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1.
N Engl J Med ; 391(15): 1402-1412, 2024 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-38767244

RESUMEN

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (ICD) is associated with fewer lead-related complications than a transvenous ICD; however, the subcutaneous ICD cannot provide bradycardia and antitachycardia pacing. Whether a modular pacing-defibrillator system comprising a leadless pacemaker in wireless communication with a subcutaneous ICD to provide antitachycardia and bradycardia pacing is safe remains unknown. METHODS: We conducted a multinational, single-group study that enrolled patients at risk for sudden death from ventricular arrhythmias and followed them for 6 months after implantation of a modular pacemaker-defibrillator system. The safety end point was freedom from leadless pacemaker-related major complications, evaluated against a performance goal of 86%. The two primary performance end points were successful communication between the pacemaker and the ICD (performance goal, 88%) and a pacing threshold of up to 2.0 V at a 0.4-msec pulse width (performance goal, 80%). RESULTS: We enrolled 293 patients, 162 of whom were in the 6-month end-point cohort and 151 of whom completed the 6-month follow-up period. The mean age of the patients was 60 years, 16.7% were women, and the mean (±SD) left ventricular ejection fraction was 33.1±12.6%. The percentage of patients who were free from leadless pacemaker-related major complications was 97.5%, which exceeded the prespecified performance goal. Wireless-device communication was successful in 98.8% of communication tests, which exceeded the prespecified goal. Of 151 patients, 147 (97.4%) had pacing thresholds of 2.0 V or less, which exceeded the prespecified goal. The percentage of episodes of arrhythmia that were successfully terminated by antitachycardia pacing was 61.3%, and there were no episodes for which antitachycardia pacing was not delivered owing to communication failure. Of 162 patients, 8 died (4.9%); none of the deaths were deemed to be related to arrhythmias or the implantation procedure. CONCLUSIONS: The leadless pacemaker in wireless communication with a subcutaneous ICD exceeded performance goals for freedom from major complications related to the leadless pacemaker, for communication between the leadless pacemaker and subcutaneous ICD, and for the percentage of patients with a pacing threshold up to 2.0 V at a 0.4-msec pulse width at 6 months. (Funded by Boston Scientific; MODULAR ATP ClinicalTrials.gov NCT04798768.).


Asunto(s)
Arritmias Cardíacas , Bradicardia , Muerte Súbita Cardíaca , Desfibriladores Implantables , Marcapaso Artificial , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Bradicardia/terapia , Estimulación Cardíaca Artificial/efectos adversos , Estimulación Cardíaca Artificial/métodos , Muerte Súbita Cardíaca/prevención & control , Muerte Súbita Cardíaca/etiología , Desfibriladores Implantables/efectos adversos , Diseño de Equipo , Estudios de Seguimiento , Marcapaso Artificial/efectos adversos , Tecnología Inalámbrica , Arritmias Cardíacas/complicaciones , Arritmias Cardíacas/terapia
2.
Annu Rev Med ; 75: 417-426, 2024 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-37788487

RESUMEN

Dilated cardiomyopathy (DCM) is defined as dilation and/or reduced function of one or both ventricles and remains a common disease worldwide. An estimated 40% of cases of familial DCM have an identifiable genetic cause. Accordingly, there is a fast-growing interest in the field of molecular genetics as it pertains to DCM. Many gene mutations have been identified that contribute to phenotypically significant cardiomyopathy. DCM genes can affect a variety of cardiomyocyte functions, and particular genes whose function affects the cell-cell junction and cytoskeleton are associated with increased risk of arrhythmias and sudden cardiac death. Through advancements in next-generation sequencing and cardiac imaging, identification of genetic DCM has improved over the past couple decades, and precision medicine is now at the forefront of treatment for these patients and their families. In addition to standard treatment of heart failure and prevention of arrhythmias and sudden cardiac death, patients with genetic cardiomyopathy stand to benefit from gene mechanism-specific therapies.


