Experimental model of focal atrial tachycardia: clinical correlates.

BACKGROUND: The mechanisms underlying focal atrial tachycardia (AT) are unclear. METHODS: In 14 pentobarbital anesthetized dogs, a right thoracotomy allowed electrical stimulation (ES) of the anterior right ganglionated plexi (ARGP). After ES was applied to the ARGP at baseline, atropine, 1 mg/cc, was injected into the ARGP and repeat stimulation applied. After a left thoracotomy (n = 8), a similar procedure was followed by atropine injected into the superior left (SL) GP. RESULTS: ES (0.6-3.2 V) applied to the ARGP and SLGP caused an average reduction in sinus rate from 151 ± 14/min to 60 ± 11/min. At ≥4.5 V atrial fibrillation (AF) was induced (duration 48 ± 14 seconds). After injection of atropine into the ARGP or SLGP, ES applied to these GP induced no slowing of the sinus rate. Runs of AT were induced at an average voltage of 10 ± 2 V in 14 experiments (duration ≥4 minutes). AT was localized by ice mapping or by 3D noncontact mapping to the crista terminalis (n = 6), AV junction (n = 2) or a focal site at the left superior pulmonary vein (6). In AT lasting <4 minutes (n = 2), epinephrine injected into the GP significantly increased the AT duration. In 4/4 experiments, sustained AT could be terminated by intravenous esmolol. CONCLUSIONS: Atropine injected into the ARGP or SLGP promotes ES-induced AT whose duration is increased by adrenergic agonists and terminated by beta blockade. Presumably cholinergic blockade and accentuated release of adrenergic neurotransmitters provide the AT mechanism. The induced AT was found to be localized at sites similar to those reported clinically.

Inhibition of atrial fibrillation by low-level vagus nerve stimulation: the role of the nitric oxide signaling pathway.

PURPOSE: We examined the role of the phosphatidylinositol-3 kinase (PI3K)/nitric oxide (NO) signaling pathway in low-level vagus nerve stimulation (LLVNS)-mediated inhibition of atrial fibrillation (AF). METHODS: In 17 pentobarbital anesthetized dogs, bilateral thoracotomies allowed the attachment of electrode catheters to the superior and inferior pulmonary veins and atrial appendages. Rapid atrial pacing (RAP) was maintained for 6 h. Each hour, programmed stimulation was used to determine the window of vulnerability (WOV), a measure of AF inducibility, at all sites. During the last 3 h, RAP was overlapped with right LLVNS (50 % below that which slows the sinus rate). In group 1 (n = 7), LLVNS was the only intervention, whereas in groups 2 (n = 6) and 3 (n = 4), the NO synthase inhibitor N (G)-nitro-L-arginine methyl ester (L-NAME) and the PI3K inhibitor wortmannin, respectively, were injected in the right-sided ganglionated plexi (GP) during the last 3 h. The duration of acetylcholine-induced AF was determined at baseline and at 6 h. Voltage-sinus rate curves were constructed to assess GP function. RESULTS: LLVNS significantly decreased the acetylcholine-induced AF duration by 8.2 ± 0.9 min (p < 0.0001). Both L-NAME and wortmannin abrogated this effect. The cumulative WOV (the sum of the individual WOVs) decreased toward baseline with LLVNS (p < 0.0001). L-NAME and wortmannin blunted this effect during the fifth (L-NAME only, p < 0.05) and the sixth hour (L-NAME and wortmannin, p < 0.05). LLVNS suppressed the ability of GP stimulation to slow the sinus rate, whereas L-NAME and wortmannin abolished this effect. CONCLUSION: The anti-arrhythmic effects of LLVNS involve the PI3K/NO signaling pathway.

Low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve: a noninvasive approach to treat the initial phase of atrial fibrillation.

BACKGROUND: We studied the effects of transcutaneous electrical stimulation at the tragus, the anterior protuberance of the outer ear, for inhibiting atrial fibrillation (AF). OBJECTIVE: To develop a noninvasive transcutaneous approach to deliver low-level vagal nerve stimulation to the tragus in order to treat cardiac arrhythmias such as AF. METHODS: In 16 pentobarbital anesthetized dogs, multielectrode catheters were attached to pulmonary veins and atria. Three tungsten-coated microelectrodes were inserted into the anterior right ganglionated plexi to record neural activity. Tragus stimulation (20 Hz) in the right ear was accomplished by attaching 2 alligator clips onto the tragus. The voltage slowing the sinus rate or atrioventricular conduction was used as the threshold for setting the low-level tragus stimulation (LL-TS) at 80% below the threshold. At baseline, programmed stimulation determined the effective refractory period (ERP) and the window of vulnerability (WOV), a measure of AF inducibility. For hours 1-3, rapid atrial pacing (RAP) was applied alone, followed by concomitant RAP+LL-TS for hours 4-6 (N = 6). The same parameters were measured during sinus rhythm when RAP stopped after each hour. In 4 other animals, bivagal transection was performed before LL-TS. RESULTS: During hours 1-3 of RAP, there was a progressive and significant decrease in ERP, increase in WOV, and increase in neural activity vs baseline (all P < .05). With RAP+LL-TS during hours 4-6, there was a linear return of ERP, WOV, and neural activity toward baseline levels (all P < .05, compared to the third-hour values). In 4 dogs, bivagal transection prevented the reversal of ERP and WOV despite 3 hours of RAP+LL-TS. CONCLUSIONS: LL-TS can reverse RAP-induced atrial remodeling and inhibit AF inducibility, suggesting a potential noninvasive treatment of AF.

