Variant patterns of electrical activation and recovery in normal human hearts revealed by noninvasive electrocardiographic imaging.

AIMS: Although electrical activity of the normal human heart is well characterized by the electrocardiogram, detailed insights into within-subject and between-subject variations of ventricular activation and recovery by noninvasive electroanatomic mapping are lacking. We characterized human epicardial activation and recovery within and between normal subjects using non-invasive electrocardiographic imaging (ECGI) as a basis to better understand pathology. METHODS AND RESULTS: Epicardial activation and recovery were assessed by ECGI in 22 normal subjects, 4 subjects with bundle branch block (BBB) and 4 with long-QT syndrome (LQTS). We compared characteristics between the ventricles [left ventricle (LV) and right ventricle (RV)], sexes, and age groups (<50/≥50years). Pearson's correlation coefficient (CC) was used for within-subject and between-subject comparisons. Age of normal subjects averaged 49 ± 14 years, 6/22 were male, and no structural/electrical heart disease was present. The average activation time was longer in LV than in RV, but not different by sex or age. Electrical recovery was similar for the ventricles, but started earlier and was on average shorter in males. Median CCs of between-subject comparisons of the ECG signals, activation, and recovery patterns were 0.61, 0.32, and 0.19, respectively. Within-subject beat-to-beat comparisons yielded higher CCs (0.98, 0.89, and 0.82, respectively). Activation and/or recovery patterns of patients with BBB or LQTS contrasted significantly with those found in the normal population. CONCLUSION: Activation and recovery patterns vary profoundly between normal subjects, but are stable individually beat to beat, with a male preponderance to shorter recovery. Individual characterization by ECGI at baseline serves as reference to better understand the emergence, progression, and treatment of electrical heart disease.

Transmural APD heterogeneity determines ventricular arrhythmogenesis in LQT8 syndrome: Insights from Bidomain computational modeling.

Long QT Syndrome type 8 (LQT8) is a cardiac arrhythmic disorder associated with Timothy Syndrome, stemming from mutations in the CACNA1C gene, particularly the G406R mutation. While prior studies hint at CACNA1C mutations' role in ventricular arrhythmia genesis, the mechanisms, especially in G406R presence, are not fully understood. This computational study explores how the G406R mutation, causing increased transmural dispersion of repolarization, induces and sustains reentrant ventricular arrhythmias. Using three-dimensional numerical simulations on an idealized left-ventricular model, integrating the Bidomain equations with the ten Tusscher-Panfilov ionic model, we observe that G406R mutation with 11% and 50% heterozygosis significantly increases transmural dispersion of repolarization. During S1-S4 stimulation protocols, these gradients facilitate conduction blocks, triggering reentrant ventricular tachycardia. Sustained reentry pathways occur only with G406R mutation at 50% heterozygosis, while neglecting transmural heterogeneities of action potential duration prevents stable reentry, regardless of G406R mutation presence.

T-Wave Alternans Measured by 24-Hour Ambulatory Recordings Rather Than Exercise Stress Tests as a Risk Stratification Marker in Patients With Long QT Syndrome.

BACKGROUND: Few small-sample studies have quantified the T-wave alternans (TWA) value by 24-hour ambulatory recordings or exercise stress tests in patients with long QT syndrome (LQTS). The cutoff point of TWA ≥47 µV was based on patients with myocardial infarction. In our study, we aimed to (1) evaluate the association of TWA with life-threatening arrhythmic events (LAEs); (2) compare the predictive model of LAEs according to the TWA value measured by 24-hour ambulatory recordings and exercise stress tests; and (3) propose a cutoff point for the high risk of LAEs in patients with LQTS. METHODS AND RESULTS: The study cohort included 110 patients with LQTS referred to our hospital, and the primary outcome was LAEs. Thirty-one patients with LQTS (31/110 [28.2%]) developed LAEs during the following 24 (12-47) months. Peak TWA value quantified from 12 leads by 24-hour ambulatory recordings in patients with LQTS with LAEs (LQTS-LAEs group) was significantly higher than LQTS without LAEs (LQTS-non-LAEs group) (64.0 [42.0-86.0] µV versus 43.0 [36.0-53.0] µV; P<0.01). There was no statistical difference in TWA value measured by exercise stress tests between the 2 groups (69.0 [54.5-127.5] µV versus 68.5 [53.3-99.8] µV; P=0.871). The new cutoff point of the peak TWA value measured by 24-hour ambulatory recordings was 55.5 µV, with a sensitivity of 75.0% and a specificity of 78.6%. A univariate Cox regression analysis revealed that TWA value ≥55.5 µV was a strong predictor of LAEs (hazard ratio [HR], 4.5 [2.1-9.6]; P<0.001]. A multivariate Cox regression analysis indicated that TWA value ≥55.5 µV remained significant (HR, 2.7 [1.1-6.8]; P=0.034). CONCLUSIONS: Peak TWA measured by 24-hour ambulatory recordings was a more favorable risk stratification marker than exercise stress tests for patients with LQTS.

