Class Ic Antiarrhythmic Drug Research Articles

Use of Pharmacogenetic Information for Therapeutic Drug Monitoring of an Antiarrhythmic Drug

Antiarrhythmic drugs require therapeutic drug monitoring (TDM) to avoid adverse effects such as proarrhythmia. However, TDM is not necessarily used to adjust the dosage of antiarrhythmic drugs because there is a lack of information regarding the therapeutic range of the serum concentration and the selection of patients who require TDM. The aim of this review was to provide an overview of the pharmacogenetic information on the pharmacokinetics and drug response of flecainide, a class Ic antiarrhythmic drug with a sodium channel-blocking effect. A population pharmacokinetic analysis revealed that the CYP2D6 genotype was a determining factor of the age-related decline in flecainide clearance. Elderly patients show large interindividual variability of flecainide clearance because they have a more pronounced effect of the CYP2D6 genotype and require more frequent monitoring of serum flecainide concentrations. Carriers of an Asian-specific promoter haplotype B of the cardiac sodium channel gene (SCN5A) more frequently achieve clinically relevant flecainide efficacy even at lower concentrations. This suggests that the therapeutic range of serum flecainide concentrations is lower in SCN5A promoter haplotype B carriers than in the wild-type haplotype A homozygotes. The β1-adrenergic receptor Gly389 polymorphism decreases the antiarrhythmic efficacy of flecainide when co-administered with β-blockers. Carriers of Gly389 with co-administration of β-blockers may not achieve clinically relevant flecainide efficacy even when the serum flecainide concentrations are within the therapeutic range. These findings provide pharmacogenetic information for the effective utilization of TDM in antiarrhythmic drug therapy.

Slow Recovery of Excitability Increases Ventricular Fibrillation Risk as Identified by Emulation.

Purpose: Rotor stability and meandering are key mechanisms determining and sustaining cardiac fibrillation, with important implications for anti-arrhythmic drug development. However, little is yet known on how rotor dynamics are modulated by variability in cellular electrophysiology, particularly on kinetic properties of ion channel recovery.Methods: We propose a novel emulation approach, based on Gaussian process regression augmented with machine learning, for data enrichment, automatic detection, classification, and analysis of re-entrant biomarkers in cardiac tissue. More than 5,000 monodomain simulations of long-lasting arrhythmic episodes with Fenton-Karma ionic dynamics, further enriched by emulation to 80 million electrophysiological scenarios, were conducted to investigate the role of variability in ion channel densities and kinetics in modulating rotor-driven arrhythmic behavior.Results: Our methods predicted the class of excitation behavior with classification accuracy up to 96%, and emulation effectively predicted frequency, stability, and spatial biomarkers of functional re-entry. We demonstrate that the excitation wavelength interpretation of re-entrant behavior hides critical information about rotor persistence and devolution into fibrillation. In particular, whereas action potential duration directly modulates rotor frequency and meandering, critical windows of excitability are identified as the main determinants of breakup. Further novel electrophysiological insights of particular relevance for ventricular arrhythmias arise from our multivariate analysis, including the role of incomplete activation of slow inward currents in mediating tissue rate-dependence and dispersion of repolarization, and the emergence of slow recovery of excitability as a significant promoter of this mechanism of dispersion and increased arrhythmic risk.Conclusions: Our results mechanistically explain pro-arrhythmic effects of class Ic anti-arrhythmics in the ventricles despite their established role in the pharmacological management of atrial fibrillation. This is mediated by their slow recovery of excitability mode of action, promoting incomplete activation of slow inward currents and therefore increased dispersion of repolarization, given the larger influence of these currents in modulating the action potential in the ventricles compared to the atria. These results exemplify the potential of emulation techniques in elucidating novel mechanisms of arrhythmia and further application to cardiac electrophysiology.

Inhibition of the voltage-dependent K+ current by the class Ic antiarrhythmic drug flecainide in rabbit coronary arterial smooth muscle cells.

