Prolongation Of Refractory Period Research Articles

Insights into Nerve Signal Propagation: The Effect of Extracellular Space in Governing Neuronal Signal for healthy and injured Nerve Fiber using Modified Cable Model

Nerve injuries are complex medical conditions that may arise from a variety of traumatic events or diseases, altering the intricate structure of neural pathways. During neuronal injury, the potassium and sodium ion concentration that controls signaling endures significant changes such as the ion channels getting blocked or an increase in the intracellular ionic concentration. The Extracellular Space which surrounds a nerve fiber has a significant impact on the neuronal signal and variation in its size can alter neuronal signal transmission. Hence, to fully understand neuronal signal transmission, it is essential to explore the effect that the Extracellular Space exerts on the neuronal signal. The aim of this study is to develop a mathematical model which yields a simplistic yet robust mathematical expression of the nerve membrane potential, incorporating the Extracellular Space dependent parameters for having a holistic approach towards understanding neuronal signal transmission in healthy and injured nerve fiber. The conventional cable model focuses solely on the intrinsic properties of the nerve fiber, but the current work expands this model by incorporating the Extracellular Space dependent parameters into the final membrane potential expression. The results obtained from this study shows that certain combination of the Extracellular Space and fiber diameter could bring about hyperexcitation whereas in some cases it may lead to hypoexcitation to the neuronal signal as it propagates along the nerve fiber. Moreover, prolonged refractory period and delayed refractory period are also observed in certain combination of the Extracellular Space and fiber diameter. The proposed framework manages to show trends associated with certain medical conditions and may also be useful to further understand, and early diagnosis of various neurological conditions under the effect of an Extracellular Space of varied sizes.

P164 PERCUTANEOUS LEFT STELLATE GANGLION BLOCK IN REFRACTORY LEFT ATRIAL TACHYCARDIA

Abstract Percutaneous left stellate ganglion block (PLSGB) has been recently implemented for the acute treatment of refractory ventricular arrhythmias (VAs). The beneficial effect on supraventricular arrhythmias susceptibility and their ventricular response is well characterized in animal models, less so in humans. Available data suggest a significant prolongation of atrial refractory period, a reduction in inducibility and duration of atrial fibrillation and of all spontaneous intra– and postoperative atrial arrhythmias after thoracic and cardiac surgery. Here we describe a case of PLSGB for focal atrial tachycardia (AT). Case: we present a 68–year–old men with hypertension, obesity, OSAS and previous anterior myocardial infarction in the setting of a trivessel coronary disease, treated with PCI and complicated by apical aneurysm, with a LVEF of 38% and a moderate mitral and aortic regurgitation. He was on chronic antiarrhythmic therapy with bisoprolol 1.25 mg and ranolazine. He presented in the ED due to palpitations, pre–syncopal episodes, and worsening dyspnea. The ECG showed very frequent, self–limiting episodes of AT with a 1:1 atrioventricular (AV) conduction and a variable heart rate (HR) between 100 and 160 bpm, alternating with sinus rhythm at 45–50 bpm, sometimes conducted with aberrancy. Isolated and repetitive premature ventricular beats (PVB, maximum 8 beats) were also documented. Amiodarone, lidocaine, and intravenous unloading therapy were tried, without benefit. Coronary angiography was negative. PLSGB with an ultrasound–guided lateral approach (local bolus of lidocaine 100 mg+ropivacaine 20 mg) was performed, without complications, inducing palpebral ptosis. Over the next 15 hours we observed the disappearance of non–sustained VAs, the reduction of PVBs, and a progressive reduction of AT burden, of mean hourly HR (from 84 to 50 bpm, –40%) and of mean HR during AT (from 158 to 84 bpm, –47%, with AV 1:1 conduction). The patient subsequently underwent ablation of an extra systolic focus found near the ostium of the right inferior pulmonary vein, with no recurrences after 18 months. Conclusions This case highlights the potential efficacy of PLSGB in the acute treatment of supraventricular arrhythmias refractory to medical therapy. Prospective studies will help us to identify the extent, time of onset, and duration of its benefit depending on the type and mechanism of the underlying arrhythmia and the clinical characteristics of the patient.

