Comparative specialization of intrinsic cardiac neurons in humans, mice, and pigs.

Intrinsic cardiac neurons (ICNs) play a crucial role in the proper functioning of the heart; yet a paucity of data pertaining to human ICNs exists. We took a multidisciplinary approach to complete a detailed cellular comparison of the structure and function of ICNs from mice, pigs, and humans. Immunohistochemistry of whole and sectioned ganglia, transmission electron microscopy, intracellular microelectrode recording and dye filling for quantitative morphometry were used to define the neurophysiology, histochemistry, and ultrastructure of these cells across species. The densely packed, smaller ICNs of mouse lacked dendrites, formed axosomatic connections, and had high synaptic efficacy constituting an obligatory synapse. At Pig ICNs, a convergence of subthreshold cholinergic inputs onto extensive dendritic arbors supported greater summation and integration of synaptic input. Human ICNs were tonically firing, with synaptic stimulation evoking large suprathreshold excitatory postsynaptic potentials like mouse, and subthreshold potentials like pig. Ultrastructural examination of synaptic terminals revealed conserved architecture, yet small clear vesicles (SCVs) were larger in pigs and humans. The presence and localization of ganglionic neuropeptides was distinct, with abundant VIP observed in human but not pig or mouse ganglia, and little SP or CGRP in pig ganglia. Action potential waveforms were similar, but human ICNs had larger after-hyperpolarizations. Intrinsic excitability differed; 93% of human cells were tonic, all pig neurons were phasic, and both phasic and tonic phenotypes were observed in mouse. In combination, this publicly accessible, multimodal atlas of ICNs from mice, pigs, and humans identifies similarities and differences in the evolution of ICNs.

Anatomical and functional organization of cardiac fibers in the porcine cervical vagus nerve allows spatially selective efferent neuromodulation.

Cardiac disease progression reflects the dynamic interaction between adversely remodeled neurohumoral control systems and an abnormal cardiac substrate. Vagal nerve stimulation (VNS) is an attractive neuromodulatory option to dampen this dynamic interaction; however, it is limited by off-target effects. Spatially-selective VNS (sVNS) offers a promising solution to induce cardioprotection while mitigating off-target effects by specifically targeting pre-ganglionic parasympathetic efferent cardiac fibers. This approach also has the potential to enhance therapeutic outcomes by eliminating time-consuming titration required for optimal VNS. Recent studies have demonstrated the independent modulation of breathing rate, heart rate, and laryngeal contraction through sVNS. However, the spatial organization of afferent and efferent cardiac-related fibers within the vagus nerve remains unexplored. By using trial-and-error sVNS in vivo in combination with ex vivo micro-computed tomography fascicle tracing, we show the significant spatial separation of cardiac afferent and efferent fibers (179±55° SD microCT, p<0.05 and 200±137° SD, p<0.05 sVNS - degrees of separation across a cross-section of nerve) at the mid-cervical level. We also show that cardiac afferent fibers are located in proximity to pulmonary fibers consistent with recent findings of cardiopulmonary convergent neurons and circuits. We demonstrate the ability of sVNS to selectively elicit desired scalable heart rate decrease without stimulating afferent-related reflexes. By elucidating the spatial organization of cardiac-related fibers within the vagus nerve, our findings pave the way for more targeted neuromodulation, thereby reducing off-target effects and eliminating the need for titration. This, in turn, will enhance the precision and efficacy of VNS therapy in treating cardiac pathology, allowing for improved therapeutic efficacy.

Pseudo-vagal Responses Elicited by Cryoballoon Ablation.

Pulmonary vein isolation via cryoballoon (CB) ablation is the cornerstone ablation strategy for the treatment of atrial fibrillation (AF). Acute intraprocedural hypotensive and/or bradycardic responses have been reported in patients undergoing CB ablation for AF. However, it remains unclear as to whether these are due to a true vagal response (VR), which can be used to predict long-term outcomes of CB ablation. We analyzed 139 freezes across 17 patients who received CB ablation for paroxysmal AF, measuring vital signs and freeze characteristics. Only one freeze was associated with both hypotension and bradycardia, constituting a true VR. Several freezes were associated with hypotension only that did not respond to atropine administration, suggesting that these responses are not associated with a VR. Hypotensive responses were significantly associated with ice bubble bursts during CB deflation. Unlike the true VR reported in patients undergoing conscious sedation, the presence of acute hypotension shortly after CB deflation cannot be used as a predictor for long-term ablation outcomes.