This study examined the inhibitory effect of flecainide, a class 1c antiarrhythmic agent (Na+ channel blocker), on voltage-dependent K+ (Kv) channels in smooth muscle cells isolated from coronary arteries. Flecainide decreased the vascular Kv channel current in a dose-dependent manner with an IC50 value of 5.90±0.87μmol/L and a Hill coefficient of 0.77±0.06. Although the steady-state activation curve was not affected by flecainide, it shifted the steady-state inactivation curves toward a more negative potential. Application of train pulses such as 1 or 2Hz did not change the flecainide-induced inhibition of Kv channels, indicating that the inhibitory effect of flecainide was not use-dependent. Using perforated-patch clamp experiments, we found that inhibition of Kv channels by flecainide caused membrane depolarization. Together, these results suggest that flecainide inhibits Kv channels in a concentration-dependent, but not use-dependent manner by changing the inactivation gating properties. Furthermore, Kv channel inhibition by flecainide occurs regardless of Na+ channel inhibition.

Substrates and potential therapeutics of ventricular arrhythmias in heart failure

Heart failure (HF) is a clinical syndrome characterized by ventricular contractile dysfunction. About 50% of death in patients with HF are due to fetal ventricular arrhythmias including ventricular tachycardia and ventricular fibrillation. Understanding ventricular arrhythmic substrates and discovering effective antiarrhythmic interventions are extremely important for improving the prognosis of patients with HF and reducing its mortality. In this review, we discussed ventricular arrhythmic substrates and current clinical therapeutics for ventricular arrhythmias in HF. Base on the fact that classic antiarrhythmic drugs have the limited efficacy, side effects, and proarrhythmic potentials, we also updated some therapeutic strategies for the development of potential new antiarrhythmic interventions for patients with HF.

Inhibition of Small Conductance Calcium-Activated Potassium (SK) Channels Prevents Arrhythmias in Rat Atria During β-Adrenergic and Muscarinic Receptor Activation.

Sympathetic and vagal activation is linked to atrial arrhythmogenesis. Here we investigated the small conductance Ca2+-activated K+ (SK)-channel pore-blocker N-(pyridin-2-yl)-4-(pyridine-2-yl)thiazol-2-amine (ICA) on action potential (AP) and atrial fibrillation (AF) parameters in isolated rat atria during β-adrenergic [isoprenaline (ISO)] and muscarinic M2 [carbachol (CCh)] activation. Furthermore, antiarrhythmic efficacy of ICA was benchmarked toward the class-IC antiarrhythmic drug flecainide (Fleca). ISO increased the spontaneous beating frequency but did not affect other AP parameters. As expected, CCh hyperpolarized resting membrane potential (-6.2 ± 0.9 mV), shortened APD90 (24.2 ± 1.6 vs. 17.7 ± 1.1 ms), and effective refractory period (ERP; 20.0 ± 1.3 vs. 15.8 ± 1.3 ms). The duration of burst pacing triggered AF was unchanged in the presence of CCh compared to control atria (12.8 ± 5.3 vs. 11.2 ± 3.6 s), while β-adrenergic activation resulted in shorter AF durations (3.3 ± 1.7 s) and lower AF-frequency compared to CCh. Treatment with ICA (10 μM) in ISO -stimulated atria prolonged APD90 and ERP, while the AF burden was reduced (7.1 ± 5.5 vs. 0.1 ± 0.1 s). In CCh-stimulated atria, ICA treatment also resulted in APD90 and ERP prolongation and shorter AF durations. Fleca treatment in CCh-stimulated atria prolonged APD90 and ERP and abbreviated the AF duration to a similar extent as with ICA. Muscarinic activated atria constitutes a more arrhythmogenic substrate than β-adrenoceptor activated atria. Pharmacological inhibition of SK channels by ICA is effective under both conditions and equally efficacious to Fleca.

Class IC antiarrhythmic drugs for suspected premature ventricular contraction–induced cardiomyopathy

