Mapping cardiac innervation in the long QT syndrome type 1 transgenic mouse model using whole heart imaging.

Long QT syndrome (LQTS) type 3 although less common than the first two forms, differs in that arrhythmic events are less likely triggered by adrenergic stimuli and are more often lethal. Effective pharmacological treatment is challenged by interindividual differences, mutation dependence, and adverse effects, translating into an increased use of invasive measures (implantable cardioverter-defibrillator, sympathetic denervation) in patients with LQTS type 3. Previous studies have demonstrated the therapeutic potential of polyclonal KCNQ1 antibody for LQTS type 2. Here, we sought to identify a monoclonal KCNQ1 antibody that preserves the electrophysiological properties of the polyclonal form. Using hybridoma technology, murine monoclonal antibodies were generated, and patch clamp studies were performed for functional characterization. We identified a monoclonal KCNQ1 antibody able to normalize cardiac action potential duration and to suppress arrhythmias in a pharmacological model of LQTS type 3 using human-induced pluripotent stem cell-derived cardiomyocytes.NEW & NOTEWORTHY Long QT syndrome is a leading cause of sudden cardiac death in the young. Recent research has highlighted KCNQ1 antibody therapy as a new treatment modality for long QT syndrome type 2. Here, we developed a monoclonal KCNQ1 antibody that similarly restores cardiac repolarization. Moreover, the identified monoclonal KCNQ1 antibody suppresses arrhythmias in a cellular model of long QT syndrome type 3, holding promise as a first-in-class antiarrhythmic immunotherapy.

Long QT syndrome and anaesthesia

<i>Circulation</i> Editors’ Picks

Circumstance-dependent functional variants in the major long QT syndrome genes in patients with recurrent polymorphic ventricular arrhythmias: A case series

Normalization of QT interval duration in a long QT syndrome patient during pregnancy and the postpartum period due to sex hormone effects on cardiac repolarization

Inherited arrhythmia syndromes encompass several different diseases, including long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS), idiopathic ventricular fibrillation (IVF), and progressive cardiac conduction system disease (PCCD).1 The heart is typically structurally normal with no evidence of disease macroscopically. They are an important cause for sudden cardiac death in the young, and an autopsy is typically negative.2,3 Ventricular arrhythmias are caused by mutations of ion channels and their interacting proteins, predominantly involving potassium, sodium, and calcium handling.4 Genetic studies have identified the specific genetic abnormalities that underpin these diseases, even permitting diagnosis in the deceased using postmortem genetic testing (the molecular autopsy).3 Most arrhythmia syndromes are inherited in an autosomal dominant manner, such that first-degree family members have a 50% chance of inheriting the disease. Identification of the mutation allows for predictive genetic testing in other living family members.4 Variable penetrance is common in all arrhythmia syndromes, the same mutation in the same family causing wide variation in phenotype.4 This suggests that other factors such as genetic modifiers and environmental factors may influence the phenotype. This review will highlight the latest developments in understanding the genetic basis of inherited arrhythmia syndromes and discusses the new opportunities and challenges faced with evolving genetic technologies including determining pathogenicity and the utility of large genetic databases. Finally, we will discuss newly described entities that continue the evolving theme of genetic syndromes with phenotypic overlap. Early views that a single genotype associates with a particular phenotype continue to be challenged by our greater understanding of the genotype–phenotype relationship. ### Long QT Syndrome Congenital LQTS is diagnosed in the presence of a prolonged corrected QT (QTc) interval after secondary causes (eg, QT-prolonging medications or electrolyte abnormalities) are excluded.1 The 2013 Heart Rhythm …

Prognostic implications of mutation-specific QTc standard deviation in congenital long QT syndrome.

