Hung I. Yeh

Electrophysiology and arrhythmogenic activity of single cardiomyocytes from canine superior vena cava

Background—The superior vena cava (SVC) has been proved to be a focal point in the initiation of paroxysmal atrial fibrillation. The autonomic nervous system plays an important role in the genesis of atrial fibrillation. However, the arrhythmogenic potentials of SVC and its responses to autonomic agents are not clear. The purpose of this study was to isolate single SVC cardiomyocytes and to investigate their electrophysiological characteristics, as well as the direct effects of autonomic agents. Methods and Results—Canine SVC cardiomyocytes were isolated by perfusion with digestive enzymes. The action potentials and ionic currents were investigated in single SVC cardiomyocytes using the whole-cell clamp technique. Dissociation of the SVC yielded rod-shaped single cardiomyocytes with (n=74, 51%) or without (n=71, 49%) pacemaker activities. There were similar densities of inward Ca2+, delayed rectifier K+, transient inward, inward rectifier K+, and pacemaker currents between SVC cardiomyocytes with and without pacemaker activity. SVC cardiomyocytes with pacemaker activity have, however, greater transient outward currents than those without pacemaker activity. In SVC cardiomyocytes, acetylcholine (5.5 &mgr;mol/L) abolished the spontaneous activities, but isoproterenol (10 nmol/L), atropine (10 &mgr;mol/L), and phenylephrine (10 &mgr;mol/L) accelerated the spontaneous activity and induced the occurrences of early or delayed afterdepolarizations. Conclusions—These findings suggest that SVC cardiomyocytes have distinct action potentials and ionic current profiles that may be responsible for the arrhythmogenic activity of the SVC.

Angiotensin II and angiotensin II receptor blocker modulate the arrhythmogenic activity of pulmonary veins

Angiotensin II receptor blockers (AIIRBs) have been shown to prevent atrial fibrillation. The pulmonary veins (PVs) are the most important focus for the generation of atrial fibrillation. The aim of this study was to evaluate whether angiotensin II or AIIRB may change the arrhythmogenic activity of the PVs. Conventional microelectrodes and whole‐cell patch clamps were used to investigate the action potentials (APs) and ionic currents in isolated rabbit PV tissue and single cardiomyocytes before and after administering angiotensin II or losartan (AIIRB). In the tissue preparations, angiotensin II induced delayed after‐depolarizations (1, 10, and 100u2003nM) and accelerated the automatic rhythm (10 and 100u2003nM). Angiotensin II (100u2003nM) prolonged the AP duration and increased the contractile force (10 and 100u2003nM). Losartan (1 and 10u2003μM) inhibited the automatic rhythm. Losartan (10u2003μM) prolonged the AP duration and reduced the contractile force (1 and 10u2003μM). Angiotensin II reduced the transient outward potassium current (Ito) but increased the L‐type calcium, delayed rectifier potassium (IK), transient inward (Iti), pacemaker, and Na+–Ca2+ exchanger (NCX) currents in the PV cardiomyocytes. Losartan decreased the Ito, IK, Iti, and NCX currents. In conclusion, angiotensin II and AIIRB modulate the PV electrical activity, which may play a role in the pathophysiology of atrial fibrillation.

Epicardial Adipose Tissue Thickness and Ablation Outcome of Atrial Fibrillation

Objectives Epicardial fat was closely related to atrial fibrillation (AF). Transthoracic echocardiography (TTE) has been proposed to be a convenient imaging tool in assessing epicardial adipose tissue (EAT). The goal of the present study was to investigate whether the EAT thickness measured on TTE was a useful parameter in predicting procedural outcomes of AF ablations. Methods and Results A total of 227 paroxysmal AF (PAF) and 56 non-paroxysmal AF (non-PAF) patients receiving catheter ablations from 2008-2010 were enrolled. Echocardiography-derived regional EAT thickness from parasternal long-axis view was quantified for each patient. Free of recurrence was defined as the absence of atrial arrhythmias without using antiarrhythmic agents after ablations. The mean EAT thickness of the study population was 6.1 ± 0.8 mm. Non-PAF patients had a thicker EAT than that of PAF patients (7.0 ± 0.7 mm versus 5.9 ± 0.7 mm, p value <0.001). During the follow-up of 16 ± 9 months, there were 95 patients (33.6%) suffering from recurrences of atrial arrhythmias. Non-PAF, chads2 score, left atrial diameter and EAT thickness were independent predictors of recurrence after catheter ablations. At a cutoff value of 6 mm for PAF and 6.9 mm for non-PAF, the measurement of EAT thickness could help us to identify patients at risk of recurrences. Conclusions EAT thickness may serve as a useful parameter in predicting recurrences after AF ablations. Compared to other imaging modalities, TTE can be an alternative choice with less cost and time in assessing the effects of EAT on ablation outcomes.

