Asunto(s)

Trastorno Autístico , Modelos Animales de Enfermedad , Síndrome de QT Prolongado , Sindactilia , Animales , Humanos , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatología , Trastorno Autístico/genética , Trastorno Autístico/fisiopatología , Discapacidades del Desarrollo/genética , Técnicas de Sustitución del Gen , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/diagnóstico , Porcinos , Sindactilia/genética

RESUMEN

Heart failure (HF) with reduced ejection fraction (HFrEF) is a risk factor for drug-induced QT interval prolongation. It is unknown if HF with preserved ejection fraction (HFpEF) is also associated with an increased risk. Dofetilide and sotalol are potent QT interval-prolonging agents that are frequently used in patients with HFpEF, in whom atrial fibrillation is a common comorbidity. We tested the hypothesis that the risk of QT interval prolongation associated with dofetilide and sotalol is increased in patients with HFpEF. We conducted a retrospective cohort study conducted using electronic health records from the Indiana Network for Patient Care (January 31, 2010 -May 3, 2021). After removing patients with overlapping diagnoses of HFpEF and HFrEF, no diagnosis code, and absence of QT interval records, we identified patients taking dofetilide or sotalol among three groups: HFrEF (n = 138), HFpEF (n = 109), and no HF (n = 729). QT prolongation was defined as heart rate-corrected QT (QTc) > 500 ms during dofetilide/sotalol therapy. Unadjusted odds ratios (OR) for QT prolongation were determined by univariate analysis. Adjusted ORs were determined by generalized estimating equations (GEE) with logit link to account for an individual cluster with different times of hospitalization and covariates. QTc prolongation associated with dofetilide or sotalol occurred in 53.2%, 71.7% and 30.0% of patients with HFpEF, HFrEF, and patients with no HF, respectively. After adjusting for age, sex, race, serum potassium and magnesium concentrations, kidney function, concomitant drug therapy, and comorbid conditions, the adjusted odds of QTc prolongation were significantly higher in patients with HFpEF [OR = 1.98 (95% CI 1.17-3.33)], and in those with HFrEF [OR = 5.23, (3.15-8.67)], compared to those with no evidence of HF. The odds of QT prolongation among inpatients receiving dofetilide or sotalol were increased in patients with HFpEF and HFrEF compared to those who did not have HF.

Asunto(s)

Insuficiencia Cardíaca , Síndrome de QT Prolongado , Fenetilaminas , Sotalol , Volumen Sistólico , Sulfonamidas , Humanos , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/tratamiento farmacológico , Femenino , Masculino , Anciano , Fenetilaminas/efectos adversos , Sotalol/efectos adversos , Volumen Sistólico/efectos de los fármacos , Estudios Retrospectivos , Sulfonamidas/efectos adversos , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/epidemiología , Persona de Mediana Edad , Anciano de 80 o más Años , Electrocardiografía , Antiarrítmicos/efectos adversos , Factores de Riesgo

RESUMEN

BACKGROUND: Whether vigorous exercise increases risk of ventricular arrhythmias for individuals diagnosed and treated for congenital long QT syndrome (LQTS) remains unknown. METHODS: The National Institutes of Health-funded LIVE-LQTS study (Lifestyle and Exercise in the Long QT Syndrome) prospectively enrolled individuals 8 to 60 years of age with phenotypic and/or genotypic LQTS from 37 sites in 5 countries from May 2015 to February 2019. Participants (or parents) answered physical activity and clinical events surveys every 6 months for 3 years with follow-up completed in February 2022. Vigorous exercise was defined as ≥6 metabolic equivalents for >60 hours per year. A blinded Clinical Events Committee adjudicated the composite end point of sudden death, sudden cardiac arrest, ventricular arrhythmia treated by an implantable cardioverter defibrillator, and likely arrhythmic syncope. A National Death Index search ascertained vital status for those with incomplete follow-up. A noninferiority hypothesis (boundary of 1.5) between vigorous exercisers and others was tested with multivariable Cox regression analysis. RESULTS: Among the 1413 participants (13% <18 years of age, 35% 18-25 years of age, 67% female, 25% with implantable cardioverter defibrillators, 90% genotype positive, 49% with LQT1, 91% were treated with beta-blockers, left cardiac sympathetic denervation, and/or implantable cardioverter defibrillator), 52% participated in vigorous exercise (55% of these competitively). Thirty-seven individuals experienced the composite end point (including one sudden cardiac arrest and one sudden death in the nonvigorous group, one sudden cardiac arrest in the vigorous group) with overall event rates at 3 years of 2.6% in the vigorous and 2.7% in the nonvigorous exercise groups. The unadjusted hazard ratio for experience of events for the vigorous group compared with the nonvigorous group was 0.97 (90% CI, 0.57-1.67), with an adjusted hazard ratio of 1.17 (90% CI, 0.67-2.04). The upper 95% one-sided confidence level extended beyond the 1.5 boundary. Neither vigorous or nonvigorous exercise was found to be superior in any group or subgroup. CONCLUSIONS: Among individuals diagnosed with phenotypic and/or genotypic LQTS who were risk assessed and treated in experienced centers, LQTS-associated cardiac event rates were low and similar between those exercising vigorously and those not exercising vigorously. Consistent with the low event rate, CIs are wide, and noninferiority was not demonstrated. These data further inform shared decision-making discussions between patient and physician about exercise and competitive sports participation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02549664.