Vagal Nerve Stimulation Reduces Ventricular Arrhythmias and Mitigates Adverse Neural Cardiac Remodeling Post-Myocardial Infarction.

This study sought to evaluate the impact of chronic vagal nerve stimulation (cVNS) on cardiac and extracardiac neural structure/function after myocardial infarction (MI). Groups were control, MI, and MI + cVNS; cVNS was started 2 days post-MI. Terminal experiments were performed 6 weeks post-MI. MI impaired left ventricular mechanical function, evoked anisotropic electrical conduction, increased susceptibility to ventricular tachycardia and fibrillation, and altered neuronal and glial phenotypes in the stellate and dorsal root ganglia, including glial activation. cVNS improved cardiac mechanical function and reduced ventricular tachycardia/ventricular fibrillation post-MI, partly by stabilizing activation/repolarization in the border zone. MI-associated extracardiac neural remodeling, particularly glial activation, was mitigated with cVNS.

Spinal neuromodulation mitigates myocardial ischemia-induced sympathoexcitation by suppressing the intermediolateral nucleus hyperactivity and spinal neural synchrony.

Introduction: Myocardial ischemia disrupts the cardio-spinal neural network that controls the cardiac sympathetic preganglionic neurons, leading to sympathoexcitation and ventricular tachyarrhythmias (VTs). Spinal cord stimulation (SCS) is capable of suppressing the sympathoexcitation caused by myocardial ischemia. However, how SCS modulates the spinal neural network is not fully known. Methods: In this pre-clinical study, we investigated the impact of SCS on the spinal neural network in mitigating myocardial ischemia-induced sympathoexcitation and arrhythmogenicity. Ten Yorkshire pigs with left circumflex coronary artery (LCX) occlusion-induced chronic myocardial infarction (MI) were anesthetized and underwent laminectomy and a sternotomy at 4-5 weeks post-MI. The activation recovery interval (ARI) and dispersion of repolarization (DOR) were analyzed to evaluate the extent of sympathoexcitation and arrhythmogenicity during the left anterior descending coronary artery (LAD) ischemia. Extracellular in vivo and in situ spinal dorsal horn (DH) and intermediolateral column (IML) neural recordings were performed using a multichannel microelectrode array inserted at the T2-T3 segment of the spinal cord. SCS was performed for 30 min at 1 kHz, 0.03 ms, 90% motor threshold. LAD ischemia was induced pre- and 1 min post-SCS to investigate how SCS modulates spinal neural network processing of myocardial ischemia. DH and IML neural interactions, including neuronal synchrony as well as cardiac sympathoexcitation and arrhythmogenicity markers were evaluated during myocardial ischemia pre- vs. post-SCS. Results: ARI shortening in the ischemic region and global DOR augmentation due to LAD ischemia was mitigated by SCS. Neural firing response of ischemia-sensitive neurons during LAD ischemia and reperfusion was blunted by SCS. Further, SCS showed a similar effect in suppressing the firing response of IML and DH neurons during LAD ischemia. SCS exhibited a similar suppressive impact on the mechanical, nociceptive and multimodal ischemia sensitive neurons. The LAD ischemia and reperfusion-induced augmentation in neuronal synchrony between DH-DH and DH-IML pairs of neurons were mitigated by the SCS. Discussion: These results suggest that SCS is decreasing the sympathoexcitation and arrhythmogenicity by suppressing the interactions between the spinal DH and IML neurons and activity of IML preganglionic sympathetic neurons.

A combined cuff electrode array for organ-specific selective stimulation of vagus nerve enabled by Electrical Impedance Tomography.

