Browsing by Author "Everett, Thomas H."

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Antiarrhythmic effects of stimulating the left dorsal branch of the thoracic nerve in a canine model of paroxysmal atrial tachyarrhythmias
(2018-08-01)
Zhao, Ye
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Yuan, Yuan
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Tsai, Wei-Chung
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Jiang, Zhaolei
;
Tian, Zhi-peng
BACKGROUND Stellate ganglion nerve activity (SGNA) precedes paroxysmal atrial tachyarrhythmia (PAT) episodes in dogs with intermittent rapid left atrial (LA) pacing. The left dorsal branch of the thoracic nerve (LDTN) contains sympathetic nerves originating from the stellate ganglia. OBJECTIVE The purpose of this study was to test the hypothesis that high-frequency electrical stimulation of the LDTN can cause stellate ganglia damage and suppress PATs. METHODS We performed long-term LDTN stimulation in 6 dogs with and 2 dogs without intermittent rapid LA pacing while monitoring SGNA. RESULTS LDTN stimulation reduced average SGNA from 4.36 mu V (95% confidence interval [CI] 4.10-4.62 mu V) at baseline to 3.22 mu V (95% CI 3.04-3.40 mu V) after 2 weeks (P5.028) and completely suppressed all PAT episodes in all dogs studied. Tyrosine hydroxylase staining showed large damaged regions in both stellate ganglia, with increased percentages of tyrosine hydroxylase-negative cells. The terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that 23.36% (95% CI 18.74%-27.98%) of ganglion cells in the left stellate ganglia and 11.15% (95% CI 9.34%-12.96%) ganglion cells in the right stellate ganglia were positive, indicating extensive cell death. A reduction of both SGNA and heart rate was also observed in dogs with LDTN stimulation but without rapid LA pacing. Histological studies in the 2 dogs without intermittent rapid LA pacing confirmed the presence of extensive stellate ganglia damage, along with a high percentage of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. CONCLUSION LDTN stimulation damages both left and right stellate ganglia, reduces left SGNA, and is antiarrhythmic in this canine model of PAT.
Concomitant SK current activation and sodium current inhibition cause J wave syndrome
(2018-11-15)
Chen, Mu
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Xu, Dong-Zhu
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Wu, Adonis Z.
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Guo, Shuai
;
Wan, Juyi
The mechanisms of J wave syndrome (JWS) are incompletely understood. Here, we showed that the concomitant activation of small-conductance calcium-activated potassium (SK) current (I-KAS) and inhibition of sodium current by cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) recapitulate the phenotypes of JWS in Langendorff-perfused rabbit hearts. CyPPA induced significant J wave elevation and frequent spontaneous ventricular fibrillation (SVF), as well as sinus bradycardia, atrioventricular block, and intraventricular conduction delay. I-KAS activation by CyPPA resulted in heterogeneous shortening of action potential (AP) duration (APD) and repolarization alternans. CyPPA inhibited cardiac sodium current (I-Na) and decelerated AP upstroke and intracellular calcium transient. SVFs were typically triggered by short-coupled premature ventricular contractions, initiated with phase 2 reentry and originated more frequently from the right than the left ventricles. Subsequent I-KAS blockade by apamin reduced J wave elevation and eliminated SVF. beta-Adrenergic stimulation was antiarrhythmic in CyPPA-induced electrical storm. Like CyPPA, hypothermia (32.0 degrees C) also induced J wave elevation and SVF. It facilitated negative calcium-voltage coupling and phase 2 repolarization alternans with spatial and electromechanical discordance, which were ameliorated by apamin. These findings suggest that I-KAS activation contributes to the development of JWS in rabbit ventricles.
Effects of ondansetron on apamin-sensitive small conductance calcium-activated potassium currents in pacing-induced failing rabbit hearts
(2020-02-01)
Yin, Dechun
;
Yang, Na
;
Tian, Zhipeng
;
Wu, Adonis Z.
