RESUMEN
BACKGROUND: Collection of real-world evidence (RWE) is important in achondroplasia. Development of a prospective, shared, international resource that follows the principles of findability, accessibility, interoperability, and reuse of digital assets, and that captures long-term, high-quality data, would improve understanding of the natural history of achondroplasia, quality of life, and related outcomes. METHODS: The Europe, Middle East, and Africa (EMEA) Achondroplasia Steering Committee comprises a multidisciplinary team of 17 clinical experts and 3 advocacy organization representatives. The committee undertook an exercise to identify essential data elements for a standardized prospective registry to study the natural history of achondroplasia and related outcomes. RESULTS: A range of RWE on achondroplasia is being collected at EMEA centres. Whereas commonalities exist, the data elements, methods used to collect and store them, and frequency of collection vary. The topics considered most important for collection were auxological measures, sleep studies, quality of life, and neurological manifestations. Data considered essential for a prospective registry were grouped into six categories: demographics; diagnosis and patient measurements; medical issues; investigations and surgical events; medications; and outcomes possibly associated with achondroplasia treatments. CONCLUSIONS: Long-term, high-quality data are needed for this rare, multifaceted condition. Establishing registries that collect predefined data elements across age spans will provide contemporaneous prospective and longitudinal information and will be useful to improve clinical decision-making and management. It should be feasible to collect a minimum dataset with the flexibility to include country-specific criteria and pool data across countries to examine clinical outcomes associated with achondroplasia and different therapeutic approaches.
Asunto(s)
Acondroplasia , Calidad de Vida , Humanos , Europa (Continente) , Sistema de Registros , Acondroplasia/epidemiologíaRESUMEN
Effective therapeutic interventions for the treatment and prevention of coronavirus disease 2019 (COVID-19) are urgently needed. A systematic review was conducted to identify clinical trials of pharmacological interventions for COVID-19 published between 1 December 2019 and 14 October 2020. Data regarding efficacy of interventions, in terms of mortality, hospitalisation and need for ventilation, were extracted from identified studies and synthesised qualitatively. In total, 42 clinical trials were included. Interventions assessed included antiviral, mucolytic, antimalarial, anti-inflammatory and immunomodulatory therapies. Some reductions in mortality, hospitalisation and need for ventilation were seen with interferons and remdesivir, particularly when administered early, and with the mucolytic drug, bromhexine. Most studies of lopinavir/ritonavir and hydroxychloroquine did not show significant efficacy over standard care/placebo. Dexamethasone significantly reduced mortality, hospitalisation and need for ventilation versus standard care, particularly in patients with severe disease. Evidence for other classes of interventions was limited. Many trials had a moderate-to-high risk of bias, particularly in terms of blinding; most were short-term and some included low patient numbers.This review highlights the need for well-designed clinical trials of therapeutic interventions for COVID-19 to increase the quality of available evidence. It also emphasises the importance of tailoring interventions to disease stage and severity for maximum efficacy.
Asunto(s)
Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , SARS-CoV-2/efectos de los fármacos , Antivirales/efectos adversos , COVID-19/diagnóstico , COVID-19/mortalidad , COVID-19/terapia , COVID-19/virología , Ensayos Clínicos como Asunto , Hospitalización , Interacciones Huésped-Patógeno , Humanos , Inmunización Pasiva , Respiración Artificial , SARS-CoV-2/patogenicidad , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Sueroterapia para COVID-19RESUMEN
Atrial fibrillation is associated with a markedly increased risk of thromboembolic stroke. At present, lifelong antithrombotic therapy with warfarin or a novel oral anticoagulant is indicated for prophylaxis in the majority of patients. Left atrial appendage occlusion devices have been developed as an alternative to these agents, aiming to avoid issues around consistency of anticoagulation, bleeding risk, and drug-related side effects. The best evidence is available for Boston Scientific's WATCHMAN device. The safety and efficacy of WATCHMAN and other similar devices have been questioned, although the increasing body of evidence supports a role in selected settings. A recently updated randomized controlled trial of WATCHMAN (WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients with Atrial Fibrillation [PROTECT-AF]) demonstrates its noninferiority to warfarin and suggests an advantage in terms of functional outcome for patients, with superior net clinical benefit 6 to 9 months after starting treatment. The procedural risk associated with device implantation remains substantial, although improving device design and increasing operator experience means that this should decrease in the future. As the body of data and overall experience around WATCHMAN grow, it may come to be recognized as the best option in selected patients.