Previously developed spatially-selective Vagus Nerve Stimulation (sVNS) allows the targeting of specific nerve fascicles through current steering in a multi-electrode nerve cuff but relies on a trial-and-error strategy to identify the relative orientation between electrodes and fascicles. Fast Neural Electrical Impedance Tomography (FN-EIT) has been recently used for imaging neural traffic in the vagus nerves of pigs in a cross-correlation study with sVNS and MicroCT fascicle tracking. FN-EIT has the potential for allowing targeted sVNS; however, up to now, stimulation and imaging have been performed with separate electrode arrays. In this study, different options were evaluated in-silico to integrate EIT and stimulation into a single electrode array without affecting spatial selectivity. The original pig vagus EIT electrode array geometry was compared with a geometry integrating sVNS and EIT electrodes, and with direct use of sVNS electrodes for EIT imaging. Modelling results indicated that both new designs could achieve image quality similar to the original electrode geometry in all tested markers (e.g., co-localisation error <100 µm). The sVNS array was considered to be the simplest due to the lower number of electrodes. Experimental results from testing evoked EIT imaging of recurrent laryngeal activity using electrodes from the sVNS cuff returned a signal-to-noise ratio similar to our previous study (3.9 ± 2.4 vs. 4.1 ± 1.5, N = 4 nerves from 3 pigs) and a lower co-localisation error (≈14% nerve diameter vs. ≈25%, N = 2 nerves from 2 pigs). Performing FN-EIT and sVNS on the same nerve cuff will facilitate translation to humans, simplify surgery and enable targeted neuromodulation strategies.

Superior cervical ganglion stimulation results in potent cerebral vasoconstriction in swine.

Introduction: Sympathetic activity from the superior cervical ganglion (SCG) has been shown to cause cerebral hypoperfusion in swine, similar to that seen with clinical cerebral vasospasm. Although the mechanism of such perfusion deficit has been speculated to be from pathologic cerebral vasoconstriction, the extent of sympathetic contribution to vasoconstriction has not been wellestablished. Objective: We aimed to demonstrate that SCG stimulation in swine leads to significant cerebral vasoconstriction on digital subtraction angiography (DSA). Additionally, we aimed to show that inhibition of SCG can mitigate the effects of sympathetic-mediated cerebral vasoconstriction. Methods: Five SCGs were surgically identified in Yorkshire swine and were electrically stimulated to achieve sympathetic activation. DSA was performed to measure and compare changes in cerebral vessel diameter. Syngo iFlow was also used to quantify changes in contrast flow through the cerebral and neck vessels. Results: SCG stimulation resulted in 35-45% narrowing of the ipsilateral ascending pharyngeal, anterior middle cerebral and anterior cerebral arteries. SCG stimulation also decreased contrast flow through ipsilateral ascending pharyngeal, internal carotid and anterior cerebral arteries as seen on iFLow. These effects were prevented with prior SCG blockade. Minimal vessel caliber changes were seen in the posterior cerebral, posterior middle cerebral and internal carotid arteries with SCG stimulation. Conclusion: SCG stimulation results in significant luminal narrowing and reduction in flow through various intracranial arteries in swine. The results of sympathetic hyperactivity from the SCG closely models cerebral vasoconstriction seen in human cerebral vasospasm. SCG inhibition is a potential promising therapeutic approach to treating cerebral vasospasm.

Vagally-mediated heart block after myocardial infarction associated with plasticity of epicardial neurons controlling the atrioventricular node.

Imbalances in the opposing actions of sympathetic and parasympathetic nerves controlling the heart enhance risk for arrhythmia and sudden cardiac death after myocardial infarction (MI). Plasticity in peripheral neuron function may underlie the observed changes in cardiomotor nerve activity. We studied vagal control of the heart in pigs after chronic infarction of the left ventricle. Stimulation of the cervical vagus nerve produced greater bradycardic responses 8-weeks after MI. Recordings of epicardial electrocardiograms demonstrate increased severity and duration of atrioventricular (AV) block in MI-pigs during 20 Hz vagal stimulation. Intracellular voltage recordings from isolated neurons of the inferior vena cava-inferior left atrium (IVC-ILA) ganglionated plexus, a cluster of epicardial neurons receiving innervation from the vagus known to regulate the AV node, were used to assess plasticity of membrane and synaptic physiology of intrinsic cardiac neurons (ICNs) after MI. Changes to both passive and active membrane properties were observed, including more negative resting membrane potentials and greater input resistances in MI-pig ICNs, concomitant with a depression of neuronal excitability. Immunoreactivity to pituitary adenylate cyclase-activating polypeptide (PACAP), a cardiotropic peptide known to modulate cardiac neuron excitability, was localized to perineuronal varicosities surrounding pig IVC-ILA neurons. Exogenous application of PACAP increased excitability of control but not MI-ICNs. Stimulation (20 Hz) of interganglionic nerves in the ex vivo whole-mount preparations elicited slow excitatory postsynaptic potentials (sEPSPs) which persisted in hexamethonium (500 µM), but were blocked by atropine (1 µM), indicating muscarinic receptor-mediated inhibition of M-current. Extracellular application of 1 mM BaCl2 to inhibit M-current increased neuronal excitability. The muscarine-sensitive sEPSPs were observed more frequently and were of larger amplitude in IVC-ILA neurons from MI animals. In conclusion, we suggest the increased probability of muscarinic sEPSPs play a role in the potentiation of the vagus nerve mediated-slowing of AV nodal conduction following chronic MI. We identify both a novel role of a muscarinic sensitive current in the regulation of synaptic strength at ICNs projecting to the AV node, and demonstrate changes to both intrinsic plasticity and synaptic plasticity of IVC-ILA neurons which may contribute to greater risk for heart block and sudden cardiac death after MI.

