Songyun Wang

Chronic Intermittent Low-Level Transcutaneous Electrical Stimulation of Auricular Branch of Vagus Nerve Improves Left Ventricular Remodeling in Conscious Dogs With Healed Myocardial Infarction

Background—Vagus nerve stimulation attenuates left ventricular (LV) remodeling after myocardial infarction (MI). Our previous study found a noninvasive approach to deliver vagus nerve stimulation by transcutaneous electric stimulation of auricular branch of vagus nerve. So we hypothesize that chronic intermittent low-level tragus stimulation (LL-TS) could attenuate LV remodeling in conscious dogs with healed MI. Methods and Results—Thirty beagle dogs were randomly divided into 3 groups, MI group (left anterior descending artery and major diagonal branches ligation to introduce MI, n=10), LL-TS group (MI plus chronic intermittent LL-TS, n=10), and control group (sham surgery without stimulation, n=10). Tragus stimulation was delivered to bilateral tragus with ear-clips connected to a custom-made stimulator. The voltage slowing sinus rate was used as the threshold for setting LL-TS at 80% below that. LL-TS group was given 4 hours stimulation at 7–9 AM and 4–6 PM on conscious dogs. At the end of 90-day follow-up, LL-TS group significantly reduced LA and LV dilatation, improved LV contractile and diastolic function, reduced infarct size by ≈50% compared with MI group. LL-TS treatment alleviated cardiac fibrosis and significantly decreased protein expression level of collagen I, collagen III, transforming growth factor &bgr;1, and matrix metallopeptidase 9 in LV tissues. The plasma level of high-specific C-reactive protein, norepinephrine, N-terminal pro-B-type-natriuretic peptide in LL-TS group was significantly lower than those in MI group from the 7th day to the end of follow-up. Conclusions—Chronic intermittent low-level transcutaneous electric stimulation of auricular branch of vagus nerve can attenuate LV remodeling in conscious dogs with healed MI.

Spinal cord stimulation protects against ventricular arrhythmias by suppressing left stellate ganglion neural activity in an acute myocardial infarction canine model.

BACKGROUND Previous studies have shown that spinal cord stimulation (SCS) may reduce ventricular arrhythmias (VAs) induced by acute myocardial infarction (AMI). Furthermore, activation of left stellate ganglion (LSG) appears to facilitate VAs after AMI. OBJECTIVE The purpose of this study was to investigate whether pretreatment with SCS could protect against VAs by reducing LSG neural activity in an AMI canine model. METHODS Thirty dogs were anesthetized and randomly divided into SCS group (with SCS, n = 15) and sham group (sham operation without SCS, n = 15). SCS was performed for 1 hour before AMI. Heart rate variability (HRV), ventricular effective refractory period (ERP), serum norepinephrine level, LSG function measured by blood pressure increases in response to LSG stimulation, and LSG neural activity were measured for 1 minute at baseline and 1 hour after SCS. AMI was induced by left anterior descending coronary artery ligation, and then HRV, LSG neural activity, and VAs were measured. RESULTS Compared to baseline, SCS for 1 hour significantly prolonged ventricular ERP, increased HRV, and attenuated LSG function and LSG activity in the SCS group, whereas no significant change was shown in the sham group. AMI resulted in a significant decrease in HRV and increase in LSG neural activity in the sham group, which were attenuated in the SCS group (frequency: 99 ± 34 impulses/min vs 62 ± 22 impulses/min; amplitude: 0.41 ± 0.12 mV vs 0.18 ± 0.05 mV; both P <.05). The incidence of VAs was significantly lower in the SCS group than in the sham group. CONCLUSION SCS may prevent AMI-induced VAs, possibly by suppressing LSG activity.

Renal sympathetic denervation modulates ventricular electrophysiology and has a protective effect on ischaemia-induced ventricular arrhythmia

What is the central question of this study? It is well known that modulation of the autonomic nervous system affects cardiac electrophysiology. Renal sympathetic denervation has been shown to reduce systemic sympathetic activity. However, it is unknown whether renal sympathetic denervation could modulate ventricular electrophysiology and decrease the occurrence of ventricular arrhythmias associated with ischaemia. What is the main finding and its importance? Our data show that renal sympathetic denervation stabilizes ventricular electrophysiological properties in normal hearts and reduces the occurrence of ventricular arrhythmia in hearts experiencing acute myocardial ischaemia. These findings suggest that renal sympathetic denervation may become a new treatment option for ventricular arrhythmia.