Asunto(s)
Cardiomiopatía Dilatada , Insuficiencia Cardíaca , Humanos , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/terapia , Arritmias Cardíacas/genética , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & control , Mutación/genética
3.
Circ Res ; 134(6): 659-674, 2024 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-38484028

RESUMEN

Circadian rhythms in physiology and behavior are ≈24-hour biological cycles regulated by internal biological clocks (ie, circadian clocks) that optimize organismal homeostasis in response to predictable environmental changes. These clocks are present in virtually all cells in the body, including cardiomyocytes. Many decades ago, clinicians and researchers became interested in studying daily patterns of triggers for sudden cardiac death, the incidence of sudden cardiac death, and cardiac arrhythmias. This review highlights historical and contemporary studies examining the role of day/night rhythms in the timing of cardiovascular events, delves into changes in the timing of these events over the last few decades, and discusses cardiovascular disease-specific differences in the timing of cardiovascular events. The current understanding of the environmental, behavioral, and circadian mechanisms that regulate cardiac electrophysiology is examined with a focus on the circadian regulation of cardiac ion channels and ion channel regulatory genes. Understanding the contribution of environmental, behavioral, and circadian rhythms on arrhythmia susceptibility and the incidence of sudden cardiac death will be essential in developing future chronotherapies.


Asunto(s)
Arritmias Cardíacas , Relojes Circadianos , Humanos , Ritmo Circadiano , Miocitos Cardíacos , Muerte Súbita Cardíaca/etiología , Electrofisiología Cardíaca
4.
Circulation ; 150(6): 488-503, 2024 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-39102482

RESUMEN

The pro- and antiarrhythmic effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been extensively studied in preclinical and human trials. Despite early evidence of an antiarrhythmic role of n-3 PUFA in the prevention of sudden cardiac death and postoperative and persistent atrial fibrillation (AF), subsequent well-designed randomized trials have largely not shown an antiarrhythmic benefit. Two trials that tested moderate and high-dose n-3 PUFA demonstrated a reduction in sudden cardiac death, but these findings have not been widely replicated, and the potential of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to reduce arrhythmic death in combination, or as monotherapy, remains uncertain. The accumulated clinical evidence does not support supplementation of n-3 PUFA for postoperative AF or secondary prevention of AF. Several large, contemporary, randomized controlled trials of high-dose n-3 PUFA for primary or secondary cardiovascular prevention have demonstrated a small, significant, dose-dependent increased risk of incident AF compared with mineral oil or corn oil comparator. These findings were reproduced with both icosapent ethyl monotherapy and a mixed EPA+DHA formulation. The proarrhythmic mechanism of increased AF in contemporary cohorts exposed to high-dose n-3 PUFA is unknown. EPA and DHA and their metabolites have pleiotropic cardiometabolic and pro- and antiarrhythmic effects, including modification of the lipid raft microenvironment; alteration of cell membrane structure and fluidity; modulation of sodium, potassium, and calcium currents; and regulation of gene transcription, cell proliferation, and inflammation. Further characterization of the complex association between EPA, EPA+DHA, and DHA and AF is needed. Which formulations, dose ranges, and patient subgroups are at highest risk, remain unclear.


Asunto(s)
Arritmias Cardíacas , Ácidos Grasos Omega-3 , Humanos , Ácidos Grasos Omega-3/uso terapéutico , Arritmias Cardíacas/prevención & control , Animales , Fibrilación Atrial/prevención & control , Fibrilación Atrial/tratamiento farmacológico , Muerte Súbita Cardíaca/prevención & control , Muerte Súbita Cardíaca/etiología , Antiarrítmicos/uso terapéutico , Suplementos Dietéticos , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Ácidos Docosahexaenoicos/uso terapéutico
5.
Blood ; 142(5): 409-420, 2023 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-37216685