Asunto(s)

Ejercicio Físico , Síndrome de QT Prolongado , Humanos , Síndrome de QT Prolongado/terapia , Síndrome de QT Prolongado/congénito , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/mortalidad , Femenino , Masculino , Adolescente , Niño , Estudios Prospectivos , Adulto , Persona de Mediana Edad , Adulto Joven , Muerte Súbita Cardíaca/prevención & control , Muerte Súbita Cardíaca/epidemiología , Factores de Riesgo

RESUMEN

BACKGROUND: CaM (calmodulin)-mediated long-QT syndrome is a genetic arrhythmia disorder (calmodulinopathies) characterized by a high prevalence of life-threatening ventricular arrhythmias occurring early in life. Three distinct genes (CALM1, CALM2, and CALM3) encode for the identical CaM protein. Conventional pharmacotherapies fail to adequately protect against potentially lethal cardiac events in patients with calmodulinopathy. METHODS: Five custom-designed CALM1-, CALM2-, and CALM3-targeting short hairpin RNAs (shRNAs) were tested for knockdown (KD) efficiency using TSA201 cells and reverse transcription-quantitative polymerase chain reaction. A dual-component suppression and replacement (SupRep) CALM gene therapy (CALM-SupRep) was created by cloning into a single construct CALM1-, CALM2-, and CALM3-specific shRNAs that produce KD (suppression) of each respective gene and a shRNA-immune CALM1 cDNA (replacement). CALM1-F142L, CALM2-D130G, and CALM3-D130G induced pluripotent stem cell-derived CMs were generated from patients with CaM-mediated long-QT syndrome. A voltage-sensing dye was used to measure action potential duration at 90% repolarization (APD90). RESULTS: Following shRNA KD efficiency testing, a candidate shRNA was identified for CALM1 (86% KD), CALM2 (71% KD), and CALM3 (94% KD). The APD90 was significantly prolonged in CALM2-D130G (647±9 ms) compared with CALM2-WT (359±12 ms; P<0.0001). Transfection with CALM-SupRep shortened the average APD90 of CALM2-D130G to 457±19 ms (66% attenuation; P<0.0001). Additionally, transfection with CALM-SupRep shortened the APD90 of CALM1-F142L (665±9 to 410±15 ms; P<0.0001) and CALM3-D130G (978±81 to 446±6 ms; P<0.001). CONCLUSIONS: We provide the first proof-of-principle suppression-replacement gene therapy for CaM-mediated long-QT syndrome. The CALM-SupRep gene therapy shortened the pathologically prolonged APD90 in CALM1-, CALM2-, and CALM3-variant CaM-mediated long-QT syndrome induced pluripotent stem cell-derived CM lines. The single CALM-SupRep construct may be able to treat all calmodulinopathies, regardless of which of the 3 CaM-encoding genes are affected.

Asunto(s)

Calmodulina , Terapia Genética , Síndrome de QT Prolongado , Humanos , Calmodulina/genética , Calmodulina/metabolismo , Terapia Genética/métodos , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/terapia , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/metabolismo , Síndrome de QT Prolongado/diagnóstico , Miocitos Cardíacos/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Potenciales de Acción , Predisposición Genética a la Enfermedad , Mutación , Interferencia de ARN , Frecuencia Cardíaca/genética

