Rate-dependent effects of lidocaine on cardiac dynamics: Development and analysis of a low-dimensional drug-channel interaction model.

State-dependent sodium channel blockers are often prescribed to treat cardiac arrhythmias, but many sodium channel blockers are known to have pro-arrhythmic side effects. While the anti and proarrhythmic potential of a sodium channel blocker is thought to depend on the characteristics of its rate-dependent block, the mechanisms linking these two attributes are unclear. Furthermore, how specific properties of rate-dependent block arise from the binding kinetics of a particular drug is poorly understood. Here, we examine the rate-dependent effects of the sodium channel blocker lidocaine by constructing and analyzing a novel drug-channel interaction model. First, we identify the predominant mode of lidocaine binding in a 24 variable Markov model for lidocaine-sodium channel interaction by Moreno et al. Specifically, we find that (1) the vast majority of lidocaine bound to sodium channels is in the neutral form, i.e., the binding of charged lidocaine to sodium channels is negligible, and (2) neutral lidocaine binds almost exclusively to inactivated channels and, upon binding, immobilizes channels in the inactivated state. We then develop a novel 3-variable lidocaine-sodium channel interaction model that incorporates only the predominant mode of drug binding. Our low-dimensional model replicates an extensive amount of the voltage-clamp data used to parameterize the Moreno et al. model. Furthermore, the effects of lidocaine on action potential upstroke velocity and conduction velocity in our model are similar to those predicted by the Moreno et al. model. By exploiting the low-dimensionality of our model, we derive an algebraic expression for level of rate-dependent block as a function of pacing frequency, restitution properties, diastolic and plateau potentials, and drug binding rate constants. Our model predicts that the level of rate-dependent block is sensitive to alterations in restitution properties and increases in diastolic potential, but it is insensitive to variations in the shape of the action potential waveform and lidocaine binding rates.

In Silico Assessment of Class I Antiarrhythmic Drug Effects on Pitx2-Induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues.

Electrical remodelling as a result of homeodomain transcription factor 2 (Pitx2)-dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of the AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action po-tential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmaco-logical effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax), and decreased AP duration (APD), conduction velocity (CV), and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that disopyramide may be more effective against Pitx2-induced AF than propafenone and quinidine by prolonging WL.

Reliable identification of cardiac liability in drug discovery using automated patch clamp: Benchmarking best practices and calibration standards for improved proarrhythmic assessment.

INTRODUCTION: Screening compounds for activity on the hERG channel using patch clamp is a crucial part of safety testing. Automated patch clamp (APC) is becoming widely accepted as an alternative to manual patch clamp in order to increase throughput whilst maintaining data quality. In order to standardize APC experiments, we have investigated the effects on IC50 values under different conditions using several devices across multiple sites. METHODS: APC instruments SyncroPatch 384i, SyncroPatch 384PE and Patchliner, were used to record hERG expressed in HEK or CHO cells. Up to 27 CiPA compounds were used to investigate effects of voltage protocol, incubation time, labware and time between compound preparation and experiment on IC50 values. RESULTS: All IC50 values of 21 compounds recorded on the SyncroPatch 384PE correlated well with IC50 values from the literature (Kramer et al., 2013) regardless of voltage protocol or labware, when compounds were used immediately after preparation, but potency of astemizole decreased if prepared in Teflon or polypropylene (PP) compound plates 2-3 h prior to experiments. Slow acting compounds such as dofetilide, astemizole, and terfenadine required extended incubation times of at least 6 min to reach steady state and therefore, stable IC50 values. DISCUSSION: Assessing the influence of different experimental conditions on hERG assay reliability, we conclude that either the step-ramp protocol recommended by CiPA or a standard 2-s step-pulse protocol can be used to record hERG; a minimum incubation time of 5 min should be used and although glass, Teflon, PP or polystyrene (PS) compound plates can be used for experiments, caution should be taken if using Teflon, PS or PP vessels as some adsorption can occur if experiments are not performed immediately after preparation. Our recommendations are not limited to the APC devices described in this report, but could also be extended to other APC devices.