Asunto(s)
Apéndice Atrial/cirugía , Fibrilación Atrial/cirugía , Accidente Cerebrovascular/prevención & control , Fibrilación Atrial/complicaciones , Fibrilación Atrial/tratamiento farmacológico , Enfermedades Cardiovasculares/complicaciones , Complicaciones de la Diabetes , Equipos y Suministros , Fibrinolíticos/uso terapéutico , Humanos , Estimación de Kaplan-Meier , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Four non-vitamin-K antagonist oral anticoagulants (NOACs) are now available and are variously approved for stroke prevention in atrial fibrillation and the management of venous thromboembolism. On the whole, these drugs offer clear benefits over warfarin, overcoming problems with unpredictable individual responses and avoiding the need for frequent and resource-intensive monitoring. Sufficient data are now available to recommend the use of particular NOACs in defined settings. As a group these drugs offer a real alternative to warfarin; their more widespread use for stroke prevention in atrial fibrillation, in the management of venous thromboembolism, and perhaps in other settings promises to bring real clinical gains for at-risk populations worldwide. This review highlights the growing importance of effective anticoagulation therapy at a time when cardiovascular risk profiles are evolving, discusses the relative merits of the NOACs over warfarin, and describes the use of specific agents in specific patient populations.
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Anticoagulantes/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Inhibidores del Factor Xa/uso terapéutico , Tromboembolia Venosa/prevención & control , Bencimidazoles/uso terapéutico , Investigación Biomédica , Dabigatrán , Humanos , beta-Alanina/análogos & derivados , beta-Alanina/uso terapéuticoRESUMEN
Anticoagulation is the most-important intervention to prevent stroke in patients with atrial fibrillation (AF). Despite a lower point prevalence of AF in Asian communities and Asian countries than in other populations, individuals of Asian ethnicity are at a disproportionately high risk of stroke and have greater consequent mortality. Warfarin and other vitamin K antagonists are conventionally used for anticoagulation, and demonstrably reduce the risk of stroke and all-cause mortality in patients with AF. The use of warfarin in Asian countries is suboptimal, primarily owing to the universal challenge of achieving controlled anticoagulation with an unpredictable drug as well as concerns about the particularly high-risk of haemorrhage in Asian patients. Instead, antiplatelet therapy has been favoured in Asian communities, this strategy is neither safe nor effective for stroke prevention in these individuals. The non-vitamin K antagonist, oral anticoagulant drugs offer a solution to this challenge. The direct thrombin inhibitor dabigatran, and the direct factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, have demonstrated noninferiority to warfarin in the prevention of stroke and systemic embolism in international, randomized, controlled trials. Importantly, some of these drugs are also associated with a significantly lower incidence of major haemorrhage, and all result in lower rates of intracranial haemorrhage and haemorrhagic stroke than warfarin. In this article, we review the use of the non-vitamin K antagonist anticoagulants in the management of AF in Asian populations.
Asunto(s)
Anticoagulantes/uso terapéutico , Pueblo Asiatico/estadística & datos numéricos , Fibrilación Atrial/tratamiento farmacológico , Accidente Cerebrovascular/prevención & control , Tromboembolia/prevención & control , Vitamina K/antagonistas & inhibidores , Warfarina/uso terapéutico , Administración Oral , Anticoagulantes/administración & dosificación , Antifibrinolíticos , Antitrombinas/uso terapéutico , Asia/epidemiología , Fibrilación Atrial/complicaciones , Fibrilación Atrial/etnología , Fibrilación Atrial/mortalidad , Ensayos Clínicos como Asunto , Medicina Basada en la Evidencia , Humanos , Incidencia , Prevalencia , Accidente Cerebrovascular/etnología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/mortalidad , Tromboembolia/etnología , Tromboembolia/etiología , Tromboembolia/mortalidad , Resultado del Tratamiento , Warfarina/administración & dosificaciónRESUMEN
BACKGROUND: The early repolarization (ER) pattern on ECG is associated with an increased risk of idiopathic ventricular fibrillation (ID-VF). Hypothermia is known to result in similar electrocardiographic changes. In this retrospective cohort study, we examine the impact of therapeutic hypothermia on ER in survivors of cardiac arrest attributed to ID-VF and draw comparisons with a control group who experienced coronary artery disease-related VF (CAD-VF). METHODS AND RESULTS: All patients who had cardiac arrest and were treated with therapeutic hypothermia over a 7-year period were considered for inclusion in the study. Forty-three patients were identified with ID-VF or CAD-VF arrest. ECGs were obtained during cooling and again after rewarming. ECGs were digitized and assessed for the presence of ER by 2 independent observers. Cooling significantly increased the prevalence (74% during cooling versus 51% at baseline temperature; P=0.044) and mean amplitude (0.78±0.10 mV during cooling versus 0.56±0.09 mV at baseline temperature; P=0.038) of ER in the overall cohort. During cooling, ER was more common among survivors of ID-VF than of CAD-VF (100% versus 67%; P=0.043). ER magnitude was significantly greater among ID-VF survivors than CAD-VF survivors both during cooling (1.16±0.18 versus 0.70±0.11 mV; P=0.044) and at baseline temperature (1.02±0.21 versus 0.42±0.09 mV; P=0.005). CONCLUSIONS: Hypothermia increases both the prevalence and magnitude of ER in cardiac arrest survivors. Despite the association of ER with ID-VF, therapeutic hypothermia only increases ER amplitude in CAD-VF survivors.