Risk stratification of patients with long QT syndrome (LQTS) represents a difficult task. In 2018, we proposed a granular estimate of the baseline 5-year risk of life-threatening arrhythmias (LAE) for patients with LQTS, based on the genotype (long QT syndrome Type 1, long QT syndrome Type 2, and long QT syndrome Type 3) and the duration of the QTc interval. We sought to externally validate a novel risk score model (1-2-3-LQTS-Risk model) in a geographically diverse cohort from the USA and to evaluate its performance and assess potential clinical implication of this novel model. The prognostic model (1-2-3-LQTS-Risk model) was derived using data from a prospective, single-centre longitudinal cohort study published in 2018 (discovery cohort) and was validated using an independent cohort of 1689 patients enrolled in the International LQTS Registry (Rochester NY, USA). The validation study revealed a C-index of 0.69 [95% confidence interval (CI): 0.61-0.77] in the validation cohort, when compared with C-index of 0.79 (95% CI: 0.70-0.88) in the discovery cohort. Adopting a 5-year risk ≥5%, as suggested by the ROC curve analysis as the most balanced threshold for implantable cardioverter-defibrillator (ICD) implantation, would result in a number needed to treat (NNT) of nine (NNT = 9; 95% CI: 6.3-13.6). The 1-2-3-LQTS-Risk model, the first validated 5-year risk score model for patients with LQTS, can be used to aid clinicians to identify patients at the highest risk of LAE who could benefit most from an ICD implant and avoid unnecessary implants.

Variant-specific therapy for long QT syndrome type 3

Sex hormones and cardiac arrest in long QT syndrome: Does progesterone represent a potential new antiarrhythmic therapy?

Electrical storm treated successfully in a patient with TANGO2 gene mutation and long QT syndrome: A case report

Novel CALM3 mutations in pediatric long QT syndrome patients support a CALM3-specific calmodulinopathy

Introduction:Long QT syndrome (LQTS) is a congenital disorder characterized by a prolongation of the QT interval on electrocardiograms (ECGs) and a propensity to ventricular tachyarrhythmias, which may lead to syncope, cardiac arrest, or sudden death. T-wave alternans (TWA) refers to the periodic beat-to-beat alternation of T-wave shape, polarity and amplitude on surface ECG during regular heart rhythm. In this report, a case of long QT syndrome with KCNQ1 gene mutation induced TWA in the head-up tilt test (HUTT), which has not been reported yet.Patient concerns:A 6-year-old boy presented with loss of consciousness twice, 5 months in duration. The boy's ECG showed prolonged QT interval (QTc = 600 ms, QTc = QT/RR1/2). During HUTT test, QT interval was significantly prolonged (QTc = 716 ms) based on macroscopic TWA.Diagnosis:The patient was diagnosed with 1. Long QT syndrome type 1(LQT1); 2. Vasovagal syncope (VVS)Interventions:Metoprolol 12.5 mg was given orally twice a day. The child was told avoid standing for a long time and strenuous exercises.Outcomes:There was no syncope or arrhythmia occurred during hospitalization and follow-up for 1 year.Conclusions:VVS may exist in patients with long QT syndrome. Increased sympathetic tone during the early stage of HUTT may induce macroscopic TWA in long QT syndrome with KCNQ1 gene mutation.