RESUMEN

Sudden death is 1 of the leading causes of death in adults with sickle cell anemia (SCA) but its etiology remains mostly unknown. Ventricular arrhythmia (VA) carries an increased risk of sudden death; however, its prevalence and determinants in SCA are poorly studied. This study aimed to identify the prevalence and predictors of VA in patients with SCA. From 2019 to 2022, 100 patients with SCA were referred to the physiology department to specifically analyze cardiac function and prospectively included in the DREPACOEUR registry. They underwent a 24-hour electrocardiogram monitoring (24h-Holter), transthoracic echocardiography, and laboratory tests on the same day. The primary end point was the occurrence of VA, defined as sustained or nonsustained ventricular tachycardia (VT), >500 premature ventricular contractions (PVCs) on 24h-Holter, or a recent history of VT ablation. The mean patient age was 46 ± 13 years, and 48% of the patients were male. Overall, VA was observed in 22 (22%) patients. Male sex (81% vs 34%; P = .02), impaired global longitudinal strain (GLS): -16% ± 1.9% vs -18.3% ± 2.7%; P = .02), and decreased platelet count (226 ± 96 giga per liter [G/L] vs 316 ± 130 G/L) were independently associated with VA. GLS correlated with PVC load every 24 hours (r = 0.39; P < .001) and a cutoff of -17.5% could predict VA with a sensitivity of 82% and a specificity of 63%. VAs are common in patients with SCA, especially in men. This pilot study uncovered GLS as a valuable parameter for improving rhythmic risk stratification.


Asunto(s)
Anemia de Células Falciformes , Taquicardia Ventricular , Adulto , Humanos , Masculino , Persona de Mediana Edad , Femenino , Proyectos Piloto , Arritmias Cardíacas/etiología , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & control , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/etiología , Anemia de Células Falciformes/complicaciones
6.
Hum Genomics ; 18(1): 102, 2024 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-39285490

RESUMEN

BACKGROUND: Juvenile sudden cardiac death (SCD) remains unexplained in approximately 40% of cases, leading to a significant emotional burden for the victims' families and society. Comprehensive investigations are essential to uncover its elusive causes and enable cascade family screening. This study aimed to enhance the identification of likely causative variants in juvenile SCD cases (age ≤ 50 years), particularly when autopsy findings are inconclusive. RESULTS: Autopsy revealed diagnostic structural abnormalities in 46%, non-diagnostic findings in 23%, and structurally normal hearts in 31% of cases. Whole-exome sequencing (WES), refined through a customized virtual gene panel was used to identify variants. These variants were then evaluated using a multidisciplinary approach and a structured variant prioritization scheme. Our extended approach identified likely causative variants in 69% of cases, outperforming the diagnostic yields of both the cardio panel and standard susceptibility gene analysis (50% and 16%, respectively). The extended cardio panel achieved an 80% diagnostic yield in cases with structurally normal hearts, demonstrating its efficacy in challenging scenarios. Notably, half of the positive cases harboured a single variant, while the remainder had two or more variants. CONCLUSION: This study highlights the efficacy of a multidisciplinary approach employing WES and a tailored virtual gene panel to elucidate the aetiology of juvenile SCD. The findings support the expansion of genetic testing using tailored gene panels and prioritization schemes as part of routine autopsy evaluations to improve the identification of causative variants and potentially facilitate early diagnosis in first-degree relatives.


Asunto(s)
Muerte Súbita Cardíaca , Secuenciación del Exoma , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Muerte Súbita Cardíaca/patología , Muerte Súbita Cardíaca/etiología , Masculino , Femenino , Adolescente , Adulto , Niño , Pruebas Genéticas/métodos , Adulto Joven , Autopsia , Persona de Mediana Edad , Exoma/genética , Preescolar , Lactante
7.
Circ Res ; 132(1): 127-149, 2023 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-36603066

RESUMEN

Cardiac alternans arises from dynamical instabilities in the electrical and calcium cycling systems of the heart, and often precedes ventricular arrhythmias and sudden cardiac death. In this review, we integrate clinical observations with theory and experiment to paint a holistic portrait of cardiac alternans: the underlying mechanisms, arrhythmic manifestations and electrocardiographic signatures. We first summarize the cellular and tissue mechanisms of alternans that have been demonstrated both theoretically and experimentally, including 3 voltage-driven and 2 calcium-driven alternans mechanisms. Based on experimental and simulation results, we describe their relevance to mechanisms of arrhythmogenesis under different disease conditions, and their link to electrocardiographic characteristics of alternans observed in patients. Our major conclusion is that alternans is not only a predictor, but also a causal mechanism of potentially lethal ventricular and atrial arrhythmias across the full spectrum of arrhythmia mechanisms that culminate in functional reentry, although less important for anatomic reentry and focal arrhythmias.


