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Atrial fibrillation (AF) is the most common form of arrhythmia and increases the risk of stroke and heart failure (HF). Pulmonary veins (PVs) are important sources of triggers that generate AF, and calcium (Ca2+ ) overload participates in PV arrhythmogenesis. Neurohormonal activation is an important cause of AF. Higher atrial natriuretic peptide (ANP) level predicts paroxysmal AF occurrence in HF patients. However, it is not clear if ANP directly modulates electrophysiological characteristics and Ca2+ homeostasis in the PVs. Conventional microelectrodes, whole-cell patch-clamp, and the Fluo-3 fluorimetric ratio technique were performed using isolated rabbit PV preparations or single isolated PV cardiomyocytes before and after ANP administration. We found that ANP (1, 10, and 100 nmol/L) concentration-dependently decreased spontaneous activity in PV preparations. ANP (100 nmol/L) decreased isoproterenol (1 μmol/L)-induced PV spontaneous activity and burst firing. AP811 (100 nmol/L, NPR-C agonist), H89 (1μmol/L, PKA inhibitor) decreased isoproterenol-induced PV spontaneous activity or burst firing, but successive administration of ANP had no further effect on PV activity. KT5823 (1 μmol/L, PKG inhibitor) decreased isoproterenol-induced PV spontaneous activity but did not change isoproterenol-induced PV burst firing, whereas successive administration of ANP did not change isoproterenol-induced PV burst firing. ANP decreased intracellular Ca2+ transient and sarcoplasmic reticulum Ca2+ content in single PV cardiomyocytes. ANP decreased the late sodium current, L-type Ca2+ current, but did not change nickel-sensitive Na+ -Ca2+ exchanger current in single PV cardiomyocytes. In conclusion, ANP directly regulates PV electrophysiological characteristics and Ca2+ homeostasis and attenuates isoproterenol-induced arrhythmogenesis through NPR-C/cAMP/PKA signal pathway.

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 (INa-late) in isolated single rabbit PV cardiomyocytes. Edoxaban significantly reduced PV spontaneous beating rates at 0.3 and 1 μM (N = 6 rabbits, P

Atrial fibrillation (AF) is a common form of arrhythmia with serious public health impacts, but its underlying mechanisms are not yet fully understood. Vascular endothelial growth factor (VEGF) is highly expressed in the atrium of patients with AF, but whether VEGF affects AF pathogenesis remains unclear. Pulmonary veins (PVs) are important sources for the genesis of atrial tachycardia or AF. Therefore, this study assessed the effects of VEGF on PV electrophysiological properties and evaluated its underlying mechanisms. Conventional microelectrodes and whole-cell patch clamps were performed using isolated rabbit PV preparations or single isolated PV cardiomyocytes before and after VEGF or VEGF receptor (VEGFR), Akt, NOS inhibitor administration. We found that VEGF (0.1, 1, and 10 ng/mL) reduced the PV beating rate in a dose-dependent manner. Furthermore, VEGF (10 ng/mL) reduced late diastolic depolarization and diastolic tension. Isoproterenol increased PV beating and burst firing, which was attenuated by VEGF (1 ng/mL). In the presence of VEGFR-1 inhibition (ZM306416 at 10 μM) and L-NAME (100 μM), VEGF (1 ng/mL) did not alter PV spontaneous activity. In isolated PV cardiomyocytes, VEGF (1 ng/mL) decreased L-type calcium, sodium/calcium exchanger, and late sodium currents. In conclusion, we found that VEGF reduces PV arrhythmogenesis by modulating sodium/calcium homeostasis through VEGFR-1/NOS signaling pathway.

Phosphodiesterase (PDE)3-5 are expressed in cardiac tissue and play critical roles in the pathogenesis of heart failure and atrial fibrillation. PDE inhibitors are widely used in the clinic, but their effects on the electrical activity of the heart are not well understood. The aim of the present study was to examine the effects of various PDE inhibitors on spontaneous cardiac activity and compare those effects between sinoatrial nodes (SANs) and pulmonary veins (PVs). Conventional microelectrodes were used to record action potentials in isolated rabbit SAN and PV tissue preparations, before and after administration of different concentrations (0.1, 1 and 10 µM) of milrinone (PDE3 inhibitor), rolipram (PDE4 inhibitor) and sildenafil (PDE5 inhibitor), with or without the application of isoproterenol (cAMP and PKA activator), KT5823 (PKG inhibitor) or H89 (PKA inhibitor). Milrinone (1 and 10 µM) increased the spontaneous activity in PVs by 10.6±4.9 and 16.7±5.3% and in SANs by 9.3±4.3 and 20.7±4.6%, respectively. In addition, milrinone (1 and 10 µM) induced the occurrence of triggered activity (0/8 vs. 5/8; P

Atrial fibrillation (AF) is the most common form of arrhythmia and increases the risk of stroke and heart failure (HF). Pulmonary veins (PVs) are important sources of triggers that generate AF, and calcium (Ca

a Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan b Division of Cardiology, Chi-Mei Medical Center, Tainan, Taiwan c School of Medicine, Chung Shan Medical University, Taichung, Taiwan d Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan e Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan f Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

Ventricular arrhythmias commonly arise from the right (RVOT) and left ventricular outflow tracts (LVOT) in patients without structural heart disease. Heart failure (HF) significantly increases the risk of ventricular arrhythmias. The regional differences and how HF affects the electrophysiological characteristics of RVOT and LVOT cardiomyocytes remain unclear. The whole-cell patch-clamp technique was used to investigate the action potentials and ionic currents in isolated single RVOT and LVOT cardiomyocytes from control rabbits and rabbits with HF induced by rapid ventricular pacing. Comparison with control LVOT cardiomyocytes showed that control RVOT cardiomyocytes have a shorter action potential duration (APD), smaller late Na+ currents (INa-late), larger transient outward (Ito) and larger delayed rectifier K+ currents (IKr-tail), but had similar L-type Ca2+ currents (ICa-L) and Na+/Ca2+ exchanger (NCX) current. HF increased APD, INa-late and NCX, but decreased ICa-L and Ito in RVOT cardiomyocytes. In contrast with this, HF decreased APD and ICa-L, but increased Ito and IKr-tail in LVOT cardiomyocytes. In conclusion, RVOT and LVOT cardiomyocytes had distinctive electrophysiological characteristics. HF differentially modulates action potential morphology and ionic currents in RVOT and LVOT cardiomyocytes.

Atrial fibrillation (AF) is the most common sustained arrhythmia. Both the incidence and prevalence of AF are increasing, and the burden of AF is becoming huge. Many innovative advances have emerged in the past decade for the diagnosis and management of AF, including a new scoring system for the prediction of stroke and bleeding events, the introduction of non-vitamin K antagonist oral anticoagulants and their special benefits in Asians, new rhythm- and rate-control concepts, optimal endpoints of rate control, upstream therapy, life-style modification to prevent AF recurrence, and new ablation techniques. The Taiwan Heart Rhythm Society and the Taiwan Society of Cardiology aimed to update the information and have appointed a jointed writing committee for new AF guidelines. The writing committee members comprehensively reviewed and summarized the literature, and completed the 2016 Guidelines of the Taiwan Heart Rhythm Society and the Taiwan Society of Cardiology for the Management of Atrial Fibrillation. This guideline presents the details of the updated recommendations, along with their background and rationale, focusing on data unique for Asians. The guidelines are not mandatory, and members of the writing committee fully realize that treatment of AF should be individualized. The physician's decision remains most important in AF management.

