Wireless Self-Powered Optogenetic System for Long-Term Cardiac Neuromodulation to Improve Post-MI Cardiac Remodeling and Malignant Arrhythmia.

Autonomic imbalance is an important characteristic of patients after myocardial infarction (MI) and adversely contributes to post-MI cardiac remodeling and ventricular arrhythmias (VAs). A previous study proved that optogenetic modulation could precisely inhibit cardiac sympathetic hyperactivity and prevent acute ischemia-induced VAs. Here, a wireless self-powered optogenetic modulation system is introduced, which achieves long-term precise cardiac neuromodulation in ambulatory canines. The wireless self-powered optical system based on a triboelectric nanogenerator is powered by energy harvested from body motion and realized the effective optical illumination that is required for optogenetic neuromodulation (ON). It is further demonstrated that long-term ON significantly mitigates MI-induced sympathetic remodeling and hyperactivity, and improves a variety of clinically relevant outcomes such as improves ventricular dysfunction, reduces infarct size, increases electrophysiological stability, and reduces susceptibility to VAs. These novel insights suggest that wireless ON holds translational potential for the clinical treatment of arrhythmia and other cardiovascular diseases related to sympathetic hyperactivity. Moreover, this innovative self-powered optical system may provide an opportunity to develop implantable/wearable and self-controllable devices for long-term optogenetic therapy.

Non-invasive transcutaneous vagal nerve stimulation improves myocardial performance in doxorubicin-induced cardiotoxicity.

AIMS: The clinical use of antitumour agent doxorubicin (DOX) is hampered by its dose-dependent cardiotoxicity. Development of highly efficient and safe adjuvant intervention for preventing DOX-induced adverse cardiac events is urgently needed. We aimed to investigate whether transcutaneous vagal nerve stimulation (tVNS) plays a cardio-protective role in DOX-induced cardiotoxicity. METHODS AND RESULTS: Healthy male adult Sprague Dawley rats were used in the experiment and were randomly divided into four groups including control, DOX, tVNS, and DOX+tVNS groups. A cumulative dose of 15 mg/kg DOX was intraperitoneally injected into rats to generate cardiotoxicity. Non-invasive tVNS was conducted for 6 weeks (30 min/day). After 6-week intervention, the indices from the echocardiography revealed that tVNS significantly improved left ventricular function compared to the DOX group. The increased malondialdehyde and Interleukin-1ß, and decreased superoxide dismutase were observed in the DOX group, while tVNS significantly prevented these changes. From cardiac histopathological analysis, the DOX+tVNS group showed a mild myocardial damage, and decreases in cardiac fibrosis and myocardial apoptosis compared to the DOX group. Heart rate variability analysis showed that tVNS significantly inhibited DOX-induced sympathetic hyperactivity compared to the DOX group. Additionally, the results of RNA-sequencing analysis showed that there were 245 differentially expressed genes in the DOX group compared to the control group, among which 39 genes were down-regulated by tVNS and most of these genes were involved in immune system. Moreover, tVNS significantly down-regulated the relative mRNA expressions of chemokine-related genes and macrophages recruitment compared to the DOX group. CONCLUSION: These results suggest that tVNS prevented DOX-induced cardiotoxicity by rebalancing autonomic tone, ameliorating cardiac dysfunction and remodelling. Notably, crosstalk between autonomic neuromodulation and innate immune cells macrophages mediated by chemokines might be involved in the underlying mechanisms.

Vagus Nerve Stimulation Ameliorates Renal Ischemia-Reperfusion Injury through Inhibiting NF-κB Activation and iNOS Protein Expression.

