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Interleukin (IL)-33, a cytokine involved in immune responses, can activate its receptor, suppression of tumorigenicity 2 (ST2), is elevated during atrial fibrillation (AF). However, the role of IL-33/ST2 signaling in atrial arrhythmia is unclear. This study explored the pathological effects of the IL-33/ST2 axis on atrial remodeling and arrhythmogenesis. Patch clamping, confocal microscopy, and Western blotting were used to analyze the electrical characteristics of and protein activity in atrial myocytes (HL-1) treated with recombinant IL-33 protein and/or ST2-neutralizing antibodies for 48 hrs. Telemetric electrocardiographic recordings, Masson's trichrome staining, and immunohistochemistry staining of the atrium were performed in mice receiving tail vein injections with nonspecific immunoglobulin (control), IL-33, and IL-33 combined with anti-ST2 antibody for 2 weeks. IL-33-treated HL-1 cells had a reduced action potential duration, lower L-type Ca2+ current, greater sarcoplasmic reticulum (SR) Ca2+ content, increased Na+/Ca2+ exchanger (NCX) current, elevation of K+ currents, and increased intracellular calcium transient. IL-33-treated HL-1 myocytes had greater activation of the calcium–calmodulin-dependent protein kinase II (CaMKII)/ryanodine receptor 2 (RyR2) axis and nuclear factor kappa B (NF-κB) / NLR family pyrin domain containing 3 (NLRP3) signaling than did control cells. IL-33 treated cells also had greater expression of Nav1.5, Kv1.5, NCX, and NLRP3 than did control cells. Pretreatment with neutralizing anti-ST2 antibody attenuated IL-33-mediated activation of CaMKII/RyR2 and NF-κB/NLRP3 signaling. IL-33-injected mice had more atrial ectopic beats and increased AF episodes, greater atrial fibrosis, and elevation of NF-κB/NLRP3 signaling than did controls or mice treated with IL-33 combined with anti-ST2 antibody. Thus, IL-33 recombinant protein treatment promotes atrial remodeling through ST2 signaling. Blocking the IL-33/ST2 axis might be an innovative therapeutic approach for patients with atrial arrhythmia and elevated serum IL-33. [ABSTRACT FROM AUTHOR]

• Angiotensin receptor-neprilysin inhibitor (ARNi) reverses electrical and structural remodeling caused by heart failure (HF), which accounts for the suppression of ventricular arrhythmia. • Fibrosis could be reduced by ARNi treatment in an ischemic HF model. • ARNi treatment decreases T-cell count, suggesting its anti-inflammatory effect. The mechanisms underlying angiotensin receptor-neprilysin inhibitor (ARNi) suppression of ventricular arrhythmia (VA) are unclear. This study aimed to investigate the mechanism of ARNi-related suppression of VA in a heart failure (HF) model. New Zealand white rabbits (n = 6 per group) were assigned to normal, HF [4 weeks of left ascending artery (LAD) ligation], angiotensin receptor blocker (ARB, valsartan at 27 mg/kg/day for 3 weeks after 1 week of LAD ligation), and ARNi (sacubitril at 34 mg/kg/day and valsartan at 27 mg/kg/day for 3 weeks after 1 week of LAD ligation) groups. Experiments involving echocardiogram, optical mapping, histological of trichrome stain and immunostain, and flow cytometry were performed. HF group had larger left ventricular (LV) internal dimensions in diastole and systole, and lower LV ejection fraction and fractional shortening than normal, ARB, and ARNi groups. HF group had a prolonged action potential duration (APD) and decreased conduction velocity (CV), which was mitigated in ARB and ARNi groups. HF group had a prolonged QRS duration, QT and QTc intervals, which was reversed in ARB and ARNi groups. HF group had a steeper maximum slope of APD restitutions, which was attenuated in normal, ARB, and ARNi groups. HF group had increased number of phase singularities (PSs) and VA inducibility than normal, ARB, and ARNi groups. A higher content of fibrosis was found in HF group than that in normal, ARB, and ARNi groups. Compared to ARB group, ARNi had a lower context of fibrosis. HF group had more peripheral blood CD4+ and CD8+ cells count than normal, ARB, and ARNi group. In a rabbit model of ischemic HF, ventricular arrhythmogenesis could be suppressed by ARNi treatment. This appears to be mediated by reversing changes in the APD, CV, maximum slope of the APDR, PSs, fibrosis, and inflammation. [Display omitted] [ABSTRACT FROM AUTHOR]