Background Gap junction (GJ) dysfunctions predispose cardiac tissues to various arrhythmias. Sinoatrial node (SAN) and pulmonary veins (PVs) are closely related atrial dysrhythmia. This study evaluated whether GJ modifications modulate SAN and PVs electrical activities. Methods Conventional microelectrodes were used to record action potentials in isolated rabbit SAN, PVs, and connected PV-SAN tissue preparations before and after heptanol (GJ inhibitor) and PQ1 (GJ enhancer) administration with and without isoproterenol. A whole-cell patch clamp was used to record the electrical activities before and after heptanol in single SAN and PV cardiomyocytes. Results Heptanol (1, 3, and 10μM) reduced the spontaneous beating rates of isolated SAN preparations but not PVs. Heptanol (10μM) decelerated the SAN leading rhythm in the PV-SAN preparations and induced PV burst firings without (3 of 6, 50%) and with (6 of 6, 100%) isoproterenol (1μM). Heptanol (10μM) also reduced the spontaneous beating rates in single SAN cardiomyocyte, but not PV cardiomyocyte, with a decreased pacemaker current. PQ1 (50 and 500nM) treatment did not change the spontaneous beating rates in isolated SAN and PV preparations. In the connected PV-SAN preparations, PQ1 (500nM) did not induce any PV firing even having additional isoproterenol treatment (1μM). Moreover, PQ1 (500nM) prevented heptanol-induced electrical changes in SAN and PVs preparations. Conclusion GJ dysfunction modulates SAN and PV electrical activity, which may contribute to atrial arrhythmogenesis. GJ enhancer has a therapeutic potential in SAN dysfunction and atrial arrhythmogenesis.

Eur J Clin Invest 2012 Abstract Backgroud Apelin, a potential agent for treating heart failure, has various ionic effects on ventricular myocytes. However, the effects of apelin on the atrium are not clear. The purpose of this study was to investigate the acute effects of apelin on the electrophysiological characteristics of atrial myocytes. Method Whole-cell patch-clamp techniques were used to investigate the action potential (AP) and ionic currents in isolated rabbit left atrial (LA) myocytes before and after the administration of apelin. Result Apelin reduced LA AP duration measured at 90%, 50% and 20% repolarization of the amplitude by 11 ± 3%, 24 ± 5%, 30 ± 7% at 1 nM (n = 11), and by 14 ± 4%, 36 ± 6% and 45 ± 5% at 10 nM (n = 11), but not at 0·1 nM. Apeline (0·1, 1, 10 nM) did not change the amplitude, or resting membrane potential in LA myocytes. Apelin (1 nM) increased sodium currents, ultra-rapid potassium currents and the reverse mode of sodium-calcium exchanger currents, but decreased late sodium currents and L-type calcium currents and did not change transient outward currents or inward rectifier potassium currents in LA myocytes. Conclusions Apelin significantly changed the atrial electrophysiology with a shortening of AP duration, which may be caused by its effects on multiple ionic currents.

Eur J Clin Invest 2012; Abstract Background Long QT syndrome (LQTS) is associated with a high incidence of atrial fibrillation (AF), but the underlying mechanisms are unclear. Pulmonary veins (PVs) play a critical role in AF genesis. Type 3 LQTS increases late sodium current (INa,L), which may increase PV arrhythmogenesis and AF. Therefore, this study examines PV arrhythmogenesis in anemonia sulcata toxin II (ATX-II)-induced type 3 LQTS and evaluates whether the INa,L inhibitor ranolazine can suppress PV arrhythmogenesis. Materials and methods Conventional microelectrodes were used to record the action potentials (AP) and contractility in isolated rabbit PV specimens before and after ATX-II administration with or without ranolazine. Results Anemonia sulcata toxin II (100 nM) increased the PV spontaneous rates from 2·0 ± 0·1 to 2·9 ± 0·2 Hz (n = 7), induced PV burst firing (100%) with the genesis of early afterdepolarization (EAD) (86%) and prolonged the AP duration. Ranolazine (0·1, 1 and 10 μM) dose dependently reduced the PV spontaneous rates from 2·5 ± 0·2 to 2·3 ± 0·2 Hz, 1·9 ± 0·2 and 1·5 ± 0·3 Hz (P

Ischaemia and reperfusion contribute to the genesis of AF (atrial fibrillation). PVs (pulmonary veins) and the atria are important foci for AF initiation and maintenance. However, the effect of ischaemia and reperfusion on PVs and the atria has not yet been fully elucidated. In the present study, conventional microelectrodes were used to record the APs (action potentials) in isolated rabbit PV, LA (left atrium) and RA (right atrium) specimens during hypoxia and reoxygenation, and pharmacological interventions. Hypoxia reduced the PV beating rates from 1.8±0.1 to 1.3±0.2 and 0.8±0.1 Hz at 30 and 60 min respectively (n=8, P

Effects of Ivabradine on Pulmonary Veins. Introduction: Ivabradine is a novel heart rate decreasing agent with selective and specific antagonist effects on the pacemaker current (If). The aim of this study was to investigate the pharmacological effects of ivabradine on the pulmonary vein (PV) cardiomyocytes. Methods and Results: Whole-cell patch-clamp techniques and the indo-1 fluorimetric ratio technique were used to investigate the characteristics of the If and intracellular calcium (Ca 2+i) in single isolated rabbit PV cardiomyocytes with pacemaker activity before and after an ivabradine administration (0.3, 3, 10, and 30 μM). Ivabradine (0.3, 3, 10, and 30 μM) concentration dependently decreased the spontaneous activity by 6 ± 3%, 32 ± 6%, 49 ± 5%, and 85 ± 4%, and decreased the If by 35 ± 8%, 47 ± 9%, 62 ± 5%, and 65 ± 7%, respectively, in PV cardiomyocytes. The decreased extent of the PV beating rate or If by the different concentrations of ivabradine correlated well with the baseline PV beating rates. The IC50 of the spontaneous activity and If induced by ivabradine were 9.5 and 3.5 μM, respectively. Moreover, ivabradine (30 μM, but not 3 μM) decreased the Ca 2+i transient in the PV cardiomyocytes and ivabradine (30 μM) decreased the L-type calcium current in the PV cardiomyocytes. Conclusion: Ivabradine decreased the Ifs and Ca 2+i transient in the PV cardiomyocytes, which may contribute to its inhibitory effects on the PV spontaneous activity. (J Cardiovasc Electrophysiol, Vol. 23, pp. 200-206, February 2012)

Background The CHADS 2 score (congestive heart failure, hypertension, age >75 years, diabetes, and previous stroke/transient ischemic attack) is used for the risk stratification of strokes in patients with atrial fibrillation (AF). Objective This study aimed to investigate the associations between the CHADS 2 score, atrial substrate, and outcome of catheter ablation in patients with paroxysmal AF. Methods A total of 247 paroxysmal AF patients who received catheter ablation were enrolled. The patients were divided into 3 groups according to their CHADS 2 score (group 1: score 0, group 2: score 1 to 2, and group 3: score 3 to 6). The bi-atrial substrate properties and outcome of catheter ablation were analyzed. Results The CHADS 2 scores in these 3 groups were 0 (group 1), 1.24 ± 0.48 (group 2), and 3.60 ± 0.83 (group 3), respectively. The left atrial voltage became lower (group 1 vs. 2 vs. 3=2.08 ± 0.73 mV vs. 1.80 ± 0.81 mV vs. 1.06 ± 0.69 mV) and the activation time longer (group 1 vs. 2 vs. 3=93.4 ± 17.7 ms vs. 101.9 ± 21.2 ms vs. 112.2 ± 21.7 ms), whereas the CHADS 2 score increased. During a follow-up of 17.3 ± 7.0 months, 23.1% of the study population suffered from recurrences. The recurrence rates of these 3 groups were 13.0% (group 1), 27.6% (group 2), and 45.9% (group 3), respectively. The groups of different CHADS 2 scores remained as the independent predictor of recurrence in the multivariate analysis. Conclusion A high CHADS 2 score was associated with different left atrial substrate properties and a poor outcome after catheter ablation of paroxysmal AF.