Optogenetic termination of atrial tachyarrhythmias by brief pulsed light stimulation

AimsThe most efficient way to acutely restore sinus rhythm from atrial fibrillation (AF) is electrical cardioversion, which is painful without adequate sedation. Recent studies in various experimental models have indicated that optogenetic termination of AF using light-gated ion channels may provide a myocardium-specific and potentially painless alternative future therapy. However, its underlying mechanism(s) remain(s) incompletely understood. As brief pulsed light stimulation, even without global illumination, can achieve optogenetic AF termination, besides direct conduction block also modulation of action potential (AP) properties may be involved in the termination mechanism. We studied the relationship between optogenetic AP duration (APD) and effective refractory period (ERP) prolongation by brief pulsed light stimulation and termination of atrial tachyarrhythmia (AT). Methods and resultsHearts from transgenic mice expressing the H134R variant of channelrhodopsin-2 in atrial myocytes were explanted and perfused retrogradely. AT induced by electrical stimulation was terminated by brief pulsed blue light stimulation (470 nm, 10 ms, 16 mW/mm2) with 68% efficacy. The termination rate was dependent on pulse duration and light intensity. Optogenetically imposed APD and ERP changes were systematically examined and optically monitored. Brief pulsed light stimulation (10 ms, 6 mW/mm2) consistently prolonged APD and ERP when light was applied at different phases of the cardiac action potential. Optical tracing showed light-induced APD prolongation during the termination of AT. ConclusionOur results directly demonstrate that cationic channelrhodopsin activation by brief pulsed light stimulation prolongs the atrial refractory period suggesting that this is one of the key mechanisms of optogenetic termination of AT.

Novel preventive effect of isorhamnetin on electrical and structural remodeling in atrial fibrillation.

Isorhamnetin, a natural flavonoid, has strong antioxidant and antifibrotic effects, and a regulatory effect against Ca2+-handling. Atrial remodeling due to fibrosis and abnormal intracellular Ca2+ activities contributes to initiation and persistence of atrial fibrillation (AF). The present study investigated the effect of isorhamnetin on angiotensin II (AngII)-induced AF in mice. Wild-type male mice (C57BL/6J, 8 weeks old) were assigned to three groups: (1) control group, (2) AngII-treated group, and (3) AngII- and isorhamnetin-treated group. AngII (1000 ng/kg/min) and isorhamnetin (5 mg/kg) were administered continuously via an implantable osmotic pump for two weeks and intraperitoneally one week before initiating AngII administration, respectively. AF induction and electrophysiological studies, Ca2+ imaging with isolated atrial myocytes and HL-1 cells, and action potential duration (APD) measurements using atrial tissue and HL-1 cells were performed. AF-related molecule expression was assessed and histopathological examination was performed. Isorhamnetin decreased AF inducibility compared with the AngII group and restored AngII-induced atrial effective refractory period prolongation. Isorhamnetin eliminated abnormal diastolic intracellular Ca2+ activities induced by AngII. Isorhamnetin also abrogated AngII-induced APD prolongation and abnormal Ca2+ loading in HL-1 cells. Furthermore, isorhamnetin strongly attenuated AngII-induced left atrial enlargement and atrial fibrosis. AngII-induced elevated expression of AF-associated molecules, such as ox-CaMKII, p-RyR2, p-JNK, p-ERK, and TRPC3/6, was improved by isorhamnetin treatment. The findings of the present study suggest that isorhamnetin prevents AngII-induced AF vulnerability and arrhythmogenic atrial remodeling, highlighting its therapeutic potential as an anti-arrhythmogenic pharmaceutical or dietary supplement.

P4424Detailed characterization of atrial remodeling induced by exercise training in a rodent model of exercise-induced cardiac hypertrophy