Class IC antiarrhythmic drugs (IC-AADs) can effectively suppress premature ventricular contractions (PVCs). However, IC-AADs increase mortality in patients with PVCs and left ventricular dysfunction after myocardial infarction. Whether IC-AADs can be safely used to treat premature ventricular contraction-induced cardiomyopathy (PVC-CM) remains to be established. The purpose of this study was to determine the safety and efficacy of IC-AADs in patients suspected of having PVC-CM. The electronic medical records at the Hospital of the University of Pennsylvania were screened to identify all patients suspected of having PVC-CM treated with flecainide or propafenone. Clinical, electrocardiographic, and imaging studies were reviewed. Twenty patients suspected of having PVC-CM were treated with IC-AADs. Patients had undergone an average of 1.3 ± 0.2 previous unsuccessful ablations. Six had an implantable or wearable defibrillator. With IC-AAD treatment, mean PVC burden decreased from 36.2% ± 3.5% to 10.0% ± 2.4% (P <.001). Mean left ventricular ejection fraction (LVEF) increased from 37.4% ± 2.0% to 49.0% ± 1.9% (P <.001). Seven patients with myocardial delayed enhancement on cardiac magnetic resonance imaging (all <5% of the total myocardium) experienced similar improvement in LVEF (from 36.8% ± 4.3% before IC-AAD to 51.7% ± 3.7% afterward; P <.01). Over an average 3.8 ± 0.9 treatment-years, no sustained ventricular arrhythmias or sudden cardiac deaths occurred. In patients suspected of having PVC-CM, IC-AADs effectively suppressed PVCs, leading to LVEF recovery in the majority. No adverse events occurred in this small cohort.

L-Type Calcium Channel Gating Modifiers as a New Class of Antiarrhythmic Drugs

Pharmacological treatment of cardiac arrhythmias includes the use of Ca2+ channel blockers (Class IV antiarrhythmics), that while suppressing arrhythmias, also block peak ICa,L, compromising EC coupling and contractility. To circumvent these limitations, we are studying and testing the properties of L-type Ca channel gating modifiers, rather than blockers, to selectively reduce the non-inactivating component (late ICa,L), leaving peak ICa,L minimally affected, thus preserving cardiac contractility. This strategy is based on our discovery that the selective reduction of late ICa,L potently suppress early afterdepolarizations (EADs) of the cardiac action potential (AP), recognized cellular triggers of arrhythmias (Madhvani et al., 2015). We previously reported that roscovitine, a purine analog known to reduce late ICa,L, potently suppressed H2O2-mediated EADs in rabbit ventricular myocytes. We are evaluating the robustness of this pharmacological intervention in a new model of EAD favoring condition using 600μM H2O2+1-2μM Isoproterenol. H2O2 alone (n=7) caused EADs in 83.2±5.39% APs and 85.7±7.83% APs in presence of H2O2+Isoproterenol (n=5); the perfusion of roscovitine (20 µM) efficiently suppressed EAD occurrence restoring normal AP duration in all myocytes tested. This antiarrhythmic effect was achieved without significantly perturbing calcium transients and cell shortening, indicating maintenance of normal EC coupling. We also tested roscovitine ability to suppress EAD-triggered ventricular fibrillation (VF) in isolated-perfused aged rat and rabbit hearts. We found that roscovitine suppressed VF induced by H2O2 (8/8 rat hearts, average time: 13±2.8 min) and H2O2+Isoproterenol (4/4 rabbit hearts, average time: 21±7 min), restoring sinus rhythm. Roscovitine had no significant effect on the rate-pressure product (RPP) as a measure of myocardial workload in isolated rat hearts (n=5). We propose that these findings establish roscovitine as a pilot compound to drive the development of a new class of antiarrhythmics based on Ca channel gating modification.

Failure of Intracardiac Pacing After Fatal Propafenone Overdose: A Case Report

BackgroundPropafenone is a sodium-channel blocker, class IC antiarrhythmic drug, frequently used to manage supraventricular dysrhythmias, especially atrial fibrillation. We report a self mono-intoxication with propafenone. Case ReportA 68-year-old woman presented with a decreased level of consciousness, hypotension, and electrocardiogram showing QRS widening with atrial asystole and extreme bradycardia < 20 beats/min. After initial stabilization with transcutaneous pacing, laboratory findings detected normal electrolyte ranges and metabolic acidosis, and her medical history revealed availability of propafenone due to paroxysmal atrial fibrillation and depressive syndrome, which led to the suspicion of intoxication. Despite intravenous sodium bicarbonate, calcium, norepinephrine, and aggressive fluid replacement (10% glucose with insulin), hemodynamic stability was not achieved. Temporary intracardiac pacing was implanted. However, even with multiple electrode positions, effective capture could not be achieved. At that time, transcutaneous pacing was also ineffective. Consequently, the patient died in refractory asystole due to complete myocardial nonexcitability. The concentration of 5270 ng/mL of propafenone was found in the blood at autopsy, using gas spectrometry–mass chromatography. It is the third highest reported propafenone lethal concentration and the first case in which the myocardial nonexcitability refractory to intracardiac pacing was seen despite normal electrode position in the right ventricle, with failure to achieve the patient's hemodynamic stability. Why Should an Emergency Physician Be Aware of This?Emergency physicians should be aware of possible propafenone ingestion causing toxicity, which is probably more frequent than previously described, especially because propafenone is widely available due to its use in managing atrial fibrillation, the most common arrhythmia nowadays.