Omega-3 polyunsaturated fatty acids can modulate cardiac electrophysiology and reduce the genesis of atrial fibrillation. This study investigates the potential mechanisms through which eicosapentaenoic acid (EPA) reduces pulmonary vein (PV) arrhythmogenesis.Conventional microelectrodes were used to record the action potentials (APs), before and after the EPA (0.1 μM and 1.0 μM) administration with and without the presence of a nitric oxide (NO) synthase inhibitor (L-NAME, 100 μM) in isolated rabbit PV tissue preparations. Furthermore, indo-1 fluorimetric ratio technique was used to evaluate intracellular calcium in isolated single PV cardiomyocytes with or without incubation of EPA (1.0 μM, 30 min).EPA concentration-dependently reduced the PV spontaneous beating rate (P0.05). EPA (1.0 μM) also reduced the amplitude of delayed afterdepolarizations (P0.05). EPA hyperpolarized the maximal diastolic potential (MDP), shortened AP duration, increased AP amplitude (APA), and reduced diastolic tension and contractility. However, EPA in the presence of L-NAME or omega-9 fatty acids (oleic acid, 1.0 μM) did not have any effect on PV spontaneous activity, AP morphology, or contractile force. A linear regression shows that the decrease in PV spontaneous beating rates induced by EPA correlated well with the changes of MDP, APA, diastolic tension, and contractile force of PVs. In addition, intracellular Ca(2+) transient and sarcoplasmic reticulum Ca(2+) content were significantly more decreased in the EPA-treated cardiomyocytes than in control PV cardiomyocytes as observed by indo-1 fluorescence.EPA reduces PV arrhythmogenesis through the mechanoelectrical feedback generated by NO production.

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

The left atrial (LA) posterior wall has been demonstrated to have regional electrophysiological differences with a higher arrhythmogenic potential leading to atrial fibrillation (AF). However, the ionic characteristics and calcium regulation in the LA anterior and posterior myocytes have not been fully elucidated. The purpose of this study was to investigate the electrical characteristics of the LA anterior and posterior myocytes. Whole-cell patch-clamp techniques and the indo-1 fluorimetric ratio technique were used to investigate the characteristics of the ionic currents, action potentials, and intracellular calcium in single isolated rabbit myocytes in the LA anterior and posterior walls. The expression of the Na(+)-Ca(2+) exchanger (NCX) and ryanodine receptor (RyR) were evaluated by a Western blot. The LA posterior myocytes (n = 15) had a higher incidence (53 vs. 19%, P 0.05) of delayed afterdepolarizations than the LA anterior myocytes (n = 16). The LA posterior myocytes had larger sodium currents and late sodium currents, but smaller inward rectifier potassium currents than the LA anterior myocytes. The LA posterior myocytes had larger intracellular Ca(2+) transient and sarcoplasmic reticulum Ca(2+) contents as compared with the LA anterior myocytes. However, the NCX currents in the LA posterior myocytes were smaller than those in the LA anterior myocytes. The LA posterior myocytes had a smaller protein expression of NCX, but a larger protein expression of RyR than the LA anterior myocytes. In conclusion, LA posterior myocytes contain a high arrhythmogenic potential and distinctive electrophysiological characteristics, which may contribute to the pathophysiology of AF.

Objectives Sarcoplasmic reticulum Ca-ATPases (SERCA2a) plays an essential role in the Ca homeostasis and cardiac functions. Tumor necrosis factor-alpha (TNF-alpha) decreases the SERCA2a, which may underlie cardiac dysfunction during sepsis and heart failure. Because the promoter region of SERCA2a contains CpG islands, gene methylation should be critical in regulating SERCA2a. The present study was to evaluate whether TNF-alpha can modulate SERCA2a via enhancing methylation and to investigate the underlying mechanisms. Design Controlled laboratory experiment. Setting University research laboratory. Subjects HL-1 cardiomyocytes. Interventions TNF-alpha (1-50 ng/mL) was administered in HL-1 cardiomyocytes with and without co-administration of an NF-kappaB inhibitor (SN-50, 50 microg/mL), antioxidant agents (ascorbic acid, 100 microM, or coenzyme Q10, 10 microM), or methylation inhibitor (5-aza-2'-deoxycytidine, 0.1, 1 microM). Measurements and main results TNF-alpha (50 ng/mL) decreased the SERCA2a RNA and protein by quantitative polymerase chain reaction and immunoblot. Furthermore, TNF-alpha (50 ng/mL) increased the methylation in the SERCA2a promoter region, which was not influenced by the co-administration of SN-50, ascorbic acid, or coenzyme Q10, but was attenuated by 5-aza-2'-deoxycytidine (0.1 microM). Additionally, TNF-alpha (50 ng/mL) increased the expression of DNA methyltransferase 1. Conclusions TNF-alpha increased DNA methyltransferase levels, thus enhancing the methylation in the SERCA2a promoter region with a result of reducing SERCA2a. These findings suggest that inhibition of hypermethylation may be a novel treatment strategy for cardiac dysfunction.

INTRODUCTION: The relationship between the determining factors and beating rates of pulmonary vein (PV) pacemaker cardiomyocytes has not been fully elucidated. The purposes of this study were to compare the electrophysiological characteristics between PV fast and slow pacemaker cardiomyocytes. METHODS: Whole-cell patch clamp was used to investigate the action potentials, transient outward currents (I(to)), sustained outward potassium currents (I(Ksus)), rapid delayed rectifier potassium currents (I(Kr)), inward rectifier potassium current (I(K1)), pacemaker currents (I(f)), and transient inward currents in isolated rabbit PV single fast (> or =2.5 Hz) and slow (

Introduction: Pulmonary veins (PVs) are the most important focus for the generation of atrial fibrillation. The HMG-CoA reductase inhibitors (statins) can reduce the occurrence of atrial fibrillation. The purposes of this study were to evaluate whether statins may inhibit the PV arrhythmogenic activity to prevent atrial arrhythmias from PVs and to investigate the link between fluvastatin, nitric oxide synthase (NOS) activity, mechanical activity, and electrical activity. Methods: Conventional microelectrodes and Western blot were used to record the electrical activity, diastolic tension, contractility and expression of Akt, endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), and phosphorylated Akt and eNOS before and after the administration of fluvastatin in rabbit PVs or atria. Results: Fluvastatin decreased the PV spontaneous activity, diastolic tension, and contractility, but did not change the action potential duration or resting membrane potential. The effects of fluvastatin on the PV firing rate and diastolic tension were attenuated in the presence of L-NAME (100 μM), wortmannin (100 nM), and ODQ (3 μM). Fluvastatin (1 μM) increased the phosphorylated Akt and eNOS, but did not change the total Akt or eNOS in the PVs and atria. In contrast, fluvastatin (1 μM) decreased the total nNOS in the PVs and atria. Conclusions and implications: Fluvastatin produced nitric oxide through the PI3kinase/Akt pathway, thus reducing the PV vascular diastolic tension and PV spontaneous activity. These results may contribute to the beneficial effects of statins.

