Publications by authors named "Jeffrey L Ardell"

85 Publications

Neuroscientific therapies for atrial fibrillation.

Cardiovasc Res 2021 Jun;117(7):1732-1745

University of California Los Angeles (UCLA) Cardiac Arrhythmia Center, David Geffen School of Medicine, UCLA, 100 Medical Plaza, Suite 660, Los Angeles, CA 90095, USA.

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.
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http://dx.doi.org/10.1093/cvr/cvab172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208752PMC
June 2021

Innervation and Neuronal Control of the Mammalian Sinoatrial Node a Comprehensive Atlas.

Circ Res 2021 Apr 25;128(9):1279-1296. Epub 2021 Feb 25.

Department of Medicine, Cardiac Arrhythmia Center and Neurocardiology Research Program of Excellence, University of California, Los Angeles (UCLA; P.H., M.J.D., M.A.S., P.S.R., S.M., J.E.H., R.L.L., J.D.T., J.L.A., K.S.).

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.120.318458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284939PMC
April 2021

Optical vagus nerve modulation of heart and respiration via heart-injected retrograde AAV.

Sci Rep 2021 Feb 11;11(1):3664. Epub 2021 Feb 11.

Departments of Bioengineering, University of Colorado - Anschutz Medical Campus, Aurora, CO, USA.

Vagus nerve stimulation has shown many benefits for disease therapies but current approaches involve imprecise electrical stimulation that gives rise to off-target effects, while the functionally relevant pathways remain poorly understood. One method to overcome these limitations is the use of optogenetic techniques, which facilitate targeted neural communication with light-sensitive actuators (opsins) and can be targeted to organs of interest based on the location of viral delivery. Here, we tested whether retrograde adeno-associated virus (rAAV2-retro) injected in the heart can be used to selectively express opsins in vagus nerve fibers controlling cardiac function. Furthermore, we investigated whether perturbations in cardiac function could be achieved with photostimulation at the cervical vagus nerve. Viral injection in the heart resulted in robust, primarily afferent, opsin reporter expression in the vagus nerve, nodose ganglion, and brainstem. Photostimulation using both one-photon stimulation and two-photon holography with a GRIN-lens incorporated nerve cuff, was tested on the pilot-cohort of injected mice. Changes in heart rate, surface electrocardiogram, and respiratory responses were observed in response to both one- and two-photon photostimulation. The results demonstrate feasibility of retrograde labeling for organ targeted optical neuromodulation.
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http://dx.doi.org/10.1038/s41598-021-83280-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878800PMC
February 2021

Autonomic Modulation for Cardiovascular Disease.

Front Physiol 2020 22;11:617459. Epub 2020 Dec 22.

University of California, Los Angeles (UCLA) Cardiac Arrhythmia Center, David Geffen School of Medicine, Los Angeles, CA, United States.

Dysfunction of the autonomic nervous system has been implicated in the pathogenesis of cardiovascular disease, including congestive heart failure and cardiac arrhythmias. Despite advances in the medical and surgical management of these entities, progression of disease persists as does the risk for sudden cardiac death. With improved knowledge of the dynamic relationships between the nervous system and heart, neuromodulatory techniques such as cardiac sympathetic denervation and vagal nerve stimulation (VNS) have emerged as possible therapeutic approaches for the management of these disorders. In this review, we present the structure and function of the cardiac nervous system and the remodeling that occurs in disease states, emphasizing the concept of increased sympathoexcitation and reduced parasympathetic tone. We review preclinical evidence for vagal nerve stimulation, and early results of clinical trials in the setting of congestive heart failure. Vagal nerve stimulation, and other neuromodulatory techniques, may improve the management of cardiovascular disorders, and warrant further study.
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http://dx.doi.org/10.3389/fphys.2020.617459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783451PMC
December 2020

Neuromodulation of Dorsal Root Ganglia: Chronic Pain Mitigation and Autonomic Implications.

Authors:
Jeffrey L Ardell

JACC Basic Transl Sci 2020 Oct 26;5(10):986-987. Epub 2020 Oct 26.

University of California-Los Angeles Cardiac Arrhythmia Center, David Geffen School of Medicine, Los Angeles, California.

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http://dx.doi.org/10.1016/j.jacbts.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591929PMC
October 2020

Rapid measurement of cardiac neuropeptide dynamics by capacitive immunoprobe in the porcine heart.

Am J Physiol Heart Circ Physiol 2021 01 23;320(1):H66-H76. Epub 2020 Oct 23.

Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio.

Sympathetic control of regional cardiac function occurs through postganglionic innervation from stellate ganglia and thoracic sympathetic chain. Whereas norepinephrine (NE) is their primary neurotransmitter, neuropeptide Y (NPY) is an abundant cardiac cotransmitter. NPY plays a vital role in homeostatic processes including angiogenesis, vasoconstriction, and cardiac remodeling. Elevated sympathetic stress, resulting in increased NE and NPY release, has been implicated in the pathogenesis of several cardiovascular disorders including hypertension, myocardial infarction, heart failure, and arrhythmias, which may result in sudden cardiac death. Current methods for the detection of NPY in myocardium are limited in their spatial and temporal resolution and take days to weeks to provide results [e.g., interstitial microdialysis with subsequent analysis by enzyme-linked immunosorbent assay (ELISA), high performance liquid chromatography (HPLC), or mass spectrometry]. In this study, we report a novel approach for measurement of interstitial and intravascular NPY using a minimally invasive capacitive immunoprobe (C.I. probe). The first high-spatial and temporal resolution, multichannel measurements of NPY release in vivo are provided in both myocardium and transcardiac vascular space in a beating porcine heart. We provide NPY responses evoked by sympathetic stimulation and ectopic ventricular pacing and compare these to NE release and hemodynamic responses. We extend this approach to measure both NPY and vasoactive intestinal peptide (VIP) and show differential release profiles under sympathetic stimulation. Our data demonstrate rapid and local changes in neurotransmitter profiles in response to sympathetic cardiac stressors. Future implementations include real-time intraoperative determination of cardiac neuropeptides and deployment as a minimally invasive catheter. The sympathetic nervous system regulates cardiac function through release of neurotransmitters and neuropeptides within the myocardium. Neuropeptide Y (NPY) acts as an acute cardiac vasoconstrictor and chronically to regulate angiogenesis and cardiac remodeling. Current methodologies for the measure of NPY are not capable of providing rapid readouts on a single-sample basis. Here we provide the first in vivo methodology to report dynamic, localized NPY levels within both myocardium and vascular compartments in a beating heart.
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http://dx.doi.org/10.1152/ajpheart.00674.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847069PMC
January 2021