RESUMEN

The studies regarding prevalence, outcomes, and predictors of prolonged corrected QT (QTc) among COVID-19 patients not on QTc-prolonging medication are not available in the literature. In this retrospective cohort study, the QTc of 295 hospital-admitted COVID-19 patients was analyzed and its association with in-hospital mortality was determined. The QTc was prolonged in 14.6% (43/295) of the study population. Prolonged QTc was seen in patients with older age (P = 0.018), coronary artery disease (P = 0.001), congestive heart failure (P = 0.042), elevated N-terminal-pro-B-type natriuretic peptide (NT-ProBNP) (P < 0.0001), and on remdesivir (P = 0.046). No episode of torsades de pointes arrhythmia or any arrhythmic death was observed among patients with prolonged QTc. The mortality was significantly high in patients with prolonged QTc (P = 0.003). The multivariate logistic regression analysis showed coronary artery disease (odds ratio (OR): 4.153, 95% CI 1.37-14.86; P = 0.013), and NT-ProBNP (ng/L) (OR: 1.000, 95% CI 1.000-1.000; P = 0.007) as predictors of prolonged QTc. The prolonged QTc was associated with the worst in-hospital survival (p by log-rank 0.001). A significant independent association was observed between prolonged QTc and in-hospital mortality in multivariate cox-regression analysis (adjusted hazard ratio: 3.861; (95% CI 1.719-6.523), P < 0.0001). QTc was found to be a marker of underlying comorbidities among COVID-19 patients. Prolonged QTc in hospitalized COVID-19 patients was independently associated with in-hospital mortality.

Asunto(s)

COVID-19 , Mortalidad Hospitalaria , Síndrome de QT Prolongado , Humanos , Masculino , Femenino , COVID-19/mortalidad , COVID-19/diagnóstico , COVID-19/epidemiología , COVID-19/complicaciones , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/epidemiología , Síndrome de QT Prolongado/mortalidad , Síndrome de QT Prolongado/fisiopatología , Prevalencia , Factores de Riesgo , Hidroxicloroquina/uso terapéutico , Hidroxicloroquina/efectos adversos , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19 , Electrocardiografía , Hospitalización , Medición de Riesgo , Anciano de 80 o más Años , Frecuencia Cardíaca

RESUMEN

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.

Asunto(s)

Potenciales de Acción , Canales de Calcio Tipo L , Simulación por Computador , Síndrome de QT Prolongado , Sindactilia , Humanos , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/fisiopatología , Canales de Calcio Tipo L/genética , Sindactilia/genética , Sindactilia/fisiopatología , Mutación , Trastorno Autístico/genética , Trastorno Autístico/fisiopatología , Ventrículos Cardíacos/fisiopatología , Modelos Cardiovasculares , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatología , Taquicardia Ventricular/genética , Taquicardia Ventricular/fisiopatología

Asunto(s)

Potenciales de Acción , Células Madre Pluripotentes Inducidas , Síndrome de QT Prolongado , Miocitos Cardíacos , Humanos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/fisiopatología , Potenciales de Acción/efectos de los fármacos , Fenotipo , Frecuencia Cardíaca/efectos de los fármacos , Variantes Farmacogenómicas

Asunto(s)

Potenciales de Acción , Células Madre Pluripotentes Inducidas , Síndrome de QT Prolongado , Miocitos Cardíacos , Humanos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Femenino , Estrógenos/farmacología , Estrógenos/metabolismo , Estradiol/farmacología , Fenotipo

RESUMEN

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.

Asunto(s)

Arritmias Cardíacas , Síndrome de Brugada , Canalopatías , Humanos , Arritmias Cardíacas/genética , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/terapia , Arritmias Cardíacas/fisiopatología , Canalopatías/genética , Canalopatías/diagnóstico , Canalopatías/terapia , Síndrome de Brugada/genética , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/fisiopatología , Síndrome de Brugada/terapia , Taquicardia Ventricular/genética , Taquicardia Ventricular/terapia , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatología , Adolescente , Niño , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/terapia , Síndrome de QT Prolongado/fisiopatología , Muerte Súbita Cardíaca/prevención & control , Muerte Súbita Cardíaca/etiología , Adulto , Desfibriladores Implantables , Electrocardiografía

RESUMEN

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.

Asunto(s)

Potenciales de Acción , Bloqueo de Rama , Electrocardiografía , Síndrome de QT Prolongado , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Bloqueo de Rama/fisiopatología , Bloqueo de Rama/diagnóstico , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/diagnóstico , Frecuencia Cardíaca , Valor Predictivo de las Pruebas , Anciano , Estudios de Casos y Controles , Factores de Tiempo , Ventrículos Cardíacos/fisiopatología , Ventrículos Cardíacos/diagnóstico por imagen , Factores de Edad , Mapeo Epicárdico

RESUMEN

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.