;
Xu, Dongzhu
BACKGROUND Ondansetron, a widely prescribed antiemetic, has been implicated in drug-induced long QT syndrome. Recent patch clamp experiments have shown that ondansetron inhibits the apamin-sensitive small conductance calcium-activated potassium current (I-KAS). OBJECTIVE The purpose of this study was to determine whether ondansetron causes action potential duration (APD) prolongation by I-KAS inhibition. METHODS Optical mapping was performed in rabbit hearts with pacing-induced heart failure (HF) and in normal hearts before and after ondansetron (100 nM) infusion. APD at 80% repolarization (APD(80)) and arrhythmia inducibility were determined. Additional studies with ondansetron were performed in normal hearts perfused with hypokalemic Tyrode's (2.4 mM) solution before or after apamin administration. RESULTS The corrected QT interval in HF was 326 ms (95% confidence interval [CI] 306-347 ms) at baseline and 364 ms (95% CI 351-378 ms) after ondansetron infusion (P < .001). Ondansetron significantly prolonged APD(80) in the HF group and promoted early afterdepolarizations, steepened the APD restitution curve, and increased ventricular vulnerability. Ventricular fibrillation was not inducible in HF ventricles at baseline, but after ondansetron infusion, ventricular fibrillation was induced in 5 of the 7 ventricles (P = .021). In hypokalemia, apamin prolonged APD(80) from 163 ms (95% CI 146-180 ms) to 180 ms (95% CI 156-204 ms) (P = .018). Subsequent administration of ondansetron failed to further prolong APD(80) (180 ms [95% CI 156-204 ms] vs 179 ms [95% CI 165-194 ms]; P = .789). The results were similar when ondansetron was administered first, followed by apamin. CONCLUSION Ondansetron is a specific I-KAS blocker at therapeutic concentrations. Ondansetron may prolong the QT interval in HF by inhibiting small conductance calcium-activated potassium channels, which increases the vulnerability to ventricular arrhythmias.
Effects of renal sympathetic denervation on the stellate ganglion and brain stem in dogs
(2017-02-01)
Tsai, Wei-Chung
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Chan, Yi-Hsin
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Chinda, Kroekkiat
;
Chen, Zhenhui
;
Patel, Jheel
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 mu V, 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.
Estimating Sympathetic Tone by Recording Subcutaneous Nerve Activity in Ambulatory Dogs
(2015-01-01)
Robinson, Eric A.
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Rhee, Kyoung-Suk
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Doytchinova, Anisiia
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Kumar, Mohineesh
;
Shelton, Richard
Subcutaneous Nerve Activity IntroductionWe tested the hypothesis that subcutaneous nerve activity (SCNA) of the thorax correlates with the stellate ganglion nerve activity (SGNA) and can be used to estimate the sympathetic tone. Methods and ResultsWe implanted radio transmitters in 11 ambulatory dogs to record left SGNA, left thoracic vagal nerve activity (VNA), and left thoracic SCNA, including 3 with simultaneous video monitoring and nerve recording. Two additional dogs were studied under general anesthesia with apamin injected into the right stellate ganglion while the right SGNA and the right SCNA were recorded. There was a significant positive correlation between integrated SGNA (iSGNA) and integrated SCNA (iSCNA) in the first 7 ambulatory dogs, with correlation coefficient of 0.70 (95% confidence interval [CI] 0.61-0.84, P < 0.05 for each dog). Tachycardia episodes (heart rate exceeding 150 bpm for 3 seconds) were invariably preceded by SGNA and SCNA. There was circadian variation of both SCNA and SGNA. Crosstalk was ruled out because SGNA, VNA, and SCNA bursts had different timing and activation patterns. In an eighth dog, closely spaced bipolar subcutaneous electrodes also recorded SCNA, but with reduced signal to noise ratio. Video monitoring in additional 3 dogs showed that movement was not a cause of high frequency SCNA. The right SGNA correlated strongly with right SCNA and heart rate in 2 anesthetized dogs after apamin injection into the right stellate ganglion. ConclusionsSCNA recorded by bipolar subcutaneous electrodes correlates with the SGNA and can be used to estimate the sympathetic tone.
