Cheng I. Lin

Effects of thyroid hormone on the arrhythmogenic activity of pulmonary vein cardiomyocytes

OBJECTIVES This study was conducted to investigate the effects of thyroid hormone on the electrophysiological characteristics of pulmonary vein (PV) cardiomyocytes. BACKGROUND Hyperthyroidism is an important etiology of paroxysmal atrial fibrillation (AF). Pulmonary veins are known to initiate paroxysmal AF. METHODS The action potential and ionic currents were investigated in single rabbit PV and atrial cardiomyocytes with (hyperthyroid) and without (control) incubation of L-triiodothyronine using the whole-cell clamp technique. RESULTS Compared with the control cardiomyocytes, hyperthyroid PV and atrial cardiomyocytes had shorter action potential duration. Hyperthyroid PV cardiomyocytes had faster beating rates (1.82 +/- 0.13 Hz vs. 1.03 +/- 0.15 Hz, p < 0.005) and a higher incidence of delayed after depolarization (beating: 92% vs. 6%, p < 0.0001; non-beating: 45% vs. 3%, p < 0.005). However, only hyperthyroid PV beating cardiomyocytes had a higher incidence of early after depolarization (46% vs. 0%, p < 0.0001). The ionic current experiments showed that hyperthyroid PV beating cardiomyocytes had larger densities of overall slow inward (2.72 +/- 0.21 pA/pF vs. 2.07 +/- 0.19 pA/pF, p < 0.05), overall transient outward (1.39 +/- 0.21 pA/pF vs. 0.48 +/- 0.08 pA/pF, p < 0.001) and steady state outward currents (0.78 +/- 0.06 pA/pF vs. 0.58 +/- 0.04 pA/pF, p < 0.05) on depolarization and larger transient inward (0.021 +/- 0.004 pA/pF vs. 0.005 +/- 0.001 pA/pF, p < 0.001) on repolarization. By contrast, the hyperthyroid PV non-beating cardiomyocytes had larger densities of overall transient outward (1.01 +/- 0.14 pA/pF vs. 0.37 +/- 0.07 pA/pF, p < 0.001), steady state outward (0.61 +/- 0.06 pA/pF vs. 0.44 +/- 0.04 pA/pF, p < 0.05) and transient inward currents (0.011 +/- 0.002 pA/pF vs. 0.003 +/- 0.001 pA/pF, p < 0.05). CONCLUSIONS Thyroid hormone changes the electrophysiological activity of the PV cardiomyocytes. Increased automaticity and enhanced triggered activity may increase the arrhythmogenic activity of PVs in hyperthyroidism.

Electrophysiology of single cardiomyocytes isolated from rabbit pulmonary veins: implication in initiation of focal atrial fibrillation.

Abstract Pulmonary veins (PVs) are important foci in initiation of paroxysmal atrial fibrillation. However, the mechanisms of the high arrhythmogenic activity of PVs are unclear. This study aimed to isolate single cardiomyocytes from PVs and evaluate their electrophysiological characteristics and arrhythmogenic potential. Cardiomyocytes of rabbit PVs were isolated by retrograde perfusion with digestive enzymes from aorta via left ventricle and left atrium. The action potentials and ionic currents were investigated in isolated single PV cardiomyocytes using the whole-cell clamp technique. Dissociation of PVs yielded single pacemaker cardiomyocytes (76 %) and non-pacemaker cardiomyocytes with a fast response action potential. Both the pacemaker and non-pacemaker cardiomyocytes had similar inward Ca2+ currents and transient outward K+ currents. However, the pacemaker cardiomyocytes had a smaller inward rectifier K+ current (1.50 ± 0.22 versus 4.21 ± 1.15 pA/pF, P < 0.005) and a larger delayed rectifier K+ current (0.60 ± 0.05 versus 0.24 ± 0.05 pA/pF, P < 0.005) than non-pacemaker cardiomyocytes. Acetylcholine induced hyperpolarization and inhibited the spontaneous action potential. Isoproterenol (10 nM) accelerated the spontaneous activity and induced early or delayed afterdepolarization, which could be suppressed by nifedipine. The PV cardiomyocytes with early afterdepolarization have a greater prolongation of action potential duration (ΔAPD, + 67 ± 17 versus −109 ± 20 ms, P < 0.0001) and a greater increase of inward Ca2+ current (0.90 ± 0.23 versus 0.38 ± 0.08 pA/pF, P < 0.05) after isoproterenol than those without early afterdepolarization. These findings suggest that PV cardiomyocytes have distinct action potentials and ionic current profiles, which may be responsible for the high arrhythmogenic activity of the PVs.

