Yao Chang Chen

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 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.

Mechanoelectrical feedback regulates the arrhythmogenic activity of pulmonary veins

Background: Atrial fibrillation is commonly associated with dilated pulmonary veins. Stretch has been shown to have mechano-electrical effects. Objective: To investigate whether stretch can increase the arrhythmogenic activity of the pulmonary veins. Methods: The transmembrane action potentials were recorded from rabbit pulmonary veins before and after stretch (100 and 300 mg). Gadolinium and streptomycin (stretch-activated ion channel blockers) were each perfused into the pulmonary veins under a 300-mg stretch. Results: Stretch (0, 100 and 300 mg) force dependently increased the incidence of spontaneous activity (22%, 48% and 83%; p<0.05), mean (standard deviation (SD)) firing rates of spontaneous activity (1.7 (0.2), 2.1 (0.3) and 3 (0.2) Hz; p<0.05) and incidence of early post-depolarisations (9%, 26% and 61%; p<0.05) and delayed post-depolarisations (0%, 4% and 30%; p<0.05) in 23 pulmonary veins. In the seven preparations with spontaneous activity after the 300-mg stretch, gadolinium (1, 3 and 10 μmol/l) decreased the incidence of spontaneous activity by 43%, 29% and 14%, respectively (p<0.05), and decreased the firing rate from 2.9 (0.1) Hz to 0.8 (0.4), 0.3 (0.1) and 0.1 (0.1) Hz, respectively (p<0.05). Streptomycin (10 and 40 μmol/l) decreased the incidence of spontaneous activity by 71% and 29%, respectively (p<0.05), and decreased the firing rate from 2.9 (0.1) Hz to 1.6 (0.4) and 0.5 (0.3) Hz, respectively (p<0.05). Conclusion: Stretch is an important factor in the electrical activity of the pulmonary vein. Stretch-induced arrhythmogenic activity of the pulmonary vein may contribute to the genesis of atrial fibrillation.

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.

Tumor necrosis factor-α decreases sarcoplasmic reticulum Ca2+-ATPase expressions via the promoter methylation in cardiomyocytes

Objectives:Sarcoplasmic reticulum Ca2+-ATPases (SERCA2a) plays an essential role in the Ca2+ homeostasis and cardiac functions. Tumor necrosis factor-&agr; (TNF-&agr;) 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-&agr; 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-&agr; (1-50 ng/mL) was administered in HL-1 cardiomyocytes with and without co-administration of an NF-&kgr;B inhibitor (SN-50, 50 &mgr;g/mL), antioxidant agents (ascorbic acid, 100 &mgr;M, or coenzyme Q10, 10 &mgr;M), or methylation inhibitor (5-aza-2′-deoxycytidine, 0.1, 1 &mgr;M). Measurements and Main Results:TNF-&agr; (50 ng/mL) decreased the SERCA2a RNA and protein by quantitative polymerase chain reaction and immunoblot. Furthermore, TNF-&agr; (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 &mgr;M). Additionally, TNF-&agr; (50 ng/mL) increased the expression of DNA methyltransferase 1. Conclusions:TNF-&agr; 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.

T-Type Calcium Current in Electrical Activity of Cardiomyocytes Isolated from Rabbit Pulmonary Vein

Introduction: Pulmonary veins (PVs) are known to initiate paroxysmal atrial fibrillation. T‐type calcium current (ICa‐T) has a role in normal and abnormal automaticity of cardiomyocytes. The aim of this study was to evaluate whether ICa‐T contributes to PV electrical activity.

Heterogeneous expression of potassium currents and pacemaker currents potentially regulates arrhythmogenesis of pulmonary vein cardiomyocytes.

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.

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.

Electromechanical Effects of 1,25‐Dihydroxyvitamin D with Antiatrial Fibrillation Activities

Treatment with 1,25‐dihydroxyvitamin D (1,25[OH]2D) has several cardiovascular benefits. 1,25[OH]2D has direct cellular effects, but its effects on the atrium are not clear. We evaluated the effects of 1,25[OH]2D on the atrial electrophysiology and atrial fibrillation (AF).

Oxidative stress and inflammation modulate peroxisome proliferator-activated receptors with regional discrepancy in diabetic heart.

Eur J Clin Invest 2010; 40 (8): 692–699