Spinal cord stimulation suppresses atrial fibrillation by inhibiting autonomic remodeling

BACKGROUND Previous study has shown that spinal cord stimulation (SCS) may suppress atrial fibrillation (AF) inducibility, but the mechanism for this is elusive. OBJECTIVE The purpose of this study was to determine whether SCS could inhibit AF inducibility by suppressing autonomic remodeling in a canine model of rapid atrial pacing (RAP)-induced AF. METHODS Eighteen canines were randomly divided into an RAP group (n = 9) and an RAP+SCS group (n = 9). Effective refractory period (ERP), window of vulnerability (WOV), AF inducibility, autonomic neural function, and activity from the anterior right ganglionated plexus (ARGP) and left stellate ganglion (LSG) were measured at baseline, at 3 hours of RAP, and at 6 hours of RAP. Then, ARGP and LSG were excised for Western blot and messenger RNA analysis. In another 4 dogs (control group, which received sham RAP and sham SCS), tissues were also excised for analysis. RESULTS In the RAP group, RAP resulted in (1) a significant decrease in ERP and an increase in ERP dispersion, ΣWOV, and AF inducibility and (2) activation of ARGP and LSG versus baseline. In the RAP+SCS group, however, these changes were significantly attenuated by SCS. Compared with the control group, c-fos and nerve growth factor (NGF) were significantly up-regulated and small conductance calcium-activated potassium channel type 2 (SK2) was significantly down-regulated in the RAP group. In the RAP+SCS group, however, c-fos, NGF, and SK2 remained at a normal level compared with the control group. CONCLUSION SCS may suppress RAP-induced AF by inhibiting autonomic remodeling, and the underlying mechanism of the salutary effect of SCS might contribute to modulation of the expression of c-fos, NGF, and SK2.

Carotid baroreceptor stimulation prevents arrhythmias induced by acute myocardial infarction through autonomic modulation.

Abstract: Electrical carotid baroreceptor stimulation (CBS) has shown therapeutic potential for resistant hypertension and heart failure by resetting autonomic nervous system, but the impacts on arrhythmias remains unclear. This study evaluated the effects of CBS on ventricular electrophysiological properties in normal dog heart and arrhythmias after acute myocardial infarction (AMI). In the acute protocol, anesthetized open chest dogs were exposed to 1 hour left anterior descending coronary occlusion as AMI model. Dogs were received either sham treatment (Control group, n = 8) or CBS (CBS group, n = 8), started 1 hour before AMI. CBS resulted in pronounced prolongation of ventricular effective refractory period and reduction of the maximum action potential duration restitution slope (from 0.85 ± 0.15 in the baseline state to 0.67 ± 0.09 at the end of 1 hour, P < 0.05) before AMI. Number of premature ventricular contractions (277 ± 168 in the Control group vs. 103 ± 84 in the CBS group, P < 0.05) and episodes of ventricular tachycardia/ventricular fibrillation (7 ± 3 in the Control group vs. 3 ± 2 in the CBS group, P < 0.05) was decreased compared with the control group during AMI. CBS buffered low-frequency/high-frequency ratio raise during AMI. Ischemic size was not affected by CBS. CBS may have a beneficial impact on ventricular arrhythmias induced by AMI through modulation of autonomic tone.

Low level tragus nerve stimulation is a non-invasive approach for anti-atrial fibrillation via preventing the loss of connexins

