database at King Khaled University Hospital. Manual QT was measured by a trained physician using the tangent method and was corrected for heart rate and QRS duration. Automated QTc measurement was recorded by the ECG machine. "Long QT (LQT)" was defined as QTc≥470 ms for males and ≥480 for females. False positive LQT was defined as LQT by automated QTc but not manual QTc. Pre-determined factors were included in a multivariate logistic regression to assess predictors of false positive LQT. A total of 567 ECGs were included in this study. Automated QTc was longer than manual QTc (440 ms [±35] vs. 417 ms [±35], respectively) which resulted in a high negative predictive value (NPV) (99%) and a low positive predictive value (PPV) (32%). Male gender and abnormal rhythm were found to be independently associated with false positive LQT (OR = 1.9 [95% 1.1-3.5], p = 0.03 and OR = 3.1 [95% 1.2-8.3], p = 0.02; respectively). Automated QTc measurement is unreliable for detecting long QT, necessitating manual verification and further research to enhance its accuracy.

Effects of cohort, genotype, variant, and maternal β-blocker treatment on foetal heart rate predictors of inherited long QT syndrome.

In long QT syndrome (LQTS), primary prevention improves outcome; thus, early identification is key. The most common LQTS phenotype is a foetal heart rate (FHR) < 3rd percentile for gestational age (GA) but the effects of cohort, genotype, variant, and maternal β-blocker therapy on FHR are unknown. We assessed the influence of these factors on FHR in pregnancies with familial LQTS and developed a FHR/GA threshold for LQTS. In an international cohort of pregnancies in which one parent had LQTS, LQTS genotype, familial variant, and maternal β-blocker effects on FHR were assessed. We developed a testing algorithm for LQTS using FHR and GA as continuous predictors. Data included 1966 FHRs at 7-42 weeks' GA from 267 pregnancies/164 LQTS families [220 LQTS type 1 (LQT1), 35 LQTS type 2 (LQT2), and 12 LQTS type 3 (LQT3)]. The FHRs were significantly lower in LQT1 and LQT2 but not LQT3 or LQTS negative. The LQT1 variants with non-nonsense and severe function loss (current density or β-adrenergic response) had lower FHR. Maternal β-blockers potentiated bradycardia in LQT1 and LQT2 but did not affect FHR in LQTS negative. A FHR/GA threshold predicted LQT1 and LQT2 with 74.9% accuracy, 71% sensitivity, and 81% specificity. Genotype, LQT1 variant, and maternal β-blocker therapy affect FHR. A predictive threshold of FHR/GA significantly improves the accuracy, sensitivity, and specificity for LQT1 and LQT2, above the infant's a priori 50% probability. We speculate this model may be useful in screening for LQTS in perinatal subjects without a known LQTS family history.

Ecological and toxicological features of the effect of stable cesium on striated muscle tissue (myocardium and skeletal muscles) of mammals

Recently, the risks of radiation danger have significantly increased. This is connected with the start of a full-scale war against Ukraine and the seizure of the Zaporizhzhya NPP by the Russian Federation, which has the second most powerful arsenal of nuclear weapons in the world. The majority of studies devoted to the effect of radioactive radiation on the human body and animals absolutely do not take into account the ecotoxic effect of the carrier and a chemical element. At the same time, the body does not distinguish between radioactive and non-radioactive isotopes of chemical elements and interacts with them during exchange processes. The aim of the work was to study the influence of stable cesium on the microscopic structure of striated muscle tissue, both skeletal and cardiac ones. The results of our research revealed that intensive accumulation of cesium for 24 days occurred in all the examined organs and tissues. In fact, the most intensive accumulative process appeared to be in the heart by 214.9 times and by 695.3 times with skeletal muscles, with a simultaneous decrease in potassium content by 19.2% and 29.1%, respectively, compared to intact rats. We can talk about the presence of two mechanisms of action of cesium on tissues, including striated muscles: as an antagonist of potassium, which concerns the transport system of the latter and as a toxic element that initiates peroxide processes with subsequent modification of membranes and their potassium channels. Functional disturbances in the work of potassium channels of excitable tissues in the repolarization phase occur in the conditions of an increase in intracellular cesium in striated muscles. These disorders can proceed according to the type of acquired "potassium" channelopathies, which in the myocardium can manifest in the form of rhythm disorders, prolonged QT syndrome, etc. This leads to the appearance of significant violations of the histological structure of the examined tissues. Cesium has pronounced damaging effects on both skeletal and cardiac striated muscle tissue, with morphological changes in skeletal and cardiac striated muscle tissue being generally similar. Dystrophic changes in the nuclei and cytoplasm of cardiomyocytes and striated muscles, signs of impaired blood circulation in the microcirculatory channel with the formation of vascular wall edema, destruction of endothelial cells, various types of hemorrhages and lymphohistiocytic infiltration of the stroma of fibers are the consequences of the toxic effect of cesium on tissues. Thus, the results of changes in the histological structure of striated muscles under the action of cesium chloride obtained by us indicate a fairly high cytocidal activity of stable cesium.