Ganglionated plexi and ligament of Marshall ablation reduces atrial vulnerability and causes stellate ganglion remodeling in ambulatory dogs
(2016-10)
Zhao, Ye
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Jiang, Zhaolei
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Tsai, Wei-Chung
;
Yuan, Yuan
;
Chinda, Kroekkiat
BACKGROUND Simultaneous activation of the stellate ganglion (SG), the ligament of Marshall (LOM), and the ganglionated plexi often precedes the onset of paroxysmal atrial tachyarrhythmia (PAT). OBJECTIVE The purpose of this study was to test the hypothesis that ablation of the LOM and the superior left ganglionated plexi (SLGP) reduces atrial vulnerability and results in remodeling of the SG. METHODS Nerve activity was correlated to PAT and ventricular rate (VR) at baseline, after ablation of the LOM and SLGP, and after atrial fibrillation. Neuronal cell death was assessed with tyrosine hydroxylase 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 SG nerve activity and VR increased from 2.2 mu V (95% confidence interval [CI] 1.2-3.3 mu V) and 80 bpm (95% CI 68-92 bpm) at baseline, to 3.0 mu V (95% CI 2.6-3.4 mu V, P = .046) and 90 bpm (95% CI 75-108 bpm, P = .026) after ablation, and to 3.1 mu V (95% CI 1.7-4.5 mu V, P = .116) and 95 bpm (95% CI 79-110 bpm, P = .075) after atrial fibrillation. There was an increase in tyrosine hydroxylase negative cells in the ablation group and 19.7% (95% CI 8.6%-30.8%) TUN EL-positive staining in both the left and right SG. None were observed in the control group. CONCLUSION LOM and SLGP ablation caused left SG remodeling and cell death. There was reduced correlation of the VR response and PAT to SG nerve activity. These findings support the importance of SLGP and LOM in atrial arrhythmogenesis.
Left cervical vagal nerve stimulation reduces skin sympathetic nerve activity in patients with drug resistant epilepsy
(2017-12-01)
Yuan, Yuan
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Hassel, Jonathan L.
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Doytchinova, Anisiia
;
Adams, David
;
Wright, Keith C.
BACKGROUND We recently reported that skin sympathetic nerve activity (SKNA) can be used to estimate sympathetic tone in humans. In animal models, vagal nerve stimulation (VNS) can damage the stellate ganglion, reduce stellate ganglion nerve activity, and suppress cardiac arrhythmia. Whether VNS can suppress sympathetic tone in humans remains unclear. OBJECTIVE The purpose of this study was to test the hypothesis that VNS suppresses SKNA in patients with drug-resistant epilepsy. METHODS ECG patch electrodes were used to continuously record SKNA in 26 patients with drug-resistant epilepsy who were admitted for video electroencephalographic monitoring. Among them, 6 (2 men, age 40 +/- 11 years) were previously treated with VNS and 20 (7 men, age 37 +/- 8 years) were not. The signals from ECG leads I and II were filtered to detect SKNA. RESULTS VNS had an on-time of 30 seconds and off-time of 158672 seconds, with output of 1.9260.42 mA at 24.17 +/- 2.01 Hz. Average SKNA during VNS off-time was 1.06 mV (95% confidence interval [CI] 0.93-1.18) in lead I and 1.13 mV (95% CI 0.99-1.27) in lead II, which was significantly lower than 1.38 mV (95% CI 1.01-1.75; P = .036) and 1.38 mV (95% CI 0.98-1.78; P = .035) in the control group, respectively. Heart rate was 65 bpm (95% CI 59-71) in the VNS group, which was significantly lower than 77 bpm (95% CI 71-83) in the control group. CONCLUSION Patients with VNS had significantly lower SKNA than those without VNS.
Long-term intermittent high-amplitude subcutaneous nerve stimulation reduces sympathetic tone in ambulatory dogs
(2018-03-01)
Yuan, Yuan
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Jiang, Zhaolei
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Zhao, Ye
;
Tsai, Wei-Chung
;
Patel, Jheel
BACKGROUND Reducing sympathetic efferent outflow from the stellate ganglia (SG) may be antiarrhythmic. OBJECTIVE The purpose of this study was to test the hypothesis that chronic thoracic subcutaneous nerve stimulation (ScNS) could reduce SG nerve activity (SGNA) and control paroxysmal atrial tachycardia (PAT). METHODS Thoracic ScNS was performed in 8 dogs while SGNA, vagal nerve activity (VNA), and subcutaneous nerve activity (ScNA) were monitored. An additional 3 dogs were used for sham stimulation as controls. RESULTS Xinshu ScNS and left lateral thoracic nerve ScNS reduced heart rate (HR). Xinshu ScNS at 3.5 mA for 2 weeks reduced mean average SGNA from 5.32 mV (95% confidence interval [ CI] 3.89-6.75) at baseline to 3.24 mV (95% CI 2.16-4.31; P = .015) and mean HR from 89 bpm (95% CI 80-98) at baseline to 83 bpm (95% CI 76-90; P = .007). Bilateral SG showed regions of decreased tyrosine hydroxylase staining with increased terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive nuclei in 18.47% (95% CI 9.68-46.62) of all ganglion cells, indicating cell death. Spontaneous PAT episodes were reduced from 9.83 per day (95% CI 5.77-13.89) in controls to 3.00 per day (95% CI 0.11-5.89) after ScNS (P = .027). Left lateral thoracic nerve ScNS also led to significant bilateral SG neuronal death and significantly reduced average SGNA and HR in dogs. CONCLUSION ScNS at 2 different sites in the thorax led to SG cell death, reduced SGNA, and suppressed PAT in ambulatory dogs.