Targeting pathological leak of ryanodine receptors: preclinical progress and the potential impact on treatments for cardiac arrhythmias and heart failure.

Introduction: Type-2 ryanodine receptor (RyR2) located on the sarcoplasmic reticulum initiate systolic Ca2+ transients within cardiomyocytes. Proper functioning of RyR2 is therefore crucial to the timing and force generated by cardiomyocytes within a healthy heart. Improper intracellular Ca2+ handing secondary to RyR2 dysfunction is associated with a variety of cardiac pathologies including catecholaminergic polymorphic ventricular tachycardia (CPVT), atrial fibrillation (AF), and heart failure (HF). Thus, RyR2 and its associated accessory proteins provide promising drug targets to scientists developing therapeutics for a variety of cardiac pathologies.Areas covered: In this article, we review the role of RyR2 in a variety of cardiac pathologies. We performed a literature search utilizing PubMed and MEDLINE as well as reviewed registries of trials from clinicaltrials.gov from 2010 to 2019 for novel therapeutic approaches that address the cellular mechanisms underlying CPVT, AF, and HF by specifically targeting defective RyR2 channels.Expert opinion: The negative impact of cardiac dysfunction on human health and medical economics are major motivating factors for establishing new and effective therapeutic approaches. Focusing on directly impacting the molecular mechanisms underlying defective Ca2+ handling by RyR2 in HF and arrhythmia has great potential to be translated into novel and innovative therapies.

Muscarinic receptors promote pacemaker fate at the expense of secondary conduction system tissue in zebrafish.

Deterioration or inborn malformations of the cardiac conduction system (CCS) interfere with proper impulse propagation in the heart and may lead to sudden cardiac death or heart failure. Patients afflicted with arrhythmia depend on antiarrhythmic medication or invasive therapy, such as pacemaker implantation. An ideal way to treat these patients would be CCS tissue restoration. This, however, requires precise knowledge regarding the molecular mechanisms underlying CCS development. Here, we aimed to identify regulators of CCS development. We performed a compound screen in zebrafish embryos and identified tolterodine, a muscarinic receptor antagonist, as a modifier of CCS development. Tolterodine provoked a lower heart rate, pericardiac edema, and arrhythmia. Blockade of muscarinic M3, but not M2, receptors induced transcriptional changes leading to amplification of sinoatrial cells and loss of atrioventricular identity. Transcriptome data from an engineered human heart muscle model provided additional evidence for the contribution of muscarinic M3 receptors during cardiac progenitor specification and differentiation. Taken together, we found that muscarinic M3 receptors control the CCS already before the heart becomes innervated. Our data indicate that muscarinic receptors maintain a delicate balance between the developing sinoatrial node and the atrioventricular canal, which is probably required to prevent the development of arrhythmia.

Eficacia y seguridad de ivabradina en pacientes adultos con falla cardiaca y fracción de eyección reducida, que permanecen sintomáticos a pesar del tratamiento con la terapia médica óptima, con un enfoque sobre el potencial rol de modificador de efecto de la frecuencia cardiaca / Efficacy and safety of ivabradine in adult patients with heart failure and reduced ejection fraction, who remain symptomatic despite treatment with optimal medical therapy, with a focus on the potential role of heart rate modifier effect