Gap junction modifier rotigaptide decreases the susceptibility to ventricular arrhythmia by enhancing conduction velocity and suppressing discordant alternans during therapeutic hypothermia in isolated rabbit hearts

BACKGROUNDnTherapeutic hypothermia (TH) may increase the susceptibility to ventricular arrhythmias by decreasing ventricular conduction velocity (CV) and facilitating arrhythmogenic spatially discordant alternans (SDA).nnnOBJECTIVEnThe purpose of this study was to test the hypothesis that rotigaptide, a gap junction enhancer, can increase ventricular CV, delay the onset of SDA, and decrease the susceptibility to pacing-induced ventricular fibrillation (PIVF) during TH.nnnMETHODSnLangendorff-perfused isolated rabbit hearts were subjected to 30-minute moderate hypothermia (33°C) followed by 20-minute treatment with rotigaptide (300 nM, n = 8) or vehicle (n = 5). The same protocol was also performed at severe hypothermia (30°C; n = 8 for rotigaptide, n = 5 for vehicle). Using an optical mapping system, epicardial CV and SDA threshold were evaluated by S1 pacing. Ventricular fibrillation inducibility was evaluated by burst pacing for 30 seconds at the shortest pacing cycle length (PCL) that achieved 1:1 ventricular capture.nnnRESULTSnRotigaptide increased ventricular CV during 33°C (PCL 300 ms, from 76 ± 6 cm/s to 84 ± 7 cm/s, P = .039) and 30°C (PCL 300 ms, from 62 ± 6 cm/s to 68 ± 4 cm/s, P = .008). Rotigaptide decreased action potential duration dispersion at 33°C (P = .01) and 30°C (P = .035). During 30°C, SDA thresholds (P = .042) and incidence of premature ventricular complexes (P = .025) were decreased by rotigaptide. PIVF inducibility was decreased by rotigaptide at 33°C (P = .039) and 30°C (P = .042). Rotigaptide did not change connexin43 expressions and distributions during hypothermia.nnnCONCLUSIONnRotigaptide protects the hearts against ventricular arrhythmias by increasing ventricular CV, delaying the onset of SDA, and reducing repolarization heterogeneity during TH. Enhancing cell-to-cell coupling by rotigaptide might be a novel approach to prevent ventricular arrhythmias during TH.

Impact of circulating monocyte CD36 level on atrial fibrillation and subsequent catheter ablation.

BACKGROUNDnInflammation, an important mechanism in the pathogenesis of atrial fibrillation (AF), can be regulated by CD36 in monocytes.nnnOBJECTIVEnThe purpose of this study was to test the hypothesis that CD36 in monocytes contributes to the pathogenesis of AF.nnnMETHODSnA prospective study that enrolled 87 patients with AF and 70 without AF was conducted.nnnRESULTSnCompared to patients without AF, patients with AF had monocytes with a lower level of CD36 protein, which correlated with left atrial diameter, left atrial emptying fraction, and left atrial mean voltage. In AF patients after catheter ablation, Kaplan-Meier analysis showed that the sinus rhythm maintenance rate was higher in patients with high CD36 levels. Low CD36 level was an independent predictor of recurrence. After successful ablation, the CD36 level increased by 57%, reaching that of control patients. CD36 level was not correlated with the level of high-sensitivity C-reactive protein. Analysis of mRNA levels from a buffy coat revealed that AF patients had lower CD36 and interleukin-10 levels and higher peroxisome proliferator-activated receptor-γ and tumor necrosis factor-α levels, with CD36 level positively correlated with interleukin-10 level but inversely correlated with peroxisome proliferator-activated receptor-γ and tumor necrosis factor-α levels.nnnCONCLUSIONnLow CD36 levels in circulating monocytes were associated with AF occurrence and predicted recurrence after catheter ablation. The link between CD36 and AF identified a novel AF-related inflammatory pathway.

Heart failure enhances arrhythmogenesis in pulmonary veins

1.u2002Heart failure (HF) predisposes to atrial fibrillation (AF) as a result of substrate remodelling. The present study aimed to investigate the impact of HF on the electrical remodelling of the pulmonary veins (PV) and left atrium (LA).