Role of Apamin-Sensitive Calcium-Activated Small-Conductance Potassium Currents on the Mechanisms of Ventricular Fibrillation in Pacing-Induced Failing Rabbit Hearts
(2017-02-01)
Yin, Dechun
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Hsieh, Yu-Cheng
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Tsai, Wei-Chung
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Wu, Adonis Zhi-Yang
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Jiang, Zhaolei
Background-Ventricular fibrillation (VF) during heart failure is characterized by stable reentrant spiral waves (rotors). Apamin-sensitive small-conductance calcium-activated potassium currents (I-KAS) are heterogeneously upregulated in failing hearts. We hypothesized that I-KAS influences the location and stability of rotors during VF. Methods and Results-Optical mapping was performed on 9 rabbit hearts with pacing-induced heart failure. The epicardial right ventricular and left ventricular surfaces were simultaneously mapped in a Langendorff preparation. At baseline and after apamin (100 nmol/L) infusion, the action potential duration (APD(80)) was determined, and VF was induced. Areas with a >50% increase in the maximum action potential duration (Delta APD) after apamin infusion were considered to have a high I-KAS distribution. At baseline, the distribution density of phase singularities during VF in high I-KAS distribution areas was higher than in other areas (0.0035 +/- 0.0011 versus 0.0014 +/- 0.0010 phase singularities/pixel; P=0.004). In addition, high dominant frequencies also colocalized to high I-KAS distribution areas (26.0 versus 17.9 Hz; P=0.003). These correlations were eliminated during VF after apamin infusion, as the number of phase singularities (17.2 versus 11.0; P=0.009) and dominant frequencies (22.1 versus 16.2 Hz; P=0.022) were all significantly decreased. In addition, reentrant spiral waves became unstable after apamin infusion, and the duration of VF decreased. Conclusions-The I-KAS current influences the mechanism of VF in failing hearts as phase singularities, high dominant frequencies, and reentrant spiral waves all correlated to areas of high I-KAS. Apamin eliminated this relationship and reduced VF vulnerability.
Role of apamin-sensitive small conductance calcium-activated potassium currents in long-term cardiac memory in rabbits
(2018-05-01)
Yin, Dechun
;
Chen, Mu
;
Yang, Na
;
Wu, Adonis Z.
;
Xu, Dongzhu
BACKGROUND Apamin-sensitive small conductance calcium-activated K current (I-KAS) is up-regulated during ventricular pacing and masks short-term cardiac memory (CM). OBJECTIVE The purpose of this study was to determine the role of I-KAS in long-term CM. METHODS CM was created with 3-5 weeks of ventricular pacing and defined by a flat or inverted T wave off pacing. Epicardial optical mapping was performed in both paced and normal ventricles. Action potential duration (APD(80)) was determined during right atrial pacing. Ventricular stability was tested before and after I-KAS blockade. Four paced hearts and 4 normal hearts were used for western blotting and histology. RESULTS There were no significant differences in either echocardiographic parameters or fibrosis levels between groups. Apamin induced more APD(80) prolongation in CM than in normal ventricles (mean [95% confidence interval]: 9.6% [8.8%-10.5%] vs 3.1% [1.9%-4.3%]; P <.001). Apamin significantly lengthened APD(80) in the CM model at late activation sites, indicating significant I-KAS up-regulation at those sites. The CM model also had altered Ca2+ handling, with the 50% Ca2+ transient duration and amplitude increased at distal sites compared to a proximal site (near the pacing site). After apamin, the CM model had increased ventricular fibrillation (VF) inducibility (paced vs control: 33/40 (82.5%) vs 7/20 (35%); P < .001) and longer VF durations (124 vs 26 seconds; P < .001). CONCLUSION Chronic ventricular pacing increases Ca2+ transients at late activation sites, which activates I-KAS to maintain repolarization reserve. I-KAS blockade increases VF vulnerability in chronically paced rabbit ventricles.