SK is a 12-year-old girl who was diagnosed 1 year ago with a generalized seizure disorder. Both her mother and maternal uncle had histories of seizures. She has been taking antiepileptic medication and has been seizure-free since the diagnosis. Six months after her seizure medication was discontinued, she died suddenly. Following her death,electrocardiograms (ECGs) revealed marked prolongation of the QT interval in the child’s mother and maternal uncle.JA, a 3-month-old boy, was diagnosed with gastroesophageal reflux disease and treated with ranitidine (a histamine-2-blocker) and cisapride (a promotility agent). He was brought to the emergency department after his mother found him cyanotic and unresponsive in his crib. Cardiac monitoring documented ventricular tachycardia. Cardioversion was successful, and follow-up ECG demonstrated a prolonged QT interval. Additionally, the serum level of cisapride was elevated.JK is a previously healthy 10-year-old boy who was retrieved from the bottom of a public swimming pool and defibrillated at poolside from a torsade de pointes ventricular arrhythmia. He was racing his younger brother at the time of the near-drowning. ECGs obtained from the boy and available family members confirmed the diagnosis of congenital long QT syndrome in the boy and several others.LA is a 15-year-old boy who has marked seasonal allergic rhinitis that has been well controlled for 3 years with astemizole (a nonsedating antihistamine). This fall he presented to his pediatrician after having multiple syncopal events over a 2-week period. After careful inquiry, the physician discovered that the boy had been taking ketoconazole for a short time for a presumed fungal infection. Suspecting acquired long QT syndrome,the pediatrician obtained an ECG, which demonstrated a prolonged corrected QT interval (QTc ˜0.5 sec½). The patient has remained free of syncope since discontinuing the ketoconazole. Further,management of his allergic rhinitis was changed to a “heart-friendly” antihistamine (eg, loratidine).MK is a 2-year-old girl who is being evaluated for speech delay. She is the youngest of three living siblings. Another child died at 4 months of age from sudden infant death syndrome (SIDS). Hearing evaluation confirms the parent’s suspicion that the child is deaf. ECGs identified the presence of Jervell and Lange-Nielsen syndrome. Both this child and her parents had prolonged QT intervals.LD is a 6-week-old infant who was admitted to the hospital following paroxysmal coughing spells. Pertussis infection was established by nasopharyngeal culture, and the infant was started on a 14-day course of erythromycin. Ten days into the antibiotic therapy, a code 45 was called after her monitor indicated a ventricular arrhythmia and apnea. She was revived. A review of her medications showed that her reflux medication(cisapride) had not been discontinued when antibiotic therapy was initiated. An ECG confirmed the prolonged QT interval.TA is a 17-year-old competitive athlete who collapsed suddenly during overtime of the state basketball championships. Hypertrophic cardiomyopathy was suspected, but an echocardiogram revealed no abnormalities. An ECG demonstrated a corrected QT interval of 0.44 sec½(borderline). However, closer inspection of the ECG revealed bizarre, notched T waves. The young man reported taking no medications, the drug screen was negative, and there were no electrolyte abnormalities. After the young man was stabilized, careful questioning revealed that this was not his first spell;he had had several previous syncopal episodes. He recalled passing out once when a teammate had “scared” him in the locker room. The initial negative family history was later amended to include a paternal uncle who had died at age 30 in an unexplained single-vehicle automobile accident. ECGs revealed clearly prolonged QT intervals in the patient’s father and in one of the deceased uncle’s children.These cases illustrate the myriad ways that the long QT syndrome (LQTS)conceals itself, lying in wait for the opportunity to transform the once peaceful, periodic lub-dub of the heart into a chaotic heap of asynchrony. Detective-like inquiry is required to unveil LQTS in individuals and families. LQTS crosses all pediatric disciplines, requiring the pediatrician to understand the syndrome, what triggers it, how and in whom this diagnosis should be sought and verified, and what can be done for those who harbor this ticking time bomb.LQTS is so named because of its trademark feature on ECG(Fig. 1A)in which the QT interval measured from the start of the QRS complex to the end of the T wave is prolonged. In addition, the morphology of the T waves often is peculiar. With appropriate stimuli, the orderly periodicity of the heart degenerates into a polymorphic ventricular tachycardia known as torsade de pointes (“twisting of the points”), the hallmark arrhythmia heralded by LQTS. Individuals who have LQTS are susceptible to syncope,seizures, and sudden cardiac death.Over the past 5 years, scientific breakthroughs have revealed the molecular basis for LQTS (Fig. 1B). Ion channels, fundamental membrane proteins that govern the electrical activity in the heart, are defective. More than 50 genetic mutations in four critical cardiac ion channels have been demonstrated in inherited LQTS. Moreover, many drugs implicated in acquired LQTS alter the behavior of these same ion channels.Once considered an exceedingly rare condition, LQTS more correctly should be viewed as an unrecognized one. The diagnosis often remains concealed because the substantial variety of drugs, electrolyte abnormalities, and underlying medical conditions that can give rise to the acquired (iatrogenic)forms of LQTS are not disclosed (Table 1). Numerous drugs can cause QT interval prolongation and torsade de pointes. Antiarrhythmics, especially quinidine, are implicated most commonly in acquired LQTS, but other drugs have the potential to cause the syndrome,including certain antibiotics such as erythromycin, pentamidine, and trimethoprim-sulfamethoxazole; antifungal agents such as fluconazole,itraconazole, and ketoconazole; and promotility drugs such as cisapride. Concomitant use of the agents appears to carry particularly significant risk. Antidepressants such as amitriptyline