NaV1.6 dysregulation within myocardial T-tubules by D96V calmodulin enhances proarrhythmic sodium and calcium mishandling.

Calmodulin (CaM) plays critical roles in cardiomyocytes, regulating Na+ (NaV) and L-type Ca2+ channels (LTCCs). LTCC dysregulation by mutant CaMs has been implicated in action potential duration (APD) prolongation and arrhythmogenic long QT (LQT) syndrome. Intriguingly, D96V-CaM prolongs APD more than other LQT-associated CaMs despite inducing comparable levels of LTCC dysfunction, suggesting dysregulation of other depolarizing channels. Here, we provide evidence implicating NaV dysregulation within transverse (T) tubules in D96V-CaM-associated arrhythmias. D96V-CaM induced a proarrhythmic late Na+ current (INa) by impairing inactivation of NaV1.6, but not the predominant cardiac NaV isoform NaV1.5. We investigated arrhythmia mechanisms using mice with cardiac-specific expression of D96V-CaM (cD96V). Super-resolution microscopy revealed close proximity of NaV1.6 and RyR2 within T-tubules. NaV1.6 density within these regions increased in cD96V relative to WT mice. Consistent with NaV1.6 dysregulation by D96V-CaM in these regions, we observed increased late NaV activity in T-tubules. The resulting late INa promoted aberrant Ca2+ release and prolonged APD in myocytes, leading to LQT and ventricular tachycardia in vivo. Cardiac-specific NaV1.6 KO protected cD96V mice from increased T-tubular late NaV activity and its arrhythmogenic consequences. In summary, we demonstrate that D96V-CaM promoted arrhythmias by dysregulating LTCCs and NaV1.6 within T-tubules and thereby facilitating aberrant Ca2+ release.

Proarrhythmic toxicity of low dose bisphenol A and its analogs in human iPSC-derived cardiomyocytes and human cardiac organoids through delay of cardiac repolarization

Bisphenol A (BPA) and its analogs are common environmental chemicals with many potential adverse health effects. The impact of environmentally relevant low dose BPA on human heart, including cardiac electrical properties, is not understood. Perturbation of cardiac electrical properties is a key arrhythmogenic mechanism. In particular, delay of cardiac repolarization can cause ectopic excitation of cardiomyocytes and malignant arrhythmia. This can occur as a result of genetic mutations (i.e., long QT (LQT) syndrome), or cardiotoxicity of drugs and environmental chemicals. To define the impact of low dose BPA on electrical properties of cardiomyocytes in a human-relevant model system, we examined the rapid effects of 1 nM BPA in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using patch-clamp and confocal fluorescence imaging. Acute exposure to BPA delayed repolarization and prolonged action potential duration (APD) in hiPSC-CMs through inhibition of the hERG K+ channel. In nodal-like hiPSC-CMs, BPA acutely increased pacing rate through stimulation of the If pacemaker channel. Existing arrhythmia susceptibility determines the response of hiPSC-CMs to BPA. BPA resulted in modest APD prolongation but no ectopic excitation in baseline condition, while rapidly promoted aberrant excitations and tachycardia-like events in myocytes that had drug-simulated LQT phenotype. In hiPSC-CM-based human cardiac organoids, the effects of BPA on APD and aberrant excitation were shared by its analog chemicals, which are often used in “BPA-free” products, with bisphenol AF having the largest effects. Our results reveal that BPA and its analogs have repolarization delay-associated pro-arrhythmic toxicity in human cardiomyocytes, particularly in myocytes that are prone to arrhythmias. The toxicity of these chemicals depends on existing pathophysiological conditions of the heart, and may be particularly pronounced in susceptible individuals. An individualized approach is needed in risk assessment and protection.