Background Hypokalemia and hyponatremia increase the occurrence of atrial fibrillation. Sinoatrial nodes (SANs) and pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation. Objective The purpose of this study was to evaluate whether electrolyte disturbances with low concentrations of potassium ([K + ]) or sodium ([Na + ]) modulate SAN and PV electrical activity and arrhythmogenesis, and to investigate potential underlying mechanisms. Methods Conventional microelectrodes were used to record electrical activity in rabbit SAN and PV tissue preparations before and after perfusion with different low [K + ] or [Na + ], interacting with the Na + –Ca 2+ exchanger inhibitor KB-R7943 (10 μΜ). Results Low [K + ] (3.5, 3, 2.5, and 2 mM) decreased beating rates in PV cardiomyocytes with genesis of delayed afterdepolarizations (DADs), burst firing, and increased diastolic tension. Low [K + ] (3.5, 3, 2.5, and 2 mM) also decreased SAN beating rates, with genesis of DADs. Low [Na + ] increased PV diastolic tension, DADs, and burst firing, which was attenuated in the co-superfusion with low [K + ] (2 mM). In contrast, low [Na + ] had little effect on SAN electrical activities. KB-R7943 (10 μΜ) reduced the occurrences of low [K + ] (2 mM)– or low [Na + ] (110 mM)–induced DAD and burst firing in both PVs and SANs. Conclusion Low [K + ] and low [Na + ] differentially modulate SAN and PV electrical properties. Low [K + ]– or low [Na + ]–induced slowing of SAN beating rate and genesis of PV burst firing may contribute to the high occurrence of atrial fibrillation during hypokalemia or hyponatremia.

Background Atrial fibrillation (AF) is the most common sustained arrhythmia, and pulmonary veins (PVs) play a critical role in triggering AF. Angiotensin (Ang)-(1-7) regulates calcium (Ca2+) homeostasis and also plays a critical role in cardiovascular pathophysiology. However, the role of Ang-(1-7) in PV arrhythmogenesis remains unclear. Materials and methods Conventional microelectrodes, whole-cell patch-clamp, and the Fluo-3 fluorimetric ratio technique were used to record ionic currents and intracellular Ca2+ in isolated rabbit PV preparations, and in single isolated PV cardiomyocytes, before and after administration of Ang-(1-7). Results Ang (1-7) concentration-dependently (0.1, 1, 10, and 100 nM) decreased PV spontaneous electrical activity. Ang-(1-7) (100 nM) decreased the late-sodium (Na+), L-type Ca2+, and Na+-Ca2+ exchanger currents, but did not affect the voltage-dependent Na+ current in PV cardiomyocytes. In addition, Ang-(1-7) decreased intracellular Ca2+ transient and sarcoplasmic reticulum Ca2+ content in PV cardiomyocytes. A779 (a Mas receptor blocker, 3 μM), L-NAME (a NO synthesis inhibitor, 100 μM) or wortmannin (a specific PI3K inhibitor, 10 nM) attenuated the effects of Ang-(1-7) (100 nM) on PV spontaneous electric activity. Conclusion Ang-(1-7) regulates PV electrophysiological characteristics and Ca2+ homeostasis via Mas/PI3K/eNOS signaling pathway. This article is protected by copyright. All rights reserved.

Non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of atrial fibrillation (AF). This study investigated whether selective and non-selective NSAIDs differentially regulate the arrhythmogenesis of pulmonary veins and atria.Conventional microelectrodes were used to record action potentials (APs) in isolated rabbit PVs, sinoatrial node (SAN), left atrium (LA), and right atrium (RA) preparations before and after celecoxib or indomethacin administration. A whole-cell patch clamp was used to record the sodium-calcium exchanger (NCX) current, L-type calcium current (ICa-L), and late sodium current (INa-late) before and after celecoxib administration in isolated PV cardiomyocytes.Celecoxib (0.3, 1, and 3 μM) reduced PV spontaneous beating rates, and induced delayed afterdepolarizations and burst firings in four of eight PV preparations (50%, p0.05). Celecoxib also reduced SAN beating rates and decreased AP durations (APDs) in RA and LA, but did not change the resting membrane potential. Indomethacin (0.3, 1, 3, and 10 μM) changed neither the PV or SAN beating rates nor RA APDs, but it reduced LA APDs. Celecoxib (3 μM) significantly increased the NCX current and decreased the ICa-L, but did not change the INa-late. Ranolazine (10 μM) suppressed celecoxib (3 μM)-induced PV burst firings in 6 (86%, p0.05) of 7 PVs. KB-R7943 (10 μM) suppressed celecoxib (3 μM)-induced PV burst firings in 5 (71%, p0.05) of 7 PVs.Selective and non-selective NSAIDs differentially modulate PV and atrial electrophysiological characteristics. Celecoxib increased PV triggered activity through enhancement of the NCX current, which contributed to its arrhythmogenesis.

Background Mechanisms and changes of electrophysiological (EP) characteristics in successful radiofrequency (RF) modification of right midseptal and posteroseptal areas for controlling rapid ventricular response to atrial fibrillation (Af) are not clear. Methods and Results We studied 50 patients with medically refractory paroxysmal Af. Group 1 consisted of 40 patients without dual atrioventricular (AV) node physiology with modification sites located in the mid/posteroseptal area. Of the 40 patients, 36 had successful modification (follow-up of 14±8 months), and 3 had AV block. Late follow-up electrophysiological study (98±10 days) showed pattern 1 (67%) with prolongation of AV node effective refractory period (ERP, ≥40 milliseconds) and Wenckebach block cycle length (WBCL, ≥40 milliseconds); pattern 2 (22%) with prolongation of AH interval (≥20 milliseconds), ERP, and WBCL; and pattern 3 (11%) without any change in AV node conduction parameter. Change in ventricular rate negatively correlated with change of WBCL in patterns 1 ( r =−.691, P =.019) and 2 ( r =−.90, P =.01). Group 2 consisted of 10 patients with dual AV node pathway; elimination of slow pathway property was performed. Late follow-up electrophysiological study (92±7 days) showed that change in ventricular rate negatively correlated with change in AV node ERP ( r =−.926, P =.0001) and WBCL ( r =−.969, P =.0001). Four patients without significant modification effect had success after RF energy was delivered to higher levels (follow-up, 15±7 months). Conclusions RF modification of right mid/posteroseptal area is feasible in 92% of patients with paroxysmal Af. Mechanisms of successful modification might be elimination of posterior input and/or partial injury of the compact node. Furthermore, simple elimination of slow pathway might be inadequate for control of ventricular rate in patients with little difference in conduction properties between fast and slow pathways.