can elicit cardiac arrhythmias. Patients who have eating disorders are at particular risk of LQTS and ventricular arrhythmias because of the combination of prolonged QT interval and severe bradycardia in many who suffer from anorexia nervosa.Electrolyte derangements (low “lytes” cause long QT) also can yield the acquired LQTS. Syncope, seizures, or cardiac events that occur in the setting of brisk diuresis (acute hypokalemia); in head trauma that is associated with aggressive hyperventilation (acute hypokalemia); and in transplantation in which the immunosuppression regimen includes cyclosporin(chronic hypomagnesemia) should prompt the consideration of acquired LQTS and assessment of electrolyte status.The congenital forms of LQTS often masquerade as epilepsy or vasovagal events or remain completely concealed. Key family facts, such as unexplained fatal accidents, SIDS, and familial epilepsy or familial fainting spells,either are not sought or, if elicited, are not considered pertinent in the evaluation of a child having syncope. The Jervell and Lange-Nielsen syndrome is very rare, occurring in 1 to 6 per 1 million individuals and inherited in an autosomal recessive manner. Four decades after the original clinical description of a Norwegian family in whom four of six children had prolonged QT interval, congenital sensorineural hearing loss, and recurrent syncope and three of the children died suddenly, the molecular basis (mutations in a cardiac potassium channel, KVLQT1, and its beta-subunit, minK) is now known(Fig. 1B, Table 2).The other inherited form of LQTS, autosomal dominant in Romano-Ward syndrome, is not rare. Rather, it is vastly under-diagnosed. This syndrome initially was described in the early 1960s after noting families who exhibited QT prolongation, syncope, and sudden death. Today, Romano-Ward syndrome is viewed as a heterogeneous collection of at least six distinct molecular genotypes, with LQT1-3, 5 resulting from defective cardiac ion channels,LQT4 linked to chromosome 4q25–27 (no candidate gene has been identified),and LQT6 reserved for future assignments because several families remain unlinked.Romano-Ward syndrome is estimated to occur in at least 1 in 10, 000 individuals (up to 50,000 persons in the United States). There is no gender or ancestral preference. Furthermore, inherited LQTS is believed to account for 4,000 sudden deaths in children and young adults annually. To place this incidence in context, the Romano-Ward syndrome may occur three times as often as the most common childhood malignancy, acute lymphoblastic leukemia; one third as often as cystic fibrosis, the most common ultimately fatal genetic condition in Caucasians; and twice as often as phenylketonuria, a common disease revealed in routine newborn screening in Caucasians.The inherited LQTS can strike swiftly. One third of previously“healthy” children and young adults killed suddenly by LQTS may have sudden death as their first and last symptom. In general, approximately 60% of patients present with activity- or emotion-related symptoms—primarily syncope, seizures, and palpitations (Fig. 2). If these symptoms are related to the “fight, flight, or fright”response, LQTS should be considered strongly. Syncope, which accounts for one third of LQTS presentations, occurs in the setting of intense adrenergic arousal 60% of the time, with intense emotion and rigorous exercise implicated in more than 50% of cases. Interestingly, swimming appears to be a particular trigger (15%), as are abrupt auditory signals(8%), such as the doorbell, alarm clock, telephone, or smoke detector.Inherited LQTS often is misdiagnosed as epilepsy because it presents with a generalized seizure in 10% of cases. It is not known how frequently a diagnosis of a primary generalized seizure disorder actually is LQTS (see the first case study). A careful history may reveal LQTS as the etiology of“epilepsy.” In LQTS, the seizures are due to the cerebral ischemia that results from the ventricular arrhythmia. Therefore, LQTS should be considered strongly in an adolescent or young adult who describes the following sequence: dizziness, lightheadedness, blackouts, loss of consciousness, and then seizure. In young children who cannot provide such a chronology, a history of loss of consciousness preceding a seizure may suggest LQTS.Importantly, more than one third of patients who have LQTS are asymptomatic. Most (75%) of these individuals are identified during routine screening of family members.Figure 3illustrates individuals in whom LQTS should be suspected and the evaluation they should receive. A 12-lead ECG is the current screening tool for identification of LQTS. If an ECG is obtained for this purpose, the physician must carefully inspect and determine the corrected QT interval (QTc),verifying the computer read-out. The QTc is derived by dividing the measured QT interval by the square root of the preceding R-R interval (Bazett’s formula used to “correct” the QT interval for heart rate). However, it is impractical to recall this formula, and few readily know how to calculate the QTc based upon it.Figure 3 provides a simple nomogram that enables the physician to measure the QT interval and pre-ceding R-R interval in millimeters with a ruler/caliper and plot it on the chart. The QTc lines of 0.42 sec½ and 0.46 sec½ have been drawn. A plot falling on or above the top (solid, 0.46 sec½) line is abnormal and represents LQTS with a positive and negative predictive value exceeding 90%. A plot landing in the borderline zone indicates a QTc between 0.42 sec½ and 0.46 sec½ and requires careful decision-making. At least 5% of known LQTS carriers(by genetic mutation) exhibit such a QTc. A borderline QTc in the setting of compatible symptoms or strong family history is consistent with LQTS. Figure 3 also highlights some of the peculiar T wave morphologies noted in LQTS. If such abnormalities are recognized on the ECG,the diagnosis of LQTS still is possible even with a borderline QTc. Finally,a plot falling below the bottom (dashed, 0.42 sec½) line is not likely to be LQTS(˜99% negative predictive value). Examining whether the measured QT interval is greater than 50% of the R-R interval has been suggested as a quick screen for LQTS, but this approach should be abandoned in preference