Abstract Introduction Atrial fibrillation and heart failure share common risk factors and frequently coexist as atrial fibrillation leads to impaired myocardial function. Although regular exercise training is associated with cardiovascular benefits, the increased risk of atrial arrhythmias has been observed, with differences regarding prevalence between genders. While multiple mechanisms are likely, the atrial alterations induced by long-term physical exercise still need to be elucidated. Purpose We aimed at investigating exercise-induced atrial remodeling in a rat model of athlete's heart and determining sex-specific differences. Methods Age-matched young adult rats were divided into female exercised (FEx), female control (FCo), male exercised (MEx) and male control (MCo) groups. After exercised animals completed a 12-week-long swim training protocol, echocardiography was used to describe atrial alterations. In vivo electrophysiologic investigation was performed by programmed stimulation with an octapolar catheter inserted into the right atrium and atrial gene expression analysis was carried out. Results Post-mortem atrial weight data revealed marked atrial hypertrophy (atrial weight to tibial length: 18.6±2.7g/cm FEx, 10.3±1.0g/cm FCo, 23.7±2.2g/cm MEx, 15.8±1.9g/cm MCo pex<0.01), while echocardiography data showed slight atrial dilatation and improved contraction in both exercised groups. Exercise training was associated with bradycardia, P-wave enlargement and prolonged right atrial effective refractory period (RAERP: 45.7±4.3ms FEx, 40.2±5.9ms, FCo, 49.8±4.2ms MEx, 43.1±4.6ms MCo pex<0.01). Sinus node recovery time (SNRT) did not differ between groups and we could not induce significant number of arrhytmias by programmed stimulation (double extrastimulation, burst pacing) in any groups. We found increased atrial gene expression of antioxidant enzymes (e.g. NADPH oxidase 2, superoxide dismutase 2) in both genders. Despite the marked atrial hypertrophy, no gene expression alteration was found regarding markers that describe pathological remodeling (atrial natriuretic factor), proinflammatoric (tumor necrosis factor-α) and profibrotic [e.g. transforming growth factor-β (TGF-β), matrix metalloproteinase-2 (MMP-2)] processes. While exercise training did not affect on the expression of profibrotic markers, female gender was associated with lower TGF-β and MMP-2 expression. We found altered expression of ion channels participating in atrial depolarization and repolarization. Conclusions Our data suggests that long-term exercise-induced atrial hypertrophy is not associated with harmful electrical remodeling and no inflammatory or profibrotic response was observed in the atrium of exercised rats. Acknowledgement/Funding NKFIH (K 120277), ÚNKP-17-4 (to A.O.), STIA-KF-17 (to A.O.)

Dose-Dependent Effects of Ranolazine on Reentrant Ventricular Arrhythmias Induced After Subacute Myocardial Infarction in Rabbits.

Ranolazine has been found to prevent ventricular arrhythmias (VAs) during acute myocardial infarction (AMI). This study aimed to investigate its efficacy on VAs induced several days post-MI. For this purpose, 13 anesthetized rabbits underwent coronary artery ligation. Ten of these animals that survived AMI were reanesthetized 3 to 7 days later for electrophysiologic testing. An endocardial monophasic action potential combination catheter was placed in the right ventricle for simultaneous pacing and recording. Monophasic action potential duration, ventricular effective refractory period (VERP), and VAs induced by programmed stimulation were assessed. Measurements were performed during control pacing, and following an intravenous infusion of either a low-dose ranolazine (2.4 mg/kg, R1) or a higher dose ranolazine (4.8 mg/kg cumulative dose, R2). During control stimulation, 2 animals developed primary ventricular fibrillation (VF), 6 sustained ventricular tachycardia (sVT), and 2 nonsustained VT (nsVT). R1 did not prevent the appearance of VAs in any of the experiments; in contrast, it aggravated nsVT into sVT and complicated sVT termination in 2 of 6 animals. Sustained ventricular tachycardia cycle length and VERP were only slightly decreased after R1 (112 ± 5 vs 110 ± 6 ms and 101 ± 11 vs 98 ± 10 ms, respectively). R2 suppressed inducibility of control nsVT, VF, and sVT in 2 animals. In 4 animals with still inducible sVT, R2 significantly prolonged VT cycle length by 150 ± 23 ms (P < .01), and VERP by 120 ± 7 ms (P < .001) versus control. In conclusion, R2 exerted antiarrhythmic efficacy against subacute-MI VAs, whereas R1 rather aggravated than prevented these arrhythmias. Ventricular effective refractory period prolongation could partially explain the antiarrhythmic action of R2 in this rabbit model.