Objectives. The purpose of this study was to study electrophysiologic characteristics and compare the electrophysiologically guided focal ablation technique and linear ablation technique in patients with common atrial flutter in a prospective randomized fashion. Background. Catheter ablation of the common atrial flutter circuit can be performed with different techniques. To date, these two techniques have not been compared prospectively in a randomized study. Methods. Sixty patients with drug-refractory common atrial flutter were randomly assigned to undergo radiofrequency catheter ablation performed with the electrophysiologically guided focal ablation (Group I) or linear ablation technique (Group II). In Group I, radiofrequency energy was delivered to the site characterized by concealed entrainment with a short stimulus-P wave interval (

Prediction of accessory pathway location before radio-frequency ablation has become increasingly important for patients with Wolff-Parkinson-White syndrome. However, existing electrocardiographic (ECG) criteria for localization of accessory pathways have several limitations, and the polarity of delta waves has not been well defined. In the present study, 369 patients with a single anterogradely conducting accessory pathway who underwent successful radiofrequency ablation were included. The polarity of delta waves was defined and categorized in detail, and various ECG characteristics of the most preexcited QRS complexes were examined and compared with QRS complexes after successful ablation in the initial 182 patients, which included morphology and polarity of delta waves, initial 20, 40, and 60 ms segments of the preexcited QRS complex, R/S ratio in the precordial leads, R/S ratio in the frontal leads, delta wave axis in the frontal plane, polarity of delta waves in the frontal leads, and polarity of delta waves in the precordial leads. The polarity of the initial 40 ms segment of the most preexcited QRS complexes in each of the frontal leads, and the polarity of the initial 60 ms segment of the most preexcited QRS complex in each of the precordial leads proved to be the best representatives of delta wave polarity in the respective leads.(ABSTRACT TRUNCATED AT 250 WORDS)

Apelin, a potential agent for treating heart failure, has various ionic effects on ventricular myocytes. However, the effects of apelin on the atrium are not clear. The purpose of this study was to investigate the acute effects of apelin on the electrophysiological characteristics of atrial myocytes.Whole-cell patch-clamp techniques were used to investigate the action potential (AP) and ionic currents in isolated rabbit left atrial (LA) myocytes before and after the administration of apelin.Apelin reduced LA AP duration measured at 90%, 50% and 20% repolarization of the amplitude by 11 ± 3%, 24 ± 5%, 30 ± 7% at 1 nM (n = 11), and by 14 ± 4%, 36 ± 6% and 45 ± 5% at 10 nM (n = 11), but not at 0·1 nM. Apeline (0·1, 1, 10 nM) did not change the amplitude, or resting membrane potential in LA myocytes. Apelin (1 nM) increased sodium currents, ultra-rapid potassium currents and the reverse mode of sodium-calcium exchanger currents, but decreased late sodium currents and L-type calcium currents and did not change transient outward currents or inward rectifier potassium currents in LA myocytes.Apelin significantly changed the atrial electrophysiology with a shortening of AP duration, which may be caused by its effects on multiple ionic currents.

Background— The characteristics of atrial electrograms associated with atrial fibrillation (AF) termination are controversial. We investigated the electrogram characteristics that indicate procedural AF termination during continuous complex fractionated electrogram ablation. Methods and Results— Fifty-two consecutive patients with persistent AF (47 men; aged 54±9 years), who underwent electrogram-based catheter ablation in the left atrium and coronary sinus after pulmonary vein isolation, were enrolled. The intracardiac bipolar atrial electrogram recordings were characterized by (1) fractionation interval (FI) analysis (>6 seconds), (2) kurtosis (shape of the FI histogram), and (3) skewness (asymmetry of the FI histogram). Sites showing complex, fractionated electrograms (mean FI ≤60 ms) were targeted, and AF was terminated in 20 patients (38%) after the pulmonary vein isolation. The conventional complex fractionated electrogram sites (mean ≤120 ms) in patients with AF termination exhibited higher median kurtosis (2.69 [interquartile range, 2.03–3.46] versus 2.35 [interquartile range, 1.79–2.48]; P =0.024) and higher complex fractionated electrogram-mean interval (102.7±19.8 versus 87.7±15.0; P =0.008) than patients without AF termination. Furthermore, AF termination sites had higher median kurtosis than targeted sites without AF termination (5.13 [interquartile range, 3.51–6.47] versus 4.18 [interquartile range, 2.91–5.34]; P P =0.007). Conclusions— A kurtosis analysis using the FI histogram may be a useful tool in identifying the critical substrate for persistent AF and potential responders to catheter ablation.

Long-Term Outcome of SVC AF Ablation. Introduction: Data of the long-term clinical outcome after superior vena cava (SVC) isolation are limited. We aimed to evaluate the long-term outcome in patients with atrial fibrillation (AF) who had triggers originating from the SVC and received catheter ablation of AF. Methods and Results: The study consisted of 68 patients (age 56 ± 12 years old, 32 males) who underwent the ablation procedure for drug-refractory, symptomatic paroxysmal AF originating from the SVC since 1999. Group 1 consisted of 37 patients with AF initiated from the SVC only, and group 2 consisted of 31 patients with both SVC and pulmonary vein (PV) triggers. During a follow-up period of 88 ± 50 months, the AF recurrence rate was 35.3% after a single procedure. The freedom-from-AF rates were 85.3% at 1 year and 73.3% at 5 years. In the baseline study, group 2 had larger left atrium (38 ± 4 mm vs 36 ± 5 mm, P = 0.04), left ventricle (50 ± 5 mm vs 46 ± 5 mm, P = 0.003), and PV diameters. Kaplan–Meier survival analysis showed a higher AF recurrence rate in group 2 compared to that in group 1 (P = 0.012). The independent predictor of an AF recurrence was a larger SVC diameter (P = 0.02, HR 1.4, 95% CI 1.1–1.8). Conclusion: Among the patients with paroxysmal AF originating from the SVC, 73% remained free of AF for 5 years after a single catheter ablation procedure. Superior vena cava isolation without PV isolation is an acceptable therapeutic strategy in those patients with AF originating from the SVC only. The SVC diameter was an independent predictor of AF recurrence. (J Cardiovasc Electrophysiol, Vol. 23, pp. 955-961, September 2012)

Long-Term Prognosis in Patients with ARVC. Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a major cause of sudden cardiac death due to tachyarrhythmias. The purpose of this study was to investigate the long-term prognosis in patients with ARVC and the incidence of rapid ventricular arrhythmias during follow-up. Methods: Thirty ARVC patients (19 male, 63.3%, mean age 48 ± 15 years) fulfilling modified Task Force criteria 2010 were included. Of them, 13 patients (43.3%) received implantable cardioverter-defibrillator (ICD) implantation. Rapid ventricular arrhythmia was defined as electrical storm or the occurrence of ventricular tachycardia (VT) or ventricular fibrillation (VF) with a cycle length of 240 ms or less that necessitate shock delivery to 2 or more times within a 24-hour period. Results: With a mean follow-up of 68 ± 10 months, 6 patients (20%) with ICD implantation had recurrent rapid VT/VF. One (3.3%) of them died of multiple shocks and SCD, and 5 (16.7%) had multiple ICD therapies due to VT/VF and electrical storm. The interval between the diagnosis of ARVC and occurrence of rapid VT/VF was 13.4 ± 4.9 months. Most (5/6, 83.3%) events of recurrent rapid VT/VF occurred within 2 years. Ablated patients who did not receive an ICD implant were totally free of rapid VT/VF. Conclusions: For patients with ARVC, long-term prognosis is favorable. During a long-term follow-up, patients meeting the criteria for ICD implantation have a higher rate of rapid and potentially life-threatening arrhythmias. However, early and clustered recurrence of rapid VT/VF in patients with an ICD is common, whereas late occurrence of rapid VT/VF is very rare. (J Cardiovasc Electrophysiol, Vol. 23, pp. 750-756, July 2012)