[Cardiac channelopathies in the context of hereditary arrhythmia syndromes]. / Kardiale Kanalopathien im Kontext hereditärer Arrhythmiesyndrome.

Genetic arrhythmia disorders are rare diseases; however, they are a common cause of sudden cardiac death in children, adolescents, and young adults. In principle, a distinction can be made between channelopathies and cardiomyopathies in the context of genetic diseases. This paper focuses on the channelopathies long and short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). Early diagnosis of these diseases is essential, as drug therapy, behavioral measures, and if necessary, implantation of a cardioverter defibrillator can significantly improve the prognosis and quality of life of patients. This paper highlights the pathophysiological and genetic basis of these channelopathies, describes their clinical manifestations, and comments on the principles of diagnosis, risk stratification and therapy.

Sudden cardiac arrest occurring in temporal proximity to consumption of energy drinks.

BACKGROUND: Energy drinks potentially can trigger life-threatening cardiac arrhythmias. It has been postulated that the highly stimulating and unregulated ingredients alter heart rate, blood pressure, cardiac contractility, and cardiac repolarization in a potentially proarrhythmic manner. OBJECTIVE: The purpose of this study was to describe our experience regarding sudden cardiac arrest (SCA) occurring in proximity to energy drink consumption in patients with underlying genetic heart diseases. METHODS: The electronic medical records of all SCA survivors with proven arrhythmias referred to the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic for evaluation were reviewed to identify those who consumed an energy drink before their event. Patient demographics, clinical characteristics, documented energy drink consumption, and temporal relationship of energy drink consumption to SCA were obtained. RESULTS: Among 144 SCA survivors, 7 (5%; 6 female; mean age at SCA 29 ± 8 years) experienced an unexplained SCA associated temporally with energy drink consumption. Of these individuals, 2 had long QT syndrome and 2 had catecholaminergic polymorphic ventricular tachycardia; the remaining 3 were diagnosed with idiopathic ventricular fibrillation. Three patients (43%) consumed energy drinks regularly. Six patients (86%) required a rescue shock, and 1 (14%) was resuscitated manually. All SCA survivors have quit consuming energy drinks and have been event-free since. CONCLUSION: Overall, 5% of SCA survivors experienced SCA in proximity to consuming an energy drink. Although larger cohort studies are needed to elucidate the incidence/prevalence and quantify its precise risk, it seems prudent to sound an early warning on this potential risk.

Holter study of heart rate variability in children and adolescents with long QT syndrome.

OBJECTIVES: This study aimed to retrospectively assess cardiac autonomic activity in children with LQTS, considering genotype, symptoms, sex, age, and beta-blocker therapy (BB) and compare it to healthy controls. METHODS: Heart rate variability (HRV), using power spectrum analysis, was analyzed in 575 Holter recordings from 116 children with LQTS and in 69 healthy children. The data were categorized into four age-groups and four heart rate (HR) ranges. RESULTS: In LQT1 and LQT2, increasing HR corresponded to significantly lower low (LF) and high frequency (HF) compared to controls. Total power (PTOT) was lower in all LQT1 age-groups compared to controls at HR 120-140 bpm (1-15 years: p < .01; 15-18 years: p = .03). At HR 80-100, LQT1 patients aged 1-10 years had lower HF than LQT2 patients (1-5 years: p = .05; 5-10 years: p = .02), and LQT2 patients aged 15-18 years had lower HF than LQT1 patients (p < .01). Symptomatic patients aged 10-15 years had lower PTOT at HR 100-120 bpm than asymptomatic patients (p = .04). LQT1 girls aged 10-15 and 15-18 years had a lower PTOT (10-15 years: p = .04; 15-18 years: p = .02) than boys. CONCLUSION: This study shows a correlation between HR and changes in HRV parameters. At higher HRs, LQTS patients generally had lower HRV values than controls, suggesting an abnormal autonomic response. These results may strengthen the link between physical activity and arrhythmias in LQTS.