Risk factors including cardiometabolic and endocrine disorders have a significant impact on atrial remodeling causing atrial fibrillation (AF). Diabetes mellitus and hyperthyroidism are strong independent risk factors for AF and worsen outcomes of rhythm control strategies. An early diagnosis and intervention for these risk factors combined with rhythm control strategies may improve the overall cardiovascular mortality and morbidity. This review summarizes the current state of knowledge about the AF risk factors diabetes mellitus and thyroid disease, and discusses the impact of the modification of these risk factors on primary and secondary prevention of AF. [ABSTRACT FROM AUTHOR]

Background Resveratrol has shown benefits in reducing ventricular remodeling and arrhythmias. Objective This study aimed to assess the therapeutic efficacy of resveratrol in reducing atrial fibrillation (AF) in a heart failure (HF) model and to explore the underlying mechanisms. Methods HF rabbits were created 4 weeks after undergoing coronary ligation. Group 1 (n = 6) was divided into subgroups of (a) normal rabbits, (b) HF sham rabbits, and (c) HF rabbits treated for 1 week with intraperitoneal injections of resveratrol, (d) resveratrol plus wortmannin, or (e) resveratrol plus diphenyleneiodonium chloride (DPI). All rabbits underwent epicardial catheter stimulation. Collagen content, messenger RNA and protein expression in ion channels, and phosphoinositide 3-kinase (PI3K)/AKT/endothelial nitric oxide synthase (eNOS) signaling pathways were studied in left atrial appendage (LAA) preparations. To investigate acute drug effects on left atrial electrophysiology, groups 2 a through 2e (n = 6 per group) were subjected to Langendorff perfusion. Results Higher AF inducibility was found in the HF group and groups that were given PI3K and eNOS inhibitors than in the normal and resveratrol-treated groups ( P < .001). Histologic analysis of the LAA revealed a decrease in fibrosis in resveratrol-treated groups compared with the HF group (8.95% ± 1.53% vs 26.62% ± 2.19%, P < .001). In real-time polymerase chain reaction analysis, ion channels including Kv1.4, Kv1.5, KvLQT1, Kir2.1, Nav1.5, Cav1.2, NCX, SERCA2a, and phospholamban were upregulated by resveratrol. PI3K, AKT, and eNOS messenger RNA and protein expression were upregulated by resveratrol but were inhibited by the coadministration of wortmannin and DPI. Conclusion Resveratrol decreases left atrial fibrosis and regulates variation in ion channels to reduce AF through the PI3K/AKT/eNOS signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Alteration in ventricular repolarization has been reported in patients with spinal cord injuries (SCIs). However, its clinical impact remains unclear. Objective: The purpose of this study was to investigate the correlation between SCIs and ventricular repolarization and the associated clinical impact. Methods: One hundred forty-four patients with an SCI were retrospectively reviewed and were divided into two groups (SCI level ≤T6, n = 110; SCI level >T6, n = 34). The electrocardiograms were reviewed during acute phase (at emergency room) and chronic phase (>1 year). Results: There were no differences in the underlying diseases or in ASIA score between the two groups, except there were more patients with tetraplegia among those with an SCI level ≤T6. For the electrophysiological parameters from the electrocardiograms, the patients with an SCI level ≤T6 had longer QTc and PR interval than those with an SCI level >T6 during acute phase. In the chronic phase, there were no differences in the electrophysiological parameters between the two groups. Only in patients with an SCI level ≤T6 did a Kaplan-Meier analysis show that QTc prolongation could predict 30-day mortality after the acute injury. After multivariate Cox regression analysis, only tetraplegia and QTc prolongation were independent predictors of 30-day mortality (odds ratios 7.85 and 34.62, respectively). In patients with an SCI level ≤T6, the QTc intervals were shorter in the chronic phase than those during the acute phase. Conclusion: QTc interval was associated with the level of acute SCI and predicted the 30-day mortality. [ABSTRACT FROM AUTHOR]