Asunto(s)
Paro Cardíaco/terapia , Sistema de Conducción Cardíaco/fisiopatología , Hipotermia Inducida , Sobrevivientes , Fibrilación Ventricular/fisiopatología , Potenciales de Acción , Adulto , Enfermedad de la Arteria Coronaria/complicaciones , Electrocardiografía , Femenino , Paro Cardíaco/diagnóstico , Paro Cardíaco/etiología , Paro Cardíaco/fisiopatología , Humanos , Hipotermia Inducida/efectos adversos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estudios Retrospectivos , Procesamiento de Señales Asistido por Computador , Factores de Tiempo , Resultado del Tratamiento , Fibrilación Ventricular/diagnóstico , Fibrilación Ventricular/etiologíaRESUMEN
Dipeptidyl-peptidase-IV (DPP-IV) inhibitors are a new class of oral hypoglycaemic agents recently approved for the management of type 2 diabetes mellitus. Early data suggested that they had a positive impact on the cardiovascular system: treatment appeared to result in improvements in cardiac performance, blood pressure and lipid levels. However, recent clinical findings bring this into question. Our understanding of the physiological actions of these agents is complicated by the fact that DPP-IV has a wide range of substrates in addition to glucagon-like peptide 1. Indeed, DPP-IV inhibition alters concentrations of a wide variety of cytokines and neuropeptides. A deeper understanding of the physiological effects of these drugs as well as their true impact on cardiovascular risk is needed before consideration can be given to extending their use beyond the treatment of diabetes.
Asunto(s)
Fármacos Cardiovasculares/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Animales , Enfermedades Cardiovasculares/enzimología , Diabetes Mellitus Tipo 2/enzimología , Humanos , Transducción de Señal/efectos de los fármacos , Resultado del TratamientoRESUMEN
The Brugada syndrome is a rare but well-defined cause of sudden cardiac death. The key underlying abnormality is a decrease in net depolarising current due to a genetic defect, though recent evidence also implicates structural abnormalities in some patients. Diagnosis requires a Brugada-type ECG as well as typical clinical features: such clinical considerations are currently key in guiding risk stratification and hence management. Whilst pharmacological therapies are under investigation, the only intervention with a robust evidence base remains insertion of an implantable cardioverter defibrillator. Further research will be required to allow more effective risk stratification and hence more rational therapy.