Time-Resolved In Vivo Measurement of Neuropeptide Dynamics by Capacitive Immunoprobe in Porcine Heart.

The ability to measure biomarkers in vivo relevant to the assessment of disease progression is of great interest to the scientific and medical communities. The resolution of results obtained from current methods of measuring certain biomarkers can take several days or weeks to obtain, as they can be limited in resolution both spatially and temporally (e.g., fluid compartment microdialysis of interstitial fluid analyzed by enzyme-linked immunosorbent assay [ELISA], high-performance liquid chromatography [HPLC], or mass spectrometry); thus, their guidance of timely diagnosis and treatment is disrupted. In the present study, a unique technique for detecting and measuring peptide transmitters in vivo through the use of a capacitive immunoprobe biosensor (CI probe) is reported. The fabrication protocol and in vitro characterization of these probes are described. Measurements of sympathetic stimulation-evoked neuropeptide Y (NPY) release in vivo are provided. NPY release is correlated to the sympathetic release of norepinephrine for reference. The data demonstrate an approach for the fast and localized measurement of neuropeptides in vivo. Future applications include intraoperative real-time assessment of disease progression and minimally invasive catheter-based deployment of these probes.

Vagus nerve stimulation using a miniaturized wirelessly powered stimulator in pigs.

Neuromodulation of peripheral nerves has been clinically used for a wide range of indications. Wireless and batteryless stimulators offer important capabilities such as no need for reoperation, and extended life compared to their wired counterparts. However, there are challenging trade-offs between the device size and its operating range, which can limit their use. This study aimed to examine the functionality of newly designed wirelessly powered and controlled implants in vagus nerve stimulation for pigs. The implant used near field inductive coupling at 13.56 MHz industrial, scientific, and medical band to harvest power from an external coil. The circular implant had a diameter of 13 mm and weighed 483 mg with cuff electrodes. The efficiency of the inductive link and robustness to distance and misalignment were optimized. As a result, the specific absorption rate was orders of magnitude lower than the safety limit, and the stimulation can be performed using only 0.1 W of external power. For the first time, wireless and batteryless VNS with more than 5 cm operation range was demonstrated in pigs. A total of 84 vagus nerve stimulations (10 s each) have been performed in three adult pigs. In a quantitative comparison of the effectiveness of VNS devices, the efficiency of systems on reducing heart rate was similar in both conventional (75%) and wireless (78.5%) systems. The pulse width and frequency of the stimulation were swept on both systems, and the response for physiological markers was drawn. The results were easily reproducible, and methods used in this study can serve as a basis for future wirelessly powered implants.

Sympathetic nervous system hyperactivity results in potent cerebral hypoperfusion in swine.