A novel stop-gain pathogenic variant in the KCNQ1 gene causing long QT syndrome 1

BackgroundInherited primary arrhythmias, such as long QT (LQT) syndromes, are electrical abnormalities of the heart mainly due to variants in 3 genes. We herein describe a novel stop-gain pathogenic variant in the KCNQ1 gene in an Iranian child with LQT syndrome 1.MethodsThe patient and his family underwent clinical evaluation, electrocardiographic Holter monitoring, and whole-exome sequencing. Sanger sequencing and segregation analysis were used to confirm the variant in the patient and his family, respectively. The pathogenicity of the variant was checked via an in silico analysis.ResultsThe proband suffered from bradycardia and had experienced syncope without stress. The corrected QT interval was 470 ms (the Schwartz score ≥ 3.5), and the Holter monitoring showed sinus rhythm, infrequent premature atrial contractions, and a prolonged QT interval in some leads. Whole-exome and Sanger sequencing showed c.968G > A in 3 affected family members. According to the American College of Medical Genetics and Genomics criteria, c.968G > A was classified as a pathogenic variant.ConclusionsThe KCNQ1 gene is the main cause of LQT syndromes in our population. The common genes of LQT syndromes should be studied in our country’s different ethnicities to determine the exact role of these genes in these subpopulations.

Vicious LQT induced by a combination of factors different from hERG inhibition.

Clinically, drug-induced torsades de pointes (TdP) are rare events, whereas the reduction of the human ether-à-go-go-related gene (hERG) current is common. In this study, we aimed to explore the specific factors that contribute to the deterioration of hERG inhibition into malignant ventricular arrhythmias. Cisapride, a drug removed from the market because it caused long QT (LQT) syndrome and torsade de pointes (TdP), was used to induce hERG inhibition. The effects of cisapride on the hERG current were evaluated using a whole-cell patch clamp. Based on the dose-response curve of cisapride, models of its effects at different doses (10, 100, and 1,000 nM) on guinea pig heart in vitro were established. The effects of cisapride on electrocardiogram (ECG) signals and QT interval changes in the guinea pigs were then comprehensively evaluated by multi-channel electrical mapping and high-resolution fluorescence mapping, and changes in the action potential were simultaneously detected. Cisapride dose-dependently inhibited the hERG current with a half inhibitory concentration (IC50) of 32.63 ± 3.71 nM. The complete hERG suppression by a high dose of cisapride (1,000 nM) prolonged the action potential duration (APD), but not early after depolarizations (EADs) and TdP occurred. With 1 μM cisapride and lower Mg2+/K+, the APD exhibited triangulation, dispersion, and instability. VT was induced in two of 12 guinea pig hearts. Furthermore, the combined administration of isoproterenol was not therapeutic and increased susceptibility to ventricular fibrillation (VF) development. hERG inhibition alone led to QT and ERP prolongation and exerted an anti-arrhythmic effect. However, after the combination with low concentrations of magnesium and potassium, the prolonged action potential became unstable, triangular, and dispersed, and VT was easy to induce. The combination of catecholamines shortened the APD, but triangulation and dispersion still existed. At this time, VF was easily induced and sustained.

Hyperinsulinemic Hypoglycemia Associated with a CaV1.2 Variant with Mixed Gain- and Loss-of-Function Effects.