Abstract WP335: Role of Sorbs2 Gene in the Development of Atrial Cardiomyopathy and Atrial Fibrillation in Mice

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is a major cause of thromboembolic stroke in the United States. The risk of stroke is a 5-fold increase in patients with AF. The Sorbin and SH3 domain-containing protein 2 (Sorbs2) is a scaffolding protein known to interact with actin and several other cytoskeletal proteins in the intercalated discs and Z band of cardiomyocytes. However, the role of Sorbs2 gene in cardiovascular diseases is largely unknown. Using the loss-of-function of Sorbs2 ( Sorbs2 e8/e8 ) mice, we found that Sorbs2 e8/e8 mice had an abnormal lifespan and die at 4 to 7 months of age. Echocardiogram examine revealed that there was a significant decrease in right ventricle (RV) and left ventricular (LV) ejection fraction (EF), increase in RV end-diastolic volume (EDV) and end-systolic volume (ESV), and progressive chamber enlargement in left atria (LA) and RV, particularly in LA with severe fibrosis and intramural thrombus formation, in Sorbs2 e8/e8 mice after 3 months of age. Surface electrocardiograph also showed a significant conduction delay and spontaneous arrhythmias including those of bifid P wave configuration, right bundle branch block (RBBB), spontaneous AF and non-sustained ventricular tachycardia (VT) in Sorbs2 e8/e8 mice. Intracellular recordings in the freshly isolated LA demonstrated that Sorbs2 e8/e8 myocardium had a delayed action potential activation in response to electrical impulse excitation, reduced amplitude and upstroke velocity (dV/dt) at phase 0, slowed repolarization at phase 1 and phase 2, prolonged atrial effective refractory period (aERP), action potential durations at 50% (APD 50 ) and 90% (APD 90 ) repolarization, and decreased resting potentials. Moreover, the mRNA and protein expressions of voltage-gated Na + channels, L-type Ca 2+ channels, transient outward K + channels and inward rectifier K + channels were significantly downregulated in the LA of Sorbs2 e8/e8 mice, compared wo those of wild type mice. Our results indicate that Sorbs2 gene plays an important role in atrial myocardium architecture and electrophysiology. Sorbs2 dysfunction leads to atrial cardiomyopathy, spontaneous AF and cardiac embolism in mice. Hence, Sorbs2 is a new genetic association with cardioembolic stroke.

A new negative allosteric modulator, AP14145, for the study of small conductance calcium-activated potassium (KCa 2) channels.

Small conductance calcium-activated potassium (KCa 2) channels represent a promising atrial-selective target for treatment of atrial fibrillation. Here, we establish the mechanism of KCa 2 channel inhibition by the new compound AP14145. Using site-directed mutagenesis, binding determinants for AP14145 inhibition were explored. AP14145 selectivity and mechanism of action were investigated by patch-clamp recordings of heterologously expressed KCa 2 channels. The biological efficacy of AP14145 was assessed by measuring atrial effective refractory period (AERP) prolongation in anaesthetized rats, and a beam walk test was performed in mice to determine acute CNS-related effects of the drug. AP14145 was found to be an equipotent negative allosteric modulator of KCa 2.2 and KCa 2.3 channels (IC50 =1.1±0.3μM). The presence of AP14145 (10μM) increased the EC50 of Ca2+ on KCa 2.3 channels from 0.36±0.02 to 1.2±0.1μM. The inhibitory effect strongly depended on two amino acids, S508 and A533 in the channel. AP14145 concentration-dependently prolonged AERP in rats. Moreover, AP14145 (10mg·kg-1 ) did not trigger any apparent CNS effects in mice. AP14145 is a negative allosteric modulator of KCa 2.2 and KCa 2.3 channels that shifted the calcium dependence of channel activation, an effect strongly dependent on two identified amino acids. AP14145 prolonged AERP in rats and did not trigger any acute CNS effects in mice. The understanding of how KCa 2 channels are inhibited, at the molecular level, will help further development of drugs targeting KCa 2 channels.

2:1 Atrioventricular Conduction due to Congenital Long QT Syndrome

AbstractLong QT syndrome patients can present as second-degree AV block due to prolongation of refractory period. We report a case of pseudo 2:1 AV block due to long QT syndrome in which treatment differs from conventional second-degree AV block because of uncommon presentation and poor prognosis with no consensus.

Revealing kinetics and state-dependent binding properties of IKur-targeting drugs that maximize atrial fibrillation selectivity.