Long-term Follow-Up of Patients with Heart Failure and Reduced Ejection Fraction Receiving Autonomic Regulation Therapy in the ANTHEM-HF Pilot Study.

Int J Cardiol 2021 01 7;323:175-178. Epub 2020 Oct 7.

University of Minnesota, Minneapolis, MN, United States of America. Electronic address:

Background: The ANTHEM-HF pilot study was an open-label study that evaluated the safety and feasibility of autonomic regulation therapy (ART) utilizing cervical vagus nerve stimulation (VNS) for patients with chronic HF with reduced EF (HFrEF). Patients in NYHA class II-III with EF ≤40% (n = 60) received ART for 6 months post-titration. ART was associated with sustained improvement in left ventricular (LV) function and HF symptoms at 6 and 12 months.

Methods: Continuously cyclic VNS was maintained to determine longer-term safety and chronic effects of ART. Echocardiographic parameters and HF symptoms were assessed throughout a follow-up period of at least 42 months.

Results: Between 12 and 42 months after initial titration, there were no device-related SAEs or malfunctions. There were 10 SAEs adjudicated to be unrelated to VNS, including 5 deaths. There were 6 non-serious adverse events that were adjudicated to be device-related (2 oropharyngeal pain, 1 implant site pain, 2 voice alteration, and 1 hoarseness). At 42 months, there was significant improvement from baseline in LVEF, NYHA class, 6-min walk distance, and MLHFQ score. However, these improvements at 42 months were not significantly different from mean values at 6 and 12 months.

Conclusions: In a 42-month follow-up, ART was durable, safe, and was associated with beneficial effects on LVEF and 6-min walk distance. Long term, chronic, open-loop ART continued to be well-tolerated in patients with HFrEF. The open label, randomized, controlled, ANTHEM-HFrEF Pivotal Study is currently underway to further evaluate ART in patients with advanced HF.
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http://dx.doi.org/10.1016/j.ijcard.2020.09.072DOI Listing
January 2021

Cardiac Neuroanatomy for the Cardiac Electrophysiologist.

J Atr Fibrillation 2020 Jun-Jul;13(1):2407. Epub 2020 Jun 30.

University of California Los Angeles (UCLA) Cardiac Arrhythmia Center and Neurocardiology Research Program of Excellence, Department of Medicine, UCLA, Los Angeles, CA.

The cardiac neuraxis is integral to cardiac physiology, and its dysregulation is implicated in cardiovascular disease. Neuromodulatory therapies are being developed that target the cardiac autonomic nervous system (ANS) to treat cardiac pathophysiology. An appreciation of the cardiac neuroanatomy is a prerequisite for development of such targeted therapies. Here, we provide a review of the current understanding of the cardiac ANS. The parasympathetic and sympathetic nervous system are composed of higher order cortical centers, brainstem, spinal cord, intrathoracic extracardiac ganglia and intrinsic cardiac ganglia. A series of interacting feedback loops mediates reflex pathways to exert control over the cardiac conduction system and contractile tissue. Further exploration of this complex regulatory system promises to yield neuroscience-based therapeutics for cardiac disease.
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http://dx.doi.org/10.4022/jafib.2407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533134PMC
June 2020

Mechanism of ventricular premature beats elicited by left stellate ganglion stimulation during acute ischaemia of the anterior left ventricle.

Cardiovasc Res 2021 Jul;117(9):2083-2091

Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Heart Center, Meibergdreef 9, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands.

Aims: Enhanced sympathetic activity during acute ischaemia is arrhythmogenic, but the underlying mechanism is unknown. During ischaemia, a diastolic current flows from the ischaemic to the non-ischaemic myocardium. This 'injury' current can cause ventricular premature beats (VPBs) originating in the non-ischaemic myocardium, especially during a deeply negative T wave in the ischaemic zone. We reasoned that shortening of repolarization in myocardium adjacent to ischaemic myocardium increases the 'injury' current and causes earlier deeply negative T waves in the ischaemic zone, and re-excitation of the normal myocardium. We tested this hypothesis by activation and repolarization mapping during stimulation of the left stellate ganglion (LSG) during left anterior descending coronary artery (LAD) occlusion.

Methods And Results: In nine pigs, five subsequent episodes of acute ischaemia, separated by 20 min of reperfusion, were produced by occlusion of the LAD and 121 epicardial local unipolar electrograms were recorded. During the third occlusion, left stellate ganglion stimulation (LSGS) was initiated after 3 min for a 30-s period, causing a shortening of repolarization in the normal myocardium by about 100 ms. This resulted in more negative T waves in the ischaemic zone and more VPBs than during the second, control, occlusion. Following the decentralization of the LSG (including removal of the right stellate ganglion and bilateral cervical vagotomy), fewer VPBs occurred during ischaemia without LSGS. During LSGS, the number of VPBs was similar to that recorded before decentralization.