Asunto(s)
Calcio , Corazón , Humanos , Arritmias Cardíacas , Muerte Súbita Cardíaca/etiología , Electrocardiografía/métodos
8.
Nature ; 569(7756): 418-422, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31068698

RESUMEN

Prompt coronary catheterization and revascularization have markedly improved the outcomes of myocardial infarction, but have also resulted in a growing number of surviving patients with permanent structural damage of the heart, which frequently leads to heart failure. There is an unmet clinical need for treatments for this condition1, particularly given the inability of cardiomyocytes to replicate and thereby regenerate the lost contractile tissue2. Here we show that expression of human microRNA-199a in infarcted pig hearts can stimulate cardiac repair. One month after myocardial infarction and delivery of this microRNA through an adeno-associated viral vector, treated animals showed marked improvements in both global and regional contractility, increased muscle mass and reduced scar size. These functional and morphological findings correlated with cardiomyocyte de-differentiation and proliferation. However, subsequent persistent and uncontrolled expression of the microRNA resulted in sudden arrhythmic death of most of the treated pigs. Such events were concurrent with myocardial infiltration of proliferating cells displaying a poorly differentiated myoblastic phenotype. These results show that achieving cardiac repair through the stimulation of endogenous cardiomyocyte proliferation is attainable in large mammals, however dosage of this therapy needs to be tightly controlled.


Asunto(s)
Muerte Súbita Cardíaca/etiología , MicroARNs/efectos adversos , MicroARNs/genética , MicroARNs/uso terapéutico , Infarto del Miocardio/genética , Infarto del Miocardio/terapia , Sus scrofa/genética , Animales , Proliferación Celular/genética , Corazón/fisiología , Corazón/fisiopatología , Masculino , MicroARNs/administración & dosificación , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Regeneración/genética
9.
J Med Genet ; 61(5): 420-422, 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38296631

RESUMEN

Up to 20% of children with sarcomeric hypertrophic cardiomyopathy (HCM) have disease-causing variants in genes coding for thin-filament proteins. However, data on genotype-phenotype correlations for thin-filament disease are limited. This study describes the natural history and outcomes of children with thin-filament-associated HCM and compares it to thick-filament-associated disease.Longitudinal data were collected from 40 children under 18 years with a disease-causing variant in a thin-filament protein from a single quaternary referral centre. Twenty-one (female n=6, 35.5%) were diagnosed with HCM at a median age of 13.0 years (IQR 8.3-14.0). Over a median follow-up of 5.0 years (IQR 4.0-8.5), three (14.3%) experienced one or more major adverse cardiac events (MACE) (two patients had an out-of-hospital arrest and eight appropriate implantable cardiac defibrillator (ICD) therapies in three patients). One gene carrier died suddenly at age 9 years. Compared with those with thick-filament disease, children with thin-filament variants more commonly experienced non-sustained ventricular tachycardia [NSVT; n=6 (28.6%) vs n=14 (10.8%), p=0.024] or underwent ICD insertion (thin, n=13 (61.9%) vs thick, n=50 (38.5%), p=0.040). However, there was no difference in the incidence of MACE (thin 2.47/100 pt years (95% CI 0.80 to 7.66) vs thick 3.63/100 pt years (95% CI 2.25 to 5.84)) or an arrhythmic event (thin 1.65/100 pt years (95% CI 0.41 to 6.58) vs thick 2.55/100 pt years (95% CI 1.45 to 4.48), p value 0.43).This study suggests that adverse events in thin-filament disease are predominantly arrhythmic and may occur in the absence of hypertrophy, but overall short-term outcomes do not differ significantly from thick-filament disease.