The KV1.5 potassium channel, which underlies the ultra-rapid delayed-rectifier current (IKur) and is predominantly expressed in atria vs. ventricles, has emerged as a promising target to treat atrial fibrillation (AF). However, while numerous KV1.5-selective compounds have been screened, characterized, and tested in various animal models of AF, evidence of antiarrhythmic efficacy in humans is still lacking. Moreover, current guidelines for pre-clinical assessment of candidate drugs heavily rely on steady-state concentration-response curves or IC50 values, which can overlook adverse cardiotoxic effects. We sought to investigate the effects of kinetics and state-dependent binding of IKur-targeting drugs on atrial electrophysiology in silico and reveal the ideal properties of IKur blockers that maximize anti-AF efficacy and minimize pro-arrhythmic risk. To this aim, we developed a new Markov model of IKur that describes KV1.5 gating based on experimental voltage-clamp data in atrial myocytes from patient right-atrial samples in normal sinus rhythm. We extended the IKur formulation to account for state-specificity and kinetics of KV1.5-drug interactions and incorporated it into our human atrial cell model. We simulated 1- and 3-Hz pacing protocols in drug-free conditions and with a [drug] equal to the IC50 value. The effects of binding and unbinding kinetics were determined by examining permutations of the forward (kon) and reverse (koff) binding rates to the closed, open, and inactivated states of the KV1.5 channel. We identified a subset of ideal drugs exhibiting anti-AF electrophysiological parameter changes at fast pacing rates (effective refractory period prolongation), while having little effect on normal sinus rhythm (limited action potential prolongation). Our results highlight that accurately accounting for channel interactions with drugs, including kinetics and state-dependent binding, is critical for developing safer and more effective pharmacological anti-AF options.

Effects of Kinetics and State-Dependent Binding Properties of IKur Targeting Drugs on Atrial Electrophysiology

Background: The Kv1.5 potassium channel, which underlies the ultra-rapid delayed-rectifier current (IKur) and is predominantly expressed in atria vs. ventricles, has emerged as a promising target to treat atrial fibrillation (AF). However, while numerous Kv1.5-selective compounds have been screened, characterized, and tested in various animal models of AF, evidence of antiarrhythmic efficacy in humans is still lacking. Moreover, current guidelines for pre-clinical assessment of candidate drugs heavily rely on steady-state concentration-response curves or EC50 values, which can overlook adverse cardiotoxic events.Aim: We sought to investigate the effects of kinetics and state-dependent binding of IKur-targeting drugs on atrial electrophysiology in silico, and reveal the ideal therapeutic properties of IKur-blocking drugs that maximize efficacy and minimize pro-arrhythmic risk.Methods and results: A Markov model of IKur, based on experimental voltage-clamp data in atrial myocytes from patient samples in normal sinus rhythm (nSR) and chronic AF (cAF), was developed to describe Kv1.5 gating and state-specific Kv1.5-drug interactions and was incorporated into our human atrial cell models. We simulated 1Hz and 4Hz pacing protocols in drug-free conditions, and with [drug] equal to EC50. The effects of binding and unbinding kinetics were determined by examining permutations of the forward (Kon) and reverse (Koff) rates to the closed, open, and inactivated state of the Kv1.5 channel. We identified a subset of ideal drugs exhibiting anti-AF electrophysiological parameter changes in cAF (effective refractory period prolongation) at fast pacing rate, while having little effect in nSR (limited action potential prolongation and no early afterdepolarization formation) at normal heart rate.Conclusions: Our results highlight that accurately accounting for channel interaction with drugs, including kinetics and state-dependent binding, is critical for developing safer and more effective pharmacological anti-AF options.

TREK-1 (K2P2.1) K+ channels are suppressed in patients with atrial fibrillation and heart failure and provide therapeutic targets for rhythm control.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Concomitant heart failure (HF) poses a particular therapeutic challenge and is associated with prolonged atrial electrical refractoriness compared with non-failing hearts. We hypothesized that downregulation of atrial repolarizing TREK-1 (K2P2.1) K+ channels contributes to electrical remodeling during AF with HF, and that TREK-1 gene transfer would provide rhythm control via normalization of atrial effective refractory periods in this AF subset. In patients with chronic AF and HF, atrial TREK-1 mRNA levels were reduced by 82% (left atrium) and 81% (right atrium) compared with sinus rhythm (SR) subjects. Human findings were recapitulated in a porcine model of atrial tachypacing-induced AF and reduced left ventricular function. TREK-1 mRNA (-66%) and protein (-61%) was suppressed in AF animals at 14-day follow-up compared with SR controls. Downregulation of repolarizing TREK-1 channels was associated with prolongation of atrial effective refractory periods versus baseline conditions, consistent with prior observations in humans with HF. In a preclinical therapeutic approach, pigs were randomized to either atrial Ad-TREK-1 gene therapy or sham treatment. Gene transfer effectively increased TREK-1 protein levels and attenuated atrial effective refractory period prolongation in the porcine AF model. Ad-TREK-1 increased the SR prevalence to 62% during follow-up in AF animals, compared to 35% in the untreated AF group. In conclusion, TREK-1 downregulation and rhythm control by Ad-TREK-1 transfer suggest mechanistic and potential therapeutic significance of TREK-1 channels in a subgroup of AF patients with HF and prolonged atrial effective refractory periods. Functional correction of ionic remodeling through TREK-1 gene therapy represents a novel paradigm to optimize and specify AF management.