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de ivabradina en pacientes con falla cardiaca (FC) crónica y con fracción de eyección (FE) ventricular izquierda reducida (FC-FEr) que persisten sintomáticos a pesar del tratamiento con la terapia médica óptima (TMO) que incluye el uso de la dosis máxima tolerada (DMT) de beta-bloqueadores (BB) teniendo en cuenta el rol potencial de la frecuencia cardiaca como modificador de efecto. En ese sentido, de ahora en adelante, para efectos del presente dictamen, se hará referencia a la falla cardíaca crónica como FC, y a la fracción de eyección ventricular izquierda como FE. La falla cardíaca (FC) con fracción de eyección (FE) reducida (FC-FEr) se define como la presencia de signos y síntomas de FC crónica, con una FE ventricular izquierda ≤ 40 %. La clasificación sintomática de los pacientes con FC considera a las escalas de la clase funcional (CF) de la New York Heart Association, que va desde la I (sin síntomas durante el ejercicio común) hasta el IV (síntomas al reposo). El tratamiento de los pacientes con FC-FEr se realiza con la terapia médica óptima (TMO), la cual incluye el uso de la dosis máxima tolerada (DMT) de inhibidores de la enzima convertidora de angiotensina, antagonistas de receptores de angiotensina II, de betabloqueadores (BB), y de antagonistas de mineralocorticoides. El Petitorio Farmacológico de EsSalud cuenta con la TMO para el tratamiento de los pacientes con FC-FEr. Así, el Instituto de Evaluación de Tecnología Sanitaria - IETSI recibió una solicitud de evaluación de ivabradina, en el contexto de la elaboración de la Guía de Práctica Clínica de Diagnóstico y Tratamiento de Falla Cardíaca. Los expertos del grupo elaborador de dicha guía propusieron se evalué ivabradina bajo la hipótesis que ofrecería un beneficio adicional al uso de la DMT de BB, para el control de la frecuencia cardíaca en los pacientes con FC-FEr sintomáticos a pesar del uso de TMO. METODOLOGÍA: Se llevó a cabo una búsqueda bibliográfica exhaustiva y jerárquica de la literatura con respecto a la eficacia y seguridad de ivabradina en pacientes con FC-FEr, sintomática a pesar del tratamiento con la TMO, que incluye el uso de la DMT de BB, con un enfoque especial sobre el potencial rol de modificador del efecto de la frecuencia cardiaca. La búsqueda se inició revisando la información sobre el uso del medicamento de acuerdo con entidades reguladoras como FDA, EMA, y DIGEMID en el Perú. Se realizó tanto una búsqueda sistemática en las principales bases de datos, tales como MEDLINE vía PubMed, Cochrane Library y LILACS. Así mismo, se realizó una búsqueda manual en las páginas web de grupos dedicados a la investigación y educación en salud que elaboran guías de práctica clínica: National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Haute Authorité de Santé (HAS), Institute for Quality and Efficiency in Healthcare (IQWiG) y el Ministerio de Salud del Perú y (MINSA). Además, se realizó una búsqueda de las guías de las principales sociedades o instituciones especializadas en cardiología, tales como el Instituto Nacional del Corazón (INCOR) del Perú, la American Heart Association (AHA), la American College of Cardiology (ACC), la European Society of Cardiology (ESC), la Sociedad Española de Cardiología (SEC). Por último, se buscaron ensayos clínicos en desarrollo o que no hayan sido publicados aún en la página web www.clinicaltrials.gov que ayuden a responder la pregunta PICO, con el fin de disminuir el sesgo de publicación. RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de ivabradina en pacientes con FC-FEr, sintomáticos a pesar del tratamiento con la TMO, la cual incluye la DMT de BB, con enfoque especial sobre el potencial rol de modificador de efecto de la frecuencia cardiaca. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). CONCLUSIONES: El presente dictamen evaluó la evidencia científica disponible a la actualidad en relación a la eficacia y seguridad del uso de la terapia médica óptima (TMO) con ivabradina comparado con la TMO con placebo en pacientes adultos con falla cardíaca con fracción de eyección reducida (FC-FEr) que permanecen sintomáticos a pesar del tratamiento con la TMO que incluye el uso de la dosis máxima tolerada (DMT) de betabloqueadores (BB), con un especial enfoque sobre el potencial rol de la frecuencia cardíaca como modificador del efecto. La evidencia principal que responde a la pregunta PICO establecida en el presente dictamen proviene de los ensayos clínicos aleatorizados (ECA) de fase III BEAUTIFUL y SHIFT, los cuales son estudios de doble ciego, controlados con placebo, y financiados por la compañía farmacéutica que produce ivabradina, Servier, que evaluaron la eficacia y seguridad de ivabradina comparada con placebo para los pacientes con FC-FEr que se encontraban sintomáticos a pesar de la TMO. Dichos ECA fueron incluidos en el meta-análisis (MA) llevado a cabo por Hartmann et al., 2018, cuyos resultados se usaron para derivar las conclusiones del presente dictamen. El análisis combinado de los ECA SHIFT y BEAUTIFUL, llevado a cabo por el MA de Hartmann et al., 2018, mostró que el uso de la TMO e ivabradina, en comparación con el uso de la TMO y placebo, no presentaron diferencias estadísticamente significativas respecto a la mortalidad por cualquier causa, mortalidad cardiovascular y hospitalizaciones por FC; ni en los principales desenlaces de seguridad, tales como eventos adversos (EA) serios totales, la descontinuación del tratamiento y los EA serios cardíacos, respiratorios, neurológicos y renales, entre los grupos de tratamiento, en una población representativa de la población de la PICO. Sobre el potencial rol de la frecuencia cardíaca como modificador de los desenlaces de interés del presente dictamen se tiene que la evidencia que sustenta las restricciones de uso de ivabradina en pacientes con FC-FEr con frecuencias cardíacas por encima de 70, 75, o 77 LPM provienen únicamente de análisis por subgrupos de los ECA SHIFT y BEAUTIFUL, lo cual introduce un potencial riesgo de sesgo de selección en dichos resultados. Siendo que, no se cuenta a la fecha con evidencia empírica adicional que justifique valorar los resultados de manera separada sólo para aquellos pacientes con una frecuencia cardíaca mayor de 70 LPM, o 77 latidos por minuto (LPM). En relación a las recomendaciones de las guías de práctica clínica (GPC) y evaluación de tecnologías sanitarias (ETS) incluidas en el presente dictamen, sobre el uso de ivabradina en la población de la pregunta PICO, se tiene que todas usaron la evidencia proveniente del ECA SHIFT mientras que unas pocas también usaron la evidencia proveniente del ECA BEAUTIFUL, y que fueron elaborados en contextos diferentes al nuestro. Además, dichas GPC y ETS fueron elaboradas antes de la publicación del MA de Hartmann et al., 2018, el cual mostró que ivabradina presentaría una eficacia y seguridad similar al placebo en la población de la pregunta PICO. En consecuencia, se dificulta la extrapolación de dichas recomendaciones para la población de interés del presente dictamen. En consecuencia, actualmente se desconoce si la frecuencia cardíaca ejerce un potencial rol de modificador del efecto sobre los desenlaces planteados en la pregunta PICO para la población de interés del presente dictamen. Y la mejor evidencia disponible a la fecha, surgida del MA de Hartmann et al., 2018, indica que ivabradina no ofrecería un beneficio adicional frente al placebo en los desenlaces clínicos de interés planteados en la pregunta PICO, para la población de interés del presente dictamen preliminar. Por lo tanto, no existen argumentos técnicos para recomendar el uso ivabradina en EsSalud.