Asunto(s)
Síndrome de Brugada , Síndrome de Brugada/complicaciones , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/fisiopatología , Síndrome de Brugada/terapia , Fármacos Cardiovasculares/uso terapéutico , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & control , Desfibriladores Implantables , Cardioversión Eléctrica/instrumentación , Electrocardiografía , Sistema de Conducción Cardíaco/fisiopatología , Frecuencia Cardíaca , Humanos , Medición de Riesgo , Factores de Riesgo , Resultado del TratamientoRESUMEN
Reductions in cardiac action potential wavelength, and the consequent wavebreak, have been implicated in arrhythmogenesis. Tachyarrhythmias are more common in the Brugada syndrome, particularly following pharmacological challenge, previously modelled using Scn5a(+/-) murine hearts. Propagation latencies and action potential durations (APDs) from monophasic action potential recordings were used to assess wavelength changes with heart rate in Langendorff-perfused wild-type (WT) and Scn5a(+/-) hearts. Recordings were obtained from right (RV) and left (LV) ventricular, epicardial and endocardial surfaces during incremental pacing, before and following flecainide or quinidine challenge. Conduction velocities (θ'), action potential wavelengths (λ' = APD × Î¸'), and their corresponding alternans depended non-linearly upon diastolic interval (DI). Maximum θ' was lower in Scn5a(+/-) RV epicardium than endocardium. Flecainide further reduced θ', accentuating this RV conduction block. Quinidine reduced maximum θ' in WT and caused earlier conduction failure in the RV of both Scn5a(+/-) and WT. Use of recovery wavelengths (λ'0 = DI × Î¸') rather than DI, provided novel λ restitution plots of λ' against λ'0, which sum to a basic cycle distance permitting feedback analysis. λ' restitution gradient better correlated with alternans magnitude than either APD or θ restitution gradient. The large differences in θ' and APD restitution contrasted with minor differences in maximum λ' between epi- and endocardia of untreated hearts, and quinidine-treated WT hearts. Strikingly, all regions and conditions converged to a common instability point, implying a conserved relationship. Flecainide or quinidine decreased the pacing rates at which this occurred, through reducing basic cycle distance, in the Scn5a(+/-) RV epicardium, directly predictive of its arrhythmic phenotype.
Asunto(s)
Potenciales de Acción , Arritmias Cardíacas/fisiopatología , Contracción Miocárdica , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Función Ventricular , Animales , Antiarrítmicos/farmacología , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Femenino , Flecainida/farmacología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Heterocigoto , Masculino , Ratones , Mutación , Reperfusión Miocárdica , Canal de Sodio Activado por Voltaje NAV1.5/genética , Pericardio/fisiopatología , Quinidina/farmacología , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacologíaRESUMEN
Atrial fibrillation, the commonest cardiac arrhythmia, predisposes to thrombus formation and consequently increases risk of ischaemic stroke. Recent years have seen approval of a number of novel oral anticoagulants. Nevertheless, warfarin and aspirin remain the mainstays of therapy. It is widely appreciated that both these agents increase the likelihood of bleeding: there is a popular conception that this risk is greater with warfarin. In fact, well-managed warfarin therapy (INR 2-3) has little effect on bleeding risk and is twice as effective as aspirin at preventing stroke. Patients with atrial fibrillation and a further risk factor for stroke (CHA2DS2-VASc >0) should therefore either receive warfarin or a novel oral agent. The remainder who are at the very lowest risk of stroke are better not prescribed antithrombotic therapy. For stroke prevention in atrial fibrillation; aspirin is rarely the right choice.
Asunto(s)
Anticoagulantes/efectos adversos , Aspirina/efectos adversos , Fibrilación Atrial/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/efectos adversos , Accidente Cerebrovascular/tratamiento farmacológico , Warfarina/efectos adversos , Anticoagulantes/administración & dosificación , Aspirina/administración & dosificación , Fibrilación Atrial/fisiopatología , Esquema de Medicación , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Metaanálisis como Asunto , Selección de Paciente , Inhibidores de Agregación Plaquetaria/administración & dosificación , Guías de Práctica Clínica como Asunto , Medición de Riesgo , Factores de Riesgo , Prevención Secundaria , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/prevención & control , Warfarina/administración & dosificaciónRESUMEN
This review presents a simple trigger-substrate model of arrhythmogenesis and its application to the generation of reentrant ventricular arrhythmias. We demonstrate its broad applicability to the understanding of arrhythmic phenomena in a wide range of both hereditary and acquired arrhythmic disorders.