Clinical and Electrophysiologic Characteristics Before and After Radiofrequency Ablation of SustainedSlow Atrioventricular NodalPathway Conduction.

This study examined the clinical and electrocardiographic characteristics and electrophysiologic determinants of sustained slow pathway conduction (SSPC) during sinus rhythm. SSPC during sinus rhythm in presence of dual atrioventricular (AV) nodal pathways has not been thoroughly studied. We studied 30 consecutive patients (19 men), whose median age was 31 years (interquartile range: 22 to 48 years); their electrocardiograms revealed 2 different PR intervals during nearly identical sinus rates. We measured the short and long PR intervals and their differences and examined the electrophysiologic determinants of SSPC during slow pathway (SP) ablation in 12 patients. Among the 30 patients, 21 (70%) complained of major symptoms. The short and long PR intervals measured 202 ± 42 ms and 472 ± 110 ms, respectively, and their mean difference measured 270 ± 101 ms. During electrophysiologic studies, dual AV nodal and SSPC were observed in all patients. A markedly prolonged refractory period (593 ± 116ms) and retrograde conduction block over the fast pathway (FP) were observed over a range of sinus cycle lengths (CLs). Ablation of the SP in 11 patients promoted FP conduction and shortened its effective refractory period from 593 ± 116 ms to 288 ± 90 ms. Over a median follow-up of 2 years (interquartile range: 1 to 3 years), all patients remained asymptomatic and without recurrences of SSPC or AV block. Two distinct PR intervals during sinus rhythm indicated the presence of dual AV nodal pathways. SSPC was promoted by a markedly impaired bidirectional conduction over the FP at critical sinus CL. SP ablation safely and effectively eliminated SSPC in symptomatic patients.

A Statistical Atrioventricular Node Model Accounting for Pathway Switching During Atrial Fibrillation.

The atrioventricular (AV) node plays a central role in atrial fibrillation (AF), as it influences the conduction of impulses from the atria into the ventricles. In this paper, the statistical dual pathway AV node model, previously introduced by us, is modified so that it accounts for atrial impulse pathway switching even if the preceding impulse did not cause a ventricular activation. The proposed change in model structure implies that the number of model parameters subjected to maximum likelihood estimation is reduced from five to four. The model is evaluated using the data acquired in the RATe control in atrial fibrillation (RATAF) study, involving 24-h ECG recordings from 60 patients with permanent AF. When fitting the models to the RATAF database, similar results were obtained for both the present and the previous model, with a median fit of 86%. The results show that the parameter estimates characterizing refractory period prolongation exhibit considerably lower variation when using the present model, a finding that may be ascribed to fewer model parameters. The new model maintains the capability to model RR intervals, while providing more reliable parameters estimates. The model parameters are expected to convey novel clinical information, and may be useful for predicting the effect of rate control drugs.

SEARCH FOR THE COMPOUNDS WHICH PROLONG EFFICIENT REFRACTORY PERIOD AMONG AMINOBENZOTHIAZOLES DERIVATIVES

The article reviews the experimental research in vitro on a revelation of effective refractory period prolongation properties in aminobenzothiazoles derivatives for isolated atrium of rats. We have provided the comparative characteristics of these compounds in relation with amiodarone.

