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The complexity of cardiac electrophysiology, involving dynamic changes in numerous components across multiple spatial (from ion channel to organ) and temporal (from milliseconds to days) scales, makes an intuitive or empirical analysis of cardiac arrhythmogenesis challenging. Multiscale mechanistic computational models of cardiac electrophysiology provide precise control over individual parameters, and their reproducibility enables a thorough assessment of arrhythmia mechanisms. This review provides a comprehensive analysis of models of cardiac electrophysiology and arrhythmias, from the single cell to the organ level, and how they can be leveraged to better understand rhythm disorders in cardiac disease and to improve heart patient care. Key issues related to model development based on experimental data are discussed, and major families of human cardiomyocyte models and their applications are highlighted. An overview of organ-level computational modeling of cardiac electrophysiology and its clinical applications in personalized arrhythmia risk assessment and patient-specific therapy of atrial and ventricular arrhythmias is provided. The advancements presented here highlight how patient-specific computational models of the heart reconstructed from patient data have achieved success in predicting risk of sudden cardiac death and guiding optimal treatments of heart rhythm disorders. Finally, an outlook toward potential future advances, including the combination of mechanistic modeling and machine learning/artificial intelligence, is provided. As the field of cardiology is embarking on a journey toward precision medicine, personalized modeling of the heart is expected to become a key technology to guide pharmaceutical therapy, deployment of devices, and surgical interventions.
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Arritmias Cardíacas , Modelos Cardiovasculares , Humanos , Arritmias Cardíacas/fisiopatología , Animales , Simulación por Computador , Investigación Biomédica Traslacional , Miocitos Cardíacos/fisiología , Fenómenos Electrofisiológicos/fisiología , Potenciales de Acción/fisiologíaRESUMEN
AIM: The "2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy" provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy. METHODS: A comprehensive literature search was conducted from September 14, 2022, to November 22, 2022, encompassing studies, reviews, and other evidence on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through May 23, 2023, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE: Hypertrophic cardiomyopathy remains a common genetic heart disease reported in populations globally. Recommendations from the "2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy" have been updated with new evidence to guide clinicians.
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American Heart Association , Cardiología , Cardiomiopatía Hipertrófica , Humanos , Cardiología/normas , Cardiomiopatía Hipertrófica/terapia , Cardiomiopatía Hipertrófica/diagnóstico , Manejo de la Enfermedad , Estados UnidosRESUMEN
BACKGROUND: Ventricular arrhythmia and sudden cardiac death are the most common lethal complications after myocardial infarction. Antiarrhythmic pharmacotherapy remains a clinical challenge and novel concepts are highly desired. Here, we focus on the cardioprotective CNP (C-type natriuretic peptide) as a novel antiarrhythmic principle. We hypothesize that antiarrhythmic effects of CNP are mediated by PDE2 (phosphodiesterase 2), which has the unique property to be stimulated by cGMP to primarily hydrolyze cAMP. Thus, CNP might promote beneficial effects of PDE2-mediated negative crosstalk between cAMP and cGMP signaling pathways. METHODS: To determine antiarrhythmic effects of cGMP-mediated PDE2 stimulation by CNP, we analyzed arrhythmic events and intracellular trigger mechanisms in mice in vivo, at organ level and in isolated cardiomyocytes as well as in human-induced pluripotent stem cell-derived cardiomyocytes. RESULTS: In ex vivo perfused mouse hearts, CNP abrogated arrhythmia after ischemia/reperfusion injury. Upon high-dose catecholamine injections in mice, PDE2 inhibition prevented the antiarrhythmic effect of CNP. In mouse ventricular cardiomyocytes, CNP blunted the catecholamine-mediated increase in arrhythmogenic events as well as in ICaL, INaL, and Ca2+ spark frequency. Mechanistically, this was driven by reduced cellular cAMP levels and decreased phosphorylation of Ca2+ handling proteins. Key experiments were confirmed in human iPSC-derived cardiomyocytes. Accordingly, the protective CNP effects were reversed by either specific pharmacological PDE2 inhibition or cardiomyocyte-specific PDE2 deletion. CONCLUSIONS: CNP shows strong PDE2-dependent antiarrhythmic effects. Consequently, the CNP-PDE2 axis represents a novel and attractive target for future antiarrhythmic strategies.