Multi-dry-electrode plate sensor for non-invasive electrocardiogram and heart rate monitoring for the assessment of drug responses in freely behaving mice.

Monitoring of electrocardiogram (ECG) and heart rate (HR) is essential in a wide range of experiments. For conscious animal studies, telemetry is the preferred approach; however, it requires 1-3 weeks of recovery after surgical device-implantation. The present paper describes a novel multi-dry-electrode plate (MDEP) sensor system to monitor ECG/HR in freely behaving mice without the need for surgery for device/electrode implantation. The MDEP sensor is a rectangular plate with 15 gold-plated stripe pattern electrodes, on which a mouse can walk around freely, and detects ECG whenever ≥2 paws (footpads) come in contact with the electrodes. Here we show that the MDEP sensor detected distinct QRS complexes which, were fragmented due to locomotion and insufficient perspiration on the footpads. Nonetheless, the HR calculated from the QRS complexes were similar to the HR calculated from R-R intervals simultaneously recorded from lead-II ECG (difference = 0.0 ±â€¯0.16 ms) as part of the validation exercise. Also, the archetypal responses to isoproterenol and metoprolol injections were successfully detected as a significantly elevation (+151 ±â€¯15 bpm) and reduction (-77 ±â€¯6 bpm) in HR, respectively, compared to vehicle at 20-60 min postdose. Conversely, the P wave was rarely identifiable unless signal averaging was undertaken. These results indicate a potential utility for the MDEP-sensor system for cardiac pharmacological studies. In addition, signal averaging appeared to be effective for detection of ECG intervals such as PR and QT, although the QT cannot be measured in the mouse heart as there is no T wave.