The voltage-dependent L-type calcium channel isoform CaV1.2 is critically involved in many physiological processes, e.g., in cardiac action potential formation, electromechanical coupling and regulation of insulin secretion by beta cells. Gain-of-function mutations in the calcium voltage-gated channel subunit alpha 1 C (CACNA1C) gene, encoding the CaV1.2 α1-subunit, cause Timothy syndrome (TS), a multisystemic disorder that includes autism spectrum disorders and long QT (LQT) syndrome. Strikingly, TS patients frequently suffer from hypoglycemia of yet unproven origin. Using next-generation sequencing, we identified a novel heterozygous CACNA1C mutation in a patient with congenital hyperinsulinism (CHI) and associated hypoglycemic episodes. We characterized the electrophysiological phenotype of the mutated channel using voltage-clamp recordings and in silico action potential modeling experiments. The identified CaV1.2L566P mutation causes a mixed electrophysiological phenotype of gain- and loss-of-function effects. In silico action potential modeling supports that this mixed electrophysiological phenotype leads to a tissue-specific impact on beta cells compared to cardiomyocytes. Thus, CACNA1C variants may be associated with non-syndromic hyperinsulinemic hypoglycemia without long-QT syndrome, explained by very specific electrophysiological properties of the mutated channel. We discuss different biochemical characteristics and clinical impacts of hypoglycemia in the context of CACNA1C variants and show that these may be associated with significant morbidity for Timothy Syndrome patients. Our findings underline that the potential of hypoglycemia warrants careful attention in patients with CACNA1C variants, and such variants should be included in the differential diagnosis of non-syndromic congenital hyperinsulinism.

Abstract 11386: Self-Service Analysis of Best Practice Alert Acknowledgement Comments as a Method for Evaluation Reveals Opportunities for Optimization of Clinical Decision Support for Patients with Prolonged QT Syndrome

Introduction: The main goal of Clinical Decision Support (CDS) is to provide timely and useful information for providers to deliver high-quality and safe care. Issues, like alert fatigue and provider burnout are commonly cited as unintended consequences of the CDS systems. Herein, we describe leveraging electronic health record (EHR) self-service reporting tools to gain insights on a CDS rule designed to avoid providers from ordering QT-prolonging medication in patients with history of QT-prolongation. Methods: Our EHR (Epic) SlicerDicer reporting tool was used to identify the frequency of QT-prolongation Best Practice Advisory (BPA) triggerings from 1/1/2020 to 12/31/2020 across Mayo Clinic sites. Additionally, associated patient encounter and BPA-specific data were queried. Text from acknowledgement comments to the BPA were reviewed and central themes and comments were categorized. Epic Clarity Data Warehouse was queried to identify the BPA-triggering medications and frequencies. Comparisons of percent action taken on the BPA were compared internally to Mayo Clinic’s BPA benchmark, and with national benchmarks using Epic BestPractice Pulse dashboard. Results: A total of 17,538 BPAs of interest were triggered across the Mayo Clinic sites in 2020, of which 3,696 (20.1%) were acted upon through either monitoring or medication discontinuation. This is below Mayo Clinic’s median of 29.2% for inpatient BPAs and 45.6% BPAs for outpatient, but above the national median of 10% (IQR 6.1-13.1%) for inpatient and 10% (IQR 4.3-19.5%) for outpatient BPAs actioned upon. A total of 30 different medications triggered the BPA, with the most common being ondansetron (41.5%), amiodarone (11.3%), and haloperidol (10.1%). User comments were left on 2,382 orders (13.5%) that acknowledged the BPA, but provided argument to prescribe drug. Three most common themes identified from comments on overridden BPAs: patient previously tolerated medication (19.0%), QT interval not prolonged on recent ECG (14.2%), and patient on hospice care (5.2%). Conclusion: Analysis of free text comments of CDS can be and should be performed to reveal opportunities for further improvement of CDS. Providers should be encouraged to provide comments when encountering CDS interventions.

Cardiomyocyte Na+ and Ca2+ mishandling drives vicious cycle involving CaMKII, ROS, and ryanodine receptors