Sex-specific activation of SK current by isoproterenol facilitates action potential triangulation and arrhythmogenesis in rabbit ventricles
(2018-09-15)
Chen, Mu
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Yin, Dechun
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Guo, Shuai
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Xu, Dong-Zhu
;
Wang, Zhuo
Sex has a large influence on cardiac electrophysiological properties. Whether sex differences exist in apamin-sensitive small conductance Ca2+-activated K+ (SK) current (I-KAS) remains unknown. We performed optical mapping, transmembrane potential, patch clamp, western blot and immunostaining in 62 normal rabbit ventricles, including 32 females and 30 males. I-KAS blockade by apamin only minimally prolonged action potential (AP) duration (APD) in the basal condition for both sexes, but significantly prolonged APD in the presence of isoproterenol in females. Apamin prolonged APD at the level of 25% repolarization (APD(25)) more prominently than APD at the level of 80% repolarization (APD(80)), consequently reversing isoproterenol-induced AP triangulation in females. In comparison, apamin prolonged APD to a significantly lesser extent in males and failed to restore the AP plateau during isoproterenol infusion. I-KAS in males did not respond to the L-type calcium current agonist BayK8644, but was amplified by the casein kinase 2 (CK2) inhibitor 4,5,6,7-tetrabromobenzotriazole. In addition, whole-cell outward I-KAS densities in ventricular cardiomyocytes were significantly larger in females than in males. SK channel subtype 2 (SK2) protein expression was higher and the CK2/SK2 ratio was lower in females than in males. I-KAS activation in females induced negative intracellular Ca2+-voltage coupling, promoted electromechanically discordant phase 2 repolarization alternans and facilitated ventricular fibrillation (VF). Apamin eliminated the negative Ca2+-voltage coupling, attenuated alternans and reduced VF inducibility, phase singularities and dominant frequencies in females, but not in males. We conclude that beta-adrenergic stimulation activates ventricular I-KAS in females to a much greater extent than in males. I-KAS activation plays an important role in ventricular arrhythmogenesis in females during sympathetic stimulation.
Simultaneous noninvasive recording of electrocardiogram and skin sympathetic nerve activity (neuECG)
(2020-05-01)
Kusayama, Takashi
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Wong, Johnson
;
Liu, Xiao
;
He, Wenbo
;
Doytchinova, Anisiia
neuECG is the simultaneous noninvasive recording of ECG and skin sympathetic nerve activity and thus can directly record sympathetic nerve activity over a long period of time without the need for invasive procedures. neuECG, the simultaneous noninvasive recording of ECG and skin sympathetic nerve activity (SKNA), directly records sympathetic nerve activity over a long period of time. It can be used to measure sympathetic tone in healthy subjects and in subjects with non-cardiovascular diseases. The electrical activity that can be measured on the surface of the skin originates from the heart, the muscle or nerve structures. Because the frequency content of nerve activity falls in a higher frequency range than that of the ECG and myopotential, it is possible to use high-pass or band-pass filtering to specifically isolate the SKNA. neuECG is voltage calibrated and does not require invasive procedures to impale electrodes in nerves and thus has advantages over microneurography. Here, we present a protocol that takes <10 min to set up. The neuECG can be continuously recorded over a 24-h period or longer. We also describe methods to efficiently analyze neuECG from humans using commercially available hardware and software to facilitate adoption of this technology in clinical research.
Simultaneous noninvasive recording of skin sympathetic nerve activity and electrocardiogram
(2017-01)
Doytchinova, Anisiia
;
Hassel, Jonathan L.
;
Yuan, Yuan
;
Lin, Hongbo
;
Yin, Dechun
BACKGROUND Sympathetic nerve activity is important to cardiac arrhythmogenesis. OBJECTIVE The purpose of this study was to develop a method for simultaneous noninvasive recording of skin sympathetic nerve activity (SKNA) and electrocardiogram (ECG) using conventional ECG electrodes. This method (neuECG) can be used to adequately estimate sympathetic tone. METHODS We recorded neuECG signals from the skin of 56 human subjects. The signals were low-pass filtered to show the ECG and high-pass filtered to show nerve activity. Protocol 1 included 12 healthy volunteers who underwent cold water pressor test and Valsalva maneuver. Protocol 2 included 19 inpatients with epilepsy but without known heart diseases monitored for 24 hours. Protocol 3 included 22 patients admitted with electrical storm and monitored for 39.0 +/- 28.2 hours. Protocol 4 included 3 patients who underwent bilateral stellate ganglion blockade with lidocaine injection. RESULTS In patients without heart diseases, spontaneous nerve discharges were frequently observed at baseline and were associated with heart rate acceleration. SKNA recorded from chest leads (V1V6) during cold water pressor test and Valsalva maneuver (protocol 1) was invariably higher than during baseline and recovery periods (P <.001). In protocol 2, the average SKNA correlated with heart rate acceleration (r = 0.73 +/- 0.14, P <.05) and shortening of QT interval (P <.001). Among 146 spontaneous ventricular tachycardia episodes recorded in 9 patients of protocol 3, 106 episodes (73%) were preceded by SKNA within 30 seconds of onset. Protocol 4 showed that bilateral stellate ganglia blockade by lidocaine inhibited SKNA. CONCLUSION SKNA is detectable using conventional ECG electrodes in humans and may be useful in estimating sympathetic tone.