QT Assessment in Early Drug Development: The Long and the Short of It.

The QT interval occupies a pivotal role in drug development as a surface biomarker of ventricular repolarization. The electrophysiologic substrate for QT prolongation coupled with reports of non-cardiac drugs producing lethal arrhythmias captured worldwide attention from government regulators eventuating in a series of guidance documents that require virtually all new chemical compounds to undergo rigorous preclinical and clinical testing to profile their QT liability. While prolongation or shortening of the QT interval may herald the appearance of serious cardiac arrhythmias, the positive predictive value of an abnormal QT measurement for these arrhythmias is modest, especially in the absence of confounding clinical features or a congenital predisposition that increases the risk of syncope and sudden death. Consequently, there has been a paradigm shift to assess a compound's cardiac risk of arrhythmias centered on a mechanistic approach to arrhythmogenesis rather than focusing solely on the QT interval. This entails both robust preclinical and clinical assays along with the emergence of concentration QT modeling as a primary analysis tool to determine whether delayed ventricular repolarization is present. The purpose of this review is to provide a comprehensive understanding of the QT interval and highlight its central role in early drug development.

On-chip spatiotemporal electrophysiological analysis of human stem cell derived cardiomyocytes enables quantitative assessment of proarrhythmia in drug development.

We examined a simultaneous combined spatiotemporal field potential duration (FPD) and cell-to-cell conduction time (CT) in lined-up shaped human embryonic stem cell-derived cardiomyocytes (hESC-CMs) using an on-chip multielectrode array (MEA) system to evaluate two origins of lethal arrhythmia, repolarization and depolarization. The repolarization index, FPD, was prolonged by E-4031 and astemizole, and shortened by verapamil, flecainide and terfenadine at 10 times higher than therapeutic plasma concentrations of each drug, but it did not change after lidocaine treatment up to 100 µM. CT was increased by astemizol, flecainide, terfenadine, and lidocaine at equivalent concentrations of Nav1.5 IC50, suggesting that CT may be an index of cardiac depolarization because the increase in CT (i.e., decrease in cell-to-cell conduction speed) was relevant to Nav1.5 inhibition. Fluctuations (short-term variability; STV) of FPD and CT, STVFPD and STVCT also discriminated between torsadogenic and non-torsadogenic compounds with significant increases in their fluctuation values, enabling precise prediction of arrhythmogenic risk as potential new indices.

Hyperinflation of Isoproterenol.

The hyperinflation of isoproterenol, a 75-year-old drug, in early 2015 was unbelievable. The attention of health-care professionals, health system administrators, legislators, and the general public was quickly focused on Valeant Pharmaceuticals, purchaser of several generics solely to raise their price. With isoproterenol easily launched toward the top of drug expenditures, pharmacists in many hospitals were forced to engage stakeholders in the investigation and implementation of alternatives, explore utilization and optimize inventory, reduce cost through sterile product preparation, where possible, restrict use to settings that were beneficial to their budget, and become legislative advocates. The alternatives drugs and strategies will be reviewed.

In silico assessment of the effects of quinidine, disopyramide and E-4031 on short QT syndrome variant 1 in the human ventricles.