Clinical effectiveness of a systematic “pill-in-the-pocket” approach for the management of paroxysmal atrial fibrillation

For patients with symptomatic, sustained atrial fibrillation (AF), a "pill-in-the-pocket" antiarrhythmic drug (PIP-AAD) strategy has been proposed to reduce emergency department (ED) use. To assess the clinical utility of a protocolled PIP-AAD approach within contemporary practice. Consecutive patients who hemodynamically tolerated symptomatic, sustained AF were prospectively managed with the PIP-AAD strategy. All patients were given an atrioventricular nodal blocker 30 minutes prior to a single oral dose of a class Ic antiarrhythmic drug. If the initial PIP-AAD in the ED was efficacious and tolerated, PIP-AADs were given out of hospital for subsequent sustained AF episodes. Usage and complications were systematically recorded. During a median follow-up period of 565 days, 43 of 80 patients presented to the ED for initial PIP-AAD. Sinus rhythm was restored without complication in 30 of 43 patients. The reasons for initial PIP-AAD failure were inefficacy (6 patients), significant hypotension (4 patients), conversion to flutter necessitating cardioversion (2 patients), and syncopal conversion pause (1 patient). For the 30 patients with successful initial PIP-AAD, 159 out-of-hospital PIP-AAD treatments occurred (mean 5.3 ± SD 1.3 per patient). Compared with ED visits in the period prior to PIP-AAD initiation, there was a significant reduction in visits (2.6 ± 3.0 vs. 0.4±0.9 ED visits per patient, P < .001) and the need for cardioversion (2.3 ± 3.1 vs. 0.0 ± 0.2 treatments per patient, P< .001). Adverse events associated with out-of-hospital PIP-AAD include presyncope (3 of 30 patients), syncope necessitating pacemaker implantation (1 patient), and conversion to flutter (1patient). Out-of-hospital PIP-AAD can be an effective for highly selected patients; however, the rates of treatment failure and adverse events are clinically relevant, which limits the widespread application of a PIP-AAD approach.

Inhibition of voltage-dependent K+ current in rabbit coronary arterial smooth muscle cells by the class Ic antiarrhythmic drug propafenone.

In this study, we demonstrated the inhibitory effect of the Class Ic antiarrhythmic agent propafenone on voltage-dependent K+ (Kv) channels using freshly isolated coronary artery smooth muscle cells from rabbits. The Kv current amplitude was progressively inhibited by propafenone in a dose-dependent manner, with an apparent IC50 value of 5.04±1.05 µM and a Hill coefficient of 0.78±0.06. The application of propafenone had no significant effect on the steady-state activation and inactivation curves, indicating that propafenone did not affect the voltage-sensitivity of Kv channels. The application of train pulses at frequencies of 1 or 2 Hz progressively increased the propafenone-induced inhibition of the Kv current. Furthermore, the inactivation recovery time constant was increased after the application of propafenone, suggesting that the inhibitory action of propafenone on Kv current is partially use-dependent. Pretreatment with Kv1.5, Kv2.1 or Kv7 inhibitor did not change the inhibitory effect of propafenone on the Kv current. Together, these results suggest that propafenone inhibits the vascular Kv channels in a dose- and use-dependent manner, regardless of Na+ channel inhibition.

