Yung-Kuo Lin

Sex Differences in the Electrophysiological Characteristics of Pulmonary Veins and Left Atrium and Their Clinical Implication in Atrial Fibrillation

Background— Sex and the autonomic nervous system play critical roles in the pathophysiology of atrial fibrillation (AF). Sex differences in electrophysiological characteristics of the pulmonary veins (PVs, AF initiator) and left atrium (LA, AF substrate) are not clear. Methods and Results— Conventional microelectrodes were used to record the action potential in isolated PV and LA tissue preparations from male and female (age, 8≈10 months) rabbits before and after drug administration (adenosine, acetylcholine, and isoproterenol). Male PVs (n=7) had a higher spontaneous beating rate (1.7±0.2 versus 1.2±0.1 Hz, P=0.021) and incidence of burst firing (72% versus 11%, P=0.038) than female PVs (n=9). Male PVs without spontaneous activity (n=10) and the LA (n=11) had longer action potential durations than female PVs (n=9) and LA (n=9). Additionally, male PVs had a more-positive resting membrane potential (79±3 versus 84±2 mV, P=0.022). Isoproterenol (3 &mgr;mol/L) increased the delayed afterdepolarizations to a greater extent in male than in female PVs. In PVs without spontaneous activity or LA, isoproterenol (0.1 and 3 &mgr;mol/L) consistently shortened the action potential durations in females but not in males. Acetylcholine (5.5 &mgr;mol/L) decreased the spontaneous activity of PVs and shortened the action potential durations in both groups. Adenosine (10 &mgr;mol/L) also similarly decreased the spontaneous activity of PVs and delayed afterdepolarizations in both groups. Conclusions— There are significant sex differences in PV and LA action potential characteristics in rabbits. The higher amplitude of delayed afterdepolarizations after isoproterenol superfusion in male PVs may contribute to sex-related arrhythmogenesis.

Sinoatrial node electrical activity modulates pulmonary vein arrhythmogenesis

BACKGROUND Sinoatrial node (SAN) dysfunction increases the occurrences of atrial fibrillation (AF). The pulmonary veins (PVs) play a critical role in the pathophysiology of AF. The purpose of this study was to evaluate whether SAN electrical activity can modulate PV arrhythmogenesis. METHODS Conventional microelectrodes and multi-electrode array system were used to simultaneously record the electrical activity and conduction properties of rabbit SAN and PV tissue preparations with and without SAN-PV interruptions before and after perfusion with Anemonia sulcata toxin (ATX)-II (100 nM) or isoproterenol (1 μM). RESULTS ATX-II significantly increased PV beating rates, which overdrove SAN electrical activity with the occurrences of PV burst firings in 5 (56%) of 9 tissue preparations, and induced SAN-PV conduction block in 6 (67%) of 9 preparations. After SAN-PV disconnection, ATX-II induced burst firing and early afterdepolarizations in 8 (89%) of 9 PVs. Moreover, the multi-electrode array found that ATX-II reversed the electrical conduction between the SAN and PV with an increase in electrical activity from 1.8 ± 0.6 to 2.9 ± 0.6 Hz (P<0.05) in SAN-PV preparations (n=7). In contrast, isoproterenol did not reverse electrical conduction between the SAN and PV with an increase in electrical activity from 1.8 ± 0.2 to 3.0 ± 0.3 Hz (P<0.005) in SAN-PV preparations (n=7). CONCLUSIONS SAN electrical activity modulates PV arrhythmogenesis. SAN-PV conduction blocks can increase PV arrhythmogenesis.

The Uremic Toxin Indoxyl Sulfate Increases Pulmonary Vein and Atrial Arrhythmogenesis

Chronic kidney disease (CKD) is associated with a higher incidence of atrial fibrillation (AF) with unclear mechanisms. Indoxyl sulfate (IS) accumulates in CKD patients. IS increases oxidative stress, which contributes to the genesis of AF. The arrhythmogenic effect of IS is unclear.