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Miocitos Cardíacos , Hidrolasas Diéster Fosfóricas , Ratones , Animales , Humanos , Hidrolasas Diéster Fosfóricas/metabolismo , Miocitos Cardíacos/metabolismo , Transducción de Señal , Catecolaminas/metabolismo , Arritmias Cardíacas/tratamiento farmacológico , Arritmias Cardíacas/etiología , Arritmias Cardíacas/prevención & control , Antiarrítmicos/farmacología , Antiarrítmicos/uso terapéutico , Antiarrítmicos/metabolismo , GMP Cíclico/metabolismo , Péptido Natriurético Tipo-C/farmacologíaRESUMEN
BACKGROUND AND AIMS: Electrocardiogram (ECG) abnormalities have been evaluated as static risk markers for sudden cardiac death (SCD), but the potential importance of dynamic ECG remodelling has not been investigated. In this study, the nature and prevalence of dynamic ECG remodelling were studied among individuals who eventually suffered SCD. METHODS: The study population was drawn from two prospective community-based SCD studies in Oregon (2002, discovery cohort) and California, USA (2015, validation cohort). For this present sub-study, 231 discovery cases (2015-17) and 203 validation cases (2015-21) with ≥2 archived pre-SCD ECGs were ascertained and were matched to 234 discovery and 203 validation controls based on age, sex, and duration between the ECGs. Dynamic ECG remodelling was measured as progression of a previously validated cumulative six-variable ECG electrical risk score. RESULTS: Oregon SCD cases displayed greater electrical risk score increase over time vs. controls [+1.06 (95% confidence interval +0.89 to +1.24) vs. -0.05 (-0.21 to +0.11); P < .001]. These findings were successfully replicated in California [+0.87 (+0.7 to +1.04) vs. -0.11 (-0.27 to 0.05); P < .001]. In multivariable models, abnormal dynamic ECG remodelling improved SCD prediction over baseline ECG, demographics, and clinical SCD risk factors in both Oregon [area under the receiver operating characteristic curve 0.770 (95% confidence interval 0.727-0.812) increased to area under the receiver operating characteristic curve 0.869 (95% confidence interval 0.837-0.902)] and California cohorts. CONCLUSIONS: Dynamic ECG remodelling improved SCD risk prediction beyond clinical factors combined with the static ECG, with successful validation in a geographically distinct population. These findings introduce a novel concept of SCD dynamic risk and warrant further detailed investigation.
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Arritmias Cardíacas , Muerte Súbita Cardíaca , Humanos , Estudios Prospectivos , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Arritmias Cardíacas/complicaciones , Factores de Riesgo , Electrocardiografía/efectos adversosRESUMEN
BACKGROUND AND AIMS: Pathogenic desmoplakin (DSP) gene variants are associated with the development of a distinct form of arrhythmogenic cardiomyopathy known as DSP cardiomyopathy. Patients harbouring these variants are at high risk for sustained ventricular arrhythmia (VA), but existing tools for individualized arrhythmic risk assessment have proven unreliable in this population. METHODS: Patients from the multi-national DSP-ERADOS (Desmoplakin SPecific Effort for a RAre Disease Outcome Study) Network patient registry who had pathogenic or likely pathogenic DSP variants and no sustained VA prior to enrolment were followed longitudinally for the development of first sustained VA event. Clinically guided, step-wise Cox regression analysis was used to develop a novel clinical tool predicting the development of incident VA. Model performance was assessed by c-statistic in both the model development cohort (n = 385) and in an external validation cohort (n = 86). RESULTS: In total, 471 DSP patients [mean age 37.8 years, 65.6% women, 38.6% probands, 26% with left ventricular ejection fraction (LVEF) < 50%] were followed for a median of 4.0 (interquartile range: 1.6-7.3) years; 71 experienced first sustained VA events {2.6% [95% confidence interval (CI): 2.0, 3.5] events/year}. Within the development cohort, five readily available clinical parameters were identified as independent predictors of VA and included in a novel DSP risk score: female sex [hazard ratio (HR) 1.9 (95% CI: 1.1-3.4)], history of non-sustained ventricular tachycardia [HR 1.7 (95% CI: 1.1-2.8)], natural logarithm of 24-h premature ventricular contraction burden [HR 1.3 (95% CI: 1.1-1.4)], LVEF < 50% [HR 1.5 (95% CI: .95-2.5)], and presence of moderate to severe right ventricular systolic dysfunction [HR 6.0 (95% CI: 2.9-12.5)]. The model demonstrated good risk discrimination within both the development [c-statistic .782 (95% CI: .77-.80)] and external validation [c-statistic .791 (95% CI: .75-.83)] cohorts. The negative predictive value for DSP patients in the external validation cohort deemed to be at low risk for VA (<5% at 5 years; n = 26) was 100%. CONCLUSIONS: The DSP risk score is a novel model that leverages readily available clinical parameters to provide individualized VA risk assessment for DSP patients. This tool may help guide decision-making for primary prevention implantable cardioverter-defibrillator placement in this high-risk population and supports a gene-first risk stratification approach.