Treatment for ventricular arrhythmias in the absence of structural heart disease: from guidelines to clinical practice

To determine criteria for choosing management tactics in patients with ventricular arrhythmias (VA) in the absence of structural heart disease from the point of view of physicians and patients in clinical practice and to compare the immediate results of antiarrhythmic drug therapy (ADT) and radiofrequency ablation (RFA) with the trends in arrhythmic syndrome in the non-treatment group. Examinations were made in 90 patients (23 men and 67 women) (mean age, 44 (31; 57) years) with VA in the absence of structural heart disease. Preference was given to RFA (n = 32 (36%)), ADT (n = 37 (41%)), and follow-up tactics (n = 21 (23%)). At baseline and 1 month, Holter ECG monitoring was done; quality of life (QOL) was assessed; and anxiety and depression levels were detected using the SF-36 and HADS questionnaires. In addition, 71 physicians were surveyed about their preferences to the treatment of VA in individuals without structural heart disease. In the total group of patients, VA was unambiguously accompanied by the symptoms only in 47%. The signs of anxiety and depression were identified in 41 and 14% of cases, respectively. The efficiency of RFA was comparable to that of ADT (p > 0.1): a positive antiarrhythmic effect was observed in 71.9% of the patients in the RFA group and in 67.6% in the ADT group. During one month, 38.1% of the patients in the follow-up group showed a spontaneous substantial reduction in the number of ventricular premature beats (VPBs) or disappearance of unstable ventricular tachycardia (UVT), which met the criteria for a positive effect. At baseline, the QOL indicators on a social functioning scale in the RFA group were worse than those in the ADT group. At the same time, most QOL indicators in the patients who have chosen a wait-and-see tactic were significantly higher than those in the RFA and ADT subgroups. The patients treated with ethacyzin in the ADT group more frequently achieved a positive effect. In the interviewed physicians' opinion, the choice of a tactic depended on the impact of arrhythmia on health status (68%), the number of VPBs per day (61%), and the presence of UVT (56%). RFA or ADT was most often recommended when there were 10,000-15,000 or more VPBs per day ((49 and 35% of the respondents, respectively). 46.5% of the respondents stated that β-blockers were the drug of choice for idiopathic frequent VPBs. Only 30% of the respondents considered it appropriate to restrict to a follow-up in the presence of asymptomatic VPBs. Patient management in clinical practice generally complies with the current guidelines; however, much importance is attached to the severity of arrhythmia (the number of VPBs per day, the presence of UVT) in addition to the presence of symptoms. In the opinion of most physicians, the initiation of treatment is justified when there are 10,000-15,000 and more per day. QOL assessment may be promising in choosing the optimal management tactics for these patients. Treatment should not be initiated immediately in patients with a high level of QOL, especially in those with arrhythmia lasting less than 12 months, by taking into account that there can be a spontaneous improvement in 38% of cases within the next month. The immediate results of ADT and RFA are comparable in patients with VA in the absence of structural heart disease. The Class IC antiarrhythmic drug ethacyzin is the most effective agent that ensures positive changes in arrhythmic syndrome in 66.7% of cases with the rate of side effects being in 17.8%.

Initiation and outcomes with Class Ic antiarrhythmic drug therapy

BackgroundExpert opinion recommends performing exercise testing with initiation of Class Ic antiarrhythmic medication. ObjectiveTo evaluate the rate and reason for discontinuation of Ic agent within the first year of follow up, with particular attention to rate of proarrhythmia and the value of routine treadmill testing. MethodsThis is a single center retrospective cohort study including consecutive patients with atrial arrhythmias who were initiated on a Class Ic agent from 2011 to 2016. Data was collated from chart review and pharmacy database. ResultsThe study population included 300 patients (55% male, mean age 61; mean ejection fraction, 56%) started on flecainide (n = 153; 51%) and propafenone (n = 147; 49%). Drug initiation was completed while hospitalized on telemetry and the staff electrophysiologists directed dosing. There was one proarrhythmic event during initiation (0.3%). The primary reason for not being discharged on Ic agent was due to detection of proarrhythmia (n = 15) or ischemia (n = 1) with treadmill testing (5.3%). Exercise testing was the single significant variable to affect the decision to discontinue Ic drug, p < 0.0001 (95% CI: 1.89–6.08%). During follow up, the primary reason for discontinuation of Ic agent was lack of efficacy, 32%. ConclusionsWith proper screening, initiation of Class Ic agent is associated with very low rate of proarrhythmia. Treadmill testing is of incremental value and should be completed in all patients after loading Class Ic antiarrhythmic.

Progression of late postoperative atrial fibrillation in patients with tetralogy of Fallot.