Long QT syndrome (LQTS) is associated with a high incidence of atrial fibrillation (AF), but the underlying mechanisms are unclear. Pulmonary veins (PVs) play a critical role in AF genesis. Type 3 LQTS increases late sodium current (I(Na,L) ), which may increase PV arrhythmogenesis and AF. Therefore, this study examines PV arrhythmogenesis in anemonia sulcata toxin II (ATX-II)-induced type 3 LQTS and evaluates whether the I(Na,L) inhibitor ranolazine can suppress PV arrhythmogenesis.Conventional microelectrodes were used to record the action potentials (AP) and contractility in isolated rabbit PV specimens before and after ATX-II administration with or without ranolazine.Anemonia sulcata toxin II (100 nM) increased the PV spontaneous rates from 2·0 ± 0·1 to 2·9 ± 0·2 Hz (n = 7), induced PV burst firing (100%) with the genesis of early afterdepolarization (EAD) (86%) and prolonged the AP duration. Ranolazine (0·1, 1 and 10 μM) dose dependently reduced the PV spontaneous rates from 2·5 ± 0·2 to 2·3 ± 0·2 Hz, 1·9 ± 0·2 and 1·5 ± 0·3 Hz (P0·05) and decreased the diastolic tension by 40 ± 19%, 87 ± 26% and 113 ± 28%. In the presence of ranolazine (10 μM), ATX-II (100 nM) further increased the AP duration. However, ATX-II neither increased the PV spontaneous rates (1·6 ± 0·1 vs. 1·7 ± 0·2 Hz, n = 7) nor induced PV burst firing or EAD. Moreover, ranolazine (10 μM) reduced ATX-II-induced PV acceleration and EAD.The I(Na,L) enhancer ATX-II can increase PV arrhythmogenesis, which can be attenuated or blocked by ranolazine. This suggests that AF may be related to type 3 LQTS through increased I(Na,L) .

BACKGROUND Catheter-induced mechanical trauma is unfavorable during electrophysiological study. However, its incidence, significance, and pharmacological responses in patients receiving radiofrequency ablation for supraventricular tachycardia have not been investigated. METHODS AND RESULTS A prospective study was performed in 666 consecutive patients with documented, symptomatic supraventricular tachycardia. All had been referred for electrophysiological study and radiofrequency ablation. Catheter-induced mechanical trauma was defined by either disappearance of or change in preexcitation pattern induced by the electrode catheters or noninducibility of tachycardia after the electrode catheter-induced termination of tachycardia, confirmed by electrophysiological study. Adenosine, isoproterenol, and atropine were serially administered 1 hour after the mechanical trauma to study pharmacological response. "Rescue" radiofrequency ablation was defined as delivery of radiofrequency energy just at the presumed ablation site immediately after the mechanical trauma. Of the 666 patients, 254 had atrioventricular (AV) nodal reentrant tachycardia, 367 patients had accessory pathways, 30 patients had atrial tachycardia, and 15 had atrial flutter. Catheter-induced mechanical trauma occurred in 17 patients (2.6%): 4 patients had AV nodal reentrant tachycardia, 9 had accessory pathways, and 4 had atrial tachycardia. Five patients had such episodes during the placement of electrode catheters and 12, during mapping and ablation procedures. Of the 4 patients with AV nodal reentrant tachycardia, 3 had mechanical trauma on the retrograde fast pathway and 1, on the antegrade slow pathway. In the 9 patients with accessory pathways, those pathways were located in the left free wall in 4 patients, right free wall in 1, right posteroseptum in 1, and right anteroseptum in 3. Atrial tachycardia was more easily traumatized than AV nodal reentrant tachycardia (P < .01) and than accessory pathways (P < .01). The clinical courses of mechanical trauma were variable: 1 patient had spontaneous recovery within 1 week, 5 patients had recurrence of tachycardia within 3 months, and the rest have been free of tachycardia from 3 to 35 months. The recurrence rate was higher in patients with mechanical trauma than in those without (33.3% versus 3.5%, P < .0001) despite rescue radiofrequency ablation given in 7 patients. Pharmacological agents were generally unable to revive the traumatized tissues, and recurrence was unpredictable. CONCLUSIONS Catheter-induced mechanical trauma was not common in patients receiving radiofrequency ablation for supraventricular tachycardia. Their clinical courses were variable, and pharmacological manipulation offered little assistance. More than half of the patients had long-term cures. However, the recurrence rate was, on the whole, significantly high despite rescue radiofrequency ablation. There is a need for great caution in the placement of electrode catheters in every patient during electrophysiological study and radiofrequency ablation.

Objectives. This study was designed to evaluate the clinical features, electrophysiologic characteristics and results of radio-frequency ablation in elderly patients with accessory atrioventricular (AV) pathways or AV node reentrant tachycardia. Background. Radiofrequency ablation in elderly patients with paroxysmal supraventricular tachycardia has not been well described, and comparative study between elderly and younger patients is limited. Methods. Electrophysiologic studies and radiofrequency ablation were performed in 92 elderly patients (45 with an accessory pathway, 47 with AV node reentrant tachycardia). Results. The elderly patients had poorer electrophysiologic properties in accessory pathways and dual AV node pathways than those of younger patients. The success rate of radiofrequency ablation was similar in elderly and younger patients. However, elderly patients had more complications (14%) in left-sided accessory pathways. Conclusions. Radiofrequency ablation in elderly patients with supraventricular tachycardia was effective. However, it must be performed cautiously in those patients with left-sided accessory pathways.

Reverse alternating Wenckebach periods (RAWP) have rarely been described, and the significance of dual AV nodal pathways in atrial pacing-induced RAWP is unknown. Forty-five of 50 consecutive patients (M/F=23/27, mean age 40±5 years) with common type AV nodal reentrant tachycardia had discontinuous antegrade conduction curves. Atrial pacing revealed that pattern A RAWP (23 patients) had the fourth paced beat conducted over the fast pathway, and pattern B (18 patients) over the slow pathway. Four patients had both pattern A and B RAWP during different pacing cycle lengths. All episodes of atrial pacing-induced RAWP emerged from (or started as) 3:2 AH block, which thereafter were followed by runs of 2:1 AH block. Comparisons between patterns A and B showed (1) maximal atrial pacing cycle length with RAWP was longer in pattern A; (2) A2H2-A1H1 and A4H4-A1H1 were significantly greater in pattern B; (3) A2H2-A4H4 and H2A4/A2H2 were significantly greater in pattern A.It is concluded that atrial pacing-induced RAWP is a common electrophysiologic phenomenon in patients with dual AV nodal pathways. Furthermore, intermittent slow pathway conduction associated with different AnHn and HnAn+2 parameters helped the interpretation of different conduction patterns.

