Adenosine monophosphate-regulated protein kinase inhibition modulates electrophysiological characteristics and calcium homeostasis of rabbit right ventricular outflow tract.

BACKGROUND: Metabolic stress predisposes to ventricular arrhythmias and sudden cardiac death. Right ventricular outflow tract (RVOT) is the common origin of ventricular arrhythmias. Adenosine monophosphate-regulated protein kinase (AMPK) activation is an important compensatory mechanism for cardiac remodeling during metabolic stress. OBJECTIVES: The purpose of this study was to access whether AMPK inhibition would modulate RVOT electrophysiology, calcium (Ca2+ ) regulation, and RVOT arrhythmogenesis or not. METHODS: Conventional microelectrodes were used to record electrical activity before and after compound C (10 µM, an AMPK inhibitor) in isoproterenol (1 µM)-treated rabbit RVOT tissue preparations under electrical pacing. Whole-cell patch-clamp and confocal microscopic examinations were performed in baseline and compound C-treated rabbit RVOT cardiomyocytes to investigate ionic currents and intracellular Ca2+ transients in isolated rabbit RVOT cardiomyocytes. RESULTS: Compound C decreased RVOT contractility, and reversed isoproterenol increased RVOT contractility. Compound C decreased the incidence, rate, and duration of isoproterenol-induced RVOT burst firing under rapid pacing. Compared to baseline, compound C-treated RVOT cardiomyocytes had a longer action potential duration, smaller intracellular Ca2+ transients, late sodium (Na+ ), peak L-type Ca2+ current density, Na+ -Ca2+ exchanger, transient outward potassium (K+ ) current, and rapid and slow delayed rectifier K+ currents. CONCLUSION: AMPK inhibition modulates RVOT electrophysiological characteristics and Ca2+ homeostasis, contributing to lower RVOT arrhythmogenic activity. Accordingly, AMPK inhibition might potentially reduce ventricular tachyarrhythmias.

Vascular endothelial growth factor modulates pulmonary vein arrhythmogenesis via vascular endothelial growth factor receptor 1/NOS pathway.

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.

Fibroblast Growth Factor 1 Reduces Pulmonary Vein and Atrium Arrhythmogenesis via Modification of Oxidative Stress and Sodium/Calcium Homeostasis.

RATIONALE: Atrial fibrillation is a critical health burden. Targeting calcium (Ca2+) dysregulation and oxidative stress are potential upstream therapeutic strategies. Fibroblast growth factor (FGF) 1 can modulate Ca2+ homeostasis and has antioxidant activity. The aim of this study was to investigate whether FGF1 has anti-arrhythmic potential through modulating Ca2+ homeostasis and antioxidant activity of pulmonary vein (PV) and left atrium (LA) myocytes. METHODS: Patch clamp, western blotting, confocal microscopy, cellular and mitochondrial oxidative stress studies were performed in isolated rabbit PV and LA myocytes treated with or without FGF1 (1 and 10 ng/mL). Conventional microelectrodes were used to record electrical activity in isolated rabbit PV and LA tissue preparations with and without FGF1 (3 µg/kg, i.v.). RESULTS: FGF1-treated rabbits had a slower heart rate than that observed in controls. PV and LA tissues in FGF1-treated rabbits had slower beating rates and longer action potential duration than those observed in controls. Isoproterenol (1 µM)-treated PV and LA tissues in the FGF1-treated rabbits showed less changes in the increased beating rate and a lower incidence of tachypacing (20 Hz)-induced burst firing than those observed in controls. FGF1 (10 ng/mL)-treated PV and LA myocytes had less oxidative stress and Ca2+ transient than those observed in controls. Compared to controls, FGF1 (10 ng/mL) decreased INa-L in PV myocytes and lowered I to, I Kr-tail in LA myocytes. Protein kinase C (PKC)ε inhibition abolished the effects of FGF1 on the ionic currents of LA and PV myocytes. CONCLUSION: FGF1 changes PV and LA electrophysiological characteristics possibly via modulating oxidative stress, Na+/Ca2+ homeostasis, and the PKCε pathway.

Trastuzumab increases pulmonary vein arrhythmogenesis through modulating pulmonary vein electrical and conduction properties via phosphatidylinositol 3-kinase signaling.