Conclusion: LSGS, by virtue of shortening of repolarization in the non-ischaemic myocardium by about 100 ms, causes deeply negative T waves in the ischaemic tissue and VPBs originating from the normal tissue adjacent to the ischaemic border.
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http://dx.doi.org/10.1093/cvr/cvaa253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318107PMC
July 2021

Baseline NT-proBNP and responsiveness to autonomic regulation therapy in patients with heart failure and reduced ejection fraction.

Int J Cardiol Heart Vasc 2020 Aug 30;29:100520. Epub 2020 May 30.

Vintage Hospital, Goa, India.

Background: Recent heart failure studies have associated lower baseline natriuretic peptide levels with improved morbidity/mortality outcomes during pharmaceutical treatment, and better clinical outcomes during neuromodulation (NM) with carotid nerve plexus stimulation for HFrEF when NT-proBNP < 1600 pg/ml. Whether baseline NT-proBNP is associated with HFrEF responsiveness to NM using vagus nerve stimulation (VNS) has not been examined. Hence, we evaluated the interaction of baseline NT-proBNP with changes in symptoms and function that occurred during chronic VNS in the ANTHEM-HF study.

Methods: A repeated measures, generalized-estimating, equations model evaluated the relationship of baseline NT-proBNP values above and below 1600 pg/ml to symptomatic and functional responses in ANTHEM-HF.

Results: Median (interquartile range; maximum) NT-proBNP was 868 (322, 1875; 14,656) pg/ml (N = 58). Heart rate (HR), HR variability (SDNN), 6-minute walk distance, MLWHF mean score, and NYHA improved significantly, independent of baseline NT-proBNP. While there was a statistical interaction between baseline NT-proBNP and better LVEF improvement during VNS, LVEF improved overall in the study cohort (N = 60; 32 ± 7 to 37 ± 10%; p = 0.0042), and in those patients whose baseline NT-proBNP was below the median baseline NT-proBNP value (n = 29; 36 ± 6 to 42 ± 10%; p < 0.0025)] or above this value (n = 29; 29 ± 7 to 32 ± 9%; p < 0.05).

Conclusions: In ANTHEM-HF, overall symptomatic and functional improvement during chronic VNS was independent of baseline NTproBNP. These are preliminary and hypothesis-generating findings, and the reason for a differing interaction between baseline NT-proBNP and response to CNPS and VNS remains unclear. It is anticipated that the ongoing ANTHEM-HFrEF Pivotal Study of VNS will provide additional insight.
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http://dx.doi.org/10.1016/j.ijcha.2020.100520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264752PMC
August 2020

Fast in vivo detection of myocardial norepinephrine levels in the beating porcine heart.

Am J Physiol Heart Circ Physiol 2020 05 27;318(5):H1091-H1099. Epub 2020 Mar 27.

Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio.

The sympathetic nervous system modulates cardiac function by controlling key parameters such as chronotropy and inotropy. Sympathetic control of ventricular function occurs through extrinsic innervation arising from the stellate ganglia and thoracic sympathetic chain. In the healthy heart, sympathetic release of norepinephrine (NE) results in positive modulation of chronotropy, inotropy, and dromotropy, significantly increasing cardiac output. However, in the setting of myocardial infarction or injury, sympathetic activation persists, contributing to heart failure and increasing the risk of arrhythmias, including sudden cardiac death. Methodologies for detection of norepinephrine in cardiac tissue are limited. Present techniques rely on microdialysis for analysis by high-performance liquid chromatography coupled to electrochemical detection (HPLC-ED), radioimmunoassay, or other immunoassays, such as enzyme-linked immunosorbent assay (ELISA). Although significant information about the release and action of norepinephrine has been obtained with these methodologies, they are limited in temporal resolution, require large sample volumes, and provide results with a significant delay after sample collection (hours to weeks). In this study, we report a novel approach for measurement of interstitial cardiac norepinephrine, using minimally invasive, electrode-based, fast-scanning cyclic voltammetry (FSCV) applied in a beating porcine heart. The first multispatial and high temporal resolution, multichannel measurements of NE release in vivo are provided. Our data demonstrate rapid changes in interstitial NE profiles with regional differences in response to coronary ischemia, sympathetic nerve stimulation, and alterations in preload/afterload. Pharmacological, electrical, or surgical regulation of sympathetic neuronal control can be used to modulate cardiac function and treat arrhythmias. However, present methods for monitoring sympathetic release of norepinephrine in the heart are limited in spatial and temporal resolution. Here, we provide for the first time a methodology and demonstration of practice and rapid measures of individualized regional autonomic neurotransmitter levels in a beating heart. We show dynamic, spatially resolved release profiles under normal and pathological conditions.
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http://dx.doi.org/10.1152/ajpheart.00574.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346543PMC
May 2020

Spinal cord neural network interactions: implications for sympathetic control of the porcine heart.

Am J Physiol Heart Circ Physiol 2020 04 28;318(4):H830-H839. Epub 2020 Feb 28.

Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.