Ivabradine is a novel heart rate decreasing agent with selective and specific antagonist effects on the pacemaker current (I(f)). The aim of this study was to investigate the pharmacological effects of ivabradine on the pulmonary vein (PV) cardiomyocytes.Whole-cell patch-clamp techniques and the indo-1 fluorimetric ratio technique were used to investigate the characteristics of the I(f) and intracellular calcium (Ca(2+)(i)) in single isolated rabbit PV cardiomyocytes with pacemaker activity before and after an ivabradine administration (0.3, 3, 10, and 30 μM). Ivabradine (0.3, 3, 10, and 30 μM) concentration dependently decreased the spontaneous activity by 6 ± 3%, 32 ± 6%, 49 ± 5%, and 85 ± 4%, and decreased the I(f) by 35 ± 8%, 47 ± 9%, 62 ± 5%, and 65 ± 7%, respectively, in PV cardiomyocytes. The decreased extent of the PV beating rate or I(f) by the different concentrations of ivabradine correlated well with the baseline PV beating rates. The IC(50) of the spontaneous activity and I(f) induced by ivabradine were 9.5 and 3.5 μM, respectively. Moreover, ivabradine (30 μM, but not 3 μM) decreased the Ca(2+)(i) transient in the PV cardiomyocytes and ivabradine (30 μM) decreased the L-type calcium current in the PV cardiomyocytes.Ivabradine decreased the I(f)s and Ca(2+)(i) transient in the PV cardiomyocytes, which may contribute to its inhibitory effects on the PV spontaneous activity.

Atrial Substrate Properties in Chronic AF Patients with LASEC. Background: The atrial substrate in chronic atrial fibrillation (AF) patients with a left atrial spontaneous echo contrast (LASEC) has not been previously reported. The aim of this study was to investigate the atrial substrate properties and long-term follow-up results in the patients who received catheter ablation of chronic AF. Methods: Of 36 consecutive patients with chronic AF who received a stepwise ablation approach, 18 patients with an LASEC (group I) were compared with 18 age-gender-left atrial volume matched patients without an LASEC (group II). The atrial substrate properties including the weighted peak-to-peak voltage, total activation time during sinus rhythm (SR), dominant frequency (DF), and complex fractionated electrograms (CFEs) during AF in the bi-atria were evaluated. Result: The left atrial weighted bipolar peak-to-peak voltage (1.0 ± 0.6 vs 1.6 ± 0.7 mV, P = 0.04), total activation time (119 ± 20 vs 103 ± 13 ms, P < 0.001) and DF (7.3 ± 1.3 vs 6.6 ± 0.7 Hz, P < 0.001) differed between group I and group II, respectively. Those parameters did not differ in the right atrium. The bi-atrial CFEs (left atrium: 89 ± 24 vs 92 ± 25, P = 0.8; right atrium: 92 ± 25 vs 102 ± 3, P = 0.9) did not differ between group I and group II, respectively. After a mean follow-up of 30 ± 13 month, there were significant differences in the antiarrhythmic drugs (1.1 ± 0.3 vs 0.7 ± 0.5, P = 0.02) needed after ablation, and recurrence as persistent AF (92% vs 50%, P = 0.03) between group I and group II, respectively. After multiple procedures, there were more group II patients that remained in SR, when compared with group I (78% vs 44%, P = 0.04). Conclusion: There was a poorer atrial substrate, lesser SR maintenance after catheter ablation and need for more antiarrhythmic drugs in the chronic AF patients with an LASEC when compared with those without an LASEC. (J Cardiovasc Electrophysiol, Vol. pp. 1-8)

Sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a) plays an essential role in Ca(2+) homeostasis and cardiac functions. The promoter region of SERCA2a has a high content of CpG islands; thus, epigenetic modification by inhibiting methylation can enhance SERCA2a expression in cardiomyocytes. Hydralazine, a drug frequently used in heart failure, is a potential DNA methylation inhibitor. We evaluated whether hydralazine can modulate Ca(2+) handling through an increase in SERCA2a expression via regulating methylation. We used indo-1 fluorescence, real-time RT-PCR, immunoblotting, and methylation-specific PCR to investigate intracellular Ca(2+), the expressions of RNA and protein, and methylation of SERCA2a in HL-1 cardiomyocytes with and without (control) the administration of hydralazine (1, 10, and 30 μM) for 72 h. Hydralazine (10 and 30 μM) increased the intracellular Ca(2+) transients and SR Ca(2+) contents. Hydralazine (10 and 30 μM) decreased methylation in the SERCA2a promoter region and increased the RNA and protein expressions of SERCA2a. Additionally, hydralazine (10 and 30 μM) decreased the expression of DNA methyltransferase 1. Moreover, treatment with hydralazine in isoproterenol-induced heart failure rats decreased the promoter methylation of SERCA2a and increased SERCA2a RNA expression. In conclusion, hydralazine-induced promoter demethylation may improve cardiac function through increasing SERCA2a and modulating calcium homeostasis in cardiomyocytes.

A total of 408 patients received radiofrequency catheter ablation for paroxysmal supraventricular tachycardia, and 326 patients underwent serial follow-up electrophysiologic studies (early and late) after initially successful radiofrequency catheter ablation of accessory pathways (group 1, 186 patients with Wolff-Parkinson-White syndrome) and slow atrioventricular (AV) nodal pathways (group 2, 140 patients with AV nodal reentrant tachycardia). Among the patients in group 1, early (4 +/- 1 days) and late (129 +/- 14 days) studies found recurrent conduction through the accessory pathways in 12 and 16 patients, respectively. During a follow-up period of 21 +/- 7 months, recurrence of accessory pathway-mediated tachyarrhythmias was noted in six patients. Of these six patients, all had tachycardia inducible in the late study but not in the early study. Among the patients in group 2, four had recurrence of AV nodal reentrant tachycardia during a follow-up of 16 +/- 6 months. Of the four patients, one had tachycardia inducible in the early (4 +/- 1 days) study and three in the late (130 +/- 12 days) study. The results demonstrated that the early study was not as sensitive as the late follow-up electrophysiologic study in predicting late outcome of radiofrequency ablation, but both the early and late studies had a high total predictive accuracy (90%) in groups 1 and 2. Furthermore, only 4 of the 326 patients had initial evidence of recurrent tachycardia activated by programmed electrical stimuli during follow-up studies, suggesting that follow-up electrophysiologic studies in asymptomatic patients are not warranted.