Testosterone replacement increases aged pulmonary vein and left atrium arrhythmogenesis with enhanced adrenergic activity

BACKGROUND Aging and testosterone deficiency contribute to the pathogenesis of atrial fibrillation (AF). We determine the effects of testosterone replacement on the electrophysiology and arrhythmogenesis of pulmonary vein (PV) and left atrium (LA) in aged rabbits. METHODS Electrocardiography, heart rate variability, echocardiography, Western blot and conventional microelectrodes were used in aged rabbits (age, >2 years) with and without (control) testosterone treatment (10mg/kg, 12 weeks). RESULTS Testosterone-treated aged rabbits had longer corrected QT interval, higher low frequency/high frequency, greater left ventricle (LV) mass but lower LA total emptying fraction and LV ejection fraction than control rabbits. In tissue preparations, the spontaneous rate was faster for testosterone-treated PVs than for control PVs. Angiotensin II concentration-dependently increased the amplitude of delayed afterdepolarizations (DADs) in testosterone-treated PVs but only did so at the highest angiotensin II concentration (100 nM) in control PVs. Isoproterenol increased the incidence of early afterdepolarizations (EADs) and DADs in testosterone-treated PVs but not in control PVs. Testosterone-treated PVs had more H2O2-induced burst firing and EADs than control PVs. Testosterone-treated LAs had more isoproterenol-induced DADs and spontaneous activity than did control LAs. However, acetylcholine infusion and rapid atrial pacing (10-20 Hz) induced AF in control LAs but not in testosterone-treated LAs. In addition, as compared with control LAs, testosterone-treated LAs expressed more androgen receptor, β1-adrenergic receptor, and Cav 1.2 and less G protein-coupled receptor kinase-2 and Kv 4.2. CONCLUSIONS Testosterone replacement increased arrhythmogenesis in PV and LA by enhancing adrenergic activity in aged rabbits.

Electrolyte disturbances differentially regulate sinoatrial node and pulmonary vein electrical activity: A contribution to hypokalemia- or hyponatremia-induced atrial fibrillation

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.

Fibroblast growth factor 23 dysregulates late sodium current and calcium homeostasis with enhanced arrhythmogenesis in pulmonary vein cardiomyocytes

Fibroblast growth factor 23 (FGF23), elevated in chronic renal failure, increases atrial arrhythmogenesis and dysregulates calcium homeostasis. Late sodium currents (INa-Late) critically induces ectopic activity of pulmoanry vein (the most important atrial fibrillation trigger). This study was to investigate whether FGF23 activates the INa-Late leading to calcium dysregulation and increases PV arrhythmogenesis. Patch clamp, western blot, and confocal microscopy were used to evaluate the electrical activities, calcium homeostasis, and mitochondrial reactive oxygen species (ROS) in PV cardiomyocytes with or without FGF23 (0.1 or 1 ng/mL) incubation for 4~6 h. Compared to the control, FGF23 (1 ng/mL, but not 0.1 ng/mL)-treated PV cardiomyocytes had a faster beating rate. FGF23 (1 ng/mL)-treated PV cardiomyocytes had larger INa-Late, calcium transients, and mitochondrial ROS than controls. However, ranolazine (an inhibitor of INa-Late) attenuated FGF23 (1 ng/mL)-increased beating rates, calcium transients and mitochondrial ROS. FGF23 (1 ng/mL)-treated PV cardiomyocytes exhibited larger phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII). Chelerythrine chloride (an inhibitor of protein kinase C) decreased INa-Late in FGF23 (1 ng/mL)-treated PV cardiomyocytes. However, KN93 (a selective CaMKII blocker) decreased INa-Late in control and FGF23 (1 ng/mL)-treated PV cardiomyocytes to a similar extent. In conclusion, FGF23 increased PV arrhythmogenesis through sodium and calcium dysregulation by acting protein kinase C signaling.