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Desmoplaquinas , Humanos , Desmoplaquinas/genética , Femenino , Masculino , Medición de Riesgo/métodos , Adulto , Persona de Mediana Edad , Arritmias Cardíacas/genética , Heterocigoto , Taquicardia Ventricular/genéticaRESUMEN
BACKGROUND AND AIMS: Risk scores are proposed for genetic arrhythmias. Having proposed in 2010 one such score (M-FACT) for the long QT syndrome (LQTS), this study aims to test whether adherence to its suggestions would be appropriate. METHODS: LQT1/2/3 and genotype-negative patients without aborted cardiac arrest (ACA) before diagnosis or cardiac events (CEs) below age 1 were included in the study, focusing on an M-FACT score ≥2 (intermediate/high risk), either at presentation (static) or during follow-up (dynamic), previously associated with 40% risk of implantable cardioverter defibrillator (ICD) shocks within 4 years. RESULTS: Overall, 946 patients (26 ± 19 years at diagnosis, 51% female) were included. Beta-blocker (ßB) therapy in 94% of them reduced the rate of those with a QTc ≥500â ms from 18% to 12% (P < .001). During 7 ± 6 years of follow-up, none died; 4% had CEs, including 0.4% with ACA. A static M-FACT ≥2 was present in 110 patients, of whom 106 received ßBs. In 49/106 patients with persistent dynamic M-FACT ≥2, further therapeutic optimization (left cardiac sympathetic denervation in 55%, mexiletine in 31%, and ICD at 27%) resulted in just 7 (14%) patients with CEs (no ACA), with no CEs in the remaining 57. Additionally, 32 patients developed a dynamic M-FACT ≥2 but, after therapeutic optimization, only 3 (9%) had CEs. According to an M-FACT score ≥2, a total of 142 patients should have received an ICD, but only 22/142 (15%) were implanted, with shocks reported in 3. CONCLUSIONS: Beta-blockers often shorten QTc, thus changing risk scores and ICD indications for primary prevention. Yearly risk reassessment with therapy optimization leads to fewer ICD implants (3%) without increasing life-threatening events.
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Antagonistas Adrenérgicos beta , Desfibriladores Implantables , Síndrome de QT Prolongado , Humanos , Femenino , Masculino , Adulto , Síndrome de QT Prolongado/terapia , Antagonistas Adrenérgicos beta/uso terapéutico , Medición de Riesgo , Adulto Joven , Adolescente , Niño , Persona de Mediana Edad , Muerte Súbita Cardíaca/prevención & control , Muerte Súbita Cardíaca/etiología , Antiarrítmicos/uso terapéutico , Preescolar , Electrocardiografía , Factores de RiesgoRESUMEN
BACKGROUND AND AIMS: Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. METHODS: This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%-25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. RESULTS: One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. CONCLUSIONS: North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.
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Displasia Ventricular Derecha Arritmogénica , Desfibriladores Implantables , Humanos , Desfibriladores Implantables/efectos adversos , Displasia Ventricular Derecha Arritmogénica/complicaciones , Displasia Ventricular Derecha Arritmogénica/epidemiología , Displasia Ventricular Derecha Arritmogénica/terapia , Estudios Retrospectivos , Arritmias Cardíacas/epidemiología , Arritmias Cardíacas/terapia , Arritmias Cardíacas/etiología , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/prevención & control , Muerte Súbita Cardíaca/etiología , Factores de Riesgo , América del Norte/epidemiología , Europa (Continente)/epidemiologíaRESUMEN
Patients with severe mental illness (SMI) including schizophrenia and bipolar disorder die on average 15-20 years earlier than the general population often due to sudden death that, in most cases, is caused by cardiovascular disease. This state-of-the-art review aims to address the complex association between SMI and cardiovascular risk, explore disparities in cardiovascular care pathways, describe how to adequately predict cardiovascular outcomes, and propose targeted interventions to improve cardiovascular health in patients with SMI. These patients have an adverse cardiovascular risk factor profile due to an interplay between biological factors such as chronic inflammation, patient factors such as excessive smoking, and healthcare system factors such as stigma and discrimination. Several disparities in cardiovascular care pathways have been demonstrated in patients with SMI, resulting in a 47% lower likelihood of undergoing invasive coronary procedures and substantially lower rates of prescribed standard secondary prevention medications compared with the general population. Although early cardiovascular risk prediction is important, conventional risk prediction models do not accurately predict long-term cardiovascular outcomes as cardiovascular disease and mortality are only partly driven by traditional risk factors in this patient group. As such, SMI-specific risk prediction models and clinical tools such as the electrocardiogram and echocardiogram are necessary when assessing and managing cardiovascular risk associated with SMI. In conclusion, there is a necessity for differentiated cardiovascular care in patients with SMI. By addressing factors involved in the excess cardiovascular risk, reconsidering risk stratification approaches, and implementing multidisciplinary care models, clinicians can take steps towards improving cardiovascular health and long-term outcomes in patients with SMI.