INTRODUCTION: Cerebral vasospasm is a complex disease resulting in reversible narrowing of blood vessels, stroke, and poor patient outcomes. Sympathetic perivascular nerve fibers originate from the superior cervical ganglion (SCG) to innervate the cerebral vasculature, with activation resulting in vasoconstriction. Sympathetic pathways are thought to be a significant contributor to cerebral vasospasm. OBJECTIVE: We sought to demonstrate that stimulation of SCG in swine can cause ipsilateral cerebral perfusion deficit similar to that of significant human cerebral vasospasm. Furthermore, we aimed to show that inhibition of SCG can block the effects of sympathetic-mediated cerebral hypoperfusion. METHODS: SCG were surgically identified in 15 swine and were electrically stimulated to achieve sympathetic activation. CT perfusion scans were performed to assess for changes in cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT) and time-to-maximum (TMax). Syngo.via software was used to determine regions of interest and quantify perfusion measures. RESULTS: SCG stimulation resulted in 20-30% reduction in mean ipsilateral CBF compared to its contralateral unaffected side (p < 0.001). Similar results of hypoperfusion were seen with CBV, MTT and TMax with SCG stimulation. Prior injection of lidocaine to SCG inhibited the effects of SCG stimulation and restored perfusion comparable to baseline (p > 0.05). CONCLUSION: In swine, SCG stimulation resulted in significant cerebral perfusion deficit, and this was inhibited by prior local anesthetic injection into the SCG. Inhibiting sympathetic activation by targeting the SCG may be an effective treatment for sympathetic mediated cerebral hypoperfusion.

Advances in Our Clinical Understanding of Autonomic Regulation Therapy Using Vagal Nerve Stimulation in Patients Living With Heart Failure.

The ANTHEM-HF, INOVATE-HF, and NECTAR-HF clinical studies of autonomic regulation therapy (ART) using vagus nerve stimulation (VNS) systems have collectively provided dose-ranging information enabling the development of several working hypotheses on how stimulation frequency can be utilized during VNS for tolerability and improving cardiovascular outcomes in patients living with heart failure (HF) and reduced ejection fraction (HFrEF). Changes in heart rate dynamics, comprising reduced heart rate (HR) and increased HR variability, are a biomarker of autonomic nerve system engagement and cardiac control, and appear to be sensitive to VNS that is delivered using a stimulation frequency that is similar to the natural operating frequency of the vagus nerve. Among prior studies, the ANTHEM-HF Pilot Study has provided the clearest evidence of autonomic engagement with VNS that was delivered using a stimulation frequency that was within the operating range of the vagus nerve. Achieving autonomic engagement was accompanied by improvement from baseline in six-minute walk duration (6MWD), health-related quality of life, and left ventricular EF (LVEF), over and above those achieved by concomitant guideline-directed medical therapy (GDMT) administered to counteract harmful neurohormonal activation, with relative freedom from deleterious effects. Autonomic engagement and positive directional changes have persisted over time, and an exploratory analysis suggests that improvement in autonomic tone, symptoms, and physical capacity may be independent of baseline NT-proBNP values. Based upon these encouraging observations, prospective, randomized controlled trials examining the effects on symptoms and cardiac function as well as natural history have been warranted. A multi-national, large-scale, randomized, controlled trial is well underway to determine the outcomes associated with ART using autonomic nervous system engagement as a guide for VNS delivery.

Structural and function organization of intrathoracic extracardiac autonomic projections to the porcine heart: Implications for targeted neuromodulation therapy.

BACKGROUND: Mapping the structure/function organization of the cardiac nervous system is foundational for implementation of targeted neuromodulation-based therapeutics for the treatment of cardiac disease. OBJECTIVE: The purpose of this study was to define the spatial organization of intrathoracic parasympathetic and sympathetic efferent projections to the heart. METHODS: Yucatan mini-pigs (N = 11) were anesthetized and the thoracic cavity exposed. Electrical stimulation of the cervical vagi and stellate ganglia was performed individually, and hemodynamic responses were assessed in the intact state and after progressive debranching of each thoracic vagosympathetic trunk (VST). Subsequently, residual cardiac efferent projections arising from paravertebral chain ganglia (T1-T4) were evaluated by stimulation before and after individual ganglionic debranching. RESULTS: Stimulation of the cervical vagi decreased heart rate and contractility while prolonging the activation-recovery interval (ARI). Stimulation of the stellate ganglia increased heart rate and contractility and decreased ARI. The majority of parasympathetic and sympathetic cardiac-evoked responses were mitigated after debranching of the right VST rostral to heart, whereas the left VST demonstrated a distribution with greater dispersion and caudal intrathoracic shift compared to the right. After complete thoracic VST debranching, stimulation of the T4 paravertebral chain ganglia demonstrated residual cardiac sympathetic efferent innervation to the heart in ∼50% of animals. That response was mitigated by transecting medial ganglionic branches. CONCLUSION: The nexus point for optimum neuromodulation engagement of parasympathetic efferent projections to the heart is the cervical vagus and the T1-T2 paravertebral chain ganglia for sympathetic control. Removal of principal sympathetic efferent projections to heart requires targeting the T1-T4 regions of the paravertebral chain.