Different effects of dronedarone and amiodarone on pulmonary vein electrophysiology, mechanical properties and H2O2-induced arrhythmogenicity

Dronedarone and amiodarone are anti-atrial fibrillation agents with different potency. Pulmonary veins play a critical role in the genesis of atrial fibrillation. Oxidative stress can enhance pulmonary vein arrhythmogenesis. This study was done to compare the effects of dronedarone and amiodarone on pulmonary vein electrophysiological and mechanical properties, and oxidative stress-induced arrhythmogenecity. Conventional microelectrodes were used to record action potentials in isolated rabbit pulmonary vein specimens before and after dronedarone and amiodarone with or without the presence of H2O2 (2mM). Dronedarone (0.1, 1 and 10 μM) concentration-dependently decreased pulmonary vein beating rates (from 2.2±0.1 to 1.9±0.1, 1.8±0.1 and 1.7±0.1Hz, n=8, P<0.01). Amiodarone (0.1, 1 and 10 μM) also concentration-dependent decreased pulmonary vein beating rates (from 2.5±0.2 to 2.3±0.2, 2.2±0.2 and 2.0±0.2Hz, n=7, P<0.01). However, dronedarone decreased pulmonary vein beating rates to a greater extent at 0.1 μM (12% versus 4%, P<0.005) and 1μM (17% versus 9%, P<0.005). Dronedarone or amiodarone (0.1, 1 and 10 μM) did not change the pulmonary vein contractility. However, dronedarone (1 and 10 μM) concentration-dependent reduced pulmonary vein diastolic tension by 13±2 mg (P<0.005) and 18±3 mg (P<0.005). In contrast, amiodarone did not change pulmonary vein diastolic tension. Dronedarone (10 μM) and amiodarone (10 μM) attenuated H2O2-induced pulmonary vein burst firings from 100% to 33.3% (P<0.01), and to 0% (P<0.005), respectively. In conclusion, amiodarone and dronedarone both significantly reduced pulmonary vein spontaneous beating rates and H2O2-induced pulmonary vein arrhythmogenesis. However, only dronedarone produced pulmonary vein vasodilation.

Cloud-based BP system integrated with CPOE improves self-management of the hypertensive patients

BACKGROUND Less than 50% of patients with hypertensive disease manage to maintain their blood pressure (BP) within normal levels. OBJECTIVE The aim of this study is to evaluate whether cloud BP system integrated with computerized physician order entry (CPOE) can improve BP management as compared with traditional care. METHODS A randomized controlled trial done on a random sample of 382 adults recruited from 786 patients who had been diagnosed with hypertension and receiving treatment for hypertension in two district hospitals in the north of Taiwan. Physicians had access to cloud BP data from CPOE. Neither patients nor physicians were blinded to group assignment. The study was conducted over a period of seven months. RESULTS At baseline, the enrollees were 50% male with a mean (SD) age of 58.18 (10.83) years. The mean sitting BP of both arms was no different. The proportion of patients with BP control at two, four and six months was significantly greater in the intervention group than in the control group. The average capture rates of blood pressure in the intervention group were also significantly higher than the control group in all three check-points. CONCLUSIONS Cloud-based BP system integrated with CPOE at the point of care achieved better BP control compared to traditional care. This system does not require any technical skills and is therefore suitable for every age group. The praise and assurance to the patients from the physicians after reviewing the Cloud BP records positively reinforced both BP measuring and medication adherence behaviors.

B‐Type Natriuretic Peptide Modulates Pulmonary Vein Arrhythmogenesis: A Novel Potential Contributor to the Genesis of Atrial Tachyarrhythmia in Heart Failure

Heart failure (HF) plays a critical role in the genesis of atrial fibrillation (AF). A high B‐type natriuretic peptide (BNP) level occurs in patients with HF and in patients with AF. However, the role of BNP in the pathophysiology of AF is not clear. The purposes of this study were to evaluate the effects of BNP on pulmonary vein (PV) arrhythmogenesis.

iSlide: a ‘big picture’ interactive teledermatopathology e‐learning system

Dermatopathology training is often limited by facilities and a dearth of specialists. Advancements in information and communication technologies have made possible the adoption of innovative learning techniques, especially in places where specialists are lacking.