Background: The regional distribution of the low-voltage zones (LVZs) may relate to the maintenance of atrial arrhythmias in the right atrium (RA). Objectives: The purpose of this study was to investigate the RA substrate characteristics in different types of atrial arrhythmias originating from RA and left atrium (LA). Methods: Forty-five patients (35 men, age = 62 ± 15 years) with RA atypical atrial flutter (n = 15, group 1), RA atrial fibrillation (AF; n = 15, no PV initiating foci, group 2), and LA AF (n = 1 5, no RA arrhythmias, group 3) referred for three-dimensional EnSite mapping were included. Voltage and activation maps were visualized. Results: The mean voltage of the RA was lower in group 2, and compared with group 3, a voltage reduction during atrial pacing was evident in groups 1 and 2. The fixed LVZs (independent of the rhythm) were mostly located along the lower crista terminalis (CT). A functional extension of the LVZ was located on the CT in 84% of patients, sinus venosa in 18%, and free-wall region in 27%, forming the borders of the slow conduction isthmus for the reentrant circuits. The number of slow conduction isthmuses was 1.3 ± 0.9, 2.2 ± 1.0, and 0.87 ± 0.74, for the groups 1–3 patients, respectively (P <.05). Radiofrequency ablation connecting the LVZs successfully eliminated those isthmuses. The long-term follow-up revealed that 66% of the patients remained in sinus rhythm. Conclusions: Single and multiple slow conduction isthmuses bordered by the fixed and functional LVZs were critical for the reentrant circuits in the RA. The conduction isthmuses could be identified by their substrate characteristics and ablated successfully. [Copyright &y& Elsevier]

Background: Termination of atrial fibrillation (AF) can be achieved by catheter ablation. It has been used as one of the procedural endpoints for AF ablation. Objective: The purpose of this study was to investigate the factors that predict AF termination and the association with long-term outcomes. Methods: Eighty-five consecutive AF patients (33 paroxysmal, 52 nonparoxysmal) underwent three-dimensional mapping and catheter ablation. A stepwise ablation approach included circumferential pulmonary vein (PV) isolation and left atrial (LA) linear ablation, followed by LA and right atrial (RA) electrogram-based (complex fractionated atrial electrogram) ablation. Clinical and electrophysiologic characteristics were assessed to evaluate the predictors of acute AF termination. Results: In univariate analysis, a diagnosis of paroxysmal AF, shorter AF history, absence of history of heart failure, smaller LA diameter, longer postablation coronary sinus cycle length, lower LA and RA mean dominant frequencies, lower RA max dominant frequency, and higher LA voltage were related to acute termination of AF during ablation. Multivariate analysis showed that smaller LA diameter and lower preablation mean RA dominant frequency were independent predictors of AF termination. Multivariate analysis also showed that larger LA diameter and the presence of RA non-PV ectopy during the index procedure could predict late recurrence during long-term (13 ± 8 months) follow-up. Conclusion: LA size and RA non-PV drivers are important for acute termination of AF and for long-term success. Careful selection of patients, extensive RA mapping, and LA ablation may enhance long-term ablation efficacy. [Copyright &y& Elsevier]

Background: Information about the electrophysiologic characteristics and long-term outcome of catheter ablation in patients with multiple focal atrial tachycardia (AT) is limited. Objective: The purpose of this study was to investigate the electrophysiologic characteristics and long-term outcome of catheter ablation in patients with multiple focal AT. Methods: Two hundred fifty-one patients who were referred for radiofrequency catheter ablation of focal AT were included for analysis. Results: Forty-four patients who had focal AT with more than one focus were identified. Comparing focal AT with a single focus to that with more than one focus, the existence of a left atrial focus, cardiovascular comorbidity, nonparoxysmal tachycardia, shortest tachycardia cycle length, success rate of the ablation, and procedure time all differed. Multivariate logistic analysis revealed that a left atrial focus, cardiovascular comorbidity, and shortest tachycardia cycle length were independent predictors of focal AT with more than one focus. Noncontact mapping of the right atrium revealed larger low-voltage zone and longer total activation time for focal AT with more than one focus. Patients who had focal AT with more than one focus and a failed ablation had a greater number of focal ATs and mechanisms of nonparoxysmal tachycardia. Multivariate logistic analysis revealed that only the number of focal ATs predicted a failed ablation. Conclusion: Focal ATs with more than one focus have different electrophysiologic characteristics. This study provides new insight into the development and atrial remodeling of focal AT with multiple foci. [Copyright &y& Elsevier]