Cardiomyocyte Na+ and Ca2+ mishandling, upregulated Ca2+/calmodulin-dependent kinase II (CaMKII), and increased reactive oxygen species (ROS) are characteristics of various heart diseases, including heart failure (HF), long QT (LQT) syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). These changes may form a vicious cycle of positive feedback to promote cardiac dysfunction and arrhythmias. In HF rabbit cardiomyocytes investigated in this study, the inhibition of CaMKII, late Na+ current (INaL), and leaky ryanodine receptors (RyRs) all attenuated the prolongation and increased short-term variability (STV) of action potential duration (APD), but in age-matched controls these inhibitors had no or minimal effects. In control cardiomyocytes, we enhanced RyR leak (by low [caffeine] plus isoproterenol mimicking CPVT) which markedly increased STV and delayed afterdepolarizations (DADs). These proarrhythmic changes were significantly attenuated by both CaMKII inhibition and mitochondrial ROS scavenging, with a slight synergy with INaL inhibition. Inducing LQT by elevating INaL (by Anemone toxin II, ATX-II) caused markedly prolonged APD, increased STV, and early afterdepolarizations (EADs). Those proarrhythmic ATX-II effects were largely attenuated by mitochondrial ROS scavenging, and partially reduced by inhibition of CaMKII and pathological leaky RyRs using dantrolene. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) bearing LQT3 mutation SCN5A N406K, dantrolene significantly attenuated cell arrhythmias and APD prolongation. Targeting critical components of the Na+–Ca2+–CaMKII–ROS–INaL arrhythmogenic vicious cycle may exhibit important on-target and also trans-target effects (e.g., INaL and RyR inhibition can alter INaL-mediated LQT3 effects). Incorporating this vicious cycle into therapeutic strategies provides novel integrated insight for treating cardiac arrhythmias and diseases.

Adenosine-induced ventricular fibrillation in a patient with supraventricular tachycardia.

Adenosine is frequently used for paroxysmal supraventricular tachycardia (PSVT) treatment in the emergency department (ED). Atrial and ventricular pro-arrhythmic effects of adenosine were described in the literature, but ventricular fibrillation (VF) secondary to adenosine administration was rarely reported (with an incidence of < 1%). Reported herein is the first case of a 72-year-old female patient who developed VF hemodynamic collapse after an intravenous administration of adenosine for PSVT treatment. She had no known pre-excitation or accessory pathway, nor any underlying structural heart disease or prolonged QT syndrome. Raising awareness of this potential life-threatening pro-arrhythmic effect of adenosine is important, given its frequent use for PSVT treatment in the ED.

Arrhythmogenic mechanisms of acute obstructive respiratory events in a porcine model of drug-induced long QT

Obstructive sleep apnea is associated with increased risk of sudden cardiac death. The purpose of this study was to elucidate changes in ventricular repolarization and electromechanical interaction during obstructive respiratory events simulated by intermittent negative upper airway pressure (INAP) in pigs. We also investigated the effect of a reduced repolarization reserve in drug-induced long QT (LQT) following INAP-induced changes in ventricular repolarization. In sedated spontaneously breathing pigs, 75 seconds of INAP was applied by a negative pressure device connected to the endotracheal tube. Ventricular electromechanical coupling was determined by the electromechanical window (EMW) before (pre-INAP), during (INAP), and after INAP (post-INAP). Incidence rates of premature ventricular contractions (PVCs) were measured respectively. A drug-induced LQT was modeled by treating the pigs with the hERG1 blocker dofetilide (DOF). Whereas QT interval increased during and decreased after INAP (pre-INAP: 273 ± 5 ms; INAP 281 ± 6 ms; post-INAP 254 ± 9 ms), EMW shortened progressively throughout INAP and post-INAP periods (pre-INAP 81 ± 4 ms; post-INAP 44 ± 7 ms). DOF shortened EMW at baseline. Throughout INAP, EMW decreased in a comparable fashion as before DOF (pre-INAP/+DOF 61 ± 7 ms; post-INAP/+DOF 14 ± 9 ms) but resulted in shorter absolute EMW levels. Short EMW levels were associated with increased occurrence of PVCs (pre-INAP 7 ± 2 ms vs post-INAP 26 ± 6 ms; P = .02), which were potentiated in DOF pigs (pre-INAP/+DOF 5 ± 2 ms vs post-INAP/+DOF 40 ± 8 ms; P = .006). Administration of atenolol prevented post-INAP EMW shortening and decreased occurrence of PVCs. Transient dissociation of ventricular electromechanical coupling during simulated obstructive respiratory events creates a dynamic ventricular arrhythmogenic substrate, which is sympathetically mediated and aggravated by drug-induced LQT.

