Browsing by Author "Park, Hyung-Wook"

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    Chronic Low-Level Vagus Nerve Stimulation Reduces Stellate Ganglion Nerve Activity and Paroxysmal Atrial Tachyarrhythmias in Ambulatory Canines
    (Office of the Vice Chancellor for Research, 2011-04-08) Shen, Mark J.; Shinohara, Tetsuji; Park, Hyung-Wook; Frick, Kyle; Ice, Daniel S.; Choi, Eue-Keun; Han, Seongwook; Sharma, Rahul; Shen, Changyu; Fishbein, Michael C.; Chen, Lan S.; Lopshire, John C.; Zipes, Douglas P.; Lin, Shien-Fong; Chen, Peng-Sheng
    Introduction: Left sided low-level vagus nerve stimulation (LL-VNS) is used clinically for epilepsy and depression. We hypothesize that LL-VNS can suppress sympathetic outflow and reduce atrial tachyarrhythmias in ambulatory dogs. Methods: We implanted in 12 dogs a neurostimulator in left cervical vagus nerve and a radiotransmitter for continuous recording of left stellate ganglion nerve activities (SGNA), left thoracic vagal nerve activities (VNA) and electrocardiograms. The first 6 dogs (Group 1) underwent 1 week continuous LL-VNS. Another 6 dogs (Group 2) underwent intermittent rapid atrial pacing followed by active or sham LL-VNS on alternate weeks. Results: Integrated SGNA was significantly reduced during LL-VNS (7.8±0.9 mV-s vs. 9.4±0.9 mVs at baseline, P<0.05) in Group 1.The reduction was most apparent from 7 to 9 AM, (31% reduction, 10.8±2.5 mV-s versus 15.6±2.9 mV-s at baseline, P<0.01), along with a significantly reduced heart rate (P<0.05). SGNA-induced heart rate acceleration averaged 107.9±9.0 bpm during LL-VNS and 129.2±9.3 bpm at baseline (P<0.05). LL-VNS did not change VNA. The tyrosine hydroxylase-positive nerve structures in the left stellate ganglion were 99,684±22,257 µm2/mm2 in LL-VNS dogs and 186,561±11,383 µm2/mm2 (P<0.01) in normal control dogs. In Group 2, the frequencies of paroxysmal atrial fibrillation and atrial tachycardia during active LLVNS were 1.4±2.5/d and 8.0±5.8/d, respectively, significantly lower than during sham stimulation (9.2±6.2/d, P<0.01 and 22.0±4.4/d, P<0.001, respectively). Conclusion: LL-VNS suppresses SGNA and reduces the incidences of paroxysmal atrial tachyarrhythmias in ambulatory dogs. Significant neural remodeling of the left stellate ganglion is evident one week after cessation of chronic LL-VNS.