Background: Data detailing the age-related difference in the atrial substrate for formation of typical atrial flutter (AFL) are sparse. Objective: The purpose of this study was to characterize the difference in the right atrial substrate related to aging using noncontact mapping of the right atrium. Methods: A total of 54 patients (23 young [<60 years; 45 ± 12 years] and 31 old [≥60 years; 74 ± 6 years]) with typical AFL who underwent three-dimensional noncontact mapping of typical AFL were enrolled in the study. The atrial substrate was characterized according to (1) regional wavefront activation mapping, (2) regional conduction velocity, and (3) regional voltage distribution by dynamic substrate mapping. Results: During activation mapping of the crista terminalis, two activation patterns were observed: (1) around the upper end of the crista terminalis (67%) and (2) through a gap in the crista terminalis. The presence of a crista terminalis gap was associated with a high incidence of induced atypical AFL/atrial fibrillation (P <.001). The conduction velocities of the medial cavotricuspid isthmus were slower in the old group than in the young group. In regional activation mapping of the AFL, the location of the slowest conduction shifted from the lateral cavotricuspid isthmus (71%) in the young group to the medial cavotricuspid isthmus (40%) in the old group. More cases with a low-voltage zone (≤30% peak negative voltage) extending to the medial side of the cavotricuspid isthmus occurred in the old group than in the young group (55% vs 17%, P = .012). Conclusion: The atrial substrate responsible for formation of typical AFL differed between young and old patient groups. [Copyright &y& Elsevier]

Background: Regions of rapid and multiple deflections can be identified with high dominant frequency (DF) during sinus rhythm (SR). These areas may play a role in the perpetuation of atrial fibrillation (AF) and indicate an atrial substrate abnormality. Objective: The purpose of this study was to investigate the atrial substrate properties of the high-frequency sites in patients with paroxysmal AF. Methods: Forty patients (52 ± 12 years of age) with paroxysmal AF were studied using a three-dimensional mapping system. Spectral analysis was performed on the bipolar electrograms in the left atrium (LA) during SR. Overall, 7708 electrograms were analyzed, and the DFs higher than 70 Hz were labeled as abnormal. Results: The regional distribution of the high-DF sites in the LA could be divided into two types. Type 1 includes high-DF sites existing only in the pulmonary veins (PVs; n = 19, 6.6 ± 3.4 sites/patient). Type 2 includes high-DF sites in the LA or LA plus the PVs (n = 21, 11 ± 5.6 sites/patient). In type 1, PV isolation (PVI) could eliminate the AF with negative AF inducibility testing after the PVI in 89% of patients. In type 2, additional LA substrate modification was needed in 81% of patients because sustained AF was induced after the PVI (P<.001, compared with type 1). Multivariate analysis showed that the lower mean voltage of the LA and high-frequency sites distribution both independently predicted a positive AF inducibility after the PVI (P<.05). Conclusions: Spectral analysis during SR can detect an abnormal atrial substrate. A regional distribution of the high-DF sites predicts the efficacy of the PVI. [Copyright &y& Elsevier]

Background: Temporal variation in complex fractionated atrial electrograms (CFAEs) exists during atrial fibrillation (AF). Objective: This study sought to quantify the variation in CFAEs using a fractionation interval (FI) algorithm and to define the shortest optimal recording duration required to consistently characterize the magnitude of the fractionation. Methods: Twenty-seven patients undergoing AF mapping in the left atrium were studied. The FI and frequency analysis were performed at each mapped site for recording durations of 1 to 8 seconds. The magnitude of the fractionation was quantified by the FI algorithm, which calculated the mean interval between multiple, discrete deflections during AF. The results from each duration were statistically compared with the maximal-duration recording, as a standard. The FI values were compared with the dominant frequency values obtained from the associated frequency spectra. Results: The FIs obtained from recording durations between 5 and 8 seconds had a smaller variation in the FI (P < .05) and, for those sites with a FI < 50 ms, the fractionation was typically continuous. The fast-Fourier Transform spectra obtained from the CFAE sites with recording durations of >5 seconds harbored higher dominant frequency values than those with shorter recording durations (8.1 ± 2.5 Hz vs. 6.8 ± 0.98 Hz, P < .05). The CFAE sites with continuous fractionation were located within the pulmonary veins and their ostia in 77% of patients with paroxysmal AF, and in only 29% of patients with nonparoxysmal AF (P < .05). Conclusion: The assessment of fractionated electrograms requires a recording duration of ≥5 seconds at each site to obtain a consistent fractionation. Sites with the shortest FIs consistently identified sites with the fastest electrogram activity throughout the entire left atrium and pulmonary veins. [Copyright &y& Elsevier]