Asunto(s)

Electrocardiografía Ambulatoria , Prueba de Esfuerzo , Síndrome de QT Prolongado , Humanos , Femenino , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/fisiopatología , Masculino , Prueba de Esfuerzo/métodos , Medición de Riesgo/métodos , Adulto , Electrocardiografía Ambulatoria/métodos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Factores de Riesgo , Adulto Joven , Pronóstico , Factores de Tiempo , Estudios Retrospectivos , Frecuencia Cardíaca/fisiología

Asunto(s)

Síndrome de QT Prolongado , Humanos , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/genética

RESUMEN

BACKGROUND: Despite major advances in the clinical management of long QT syndrome, some patients are not fully protected by beta-blocker therapy. Mexiletine is a well-known sodium channel blocker, with proven efficacy in patients with sodium channel-mediated long QT syndrome type 3. Our aim was to evaluate the efficacy of mexiletine in long QT syndrome type 2 (LQT2) using cardiomyocytes derived from patient-specific human induced pluripotent stem cells, a transgenic LQT2 rabbit model, and patients with LQT2. METHODS: Heart rate-corrected field potential duration, a surrogate for QTc, was measured in human induced pluripotent stem cells from 2 patients with LQT2 (KCNH2-p.A561V, KCNH2-p.R366X) before and after mexiletine using a multiwell multi-electrode array system. Action potential duration at 90% repolarization (APD90) was evaluated in cardiomyocytes isolated from transgenic LQT2 rabbits (KCNH2-p.G628S) at baseline and after mexiletine application. Mexiletine was given to 96 patients with LQT2. Patients were defined as responders in the presence of a QTc shortening ≥40 ms. Antiarrhythmic efficacy of mexiletine was evaluated by a Poisson regression model. RESULTS: After acute treatment with mexiletine, human induced pluripotent stem cells from both patients with LQT2 showed a significant shortening of heart rate-corrected field potential duration compared with dimethyl sulfoxide control. In cardiomyocytes isolated from LQT2 rabbits, acute mexiletine significantly shortened APD90 by 113 ms, indicating a strong mexiletine-mediated shortening across different LQT2 model systems. Mexiletine was given to 96 patients with LQT2 either chronically (n=60) or after the acute oral drug test (n=36): 65% of the patients taking mexiletine only chronically and 75% of the patients who performed the acute oral test were responders. There was a significant correlation between basal QTc and ∆QTc during the test (r= -0.8; P<0.001). The oral drug test correctly predicted long-term effect in 93% of the patients. Mexiletine reduced the mean yearly event rate from 0.10 (95% CI, 0.07-0.14) to 0.04 (95% CI, 0.02-0.08), with an incidence rate ratio of 0.40 (95% CI, 0.16-0.84), reflecting a 60% reduction in the event rate (P=0.01). CONCLUSIONS: Mexiletine significantly shortens cardiac repolarization in LQT2 human induced pluripotent stem cells, in the LQT2 rabbit model, and in the majority of patients with LQT2. Furthermore, mexiletine showed antiarrhythmic efficacy. Mexiletine should therefore be considered a valid therapeutic option to be added to conventional therapies in higher-risk patients with LQT2.

Asunto(s)

Animales Modificados Genéticamente , Células Madre Pluripotentes Inducidas , Síndrome de QT Prolongado , Mexiletine , Miocitos Cardíacos , Mexiletine/farmacología , Mexiletine/uso terapéutico , Animales , Humanos , Conejos , Miocitos Cardíacos/efectos de los fármacos , Síndrome de QT Prolongado/tratamiento farmacológico , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/genética , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Masculino , Femenino , Adulto , Potenciales de Acción/efectos de los fármacos , Antiarrítmicos/farmacología , Antiarrítmicos/uso terapéutico , Adolescente , Persona de Mediana Edad , Adulto Joven , Canal de Potasio ERG1/genética , Canal de Potasio ERG1/antagonistas & inhibidores , Canal de Potasio ERG1/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Modelos Animales de Enfermedad , Niño , Resultado del Tratamiento

Asunto(s)

Electrocardiografía , Síndrome de QT Prolongado , Humanos , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/diagnóstico , Electrocardiografía/métodos

RESUMEN

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.