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Enfermedades Cardiovasculares , Trastornos Mentales , Humanos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/terapia , Enfermedades Cardiovasculares/complicaciones , Factores de Riesgo , Trastornos Mentales/complicaciones , Trastornos Mentales/epidemiología , Trastornos Mentales/terapia , Medición de Riesgo , Factores de Riesgo de Enfermedad CardiacaRESUMEN
BACKGROUND AND AIMS: Available data on continuous rhythm monitoring by implantable loop recorders (ILRs) in patients with Brugada syndrome (BrS) are scarce. The aim of this multi-centre study was to evaluate the diagnostic yield and clinical implication of a continuous rhythm monitoring strategy by ILRs in a large cohort of BrS patients and to assess the precise arrhythmic cause of syncopal episodes. METHODS: A total of 370 patients with BrS and ILRs (mean age 43.5 ± 15.9, 33.8% female, 74.1% symptomatic) from 18 international centers were included. Patients were followed with continuous rhythm monitoring for a median follow-up of 3 years. RESULTS: During follow-up, an arrhythmic event was recorded in 30.7% of symptomatic patients [18.6% atrial arrhythmias (AAs), 10.2% bradyarrhythmias (BAs), and 7.3% ventricular arrhythmias (VAs)]. In patients with recurrent syncope, the aetiology was arrhythmic in 22.4% (59.3% BAs, 25.0% VAs, and 15.6% AAs). The ILR led to drug therapy initiation in 11.4%, ablation procedure in 10.9%, implantation of a pacemaker in 2.5%, and a cardioverter-defibrillator in 8%. At multivariate analysis, the presence of symptoms [hazard ratio (HR) 2.5, P = .001] and age >50 years (HR 1.7, P = .016) were independent predictors of arrhythmic events, while inducibility of ventricular fibrillation at the electrophysiological study (HR 9.0, P < .001) was a predictor of VAs. CONCLUSIONS: ILR detects arrhythmic events in nearly 30% of symptomatic BrS patients, leading to appropriate therapy in 70% of them. The most commonly detected arrhythmias are AAs and BAs, while VAs are detected only in 7% of cases. Symptom status can be used to guide ILR implantation.
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Síndrome de Brugada , Desfibriladores Implantables , Marcapaso Artificial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Arritmias Cardíacas/complicaciones , Arritmias Cardíacas/diagnóstico , Síndrome de Brugada/complicaciones , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/terapia , Electrocardiografía/métodos , Electrocardiografía Ambulatoria/métodos , AdultoRESUMEN
AIMS/HYPOTHESIS: Type 2 diabetes is associated with a high risk of sudden cardiac death (SCD), but the risk of dying from another cause (non-SCD) is proportionally even higher. The aim of the study was to identify easily available ECG-derived features associated with SCD, while considering the competing risk of dying from non-SCD causes. METHODS: In the SURDIAGENE (Survie, Diabete de type 2 et Genetique) French prospective cohort of individuals with type 2 diabetes, 15 baseline ECG parameters were interpreted among 1362 participants (mean age 65 years; HbA1c 62±17 mmol/mol [7.8±1.5%]; 58% male). Competing risk models assessed the prognostic value of clinical and ECG parameters for SCD after adjusting for age, sex, history of myocardial infarction, N-terminal pro b-type natriuretic peptide (NT-proBNP), HbA1c and eGFR. The prospective Mini-Finland cohort study was used to externally validate our findings. RESULTS: During median follow-up of 7.4 years, 494 deaths occurred including 94 SCDs. After adjustment, frontal QRS-T angle ≥90° (sub-distribution HR [sHR] 1.68 [95% CI 1.04, 2.69], p=0.032) and NT-proBNP level (sHR 1.26 [95% CI 1.06, 1.50] per 1 log, p=0.009) were significantly associated with a higher risk of SCD. Nevertheless, frontal QRS-T angle was the only marker not to be associated with causes of death other than SCD (sHR 1.08 [95% CI 0.84, 1.39], p=0.553 ). These findings were replicated in the Mini-Finland study subset of participants with diabetes (sHR 2.22 [95% CI 1.05, 4.71], p=0.04 for SCD and no association for other causes of death). CONCLUSIONS/INTERPRETATION: QRS-T angle was specifically associated with SCD risk and not with other causes of death, opening an avenue for refining SCD risk stratification in individuals with type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Humanos , Masculino , Anciano , Femenino , Estudios de Cohortes , Estudios Prospectivos , Diabetes Mellitus Tipo 2/complicaciones , Finlandia , Medición de Riesgo , Electrocardiografía/efectos adversos , Electrocardiografía/métodos , Muerte Súbita Cardíaca/etiología , Factores de RiesgoRESUMEN