Inherent and acquired factors determine the integrated autonomic response to cardiovascular stressors. Excessive sympathoexcitation to ischemic stress is a major contributor to the potential for sudden cardiac death. To define fundamental aspects of cardiac-related autonomic neural network interactions within the thoracic cord, specifically as related to modulating sympathetic preganglionic (SPN) neural activity. Adult, anesthetized Yorkshire pigs ( = 10) were implanted with penetrating high-density microarrays (64 electrodes) at the T2 level of the thoracic spinal cord to record extracellular potentials concurrently from left-sided dorsal horn (DH) and SPN neurons. Electrical stimulation of the T2 paravertebral chain allowed for antidromic identification of SPNs located in the intermediolateral cell column (57 of total 1,760 recorded neurons). Cardiac stressors included epicardial touch, occlusion of great vessels to transiently alter preload/afterload, and transient occlusion of the left anterior descending coronary artery (LAD). Spatial/temporal assessment of network interactions was characterized by cross-correlation analysis. While some DH neurons responded solely to changes in preload/afterload (8.5 ± 1.9%) or ischemic stress (10.5 ± 3.9%), the majority of cardiovascular-related DH neurons were multimodal (30.2 ± 4.7%) with ischemia sensitivity being one of the modalities (26.1 ± 4.7%). The sympathoexcitation associated with transient LAD occlusion was associated with increased correlations from baseline within DH neurons (2.43 ± 0.61 to 7.30 ± 1.84%, = 0.04) and between SPN to DH neurons (1.32 ± 0.78 to 7.24 ± 1.84%, = 0.02). DH to SPN network correlations were reduced during great vessel occlusion. In conclusion, increased intrasegmental network coherence within the thoracic spinal cord contributes to myocardial ischemia-induced sympathoexcitation. In an in vivo pig model, we demonstrate using novel high-resolution neural electrode arrays that increased intrasegmental network coherence within the thoracic spinal cord contributes to myocardial ischemia-induced sympathoexcitation.
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http://dx.doi.org/10.1152/ajpheart.00635.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191487PMC
April 2020

Comparison of symptomatic and functional responses to vagus nerve stimulation in ANTHEM-HF, INOVATE-HF, and NECTAR-HF.

ESC Heart Fail 2020 02 27;7(1):75-83. Epub 2020 Jan 27.

Section of Cardiology, San Francisco Veterans Affairs Medical Center and School of Medicine, University of California, San Francisco, CA, USA.

Aims: Clinical studies of vagal nerve stimulation (VNS) for heart failure with reduced ejection fraction have had mixed results to date. We sought to compare VNS delivery and associated changes in symptoms and function in autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure (ANTHEM-HF), increase of vagal tone in heart failure (INOVATE-HF), and neural cardiac therapy for heart failure (NECTAR-HF) for hypothesis generation.

Methods And Results: Descriptive statistics were used to analyse data from the public domain for differences in proportions using Pearson's chi-square test, differences in mean values using Student's unpaired t-test, and differences in changes of mean values using two-sample t-tests. Guideline-directed medical therapy recommendations were similar across studies. Fewer patients were in New York Heart Association 3, and baseline heart rate (HR) was higher in ANTHEM-HF. In INOVATE-HF, VNS was aimed at peripheral neural targets, using closed-loop delivery that required synchronization of VNS to R-wave sensing by an intracardiac lead. Pulse frequency was low (1-2 Hz) because of a timing schedule allowing ≤3 pulses of VNS following at most 25% of detected R waves. NECTAR-HF and ANTHEM-HF used open-loop VNS delivery (i.e. independent of any external signal) aimed at both central and peripheral targets. In NECTAR-HF, VNS delivery at 20 Hz caused off-target effects that limited VNS up-titration in a majority of patients. In ANTHEM-HF, VNS delivery at 10 Hz allowed up-titration until changes in HR dynamics were confirmed. Six months after VNS titration, significant improvements in both HR and HR variability occurred only in ANTHEM-HF. When ANTHEM-HF and NECTAR-HF were compared, greater improvements from baseline were observed in ANTHEM-HF in standard deviation in normal-to-normal R-R intervals (94 ± 26 to 111 ± 50 vs. 146 ± 48 to 130 ± 52 ms; P < 0.001), left ventricular ejection fraction (32 ± 7 to 37 ± 0.4 vs. 31 ± 6 to 33 ± 6; P < 0.05), and Minnesota Living with Heart Failure mean score (40 ± 14 to 21 ± 10 vs. 44 ± 22 to 36 ± 21; P < 0.002). When compared with INOVATE-HF, greater improvement in 6-min walk distance was observed in ANTHEM-HF (287 ± 66 to 346 ± 78 vs. 304 ± 111 to 334 ± 111 m; P < 0.04).

Conclusions: In this post-hoc analysis, differences in patient demographics were seen and may have caused the differential responses in symptoms and function observed in association with VNS. Major differences in technology platforms, neural targets, VNS delivery, and HR and HR variability responses could have also potentially played a very important role. Further study is underway in a randomized controlled trial with these considerations in mind.
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http://dx.doi.org/10.1002/ehf2.12592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083506PMC
February 2020

Impact of Autonomic Regulation Therapy in Patients with Heart Failure: ANTHEM-HFrEF Pivotal Study Design.

Circ Heart Fail 2019 11 14;12(11):e005879. Epub 2019 Nov 14.

LivaNova USA Incorporated, Houston, TX (I.L., L.A.D.).

Background: The ANTHEM-HFrEF (Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure with Reduced Ejection Fraction) pivotal study is an adaptive, open-label, randomized, controlled study evaluating whether autonomic regulation therapy will benefit patients with advanced HFrEF. While early-phase studies have supported potential use of vagus nerve stimulation to deliver autonomic regulation therapy for HFrEF, results of larger clinical trials have been inconsistent. The ANTHEM-HFrEF study uses a novel design, with adaptive sample size selection, evaluating effects on morbidity and mortality as well as symptoms and function.