ToF patients are at risk for ventricular deterioration at a relatively young age, which can be aggravated by AF development. Therefore, knowledge on AF development and its timespan of progression is essential to guide treatment strategies for AF. We examined late postoperative AF onset and progression in ToF patients during long-term follow-up after ToF correction. In addition, coexistence of AF with regular supraventricular tachyarrhythmias (SVT) and ventricular tachyarrhythmias (VTA) was analyzed. ToF patients (N=29) with AF after ToF correction referred to the electrophysiology department between 2000 and 2015 were included. All available rhythm registrations were reviewed for AF, regular SVT, and VTA. AF progression was defined as transition from paroxysmal AF to (longstanding) persistent/permanent AF or from (longstanding) persistent AF to permanent AF. At the age of 44 ± 12 years, ToF patients presented with paroxysmal (N=14, 48%), persistent (N=13, 45%) or permanent AF (N=2, 7%). Age of AF development was similar among patients who either underwent initial shunt creation (N=15, 45 ± 11 [25-57] years) or primary total ToF correction (N=14, 43 ± 13 [26-66] years) (P=0.785). AF coexisted with regular SVT (N=18, 62%) and VTA (N=13, 45%). Progression of AF occurred in 11 patients (38%) within 5 ± 5 years after AF onset despite antiarrhythmic drug class II (AAD, P=0.052) or III (P=0.587) usage. AF in our ToF population developed at a young age and showed rapid progression. Rhythm control by pharmacological therapy was ineffective in preventing AF progression.

PP.24.02] MANAGEMENT OF ORAL ANTICOAGULANTS IN OUTPATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION DAILY ATTENDED BY CARDIOLOGISTS

Objective: To analyze the management of dabigatran and vitamin K antagonists in outpatients with nonvalvular atrial fibrillation in clinical practice in Spain. Design and method: This is an ongoing observational, prospective and multicenter study in which outpatients with nonvalvular atrial fibrillation daily attended by cardiologists in Spain that have started treatment with dabigatran or vitamin K antagonists in the last month are being included. All patients will be followed during 6 months. In this abstract, baseline data of the first 649 patients were presented. Results: Mean age of patients was 73.5 ± 9.5 years, and 56.4% of patients were men. Mean CHA2-DS2-VASc score was 3.6 ± 1.5 and mean HAS-BLED score 1.4 ± 1.1. Permanent atrial fibrillation was reported in 41.7% of patients, paroxysmal atrial fibrillation in 33.5% of patients and persistent atrial fibrillation in 24.8% of patients. With regard to treatment, 69.2% of patients were taking beta blockers, 22.6% amiodarone, 12.2% digoxin, 9.3% class IC antiarrhythmic drugs, 8.5% calcium channel blockers and 1.7% dronedarone. With regard to anticoagulant therapy, 505 patients were taking dabigatran (57.9% dabigatran 150 mg bid and 42.1% dabigatran 110 mg bid) and the remaining 144 patients vitamin K antagonists. The most important reason for choosing dabigatran 110 mg bid was advanced age (64.2%) followed by concern about bleeding risk (32.5%). Conclusions: Outpatients daily attended by cardiologists in Spain have a high risk of thromboembolic events, but a low/moderate risk of bleeding. The majority of patients are polymedicated. The main reason for prescribing dabigatran 110 mg bid was advanced age.

Survey of EKG Monitoring Practices: A Necessity or Prolonged Nuisance?

Survey of EKG Monitoring Practices: A Necessity or Prolonged Nuisance?