Asunto(s)
Cardiomiopatía Hipertrófica , Desfibriladores Implantables , Humanos , Niño , Femenino , Adolescente , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/diagnóstico , Citoesqueleto de Actina , Desfibriladores Implantables/efectos adversos , Corazón , Factores de Riesgo , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología
10.
Eur Heart J ; 45(10): 809-819, 2024 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-37956651

RESUMEN

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.


Asunto(s)
Arritmias Cardíacas , Muerte Súbita Cardíaca , Humanos , Estudios Prospectivos , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Arritmias Cardíacas/complicaciones , Factores de Riesgo , Electrocardiografía/efectos adversos
11.
Eur Heart J ; 45(30): 2697-2726, 2024 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-38923509

RESUMEN

Cardiac sarcoidosis (CS) is a form of inflammatory cardiomyopathy associated with significant clinical complications such as high-degree atrioventricular block, ventricular tachycardia, and heart failure as well as sudden cardiac death. It is therefore important to provide an expert consensus statement summarizing the role of different available diagnostic tools and emphasizing the importance of a multidisciplinary approach. By integrating clinical information and the results of diagnostic tests, an accurate, validated, and timely diagnosis can be made, while alternative diagnoses can be reasonably excluded. This clinical expert consensus statement reviews the evidence on the management of different CS manifestations and provides advice to practicing clinicians in the field on the role of immunosuppression and the treatment of cardiac complications based on limited published data and the experience of international CS experts. The monitoring and risk stratification of patients with CS is also covered, while controversies and future research needs are explored.


Asunto(s)
Cardiomiopatías , Sarcoidosis , Humanos , Sarcoidosis/diagnóstico , Sarcoidosis/terapia , Sarcoidosis/complicaciones , Cardiomiopatías/diagnóstico , Cardiomiopatías/terapia , Inmunosupresores/uso terapéutico , Muerte Súbita Cardíaca/prevención & control , Muerte Súbita Cardíaca/etiología
12.
Eur Heart J ; 45(29): 2647-2656, 2024 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-38751064

RESUMEN

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 ≥500 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.


Asunto(s)
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 Riesgo
13.
Eur Heart J ; 45(7): 538-548, 2024 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-38195003

RESUMEN

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.


Asunto(s)
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)/epidemiología
14.
Diabetologia ; 67(4): 641-649, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38267653

RESUMEN

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.


Asunto(s)
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 Riesgo
15.
Mol Pharmacol ; 105(3): 194-201, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38253398

RESUMEN

Intracellular Ca2+ leak from cardiac ryanodine receptor (RyR2) is an established mechanism of sudden cardiac death (SCD), whereby dysregulated Ca2+ handling causes ventricular arrhythmias. We previously discovered the RyR2-selective inhibitor ent-(+)-verticilide (ent-1), a 24-membered cyclooligomeric depsipeptide that is the enantiomeric form of a natural product (nat-(-)-verticilide). Here, we examined its 18-membered ring-size oligomer (ent-verticilide B1; "ent-B1") in RyR2 single channel and [3H]ryanodine binding assays, and in Casq2 -/- cardiomyocytes and mice, a gene-targeted model of SCD. ent-B1 inhibited RyR2 single channels and RyR2-mediated spontaneous Ca2+ release in Casq2 -/- cardiomyocytes with sub-micromolar potency. ent-B1 was a partial RyR2 inhibitor, with maximal inhibitory efficacy of less than 50%. ent-B1 was stable in plasma, with a peak plasma concentration of 1460 ng/ml at 10 minutes and half-life of 45 minutes after intraperitoneal administration of 3 mg/kg in mice. In vivo, ent-B1 significantly reduced catecholamine-induced ventricular arrhythmias in Casq2 -/- mice in a dose-dependent manner. Hence, we have identified a novel chemical entity - ent-B1 - that preserves the mechanism of action of a hit compound and shows therapeutic efficacy. These findings strengthen RyR2 as an antiarrhythmic drug target and highlight the potential of investigating the mirror-image isomers of natural products to discover new therapeutics. SIGNIFICANCE STATEMENT: The cardiac ryanodine receptor (RyR2) is an untapped target in the stagnant field of antiarrhythmic drug development. We have confirmed RyR2 as an antiarrhythmic target in a mouse model of sudden cardiac death and shown the therapeutic efficacy of a second enantiomeric natural product.


