Ganglionated plexi and ligament of Marshall ablation reduces atrial vulnerability and causes stellate ganglion remodeling in ambulatory dogs

Background Simultaneous activation of the stellate ganglion (SGNA), the ligament of Marshall (LOM) and the ganglionated plexi (GP) often precedes the onset of paroxysmal atrial tachyarrhythmias (PAT). Objective To test the hypothesis that ablation of the LOM and the superior left GP (SLGP) reduces atrial vulnerability and results in remodeling of the stellate ganglion. Methods Nerve activity was correlated to PAT and ventricular rate (VR) at baseline, after ablation of the LOM and SLGP, and after AF. Neuronal cell death was assessed with Tyrosine hydroxylase (TH) and terminal deoxynucleotidyl transferase dUTP nick end label (TUNEL) staining. Results There were 4±2 PAT episodes per day in controls. None were observed in the ablation group; even though SGNA and VR increased from 2.2 μV (95% confidence interval (CI); 1.2 – 3.3 μV) and 80 bpm (CI 68 – 92 bpm) at baseline to 3.0 μV (CI 2.6 – 3.4 μV, p=0.046) and 90 bpm (CI 75 – 108 bpm, p=0.026) after ablation, and to 3.1 μV (CI 1.7 – 4.5 μV, p=0.116) and 95 bpm (CI 79 – 110 bpm, p=0.075) after AF. There was an increase in TH-negative cells in the ablation group and a 19.7% (CI, 8.6 – 30.8%) TUNEL-positive staining in both the left and right SG. None were observed in the control group. Conclusion LOM and SLGP ablation caused LSG remodeling and cell death. There was reduced correlation of the VR response and PAT to SGNA. These findings support the importance of SLGP and LOM in atrial arrhythmogenesis

Assessing the effects of mitofusin 2 deficiency in the adult heart using 3D electron tomography

The effects of mitofusin 2 (MFN2) deficiency, on mitochondrial morphology and the mitochondria-junctional sarcoplasmic reticulum (jSR) complex in the adult heart, have been previously investigated using 2D electron microscopy, an approach which is unable to provide a 3D spatial assessment of these imaging parameters. Here, we use 3D electron tomography to show that MFN2-deficient mitochondria are larger in volume, more elongated, and less rounded; have fewer mitochondria-jSR contacts, and an increase in the distance between mitochondria and jSR, when compared to WT mitochondria. In comparison to 2D electron microscopy, 3D electron tomography can provide further insights into mitochondrial morphology and the mitochondria-jSR complex in the adult heart

Intermittent left cervical vagal nerve stimulation damages the stellate ganglia and reduces the ventricular rate during sustained atrial fibrillation in ambulatory dogs

BACKGROUND: The effects of intermittent open-loop vagal nerve stimulation (VNS) on the ventricular rate (VR) during atrial fibrillation (AF) remain unclear. OBJECTIVE: The purpose of this study was to test the hypothesis that VNS damages the stellate ganglion (SG) and improves VR control during persistent AF. METHODS: We performed left cervical VNS in ambulatory dogs while recording the left SG nerve activity (SGNA) and vagal nerve activity. Tyrosine hydroxylase (TH) staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to assess neuronal cell death in the SG. RESULTS: We induced persistent AF by atrial pacing in 6 dogs, followed by intermittent VNS with short ON-time (14 seconds) and long OFF-time (66 seconds). The integrated SGNA and VR during AF were 4.84 mV·s (95% confidence interval [CI] 3.08-6.60 mV·s) and 142 beats/min (95% CI 116-168 beats/min), respectively. During AF, VNS reduced the integrated SGNA and VR, respectively, to 3.74 mV·s (95% CI 2.27-5.20 mV·s; P = .021) and 115 beats/min (95% CI 96-134 beats/min; P = .016) during 66-second OFF-time and to 4.07 mV·s (95% CI 2.42-5.72 mV·s; P = .037) and 114 beats/min (95% CI 83-146 beats/min; P = .039) during 3-minute OFF-time. VNS increased the frequencies of prolonged (>3 seconds) pauses during AF. TH staining showed large confluent areas of damage in the left SG, characterized by pyknotic nuclei, reduced TH staining, increased percentage of TH-negative ganglion cells, and positive TUNEL staining. Occasional TUNEL-positive ganglion cells were also observed in the right SG. CONCLUSION: VNS damaged the SG, leading to reduced SGNA and better rate control during persistent AF