A New Class of Antiarrhythmics for Late ICA,L

Early Afterdepolarizations (EADs) of the cardiac action potential (AP) are membrane potential oscillations arising during phase 2-3 and well-recognized cellular triggers of lethal cardiac arrhythmias. The L-type Ca2+ current (ICa,L) is a major regenerative inward current during these phases of the AP, and is therefore highly relevant to EAD upstroke and propagation at the tissue level. We recently discovered that late ICa,L reduction produced by minimally altering specific ICa,L biophysical properties (smaller pedestal ICa,L or more depolarized steady-state activation), potently suppresses EAD occurrence in rabbit ventricular myocytes under dynamic clamp. Based on these findings, we hypothesize that drugs able to mimic these late ICa,L modifications could constitute a new Class of antiarrhythmics that do not compromise inotropy. We are studying the antiarrhythmic effects of two pilots drugs, roscovitine and pregabalin, that we found to reduce late ICa,L in rabbit ventricular myocytes via two distinct mechanisms. Specifically, roscovitine reduced the non-inactivating (pedestal) ICa,L while leaving peak ICa,L intact and pregabalin induced a depolarizing shift of the steady-state activation. In this study we assessed the antiarrhythmic potential of these pilot compounds that reduce late ICa,L. We tested the ability of these drugs to suppress EADs in ventricular myocytes induced by oxidative stress (H2O2). The perfusion of roscovitine (20µM) or pregabalin (1mM) dramatically suppressed EAD occurrence (roscovitine: from 81.37%±8.1% to 0% APs with EADs; pregabalin from 64.5±17.7% to 6.6±3.8%) and restored normal AP duration. Moreover, both drugs suppressed EAD-mediated VT/VF in isolated perfused aged rat hearts, restoring sinus rhythm (roscovitine: 5/6; pregabalin: 2/2 hearts). These studies set the basis for the development of a conceptually new Class of antiarrhythmics (L-type Ca2+ channel gating modifiers) that selectively reduce late ICa,L, avoiding the negative inotropy caused by traditional CaV channel blockers used as Class IV Antiarrhythmics.

Repositioning FDA-Approved Drugs in Combination with Epigenetic Drugs to Reprogram Colon Cancer Epigenome.

Epigenetic drugs, such as DNA methylation inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi), are approved in monotherapy for cancer treatment. These drugs reprogram gene expression profiles, reactivate tumor suppressor genes (TSG) producing cancer cell differentiation and apoptosis. Epigenetic drugs have been shown to synergize with other epigenetic drugs or various anticancer drugs. To discover new molecular entities that enhance epigenetic therapy, we performed a high-throughput screening using FDA-approved libraries in combination with DNMTi or HDACi. As a screening model, we used YB5 system, a human colon cancer cell line, which contains an epigenetically silenced CMV-GFP locus, mimicking TSG silencing in cancer. CMV-GFP reactivation is triggered by DNMTi or HDACi and responds synergistically to DNMTi/HDACi combination, which phenocopies TSG reactivation upon epigenetic therapy. GFP fluorescence was used as a quantitative readout for epigenetic activity. We discovered that 45 FDA-approved drugs (4% of all drugs tested) in our FDA-approved libraries enhanced DNMTi and HDACi activity, mainly belonging to anticancer and antiarrhythmic drug classes. Transcriptome analysis revealed that combination of decitabine (DNMTi) with the antiarrhythmic proscillaridin A produced profound gene expression reprogramming, which was associated with downregulation of 153 epigenetic regulators, including two known oncogenes in colon cancer (SYMD3 and KDM8). Also, we identified about 85 FDA-approved drugs that antagonized DNMTi and HDACi activity through cytotoxic mechanisms, suggesting detrimental drug interactions for patients undergoing epigenetic therapy. Overall, our drug screening identified new combinations of epigenetic and FDA-approved drugs, which can be rapidly implemented into clinical trials. Mol Cancer Ther; 16(2); 397-407. ©2016 AACR.

TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT.