Asunto(s)
Productos Biológicos , Depsipéptidos , Ratones , Animales , Antiarrítmicos/farmacología , Antiarrítmicos/uso terapéutico , Canal Liberador de Calcio Receptor de Rianodina/genética , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Arritmias Cardíacas/tratamiento farmacológico , Arritmias Cardíacas/metabolismo , Depsipéptidos/metabolismo , Depsipéptidos/uso terapéutico , Muerte Súbita Cardíaca/etiología , Miocitos Cardíacos/metabolismo , Calcio/metabolismo
16.
Circulation ; 148(20): 1543-1555, 2023 11 14.
Artículo en Inglés | MEDLINE | ID: mdl-37830188

RESUMEN

BACKGROUND: Brugada syndrome poses significant challenges in terms of risk stratification and management, particularly for asymptomatic patients who comprise the majority of individuals exhibiting Brugada ECG pattern (BrECG). The aim of this study was to evaluate the long-term prognosis of a large cohort of asymptomatic patients with BrECG. METHODS: Asymptomatic patients with BrECG (1149) were consecutively collected from 2 Italian centers and followed-up at least annually for 2 to 22 years. For the 539 asymptomatic patients (men, 433 [80%]; mean age, 46±13 years) with spontaneous type 1 documented on baseline ECG (87%) or 12-lead 24-hour Holter monitoring (13%), an electrophysiologic study (EPS) was proposed; for the 610 patients with drug-induced-only type 1 (men, 420 [69%]; mean age, 44±14 years), multiple ECGs and 12-lead Holter were advised in order to detect the occurrence of a spontaneous type-1 BrECG. Arrhythmic events were defined as sudden death or documented ventricular fibrillation or tachycardia. RESULTS: Median follow-up was 6 (4-9) years. Seventeen (1.5%) arrhythmic events occurred in the overall asymptomatic population (corresponding to an event-rate of 0.2% per year), including 16 of 539 (0.4% per year) in patients with spontaneous type-1 BrECG and 1 of 610 in those with drug-induced type-1 BrECG (0.03% per year; P<0.001). EPS was performed in 339 (63%) patients with spontaneous type-1 BrECG. Patients with spontaneous type-1 BrECG and positive EPS had significantly higher event rates than patients with negative EPS (7 of 103 [0.7% per year] versus 4 of 236 [0.2% per year]; P=0.025). Among 200 patients who declined EPS, 5 events (0.4% per year) occurred. There was 1 device-related death. CONCLUSIONS: The entire population of asymptomatic patients with BrECG exhibits a relatively low event rate per year, which is important in view of the long life expectancy of these young patients. The presence of spontaneous type-1 BrECG associated with positive EPS identifies a subgroup at higher risk. Asymptomatic patients with drug-induced-only BrECG have a minimal arrhythmic risk, but ongoing follow-up with 12-lead Holter monitoring is recommended to detect the appearance of spontaneous type-1 BrECG pattern.


Asunto(s)
Síndrome de Brugada , Masculino , Humanos , Adulto , Persona de Mediana Edad , Estudios Prospectivos , Pronóstico , Arritmias Cardíacas/complicaciones , Electrocardiografía , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Medición de Riesgo
17.
Circulation ; 147(9): 759-767, 2023 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-36848410

RESUMEN

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.