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    Hypokalemia Promotes Late Phase 3 Early Afterdepolarization and Recurrent Ventricular Fibrillation During Isoproterenol Infusion in Langendorff Perfused Rabbit Ventricles
    (Elsevier, 2014-04) Maruyama, Mitsunori; Ai, Tomohiko; Chua, Su-Kiat; Park, Hyung-Wook; Lee, Young-Soo; Shen, Mark J.; Chang, Po-Cheng; Lin, Shien-Fong; Chen, Peng-Sheng; Department of Medicine, IU School of Medicine
    BACKGROUND Hypokalemia and sympathetic activation are commonly associated with electrical storm (ES) in normal and diseased hearts. The mechanisms remain unclear. OBJECTIVE To test the hypothesis that late phase 3 early afterdepolarization (EAD) induced by IKATP activation underlies the mechanisms of ES during isoproterenol infusion and hypokalemia. METHODS Intracellular calcium (Cai) and membrane voltage were optically mapped in 32 Langendorff-perfused normal rabbit hearts. RESULTS Repeated episodes of electrically-induced VF at baseline did not result in spontaneous VF (SVF). During isoproterenol infusion, SVF occurred in 1 of 15 hearts (7%) studied in normal extracellular potassium ([K+]o) (4.5 mmol/L), 3 of 8 hearts (38%) in 2.0 mmol/L [K+]o, 9 of 10 hearts (90%) in 1.5 mmol/L [K+]o, and 7 of 7 hearts (100%) in 1.0 mmol/L [K+]o (P<0.001). Optical mapping showed isoproterenol and hypokalemia enhanced Cai transient duration (CaiTD) and heterogeneously shortened action potential duration (APD) after defibrillation, leading to late phase 3 EAD and SVF. IKATP blocker (glibenclamide, 5 μmol/L) reversed the post-defibrillation APD shortening and suppressed recurrent SVF in all hearts studied despite no evidence of ischemia. Nifedipine reliably prevented recurrent VF when given before, but not after, the development of VF. IKr blocker (E-4031) and small conductance calcium activated potassium channel blocker (apamin) failed to prevent recurrent SVF. CONCLUSION Beta-adrenergic stimulation and concomitant hypokalemia could cause non-ischemic activation of IKATP, heterogeneous APD shortening and prolongation of CaiTD to provoke late phase 3 EAD, triggered activity and recurrent SVF. IKATP inhibition may be useful in managing ES during resistant hypokalemia.
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    Low-Level Vagus Nerve Stimulation Upregulates Small Conductance Calcium Activated Potassium Channels in the Stellate Ganglion
    (Elsevier, 2013) Shen, Mark J.; Chang, Hao-Che; Park, Hyung-Wook; Akingba, A. George; Chang, Po-Cheng; Zhang, Zheng; Lin, Shien-Fong; Shen, Changyu; Chen, Lan S.; Chen, Zhenhui; Fishbein, Michael C.; Chiamvimonvat, Nipavan; Chen, Peng-Sheng; Medicine, School of Medicine
    Background: Small conductance calcium-activated potassium (SK) channels are responsible for afterhyperpolarization that suppresses nerve discharges. Objectives: To test the hypothesis that low-level vagus nerve stimulation (LL-VNS) leads to the upregulation of SK2 proteins in the left stellate ganglion. Methods: Six dogs (group 1) underwent 1-week LL-VNS of the left cervical vagus nerve. Five normal dogs (group 2) were used as controls. SK2 protein levels were examined by using Western blotting. The ratio between SK2 and glyceraldehydes-3-phosphate-dehydrogenase levels was used as an arbitrary unit (AU). Results: We found higher SK2 expression in group 1 (0.124 ± 0.049 AU) than in group 2 (0.085 ± 0.031 AU; P<.05). Immunostaining showed that the density of nerve structures stained with SK2 antibody was also higher in group 1 (11,546 ± 7,271 μm(2)/mm(2)) than in group 2 (5321 ± 3164 μm(2)/mm(2); P<.05). There were significantly more ganglion cells without immunoreactivity to tyrosine hydroxylase (TH) in group 1 (11.4%±2.3%) than in group 2 (4.9% ± 0.7%; P<.05). The TH-negative ganglion cells mostly stained positive for choline acetyltransferase (95.9% ± 2.8% in group 1 and 86.1% ± 4.4% in group 2; P = .10). Immunofluorescence confocal microscopy revealed a significant decrease in the SK2 staining in the cytosol but an increase in the SK2 staining on the membrane of the ganglion cells in group 1 compared to group 2. Conclusions: Left LL-VNS results in the upregulation of SK2 proteins, increased SK2 protein expression in the cell membrane, and increased TH-negative (mostly choline acetyltransferase-positive) ganglion cells in the left stellate ganglion. These changes may underlie the antiarrhythmic efficacy of LL-VNS in ambulatory dogs.