Atrial fibrillation (AF) is the most common cardiac arrhythmia, butthe mechanism of AF maintenance remains unclear. It has been foundthat gapjunctional remodeling(connexin expression is downregulatedand distributed) is closely associated with AF maintenance [1]. Auto-nomic nervous system stimulation can exert anti-arrhythmia effects[2,3]. Recently, we reported that cervical low level vagal nerve stimula-tion (LL-VNS) could suppress AF induced high-frequency stimulation[4] and then we developed a non-invasive approach, low level tragusnervestimulation(LL-TS),andfoundthatithadthesameeffectonsup-pressing AF [5]. However, whether LL-TScould regulate Cx40 and Cx43to suppress AF remains unknown. We hypothesized that LL-TS exertedanti-atrial fibrillatory effect via the downregulation of atrial Cx40 andCx43.Fifteen adult beagle dogs weighing 8–10 kg were included in thisstudy. All dogs were anesthetized with Na-pentobarbital (40 mg/kg.iv) and ventilated with room air by a positive pressure respirator. Alldogs were randomly divided into three groups. RAP group (rapid atrialpacing was performed during 9 h, n = 5), LL-TS group (RAP with LL-TStreatment lasted for 9 h, n = 5) and control group (sham RAP withoutLL-TS, n =5). Standard surfaceelectrocardiographic leadII wascontin-uouslymonitored.Therightearwasattached2alligatorclipsforstimu-lation.Voltages(20Hz,1mssquarewave)toachieveadecreaseofsinusrateoratrioventricularblockweresetasthethreshold.LL-TSwasdeliv-ered at 80% below the voltage threshold. The left chest was opened viathe fourth intercostal space to expose the heart. Left atrial appendagewas sutured with a multi-electrode for 9 h rapid atrial pacing(1200 beats/min, 2× threshold) to induce acute atrial fibrillationmodel. After 9-h RAP, AF duration and AF cycle length were recorded.AF cycle length was measured during 30 consecutive cycles accordingto the surface electrocardiogram. After parameters were measured,the western blotting was applied for all dogs. Membrane proteinswere extracted as described previously [6]. Phosphorylated forms ofCx43 and total Cx43 were detected with mouse monoclonal antipan-Cx43 antibodies (1/1000, Chemicon). Cx40 and GAPDH were detectedwithrabbitpolyclonalanti-Cx40(1/1000,Chemicon)andmousemono-clonal anti-GAPDH (1/10,000, RDI) primary antibodies. Followingapplication of primary antibodies, membranes were incubated witheither antimouse (1/10,000, Santa Cruz Biotechnology) or anti-rabbit(1/10,000, Jackson ImmunoLabs) horseradish peroxidase-conjugatedsecondary antibodies. Signals were detected by chemiluminescenceand quantified by video densitometry. Band intensities are expressedrelative to GAPDH.All data were expressedas mean ± standard. Paired t-test and one-way ANOVA were used for comparisons. P values b 0.05 were consid-ered statistical significance.Consequently, we found that LL-TS could significantly shorten AFduration and prolong AF cycle length (Table 1). We also observed thatRAPafter 9 h could reducethelevel of atrialCx40 and Cx43expression,but LL-TS could prevent the loss of Cx40 and Cx43 expression (Fig. 1).AF maintenance depends primarily on the abnormal tissue sub-strate, which was caused by the abnormal expression and distributionofatrialgapjunctions.Gapjunctionsarespecialintermembraneproteinchannels between adjacentcells, whichpermitting theintercellularex-change of ions and small molecules. The gap junction is formed by twoconnexons (each connexon contains six connexins). In the heart, Cx40and Cx43 are abundantly expressed in the atrial myocardium, whileventricularmyocytesmainlyexpressCx43 [7]. Changesin connexinex-pression and distribution would be expected to have profound

Low-Level Carotid Baroreceptor Stimulation Suppresses Ventricular Arrhythmias during Acute Ischemia

Background The autonomic imbalance during acute ischemia is involved in the occurrence of life-threatening arrhythmias. Objective To investigate the effect of autonomic nervous system (ANS) modulation by low-level carotid baroreceptor stimulation (LL-CBS) on ventricular ischemia arrhythmias. Methods Anesthetized dogs were received either sham treatment (SHAM group, n = 10) or LL-CBS treatment (LL-CBS group, n = 10). The voltage lowering the blood pressure was used as the threshold for setting LL-CBS at 80% below the threshold. Treatment started 1 hour before left anterior descending coronary (LAD) occlusion, and continued until the end of experience. Ventricular effective refractory periods (ERP), monophasic action potential duration at 90% (APD90), ventricular arrhythmias, indices of heart rate variability, left stellate ganglion nerve activity (LSGNA) and infarct sizes were measured and analyzed. Results Ventricular ischemia resulted in an acute reduction of blood pressure, which was not significantly affected by LL-CBS. After 1 hour of LL-CBS, there was a progressive and significant increase in ERP, increase in APD90, and decrease in LSGNA vs the SHAM group (all P<0.05). LL-CBS apparently reduced premature ventricular contractions (PVC, 264±165 in the SHAM group vs 60±37 in the LL-CBS group; P<0.01) during LAD occlusion. Number of episodes of ventricular fibrillation (VF) was 8 in the Control group versus 3 in the LL-CBS group (80% versus 30%, P<0.05). LL-CBS obviously increased high frequency (HF) component (P<0.05) and decreased low frequency/high frequency ratio (P<0.05) compared with the SHAM group. Ischemic size was not affected by LL-CBS between the two groups. Conclusions LL-CBS reduced the occurrences of ventricular arrhythmias during acute ischemia without affecting blood pressure. The procedure was associated with changes of electrophysiological characteristics, nerve activity and heart rate variability. Therefore, LL-CBS may protect from ventricular arrhythmias during acute ischemic events by modulating ANS.