Antiarrhythmic effects of vasostatin-1 in a canine model of atrial fibrillation.

BACKGROUND: We examined the antiarrhythmic effects of vasostatin-1, a recently identified cardioregulatory peptide, in canine models of atrial fibrillation (AF). METHODS AND RESULTS: In 13 pentobarbital-anesthetized dogs bilateral thoracotomies allowed the attachment of multielectrode catheters to superior and inferior pulmonary veins and atrial appendages (AA). Rapid atrial pacing (RAP) was maintained for 6 hours. Each hour, programmed stimulation was performed to determine the window of vulnerability (WOV), a measure of AF inducibility, at all sites. During the last 3 hours, vasostatin-1, 33 nM, was injected into the anterior right (AR) ganglionated plexus (GP) and inferior right (IR) GP every 30 minutes (n = 6). Seven dogs underwent 6 hours of RAP only (controls). At baseline, acetylcholine, 100 mM, was applied on the right AA and AF duration was recorded before and after injection of vasostatin-1, 33 nM, into the ARGP and IRGP. In separate experiments (n = 8), voltage-sinus rate response curves (surrogate for GP function) were constructed by applying high-frequency stimulation to the ARGP with incremental voltages with or without vasostatin-1. Vasostatin-1 significantly decreased the duration of acetylcholine-induced AF (11.0 ± 4.1 vs 5.5 ± 2.6 min, P = 0.02). The cumulative WOV (the sum of individual WOVs) significantly increased (P < 0.0001) during the first 3 hours and decreased toward baseline in the presence of vasostatin-1 (P < 0.0001). Cumulative WOV in controls steadily increased. Vasostatin-1 blunted the slowing of sinus rate with increasing stimulation voltage of ARGP. CONCLUSIONS: Vasostatin-1 suppresses AF inducibility, likely by inhibiting GP function. These data may provide new insights into the role of peptide neuromodulators for AF therapy.

Dissociated pulmonary vein rhythm may predict the acute pulmonary vein reconnection post-isolation in patients with paroxysmal atrial fibrillation.

AIMS: Dissociated pulmonary vein rhythm (PVD) has been taken as a signal of PV isolation, but has been questioned recently; we assessed the relationship between PVD and acute PV reconnection after PV isolation in this study. METHODS AND RESULTS: Eighty-five consecutive patients (52 males; mean age 59±11 years) were referred for catheter ablation of drug-refractory paroxysmal AF. Following PV isolation, the presence and cycle length of PVD were recorded. Pulmonary veins were classified into veins with PVD (Group 1) and veins without PVD (Group 2). Adenosine triphosphate (ATP) was then injected during isoproterenol infusion to reveal dormant conduction gap(s), and PVs were further remapped at 30 min post-isolation. Totally, PVD was observed in 68% (58 of 85) of patients and 34.7% (112 of 323) of PVs. Seventy-nine (24.5%) PVs were found acutely reconnected, including 48 veins revealed by ATP induction [ATP(+)PV] and 64 veins by reassessment after 30 min post-isolation [Time(+)PV]. Time(+)PVs were observed more frequently in Group 1 than those in Group 2 (31.3 vs. 13.7%, P<0.01), but no significant difference was found in the occurrence of ATP(+)PVs between Group 1 and Group 2 (17.9 vs. 13.3%, P=0.27). The sequences of the PVD and the acutely reconnected PV potential were similar in 87.5% of veins. After PV re-isolation, 70% (28 of 40) of previously documented PVD disappeared. CONCLUSION: The occurrence of PVD after PV isolation was closely related to the acute PV reconnection after 30 min post-isolation.

Epigallocatechin-3 gallate, a green tea catechin, attenuated the downregulation of the cardiac gap junction induced by high glucose in neonatal rat cardiomyocytes.

AIMS: The remodeling of cardiac gap junctions has been postulated to contribute to the arrhythmias in a diabetic heart. Epigallocatechin-3 gallate (EGCG), a green tea catechin, has recently been recognized for its protection in cardiovascular disease. This study investigated the effect of EGCG on the possible remodeling of gap junctions under high glucose in cultured neonatal rat cardiomyocytes. METHODS: Cardiomyocytes pre-incubated with high glucose (30mM) were co-treated by EGCG. The expression of Connexin43 (Cx43), Cx40 and Cx45 were determined by Western blot and real-time RT-PCR. The function of cells coupling was evaluated by scrape loading dye transfer study. The Mitogen-activated protein kinases (MAPK) were quantified by Western blot. RESULTS: The protein expression of Cx43 was reduced by high glucose (30mM, 72h). Addition of EGCG to high glucose treated cardiomyocytes attenuated the Cx43 reduction in a dose- and time-dependent manner and also recovered the reduced function of cells coupling. The mRNA or protein level of Cx40 and Cx45 showed no significant change by high glucose (30mM, 72h) or EGCG co-treatment (40microM, 24h). Nor did the Cx43 mRNA level. EGCG (40muM) activated the time-dependent phosphorylated Erk, JNK and p38 MAPK. The p38 MAPK inhibitor SB203580 (10microM), however, attenuated the protective effect of EGCG. CONCLUSION: EGCG could attenuate the downregulation of gap junction induced by high glucose in cultured neonatal rat cardiomyocytes. The p38 MAPK pathway was partly involved in this effect of EGCG.