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    Neural Control of Ventricular Rate in Ambulatory Dogs with Pacing Induced Sustained Atrial Fibrillation
    (American Heart Association, 2012) Park, Hyung-Wook; Shen, Mark J.; Han, Seongwook; Shinohara, Tetsuji; Maruyama, Mitsunori; Lee, Young-Soo; Shen, Changyu; Hwang, Chun; Chen, Lan S.; Fishbein, Michael C.; Lin, Shien-Fong; Chen, Peng-Sheng; Medicine, School of Medicine
    Background: We hypothesize that inferior vena cava-inferior atrial ganglionated plexus nerve activity (IVC-IAGPNA) is responsible for ventricular rate (VR) control during atrial fibrillation (AF) in ambulatory dogs. Methods and results: We recorded bilateral cervical vagal nerve activity (VNA) and IVC-IAGPNA during baseline sinus rhythm and during pacing-induced sustained AF in 6 ambulatory dogs. Integrated nerve activities and average VR were measured every 10 seconds over 24 hours. Left VNA was associated with VR reduction during AF in 5 dogs (from 211 bpm [95% CI, 186-233] to 178 bpm [95% CI, 145-210]; P<0.001) and right VNA in 1 dog (from 208 bpm [95% CI, 197-223] to 181 bpm [95% CI, 163-200]; P<0.01). There were good correlations between IVC-IAGPNA and left VNA in the former 5 dogs and between IVC-IAGPNA and right VNA in the last dog. IVC-IAGPNA was associated with VR reduction in all dogs studied. Right VNA was associated with baseline sinus rate reduction from 105 bpm (95% CI, 95-116) to 77 bpm (95% CI, 64-91; P<0.01) in 4 dogs, whereas left VNA was associated with sinus rate reduction from 111 bpm (95% CI, 90-1250) to 81 bpm (95% CI, 67-103; P<0.01) in 2 dogs. Conclusions: IVC-IAGPNA is invariably associated with VR reduction during AF. In comparison, right or left VNA was associated with VR reduction only when it coactivates with the IVC-IAGPNA. The vagal nerve that controls VR during AF may be different from that which controls sinus rhythm.
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    Selective sinoatrial node optical mapping and the mechanism of sinus rate acceleration
    (J-Stage, 2012) Shinohara, Tetsuji; Park, Hyung-Wook; Joung, Boyoung; Maruyama, Mitsunori; Chua, Su-Kiat; Han, Seongwook; Shen, Mark J.; Chen, Peng-Sheng; Lin, Shien-Fong; Department of Medicine, IU School of Medicine
    BACKGROUND: Studies using isolated sinoatrial node (SAN) cells indicate that rhythmic spontaneous sarcoplasmic reticulum calcium release (Ca clock) plays an important role in SAN automaticity. In the intact SAN, cross-contamination of optical signals from the SAN and the right atrium (RA) prevent the definitive testing of Ca clock hypothesis. The aim of this study was to use a novel approach to selectively mapping the intact SAN to examine the Ca clock mechanism. METHODS AND RESULTS: We simultaneously mapped intracellular Ca (Ca(i)) and membrane potential (V(m)) in 10 isolated, Langendorff-perfused normal canine RAs. The excitability of the RA was suppressed with high-potassium Tyrode's solution, allowing selective optical mapping of V(m) and Ca(i) of the SAN. Isoproterenol (ISO, 0.03 µmol/L) decreased the cycle length of the sinus beats, and shifted the leading pacemaker site from the middle or inferior SAN to the superior SAN in all RAs. The Ca(i) upstroke preceded the V(m) in the leading pacemaker site by up to 18 ± 2 ms. ISO-induced changes to SAN were inhibited by ryanodine (3 µmol/L), but not ZD7288 (3 µmol/L), a selective I(f) blocker. CONCLUSIONS: We conclude that, in the isolated canine RA, a high extracellular potassium concentration can suppress atrial excitability thus leading to SAN-RA conduction block, allowing selective optical mapping of the intact SAN. Acceleration of Ca cycling in the superior SAN underlies the mechanism of sinus tachycardia during sympathetic stimulation.