Stress-related dysautonomias and neurocardiology-based treatment approaches.

Cardiovascular and psychiatric disorders are among the most commonly treated conditions worldwide. Research in neurocardiology, psychiatry, and epidemiology have defined bidirectional relationships between psychiatric disorders and heart disease, affirming the role of impaired autonomic nervous system, or dysautonomia in the prognosis and development in these disorders. These studies have fueled rapid clinical translation of experimental findings, with potential to complement existing pharmacological therapies. In this review, we comprehensively discuss the state-of-the-art investigations and novel treatment approaches for stress-related dysautonomias, emphasizing the effects of stress on the cardiac neuronal hierarchy. Increasing evidence suggests that autonomic modulation stands as an attractive therapeutic strategy in the treatment of dysautonomias that could complement existing therapies and possibly reduce the burden of drug-related side effects and treatment-resistant conditions. Further investigations regarding treatment optimization, selectivity, usability, and ethical concerns are required.

Myocardial infarction reduces cardiac nociceptive neurotransmission through the vagal ganglia.

Myocardial infarction causes pathological changes in the autonomic nervous system, which exacerbate heart failure and predispose to fatal ventricular arrhythmias and sudden death. These changes are characterized by sympathetic activation and parasympathetic dysfunction (reduced vagal tone). Reasons for the central vagal withdrawal and, specifically, whether myocardial infarction causes changes in cardiac vagal afferent neurotransmission that then affect efferent tone, remain unknown. The objective of this study was to evaluate whether myocardial infarction causes changes in vagal neuronal afferent signaling. Using in vivo neural recordings from the inferior vagal (nodose) ganglia and immunohistochemical analyses, structural and functional alterations in vagal sensory neurons were characterized in a chronic porcine infarct model and compared with normal animals. Myocardial infarction caused an increase in the number of nociceptive neurons but a paradoxical decrease in functional nociceptive signaling. No changes in mechanosensitive neurons were observed. Notably, nociceptive neurons demonstrated an increase in GABAergic expression. Given that nociceptive signaling through the vagal ganglia increases efferent vagal tone, the results of this study suggest that a decrease in functional nociception, possibly due to an increase in expression of inhibitory neurotransmitters, may contribute to vagal withdrawal after myocardial infarction.

Scalable and reversible axonal neuromodulation of the sympathetic chain for cardiac control.

Maladaptation of the sympathetic nervous system contributes to the progression of cardiovascular disease and risk for sudden cardiac death, the leading cause of mortality worldwide. Axonal modulation therapy (AMT) directed at the paravertebral chain blocks sympathetic efferent outflow to the heart and maybe a promising strategy to mitigate excess disease-associated sympathoexcitation. The present work evaluates AMT, directed at the sympathetic chain, in blocking sympathoexcitation using a porcine model. In anesthetized porcine (n = 14), we applied AMT to the right T1-T2 paravertebral chain and performed electrical stimulation of the distal portion of the right sympathetic chain (RSS). RSS-evoked changes in heart rate, contractility, ventricular activation recovery interval (ARI), and norepinephrine release were examined with and without kilohertz frequency alternating current block (KHFAC). To evaluate efficacy of AMT in the setting of sympathectomy, evaluations were performed in the intact state and repeated after left and bilateral sympathectomy. We found strong correlations between AMT intensity and block of sympathetic stimulation-evoked changes in cardiac electrical and mechanical indices (r = 0.83-0.96, effect size d = 1.9-5.7), as well as evidence of sustainability and memory. AMT significantly reduced RSS-evoked left ventricular interstitial norepinephrine release, as well as coronary sinus norepinephrine levels. Moreover, AMT remained efficacious following removal of the left sympathetic chain, with similar mitigation of evoked cardiac changes and reduction of catecholamine release. With growth of neuromodulation, an on-demand or reactionary system for reversible AMT may have therapeutic potential for cardiovascular disease-associated sympathoexcitation.NEW & NOTEWORTHY Autonomic imbalance and excess sympathetic activity have been implicated in the pathogenesis of cardiovascular disease and are targets for existing medical therapy. Neuromodulation may allow for control of sympathetic projections to the heart in an on-demand and reversible manner. This study provides proof-of-concept evidence that axonal modulation therapy (AMT) blocks sympathoexcitation by defining scalability, sustainability, and memory properties of AMT. Moreover, AMT directly reduces release of myocardial norepinephrine, a mediator of arrhythmias and heart failure.