Arrhythmogenic cardiomyopathy (AC) is a familial cardiac disease, mainly caused by mutations in desmosomal genes, which accounts for most cases of stress-related arrhythmic sudden death, in young and athletes. AC hearts display fibro-fatty lesions that generate the arrhythmic substrate and cause contractile dysfunction. A correlation between physical/emotional stresses and arrhythmias supports the involvement of sympathetic neurons (SNs) in the disease, but this has not been confirmed previously. Here, we combined molecular, in vitro and ex vivo analyses to determine the role of AC-linked DSG2 downregulation on SN biology and assess cardiac sympathetic innervation in desmoglein-2 mutant (Dsg2mut/mut) mice. Molecular assays showed that SNs express DSG2, implying that DSG2-mutation carriers would harbour the mutant protein in SNs. Confocal immunofluorescence of heart sections and 3-D reconstruction of SN network in clarified heart blocks revealed significant changes in the physiologialc SN topology, with massive hyperinnervation of the intact subepicardial layers and heterogeneous distribution of neurons in fibrotic areas. Cardiac SNs isolated from Dsg2mut/mut neonatal mice, prior to the establishment of cardiac innervation, show alterations in axonal sprouting, process development and distribution of varicosities. Consistently, virus-assisted DSG2 downregulation replicated, in PC12-derived SNs, the phenotypic alterations displayed by Dsg2mut/mut primary neurons, corroborating that AC-linked Dsg2 variants may affect SNs. Our results reveal that altered sympathetic innervation is an unrecognized feature of AC hearts, which may result from the combination of cell-autonomous and context-dependent factors implicated in myocardial remodelling. Our results favour the concept that AC is a disease of multiple cell types also hitting cardiac SNs. KEY POINTS: Arrhythmogenic cardiomyopathy is a genetically determined cardiac disease, which accounts for most cases of stress-related arrhythmic sudden death. Arrhythmogenic cardiomyopathy linked to mutations in desmoglein-2 (DSG2) is frequent and leads to a left-dominant form of the disease. Arrhythmogenic cardiomyopathy has been approached thus far as a disease of cardiomyocytes, but we here unveil that DSG2 is expressed, in addition to cardiomyocytes, by cardiac and extracardiac sympathetic neurons, although not organized into desmosomes. AC-linked DSG2 downregulation primarily affect sympathetic neurons, resulting in the significant increase in cardiac innervation density, accompanied by alterations in sympathetic neuron distribution. Our data supports the notion that AC develops with the contribution of several 'desmosomal protein-carrying' cell types and systems.
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BACKGROUND: In severely affected patients with catecholaminergic polymorphic ventricular tachycardia, beta-blockers are often insufficiently protective. The purpose of this study was to evaluate whether flecainide is associated with a lower incidence of arrhythmic events (AEs) when added to beta-blockers in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia. METHODS: From 2 international registries, this multicenter case cross-over study included patients with a clinical or genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia in whom flecainide was added to beta-blocker therapy. The study period was defined as the period in which background therapy (ie, beta-blocker type [beta1-selective or nonselective]), left cardiac sympathetic denervation, and implantable cardioverter defibrillator treatment status, remained unchanged within individual patients and was divided into pre-flecainide and on-flecainide periods. The primary end point was AEs, defined as sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter defibrillator shock, and arrhythmic syncope. The association of flecainide with AE rates was assessed using a generalized linear mixed model assuming negative binomial distribution and random effects for patients. RESULTS: A total of 247 patients (123 [50%] females; median age at start of flecainide, 18 years [interquartile range, 14-29]; median flecainide dose, 2.2 mg/kg per day [interquartile range, 1.7-3.1]) were included. At baseline, all patients used a beta-blocker, 70 (28%) had an implantable cardioverter defibrillator, and 21 (9%) had a left cardiac sympathetic denervation. During a median pre-flecainide follow-up of 2.1 years (interquartile range, 0.4-7.2), 41 patients (17%) experienced 58 AEs (annual event rate, 5.6%). During a median on-flecainide follow-up of 2.9 years (interquartile range, 1.0-6.0), 23 patients (9%) experienced 38 AEs (annual event rate, 4.0%). There were significantly fewer AEs after initiation of flecainide (incidence rate ratio, 0.55 [95% CI, 0.38-0.83]; P=0.007). Among patients who were symptomatic before diagnosis or during the pre-flecainide period (n=167), flecainide was associated with significantly fewer AEs (incidence rate ratio, 0.49 [95% CI, 0.31-0.77]; P=0.002). Among patients with ≥1 AE on beta-blocker therapy (n=41), adding flecainide was also associated with significantly fewer AEs (incidence rate ratio, 0.25 [95% CI, 0.14-0.45]; P<0.001). CONCLUSIONS: For patients with catecholaminergic polymorphic ventricular tachycardia, adding flecainide to beta-blocker therapy was associated with a lower incidence of AEs in the overall cohort, in symptomatic patients, and particularly in patients with breakthrough AEs while on beta-blocker therapy.