Low-level transcutaneous electrical stimulation of the auricular branch of vagus nerve ameliorates left ventricular remodeling and dysfunction by downregulation of matrix metalloproteinase 9 and transforming growth factor β1.

Abstract: Vagus nerve stimulation improves left ventricular (LV) remodeling by downregulation of matrix metalloproteinase 9 (MMP-9) and transforming growth factor &bgr;1 (TGF-&bgr;1). Our previous study found that low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve (LL-TS) could be substituted for vagus nerve stimulation to reverse cardiac remodeling. So, we hypothesize that LL-TS could ameliorate LV remodeling by regulation of MMP-9 and TGF-&bgr;1 after myocardial infarction (MI). Twenty-two beagle dogs were randomly divided into a control group (MI was induced by permanent ligation of the left coronary artery, n = 8), an LL-TS group (MI with long-term intermittent LL-TS, n = 8), and a normal group (sham ligation without stimulation, n = 6). At the end of 6 weeks follow-up, LL-TS significantly reduced LV end-systolic and end-diastolic dimensions, improved ejection fraction and ratio of early (E) to late (A) peak mitral inflow velocity. LL-TS attenuated interstitial fibrosis and collagen degradation in the noninfarcted myocardium compared with the control group. Elevated level of MMP-9 and TGF-&bgr;1 in LV tissue and peripheral plasma were diminished in the LL-TS treated dogs. LL-TS improves cardiac function and prevents cardiac remodeling in the late stages after MI by downregulation of MMP-9 and TGF-&bgr;1 expression.

Impacts of Renal Sympathetic Activation on Atrial Fibrillation: The Potential Role of the Autonomic Cross Talk Between Kidney and Heart

Background Recent studies have demonstrated that there is a high variability of renal sympathetic nerve density distribution from proximal to distal renal artery segments. The aim of our study was to investigate the roles of renal sympathetic nerve stimulation (RSS) on atrial fibrillation and cardiac autonomic nervous activity. Methods and Results Twenty‐eight dogs were randomly assigned to the proximal RSS group (P‐RSS, N=7), middle RSS group (M‐RSS, N=7), distal RSS group (D‐RSS, N=7), and the control group (sham RSS, N=7). RSS was performed using electrical stimulation on the bilateral renal arteries for 3 hours. Effective refractory period and the window of vulnerability were measured at atrial and pulmonary veins sites. Superior left ganglionated plexi (SLGP) and left stellate ganglion (LSG) function and neural activity were determined. C‐fos and nerve growth factor protein expression in the SLGP and LSG were examined. Only P‐RSS (1) caused pronounced blood pressure rises, induced a significant decrease in effective refractory period, and generated a marked increase in cumulative window of vulnerability and effective refractory period dispersion; (2) increased the frequency and amplitude of the neural activity in the SLGP and LSG; (3) increased SLGP and LSG function; and (4) upregulated the level of c‐fos and nerve growth factor expression in the SLGP and LSG. Conclusions This study demonstrated that renal sympathetic nerve activation induced by 3 hours of P‐RSS facilitated atrial fibrillation inducibility by upregulating cardiac autonomic nervous activity, suggesting a potential autonomic cross talk between kidney and heart.

Spinal cord stimulation suppresses focal rapid firing-induced atrial fibrillation by inhibiting atrial ganglionated plexus activity.

Objective: This study was designed to demonstrate that spinal cord stimulation (SCS) could suppress high-frequency stimulation (HFS)–induced focal atrial fibrillation (AF) at atrial and pulmonary vein (PV) sites by inhibiting atrial ganglionated plexus (GP) activity. Methods: Multielectrode catheters were attached to atria and all PV sites. SCS was performed at the T1–T5 spinal region for 1 hour. At the baseline state and the end of 1 hour of SCS, 40 milliseconds of HFS was delivered 2 milliseconds after atrial pacing to determine the AF threshold at each site. One electrode was attached to the superior left GP so that HFS to this site induced sinus rate slowing. Microelectrodes inserted into the anterior right GP recorded neural firing. Results: SCS induced a significant increase in AF threshold at all sites (all P < 0.05). The sinus rate slowing response induced by superior left GP stimulation was blunted by SCS (17% ± 3.6% vs. 39% ± 3.8%, P < 0.05). The frequency (32 ± 4 vs. 87 ± 6 impulses per minute, P < 0.05) and amplitude (0.16 ± 0.02 vs. 0.42 ± 0.04 mv, P < 0.05) of the neural activity recorded from the anterior right GP were markedly inhibited by SCS. Conclusions: SCS may prevent episodic AF caused by rapid PV and non-PV firing through modulating GP activity.