Factor Xa inhibitors reduce stroke in patients with atrial fibrillation. Pulmonary veins (PVs) and the sinoatrial node (SAN) are crucial for genesis of atrial fibrillation. However, the electrophysiological effects of factor Xa inhibitors (edoxaban and rivaroxaban) on PVs and the SAN remain unclear. Conventional microelectrodes were used to record the action potential in isolated rabbit PVs and SAN preparations before and after administration of edoxaban (0.1, 0.3, and 1 μM) or rivaroxaban (0.01, 0.03, 0.1, and 0.3 μM). A whole-cell patch-clamp was used to record the late sodium current ( I Na-late ) in isolated single rabbit PV cardiomyocytes. Edoxaban significantly reduced PV spontaneous beating rates at 0.3 and 1 μM ( N  = 6 rabbits, P  < 0.05), and reduced SAN beating rates at 1 μM ( N  = 6, P  < 0.05). Similarly, rivaroxaban reduced PV spontaneous beating rates at 0.1 and 0.3 μM ( N  = 7, P  < 0.05), and reduced SAN beating rates at 0.3 μM ( N  = 6, P  < 0.05). However, neither edoxaban (1 μM) nor rivaroxaban (0.3 μM) reduced PV spontaneous beating rates in the presence of 1 μM BMS200261 (an inhibitor of protease-activated receptors type 1, PAR1 inhibitor) or 10 μM ranolazine (an inhibitor of late sodium current, I Na-late inhibitor). Edoxaban (0.3 and 1 μM) and rivaroxaban (0.1 and 0.3 μM) respectively decreased the I Na-late by 47%, 47%, 36%, and 49% ( n  = 9 PV cardiomyocytes from 5 rabbits, P  < 0.05). In conclusion , Factor Xa inhibitors reduce PV spontaneous activities and may modulate occurrence of atrial fibrillation by inhibiting PAR1 and reducing the I Na-late in PVs. [ABSTRACT FROM AUTHOR]

Excitation-contraction (E-C) coupling, the interaction of action potential duration (APD) and contractility, plays an essential role in arrhythmogenesis. We aimed to investigate the arrhythmogenic role of E-C coupling in the right ventricular outflow tract (RVOT) in the chloroquine-induced long QT syndrome. Conventional microelectrodes were used to record electrical and mechanical activity simultaneously under electrical pacing (cycle lengths from 1000–100 ms) in rabbit RVOT tissue preparations before and after chloroquine with and without azithromycin. KB-R7943 (a Na+-Ca2+ exchanger [NCX] inhibitor), ranolazine (a late sodium current inhibitor), or MgSO 4 were used to assess their pharmacological responses in the chloroquine-induced long QT syndrome. Sequential infusion of chloroquine and chloroquine plus azithromycin triggered ventricular tachycardia (VT) (33.7%) after rapid pacing compared to baseline (6.7%, p = 0.004). There were greater post-pacing increases of the first occurrence of contractility (ΔContractility) in the VT group (VT vs. non-VT: 521.2 ± 50.5% vs. 306.5 ± 26.8%, p < 0.001). There was no difference in the first occurrence of action potential at 90% repolarization (ΔAPD 90) (VT vs. non-VT: 49.7 ± 7.4 ms vs. 51.8 ± 13.1 ms, p = 0.914). Pacing-induced VT could be suppressed to baseline levels by KB-R7943 or MgSO 4. Ranolazine did not suppress pacing-induced VT in chloroquine-treated RVOT. ΔContractility was reduced by KB-R7943 and MgSO 4 , but not by ranolazine. ΔContractility (but not ΔAPD) played a crucial role in the genesis of pacing-induced VT in the long QT tissue model, which can be modulated by NCX (but not late sodium current) inhibition or MgSO 4. [ABSTRACT FROM AUTHOR]

Abstract: Background: Geranylgeranylacetone (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. Methods and results: HF rabbits were created 4weeks 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 (200mg/kg, 24h 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 Ca2+-ATPase, and higher phosphorylation of phospholamban than HF-control LA. Conclusions: GGA 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. [Copyright &y& Elsevier]