Flecainide-induced prolongation of ventricular repolarization contributes to the proarrhythmic profile of action

Flecainide is class Ic Na + channel blocker that is used to restore sinus rhythm and to prevent the arrhythmia recurrence in patients with atrial fibrillation. Antiarrhythmic effect of flecainide is attribut- ed to prolonged atrial effective refractory period and depressed car- diac action potential upstroke. Nevertheless, flecainide has been reported to produce arrhythmogenic responses in ventricular myo- cardium. In this regard, the Cardiac Arrhythmia Suppression Trial (CAST) has shown that flecainide therapy is associated with marked- ly increased risk of sudden arrhythmic death in patients with healed myocardial infarction, an effect possibly accounted for by the drug- induced anisotropic conduction slowing in the peri-infarct zone. Based on these findings, indications for flecainide therapy are cur- rently limited to the atrial fibrillation control in patients with no structural heart disease. Although flecainide-induced conduction abnormalities are unlikely to occur in the absence of myocardial ischemia or fibrosis, there is in- creasing evidence to suggest that flecainide may promote arrhythmo- genic responses in patients with structurally normal hearts. Flecainide administration has been reported to induce torsade de pointes, a poten- tially life-threatening polymorphic ventricular tachycardia, in patients with no coronary artery disease or severe heart failure (1,2). This kind of arrhythmia is thought to be attributed to the prolonged QT interval and increased spatial dispersion of ventricular repolarization. However, the contribution of these factors to flecainide-induced proarrhythmia is often overlooked, because flecainide (along with other class Ic Na + channel blockers) is generally regarded asanagentproducingonly little or no effect on ventricular repolarization.

Thyroid Hormone Replacement Therapy Attenuates Atrial Remodeling and Reduces Atrial Fibrillation Inducibility in a Rat Myocardial Infarction–Heart Failure Model

BackgroundHeart failure (HF) is associated with increased atrial fibrillation (AF) risk. Accumulating evidence suggests the presence of myocardial tissue hypothyroidism in HF, which may contribute to HF development. In a recent report we demonstrated that hypothyroidism, like hyperthyroidism, leads to increased AF inducibility. The present study was designed to investigate the effect of thyroid hormone (TH) replacement therapy on AF arrhythmogenesis in HF. Methods and ResultsMyocardial infarction (MI) was produced in rats by means of coronary artery ligation. Rats with large MIs (>40%) were randomized into L-thyroxine (T4; n = 14) and placebo (n = 15) groups 2 weeks after MI. Rats received 3.3 mg T4 (in 60-day release form) or placebo pellets for 2 months. Compared with the placebo, T4 treatment improved cardiac function and decreased left ventricular internal diameters as well as left atrial diameter. T4 treatment attenuated atrial effective refractory period prolongation (45 ± 1.5 ms in placebo group vs 37 ± 1.6 ms in T4 group; P < .01) and reduced AF inducibility (AF/atrial flutter/tachycardia were inducible in 11/15 rats [73%] in the placebo- vs 4/14 rats [29%] in the T4-treated group; P < .05). Arrhythmia reduction was associated with decreased atrial fibrosis but was not associated with connexin 43 changes. ConclusionsTo our knowledge this is the first study demonstrating that TH replacement therapy in HF attenuates atrial remodeling and reduces AF inducibility after MI-HF. Clinical studies are needed to confirm such benefits in human patients.

Cellular mechanism of premature ventricular contraction-induced cardiomyopathy.

Frequent premature ventricular contractions (PVCs) are associated with increased risk of sudden cardiac death and can cause secondary cardiomyopathy. We sought to determine the mechanism(s) responsible for prolonged refractory period and left ventricular (LV) dysfunction demonstrated in our canine model of PVC-induced cardiomyopathy. Single myocytes were isolated from LV free wall of PVC and control canines and used for patch-clamp recording, intracellular Ca(2+) measurements, and immunocytochemistry/confocal microscopy. LV tissues adjacent to the area of myocyte isolation were used for the immunoblot quantification of protein expression. In the PVC group, LV ejection fraction decreased from 57.6% ± 1.5% to 30.4% ± 3.1% after ≥4 months of ventricular bigeminy. Compared to control myocytes, PVC myocytes had decreased densities of both outward (transient outward current [Ito] and inward rectifier current [IK1]) and inward (L-type Ca current [ICaL]) currents, but no consistent changes in rapid or slow delayed rectifier currents. The reduction in Ito, IK1, and ICaL was accompanied by decreased protein levels of their channel subunits. The extent of reduction in Ito, IK1, and ICaL varied among PVC myocytes, creating marked heterogeneity in action potential configurations and durations. PVC myocytes showed impaired Ca-induced Ca release from the sarcoplasmic reticulum (SR), without increase in SR Ca leak or decrease in SR Ca store. This was accompanied by a decrease in dyad scaffolding protein, junctophilin-2, and loss of Cav1.2 registry with Ca-releasing channels (ryanodine receptor 2). PVCs increase dispersion of action potential configuration/duration, a risk factor for sudden cardiac death, because of the heterogeneous reduction in Ito, IK1, and ICaL. The excitation-contraction coupling is impaired because of the decrease in ICaL and Cav1.2 misalignment with respect to ryanodine receptor 2.