Effects of renal sympathetic denervation on the stellate ganglion and brain stem in dogs

BACKGROUND: Renal sympathetic denervation (RD) is a promising method of neuromodulation for the management of cardiac arrhythmia. OBJECTIVE: We tested the hypothesis that RD is antiarrhythmic in ambulatory dogs because it reduces the stellate ganglion nerve activity (SGNA) by remodeling the stellate ganglion (SG) and brain stem. METHODS: We implanted a radiotransmitter to record SGNA and electrocardiogram in 9 ambulatory dogs for 2 weeks, followed by a second surgery for RD and 2 months SGNA recording. Cell death was probed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. RESULTS: Integrated SGNA at baseline and 1 and 2 months after RD were 14.0 ± 4.0, 9.3 ± 2.8, and 9.6 ± 2.0 μV, respectively (P = .042). The SG from RD but not normal control dogs (n = 5) showed confluent damage. An average of 41% ± 10% and 40% ± 16% of ganglion cells in the left and right SG, respectively, were TUNEL positive in RD dogs compared with 0% in controls dogs (P = .005 for both). The left and right SG from RD dogs had more tyrosine hydroxylase-negative ganglion cells than did the left SG of control dogs (P = .028 and P = .047, respectively). Extensive TUNEL-positive neurons and glial cells were also noted in the medulla, associated with strongly positive glial fibrillary acidic protein staining. The distribution was heterogeneous, with more cell death in the medial than lateral aspects of the medulla. CONCLUSION: Bilateral RD caused significant central and peripheral sympathetic nerve remodeling and reduced SGNA in ambulatory dogs. These findings may in part explain the antiarrhythmic effects of RD

Effects of vildagliptin, metformin, and combined drugs on intracellular calcium regulation.

<p>(A) Intracellular diastolic calcium was increased in HFDV. All treatments reduced intracellular diastolic calcium in HFD rats. (B) Calcium transient amplitude was decreased in HFDV. All treatments improved calcium transient amplitude in HFD rats. (C) Calcium transient decay rate was reduced in HFDV. All treatments increased the calcium transient decay rate in HFD rats. (D) Representative calcium transient tracing for calcium transient parameters determination. *p<0.05 vs. baseline NDV, ^†p<0.01 vs. baseline HFDV, ^‡p<0.05 vs. HFDV with H₂O₂ n = 8 cells/group</p

Effects of HFD consumption on metabolic parameters at baseline and 12-week after HFD consumption.

<p>ND  =  normal diet, HFD  =  high-fat diet. *<i>P</i><0.05 vs. Baseline, ^†<i>P</i><0.05 vs. ND week 12.</p

Effects of vildagliptin, metformin, combined drugs on arrhythmia, mortality rate, and phosphorylation of Cx43 level.

<p>(A) Combined drugs reduced arrhythmia score in HFD rats.*p<0.05 vs. HFDV, n = 11/group. (B) Combined drugs delayed time to the 1^st VT/VF onset in HFD rats. *p<0.05 vs. HFDV, n = 11/group. (C) Mortality rate was higher in HFDV, and combined drugs reduced mortality rate in both ND and HFD rats. *p<0.05 vs. NDV, ^†p<0.05 vs. HFDV, n = 11/group. (D) Combined drugs increased p-Cx43 in HFD rats. *p<0.05 vs. HFDV, n = 5/group.</p

Effects of vildagliptin, metformin, and combined drugs on infarct size, Bax, and Bcl-2 expression.

<p>(A) Infarct size was increased in HFDV, and all treatments reduced infarct size in both ND and HFD rats. *p<0.05 vs. NDV, ^†p<0.01 vs. HFDV, n = 6/group. (B) Representative images showing TTC staining for infarct size determination. (C) Bax expression was increased in HFDV, and all treatments reduced Bax expression in HFD rats. *p<0.05 vs. NDV, ^†p<0.05 vs. HFDV, n = 5/group. (D) Bcl-2 expression was decreased in HFDV, and all treatments increased Bcl-2 expression in HFD rats. *p<0.05 vs. NDV, ^†p<0.05 vs. HFDV, n = 5/group.</p