to application of this QTc nomogram because it can result in a high rate of misclassification.With this understanding of interpreting the ECG, determining the QTc, and inspecting the T waves, in whom should a physician suspect LQTS and thus obtain an ECG? Importantly, all patients who have syncope precipitated by emotions, exercise, or exertion and all first-degree relatives of a patient in whom LQTS is suspected must have an ECG. Any child who has a prolonged QTc(≥0.46 sec½) or a compelling borderline QTc(symptoms, family history, unusual T waves) should be referred to a pediatric cardiologist for further evaluation and treatment. Further evaluation may include a 24-hour ambulatory electrocardiographic monitor, a stress/exercise ECG, or repetition of the ECG in the sitting/standing position in an effort to bring out subtle abnormalities in ventricular repolarization. The cardiologist should coordinate screening of the identified patient’s family, initiate appropriate therapy, and refer the family for genetic counseling.The 10-year mortality rate of untreated LQTS may exceed 50%; with therapy, this rate decreases to approximately 5%. Standard management options include beta-blocker therapy, implantation of a pacemaker and/or defibrillator, and a surgical procedure that involves a left cervicothoracic sympathetic ganglionectomy. All symptomatic patients should be treated with one or a combination of these therapies. The role of the primary physician is to monitor compliance, watch for troublesome side effects such as depression/mood changes and bronchospasm, and facilitate treatment adjustments in the face of breakthrough symptoms. In most cases, the presence of asthma has not precluded the successful use of beta-blocker therapy. It is vital to remind these patients to avoid medications known to trigger cardiac arrhythmias (Table 1). Finally, the physician often serves as the contact point when a previously asymptomatic but suspected LQTS family member becomes symptomatic. It is paramount to institute appropriate therapy promptly.Unfortunately, the opportunity for such a lifesaving intervention is not always available, which has led some experts to suggest that every individual who has inherited LQTS, whether or not symptomatic, be treated. Proponents of this approach cite that nearly one third of individuals who die suddenly from LQTS have sudden death as their presenting symptom. In a large follow-up study of LQTS in children, two thirds of those experiencing sudden death were asymptomatic for more than 1 year prior to their death. Certainly,asymptomatic individuals whose presenting QTc exceeds 0.6 sec½ should be treated because this degree of QT prolongation is a particularly poor prognostic factor. On the other hand, it may be difficult to justify treating the asymptomatic 50-year-old who just has been identified as part of a family screening. He or she already may have passed the test of time and is likely to have a “friendly”phenotype. Risks and benefits of treating asymptomatic family members must be weighed carefully by the primary physician, the cardiologist, and the family.It also is important for the primary care provider to reinforce the no competitive sports policy because intense physical exertion can be deadly. Once properly treated, individuals who have LQTS can participate in recreational sports, but moderation and the presence of a “buddy”are key. Parents, teachers, and “buddies” must be made aware that a fainting episode or onset of seizure-like activity in a child who has LQTS requires immediate attention. If the episode persists for more than a few seconds, prompt activation of the 911 system is paramount because cardiopulmonary resuscitation and early defibrillation may be critical to saving the child’s life. Because swimming is known as an arrhythmogenic trigger, affected individuals never should enter the water alone.For acquired LQTS, intravenous magnesium is used to stabilize the heart’s rhythm while offending drugs, electrolyte abnormalities, and underlying medical conditions known to precipitate torsade de pointes are sought and ameliorated.The decade of the 1990s has ushered in the molecular era for LQTS. Revelations that defects in fundamental cardiac ion channel proteins are responsible for this syndrome have created a molecular model of arrhythmogenesis. This model offers exciting prospects to address the menace of unexpected cardiac deaths due to ventricular arrhythmias, which account for some 300,000 deaths in the United States each year.Hopefully, the next millennium will bring forth genotype-phenotype correlations as the natural clinical history of specific ion channel mutations is delineated. These discoveries will allow better patient counseling about particular risk factors for a sudden cardiac death and address the important question of which asymptomatic patients require treatment. For example,swimming may be found not to be a worrisome trigger in individuals who have mutation X.In addition, LQTS will become a molecular diagnosis rather than a clinical,ECG-based diagnosis, which will permit presymptomatic diagnosis and early,appropriate intervention. Finally, the future holds great promise for genotype-targeted therapies. Individuals who have potassium channel mutants(LQT1, LQT2, and LQT5) may benefit from potassium channel openers; those who have defective cardiac sodium channels (LQT3) may do well with sodium channel blockers such as mexiletine.The LQTS is no longer the rare “zebra” whose purpose is to ensure that trainees recall that deafness and sudden cardiac death may be related (Jervell and Lange-Nielsen syndrome). Over the past 10 to 20 years,the number of cases of inherited LQTS (Romano-Ward syndrome) has increased dramatically. It is doubtful that this reflects a true increase in incidence of disease due to a greater rate of sporadic gene mutations occurring in the heart or because of a rising incidence of consanguinity. Rather, the“incidence” of LQTS has risen because of the emerging awareness of and respect for this electrical malady in the heart. Understanding the principal elements of the LQTS, knowing the types of presentations, and being able to identify its presence electrocardiographically will allow the astute physician to expose this silent killer.

