Yung Kuo Lin

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.

Heart failure epicardial fat increases atrial arrhythmogenesis

BACKGROUND Obesity is an important risk factor for atrial fibrillation (AF) and heart failure (HF). The effects of epicardial fat on atrial electrophysiology were not clear. This study was to evaluate whether HF may modulate the effects of epicardial fat on atrial electrophysiology. METHODS Conventional microelectrodes recording was used to record the action potential in left (LA) and right (RA) atria of healthy (control) rabbits before and after application of epicardial fat from control or HF (ventricular pacing of 360-400 bpm for 4 weeks) rabbits. Adipokine profiles were checked in epicardial fat of control and HF rabbits. RESULTS The LA 90% of AP duration was prolonged by control epicardial fat (from 77 ± 6 to 87 ± 7 ms, p<0.05, n=7), and by HF epicardial fat (from 78 ± 3 to 98 ± 4 ms, p<0.001, n=9). However, control or HF epicardial fat did not change the AP morphology in RA. HF epicardial fat increased the contractility in LA (61 ± 11 vs. 35 ± 6 mg, p=0.001), but not in RA. Control fat did not change the LA or RA contractility. Moreover, control and HF epicardial fat induced early and delayed afterdepolarizations in LA and RA, but only HF epicardial fat provoked spontaneous activity and burst firing in LA (n=3/9, 33.3% vs. n=0/7, 0%, n=0/9, 0%, p<0.05). Compared to control fat, HF epicardial fat, had lower resistin, C-reactive protein and serum amyloid A, but similar interleukin-6, leptin, monocyte chemotactic protein-1, adiponectin and adipsin. CONCLUSIONS HF epicardial fat increases atrial arrhythmogenesis, which may contribute to the higher atrial arrhythmia in obesity.

Apamin modulates electrophysiological characteristics of the pulmonary vein and the Sinoatrial Node

Small‐conductance calcium‐activated potassium (SK) channels play an important role in atrial electrophysiology. Blocking SK channels prolongs action potential (AP) duration and attenuate electrical remodelling. The effects of SK blocking on the pulmonary vein (PV) and the sinoatrial node (SAN) remain unclear.

Nitroprusside modulates pulmonary vein arrhythmogenic activity

BackgroundPulmonary veins (PVs) are the most important sources of ectopic beats with the initiation of paroxysmal atrial fibrillation, or the foci of ectopic atrial tachycardia and focal atrial fibrillation. Elimination of nitric oxide (NO) enhances cardiac triggered activity, and NO can decrease PV arrhythmogensis through mechano-electrical feedback. However, it is not clear whether NO may have direct electrophysiological effects on PV cardiomyocytes. This study is aimed to study the effects of nitroprusside (NO donor), on the ionic currents and arrhythmogenic activity of single cardiomyocytes from the PVs.MethodsSingle PV cardiomyocytes were isolated from the canine PVs. The action potential and ionic currents were investigated in isolated single canine PV cardiomyocytes before and after sodium nitroprusside (80 μM,) using the whole-cell patch clamp technique.ResultsNitroprusside decreased PV cardiomyocytes spontaneous beating rates from 1.7 ± 0.3 Hz to 0.5 ± 0.4 Hz in 9 cells (P < 0.05); suppressed delayed afterdepolarization in 4 (80%) of 5 PV cardiomyocytes. Nitroprusside inhibited L-type calcium currents, transient outward currents and transient inward current, but increased delayed rectified potassium currents.ConclusionNitroprusside regulates the electrical activity of PV cardiomyocytes, which suggests that NO may play a role in PV arrhythmogenesis.

Rosiglitazone induces arrhythmogenesis in diabetic hypertensive rats with calcium handling alteration

BACKGROUND Diabetes and hypertension have significant effects on cardiac calcium (Ca(2+)) regulation, which plays an essential role in determining cardiac function. The effect of peroxisome proliferator-activated receptor (PPAR)-γ agonists on Ca(2+) regulation in the cardiomyocytes is unclear. OBJECTIVE The purpose of this study was to investigate the effects of hypertension, diabetes, and PPAR-γ agonist-rosiglitazone on the regulation of Ca(2+) and the electrophysiological characteristics of isolated ventricular myocytes. METHODS The indo-1 fluorometric ratio technique and whole-cell patch clamp were used to investigate intracellular Ca(2+) (Ca(2+)i), action potentials, and ionic currents in ventricular myocytes from rats of Wistar-Kyoto (WKY), diabetic WKY (induced by streptozotocin), diabetic WKY treated with rosiglitazone (5mg/kg), spontaneously hypertensive rats (SHR), diabetic SHR, and diabetic SHR treated with rosiglitazone. Western blot was used to evaluate protein expressions of sarcoplasmic reticulum ATPase (SERCA2a), Na(+)-Ca(2+) exchanger (NCX), and ryanodine receptor (RyR). RESULTS Diabetic WKY and diabetic SHR had smaller sarcoplasmic reticulum Ca(2+) contents, and Ca(2+)i transients with a prolonged decay portion, down-regulated SERCA2a, NCX, and RyR protein expressions and smaller L-type Ca(2+) currents than non-diabetic WKY and SHR, respectively. The Ca(2+) dysregulations in diabetes were attenuated in rats treated with rosiglitazone. Diabetes and hypertension both prolonged the action potential duration which were enhanced by the use of rosiglitazone, and induced the genesis of triggered activity. CONCLUSIONS Diabetes and hypertension modulate Ca(2+) handling. Rosiglitazone significantly changed the Ca(2+) regulation and electrophysiological characteristics, and may contain an arrhythmogenic potential in diabetes with hypertension.