OBJECTIVE: In renal ischemia/reperfusion injury (RIRI), nuclear factor κB (NF-κB (NF-κB (NF. METHODS: Eighteen male Sprague-Dawley rats were randomly allocated into the sham group, the I/R group, and the VNS+I/R group, 6 rats per group. An RIRI model was induced by a right nephrectomy and blockade of the left renal pedicle vessels for 45 min. After 6 h of reperfusion, the blood samples and renal samples were collected. The VNS treatment was performed throughout the I/R process in the VNS+I/R group using specific parameters (20 Hz, 0.1 ms in duration, square waves) known to produce a small but reliable bradycardia. Blood was used for evaluation of renal function and inflammatory state. Renal injury was evaluated via TUNEL staining. Renal samples were harvested to evaluate renal oxidative stress, NF-κB (NF. RESULTS: The VNS treatment reduces serum creatinine (Cr) and blood urea nitrogen (BUN) levels. Simultaneously, the levels of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1-beta (IL-1ß) were significantly increased in the I/R group, but VNS treatment markedly ameliorated this inflammatory response. Furthermore, the VNS ameliorated oxidant stress and renal injury, indicated by a decrease in 3-nitrotyrosine (3-NT) formation and MDA and MPO levels and an increase in the SOD level compared to that in the I/R group. Finally, the VNS also significantly decreases NF-κB (NF. CONCLUSION: Our findings indicate that NF-κB activation increased iNOS expression and promoted RIRI and that VNS treatment attenuated RIRI by inhibiting iNOS expression, oxidative stress, and inflammation via NF-κB inactivation.κB (NF-κB (NF.

Interactions between metabolism regulator adiponectin and intrinsic cardiac autonomic nervous system: A potential treatment target for atrial fibrillation.

BACKGROUND: Previous studies indicated that inhibiting the cardiac autonomic nervous system (CANS) suppressed atrial fibrillation (AF). Clinical research revealed serum adiponectin (APN) exerted a beneficial influence on sympathetic and vagal tone in patients with type 2 diabetes. However, the effects of APN on CANS is unknown. This study aims to investigate whether APN could regulate CANS and suppress rapid atrial pacing (RAP)-induced AF. METHODS: Eighteen beagles were divided into the control group (saline plus sham RAP, N = 6), the RAP group (saline plus RAP, N = 6) and the APN + RAP group (APN plus RAP, N = 6). APN (10 µg, 0.1 µg/µL) or saline was microinjected into 4 major ganglionated plexi (GP) prior to RAP. Atrial electrophysiological parameters, anterior right GP (ARGP) function, neural activity and GP tissues were detected. RESULTS: Compared with the control treatment, RAP shortened effective refractory period (ERP) values at all sites and increased cumulative window of vulnerability (ΣWOV), ARGP function and neural activity, whereas APN injection reversed these changes. Mechanistically, APN ameliorated RAP-induced inflammatory response and down-regulated the expression of c-fos protein and nerve growth factor. Moreover, the APN receptors 1 and APN receptors 2 were detected both in neurons and in non-neuronal cells. APN pretreatment activated downstream adenosine monophosphate-activated protein kinase (AMPK) signaling, inhibited nuclear factor-kappa B signaling and promoted macrophage phenotype switching from proinflammatory to anti-inflammatory state. CONCLUSIONS: This study demonstrates that administration of APN into GP can suppress RAP-induced AF by regulating the CANS. APN signaling may provide a potential therapeutic target to AF.

Interaction between Endothelin-1 and Left Stellate Ganglion Activation: A Potential Mechanism of Malignant Ventricular Arrhythmia during Myocardial Ischemia.

Endothelin-1 (ET-1) is synthesized primarily by endothelial cells. ET-1 administration in vivo enhances the cardiac sympathetic afferent reflex and sympathetic activity. Previous studies have shown that sympathetic hyperactivity promotes malignant ventricular arrhythmia (VA). The aim of this study was to investigate whether ET-1 could activate the left stellate ganglion (LSG) and promote malignant VA. Twelve male beagle dogs who received local microinjections of saline (control, n = 6) and ET-1 into the LSG (n = 6) were included. The ventricular effective refractory period (ERP), LSG function, and LSG activity were measured at different time points. VA was continuously recorded for 1 h after left anterior descending occlusion (LADO), and LSG tissues were then collected for molecular detection. Compared to that of the control group, local ET-1 microinjection significantly decreased the ERP and increased the occurrence of VA. In addition, local microinjection of ET-1 increased the function and activity of the LSG in the normal and ischemic hearts. The expression levels of proinflammatory cytokines and the protein expression of c-fos and nerve growth factor (NGF) in the LSG were also increased. More importantly, endothelin A receptor (ETA-R) expression was found in the LSG, and its signaling was significantly activated in the ET-1 group. LSG activation induced by local ET-1 microinjection aggravates LADO-induced VA. Activated ETA-R signaling and the upregulation of proinflammatory cytokines in the LSG may be responsible for these effects.