Methods: The ANTHEM-HFrEF study will randomize patients (2:1) to autonomic regulation therapy plus guideline-directed medical therapy, or guideline-directed medical therapy alone. The morbidity and mortality trial utilizes a conventional frequentist approach for analysis of the primary outcome end point-reduction in the composite of cardiovascular death or first HF hospitalization-and a Bayesian adaptive approach toward sample size selection. Embedded within the ANTHEM-HFrEF study is a second trial evaluating improvement in symptoms and function. Symptom/function success will require meeting 2 risk-related conditions (trend for reduced cardiovascular death/HF hospitalization and sufficient freedom from device-related serious adverse events) and 3 efficacy end point components (changes in left ventricular EF, 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire overall score).

Conclusions: Vagus nerve stimulation remains a promising, yet unproven treatment in HFrEF. A successful ANTHEM-HFrEF pivotal study would provide an important advance in HFrEF treatment and offer a model for expediting evaluation of new therapies.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03425422.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.005879DOI Listing
November 2019

Cardiac sympathectomy and spinal cord stimulation attenuate reflex-mediated norepinephrine release during ischemia preventing ventricular fibrillation.

JCI Insight 2019 12 5;4(23). Epub 2019 Dec 5.

UCLA Cardiac Arrhythmia Center, UCLA Health System, Los Angeles, California, USA.

The purpose of this study was to define the mechanism by which cardiac neuraxial decentralization or spinal cord stimulation (SCS) reduces ischemia-induced ventricular fibrillation (VF). Direct measurements of norepinephrine (NE) levels in the left ventricular interstitial fluid (ISF) by microdialysis, in response to transient (15-minute) coronary artery occlusion (CAO), were performed in anesthetized canines. Responses were studied in animals with intact neuraxes and were compared with those in which the intrathoracic component of the cardiac neuraxes (stellate ganglia) or the intrinsic cardiac neuronal (ICN) system was surgically delinked from the central nervous system and those with intact neuraxes with preemptive SCS (T1-T3). With intact neuraxes, animals with exaggerated NE release due to CAO were at increased risk for VF. During CAO, there was a 152% increase in NE when the neuraxes were intact compared with 114% following stellate decentralization and 16% following ICN decentralization. During SCS, CAO NE levels increased by 59%. Risk for CAO-induced VF was 38% in controls, 8% following decentralization, and 11% following SCS. These data indicate that ischemia-related afferent neuronal transmission differentially engages central and intrathoracic sympathetic reflexes and amplifies sympathoexcitation. Differences in regional ventricular NE release are associated with increased risk for VF. Surgical decentralization or SCS reduced NE release and VF.
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http://dx.doi.org/10.1172/jci.insight.131648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962015PMC
December 2019

Increased arrhythmia susceptibility in type 2 diabetic mice related to dysregulation of ventricular sympathetic innervation.

Am J Physiol Heart Circ Physiol 2019 12 18;317(6):H1328-H1341. Epub 2019 Oct 18.

University of California, Los Angeles Cardiac Arrhythmia Center, Neurocardiology Research Program of Excellence, Department of Medicine-Cardiology, Los Angeles, California.

Patients with type 2 diabetes mellitus (T2DM) have a greater risk of developing life-threatening cardiac arrhythmias. Because the underlying mechanisms and potential influence of diabetic autonomic neuropathy are not well understood, we aimed to assess the relevance of a dysregulation in cardiac autonomic tone. Ventricular arrhythmia susceptibility was increased in Langendorff-perfused hearts isolated from mice with T2DM (). Membrane properties and synaptic transmission were similar at cardiac postganglionic parasympathetic neurons from diabetic and control mice; however, a greater asynchronous neurotransmitter release was present at sympathetic postganglionic neurons from the stellate ganglia of mice. Western blot analysis showed a reduction of tyrosine hydroxylase (TH) from the ventricles of mice, which was confirmed with confocal imaging as a heterogeneous loss of TH-immunoreactivity from the left ventricular wall but not the apex. In vivo stimulation of cardiac parasympathetic (vagus) or cardiac sympathetic (stellate ganglion) nerves induced similar changes in heart rate in control and mice, and the kinetics of pacing-induced Ca transients (recorded from isolated cardiomyocytes) were similar in control and cells. Antagonism of cardiac muscarinic receptors did not affect the frequency or severity of arrhythmias in mice, but sympathetic blockade with propranolol completely inhibited arrhythmogenicity. Collectively, these findings suggest that the increased ventricular arrhythmia susceptibility of type 2 diabetic mouse hearts is due to dysregulation of the sympathetic ventricular control. Patients with type 2 diabetes mellitus have greater risk of suffering from sudden cardiac death. We found that the increased ventricular arrhythmia susceptibility in type 2 diabetic mouse hearts is due to cardiac sympathetic dysfunction. Sympathetic dysregulation is indicated by an increased asynchronous release at stellate ganglia, a heterogeneous loss of tyrosine hydroxylase from the ventricular wall but not apex, and inhibition of ventricular arrhythmias in mice after β-sympathetic blockade.
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http://dx.doi.org/10.1152/ajpheart.00249.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962614PMC
December 2019

Thoracic spinal cord neuromodulation obtunds dorsal root ganglion afferent neuronal transduction of the ischemic ventricle.

Am J Physiol Heart Circ Physiol 2019 11 20;317(5):H1134-H1141. Epub 2019 Sep 20.

Neurocardiology Research Program of Excellence, University of California, Los Angeles, California.