Abstract: Aims: Lactic acidosis causes atrial fibrillation (AF), and pulmonary veins (PVs) are the most important focus for the generation of AF. Cariporide (HOE642), a Na+/H+ blocker, can prevent atrial tachycardia-induced electrical remodeling. The purpose of this study was to investigate whether cariporide can prevent lactic acidosis-induced PV arrhythmogenesis. Main methods: Conventional microelectrodes were used to record the action potentials (APs) before and after the administration of lactic acid (10 and 20 mM) in the absence and presence of cariporide (10 µM) pretreatment in isolated rabbit PV and atrial tissue preparations. Key findings: Lactic acidosis of 10 mM (pH 7.0±0.1) and 20 mM (pH 6.7±0.1) reduced PV (n =6) spontaneous rates from 2.5±0.3 to 1.6±0.4 (by 36±1%) and 1.1±0.4 Hz (by 56±2%), respectively, but lactic acidosis (10 and 20 mM) induced 12 episodes (3.9±0.2 Hz) and 23 episodes (4.0±0.3 Hz) of non-sustained burst firings in 4 PV specimens. Lactic acidosis (10 and 20 mM) decreased the AP amplitude (APA) and velocity of depolarization (Vmax), but increased the resting membrane potential (RMP), AP duration, and strength-response interval (SRI) in the PV and atrium. In the presence of cariporide (10 µM), lactic acidosis (10 and 20 mM) only reduced PV spontaneous rates from 2.4±0.2 to 1.8±0.4 (by 25±1%) and 1.6±0.4 Hz (by 33±1%), respectively, and prevented lactic acidosis-induced PV burst firings. Cariporide also reduced the effects of lactic acidosis on the RMP, AP duration, APA, Vmax, and SRI. Significance: Lactic acidosis has significant arrhythmogenic effects on PVs, which may be attenuated by Na+/H+ blockers. [Copyright &y& Elsevier]

Gender differences of supraventricular tachycardias such as atrioventricular nodal re-entry, atrioventricular re-entry, and atrial fibrillation have been reported. There is little evidence of the effect of gender on focal atrial tachycardia (FAT). The study consisted of 298 patients who were referred to this institution for radiofrequency catheter ablation of FAT from October 1992 to April 2008 and included 156 men (52%) and 142 women (48%). Men were significantly older than women (57.9 ± 18.2 vs 47.2 ± 19.0 years old, p <0.001). Women had more associated arrhythmias (17.0% vs 28.9%, p = 0.01), mostly due to an increased incidence of atrioventricular nodal re-entrant tachycardia. Men had more cardiovascular co-morbidities (19.9% vs 9.9%, p = 0.02), a mechanism of increased automaticity (19.1% vs 8.1%, p = 0.01), and nonparoxysmal tachycardia (14.7% vs 4.4%, p = 0.01). No gender differences were noted among FAT number, left atrial involvement, shortest tachycardia cycle, success rate of catheter ablation, or recurrence rate of FAT. Mean duration of follow-up was 63.2 ± 47.5 months. Premenopausal women had a lesser cardiovascular co-morbidity (15.3% vs 4.3%, p = 0.04) and a greater incidence of a mechanism of increased automaticity (13.4% vs 2.9%, p = 0.03). In conclusion, gender differences in electrophysiologic characteristics were noted in FAT. [Copyright &y& Elsevier]

Abstract: Pulmonary veins (PVs) contain cardiomyocytes with spontaneous activity that may be responsible for PV arrhythmia. Abnormal Ca2+ regulation is known to contribute to PV arrhythmogenesis. The purpose of this study was to investigate whether PV cardiomyocytes with spontaneous activity have different intracellular Ca2+ ([Ca2+]i) transients, Ca2+ sparks and responses to isoproterenol and ryanodine receptor modulators (magnesium and FK506) than do PV cardiomyocytes without spontaneous activity and left atrial (LA) cardiomyocytes. Through fluorescence and confocal microscopy, we evaluated the [Ca2+]i transients and Ca2+ sparks in isolated rabbit PV and LA cardiomyocytes. PV cardiomyocytes with spontaneous activity had larger [Ca2+]i transients and sarcoplasmic reticulum (SR) Ca2+ stores than PV cardiomyocytes without spontaneous activity or LA cardiomyocytes. PV cardiomyocytes with spontaneous activity also had a higher incidence and frequency of Ca2+ sparks, and had Ca2+ sparks with larger amplitudes than other cardiomyocytes. Magnesium (5.4 mM) reduced the [Ca2+]i transient amplitude and beating rate in PV cardiomyocytes with spontaneous activity. However, in contrast with other cardiomyocytes, low doses (1.8 mM) of magnesium did not reduce the [Ca2+]i transients amplitude in PV cardiomyocytes with spontaneous activity. FK506 (1 μM) diminished the SR Ca2+ stores in PV cardiomyocytes with spontaneous activity to a lesser extent than that in other cardiomyocytes. Isoproterenol (10 nM) increased the [Ca2+]i transient amplitude to a lesser extent in LA cardiomyocytes than in PV cardiomyocytes with or without spontaneous activity. In conclusion, our results suggest that enhanced [Ca2+]i transients, increased Ca2+ sparks and SR Ca2+ stores may contribute to the spontaneous activity of PV cardiomyocytes. [Copyright &y& Elsevier]