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Desfibriladores Implantables , Taquicardia Ventricular , Femenino , Humanos , Adolescente , Masculino , Flecainida/efectos adversos , Incidencia , Estudios Cruzados , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/tratamiento farmacológico , Taquicardia Ventricular/epidemiología , Antagonistas Adrenérgicos beta/efectos adversos , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & controlRESUMEN
The notion that the risk of sudden cardiac death (SCD) in patients with heart failure (HF) is declining seems to be gaining traction. Numerous editorials and commentaries have suggested that SCD, specifically arrhythmic SCD, is no longer a significant risk for patients with HF on guideline-directed medical therapy. In this review, we question whether the risk of SCD has indeed declined in HF trials and in the real world. We also explore whether, despite relative risk reductions, the residual SCD risk after guideline-directed medical therapy still suggests a need for implantable cardioverter defibrillator therapy. Among our arguments is that SCD has not decreased in HF trials, nor in the real world. Moreover, we argue that data from HF trials, which have not adhered to guideline-directed device therapy, do not obviate or justify delays to implantable cardioverter defibrillator therapy. In this context, we underline the challenges of translating the findings of HF randomized, controlled trials of guideline-directed medical therapy to the real world. We also make the case for HF trials that adhere to current guideline-directed device therapy so that we can better understand the role of implantable cardioverter defibrillators in chronic HF.
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Desfibriladores Implantables , Insuficiencia Cardíaca , Humanos , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/terapia , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & controlRESUMEN
BACKGROUND: Basic life support education for schoolchildren has become a key initiative to increase bystander cardiopulmonary resuscitation rates. Our objective was to review the existing literature on teaching schoolchildren basic life support to identify the best practices to provide basic life support training in schoolchildren. METHODS: After topics and subgroups were defined, a comprehensive literature search was conducted. Systematic reviews and controlled and uncontrolled prospective and retrospective studies containing data on students <20 years of age were included. RESULTS: Schoolchildren are highly motivated to learn basic life support. The CHECK-CALL-COMPRESS algorithm is recommended for all schoolchildren. Regular training in basic life support regardless of age consolidates long-term skills. Young children from 4 years of age are able to assess the first links in the chain of survival. By 10 to 12 years of age, effective chest compression depths and ventilation volumes can be achieved on training manikins. A combination of theoretical and practical training is recommended. Schoolteachers serve as effective basic life support instructors. Schoolchildren also serve as multipliers by passing on basic life support skills to others. The use of age-appropriate social media tools for teaching is a promising approach for schoolchildren of all ages. CONCLUSIONS: Schoolchildren basic life support training has the potential to educate whole generations to respond to cardiac arrest and to increase survival after out-of-hospital cardiac arrest. Comprehensive legislation, curricula, and scientific assessment are crucial to further develop the education of schoolchildren in basic life support.
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Reanimación Cardiopulmonar , Paro Cardíaco Extrahospitalario , Niño , Humanos , Preescolar , Estudios Retrospectivos , Estudios Prospectivos , Reanimación Cardiopulmonar/educación , EscolaridadRESUMEN
Sudden cardiac death (SCD) is defined as unexpected death due to a cardiac cause that occurs rapidly. Despite the identification of prevention strategies, SCD remains a serious public health problem worldwide, accounting for 15-20% of all deaths, and is therefore a challenge for modern medicine, especially when it affects young people. Sudden cardiac death in young people affects the population aged ≤ 35 years, including athletes and non-athletes, and it is due to various hereditary and non-hereditary causes. After an autopsy, if the cause remains unknown, it is called sudden unexplained death, often attributable to genetic causes. In these cases, molecular autopsy-post-mortem genetic testing-is essential to facilitate diagnostic and therapeutic pathways and/or the monitoring of family members of the cases. This review aims to elaborate on cardiac disorders marked by genetic mutations, necessitating the post-mortem genetic investigation of the deceased for an accurate diagnosis in order to facilitate informed genetic counseling and to implement preventive strategies for family members of the cases.