Making sense of Timothy syndrome with 3D human neuronal models.

In a recent issue of Nature, Chen and colleagues1 reveal the potential for antisense oligonucleotides (ASOs) to rescue the neuropathological mechanisms underlying Timothy syndrome (TS) using three-dimensional neuronal models. Combining in vitro and in vivo approaches, the authors present a strategy to translate disease biology findings into potential therapeutics.

Pediatric and Familial Genetic Arrhythmia Syndromes: Evaluation of Bidirectional Ventricular Tachycardia-Differential Diagnosis.

Bidirectional ventricular tachycardia is a unique arrhythmia that can herald lethal arrhythmia syndromes. Using cases based on real patient stories, this article examines 3 different presentations to help clinicians learn the differential diagnosis associated with this condition. Each associated genetic disorder will be briefly discussed, and valuable tips for distinguishing them from each other will be provided.

Giant T waves and QT interval prolongation associated with guanfacine toxicity.

INTRODUCTION: Guanfacine is a central α2-adrenergic receptor agonist that produces drowsiness, bradycardia, hypotension, and occasionally QT interval prolongation. We discuss giant T waves associated with guanfacine toxicity. CASE SUMMARIES: Three patients presented to the hospital with histories and physical findings compatible with guanfacine toxicity. Supratherapeutic concentrations were confirmed in two of them. All three developed QT interval prolongation and giant T waves on the electrocardiogram. Giant T waves occur commonly in patients with acute myocardial infarct and hyperkalemia, as well as rarely with a number of other cardiac and non-cardiac causes. CONCLUSION: Guanfacine toxicity may cause the novel electrocardiographic finding of 'giant T wave with QT interval prolongation'. Further studies are warranted to investigate the association between the novel electrocardiographic finding and guanfacine toxicity, as well as its diagnostic utility in such cases.

Pediatric and Familial Genetic Arrhythmia Syndromes-Evaluation of Prolonged QTc-Differential Diagnosis and what You Need to Know.

The case series reviews differential diagnosis of a genetic arrhythmia syndrome when evaluating a patient with prolonged QTc. Making the correct diagnosis requires: detailed patient history, family history, and careful review of the electrocardiogram (ECG). Signs and symptoms and ECG characteristics can often help clinicians make the diagnosis before genetic testing results return. These skills can help clinicians make an accurate and timely diagnosis and prevent life-threatening events.

Pediatric and Familial Genetic Arrhythmia Syndromes: SCN5A-Related Disorders When It Is Not Long QT Type 3: Clinical Signs and Symptoms.

The following case series presents three different pediatric patients with SCN5A-related disease. In addition, family members are presented to demonstrate the variable penetrance that is commonly seen. Identifying features of this disease is important, because even in the very young, SCN5A disorders can cause lethal arrhythmias and sudden death.

A comparison of the performance of contemporary, historical, and cross-lab controls in QTc assessment in conscious nonhuman primates.

Cardiovascular safety pharmacology and toxicology studies include vehicle control animals in most studies. Electrocardiogram data on common vehicles is accumulated relatively quickly. In the interests of the 3Rs principles it may be useful to use this historical information to reduce the use of animals or to refine the sensitivity of studies. We used implanted telemetry data from a large nonhuman primate (NHP) cardiovascular study (n = 48) evaluating the effect of moxifloxacin. We extracted 24 animals to conduct a n = 3/sex/group analysis. The remaining 24 animals were used to generate 1000 unique combinations of 3 male and 3 female NHP to act as control groups for the three treated groups in the n = 3/sex/group analysis. The distribution of treatment effects, median minimum detectable difference (MDD) values were gathered from the 1000 studies. These represent contemporary controls. Data were available from 42 NHP from 3 other studies in the same laboratory using the same technology. These were used to generate 1000 unique combinations of 6, 12, 18, 24 and 36 NHP to act as historical control animals for the 18 animals in the treated groups of the moxifloxacin study. Data from an additional laboratory were also available for 20 NHP. The QT, RR and QT-RR data from the three sources were comparable. However, differences in the time course of QTc effect in the vehicle data from the two laboratories meant that it was not possible to use cross-lab controls. In the case of historical controls from the same laboratory, these could be used in place of the contemporary controls in determining a treatment's effect. There appeared to be an advantage in using larger (≥18) group sizes for historical controls. These data support the opportunity of using historical controls to reduce the number of animals used in new cardiovascular studies.