Abstract: Background: Atrioventricular nodal reentrant tachycardia (AVNRT) is the most common supraventricular tachycardia in adulthood. Although selective ablation of the slow AV nodal pathway can cure AVNRT, accidental AV block may occur. The details on the electrophysiologic characteristics, quantitative data on the voltage inside Koch''s triangle, and the use of three-dimensional noncontact mapping to facilitate the catheter ablation of AVNRT associated with a high-risk for AV block or other arrhythmias have been limited. Methods and results: Nine patients (M/F =5/4, 34±23 years, range 17–76) with clinically documented AVNRT were included. All patients had undergone previous sessions for slow AV nodal pathway ablation but they had failed, because of repetitive episodes of complete AV block during the RF energy applications. Further, one patient had a complex anatomy and 4 patients were associated with other tachycardias, respectively. The electrophysiologic studies revealed that 4 patients had the slow–fast, 4 the slow–intermediate and one the fast–intermediate form of AVNRT. Noncontact mapping demonstrated two types of antegrade AV nodal conduction, markedly differing sites of the earliest atrial activation during retrograde VA conduction, and a lower range of voltage within Koch''s triangle. The lowest border of the retrograde conduction region was defined on the map, and the application of the RF energy was delivered below that border to prevent the occurrence of AV block. The distance between the successful ablation lesions and the lowest border of the retrograde conduction region was significantly shorter in the patients with the slow–intermediate form of AVNRT than in those with the slow–fast form (5.5±3.4 vs. 15±7.6 mm; p <0.05). After the ablation procedure, either rapid pacing or extrastimulation could not induce any tachycardia, and there was no recurrence during the follow-up (10.3±5.4, 2 to 22 months). Conclusions: Noncontact mapping could effectively demonstrate the antegrade and retrograde atrionodal conduction patterns, electrophysiologic characteristics of Koch''s triangle, and guide the successful catheter ablation in difficult AVNRT cases. [Copyright &y& Elsevier]

Objectives: The purpose of this study was to investigate the relationship between the abnormal substrate and peak negative voltage (PNV) in the right atrium (RA) with atypical flutter. Background: The impact of a local abnormally low voltage electrogram on the local activation pattern and velocity of atrial flutter (AFL) remains unclear. Methods: Twelve patients with clinically documented AFL were included to undergo noncontact mapping of the RA. The atrial substrate was characterized by the: 1) activation mapping; 2) high-density voltage mapping; and 3) conduction velocity along the flutter re-entrant circuit. The normalized PNV (i.e., the relative ratio to the maximal PNV) in each virtual electrode recording was used to produce the voltage maps of the entire chamber. The protected isthmus was bordered by low voltage zones. Results: Atypical AFL of the RA was induced by atrial pacing in 12 patients, including 10 upper loop re-entry and 2 RA free wall re-entry flutter. These protected isthmuses were located near the crista terminalis. The mean width of the protected isthmus was 1.7 ± 0.3 cm and mean voltage at the isthmus was −0.91 ± 0.39 mV. The conduction velocities within these paths were significantly slower than outside the path (0.30 ± 0.18 m/s vs. 1.14 ± 0.41 m/s, respectively; p = 0.004). The ratiometric PNV of 37.6% of the maximal PNV had the best cut-off value to predict slow conduction, with a high sensitivity (92.3%) and specificity (85.7%). Conclusions: Characterization of the RA substrate in terms of the unipolar PNV is an effective predictor of the slow conduction path within the critical isthmus of the re-entrant circuit. [Copyright &y& Elsevier]