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Prolonged warm ischemic is the main cause discarding donated organs after cardiac death. Here, we identified that prolonged warm ischemic time induced disseminated intravascular coagulation and severe capillary vasospasm after cardiac death of rat kidneys. Additionally, we found a significant accumulation of fibrinogen in a hypoxic cell culture of human umbilical vein epithelial cells and in isolated kidneys exposed to prolonged warm ischemic following flushing out of blood. However, pre-flushing the kidney with snake venom plasmin in a 90-minute warm ischemic model maximized removal of micro thrombi and facilitated the delivery of oxygen and therapeutic agents. Application of carbon monoxide-releasing CORM-401 during ex vivo hypothermic oxygenated perfusion achieved multipath protective effects in prolonged warm ischemic kidneys. This led to significant improvements in perfusion parameters, restoration of the microcirculation, amelioration of mitochondrial injury, oxidative stress, and apoptosis. This benefit resulted in significantly prolonged warm ischemic kidney recipient survival rates of 70%, compared with none in those receiving ex vivo hypothermic oxygenated perfusion alone. Significantly, ex vivo hypothermic oxygenated perfusion combined with cytoprotective carbon monoxide releasing CORM-401 treatment meaningfully protected the donated kidney after cardiac death from ischemia-reperfusion injury by reducing inflammation, oxidative stress, apoptosis, and pathological damage. Thus, our study suggests a new combination treatment strategy to potentially expand the donor pool by increasing use of organs after cardiac death and salvaging prolonged warm ischemic kidneys.
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Trasplante de Riñón , Riñón , Preservación de Órganos , Compuestos Organometálicos , Perfusión , Isquemia Tibia , Animales , Isquemia Tibia/efectos adversos , Riñón/irrigación sanguínea , Riñón/patología , Riñón/efectos de los fármacos , Perfusión/métodos , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Humanos , Preservación de Órganos/métodos , Masculino , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/farmacología , Daño por Reperfusión/prevención & control , Daño por Reperfusión/etiología , Daño por Reperfusión/patología , Ratas , Oxígeno/metabolismo , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Microcirculación/efectos de los fármacos , Factores de Tiempo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacosRESUMEN
This analysis investigated the incidence of sudden deaths (SDs) and non-fatal and fatal ventricular arrhythmias (VAs) in five acalabrutinib clinical trials. In total, 1299 patients received acalabrutinib (exposure, 4568.4 patient-years). Sixteen (1.2%) patients experienced SD or VA (event rate, 0.350/100 patient-years). Non-fatal VAs occurred in 11 (0.8%) patients, nine (0.7%) of whom had premature ventricular contractions only. SD and fatal VAs occurred in five (0.4%) patients (event rate, 0.109/100 patient-years; median time to event: 46.2 months). SDs and VAs with acalabrutinib occurred at low rates, and there are insufficient data to point to an increased risk of SD or VA with acalabrutinib.
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Benzamidas , Pirazinas , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Benzamidas/efectos adversos , Benzamidas/uso terapéutico , Pirazinas/efectos adversos , Pirazinas/uso terapéutico , Pirazinas/administración & dosificación , Masculino , Femenino , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/mortalidad , Estudios Prospectivos , Persona de Mediana Edad , Anciano , Muerte Súbita/etiología , Muerte Súbita/epidemiología , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/epidemiología , Adulto , IncidenciaRESUMEN
Williams-Beuren syndrome (WBS) is a rare genetic condition caused by a chromosomal microdeletion at 7q11.23. It is a multisystem disorder characterized by distinct facies, intellectual disability, and supravalvar aortic stenosis (SVAS). Those with WBS are at increased risk of sudden death, but mechanisms underlying this remain poorly understood. We recently demonstrated autonomic abnormalities in those with WBS that are associated with increased susceptibility to arrhythmia and sudden cardiac death (SCD). A recently introduced method for heart rate variability (HRV) analysis called "heart rate fragmentation" (HRF) correlates with adverse cardiovascular events (CVEs) and death in studies where heart rate variability (HRV) failed to identify high-risk subjects. Some argue that HRF quantifies nonautonomic cardiovascular modulators. We, therefore, sought to apply HRF analysis to a WBS cohort to determine 1) if those with WBS show differences in HRF compared with healthy controls and 2) if HRF helps characterize HRV abnormalities in those with WBS. Similar to studies of those with coronary artery disease (CAD) and atherosclerosis, we found significantly higher HRF (4 out of 7 metrics) in those with WBS compared with healthy controls. Multivariable analyses showed a weak-to-moderate association between HRF and HRV, suggesting that HRF may reflect HRV characteristics not fully captured by traditional HRV metrics (autonomic markers). We also introduce a new metric inspired by HRF methodology, significant acute rate drop (SARD), which may detect vagal activity more directly. HRF and SARD may improve on traditional HRV measures to identify those at greatest risk for SCD both in those with WBS and in other populations.NEW & NOTEWORTHY This work is the first to apply heart rate fragmentation analyses to individuals with Williams syndrome and posits that the heart rate fragmentation parameter W3 may enable detection and investigation of phenomena underlying the proarrhythmic short-long-short RR interval sequences paradigm known to precede ventricular fibrillation and ventricular tachycardia. It also forwards a novel method for quantifying sinus arrhythmia and sinus pauses that likely correlate with parasympathetic activity.