Heat shock protein inducer modifies arrhythmogenic substrate and inhibits atrial fibrillation in the failing heart

BACKGROUNDnGeranylgeranylacetone (GGA) has been reported up-regulating heat shock protein (HSP) expression, and protecting against atrial remodeling. This study aimed to investigate the effects of GGA on atrial electrophysiology and inducibility of atrial fibrillation (AF) in heart failure (HF) model.nnnMETHODS AND RESULTSnHF rabbits were created 4 weeks after coronary artery ligation. Monophasic action potential recordings and multielectrode array were used to record the electrophysiological characteristics of left atrium (LA) in normal, or HF rabbits with (HF-GGA) and without (HF-control) oral administration of GGA (200 mg/kg, 24 h before experiments). The mRNA and protein expressions of ionic channels were measured by Western blot and PCR. HF-GGA LA (n = 10), similar to normal LA (n = 10) had a shorter action potential duration (APD) and effective refractory period than HF-control LA (n = 10). HF-GGA LA had less triggered activity and APD alternans (20% vs. 100%, P = 0.001), lower maxima slope of restitution curve of APD (0.94 ± 0.04 vs.1.69 ± 0.04, P < 0.001), and less inducibility of AF (50% vs. 100%, P = 0.033) than HF-control LA. HF-GGA LA had a shorter activation time and higher conduction velocity than HF-control LA. HF-GGA LA had a higher mRNA expression of Cav1.2, Nav1.5, Kir2.1, Kv1.4, Kv7.1, Kv11.1, sarcoplasmic reticulum Ca(2+)-ATPase, and higher phosphorylation of phospholamban than HF-control LA.nnnCONCLUSIONSnGGA decreases triggered activity, dispersion of APD and inducibility of AF in failing heart through induction of HSP, and modulation of ionic channels and calcium homeostasis.

Controversies in the Mechanisms and Ablation of Pulmonary Vein Atrial Fibrillation

It has been more than 6 years since the pioneer work of catheter ablation in patients with atrial fibrillation (AF) initiated by the pulmonary vein (PV) or non-PV ectopy, and since catheter ablation of AF became more popular in the era of interventional electrophysiology.1−13 The United States and several European countries are planning a randomized trial to prove that the catheter ablation procedure can be a first line therapy in patients with paroxysmal AF. However, compared to the ablation procedures in atrioventricular (AV) nodal reentry tachycardia, accessory AV pathway mediated tachycardia, atrial tachycardia, and atrial flutter, more controversies exist in the mechanisms and interventional procedures of PVs-AF.14−16

Electrical remodeling of the canine superior vena cava after chronic rapid atrial pacing.

AbstractBackgroundThe superior vena cava (SVC) might serve as thentrigger and/or substrate for paroxysmal atrial fibrillation (AF). However, thenelectrophysiological properties of the SVC with chronic AF are unknown. Thenpurposes of this study were to investigate the electrophysiological propertiesnof the SVC and the electropharmacological effects of intravenous dl–sotalolnon the canine SVC after chronic rapid atrial pacing (RAP).Methods and resultsIn the control group, the effective refractory period (ERP), conductionnvelocity, and AF inducibility of the SVC were assessed in 6 normal dogsnbefore and after an infusion of dl–sotalol. In the experimental group, the ERP,nconduction velocity, and AF inducibility of the SVC were assessed before andnafter dl–sotalol administration in 10 dogs after 8 weeks of RAP. The SVCnshowed a shorter ERP, decreased slope of rate–adaptation of the ERP,nincreased ERP dispersion, a decreased conduction velocity, and increasedninducibility and duration of AF initiated from the SVC in the RAP dogs. Innthe RAP dogs, intravenous dl–sotalol significantly increased the ERP, but dlsotalolndid not change the slope of rate–adaptation of the ERP, dispersion ofnthe ERP, conduction velocity, inducibility, or duration of AF initiated fromnthe SVC.ConclusionsThe present study demonstrates that the canine SVCnshows significant electrical remodeling and increased AF vulnerability afternchronic RAP. Intravenous dl–sotalol was unable to decrease the inducibilitynor duration of AF initiated from the SVC.

Atherosclerosis modulates the electrophysiological effects of a peroxisome proliferator-activated receptor-gamma activator on pulmonary veins

a Division of Cardiology, Chi-Mei Medical Center, Tainan, Taiwan b Division of Cardiovascular Medicine, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan c Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan d Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan e Department of Internal Medicine, Mackay Memorial Hospital, Mackay Medical College, Taipei, Taiwan f Institute of Physiology, National Defense Medical Center, Taipei, Taiwan g National Yang-Ming University, School of Medicine; Division of Cardiology and Cardiovascular Research Center, Veterans General Hospital-Taipei, Taipei, Taiwan