Asunto(s)

Muerte Súbita Cardíaca , Bebidas Energéticas , Humanos , Femenino , Masculino , Bebidas Energéticas/efectos adversos , Adulto , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/epidemiología , Estudios Retrospectivos , Adulto Joven , Incidencia , Electrocardiografía , Factores de Riesgo , Taquicardia Ventricular/etiología , Taquicardia Ventricular/fisiopatología , Taquicardia Ventricular/epidemiología , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/inducido químicamente

RESUMEN

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.

Asunto(s)

Electrocardiografía Ambulatoria , Frecuencia Cardíaca , Síndrome de QT Prolongado , Humanos , Adolescente , Femenino , Niño , Masculino , Frecuencia Cardíaca/fisiología , Electrocardiografía Ambulatoria/métodos , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/genética , Estudios Retrospectivos , Preescolar , Lactante , Estudios de Casos y Controles , Antagonistas Adrenérgicos beta/uso terapéutico

RESUMEN

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.

Asunto(s)

Trastorno Autístico , Síndrome de QT Prolongado , Neuronas , Sindactilia , Humanos , Trastorno Autístico/genética , Trastorno Autístico/patología , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/fisiopatología , Sindactilia/genética , Oligonucleótidos Antisentido/farmacología , Animales

RESUMEN

INTRODUCTION: Cardiovascular safety and the risk of developing the potentially fatal ventricular tachyarrhythmia, Torsades de Pointes (TdP), have long been major concerns of drug development. TdP is associated with a delayed ventricular repolarization represented by QT interval prolongation in the electrocardiogram (ECG), typically due to block of the potassium channel encoded by the human ether-a-go-go related gene (hERG). Importantly however, not all drugs that prolong the QT interval are torsadagenic and not all hERG blockers prolong the QT interval. Recent clinical reports suggest that partitioning the QT interval into early (J to T peak; JTp) and late repolarization (T peak to T end; TpTe) components may be valuable for distinguishing low-risk mixed ion channel blockers (hERG plus calcium and/or late sodium currents) from high-risk pure hERG channel blockers. This strategy, if true for nonclinical animal models, could be used to de-risk QT prolonging compounds earlier in the drug development process. METHODS: To explore this, we investigated JTp and TpTe in ECG data collected from telemetered dogs and/or monkeys administered moxifloxacin or amiodarone at doses targeting relevant clinical exposures. An optimized placement of the Tpeak fiducial mark was utilized, and all intervals were corrected for heart rate (QTc, JTpc, TpTec). RESULTS: Increases in QTc and JTpc intervals with administration of the pure hERG blocker moxifloxacin and an initial QTc and JTpc shortening followed by prolongation with the mixed ion channel blocker amiodarone were detected as expected, aligning with clinical data. However, anticipated increases in TpTec by both standard agents were not detected. DISCUSSION: The inability to detect changes in TpTec reduces the utility of these subintervals for prediction of arrhythmias using continuous single­lead ECGs collected from freely moving dogs and monkeys.

Asunto(s)

Amiodarona , Electrocardiografía , Síndrome de QT Prolongado , Moxifloxacino , Torsades de Pointes , Animales , Moxifloxacino/administración & dosificación , Moxifloxacino/farmacología , Perros , Amiodarona/administración & dosificación , Amiodarona/farmacología , Electrocardiografía/efectos de los fármacos , Electrocardiografía/métodos , Torsades de Pointes/inducido químicamente , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/fisiopatología , Masculino , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Femenino , Macaca fascicularis , Fluoroquinolonas/administración & dosificación , Fluoroquinolonas/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Bloqueadores de los Canales de Potasio/administración & dosificación , Bloqueadores de los Canales de Potasio/farmacología , Canal de Potasio ERG1/antagonistas & inhibidores , Canal de Potasio ERG1/metabolismo

Asunto(s)

Electrocardiografía , Clorhidrato de Venlafaxina , Humanos , Electrocardiografía/métodos , Epilepsia/tratamiento farmacológico , Epilepsia/fisiopatología , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/fisiopatología , Antidepresivos de Segunda Generación/envenenamiento , Masculino , Femenino , Convulsiones/inducido químicamente , Adulto

RESUMEN

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.

Asunto(s)

Agonistas de Receptores Adrenérgicos alfa 2 , Electrocardiografía , Guanfacina , Síndrome de QT Prolongado , Humanos , Electrocardiografía/efectos de los fármacos , Agonistas de Receptores Adrenérgicos alfa 2/envenenamiento , Masculino , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/fisiopatología , Femenino , Persona de Mediana Edad , Adulto