Asunto(s)
Arritmias Cardíacas/etiología , Sistema de Conducción Cardíaco/fisiopatología , Potenciales de Acción , Animales , Arritmias Cardíacas/fisiopatología , Humanos , Factores de Riesgo , Factores de TiempoRESUMEN
The relationship between alternans and arrhythmogenicity was studied in genetically modified murine hearts modeling catecholaminergic polymorphic ventricular tachycardia (CPVT) during Langendorff perfusion, before and after treatment with catecholamines and a ß-adrenergic antagonist. Heterozygous (RyR2(p/s)) and homozygous (RyR2(s/s)) RyR2-P2328S hearts, and wild-type (WT) controls, were studied before and after treatment with epinephrine (100 nM and 1 µM) and propranolol (100 nM). Monophasic action potential recordings demonstrated significantly greater incidences of arrhythmia in RyR2(p/s) and RyR2(s/s) hearts as compared to WTs. Arrhythmogenicity in RyR2(s/s) hearts was associated with alternans, particularly at short baseline cycle lengths. Both phenomena were significantly accentuated by treatment with epinephrine and significantly diminished by treatment with propranolol, in full agreement with clinical expectations. These changes took place, however, despite an absence of changes in mean action potential durations, ventricular effective refractory periods or restitution curve characteristics. Furthermore pooled data from all hearts in which arrhythmia occurred demonstrated significantly greater alternans magnitudes, but similar restitution curve slopes, to hearts that did not demonstrate arrhythmia. These findings thus further validate the RyR2-P2328S murine heart as a model for human CPVT, confirming an alternans phenotype in common with murine genetic models of the Brugada syndrome and the congenital long-QT syndrome type 3. In contrast to these latter similarities, however, this report demonstrates the dissociation of alternans from changes in the properties of restitution curves for the first time in a murine model of a human arrhythmic syndrome.
RESUMEN
Long QT(3) (LQT3) syndrome is associated with abnormal repolarisation kinetics, prolonged action potential durations (APD) and QT intervals and may lead to life-threatening ventricular arrhythmias. However, there have been few physiological studies of its effects on atrial electrophysiology. Programmed electrical stimulation and burst pacing induced atrial arrhythmic episodes in 16 out of 16 (16/16) wild-type (WT) and 7/16 genetically modified Scn5a+/Delta (KPQ) Langendorff-perfused murine hearts modelling LQT3 (P < 0.001 for both), and in 14/16 WT and 1/16 KPQ hearts (P < 0.001 for both; Fisher's exact test), respectively. The arrhythmogenic WT hearts had significantly larger positive critical intervals (CI), given by the difference between atrial effective refractory periods (AERPs) and action potential durations at 90% recovery (APD(90)), compared to KPQ hearts (8.1 and 3.2 ms, respectively, P < 0.001). Flecainide prevented atrial arrhythmias in all arrhythmogenic WT (P < 0.001) and KPQ hearts (P < 0.05). It prolonged the AERP to a larger extent than it did the APD(90) in both WT and KPQ groups, giving negative CIs. Quinidine similarly exerted anti-arrhythmic effects, prolonged AERP over corresponding APD(90) in both WT and KPQ groups. These findings, thus, demonstrate, for the first time, inhibitory effects of the KPQ mutation on atrial arrhythmogenesis and its modification by flecainide and quinidine. They attribute these findings to differences in the CI between WT and mutant hearts, in the presence or absence of these drugs. Thus, prolongation of APD(90) over AERP gave positive CI values and increased atrial arrhythmogenicity whereas lengthening of AERP over APD(90) reduced such CI values and produced the opposite effect.
Asunto(s)
Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/fisiopatología , Modelos Animales de Enfermedad , Flecainida/administración & dosificación , Síndrome de QT Prolongado/tratamiento farmacológico , Síndrome de QT Prolongado/fisiopatología , Quinidina/administración & dosificación , Canales de Sodio/metabolismo , Animales , Antiarrítmicos/administración & dosificación , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Ratones , Ratones Transgénicos , Canal de Sodio Activado por Voltaje NAV1.5 , Canales de Sodio/genética , Resultado del TratamientoRESUMEN
Ventricular arrhythmias are the key underlying cause of sudden cardiac death, a common cause of mortality and a significant public health burden. Insights into the electrophysiological basis of such phenomena have been obtained using a wide range of recording techniques and a diversity of experimental models. As in other fields of biology, the murine system presents both a wealth of opportunities and important challenges when employed to model the human case. This article begins by reviewing the extent to which the murine heart is representative of that of the human. It then presents a novel physiological classification of mechanisms of arrhythmogenesis, critically assessing the extent to which the study of murine hearts has offered worthwhile insights.