Vagus nerve stimulation protects against acute liver injury induced by renal ischemia reperfusion via antioxidant stress and anti-inflammation.

OBJECTIVE: Renal ischemia reperfusion (I/R) is not an isolated event; however, it results in remote organ dysfunction. Vagus nerve stimulation (VNS) has shown protective effects against renal I/R injury via an anti-inflammatory mechanism. This study aimed to investigate whether VNS could attenuate liver injury induced by renal I/R and identify the underlying mechanisms. METHODS: Eighteen healthy male Sprague-Dawley rats (200-250 g) were equally divided into three groups: sham group (sham surgery without I/R or VNS), I/R group (renal I/R) and VNS group (renal I/R plus VNS). The I/R model was established by excising the right kidney and then clamping the left renal pedicle with an occlusive nontraumatic microaneurysm clamp for 45 min followed by a 6-h reperfusion. The rats in the VNS group received spontaneous left cervical VNS with renal ischemia and reperfusion. At the end of the experiment, blood and liver tissues were collected to detect liver function, oxidative stress and inflammatory parameters. Additionally, TUNEL staining, real-time PCR, western blotting and hematoxylin and eosin staining of liver tissues were performed to assess liver injury and the underlying mechanisms. RESULTS: Kidney and liver function was severely damaged in the I/R group compared to the sham group. However, VNS significantly protected kidney and liver function. Rats treated with VNS revealed decreases in oxidative enzymes, apoptosis and levels of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) in serum and liver compared with rats in the I/R group. Rats in the VNS group also showed increased antioxidant stress responses compared to rats in the I/R group. CONCLUSION: VNS exerts protective effects against liver injury from renal I/R via inhibiting oxidative stress and apoptosis, downregulating inflammatory cytokines and enhancing antioxidative capability in the liver, and may become a promising adjuvant therapeutic strategy for treating liver injury induced by acute renal injury.

Bone marrow sympathetic activation regulates post-myocardial infarction megakaryocyte expansion but not platelet production.

After myocardial infarction (MI), increased platelet number and size are inversely related to the outcomes of patients. Our previous study confirmed an excessive thrombopoiesis taking place in the bone marrow after MI. However, the mechanisms remain unknown. It has been reported that the sympathetic stimulation by noise or exercise can promote megakaryocyte (MK) producing platelets which is mediated by α2-adrenoceptor. Here, using whole-mount staining combined with western blotting and ELISA assay, we vividly showed an activation of the bone marrow sympathetic nervous system (SNS) after MI. Interestingly, we observed a direct spatial attachment between MKs and the sympathetic nerves. The administration of α-adrenoceptor antagonist, phentolamine or prazosin, could effectively attenuate post-MI MK cellularity and maturity, and alter the distribution of MK away from the bone marrow vessels. Surprisingly, the antagonists did not suppress the final stage of platelet formation. MI mice treated with phentolamine or prazosin showed elevating circulating platelets comparable as those treated with PBS as the control. Together, this study demonstrated that the activation of bone marrow SNS after MI regulates megakaryocyte expansion but not platelet production. Therefore, targeting sympathetic activation might become a novel approach for controlling post-MI bone marrow MK development, but other approaches are still needed to effectively reduce the platelet numbers.

Electrical stimulation-based renal nerve mapping exacerbates ventricular arrhythmias during acute myocardial ischaemia.

OBJECTIVE: Blood pressure elevation in response to transient renal nerve stimulation (RNS) has been used to determine the ablation target and endpoint of renal denervation. This study aimed to evaluate the safety of transient RNS in canines with normal or ischaemic hearts. METHODS: In ten normal (Group 1) and six healed myocardial infarction (HMI) (Group 2) canines, a large-tip catheter was inserted into the left or right renal artery to perform transient RNS. The left stellate ganglion neural activity (LSGNA) and ventricular electrophysiological parameters were measured at baseline and during transient RNS. In another 20 acute myocardial infarction (AMI) canines, RNS (Group 3, n = 10) or sham RNS (Group 4, n = 10) was intermittently (1 min ON and 4 min OFF) performed for 1 h following AMI induction. The LSGNA and AMI-induced ventricular arrhythmias were analysed. RESULTS: In normal and HMI canines, although transient RNS significantly increased the LSGNA and facilitated the action potential duration (APD) alternans, it did not induce any ventricular arrhythmias and did not change the ventricular effective refractory period, APD or maximum slope of the APD restitution curve. In AMI canines, transient RNS significantly exacerbated LSG activation and promoted the incidence of ventricular arrhythmias. CONCLUSION: Transient RNS did not increase the risk of ventricular arrhythmias in normal or HMI hearts, but it significantly promoted the occurrence of ventricular arrhythmias in AMI hearts. Therefore, electrical stimulation-based renal nerve mapping may be unsafe in AMI patients and in patients with a high risk for malignant ventricular arrhythmias.

