Prevention of Atrial Fibrillation by Using Sarcoplasmic Reticulum Calcium ATPase Pump Overexpression in a Rabbit Model of Rapid Atrial Pacing.

BACKGROUND Recent research suggests that abnormal Ca2+ handling plays a role in the occurrence and maintenance of atrial fibrillation (AF). Therefore, Ca2+ release and ingestion depend on properties of the ryanodine receptor (RyR) and sarcoplasmic reticulum Ca2+ATPase2a (SERCA2a). This study aimed to detect whether SERCA2a gene overexpression has a preventive effect on atrial fibrillation caused by rapid pacing right atrium. MATERIAL AND METHODS Forty-eight New Zealand white rabbits were randomly divided into a control group, AF group, AAV9/GFP group, and AAV9/SERCA2a group. The right atrium was rapidly paced at 600 beats/min for 30 days after an intraperitoneal injection of an adeno-associated virus expressing the SERCA2a gene and GFP. The AF induction rate and the effective refraction period (ERP) were measured after 0, 4, 8, 12, and 24 h of pacing. Western blot analysis was used to test for the expression of SERCA2a. Changes in atrial tissue structure were observed by H&E staining and electron microscopy. RESULTS The AF induction rate was higher in the AF groups than in the AAV9/SERCA2a group at different time points of pacing. After 12 h of pacing, ERP was significantly prolonged in the AAV9/SERCA2a group compared to the AF and AAV9/GFP groups (p<0.05). SERCA2a protein expression was significantly lower in the AF and AAV9/GFP groups compared to the control group (p<0.05), while expression was significantly higher in the AAV9/SERCA2a group than in the AF and AAV9/GFP groups (p<0.05). The myocardial structure of the AAV9/SERCA2a group was significantly improved compared with the AF group, indicating that SERCA2a overexpression relieved the structural remodeling of atrial fibrillation. CONCLUSIONS SERCA2a overexpression is capable of suppressing ERP shortening and AF induced by rapid pacing atrium. SERCA2a gene therapy is expected to be a new anti-atrial fibrillation strategy.

[Efficacy of sequential ablation of sinus atrial node fat pad and atrial ventricular node fat pad on inducibility of atrial fibrillation evoked by vagus trunk stimulation].

OBJECTIVE: To explore the efficacy of sequential ablation of epicardial fat pad on inducibility of atrial fibrillation (AF) evoked by stimulating vagus trunk. METHODS: Eighteen adult mongrel dogs were randomly divided into 2 groups (n = 9 each): Group A underwent pre-ablation of sinus-atrial node fad pad (SANFP) and subsequent ablation of atria-ventricular node fad pad (AVNFP). Group B underwent pre-ablation of AVNFP and subsequent ablation of SANFP. AF was induced by high-frequency electrical stimulation of bilateral vagus trunks. The AF inducibility and effective refractory period (ERP) changes during vagus trunk stimulation were examined before and after ablation in atria and pulmonary veins. RESULTS: (1) AF could be induced by vagus trunk stimulation and the incidence was higher during right vagus trunk (RVG) stimulation than left vagus trunk (LVG) stimulation [(60.0 ± 0.0)% vs (18.4 ± 22.1)%]. (2) SANFP ablation significantly attenuated AF inducibility with LVG stimulation and RVG stimulation at 2 V (decreased 67.0% and 72.0%, respectively). Subsequent AVNFP ablation after SANFP ablation further reduced AF inducibility with LVG and RVG stimulation at 2 V (decreased 100.0% and 95.5%, respectively). (3) AVNFP ablation (decreased 95.7% and 96.3%, respectively) and subsequent SANFP ablation after AVNFP ablation (decreased 98.0% and 100.0%, respectively) significantly attenuated AF inducibility with LVG stimulation and RVG stimulation at 2V. (4) Vagal stimulation induced ERP shortening was significantly attenuated by isolated SANFP ablation or AVNFP. Subsequent AVNFP ablation after SANFP induced significant ERP shortening in right atrial site compared with isolated SANFP ablation. However, changes of ERP shortening were similar between AVNFP ablation and subsequent SANFP ablation after AVNFP ablation. CONCLUSIONS: Epicardial fat pad ablation reduced the AF inducibility and prolonged ERP of atria and pulmonary veins during vagus trunk stimulation. AVNFP, as the "integration centers" modulating the vagal innervation to the atria, may be the more effective target of ablation for treating AF.

[Metal stress-induced arrhythmia and thoracic spinal cord 1-5 nerve remodeling and myocardial electrophysiological remodeling in rats].