Objectives: This study sought to investigate the regional frequency distribution from multiple bi-atrial sites in different types of paroxysmal atrial fibrillation (AF). Background: A previous study showed a left atrium (LA) to right atrium (RA) frequency gradient in patients with paroxysmal AF. Methods: Forty-four patients (age = 60 ± 16, male patients = 27) with paroxysmal AF originating from the pulmonary veins (PVs) (n = 31) or superior vena cava (SVC) (n = 13) were included. Frequency analysis was performed on the intracardiac electrograms (7 s, 1 kHz/channel) recorded from PV, posterior LA, coronary sinus (CS), posterolateral RA, and SVC. The largest peak frequency was identified as the dominant frequency (DF). Results: In the PV-AF patients, there was a frequency gradient from the PV ostium to the LA, RA, and SVC (8.5 ± 3.3 Hz vs. 5.9 ± 1.1 Hz vs. 5.2 ± 0.85 Hz vs. 5.5 ± 0.48 Hz, respectively, p < 0.001). The highest DFs were mostly located at the arrhythmogenic PV ostium (58%). The DFs of the arrhythmogenic PV and PV ostium were significantly higher than those of the non-arrhythmogenic PVs and PV ostia (p < 0.05). In the SVC-AF patients, there was a frequency gradient from the SVC to the RA, LA, and PV (8.0 ± 2.4 Hz vs. 5.9 ± 1.1 Hz vs. 5.9 ± 0.7 Hz vs. 5.8 ± 0.7 Hz, respectively, p = 0.001). The highest DFs were mostly located inside the SVC (77%) instead of the SVC ostium (as compared with PV-AF patients, p = 0.035). Conclusions: The location of the highest DF depended on the arrhythmogenic PV or SVC. A frequency gradient was present between the arrhythmogenic thoracic vein and atrium in all patients. [Copyright &y& Elsevier]

Objectives: This study was performed to differentiate upper loop re-entry (ULR) from reverse typical atrial flutter (AFL). Background: Right atrial ULR and reverse typical AFL have different mechanisms and ablation strategies, but similar electrocardiographic characteristics. Methods: This study included 26 patients with reverse typical AFL and 20 patients with ULR. The noncontact mapping system (EnSite-3000, Endocardial Solutions, St. Paul, Minnesota) was used to confirm diagnosis and guide successful radiofrequency ablation. Flutter wave polarity and amplitude in the 12-lead surface electrocardiogram were determined by two independent electrophysiologists. Results: The flutter wave polarity in leads I and aVL was significantly different between the reverse typical AFL and ULR groups (p ≤ 0.001). Voltage measurement revealed significant differences between reverse typical AFL and ULR in leads I, II, aVR, aVF, V1, and V2 (p &#60; 0.001). A new diagnostic algorithm based on negative or isoelectric/flat flutter wave polarity and amplitude ≤0.07 mV in lead I was useful for diagnosis of ULR, with an accuracy of 90% to 97%, a sensitivity of 82% to 100%, and a specificity of 95%. Conclusions: Polarity and voltage measurement of flutter wave in lead I can differentiate reverse typical AFL from ULR. [Copyright &y& Elsevier]

: ObjectivesThe aim of the study was to investigate the conduction properties and anisotropy of the crista terminalis (CT) in patients with atrial flutter (AFL) using non-contact mapping.: BackgroundThe CT is a posterior barrier during typical AFL. However, the CT has transverse conduction capabilities in patients with upper loop re-entry (ULR).: MethodsTwenty-two patients (16 males, 63 ± 15 years) with typical AFL and ULR were included. Non-contact mapping of the right atrium during AFL and pacing from coronary sinus (CS) and low anterolateral right atrium (LARA) was performed to evaluate transverse conduction across the CT. During ULR, the longitudinal (CVL) and transverse (CVT) conduction velocity along and across the CT were measured. The width of the CT conduction gap was evaluated to guide radiofrequency ablation (RFA).: ResultsNo transverse CT gap conduction was found during typical AFL. Transverse CT gap conduction was found in three patients during CS pacing and in three patients during LARA pacing. During ULR, CVL was greater than CVT (1.28 ± 0.43 vs. 0.73 ± 0.30 m/s, p < 0.001). The CVL/CVT ratio was 1.95 ± 0.77, which was inversely related to the CT gap width (15.7 ± 6.8 mm) (p < 0.001). The RFA of the CT gap was successful in 18 patients. Four patients had recurrence of arrhythmias during the follow-up of 11 ± 3 months.: ConclusionsMost of the CT conduction gaps were functional and only appeared during ULR. The width of the CT gap was inversely related to the anisotropic ratio of the CT. The RFA of the CT gap was effective in eliminating ULR. [Copyright &y& Elsevier]