AIMS: Short QT syndrome (SQTS) is an inherited disorder associated with abnormally abbreviated QT intervals and an increased incidence of atrial and ventricular arrhythmias. SQT1 variant (linked to the rapid delayed rectifier potassium channel current, IKr) of SQTS, results from an inactivation-attenuated, gain-of-function mutation (N588K) in the KCNH2-encoded potassium channels. Pro-arrhythmogenic effects of SQT1 have been well characterized, but less is known about the possible pharmacological antiarrhythmic treatment of SQT1. Therefore, this study aimed to assess the potential effects of E-4031, disopyramide and quinidine on SQT1 using a mathematical model of human ventricular electrophysiology. METHODS: The ten Tusscher et al. biophysically detailed model of the human ventricular action potential (AP) was modified to incorporate IKr Markov chain (MC) formulations based on experimental data of the kinetics of the N588K mutation of the KCNH2-encoded subunit of the IKr channels. The modified ventricular cell model was then integrated into one-dimensional (1D) strand, 2D regular and realistic tissues with transmural heterogeneities. The channel-blocking effect of the drugs on ion currents in healthy and SQT1 cells was modeled using half-maximal inhibitory concentration (IC50) and Hill coefficient (nH) values from literatures. Effects of drugs on cell AP duration (APD), effective refractory period (ERP) and pseudo-ECG traces were calculated. Effects of drugs on the ventricular temporal and spatial vulnerability to re-entrant excitation waves were measured. Re-entry was simulated in both 2D regular and realistic ventricular tissue. RESULTS: At the single cell level, the drugs E-4031 and disopyramide had hardly noticeable effects on the ventricular cell APD at 90% repolarization (APD90), whereas quinidine caused a significant prolongation of APD90. Quinidine prolonged and decreased the maximal transmural AP heterogeneity (δV); this led to the decreased transmural heterogeneity of APD across the 1D strand. Quinidine caused QT prolongation and a decrease in the T-wave amplitude, and increased ERP and decreased temporal susceptibility of the tissue to the initiation of re-entry and increased the minimum substrate size necessary to prevent re-entry in the 2D regular model, and further terminated re-entrant waves in the 2D realistic model. Quinidine exhibited significantly better therapeutic effects on SQT1 than E-4031 and disopyramide. CONCLUSIONS: The simulated pharmacological actions of quinidine exhibited antiarrhythmic effects on SQT1. This study substantiates a causal link between quinidine and QT interval prolongation in SQT1 and suggests that quinidine may be a potential pharmacological agent for treating SQT1 patients.

Update on ranolazine in the management of angina.

Mortality rates attributable to coronary heart disease have declined in recent years, possibly related to changes in clinical presentation patterns and use of proven secondary prevention strategies. Chronic stable angina (CSA) remains prevalent, and the goal of treatment is control of symptoms and reduction in cardiovascular events. Ranolazine is a selective inhibitor of the late sodium current in myocytes with anti-ischemic and metabolic properties. It was approved by the US Food and Drug Administration in 2006 for use in patients with CSA. Multiple, randomized, placebo-controlled trials have shown that ranolazine improves functional capacity and decreases anginal episodes in CSA patients, despite a lack of a significant hemodynamic effect. Ranolazine did not improve cardiovascular mortality or affect incidence of myocardial infarction in the MERLIN (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome)-TIMI (Thrombolysis In Myocardial Infarction) 36 trial, but significantly decreased the incidence of recurrent angina. More recently, ranolazine has been shown to have beneficial and potent antiarrhythmic effects, both on supraventricular and ventricular tachyarrhythmias, largely due to its inhibition of the late sodium current. Randomized controlled trials testing these effects are underway. Lastly, ranolazine appears to be cost-effective due to its ability to decrease angina-related hospitalizations and improve quality of life.

Atrial fibrillation in a large population with Brugada electrocardiographic pattern: prevalence, management, and correlation with prognosis.