Eicosapentaenoic acid reduces the pulmonary vein arrhythmias through nitric oxide.

AIMS 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. MAIN METHODS 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). KEY FINDINGS EPA concentration-dependently reduced the PV spontaneous beating rate (P<0.05). EPA (1.0 μM) also reduced the amplitude of delayed afterdepolarizations (P<0.05). 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. SIGNIFICANCE EPA reduces PV arrhythmogenesis through the mechanoelectrical feedback generated by NO production.

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

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

Dabigatran and Thrombin Modulate Electrophysiological Characteristics of Pulmonary Vein and Left Atrium

Background— Dabigatran reduces stroke in atrial fibrillation. Pulmonary veins (PVs) and left atrium (LA) play a critical role in the pathophysiology of atrial fibrillation. We investigated the effects of thrombin, blood clot solution, and dabigatran on PVs and LA. Methods and Results— Conventional microelectrodes were used to record the action potentials in isolated PV and LA preparations before and after the administration of thrombin or blood clot solution in control and dabigatran-treated rabbits. Thrombin (0.01, 0.1, and 1 unit/mL), respectively, reduced the PV (n=6) spontaneous beating rates from 1.9±0.2 to 1.7±0.2, 1.6±0.2, and 1.4±0.3 Hz (P=0.046). Blood clot solution (0.5% and 5.0%), respectively, reduced the PV (n=5) spontaneous beating rates from 2.0±0.4 to 1.8±0.4 and 1.3±0.3 Hz (P=0.044). Thrombin (0.01, 0.1, and 1 unit/mL) and blood clot solution (0.5% and 5.0%) increased LA diastolic tension and the resting membrane potential with decreased action potential duration and contractility. Thrombin (0.01, 0.1, and 1 unit/mL) and blood clot solution (0.5% and 5%) induced delayed afterdepolarization and burst firing in PVs, but not in LA. NG-nitro-L-arginine methyl ester (100 &mgr;mol/L) or a protease-activated receptor type 1 blocker (BMS 200261, 1 &mgr;mol/L) attenuated the effects of thrombin and blood clot solution in PVs and LA. Dabigatran-treated PVs had slower spontaneous activity (1.1±0.1 Hz; n=10; P=0.0001 versus control). Their electrophysiological characteristics were not changed by thrombin (1 unit/mL) and blood clot solution (5%). Conclusions— Thrombin modulates PV and LA electric and mechanical characteristics, which were blocked by dabigatran.

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).

Electrophysiological characteristics of complex fractionated electrograms and high frequency activity in atrial fibrillation.

BACKGROUND It is unclear whether atrial substrate with complex fractionated electrograms (CFAEs) is related to arrhythmogenesis. This study aimed to investigate the electrophysiology in CFAE and high dominant frequency (DF) areas. METHODS AND RESULTS Atrial fibrillation (AF) was induced by rapid atrial pacing in heart failure (HF) rabbits (4 weeks after coronary artery ligation). Real-time substrate mapping, multielectrode array, and monophasic action potential recordings were used to study areas of CFAE and DF. Conventional microelectrode and western blot were used to record the action potentials (APs) and protein expression in isolated tissue preparations. CFAE site with high DF had the most depolarized resting membrane potential, highest incidence of early and delayed afterdepolarizations, and steepest maxima slope of 90% of AP duration (APD90) restitution curve (RC) compared to CFAE site with low DF or non-CFAE sites. CFAE site with high DF exhibited the slowest conduction velocity and shortest wavelength than the other areas. Upregulation of the Na(+)-Ca(2+) exchanger (NCX), apamin-sensitive small-conductance Ca(2+)-activated K(+) channel type 2 (SK2) and sarcoplasmic reticulum Ca(2+)-ATPase, and downregulation of the Kir2.1 were found at CFAE site with high DF compared to that observed in the 3 other areas. Inhibition of the NCX and SK channels prolonged the APD90, flattened the maximum slope of RC, and suppressed AF. CONCLUSIONS CFAE site with high DF had an arrhythmogenic property differing significantly from the other areas of LA in an HF rabbit model, which may contribute to the genesis of AF.