See related article, pages 841–847 The study by Malan et al1 in this issue of the Circulation Research presents elegant data about induced pluripotent stem cell (iPSC)-derived myocytes2 from a mouse model of long QT syndrome (LQTS) type 3.3 The study is an important contribution that adds to a highly innovative field that is trying to define the role of iPSC technology in the understanding of inherited arrhythmias. In this accompanying editorial, I provide an overview of the previous studies in the field, comment on the contribution of Malan et al,1 and conclude by discussing some of the challenges in the field. The technique to differentiate cardiac myocytes from pluripotent stem cells is quite recent and it was introduced by the seminal article published in 2006 by Takahashi and Yamanaka,2 who used a combination of four retrovirally transduced transcription factors ( Oct3/4 , Sox2 , Klf4 , and c-Myc ) to generate iPSCs from mouse somatic cells. The importance of this technology was immediately recognized and it was rapidly applied to human cells.4 In the past few years, several investigators have refined protocols to optimize differentiation of iPSCs into cardiac myocytes and to characterize their properties. In analogy with myocardial cells derived from human embryonic cells,5 iPSC-derived myocytes differentiate into three cell types: nodal, atrial, and ventricular myocytes and present physiological adaptation of action potential duration to changes in heart rate and normal response to beta adrenergic stimulation.6 Furthermore, the presence of key ion channels7 and regulators of intracellular calcium physiology,8 as well as the preservation of the sarcomeric structure,9 have been confirmed in iPSC-derived myocytes. This comprehensive set of data provided a solid background to test the hypothesis that the differentiation of iPSC-derived cardiac cells from patients with inherited cardiac …