Atrial Fibrillation in Acute Obstructive Sleep Apnea: Autonomic Nervous Mechanism and Modulation.

BACKGROUND: The mechanisms of atrial fibrillation (AF) induced by obstructive sleep apnea (OSA) are not completely understood. This study investigated the roles of the intrinsic and extrinsic cardiac autonomic nervous system in OSA-induced AF and provided noninvasive autonomic nervous modulation for the suppression of OSA-induced AF by using low-level transcutaneous electrical stimulation (LL-TS) of the auricular branch of the vagus nerve at the tragus. METHODS AND RESULTS: Eighteen dogs received tracheostomy under general anesthesia and were randomly divided into 3 groups: the OSA group (OSA was simulated via clamping of the endotracheal tube at end expiration for 1.5 minutes every 10 minutes, n=6), the LL-TS + OSA group (simulated OSA plus LL-TS, at 80% of the slowing sinus rate, n=6), and the control group (sham surgery without stimulation, n=6). The effective refractory period was significantly shortened after 1 hour of simulated OSA, and the window of vulnerability and plasma norepinephrine levels were both markedly increased in the OSA group. OSA dramatically increased the neural function and activity of the intrinsic and extrinsic cardiac autonomic nervous system, including the superior left ganglionated plexus, the left stellate ganglion, and the left renal sympathetic nerve. OSA also significantly upregulated the expression levels of c-fos and nerve growth factor in the superior left ganglionated plexus and the left stellate ganglion. However, LL-TS markedly improved these parameters. CONCLUSIONS: These findings suggest that the intrinsic and extrinsic cardiac autonomic nervous system plays crucial roles in the acute stage of OSA-induced AF. Noninvasive LL-TS suppressed shortening of atrial refractoriness and autonomic remodeling, which prevented OSA-induced AF.

Increased inflammation promotes ventricular arrhythmia through aggravating left stellate ganglion remodeling in a canine ischemia model.

BACKGROUND: Increased inflammation was found in the left stellate ganglion (LSG) in patients with malignant ventricular arrhythmia (VA). However, the role of inflammation in LSG remodeling is unknown. This study aimed to investigate whether exogenous interleukin-1ß (IL-1ß) could aggravate VA through regulating LSG remodeling. METHODS: Twenty-four canines who received saline (Control, n=8), IL-1ß injection into the LSG (n=8) or IL-1 receptor antagonist (IL-Ra) pre-injection plus IL-1ß injection (n=8) were included. Ventricular electrophysiology parameters, heart rate variability (HRV), LSG activity were measured at different time points. VA was recorded for 60min after ischemia and then LSG tissues were collected for molecular detection. RESULTS: Compared with the control group, IL-1ß injection decreased the effective refractory period, action potential duration (APD)90 and increased the maximal slope of the restitution curve in normal hearts. Besides, the occurrence of VA was significantly increased in the IL-1ß group. Additionally, IL-1ß injection increased the sympathetic indices of HRV and LSG activity in normal and ischemic hearts. Mechanically, the mRNA expression of pro-inflammatory cytokines and protein expression of c-fos, nerve growth factor and neuropeptide Y in LSG were increased, whereas the expression of neuronal nitric oxide synthase was decreased in the IL-1ß group. More importantly, all these effects induced by IL-1ß were attenuated by IL-1Ra pre-injection. CONCLUSION: Increased inflammation induced by IL-1ß injection aggravates ischemia induced VA through regulating the neuronal remodeling of the LSG. Inflammation induced neuroplasticity may be a novel mechanism and therapeutic target for VA.

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.