Therapeutic responsiveness to vagus nerve stimulation in patients receiving beta-blockade for heart failure with reduced ejection fraction.

BACKGROUND: The effect of beta-blockade (BB) on response to vagus nerve stimulation (VNS) has not been reported in patients with heart failure and reduced ejection fraction (HFrEF). In the ANTHEM-HF Study, 60 patients received chronic cervical VNS. Background pharmacological therapy remained unchanged during the study, and VNS intensity was stable once up-titrated. Significant improvement from baseline occurred in resting 24-hour heart rate (HR), 24-hour HR variability (SDNN), left ventricular EF (LVEF), 6-minute walk distance (6MWD), and quality of life (MLWHFS) at 6 months post-titration. We evaluated whether response to VNS was related to percentage of target BB dose (PTBBD) at baseline. METHODS: Patients were categorized by baseline PTBBD, then analyzed for changes from baseline in symptoms and function at 6 months after VNS titration. RESULTS: All patients received BB, either PTBBD ≥ 50 % (16 patients, 27 %; group 1) or PTBBD < 50 % (44 patients, 73 %; group 2). Heart rate, systolic blood pressure, LVEF, use of ACE/ARB, and use of MRA were similar between the two groups at baseline. Six months after up-titration, VNS reduced HR and significantly improved SDNN, LVEF, 6MWD, and MLWHFS equally in both groups. CONCLUSIONS: In the ANTHEM-HF study, VNS responsiveness appeared to be independent of the baseline BB dose administered.

A single cell transcriptomics map of paracrine networks in the intrinsic cardiac nervous system.

We developed a spatially-tracked single neuron transcriptomics map of an intrinsic cardiac ganglion, the right atrial ganglionic plexus (RAGP) that is a critical mediator of sinoatrial node (SAN) activity. This 3D representation of RAGP used neuronal tracing to extensively map the spatial distribution of the subset of neurons that project to the SAN. RNA-seq of laser capture microdissected neurons revealed a distinct composition of RAGP neurons compared to the central nervous system and a surprising finding that cholinergic and catecholaminergic markers are coexpressed, suggesting multipotential phenotypes that can drive neuroplasticity within RAGP. High-throughput qPCR of hundreds of laser capture microdissected single neurons confirmed these findings and revealed a high dimensionality of neuromodulatory factors that contribute to dynamic control of the heart. Neuropeptide-receptor coexpression analysis revealed a combinatorial paracrine neuromodulatory network within RAGP informing follow-on studies on the vagal control of RAGP to regulate cardiac function in health and disease.

Neuroscientific therapies for atrial fibrillation.

The cardiac autonomic nervous system (ANS) plays an integral role in normal cardiac physiology as well as in disease states that cause cardiac arrhythmias. The cardiac ANS, comprised of a complex neural hierarchy in a nested series of interacting feedback loops, regulates atrial electrophysiology and is itself susceptible to remodelling by atrial rhythm. In light of the challenges of treating atrial fibrillation (AF) with conventional pharmacologic and myoablative techniques, increasingly interest has begun to focus on targeting the cardiac neuraxis for AF. Strong evidence from animal models and clinical patients demonstrates that parasympathetic and sympathetic activity within this neuraxis may trigger AF, and the ANS may either induce atrial remodelling or undergo remodelling itself to serve as a substrate for AF. Multiple nexus points within the cardiac neuraxis are therapeutic targets, and neuroablative and neuromodulatory therapies for AF include ganglionated plexus ablation, epicardial botulinum toxin injection, vagal nerve (tragus) stimulation, renal denervation, stellate ganglion block/resection, baroreceptor activation therapy, and spinal cord stimulation. Pre-clinical and clinical studies on these modalities have had promising results and are reviewed here.