OBJECTIVES: Drug-induced atrial fibrillation (AF) is considered an adverse effect of chemotherapeutic drugs. AF is a crucial risk factor for stroke, heart failure, myocardial infarction, and mortality. Pulmonary veins (PVs) are considered triggers inducing AF, and the sinoatrial node (SAN) may modulate PV activity and participate in AF genesis. AF was associated with early discontinuation of trastuzumab in patients with breast cancer. However, whether trastuzumab directly modulates the electrophysiological characteristics of PV and SAN remains unclear. MATERIALS AND METHODS: ECG and conventional microelectrode system were used to record rabbit heart rhythm in vivo and electrical activities in vitro from isolated SAN, PV, and SAN-PV preparations. RESULTS: Trastuzumab reduced the beating rate in isolated PV and SAN preparations at 1, 10, and 30 µM (particularly in isolated SAN preparations) and induced burst firings in isolated PV preparations at 10 µΜ. In addition, trastuzumab (10 µM) induced SAN-PV conduction block and burst firings, which were blocked by wortmannin (a PI3K inhibitor, 100 nM). Similarly, ECG recordings showed that acute intravenous administration of trastuzumab (10 mg/kg) reduced rabbit heart rates. CONCLUSION: Trastuzumab increased PV arrhythmogenesis through interfering with PI3K signaling, which may contribute to the genesis of AF.

Various subtypes of phosphodiesterase inhibitors differentially regulate pulmonary vein and sinoatrial node electrical activities.

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<0.005) in PVs. Rolipram increased PV spontaneous activity by 7.5±1.3-9.5±4.0%, although this was not significant, and did not alter SAN spontaneous activity. Sildenafil reduced spontaneous activity in PVs to a greater extent than that seen in SANs. Both KT5823 and H89 suppressed milrinone-increased PV spontaneous activity. In the presence of isoproterenol, milrinone did not alter isoproterenol-induced PV arrhythmogenesis, suggesting that the effects of PDE3 are mediated by the protein kinase G and protein kinase A signaling pathways. In conclusion, inhibitors of different PDE subtypes exert diverse electrophysiological effects on PV and SAN activities.

Effects of ANP on pulmonary vein electrophysiology, Ca2+ homeostasis and adrenergic arrhythmogenesis via PKA.

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 differently modulate electrical activities in pulmonary veins and the sinoatrial node.

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 < 0.05), and reduced SAN beating rates at 1 µM (N = 6, P < 0.05). Similarly, rivaroxaban reduced PV spontaneous beating rates at 0.1 and 0.3 µM (N = 7, P < 0.05), and reduced SAN beating rates at 0.3 µM (N = 6, P < 0.05). However, neither edoxaban (1 µM) nor rivaroxaban (0.3 µM) reduced PV spontaneous beating rates in the presence of 1 µM BMS200261 (an inhibitor of protease-activated receptors type 1, PAR1 inhibitor) or 10 µM ranolazine (an inhibitor of late sodium current, INa-late inhibitor). Edoxaban (0.3 and 1 µM) and rivaroxaban (0.1 and 0.3 µM) respectively decreased the INa-late by 47%, 47%, 36%, and 49% (n = 9 PV cardiomyocytes from 5 rabbits, P < 0.05). In conclusion, Factor Xa inhibitors reduce PV spontaneous activities and may modulate occurrence of atrial fibrillation by inhibiting PAR1 and reducing the INa-late in PVs.

Angiotensin 1-7 modulates electrophysiological characteristics and calcium homoeostasis in pulmonary veins cardiomyocytes via MAS/PI3K/eNOS signalling pathway.

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+ ) homoeostasis 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 nmol/L) decreased PV spontaneous electrical activity. Ang-(1-7) (100 nmol/L) 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 µmol/L), L-NAME (a NO synthesis inhibitor, 100 µmol/L) or wortmannin (a specific PI3K inhibitor, 10 nmol/L) attenuated the effects of Ang-(1-7) (100 nmol/L) on PV spontaneous electric activity. CONCLUSION: Ang-(1-7) regulates PV electrophysiological characteristics and Ca2+ homoeostasis via Mas/PI3K/eNOS signalling pathway.

Mitochondrial dysfunction on sinoatrial node and pulmonary vein electrophysiological activities.