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

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

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

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

Hypoxia and reoxygenation modulate the arrhythmogenic activity of the pulmonary vein and atrium.

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<0.005), and induced EAD (early after depolarization) in three (37.5%) of the PVs and DAD (delayed after depolarization) in one (12.5%) of the PVs. Reoxygenation increased the PV spontaneous rate to 1.4±0.2 Hz (P<0.05) and induced PV burst firings (3.5±0.1 Hz, P<0.001) in six (75%) of the PVs. Hypoxia shortened the AP duration in the LA and PVs, but not in the RA. Pretreatment with glibenclamide attenuated hypoxia-induced decreases in the PV spontaneous activity and the shortening of the LA and PV AP duration. Similar to those in hypoxia, the K(ATP) (ATP-sensitive potassium) channel opener pinacidil (30 μM) decreased PV spontaneous activity and shortened the AP duration. Pretreatment with 5 mM N-MPG [N-(mercaptopropionyl)glycine; a hydroxyl (•OH) free-radical scavenger] or 300 μM chloramphenicol [a cytochrome P450 inhibitor that reduces ROS (reactive oxygen species)] attenuated the rate changes induced by hypoxia and reoxygenation, and also decreased the burst firing incidence. In conclusion, hypoxia and reoxygenation significantly increased PV arrhythmogenesis and induced different electrophysiological responses in the RA and LA, which may play a role in the pathophysiology of AF.

Pathophysiology of the pulmonary vein as an atrial fibrillation initiator: From bench to clinic

The basic electrophysiologic studies have proved the arrhythmogenic mechanisms of the pulmonary vein as an atrial fibrillation initiator; the mechanisms include enhanced automaticity, triggered activity, and microreentry from myocardial sleeves inside pulmonary veins. Immunohistology study has proved the conduction characteristics of pulmonary vein myocardium, and further study of ionic currents are important for understanding atrial fibrillation initiation from the pulmonary vein. (PACE 2003; 26[Pt. II]:1576–1582)

Heart failure enhances arrhythmogenesis in pulmonary veins

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

Temperature regulates the arrhythmogenic activity of pulmonary vein cardiomyocytes.

Temperature plays an important role in the electrophysiology of cardiomyocytes. Pulmonary veins (PVs) are known to initiate paroxysmal atrial fibrillation. The effects of temperature on the arrhythmogenic activity of rabbit single PV and atrial cardiomyocytes were assessed using the whole-cell clamp technique. PV cardiomyocytes had different beating rates at low (22-25 degrees C), normal (38-39 degrees C) and high (40-41 degrees C) temperatures (0.9 +/- 0.1, 3.2 +/- 0.4, 6.4 +/- 0.6 Hz, respectively; p < 0.001). There were different action potential durations and incidences of delayed afterdepolarization in PV cardiomyocytes with pacemaker activity (31, 59, 63%; p < 0.05), PV cardiomyocytes without pacemaker activity (16, 47, 60%; p < 0.001), and atrial myocytes (0, 0, 21%; p < 0.05). However, oscillatory afterpotentials were only found in PV cardiomyocytes with pacemaker activity at normal (50%) or high (68%) temperatures, but not at low temperatures (p < 0.001). Both PV and atrial cardiomyocytes had larger transient inward currents and inward rectified currents at high temperatures. Additionally, PV cardiomyocytes with and without pacemaker activity had larger pacemaker currents at higher temperatures. This study demonstrated that PV cardiomyocytes have an increase in arrhythmogenic activity at high temperatures because of enhanced automaticity, induced triggered activity, or shortening of action potential duration.

Controversies in the Mechanisms and Ablation of Pulmonary Vein Atrial Fibrillation

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

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

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