BACKGROUND: A high prevalence of atrial fibrillation/atrial flutter (AF/AFl) has been reported in small series of Brugada patients, with discordant data. OBJECTIVE: The purpose of this study was to analyze, in a large population of Brugada patients, the prevalence of AF/AFl, its correlation with prognosis, and the efficacy of hydroquinidine (HQ) treatment. METHODS: Among 560 patients with Brugada type 1 ECG (BrECG), 48 (9%) had AF/AFl. Three groups were considered: 23 patients with BrECG pattern recognized before AF/AFl (group 1); 25 patients first diagnosed with AF/AFl in whom Class IC antiarrhythmic drugs administered for cardioversion/prophylaxis unmasked BrECG (group 2); and 512 patients without AF/AFl (group 3). Recurrence of AF/AFl and occurrence of ventricular arrhythmias were evaluated at follow-up. RESULTS: Mean age was 47 ± 15 years, 59 ± 11 years, and 44 ± 14 years in groups 1, 2, and 3, respectively. Seven subjects (32%) in group 1 had syncope/aborted sudden death, 1 (4%) in group 2, and 122 (24%) in group 3. Ventricular arrhythmia occurred in three patients in group 1, none in group 2, and 10 in group 3 at median follow-up of 51, 68, and 41 months, respectively. Nine patients in group 1 and nine in group 2 received HQ for AF/AFl prophylaxis; on therapy, none had AF/AFl recurrence. CONCLUSION: Prevalence of AF/AFl in Brugada patients is higher than in the general population of the same age. Patients in group 1 are younger than those in group 2 and have a worse prognosis compared to both groups 2 and 3. HQ therapy has proved useful and safe in patients with AF/AFl and BrECG.

Economic burden and disparities in healthcare resource use among adult patients with cardiac arrhythmia.

BACKGROUND: As of 2012, approximately 4.3 million Americans experience some form of cardiac arrhythmia (CA). Assessment of economic burden and healthcare resource use on the overall CA population is limited. OBJECTIVES: To assess healthcare expenditure and disparities in healthcare resource use in patients with all forms of CA in the US. METHODS: Data from the Medical Expenditure Panel Survey were analyzed between 2004 and 2009. Patients aged≥18 years with any form of CA (identified via International Classification of Disorders Ninth Revision, Clinical Modification [ICD-9-CM] codes) were included. Primary independent variables included age, gender, race/ethnicity, and pharmacotherapy use. Outcomes of interest included total annual healthcare and prescription expenditures (inflation adjusted to 2011), use of anti-arrhythmic agents associated with CA, and inpatient, outpatient, or emergency room visits. Generalized linear models were used to assess the disparities across patient subgroups related to the outcomes. RESULTS: Annually, 5,750,440 individuals experienced CA in the US. Total direct annual healthcare cost of CA summed up to $US67.4 billion. Non-Hispanic whites and older adult patients had higher expenditures and use of healthcare resources (p<0.05). Female patients had significantly higher prescribed medication expenditures and a lower proportion of inpatient and emergency room visits related to arrhythmia (p<0.05). Patients taking anti-arrhythmic agents had significantly higher expenditure and a lower proportion of emergency department visits related to arrhythmia (p<0.05). CONCLUSIONS: CA represents a substantial economic burden in the US, especially for the older adult population. Patients other than non-Hispanic whites may not have adequate access to healthcare treatment for arrhythmia.

Association of patient demographics on quality of life in a sample of adult patients with cardiac arrhythmias.

PURPOSE: Identify predictors of quality of life (QOL) in patients with any form of cardiac arrhythmia (CA). METHODS: Data from the Medical Panel Expenditure Survey were analyzed from 2004 to 2009. Patients aged ≥18 with any form of CA (identified via ICD-9-CM codes) were included. Primary outcomes included the physical and mental component scores (PCS and MCS) of the Short-Form 12 version 2 (SF-12) and EuroQoL-5D (EQ-5D) utility scores (US version). Patient demographics included insurance status, urban status, geographical region, federal poverty level, education, comorbidities, and disease-related risk factors of CA. RESULTS: Approximately 5,750,440 individuals had CA. Non-Hispanic Whites had the highest SF-12 MCS (mean 50.9; p < 0.001 across racial groups) and utility scores (mean 0.76; p < 0.001 across racial groups). Patients with both private and public insurance had significantly higher PCS (p = 0.001) and MCS (p < 0.001) in comparison with patients only covered by public insurance. Patients on antiarrhythmic agents had higher SF-12 MCS (51.4 vs. 48.4; p < 0.001) compared to individuals not on antiarrhythmic agents. CONCLUSIONS: Significantly lower QOL existed in specific subpopulations (e.g., patients with only public health insurance, racial/ethnic minorities, and those not exposed to antiarrhythmic agents) within the CA population.