Genetic causes of many familial arrhythmia syndromes remain elusive. In this study, whole‐exome sequencing (WES) was carried out on patients from three different families that presented with life‐threatening arrhythmias and high risk of sudden cardiac death (SCD). Two French Canadian probands carried identical homozygous rare variant in TECRL gene (p.Arg196Gln), which encodes the trans‐2,3‐enoyl‐CoA reductase‐like protein. Both patients had cardiac arrest, stress‐induced atrial and ventricular tachycardia, and QT prolongation on adrenergic stimulation. A third patient from a consanguineous Sudanese family diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) had a homozygous splice site mutation (c.331+1G>A) in TECRL. Analysis of intracellular calcium ([Ca2+]i) dynamics in human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) generated from this individual (TECRLH om‐hiPSCs), his heterozygous but clinically asymptomatic father (TECRLH et‐hiPSCs), and a healthy individual (CTRL‐hiPSCs) from the same Sudanese family, revealed smaller [Ca2+]i transient amplitudes as well as elevated diastolic [Ca2+]i in TECRLH om‐hiPSC‐CMs compared with CTRL‐hiPSC‐CMs. The [Ca2+]i transient also rose markedly slower and contained lower sarcoplasmic reticulum (SR) calcium stores, evidenced by the decreased magnitude of caffeine‐induced [Ca2+]i transients. In addition, the decay phase of the [Ca2+]i transient was slower in TECRLH om‐hiPSC‐CMs due to decreased SERCA and NCX activities. Furthermore, TECRLH om‐hiPSC‐CMs showed prolonged action potentials (APs) compared with CTRL‐hiPSC‐CMs. TECRL knockdown in control human embryonic stem cell‐derived CMs (hESC‐CMs) also resulted in significantly longer APs. Moreover, stimulation by noradrenaline (NA) significantly increased the propensity for triggered activity based on delayed afterdepolarizations (DADs) in TECRLH om‐hiPSC‐CMs and treatment with flecainide, a class Ic antiarrhythmic drug, significantly reduced the triggered activity in these cells. In summary, we report that mutations in TECRL are associated with inherited arrhythmias characterized by clinical features of both LQTS and CPVT. Patient‐specific hiPSC‐CMs recapitulated salient features of the clinical phenotype and provide a platform for drug screening evidenced by initial identification of flecainide as a potential therapeutic. These findings have implications for diagnosis and treatment of inherited cardiac arrhythmias.

Efficacy of Intravenous and Oral Sotalol in Pharmacologic Conversion of Atrial Fibrillation: A Systematic Review and Meta-Analysis

Objectives: The role of sotalol is well established for the maintenance of sinus rhythm after successful conversion of atrial fibrillation (AF). However, its role in pharmacologic conversion of AF is poorly defined. The purpose of this study is to compare the efficacy of sotalol to that of other antiarrhythmic agents for AF conversion. Methods: Standard methods of meta-analysis were employed. Full-text publications of clinical trials in English that compared the efficacy of sotalol to that of other antiarrhythmics or placebo/no treatment were eligible for inclusion. Results: A systematic review revealed 10 eligible publications. Sotalol was superior to placebo and/or no antiarrhythmic therapy in AF conversion, with a relative success of 24 (95% CI 4.7-119, p < 0.001). Sotalol was not significantly different from class IA antiarrhythmic drugs. Similarly, sotalol was not different from class IC antiarrhythmic drugs or amiodarone in terms of conversion efficacy. In one study, sotalol was less effective than high-dose ibutilide (2 mg), with a relative success of 0.248 (95% CI 0.128-0.481, p < 0.001). Ibutilide caused more proarrhythmia. Conclusions: Sotalol is as effective as class IA and class IC antiarrhythmic agents, and it is also as effective as amiodarone for pharmacologic conversion of AF. Only ibutilide at a high dose showed a greater conversion rate of AF.

Efficacy and safety in pharmacological cardioversion of recent-onset atrial fibrillation: a propensity score matching to compare amiodarone vs class IC antiarrhythmic drugs.

The acute management of recent-onset (<48h) atrial fibrillation (AF) is still debated. Aim of our study was to compare efficacy and safety of intravenously administered class IC antidysrhythmic agents vs amiodarone in a propensity score matched series of patients acutely treated for AF in the emergency department. During a 3-year period, we retrospectively evaluated all episodes of recent-onset (<48h) AF pharmacologically treated for sinus rhythm restoration in the emergency department. By means of a propensity score matching considering the main statistically different covariates, we selected two accurately matched treatment groups. We analysed the differences between amiodarone and class IC group in terms of efficacy and safety that is conversion to sinus rhythm rates within 12 and 48h after starting treatment, time to conversion, and adverse drug effects. An overall number of 817 episodes of recent-onset AF were collected (amiodarone group=406, class IC group=411). After matching, we obtained 358 episodes equally divided (amiodarone group=179 and class IC group=179). Conversion rates within 12h were 139 (53.1%) in amiodarone group and 95 (72.6%) in class IC group (p<0.05). Median time for cardioversion was 420min (331.6-508.3 CI 95%) in amiodarone and 55min (44.9-65.1 CI 95%) in class IC group (p<0.05). The incidence of adverse events in both groups was very low and equally distributed (p=ns). Intravenously administration of class IC agents, when compared with amiodarone, proved to be more rapid and effective, and equally safe in the acute management of recent-onset AF.