Effect of Heat Stress on Pulmonary Vein Cardiomyocytes. Introduction: Heat stress-induced responses reduce the occurrence of atrial fibrillation (AF). Pulmonary vein (PV) cardiomyocytes with pacemaker activity play a critical role in the pathophysiology of AF. In this study, we examined whether heat-stress responses alter the electrophysiological characteristics of PV cardiomyocytes and protect the PV against angiotensin II- or isoproterenol-induced arrhythmogenesis. Methods and Results: We used whole-cell patch clamp techniques to investigate the spontaneous activity and ionic currents in single isolated rabbit PV pacemaker cardiomyocytes with or without (control) exposure to heat stress (43°C, 15 minutes) 5 ± 1 hours before the experiments. Compared to control cardiomyocytes, heat-stressed PV cardiomyocytes had slower beating rates. Heat-stressed PV cardiomyocytes had larger L-type calcium currents, transient outward currents, smaller inward rectifier potassium currents, but similar sodium-calcium exchanger currents. Additionally, heat-stressed PV cardiomyocytes had a lower incidence of pacemaker currents than control PV cardiomyocytes. Moreover, isoproterenol increased the beating rate of control cardiomyocytes but not heat-stressed PV cardiomyocytes. Similarly, angiotensin II also increased the beating rate of control cardiomyocytes, but not heat-stressed PV cardiomyocytes, in association with decreased expression of the angiotensin II type 1 receptor. Conclusion: Heat-stress responses altered the electrophysiological characteristics of PV cardiomyocytes and attenuated the effects of isoproterenol and angiotensin II on PV arrhythmogenesis, which may play a role in the protective potential of heat-stress responses. (J Cardiovasc Electrophysiol, Vol. 22, pp. 183-190, February 2011)

Background: Oxidative stress and pulmonary veins (PVs) play critical roles in the pathophysiology of atrial fibrillation. The purpose of the present study was to investigate whether oxidative stress and antioxidant agents can change the electrophysiological characteristics of the left atrium (LA) and PVs. Methods and Results: Conventional microelectrodes were used to record the action potentials (APs) in isolated rabbit PV and LA specimens before and after H2O2 administration with or without ascorbic acid or N-mercaptopropionyl-glycine (N-MPG, a free radical ·OH scavenger). H2O2 (0.02 and 0.2 mmol/L) decreased the PV spontaneous rates from 2.0±0.1 Hz to 1.6±0.1 Hz, and 1.7±0.1 Hz (n=10, P

Heat stress-induced responses change the ionic currents and calcium homeostasis. However, the molecular insights into the heat stress responses on calcium homeostasis remain unclear. The purposes of this study were to examine the mechanisms of heat stress responses on calcium handling and electrophysiological characteristics in atrial myocytes. We used indo-1 fluorimetric ratio technique and whole-cell patch clamp to investigate the intracellular calcium, action potentials, and ionic currents in isolated rabbit single atrial cardiomyocytes with or without (control) exposure to heat stress (43 °C, 15 min) 5 ± 1 h before experiments. The expressions of sarcoplasmic reticulum ATPase (SERCA2a), and Na+–Ca2+ exchanger (NCX) in the control and heat stress-treated atrial myocytes were evaluated by Western blot and real-time PCR. As compared with control myocytes, the heat stress-treated myocytes had larger sarcoplasmic reticulum calcium content and larger intracellular calcium transient with a shorter decay portion. Heat stress-treated myocytes also had larger L-type calcium currents, transient outward potassium currents, but smaller NCX currents. Heat stress responses increased the protein expressions, SERCA2a, NCX, and heat shock protein. However, heat stress responses did not change the RNA expression of SERCA2a and NCX. In conclusion, heat stress responses change calcium handling through protein but not RNA regulation.

1. Pulmonary veins are the most important focus for the initiation of atrial fibrillation. Diabetes mellitus may be associated with hypertonicity and increased occurrence of atrial fibrillation. 2. The purpose of the present study was to investigate whether hypertonicity alters the electrophysiological characteristics of pulmonary veins and atria to enhance the genesis of atrial fibrillation. 3. A whole-cell patch-clamp technique was used to investigate action potentials and ionic currents in rabbit isolated single pulmonary vein and atrial cardiomyocytes during immersion in isotonic and hypertonic (1.2x normal osmolality) solutions. 4. Hypertonicity increased the spontaneous beating rates of pulmonary vein cardiomyocytes from 2.3 +/- 0.3 to 3.4 +/- 0.3 Hz (n = 11; P < 0.001). Hypertonicity prolonged action potential duration to a greater extent in atrial cardiomyocytes than in pulmonary vein cardiomyocytes. Compared with atrial cardiomyocytes, hypertonicity increased the transient inward currents and Na(+)/Ca(2+) exchange currents to a greater extent in pulmonary vein cardiomyocytes, but decreased the delayed rectified potassium currents to a lesser extent. 5. Hypertonicity plays an important role in the electrical activity of pulmonary vein and atrial cardiomyocytes, which may have a potential role in the pathophysiology of atrial fibrillation.

Pulmonary veins (PVs) contain cardiomyocytes with spontaneous activity that may be responsible for PV arrhythmia. Abnormal Ca(2+) 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 Ca(2+) ([Ca(2+)](i)) transients, Ca(2+) 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 [Ca(2+)](i) transients and Ca(2+) sparks in isolated rabbit PV and LA cardiomyocytes. PV cardiomyocytes with spontaneous activity had larger [Ca(2+)](i) transients and sarcoplasmic reticulum (SR) Ca(2+) stores than PV cardiomyocytes without spontaneous activity or LA cardiomyocytes. PV cardiomyocytes with spontaneous activity also had a higher incidence and frequency of Ca(2+) sparks, and had Ca(2+) sparks with larger amplitudes than other cardiomyocytes. Magnesium (5.4 mM) reduced the [Ca(2+)](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 [Ca(2+)](i) transients amplitude in PV cardiomyocytes with spontaneous activity. FK506 (1 microM) diminished the SR Ca(2+) stores in PV cardiomyocytes with spontaneous activity to a lesser extent than that in other cardiomyocytes. Isoproterenol (10 nM) increased the [Ca(2+)](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 [Ca(2+)](i) transients, increased Ca(2+) sparks and SR Ca(2+) stores may contribute to the spontaneous activity of PV cardiomyocytes.

Objective Endothelin-1 has important cardiovascular effects and is activated during atrial fibrillation. Pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation. The aim of this study was to evaluate whether endothelin-1 affects PV arrhythmogenic activity. Methods Conventional microelectrodes were used to record the action potentials (APs) and contractility in isolated rabbit PV tissue specimens before and after the administration of endothelin-1 (0.1, 1, 10 nM). The ionic currents of isolated PV cardiomyocytes were investigated before and after the administration of endothelin-1 (10 nM) through whole-cell patch clamps. Results In the tissue preparation, endothelin-1 (1, 10 nM) concentration dependently shortened the AP duration and decreased the PV firing rates. Endothelin-1 (10 nM) decreased the resting membrane potential. Endothelin-1 (0.1, 1, 10 nM) decreased the contractility and increased the resting diastolic tension. In single PV cardiomyocytes, endothelin-1 (10 nM) decreased the PV firing rates from 2.7 +/- 1.0 Hz to 0.8 +/- 0.5 Hz (n = 16). BQ-485 (100 microM, endothelin-1 type A receptor blocker) reversed and prevented the chrono-inhibitory effects of endothelin-1 (10 nM). Endothelin-1 (10 nM) reduced the L-type calcium currents, transient outward currents, delayed rectifier currents, transient inward currents, and sodium-calcium exchanger currents in the PV cardiomyocytes with and without pacemaker activity. Endothelin-1 (10 nM) increased the inward rectifier potassium current, hyperpolarization-induced pacemaker current, and the sustained outward potassium current in PV cardiomyocytes with and without pacemaker activity. Conclusion Endothelin-1 may have an antiarrhythmic potential through its direct electrophysiological effects on the PV cardiomyocytes and its action on multiple ionic currents.