Asunto(s)
Desfibriladores Implantables , Insuficiencia Cardíaca , Humanos , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/terapia , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & control
18.
Circulation ; 148(3): 241-252, 2023 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-37459413

RESUMEN

BACKGROUND: Black Americans have a higher risk of nonischemic cardiomyopathy (NICM) than White Americans. We aimed to evaluate differences in the risk of tachyarrhythmias among patients with an implantable cardioverter-defibrillator (ICD). METHODS: The study population comprised 3895 ICD recipients in the United States enrolled in primary prevention ICD trials. Outcome measures included ventricular tachyarrhythmia (VTA), atrial tachyarrhythmia (ATA), ICD therapies, VTA burden (using Andersen-Gill recurrent event analysis), death, and the predicted benefit of the ICD. All events were adjudicated blindly. Outcomes were compared between self-reported Black patients versus White patients with cardiomyopathy (ischemic and NICM). RESULTS: Black patients were more likely to be female (35% versus 22%) and younger (57±12 versus 62±12 years) with a higher frequency of comorbidities. In NICM, Black patients had a higher rate of first VTA, fast VTA, ATA, and appropriate and inappropriate ICD therapy (VTA ≥170 bpm, 32% versus 20%; VTA ≥200 bpm, 22% versus 14%; ATA, 25% versus 12%; appropriate therapy, 30% versus 20%; and inappropriate therapy, 25% versus 11%; P<0.001 for all). Multivariable analysis showed that Black patients with NICM experienced a higher risk of all types of arrhythmia or ICD therapy (VTA ≥170 bpm, hazard ratio [HR] 1.71; VTA ≥200 bpm, HR 1.58; ATA, HR 1.87; appropriate therapy, HR 1.62; inappropriate therapy, HR 1.86; P≤0.01 for all), higher burden of tachyarrhythmias or therapies (VTA, HR 1.84; appropriate therapy, HR 1.84; P<0.001 for both), and a higher risk of death (HR 1.92; P=0.014). In contrast, in ischemic cardiomyopathy, the risk of all types of tachyarrhythmia, ICD therapy, or death was similar between Black patients and White patients. Both Black patients and White patients derived a significant and similar benefit from ICD implantation. CONCLUSIONS: Among patients with NICM with an ICD for primary prevention, Black patients compared with White patients had a high risk and burden of VTA, ATA, and ICD therapies with a lower survival rate. Nevertheless, the overall benefit of the ICD was maintained and was similar to that of White patients.


Asunto(s)
Cardiomiopatías , Desfibriladores Implantables , Taquicardia Ventricular , Humanos , Femenino , Estados Unidos/epidemiología , Masculino , Blanco , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & control , Factores de Riesgo , Arritmias Cardíacas , Taquicardia Ventricular/terapia , Taquicardia Ventricular/epidemiología , Prevención Primaria
19.
Circulation ; 147(9): 718-727, 2023 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-36335467

RESUMEN

BACKGROUND: Hypertrophic cardiomyopathy (HCM) can be associated with an abnormal exercise response. In adults with HCM, abnormal results on exercise stress testing are predictive of heart failure outcomes. Our goal was to determine whether an abnormal exercise response is associated with adverse outcomes in pediatric patients with HCM. METHODS: In an international cohort study including 20 centers, phenotype-positive patients with primary HCM who were <18 years of age at diagnosis were included. Abnormal exercise response was defined as a blunted blood pressure response and new or worsened ST- or T-wave segment changes or complex ventricular ectopy. Sudden cardiac death (SCD) events were defined as a composite of SCD and aborted sudden cardiac arrest. Using Kaplan-Meier survival, competing outcomes, and Cox regression analyses, we analyzed the association of abnormal exercise test results with transplant and SCD event-free survival. RESULTS: Of 724 eligible patients, 630 underwent at least 1 exercise test. There were no major differences in clinical characteristics between those with or without an exercise test. The median age at exercise testing was 13.8 years (interquartile range, 4.7 years); 78% were male and 39% were receiving beta-blockers. A total of 175 (28%) had abnormal test results. Patients with abnormal test results had more severe septal hypertrophy, higher left atrial diameter z scores, higher resting left ventricular outflow tract gradient, and higher frequency of myectomy compared with participants with normal test results (P<0.05). Compared with normal test results, abnormal test results were independently associated with lower 5-year transplant-free survival (97% versus 88%, respectively; P=0.005). Patients with exercise-induced ischemia were most likely to experience all-cause death or transplant (hazard ratio, 4.86 [95% CI, 1.69-13.99]), followed by those with an abnormal blood pressure response (hazard ratio, 3.19 [95% CI, 1.32-7.71]). Exercise-induced ischemia was also independently associated with lower SCD event-free survival (hazard ratio, 3.32 [95% CI, 1.27-8.70]). Exercise-induced ectopy was not associated with survival. CONCLUSIONS: Exercise abnormalities are common in childhood HCM. An abnormal exercise test result was independently associated with lower transplant-free survival, especially in those with an ischemic or abnormal blood pressure response with exercise. Exercise-induced ischemia was also independently associated with SCD events. These findings argue for routine exercise testing in childhood HCM as part of ongoing risk assessment.