Aberrant afferent signaling drives adverse remodeling of the cardiac nervous system in ischemic heart disease. The study objective was to determine whether thoracic spinal dorsal column stimulation (SCS) modulates cardiac afferent sensory transduction of the ischemic ventricle. In anesthetized canines ( = 16), extracellular activity generated by 62 dorsal root ganglia (DRG) soma (T1-T3), with verified myocardial ischemic (MI) sensitivity, were evaluated with and without 20-min preemptive SCS (T1-T3 spinal level; 50 Hz, 90% motor threshold). Transient MI was induced by 1-min coronary artery occlusion (CAO) of the left anterior descending (LAD) or circumflex (LCX) artery, randomized as to sequence. LAD and LCX CAO activated cardiac-related DRG neurons (LAD: 0.15 ± 0.04-1.05 ± 0.20 Hz, < 0.00002; LCX: 0.08 ± 0.02-1.90 ± 0.45 Hz, < 0.0003). SCS decreased basal neuronal activity of neurons that responded to LAD (0.15 ± 0.04 to 0.02 ± 0.01 Hz, < 0.006) and LCX (0.08 ± 0.02 to 0.02 ± 0.01 Hz, < 0.003). SCS suppressed responsiveness to transient MI (LAD: 1.05 ± 0.20-0.03 ± 0.01 Hz; < 0.0001; LCX: 1.90 ± 0.45-0.03 ± 0.01 Hz; < 0.001). Suprathreshold SCS (1 Hz) did not activate DRG neurons antidromically ( = 10 animals). Ventricular fibrillation (VF) was associated with a rapid increase in DRG activity to a maximum of 4.39 ± 1.07 Hz at 20 s after VF induction and a return to 90% of baseline within 10 s thereafter. SCS obtunds the capacity of DRG ventricular neurites to transduce the ischemic myocardium to second-order spinal neurons, a mechanism that would blunt reflex sympathoexcitation to myocardial ischemic stress, thereby contributing to its capacity to cardioprotect. Aberrant afferent signaling drives adverse remodeling of the cardiac nervous system in ischemic heart disease. This study determined that thoracic spinal column stimulation (SCS) obtunds the capacity of dorsal root ganglia ventricular afferent neurons to transduce the ischemic myocardium to second-order spinal neurons, a mechanism that would blunt reflex sympathoexcitation to myocardial ischemic stress. This modulation does not reflect antidromic actions of SCS but likely reflects efferent-mediated changes at the myocyte-sensory neurite interface.
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http://dx.doi.org/10.1152/ajpheart.00257.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879916PMC
November 2019

Background pharmacological therapy in the ANTHEM-HF: comparison to contemporary trials of novel heart failure therapies.

ESC Heart Fail 2019 10 24;6(5):1052-1056. Epub 2019 Jul 24.

University of Minnesota (Emeritus), Minneapolis, MN, USA.

Aims: Clinical trials of new heart failure (HF) therapies administer guideline-directed medical therapy (GDMT) as background pharmacologic treatment (BPT). In the ANTHEM-HF Pilot Study, addition of autonomic regulation therapy to GDMT significantly improved left ventricular function, New York Heart Association (NYHA) class, 6 min walk distance, and quality of life in patients with HF with reduced ejection fraction (HFrEF). A post hoc analysis was performed to compare BPT in ANTHEM-HF with two other trials of novel HF therapies: the PARADIGM-HF study of sacubitril-valsartan and the SHIFT study of ivadrabine. All three studies evaluated patients with HFrEF, and the recommendations for use of GDMT were similar. A left ventricular ejection fraction ≤40% was required for entry into ANTHEM-HF and PARADIGM-HF and ≤35% for SHIFT. NYHA 2 or 3 symptoms were required for entry into ANTHEM-HF, and patients with predominantly NYHA 2 or 3 symptoms were enrolled in PARADIGM-HF and SHIFT.

Methods And Results: Data on BPT were obtained from peer-reviewed publications and the public domain. Pearson's χ test was used to evaluate differences in proportions, and Student's unpaired t-test was used to evaluate differences in mean values. The minimum period of stable GDMT required before randomization was longer in ANTHEM-HF: 3 months vs. 1 month in PARADIGM-HF and SHIFT, respectively. When compared with PARADIGM-HF and SHIFT, more patients in ANTHEM-HF received beta-blockers (100% vs. 93% and 89%, P < 0.04 and P < 0.007) and mineralocorticoid receptor antagonists (75% vs. 55% and 61%, P < 0.002 and P < 0.03). More patients in PARADIGM-HF received an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker than in ANTHEM-HF or SHIFT (100% vs. 85%, P < 0.0001, and 100% vs. 91%, P < 0.001), which was related to PARADIGM's design. When beta-blocker doses in ANTHEM-HF and SHIFT were compared, significantly fewer patients in ANTHEM-HF received doses ≥100% of target (10% vs. 23%, P < 0.02), and fewer patients tended to receive doses ≥50% of target (17% vs. 26%, P = 0.11). When ANTHEM-HF and PARADIGM-HF were compared, more patients in ANTHEM-HF tended to receive doses ≥100% of target (10% vs. 7%, P = 0.36), and fewer patients tended to receive doses ≥50% of target (17% vs. 20%, P = 0.56).

Conclusions: Background treatment with GDMT in ANTHEM-HF compared favourably with that in two other contemporary trials of new HF therapies. The minimum period of stable GDMT required before randomization was longer, and GDMT remained unchanged for the study's duration. These findings serve to further support the potential role of autonomic regulation therapy as an adjunct to GDMT for patients with HFrEF.
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http://dx.doi.org/10.1002/ehf2.12484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816059PMC
October 2019

Premature ventricular contractions activate vagal afferents and alter autonomic tone: implications for premature ventricular contraction-induced cardiomyopathy.

