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.

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.

A novel finding of the atrial substrate properties and long-term results of catheter ablation in chronic atrial fibrillation patients with left atrial spontaneous echo contrast.

BACKGROUND: The atrial substrate in chronic atrial fibrillation (AF) patients with a left atrial spontaneous echo contrast (LASEC) has not been previously reported. The aim of this study was to investigate the atrial substrate properties and long-term follow-up results in the patients who received catheter ablation of chronic AF. METHODS: Of 36 consecutive patients with chronic AF who received a stepwise ablation approach, 18 patients with an LASEC (group I) were compared with 18 age-gender-left atrial volume matched patients without an LASEC (group II). The atrial substrate properties including the weighted peak-to-peak voltage, total activation time during sinus rhythm (SR), dominant frequency (DF), and complex fractionated electrograms (CFEs) during AF in the bi-atria were evaluated. RESULT: The left atrial weighted bipolar peak-to-peak voltage (1.0 ± 0.6 vs 1.6 ± 0.7 mV, P = 0.04), total activation time (119 ± 20 vs 103 ± 13 ms, P < 0.001) and DF (7.3 ± 1.3 vs 6.6 ± 0.7 Hz, P < 0.001) differed between group I and group II, respectively. Those parameters did not differ in the right atrium. The bi-atrial CFEs (left atrium: 89 ± 24 vs 92 ± 25, P = 0.8; right atrium: 92 ± 25 vs 102 ± 3, P = 0.9) did not differ between group I and group II, respectively. After a mean follow-up of 30 ± 13 month, there were significant differences in the antiarrhythmic drugs (1.1 ± 0.3 vs 0.7 ± 0.5, P = 0.02) needed after ablation, and recurrence as persistent AF (92% vs 50%, P = 0.03) between group I and group II, respectively. After multiple procedures, there were more group II patients that remained in SR, when compared with group I (78% vs 44%, P = 0.04). CONCLUSION: There was a poorer atrial substrate, lesser SR maintenance after catheter ablation and need for more antiarrhythmic drugs in the chronic AF patients with an LASEC when compared with those without an LASEC.

Associations among the CHADS(2) score, atrial substrate properties, and outcome of catheter ablation in patients with paroxysmal atrial fibrillation.

BACKGROUND: The CHADS2 score (congestive heart failure, hypertension, age >75 years, diabetes, and previous stroke/transient ischemic attack) is used for the risk stratification of strokes in patients with atrial fibrillation (AF). OBJECTIVE: This study aimed to investigate the associations between the CHADS2 score, atrial substrate, and outcome of catheter ablation in patients with paroxysmal AF. METHODS: A total of 247 paroxysmal AF patients who received catheter ablation were enrolled. The patients were divided into 3 groups according to their CHADS2 score (group 1: score 0, group 2: score 1 to 2, and group 3: score 3 to 6). The bi-atrial substrate properties and outcome of catheter ablation were analyzed. RESULTS: The CHADS2 scores in these 3 groups were 0 (group 1), 1.24 ± 0.48 (group 2), and 3.60 ± 0.83 (group 3), respectively. The left atrial voltage became lower (group 1 vs. 2 vs. 3 = 2.08 ± 0.73 mV vs. 1.80 ± 0.81 mV vs. 1.06 ± 0.69 mV) and the activation time longer (group 1 vs. 2 vs. 3 = 93.4 ± 17.7 ms vs. 101.9 ± 21.2 ms vs. 112.2 ± 21.7 ms), whereas the CHADS2 score increased. During a follow-up of 17.3 ± 7.0 months, 23.1% of the study population suffered from recurrences. The recurrence rates of these 3 groups were 13.0% (group 1), 27.6% (group 2), and 45.9% (group 3), respectively. The groups of different CHADS2 scores remained as the independent predictor of recurrence in the multivariate analysis. CONCLUSION: A high CHADS2 score was associated with different left atrial substrate properties and a poor outcome after catheter ablation of paroxysmal AF.

Discrepant electrophysiological characteristics and calcium homeostasis of left atrial anterior and posterior myocytes.

The left atrial (LA) posterior wall has been demonstrated to have regional electrophysiological differences with a higher arrhythmogenic potential leading to atrial fibrillation (AF). However, the ionic characteristics and calcium regulation in the LA anterior and posterior myocytes have not been fully elucidated. The purpose of this study was to investigate the electrical characteristics of the LA anterior and posterior myocytes. Whole-cell patch-clamp techniques and the indo-1 fluorimetric ratio technique were used to investigate the characteristics of the ionic currents, action potentials, and intracellular calcium in single isolated rabbit myocytes in the LA anterior and posterior walls. The expression of the Na(+)-Ca(2+) exchanger (NCX) and ryanodine receptor (RyR) were evaluated by a Western blot. The LA posterior myocytes (n = 15) had a higher incidence (53 vs. 19%, P < 0.05) of delayed afterdepolarizations than the LA anterior myocytes (n = 16). The LA posterior myocytes had larger sodium currents and late sodium currents, but smaller inward rectifier potassium currents than the LA anterior myocytes. The LA posterior myocytes had larger intracellular Ca(2+) transient and sarcoplasmic reticulum Ca(2+) contents as compared with the LA anterior myocytes. However, the NCX currents in the LA posterior myocytes were smaller than those in the LA anterior myocytes. The LA posterior myocytes had a smaller protein expression of NCX, but a larger protein expression of RyR than the LA anterior myocytes. In conclusion, LA posterior myocytes contain a high arrhythmogenic potential and distinctive electrophysiological characteristics, which may contribute to the pathophysiology of AF.

Oxidative stress on pulmonary vein and left atrium arrhythmogenesis.

BACKGROUND: Oxidative stress and pulmonary veins (PVs) play critical roles in the pathophysiology of atrial fibrillation. The purpose of the present study was to investigate whether oxidative stress and antioxidant agents can change the electrophysiological characteristics of the left atrium (LA) and PVs. METHODS AND RESULTS: Conventional microelectrodes were used to record the action potentials (APs) in isolated rabbit PV and LA specimens before and after H(2)O(2) administration with or without ascorbic acid or N-mercaptopropionyl-glycine (N-MPG, a free radical .OH scavenger). H(2)O(2) (0.02 and 0.2 mmol/L) decreased the PV spontaneous rates from 2.0+/-0.1 Hz to 1.6+/-0.1 Hz, and 1.7+/-0.1 Hz (n=10, P<0.05), but H(2)O(2) (2 mmol/L) increased PV spontaneous rates from 2.0+/-0.1 Hz to 2.8+/-0.2 Hz. H(2)O(2) easily induced PV burst firing and early afterdepolarizations, but not in the LA. H(2)O(2) shortened the AP duration and increased the contractile force to a greater extent in the LA than in PVs. In addition, the H(2)O(2)-induced PV burst firing and increasing spontaneous rates were suppressed or attenuated by pretreatment with ascorbic acid (1 mmol/L) or N-MPG (10 mmol/L). CONCLUSIONS: H(2)O(2) significantly changed the electrophysiological characteristics of PV and LA through activation of free radicals and may facilitate the occurrence of atrial fibrillation.