Simultaneous recordings of intrinsic cardiac nerve activity and skin sympathetic nerve activity from human patients during the postoperative period
(2017-11-01)
Shen, Mark J.
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Coffey, Arthur C.
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Straka, Susan
;
Adams, David E.
;
Wagner, David B.
BACKGROUND Intrinsic cardiac nerve activity (ICNA) and skin nerve activity (SKNA) are both associated with cardiac arrhythmias in dogs. OBJECTIVE The purpose of this study was to test the hypothesis that ICNA and SKNA correlate with postoperative cardiac arrhythmias in humans. METHODS Eleven patients (mean age 60 6 13 years; 4 women) were enrolled in this study. Electrical signals were simultaneously recorded from electrocardiogram (ECG) patch electrodes on the chest wall and from 2 temporary pacing wires placed during open heart surgery on the left atrial epicardial fat pad. The signals were filtered to display SKNA and ICNA. Premature atrial contractions (PACs) and premature ventricular contractions were determined manually. The SKNA and ICNA of the first 300 minutes of each patient were calculated minute by minute to determine baseline average amplitudes of nerve activities and to determine their correlation with arrhythmia RESULTS We processed 1365 6 973 minutes of recording per patient. Low-amplitude SKNA and ICNA were present at all time, while the burst discharges were observed much less frequently. Both SKNA and burst ICNA were significantly associated with the onset of PACs and premature ventricular contractions. Baseline average ICNA (aICNA), but not average SKNA, had a significant association with PAC burden. The correlation coefficient (r) between aICNA and PAC burden was 0.78 (P<.01). A patient with the greatest aICNA developed postoperative atrial fibrillation. CONCLUSION ICNA and SKNA can be recorded from human patients in the postoperative period. The baseline magnitude of ICNA correlates with PAC burden and development of postoperative atrial fibrillation.
Skin sympathetic nerve activity as a biomarker for syncopal episodes during a tilt table test
(2020-05-01)
Kumar, Awaneesh
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Wright, Keith
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Uceda, Domingo E.
;
Vasallo, Peter A., III
;
Rabin, Perry L.
BACKGROUND Autonomic imbalance is the proposed mechanism of syncope during a tilt table test (TTT). We have recently demonstrated that skin sympathetic nerve activity (SKNA) can be noninvasively recorded using electrocardiographic electrodes. OBJECTIVE The purpose of this study was to test the hypothesis that increased SKNA activation precedes tilt-induced syncope. METHODS We studied 50 patients with a history of neurocardiogenic syncope undergoing a TTT. The recorded signals were band-pass filtered at 500-1000 Hz to analyze nerve activity. RESULTS The average SKNA (aSKNA) value at baseline was 1.38 +/- 0.38 mu V in patients without syncope and 1.42 +/- 0.52 mu V in patients with syncope (P = .77). On upright tilt, aSKNA was 1.34 +/- 0.40 mu V in patients who did not have syncope and 1.39 +/- 0.43 mu V in patients who had syncope (P = .65). In all 14 patients with syncope, there was a surge of SKNA before an initial increase in heart rate followed by bradycardia, hypotension, and syncope. The peak aSKNA immediately (<1 minute) before syncope was significantly higher than baseline aSKNA (2.63 +/- 1.22 vs 1.39 +/- 0.43 mu V; P = .0005). After syncope, patients were immediately placed in the supine position and aSKNA dropped significantly to 1.26 +/- 0.43 mu V; (P = .0004). The heart rate variability during the TTT shows a significant increase in parasympathetic tone during syncope (low-frequency/high-frequency ratio: 7.15 vs 2.21; P = .04). CONCLUSION Patients with syncope do not have elevated sympathetic tone at baseline or during the TTT except immediately before syncope when there is a transient surge of SKNA followed by sympathetic withdrawal along with parasympathetic surge.