Asunto(s)
Arritmias Cardíacas/etiología , Potenciales de Acción , Animales , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatología , Modelos Animales de Enfermedad , Electrocardiografía , Fenómenos Electrofisiológicos , Humanos , Ratones , Ratones Transgénicos , Proteínas Musculares/genética , Proteínas Musculares/fisiología , Mutación , Canal de Sodio Activado por Voltaje NAV1.5 , Canales de Sodio/genética , Canales de Sodio/fisiología , Especificidad de la Especie , Fibrilación Ventricular/etiología , Fibrilación Ventricular/fisiopatologíaRESUMEN
Sudden cardiac death resulting from ventricular arrhythmogenesis is a leading cause of mortality in the developed world, accounting for up to 400,000 deaths per year in the US alone. Within the past forty years we have taken considerable leaps forward in our understanding of the causes and mechanisms underlying cardiac arrhythmias, particularly in the setting of inherited and acquired dysfunctions in ionic currents which constitute human long QT syndrome (LQTS). Impaired repolarization seen in LQTS commonly gives rise to an altered dispersion of repolarization, which is considered to provide the functional substrate necessary for the perpetuation of lethal arrhythmias. This review examines the bases for arrhythmias arising from repolarization heterogeneities and explores the applicability of the genetically amenable mouse for the study of arrhythmias arising from such mechanisms.
Asunto(s)
Arritmias Cardíacas/fisiopatología , Potenciales de Acción , Animales , Arritmias Cardíacas/etiología , Muerte Súbita Cardíaca/etiología , Modelos Animales de Enfermedad , Perros , Fenómenos Electrofisiológicos , Ventrículos Cardíacos/fisiopatología , Humanos , Síndrome de QT Prolongado/congénito , Síndrome de QT Prolongado/etiología , Síndrome de QT Prolongado/fisiopatología , RatonesRESUMEN
The experiments investigated the applicability of two established criteria for arrhythmogenicity in Scn5a+/Delta and Scn5a+/- murine hearts modelling the congenital long QT syndrome type 3 (LQT3) and the Brugada syndrome (BrS). Monophasic action potentials (APs) recorded during extrasystolic stimulation procedures from Langendorff-perfused control hearts and hearts treated with flecainide (1 microM) or quinidine (1 or 10 microM) demonstrated that both agents were pro-arrhythmic in wild-type (WT) hearts, quinidine was pro-arrhythmic in Scn5a+/Delta hearts, and that flecainide was pro-arrhythmic whereas quinidine was anti-arrhythmic in Scn5a+/- hearts, confirming clinical findings. Statistical analysis confirmed a quadratic relationship between epicardial and endocardial AP durations (APDs) in WT control hearts. However, comparisons between plots of epicardial against endocardial APDs and this reference curve failed to correlate with arrhythmogenicity. Restitution curves, relating APD to diastolic interval (DI), were then constructed for the first time in a murine system and mono-exponential growth functions fitted to these curves. Significant (P<0.05) alterations in the DI at which slopes equalled unity, an established indicator of arrhythmogenicity, now successfully predicted the presence or absence of arrhythmogenicity in all cases. We thus associate changes in the slopes of restitution curves with arrhythmogenicity in models of LQT3 and BrS.
Asunto(s)
Antiarrítmicos/toxicidad , Síndrome de Brugada/inducido químicamente , Flecainida/toxicidad , Frecuencia Cardíaca/efectos de los fármacos , Síndrome de QT Prolongado/inducido químicamente , Quinidina/toxicidad , Canales de Sodio/metabolismo , Potenciales de Acción , Animales , Síndrome de Brugada/genética , Síndrome de Brugada/fisiopatología , Síndrome de Brugada/prevención & control , Estimulación Cardíaca Artificial , Modelos Animales de Enfermedad , Electrocardiografía , Endocardio/efectos de los fármacos , Endocardio/fisiopatología , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/prevención & control , Ratones , Ratones Transgénicos , Modelos Cardiovasculares , Canal de Sodio Activado por Voltaje NAV1.5 , Perfusión , Pericardio/efectos de los fármacos , Pericardio/fisiopatología , Canales de Sodio/genética , Factores de TiempoRESUMEN