Atrial fibrillation (AF) is associated with mitochondrial dysfunction. Sinoatrial node (SAN) dysfunction increases arrhythmogenesis of pulmonary veins (PVs), which is the most important trigger of AF; however, it is not clear whether mitochondrial dysfunction differentially regulates electrical activity of SANs and PVs. In the present study, conventional microelectrodes were used to record the action potentials (APs) in isolated rabbit PVs, SANs, left atrium (LA) and right atrium (RA) before and after application of trifluorocarbonylcyanide phenylhydrazone (FCCP; a mitochondrial uncoupling agent) at 10, 100 and 300 nM. FCCP application at 100 and 300 nM decreased spontaneous rates in PVs and in SANs at 10, 100 and 300 nM. FCCP shortened the 20, 50 and 90% AP durations in the LA, and shortened only the 20% AP duration in the RA. FCCP caused a greater rate reduction in SANs than in PVs; however, in the presence of coenzyme-Q10 (10 µM), FCCP reduced the beating rate in PVs and SANs to a similar extent. In SAN-PV preparations with intact electrical connections, FCCP (100 nM) application shifted the SAN-PV electrical conduction into PV-SAN conduction in 5 (62.5%) of 8 preparations. In conclusion, mitochondrial dysfunction modulates PV and SAN electrical activities, which may contribute to atrial arrhythmogenesis.

Discrepant effects of heart failure on electrophysiological property in right ventricular outflow tract and left ventricular outflow tract cardiomyocytes.

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.

2016 Guidelines of the Taiwan Heart Rhythm Society and the Taiwan Society of Cardiology for the management of atrial fibrillation.

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.

Gap junction modifiers regulate electrical activities of the sinoatrial node and pulmonary vein: Therapeutic implications in atrial arrhythmogenesis.

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.

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.

Selective and non-selective non-steroidal anti-inflammatory drugs differentially regulate pulmonary vein and atrial arrhythmogenesis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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%, p<0.05). 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%, p<0.05) of 7 PVs. KB-R7943 (10 µM) suppressed celecoxib (3 µM)-induced PV burst firings in 5 (71%, p<0.05) of 7 PVs. CONCLUSIONS: 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.

A monounsaturated fatty acid (oleic acid) modulates electrical activity in atrial myocytes with calcium and sodium dysregulation.

BACKGROUND: Obesity and metabolic syndrome are important risk factors for atrial fibrillation. High plasma concentrations of monounsaturated fatty acids, including oleic acid (OLA), are frequently noted in obese individuals and patients with metabolic syndrome. However, it is not clear whether monounsaturated fatty acids (MUFAs) can directly modulate the electrophysiological characteristics of atrial myocytes. METHODS: Whole-cell patch clamp, indo-1 fluorescence, and Western blot analyses were used to record the action potentials (APs), ionic currents, and protein expressions of HL-1 myocytes incubated with and without (control) OLA (0.5mM) for 24h. RESULTS: Compared to control myocytes (n=14), OLA-treated myocytes (n=16) had shorter APD90 (65 ± 6 vs. 85 ± 6 ms, p<0.05) and APD50 (24 ± 6 vs. 38 ± 4 ms, p<0.05) with a higher incidence of delayed afterdepolarizations (35.7% vs. 7%, p<0.05), which were suppressed by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS, a blocker of the calcium-activated chloride current). In addition, OLA-treated myocytes (n=19) exhibited larger calcium transients (0.54 ± 0.06 vs. 0.38 ± 0.05 R410/485, p<0.05), and sarcoplasmic reticular calcium contents (0.91 ± 0.05 vs. 0.64 ± 0.08 R410/485, p<0.05) than control myocytes (n=15). OLA-treated myocytes had larger late sodium currents, smaller sodium-calcium exchanger currents, and smaller sodium-potassium pump currents. Moreover OLA-treated myocytes had higher expressions of sarcoplasmic reticular Ca(2+)-ATPase and calmodulin kinase II, but lower expression of the sodium-potassium ATPase protein than control myocytes. CONCLUSIONS: MUFAs can regulate atrial electrophysiological characteristics with calcium and sodium dysregulation, which may contribute to atrial 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.

Apelin regulates the electrophysiological characteristics of atrial myocytes.

BACKGROUND: 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.

Novel assessment of temporal variation in fractionated electrograms using histogram analysis of local fractionation interval in patients with persistent atrial fibrillation.

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<0.01) in patients with procedural termination. In addition, patients with AF termination had a higher sinus rhythm maintenance rate after a single procedure than patients without AF termination (log-rank test, 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 catheter ablation in patients with atrial fibrillation originating from the superior vena cava.

UNLABELLED: 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).