Am J Physiol Heart Circ Physiol 2019 09 19;317(3):H607-H616. Epub 2019 Jul 19.

University of California, Los Angeles Cardiac Arrhythmia Center, Los Angeles, California.

Mechanisms behind development of premature ventricular contraction (PVC)-induced cardiomyopathy remain unclear. PVCs may adversely modulate the autonomic nervous system to promote development of heart failure. Afferent neurons in the inferior vagal (nodose) ganglia transduce cardiac activity and modulate parasympathetic output. Effects of PVCs on cardiac parasympathetic efferent and vagal afferent neurotransmission are unknown. The purpose of this study was to evaluate effects of PVCs on vagal afferent neurotransmission and compare these effects with a known powerful autonomic modulator, myocardial ischemia. In 16 pigs, effects of variably coupled PVCs on heart rate variability (HRV) and vagal afferent neurotransmission were evaluated. Direct nodose neuronal recordings were obtained in vivo, and cardiac-related afferent neurons were identified based on their response to cardiovascular interventions, including ventricular chemical and mechanical stimuli, left anterior descending (LAD) coronary artery occlusion, and variably coupled PVCs. On HRV analysis before versus after PVCs, parasympathetic tone decreased (normalized high frequency: 83.6 ± 2.8 to 72.5 ± 5.3; < 0.05). PVCs had a powerful impact on activity of cardiac-related afferent neurons, altering activity of 51% of neurons versus 31% for LAD occlusion ( < 0.05 vs. LAD occlusion and all other cardiac interventions). Both chemosensitive and mechanosensitive neurons were activated by PVCs, and their activity remained elevated even after cessation of PVCs. Cardiac afferent neural responses to PVCs were greater than any other intervention, including ischemia of similar duration. These data suggest that even brief periods of PVCs powerfully modulate vagal afferent neurotransmission, reflexly decreasing parasympathetic efferent tone. Premature ventricular contractions (PVCs) are common in many patients and, at an increased burden, are known to cause heart failure. This study determined that PVCs powerfully modulate cardiac vagal afferent neurotransmission (exerting even greater effects than ventricular ischemia) and reduce parasympathetic efferent outflow to the heart. PVCs activated both mechano- and chemosensory neurons in the nodose ganglia. These peripheral neurons demonstrated adaptation in response to PVCs. This study provides additional data on the potential role of the autonomic nervous system in PVC-induced cardiomyopathy.
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http://dx.doi.org/10.1152/ajpheart.00286.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766725PMC
September 2019

Identification of peripheral neural circuits that regulate heart rate using optogenetic and viral vector strategies.

Nat Commun 2019 04 26;10(1):1944. Epub 2019 Apr 26.

Cardiac Arrhythmia Center and Neurocardiology Research Program of Excellence, David Geffen School of Medicine, University of California - Los Angeles (UCLA), Los Angeles, CA, 90095, USA.

Heart rate is under the precise control of the autonomic nervous system. However, the wiring of peripheral neural circuits that regulate heart rate is poorly understood. Here, we develop a clearing-imaging-analysis pipeline to visualize innervation of intact hearts in 3D and employed a multi-technique approach to map parasympathetic and sympathetic neural circuits that control heart rate in mice. We identify cholinergic neurons and noradrenergic neurons in an intrinsic cardiac ganglion and the stellate ganglia, respectively, that project to the sinoatrial node. We also report that the heart rate response to optogenetic versus electrical stimulation of the vagus nerve displays different temporal characteristics and that vagal afferents enhance parasympathetic and reduce sympathetic tone to the heart via central mechanisms. Our findings provide new insights into neural regulation of heart rate, and our methodology to study cardiac circuits can be readily used to interrogate neural control of other visceral organs.
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http://dx.doi.org/10.1038/s41467-019-09770-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486614PMC
April 2019

Electroceutical Targeting of the Autonomic Nervous System.

Physiology (Bethesda) 2019 03;34(2):150-162

Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.

Autonomic nerves are attractive targets for medical therapies using electroceutical devices because of the potential for selective control and few side effects. These devices use novel materials, electrode configurations, stimulation patterns, and closed-loop control to treat heart failure, hypertension, gastrointestinal and bladder diseases, obesity/diabetes, and inflammatory disorders. Critical to progress is a mechanistic understanding of multi-level controls of target organs, disease adaptation, and impact of neuromodulation to restore organ function.
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http://dx.doi.org/10.1152/physiol.00030.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586833PMC
March 2019

Calming the Nervous Heart: Autonomic Therapies in Heart Failure.

Card Fail Rev 2018 Aug;4(2):92-98

David Geffen School of Medicine, University of California Los Angeles (UCLA) Los Angeles, CA, USA.

Heart failure (HF) is associated with significant morbidity and mortality. The disease is characterised by autonomic imbalance with increased sympathetic activity and withdrawal of parasympathetic activity. Despite the use of medical therapies that target, in part, the neurohormonal axis, rates of HF progression, morbidity and mortality remain high. Emerging therapies centred on neuromodulation of autonomic control of the heart provide an alternative device-based approach to restoring sympathovagal balance. Preclinical studies have proven favourable, while clinical trials have had mixed results. This article highlights the importance of understanding structural/functional organisation of the cardiac nervous system as mechanistic-based neuromodulation therapies evolve.
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http://dx.doi.org/10.15420/cfr.2018.20.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125704PMC
August 2018

RNA Sequencing Reveals Novel Transcripts from Sympathetic Stellate Ganglia During Cardiac Sympathetic Hyperactivity.

Sci Rep 2018 06 5;8(1):8633. Epub 2018 Jun 5.