Arrhythmogenic cardiomyopathy with reduction of connexin40 and altered ion channel expression due to an inactivation of cyclase-associated protein 2

Purpose: The inactivation of Cyclase Associated Protein 2 (CAP2) by a gene trap approach (gt) in the mouse leads to a cardiomyopathy with morphological predominance of the right ventricle resulting in an increased mortality. The purpose of our investigation was to identify potential arrhythmogenic reasons leading to this premature cardiac death. Methods: We performed in vivo electrophysiological studies in CAP2gt/+, CAP2gt/gt and corresponding Wild Type (WT) mice to determine surface and intracardiac ECG parameters and to test the inducibility of Ventricular Tachycardias (VTs). Long-term-ECG recordings were used to detect spontaneous arrhythmias. mRNA expression analysis of Cardiac Connexins (Cx) and ion channels were carried out as well as quantitative cardiac fibrosis determination. Immunofluorescence of Cx40 and Cx43 was performed to visualise their distribution pattern. Results: In comparison to WT, CAP2gt/gt showed marked conduction delays on atrial and ventricular level (reduced heart rate, prolonged PQ, QRS and QT time). AV-time prolongation was due to an infra Hisian conduction delay. Functional testing revealed a trend towards a prolonged ventricular refractory period. The inducibility of VTs was significantly higher in the mutant mice. Long-term-ECG recordings showed polymorphic premature ventricular contractions and spontaneous VTs in the CAP2 deficient mice. Compared to WT, the ventricles of CAP2gt/gt mice presented enhanced myocardial fibrosis (9.1±6.7% vs. 5.6±3.3%; p=0.01) that was found predominantly in the left ventricle. CAP2gt/gt resulted in a significant reduction of Cx40 expression (septum area) and elevated ventricular expression of Cx43, desmin and the calcium channel Cav 1.2. Conclusions: Loss of CAP2 results in marked electrophysiological disturbances leading to malignant ventricular arrhythmias. Impaired sinus node function, conduction delays, and susceptibility to arrhythmias are in accordance with a reduction of Cx40 and alterations in Cx43 and calcium channel expression. Cases of right ventricular cardiomyopathy may be due to dysfunction of CAP2, so further evaluation of its influence on cardiomyopathy and arrhythmogenesis should ensue to fully understand its functioning.

Atrial-selective Prolongation of Refractory Period With AVE0118 is Due Principally to Inhibition of Sodium Channel Activity

The action of AVE0118 to prolong effective refractory period (ERP) in atria but not in ventricles is thought to be due to its inhibition of IKur. However, in nonremodeled atria, AVE0118 prolongs ERP but not action potential duration (APD70-90), which can be explained with the inhibition of sodium but not potassium channel current. ERP, APD, and the maximum rate of increase of the AP upstroke (Vmax) were measured in the canine-isolated coronary-perfused right atrial and in superfused ventricular tissue preparations. Whole-cell patch-clamp techniques were used to measure sodium channel current in HEK293 cells stably expressing SCN5A. AVE0118 (5-10 μM) prolonged ERP (P < 0.001) but not APD70 and decreased Vmax (by 15%, 10 μM, P < 0.05; n = 10 for each). Ventricular ERP, APD90, and Vmax were not changed significantly by 10 μM AVE0118 (all P = ns; n = 7). AVE0118 effectively suppressed acetylcholine-mediated persistent atrial fibrillation. AVE0118 (10 μM) reduced peak current amplitude of SCN5A-WT current by 36.5% ± 6.6% (P < 0.01; n = 7) and shifted half-inactivation voltage (V0.5) of the steady-state inactivation curve from -89.9 ± 0.5 to -96.0 ± 0.9 mV (P < 0.01; n = 7). Our data suggest that AVE0118-induced prolongation of atrial, but not ventricular ERP, is due largely to atrial-selective depression of sodium channel current, which likely contributes to the effectiveness of AVE0118 to suppress atrial fibrillation.