Skin sympathetic nerve activity precedes the onset and termination of paroxysmal atrial tachycardia and fibrillation
(2017-07-01)
Uradu, Andrea
;
Wan, Juyi
;
Doytchinova, Anisiia
;
Wright, Keith C.
;
Lin, Andrew Y. T.
BACKGROUND Skin sympathetic nerve activity (SKNA) is useful for estimating sympathetic tone in humans. OBJECTIVE The purpose of this study was to test the hypotheses that (1) increased SKNA is associated with the onset and termination of paroxysmal atrial tachycardia (AT) and atrial fibrillation (AF) and (2) sinoatrial node response to SKNA is reduced in patients with more frequent AT or AF episodes. METHODS SKNA and electrocardiogram were recorded in 11 patients (4 men and 7 women; average age 66 +/- 10 years), including 3 patients with AT (11 +/- 18 episodes per patient) and 8 patients with AF (24 +/- 26 episodes per patient). RESULTS The average SKNA (aSKNA) 10 seconds before AT onset was 1.07 +/- 0.10 mu V and 10 seconds after termination was 1.27 6 0.10 mV; both were significantly (P = .032 and P < .0001) higher than that during sinus rhythm (0.97 +/- 0.09 mu V). The aSKNA 10 seconds before AF onset was 1.34 +/- 0.07 mu V and 10 seconds after termination was 1.31 +/- 0.07 mu V; both were significantly (P < .0001) higher than that during sinus rhythm (1.04 +/- 0.07 mu V). The aSKNA before onset (P < .0001) and after termination (P < .0011) was higher in AF than in AT. The sinus rate correlated (P < .0001) with aSKNA in each patient (average r = 0.74; 95% confidence interval 0.65-0.84). The r value in each patient negatively correlated with the number of AT and AF episodes (r = -0.6493; 95% confidence interval -0.8990 to -0.08073; P = .0306). CONCLUSION Increased SKNA was observed both at the onset and termination of AT and AF. Patients with more frequent AT and AF episodes had a weak correlation between sinus rate and aSKNA, suggesting sinoatrial node remodeling by tachycardia.
Small conductance calcium-activated potassium current and the mechanism of atrial arrhythmia in mice with dysfunctional melanocyte-like cells
(2016-07)
Tsai, Wei-Chung
;
Chan, Yi-Hsin
;
Hsueh, Chia-Hsiang
;
Everett, Thomas H.
;
Chang, Po-Cheng
BACKGROUND The melanin synthesis enzyme dopachrome tautomerase (Dct) regulates intracellular Ca2+ in melanocytes. Homozygous Dct knockout (Dct(-/-)) adult mice are vulnerable to atrial arrhythmias (AA). OBJECTIVE The purpose of this study was to determine whether apamin-sensitive small conductance Ca2+-activated K+ (SK) currents are upregulated in Dct(-/-) mice and contribute to AA. METHODS Optical mapping was used to study the membrane potential of the right atrium in Langendorff perfused Dct(-/-) (n = 9) and Dct(+/-) (n = 9) mice. RESULTS Apamin prolonged action potential duration (APD) by 18.8 ms (95% confidence interval [CI] 13.4-24.1 ms) in Dct(-/-) mice and by 11.5 ms (95% CI 5.4-17.6 ms) in Dct(+/-) mice at a pacing cycle length of 150 ms (P = .047). The pacing cycle length threshold to induce APD alternans was 48 ms (95% CI 34-62 ms) for Dct(-/-) mice and 21 ms (95% CI 12-29 ms) for Dct(+/-) mice (P = .002) at baseline, and it was 35 ms (95% CI 21-49 ms) for Dct(-/-) mice and 22 ms (95% CI 11-32 ms) for Dct(+/-) mice (P = .025) after apamin administration. Apamin prolonged post-burst pacing APD by 8.9 ms (95% CI 3.9-14.0 ms) in Dct(-/-) mice and by 1.5 ms (95% CI 0.7-2.3 ms) in Dct(+/-) mice (P = .005). Immunoblot and quantitative polymerase chain reaction analyses showed that protein and transcripts levels of SK1 and SK3 were increased in the right atrium of Dct(-/-) mice. AA inducibility (89% vs 11%; P = .003) and duration (281 seconds vs 66 seconds; P = .008) were greater in Dct(-/-) mice than in Dct(+/-) mice at baseline, but not different (22% vs 11%; P = 1.00) after apamin administration. Five of 8 (63%) induced atrial fibrillation episodes in Dct(-/-) mice had focal drivers. CONCLUSION Apamin-sensitive SK current upregulation in Dct(-/-) mice plays an important role in the mechanism of AA.