OBJECTIVE: The study aimed to investigate the relationship between arrhythmia occurrence and nerve remodeling of thoracic spinal cord 1-5 nerves as well as myocardial electrophysiological remodeling in a metal stress rat model. METHODS: Thirty SD rats (weight 180-250 g) were randomly divided into control group (n = 10), stress group (n = 10) and fluoxetine group (n = 10, 10 mg/kg i.p. for 3 weeks). Stress model (given by unpredicted chronic mild stress) was established according to Cronli's protocol. Following parameters were observed:(1) ECG waveform change and arrhythmias;(2) tissue field action potential duration (FAPD) of thoracic spinal cord 1-5 and cardiac tissue mapped by microelectrode arrays (MEA) technique;(3) myocardial growth-associated protein (GAP-43), tyrosine hydroxylase (TH), choline acetyltransferase (CHAT) distribution observed by immunofluorescence and confocal laser scanning microscope (LSCM). RESULTS: Three weeks later: (1) The body weight, food intake, consumption of sugar water, the horizontal and vertical movement score, cleaning action of rats were significantly decreased, and fecal grains significantly increased, P-wave, P-R interval, QRS-wave and Q-T interval were significantly prolonged and heart rate was significantly reduced in stress group compared with control group (all P < 0.05). Incidence of ventricular premature beat was 80% in stress group and 0% in control group (P < 0.05). The FAPD of thoracic spinal cord 1-5 nerves [(144.25 ± 12.63)ms vs (79.56 ± 8.01)ms] and of cardiac tissue [LA(122.43 ± 19.34)ms vs (92.59 ± 7.61)ms, RA(149.89 ± 14.68)ms vs (105.18 ± 15.94)ms, LV(162.62 ± 7.04)ms vs (110.45 ± 6.92)ms, RV(152.21 ± 30.49)ms vs (131.06 ± 12.04)ms] were significantly prolonged, FAPD dispersion (FAPDd) significantly increased [thoracic spinal cord 1-5(13.3 ± 9.11)ms vs (9.36 ± 7.01)ms] in stress group compared with the control group. Disarrangement of myocardial cells, proliferation of collagen fiber, infiltration of neutrophil and lymphocytes in the cardiac tissue were also observed and distribution of GAP-43, TH and CHAT was significantly increased in stress group. (2) All these changes could be partly reversed by the treatment with fluoxetine. CONCLUSION: Metal stress induced cardiac autonomic nerve and myocardial electrophysiological remodeling and ventricular arrhythmia in rats which could be significantly attenuated by fluoxetine in this model.

[Impact of magnetic field exposure on cardiac autonomic tone and inducibility of atrial fibrillation in dogs].

OBJECTIVE: To observe the maximal heart rate changes, atrioventricular (A-V) conduction block and atrial fibrillation (AF) inducibility in dogs with vagosympathetic trunk exposed to electromagnetic fields (EMFs). METHODS: The vagosympathetic trunk of adult dogs was separated and exposed to EMFs 0.043 kHz (2.87 microG, n = 5) and to EMFs 2 kHz (0.34 microG, n = 6) for two to three hours. Simultaneously, the vagosympathetic trunk was stimulated with 20 Hz frequency and 1 - 8 V intensity for 0.1 ms. Heart rate, presence of A-V conduction block and AF inducibility were determined. RESULTS: After 5-minutes exposure to EMFs 0.043 kHz (2.87 microG), the maximal heart rate decreased 29%, the voltage applied to vagosympathetic trunk required to induce A-V conduction block decreased by 60% in experimental group versus 5% increase in control group. This effect lasted 2 to 3 hours. While vagosympathetic trunk exposure to EMFs 2 kHz (0.34 microG) was associated with significant increase in the incidence of atrial premature beats, atrial tachycardia and AF, these effects could be blocked by propranolol and atropine. CONCLUSIONS: Our results showed that 0.043 kHz (2.87 microG) EMFs exposure might reduce while 2 kHz (0.34 microG) EMFs exposure might increase AF inducibility. Our study thus suggested autonomic nervous system of dogs could be affected by EMFs exposure and 0.043 kHz (2.87 microG) EMFs exposure might be a novel option for AF prevention.

Renal Denervation Reduced Ventricular Arrhythmia After Myocardial Infarction by Inhibiting Sympathetic Activity and Remodeling.

Background Ventricular arrhythmia after myocardial infarction is the most important risk factor for sudden cardiac death, which poses a serious threat to human health. As the correlation between autonomic nervous systemic dysfunction and heart rhythm abnormality has been gradually revealed, remedies targeting autonomic nervous system dysfunction, especially the sympathetic nerve, have emerged. Among them, renal denervation is noted for its powerful effect on the inhibition of sympathetic nerve activity. We aim to investigate whether renal denervation can reduce ventricular arrhythmia after myocardial infarction and thus decrease the risk of sudden cardiac death. In addition, we explore the potential mechanism with respect to nerve activity and remodeling. Methods and Results Twenty-four beagles were randomized into the control (n=4), renal denervation (n=10), and sham (n=10) groups. Permanent left anterior descending artery ligation was performed to establish myocardial infarction in the latter 2 groups. Animals in the renal denervation group underwent both surgical and chemical renal denervation. Compared with dogs in the sham group, dogs in the renal denervation group demonstrated attenuated effective refractory period shortening and inhomogeneity, flattened restitution curve, increased ventricular threshold, and decreased ventricular arrhythmia. Heart rate variability assessment, catecholamine measurement, and nerve discharge recordings all indicated that renal denervation could reduce whole-body and local tissue sympathetic tone. Tissue analysis revealed a significant decrease in neural remodeling in both the heart and stellate ganglion. Conclusions Surgical and chemical renal denervation decreased whole-body and local tissue sympathetic activity and reversed neural remodeling in the heart and stellate ganglion. Consequently, renal denervation led to beneficial remodeling of the electrophysiological characteristics in the infarction border zone, translating to a decrease in ventricular arrhythmia after myocardial infarction.