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Muerte Súbita Cardíaca , Frecuencia Cardíaca , Síndrome de Williams , Síndrome de Williams/fisiopatología , Síndrome de Williams/genética , Síndrome de Williams/complicaciones , Humanos , Muerte Súbita Cardíaca/etiología , Femenino , Masculino , Adolescente , Adulto , Adulto Joven , Estudios de Casos y Controles , Factores de Riesgo , Sistema Nervioso Autónomo/fisiopatología , Niño , Medición de Riesgo , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/genética , Arritmias Cardíacas/diagnósticoRESUMEN
BACKGROUND: Comprehensive data on patients at high risk of sudden cardiac death (SCD) in emerging countries are lacking. The aim was to deepen our understanding of the SCD phenotype and identify risk factors for death among patients at high risk of SCD in emerging countries. METHODS: Patients who met the class I indication for implantable cardioverter-defibrillator (ICD) implantation according to guideline recommendations in 17 countries and regions underrepresented in previous trials were enrolled. Countries were stratified by the WHO regional classification. Patients were or were not implanted with an ICD at their discretion. The outcomes were all-cause mortality and SCD. RESULTS: We enrolled 4222 patients, and 3889 patients were included in the analysis. The mean follow-up period was 21.6 ± 10.2 months. There were 433 (11.1%) instances of all-cause mortality and 117 (3.0%) cases of SCD. All-cause mortality was highest in primary prevention (PP) patients from Southeast Asia and secondary prevention (SP) patients from the Middle East and Africa. The SCD rates among PP and SP patients were both highest in South Asia. Multivariate Cox regression modelling demonstrated that in addition to the independent predictors identified in previous studies, both geographic region and ICD use were associated with all-cause mortality in patients with high SCD risk. Primary prophylactic ICD implantation was associated with a 36% (HR = 0.64, 95% CI 0.531-0.802, p < 0.0001) lower all-cause mortality risk and an 80% (HR = 0.20, 95% CI = 0.116-0.343, p < 0.0001) lower SCD risk. CONCLUSIONS: There was significant heterogeneity among patients with high SCD risk in emerging countries. The influences of geographic regions on patient characteristics and outcomes were significant. Improvement in increasing ICD utilization and uptake of guideline-directed medical therapy in emerging countries is urgent. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02099721.
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Desfibriladores Implantables , Humanos , Factores de Riesgo , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/prevención & control , África , Medio OrienteRESUMEN
PURPOSE: Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHADD) is a rare fatty acid oxidation disorder characterized by recurrent episodes of metabolic decompensation and rhabdomyolysis, as well as retinopathy, peripheral neuropathy, and cardiac involvement, such as infantile dilated cardiomyopathy. Because LCHADD patients are surviving longer, we sought to characterize LCHADD-associated major cardiac involvement in adolescence and young adulthood. METHODS: A retrospective cohort of 16 adolescent and young adult participants with LCHADD was reviewed for cardiac phenotype. RESULTS: Major cardiac involvement occurred in 9 of 16 participants, including sudden death, out-of-hospital cardiac arrest, acute cardiac decompensations with heart failure and/or in-hospital cardiac arrest, end-stage dilated cardiomyopathy, and moderate restrictive cardiomyopathy. Sudden cardiac arrest was more common in males and those with a history of infant cardiomyopathy. CONCLUSION: The cardiac manifestations of LCHADD in adolescence and early adulthood are complex and distinct from the phenotype seen in infancy. Life-threatening arrhythmia occurs at substantial rates in LCHADD, often in the absence of metabolic decompensation or rhabdomyolysis. The potential risk factors identified here-male sex and history of infant cardiomyopathy-may hint at strategies for risk stratification and possibly the prevention of these events.