Small-Conductance Calcium-Activated Potassium Current Is Activated During Hypokalemia and Masks Short-Term Cardiac Memory Induced by Ventricular Pacing
(2015-10-13)
Chan, Yi-Hsin
;
Tsai, Wei-Chung
;
Ko, Jum-Suk
;
Yin, Dechun
;
Chang, Po-Cheng
Background-Hypokalemia increases the vulnerability to ventricular fibrillation. We hypothesize that the apamin-sensitive small-conductance calcium-activated potassium current (I-KAS) is activated during hypokalemia and that I-KAS blockade is proarrhythmic. Methods and Results-Optical mapping was performed in 23 Langendorff-perfused rabbit ventricles with atrioventricular block and either right or left ventricular pacing during normokalemia or hypokalemia. Apamin prolonged the action potential duration (APD) measured to 80% repolarization (APD(80)) by 26 milliseconds (95% confidence interval [CI], 14-37) during normokalemia and by 54 milliseconds (95% CI, 40-68) during hypokalemia (P=0.01) at a 1000-millisecond pacing cycle length. In hypokalemic ventricles, apamin increased the maximal slope of APD restitution, the pacing cycle length threshold of APD alternans, the pacing cycle length for wave-break induction, and the area of spatially discordant APD alternans. Apamin significantly facilitated the induction of sustained ventricular fibrillation (from 3 of 9 hearts to 9 of 9 hearts; P=0.009). Short-term cardiac memory was assessed by the slope of APD(80) versus activation time. The slope increased from 0.01 (95% CI, -0.09 to 0.12) at baseline to 0.34 (95% CI, 0.23-0.44) after apamin (P<0.001) during right ventricular pacing and from 0.07 (95% CI, -0.05 to 0.20) to 0.54 (95% CI, 0.06-1.03) after apamin infusion (P=0.045) during left ventricular pacing. Patch-clamp studies confirmed increased I-KAS in isolated rabbit ventricular myocytes during hypokalemia (P=0.038). Conclusions-Hypokalemia activates I-KAS to shorten APD and maintain repolarization reserve at late activation sites during ventricular pacing. I-KAS blockade prominently lengthens the APD at late activation sites and facilitates ventricular fibrillation induction.
Using skin sympathetic nerve activity to estimate stellate ganglion nerve activity in dogs
(2015-06-01)
Jiang, Zhaolei
;
Zhao, Ye
;
Doytchinova, Anisiia
;
Kamp, Nicholas J.
;
Tsai, Wei-Chung
BACKGROUND Stellate ganglion nerve activity (SGNA) is important in cardiac arrhythmogenesis. However, direct recording of SGNA requires access to the thoracic cavity. Skin of upper thorax is innervated by sympathetic nerve fibers originating from the stellate ganglia and is easily accessible. OBJECTIVE The purpose of this study was to test the hypothesis that thoracic skin nerve activity (SKNA) can be used to estimate SGNA. METHODS We recorded SGNA and SKNAs using surface electrocardiogram leads in 5 anesthetized and 4 ambulatory dogs. Apamin injected into the right stellate ganglion abruptly increased both right SGNA and SKNA in 5 anesthetized dogs. We integrated nerve activities and averaged heart rate in each 1-minure window over 10 minutes, We implanted a radiotransmitter to record Left SGNA in 4 ambulatory dogs (2 normal, 1 with myocardial infarction, 1 with intermittent rapid atrial pacing). After 2 weeks of recovery, we simultaneously recorded the SKNA and Left SGNA continuously for 30 minutes when the dogs were ambulatory. RESULTS There was a positive correlation [average r = 0.877, 95% confidence interval (CI) 0.732-1.000, P<.05 for each dog] between integrated skin nerve activity (iSKNA) and SGNA (iSGNA) and between iSKNA and heart rate (average r = 0.837, 95% CI 0.752-0.923, P<.05). Similar to that found in the anesthetized dogs, there was a positive correlation (average r = 0.746, 95% CI 0.527-0.964, P<.05) between iSKNA and iSGNA and between iSKNA and heart rate (average r = 0.706, 95% CI 0.484-0.927, P<.05). CONCLUSION SKNAs can be used to estimate SGNA in dogs.