Asunto(s)
Cardiomiopatía Hipertrófica , Prueba de Esfuerzo , Masculino , Femenino , Humanos , Estudios de Cohortes , Prevalencia , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Cardiomiopatía Hipertrófica/complicaciones , Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/cirugía , Arritmias Cardíacas/etiología , Factores de Riesgo
20.
Circulation ; 148(11): 862-871, 2023 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-37555345

RESUMEN

BACKGROUND: Ventricular arrhythmia is an important cause of mortality in patients with ischemic left ventricular dysfunction. Revascularization with coronary artery bypass graft or percutaneous coronary intervention is often recommended for these patients before implantation of a cardiac defibrillator because it is assumed that this may reduce the incidence of fatal and potentially fatal ventricular arrhythmias, although this premise has not been evaluated in a randomized trial to date. METHODS: Patients with severe left ventricular dysfunction, extensive coronary disease, and viable myocardium were randomly assigned to receive either percutaneous coronary intervention (PCI) plus optimal medical and device therapy (OMT) or OMT alone. The composite primary outcome was all-cause death or aborted sudden death (defined as an appropriate implantable cardioverter defibrillator therapy or a resuscitated cardiac arrest) at a minimum of 24 months, analyzed as time to first event on an intention-to-treat basis. Secondary outcomes included cardiovascular death or aborted sudden death, appropriate implantable cardioverter defibrillator (ICD) therapy or sustained ventricular arrhythmia, and number of appropriate ICD therapies. RESULTS: Between August 28, 2013, and March 19, 2020, 700 patients were enrolled across 40 centers in the United Kingdom. A total of 347 patients were assigned to the PCI+OMT group and 353 to the OMT alone group. The mean age of participants was 69 years; 88% were male; 56% had hypertension; 41% had diabetes; and 53% had a clinical history of myocardial infarction. The median left ventricular ejection fraction was 28%; 53.1% had an implantable defibrillator inserted before randomization or during follow-up. All-cause death or aborted sudden death occurred in 144 patients (41.6%) in the PCI group and 142 patients (40.2%) in the OMT group (hazard ratio, 1.03 [95% CI, 0.82-1.30]; P=0.80). There was no between-group difference in the occurrence of any of the secondary outcomes. CONCLUSIONS: PCI was not associated with a reduction in all-cause mortality or aborted sudden death. In patients with ischemic cardiomyopathy, PCI is not beneficial solely for the purpose of reducing potentially fatal ventricular arrhythmias. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01920048.


Asunto(s)
Desfibriladores Implantables , Disfunción Ventricular Izquierda , Humanos , Masculino , Anciano , Femenino , Volumen Sistólico , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & control , Función Ventricular Izquierda , Arritmias Cardíacas/etiología , Disfunción Ventricular Izquierda/etiología , Desfibriladores Implantables/efectos adversos , Resultado del Tratamiento
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