Alternans and arrhythmogenicity were studied in hypokalaemic (3.0 mM K(+)) Langendorff-perfused murine hearts paced at high rates. Epicardial and endocardial monophasic action potentials were recorded and durations quantified at 90% repolarization. Alternans and arrhythmia occurred in hypokalaemic, but not normokalaemic (5.2 mM K(+)) hearts (P<0.01): this was prevented by treatment with lidocaine (10 microM, P<0.01). Fourier analysis then confirmed transition from monomorphic to polymorphic waveforms for the first time in the murine heart. Alternans and arrhythmia were associated with increases in the slopes of restitution curves, obtained for the first time in the murine heart, while the anti-arrhythmic effect of lidocaine was associated with decreased slopes. Thus, hypokalaemia significantly increased (P<0.05) maximal gradients (from 0.55+/-0.14 to 2.35+/-0.67 in the epicardium and from 0.67+/-0.13 to 1.87 +/-0.28 in the endocardium) and critical diastolic intervals (DIs) at which gradients equalled unity (from -2.14+/-0.52 ms to 50.93+/-14.45 ms in the epicardium and from 8.14+/-1.49 ms to 44.64+/-5 ms in the endocardium). While treatment of normokalaemic hearts with lidocaine had no significant effect (P>0.05) on either maximal gradients (0.78+/-0.27 in the epicardium and 0.83+/-0.45 in the endocardium) or critical DIs (6.06+/-2.10 ms and 7.04+/-3.82 ms in the endocardium), treatment of hypokalaemic hearts with lidocaine reduced (P<0.05) both these parameters (1.05+/-0.30 in the epicardium and 0.89+/-0.36 in the endocardium and 30.38+/-8.88 ms in the epicardium and 31.65+/-4.78 ms in the endocardium, respectively). We thus demonstrate that alternans contributes a dynamic component to arrhythmic substrate during hypokalaemia, that restitution may furnish an underlying mechanism and that these phenomena are abolished by lidocaine, both recapitulating and clarifying clinical findings.
Asunto(s)
Arritmias Cardíacas/fisiopatología , Frecuencia Cardíaca , Hipopotasemia/complicaciones , Potenciales de Acción , Animales , Antiarrítmicos/farmacología , Arritmias Cardíacas/etiología , Arritmias Cardíacas/prevención & control , Estimulación Cardíaca Artificial , Modelos Animales de Enfermedad , Electrocardiografía , Endocardio/fisiopatología , Análisis de Fourier , Frecuencia Cardíaca/efectos de los fármacos , Hipopotasemia/fisiopatología , Lidocaína/farmacología , Ratones , Modelos Cardiovasculares , Perfusión , Pericardio/fisiopatología , Reproducibilidad de los Resultados , Factores de TiempoRESUMEN
The gain-of-function Scn5a+/DeltaKPQ mutation in the cardiac Na(+) channel causes human long QT type 3 syndrome (LQT3) associated with ventricular arrhythmogenesis. The K(ATP) channel-opener nicorandil (20muM) significantly reduced arrhythmic incidence in Langendorff-perfused Scn5a+/Delta hearts during programmed electrical stimulation; wild-types (WTs) showed a total absence of arrhythmogenicity. These observations precisely correlated with alterations in recently established criteria for re-entrant excitation reflected in: (1) shortened left-ventricular epicardial but not endocardial monophasic action potential durations at 90% repolarization (APD(90)) that (2) restored transmural repolarization gradients, DeltaAPD(90). Scn5a+/Delta hearts showed longer epicardial but not endocardial APD(90)s, giving shorter DeltaAPD(90)s than WT hearts. Nicorandil reduced epicardial APD(90) in both Scn5a+/Delta and WT hearts thereby increasing DeltaAPD(90). (3) Reduced epicardial critical intervals for re-excitation; Scn5a+/Delta hearts showed greater differences between APD(90) and ventricular effective refractory period than WT hearts that were reduced by nicorandil. (4) Reduced APD(90) alternans. Scn5a+/Delta hearts showed greater epicardial and endocardial alternans than WTs, which increased with pacing rate. Nicorandil reduced these in Scn5a+/Delta hearts to levels indistinguishable from untreated WTs. (5) Flattened restitution curves. Scn5a+/Delta hearts showed larger epicardial and endocardial critical diastolic intervals than WT hearts. Nicorandil decreased these in Scn5a+/Delta and WT hearts. The presence or absence of arrhythmogenesis in Scn5a+/Delta and WT hearts thus agreed with previously established criteria for re-entrant excitation, and alterations in these precisely correlated with the corresponding antiarrhythmic effects of nicorandil. Together these findings implicate spatial and temporal re-entrant mechanisms in arrhythmogenesis in LQT3 and their reversal by nicorandil.