Abstract 13719: Long Qt Associated Ventricular Tachycardia Caused by Sex Hormone Therapy

Introduction: Increasing number of patients are currently receiving hormonal therapies for a variety of conditions. Modulation of cardiac repolarization by sex hormones resulting in VT remains controversial. Anastrozole is an aromatase inhibitor (ANI), used as an anti-estrogen medication in women with breast cancer or as replacement therapy for hypogonadism. Arrhythmias associated with ANI are extremely rare and hence ANI is considered relatively safe to use. Case Presentation: We report two cases receiving ANI who presented with VT and long QT (LQT). Case 1, 71 year old female with breast cancer on ANI recently started on levofloxacin 750 mg qd, presented with monomorphic VT. Post-conversion ECG showed sinus rhythm (SR) QT 0.48s/QTc 0.56s. Case 2, 50 year old male with hypogonadism on ANI and clomiphene (CL) presented with monomorphic VT, post conversion ECG showed SR with QT 0.65s/QTc 0.59s. Both patients had normal electrolytes and coronaries. Discussion: Studies have shown that levofloxacin is not associated with significant LQT, however, a relationship between its concentration and the extent of LQT has been demonstrated. LQT in our first case can be explained by an increase in levofloxacin level resulting from inhibition of CYP by ANI. CL is a HERG inhibitor however has not been shown to prolong QT. ANI lower the estradiol level which blocks the membrane trafficking of KCNH2 channels, potentially lengthening the QT. LQT in the second case can be explained by the additive effect of both HERG and KCNH2 inhibition. Conclusion: Although reported as safe, ANI hormone therapy can be arrhythmogenic if combined with agents that potentially affect potassium currents. We recommend QT monitoring in such patients to prevent lethal arrhythmias.

Abstract 13743: A Tale of Syncope, Prolonged QT and ICD

Introduction: Long QT syndrome (LQTS) was first described in the 1960s. It manifests clinically as syncope, cardiac arrest or sudden cardiac death. LQTS can be caused by 15 different genes. These mutations lead to action potential prolongation by causing impaired repolarizing currents. Case Discussion: A 29-year-old previously healthy Caucasian woman was admitted after recurrent episodes of syncope that happened within 1-month prior to the presentation. She was hemodynamically stable with normal vitals. Her ECG showed normal sinus rhythm with corrected QT (QTc) of 598ms. In the ED, she suffered an episode of sustained monomorphic ventricular tachycardia (VT) and underwent cardioversion. She was started on amiodarone infusion. Serial ECGs showed prolonged QTc. She had another episode of pulseless VT that terminated without defibrillation. She was transferred to our facility for further care. Her family history was significant for paternal aunt who had died unexpectedly at the age of 39. All her lab work including electrolytes, thyroid panel, cardiac enzymes, inflammatory markers and extended drug screen was unrevealing. Transthoracic echocardiogram showed normal biventricular size and function. Decision making: She was started on propranolol for possible LQTS. Cardiac MR did not show any evidence of structural abnormalities. Genetic panel was sent. Since myocarditis or familial LQTS could not be ruled out, we proceeded with implantable cardioverter defibrillator (ICD) implantation for secondary prevention. She was discharged home on nadolol. Conclusion: In the absence of genetic information, LQTS can be diagnosed in symptomatic patients with QTc &gt;480msec on serial ECGs after excluding secondary causes. Schwartz score comprising of ECG findings, symptoms, clinical &amp; family history is diagnostic when greater than 3.5. Beta-blockers are indicated in all patients with a clinical diagnosis. Patients must avoid any QT prolonging agents and strenuous exercise. An ICD is indicated in patients who suffered cardiac arrest. ICD may also be considered for primary prevention in high risk patients.