An assessment of the reporting quality of randomised controlled trials relating to anti-arrhythmic agents (2002-2011).

BACKGROUND: Despite being the gold-standard for investigations, randomised controlled trials can deliver biased results if methodology is flawed. The CONSORT statements are intended to guide the reporting of trials. We assessed the reporting quality of anti-arrhythmic drug trials over the last decade. METHODS: Medline and Embase databases were searched for anti-arrhythmic drug trials between 2002 and 2011. Results were searched by two authors and relevant papers selected. Papers were scored according to the 2001 and 2010 CONSORT statements by two reviewers and compared against surrogate markers of paper quality. RESULTS: 694 papers were retrieved. 59 papers met the inclusion criteria. The mean CONSORT 2010 score was 15.4 out of 25 (SD 3.05). The least reported items related to abstract content (0%), randomization (6.8%), and protocol referencing (8.5%). There was a significant correlation between the CONSORT 2010 score and the annual and 5-year impact factors of the publishing journal (R=0.44 and R=0.45 respectively; p<0.001 for both). No significant correlation was found between the year of publication or number of authors, and 2010 CONSORT score. CONCLUSIONS: Although several papers gained high scores, no paper successfully met all criteria laid out in either the CONSORT 2001 or 2010 statements. Correlation between CONSORT 2010 score and impact factor lends support to this as a marker for paper quality. The lack of reporting clarity found, indicates that application of the CONSORT guidelines remains incomplete within the cardiology literature. Further work is needed collectively by trial groups, funding agencies, authors, and journals to improve reporting.

[Use of antihypertensive drugs in France and relationship with cardiovascular disease. FLAHS 2009-2010 surveys]. / Utilisation des traitements antihypertenseurs en France et relations avec les pathologies cardiovasculaires. Enquêtes FLAHS 2009-2010.

OBJECTIVE: Describe how antihypertensive drugs are prescribed in France in 2009 and 2010 and assess the effect of the presence of cardiovascular disease on the characteristics of the treatment. METHODS: The French League Against Hypertension Surveys (FLAHS) are conducted among a representative sample of individuals aged 35 years and older living in France. For the 2009 and 2010 surveys, a sample of 2292 subjects who declared to take one or more antihypertensive drug has been studied. In addition to the details of antihypertensive medications taken the day of the survey, the personal history for cardiovascular diseases was compiled. RESULTS: Of the 2292 prescriptions with at least one antihypertensive prescription frequencies are: ARB (43%), diuretics (43%), beta-blockers (34%), CCB (26%), ACEI (26%), spironolactone (8%), central and alpha (7%), DRI (1%). The prescription is performed as monotherapy (42%), bitherapy (37%), triple therapy (16%) and quadruple or more (5%). When triple therapy is prescribed, there is an association ACEI or ARB or DRI+Diu+BB in 46%, and an association ACEI or ARB or DRI+Diu+AC in 30%. Cardiovascular disease is present or past reported by 24% of hypertensive patients: coronary artery disease (13%), heart failure (6%), arrhythmias (5%), stroke (4%), PAD (4%). The use of BB is more common in hypertensive patients who have coronary artery disease, heart failure and arrhythmia. ACE inhibitors are more common in hypertensive patients with coronary artery disease, heart failure or stroke. CCB are more frequent in cases of coronary artery disease or PAD. The ARB are less frequent in patients with coronary artery disease. CONCLUSION: The ARB, diuretics and beta-blockers are the most prescribed antihypertensives in France in 2009 to 2010. Cardiovascular diseases declared in 24% of hypertensives led to a preferential prescription of an ACE inhibitor or BB.