Wearable electrocardiogram devices in patients with congenital long QT syndrome: The SMART-QT study.

BACKGROUND: In patients with congenital long QT syndrome (LQTS), the risk of ventricular arrhythmia is correlated with the duration of the corrected QT interval and the changes in the ST-T wave pattern on the 12-lead surface electrocardiogram (12L-ECG). Remote monitoring of these variables could be useful. AIM: To evaluate the abilities of two wearable electrocardiogram devices (Apple Watch and KardiaMobile 6L) to provide reliable electrocardiograms in terms of corrected QT interval and ST-T wave patterns in patients with LQTS. METHODS: In a prospective multicentre study (ClinicalTrials.gov identifier: NCT04728100), a 12L-ECG, a 6-lead KardiaMobile 6L electrocardiogram and two single-lead Apple Watch electrocardiograms were recorded in patients with LQTS. The corrected QT interval and ST-T wave patterns were evaluated manually. RESULTS: Overall, 98 patients with LQTS were included; 12.2% were children and 92.8% had a pathogenic variant in an LQTS gene. The main genotypes were LQTS type 1 (40.8%), LQTS type 2 (36.7%) and LQTS type 3 (7.1%); rarer genotypes were also represented. When comparing the ST-T wave patterns obtained with the 12L-ECG, the level of agreement was moderate with the Apple Watch (k=0.593) and substantial with the KardiaMobile 6L (k=0.651). Regarding the corrected QT interval, the correlation with 12L-ECG was strong for the Apple Watch (r=0.703 in lead II) and moderate for the KardiaMobile 6L (r=0.593). There was a slight overestimation of corrected QT interval with the Apple Watch and a subtle underestimation with the KardiaMobile 6L. CONCLUSIONS: In patients with LQTS, the corrected QT interval and ST-T wave patterns obtained with the Apple Watch and the KardiaMobile 6L correlated with the 12L-ECG. Although wearable electrocardiogram devices cannot replace the 12L-ECG for the follow-up of these patients, they could be interesting additional monitoring tools.

Determinants/Predictors of QT Abnormalities in Patients on Psychotropic Medications in a Nigerian Tertiary Hospital.

Cardiovascular disease is a major global burden and a leading cause of premature death among patients with severe mental illness. Over time, research and clinical practice have paid increased attention to the impact of psychiatric medications on cardiac repolarization. In a resource-limited setting, it is common for psychotropic medications to be initiated and maintained in an outpatient setting without baseline or follow up ECG. This study evaluated the determinants and predictors of QT abnormalities among patient taking psychotropic drugs. We conducted a cross-sectional study in a population of 150 psychiatric patients on psychotropics and 75 controls. We studied the effects of various psychotropic drugs on QT dispersion (QTd) and corrected QT interval (QTc) as well as correlation with the types and dosages of psychotropic drugs used. All the subjects had detailed clinical examination and resting electrocardiogram (ECG) at 25 mm/sec done. QTc was determined using Bazett formula and QTd was determined by subtracting shortest from longest QT in 12-lead ECG. The prevalence of prolonged QTc and QTd as well as the mean QTc and QTd were significantly higher in patients than the control group. The mean QTc was significantly higher in patient on typical antipsychotics compared to those on atypical antipsychotics. Age, heart rate and antipsychotic dose in chlorpromazine equivalent were predictors of QTc with the heart rate being the most powerful predictor among them. Psychotropic drugs use is associated with QTc and QTd prolongation with age, heart rate and antipsychotic dose as predictors of QTc.