Another Potential Mechanism for Long QT Intervals

A prolonged QT interval can be seen in people with congenital long QT syndromes or with people using medications that affect the ion channels involved

A novel SCN5A gene mutation causing LQT3 with unique phenotype in a large canadian kindred

Abstract Background SCN5A gene mutations are associated with diverse clinical phenotypes including Long QT (LQT) Syndrome, Brugada Syndrome, progressive conduction system disease and cardiomyopathy. Objective We identified a novel SCN5A variant (T731I) in a pedigree affected by QT prolongation and ventricular arrhythmia. Clinical phenotype and co-segregation with genotype within the pedigree were characterized. Methods Family members were invited to attend clinics held in their indigenous community. All subjects underwent a history, physical exam, 12 lead ECG and had blood samples collected for genetic testing. Patients were assessed by an adult or pediatric cardiologist and genetic counselors over a six year period. There were 86 females and 69 males ranging in age from 1 to 82 years (mean 36 years) at the time of first assessment. ECG analysis was performed by a cardiac electrophysiologist blinded to patient identity and genotype. The QTc was calculated using Bazett's formula. Results One hundred and fifty five family members were evaluated (86 (55%) female; mean age 36 years (range 1 to 82 years). Mean QTc was 461 + 21 ms for the gene positive group and 419 + 22 ms for the gene negative group (P&amp;lt;0.001) (Figure). There was no significant difference in age or sex between the gene positive and gene negative groups. Gene positive family members were also noted to have low right atrial p waves and frequent unifocal ventricular ectopy and non-sustained monomorphic ventricular tachycardia. One gene positive individual developed dilated cardiomyopathy with high burden ventricular tachycardia and required cardiac transplantation. Conclusion This novel SCN5A variant co-segregated with an abnormal phenotype consisting of significant QTc prolongation, low atrial rhythm, and ventricular arrhythmia. This pedigree highlights the phenotypic heterogeneity of SCN5A gene mutations and the importance of cascade family screening to identify at risk family members. Figure 1. QTc intervals Funding Acknowledgement Type of funding source: None

Frequency of Long QT in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine: A Meta-analysis

Introduction Hydroxychloroquine (HCQ) has been proposed as a SARS-CoV-2 treatment but the frequency of long QT (LQT) during use is unknown.Objective To conduct a meta-analysis of the frequency of LQT in patients with SARS-CoV-2 infection treated with HCQ.Data Sources PubMed, EMBASE, Google Scholar, the Cochrane Database of Systematic Reviews and preprint servers (medRxiv, Research Square) were searched for studies published between December 2019 and June 30, 2020.Methods Effect statistics were pooled using random effects. The quality of observational studies and randomized controlled trials was appraised with STROBE and the Cochrane Risk of Bias Assessment tools, respectively.Outcomes Critical LQT was defined as: (1) maximum QT corrected (QTc)≥500 ms (if QRS<120 ms) or QTc≥550 ms (if QRS≥120 ms), and (2) QTc increase ≥60 ms.Results In the 28 studies included (n=9124), the frequency of LQT during HCQ treatment was 6.7% (95% confidence interval [CI]: 3.7-10.2). In 20 studies (n=7825), patients were also taking other QT-prolonging drugs. The frequency of LQT in the other 8 studies (n=1299) was 1.7% (95% CI: 0.3-3.9). Twenty studies (n=6869) reported HCQ discontinuation due to LQT, with a frequency of 3.7% (95% CI: 1.5-6.6). The frequency of ventricular arrhythmias during HCQ treatment was 1.68% (127/7539) and that of arrhythmogenic death was 0.69% (39/5648). Torsades de Pointes occurred in 0.06% (3/5066). Patients aged >60 years were at highest risk of HCQ-associated LQT (P<0.001).Conclusions HCQ-associated cardiotoxicity in SARS-CoV-2 patients is uncommon but requires ECG monitoring, particularly in those aged >60 years and/or taking other QT-prolonging drugs.

Jervell and Lange-Nielsen syndrome with novel KCNQ1 and additional gene mutations

We encountered a boy with Jervell and Lange-Nielsen syndrome (JLNS) with compound heterozygous KCNQ1 mutations, maternal Trp248Phe and a novel paternal mutation, Leu347Arg. His father showed long QT (LQT) and arrhythmia. His mother was asymptomatic with no ECG abnormalities. The proband and his father had an additional mutation (SNTA1 Thr372Met), which is reportedly related to SIDS. These results suggest that multiple gene mutations influence the phenotype of KCNQ1 mutation-related arrhythmia.