Wellcome Trust OXION Initiative in Ion Channels and Disease, Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, Sherrington Building, University of Oxford, Oxford, OX1 3PT, UK.

Cardiovascular disease is the most prevalent age-related illness worldwide, causing approximately 15 million deaths every year. Hypertension is central in determining cardiovascular risk and is a strong predictive indicator of morbidity and mortality; however, there remains an unmet clinical need for disease-modifying and prophylactic interventions. Enhanced sympathetic activity is a well-established contributor to the pathophysiology of hypertension, however the cellular and molecular changes that increase sympathetic neurotransmission are not known. The aim of this study was to identify key changes in the transcriptome in normotensive and spontaneously hypertensive rats. We validated 15 of our top-scoring genes using qRT-PCR, and network and enrichment analyses suggest that glutamatergic signalling plays a key role in modulating Ca balance within these ganglia. Additionally, phosphodiesterase activity was found to be altered in stellates obtained from the hypertensive rat, suggesting that impaired cyclic nucleotide signalling may contribute to disturbed Ca homeostasis and sympathetic hyperactivity in hypertension. We have also confirmed the presence of these transcripts in human donor stellate samples, suggesting that key genes coupled to neurotransmission are conserved. The data described here may provide novel targets for future interventions aimed at treating sympathetic hyperactivity associated with cardiovascular disease and other dysautonomias.
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http://dx.doi.org/10.1038/s41598-018-26651-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988725PMC
June 2018

Vagal Neuromodulation for Atrial Arrhythmias.

JACC Clin Electrophysiol 2017 09 18;3(9):939-941. Epub 2017 Sep 18.

University of California-Los Angeles Cardiac Arrhythmia Center, David Geffen School of Medicine, Los Angeles, California; University of California-Los Angeles Neurocardiology Research Center of Excellence, David Geffen School of Medicine, Los Angeles, California.

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http://dx.doi.org/10.1016/j.jacep.2017.06.018DOI Listing
September 2017

Phosphodiesterase 2A as a therapeutic target to restore cardiac neurotransmission during sympathetic hyperactivity.

JCI Insight 2018 05 3;3(9). Epub 2018 May 3.

Burdon Sanderson Cardiac Science Centre and BHF Centre of Research Excellence, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.

Elevated levels of brain natriuretic peptide (BNP) are regarded as an early compensatory response to cardiac myocyte hypertrophy, although exogenously administered BNP shows poor clinical efficacy in heart failure and hypertension. We tested whether phosphodiesterase 2A (PDE2A), which regulates the action of BNP-activated cyclic guanosine monophosphate (cGMP), was directly involved in modulating Ca2+ handling from stellate ganglia (SG) neurons and cardiac norepinephrine (NE) release in rats and humans with an enhanced sympathetic phenotype. SG were also isolated from patients with sympathetic hyperactivity and healthy donor patients. PDE2A activity of the SG was greater in both spontaneously hypertensive rats (SHRs) and patients compared with their respective controls, whereas PDE2A mRNA was only high in SHR SG. BNP significantly reduced the magnitude of the calcium transients and ICaN in normal Wistar Kyoto (WKY) SG neurons, but not in the SHRs. cGMP levels stimulated by BNP were also attenuated in SHR SG neurons. Overexpression of PDE2A in WKY neurons recapitulated the calcium phenotype seen in SHR neurons. Functionally, BNP significantly reduced [3H]-NE release in the WKY rats, but not in the SHRs. Blockade of overexpressed PDE2A with Bay 60-7550 or overexpression of catalytically inactive PDE2A reestablished the modulatory action of BNP in SHR SG neurons. This suggests that PDE2A may be a key target in modulating the action of BNP to reduce sympathetic hyperactivity.
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http://dx.doi.org/10.1172/jci.insight.98694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6012514PMC
May 2018

Cardiac vanilloid receptor-1 afferent depletion enhances stellate ganglion neuronal activity and efferent sympathetic response to cardiac stress.

Am J Physiol Heart Circ Physiol 2018 05 16;314(5):H954-H966. Epub 2018 Jan 16.

University of California, Los Angeles (UCLA) Cardiac Arrhythmia Center and UCLA Neurocardiology Research Center of Excellence, UCLA, Los Angeles, California.

Afferent fibers expressing the vanilloid receptor 1 (VR1) channel have been implicated in cardiac nociception; however, their role in modulating reflex responses to cardiac stress is not well understood. We evaluated this role in Yorkshire pigs by percutaneous epicardial application of resiniferatoxin (RTX), a toxic activator of the VR1 channel, resulting in the depletion of cardiac VR1-expressing afferents. Hemodynamics, epicardial activation recovery intervals, and in vivo activity of stellate ganglion neurons (SGNs) were recorded in control and RTX-treated animals. Stressors included inferior vena cava or aortic occlusion and rapid right ventricular pacing (RVP) to induce dyssynchrony and ischemia. In the epicardium, stellate ganglia, and dorsal root ganglia, immunostaining for the VR1 channel, calcitonin gene-related peptide, and substance P was significantly diminished by RTX. RTX-treated animals exhibited higher basal systolic blood pressures and contractility than control animals. Reflex responses to epicardial bradykinin and capsaicin were mitigated by RTX. Cardiovascular reflex function, as assessed by inferior vena cava or aortic occlusion, was similar in RTX-treated versus control animals. RTX-treated animals exhibited resistance to hemodynamic collapse induced by RVP. Activation recovery interval shortening during RVP, a marker of cardiac sympathetic outflow, was greater in RTX-treated animals and exhibited significant delay in returning to baseline values after cessation of RVP. The basal firing rate of SGNs and firing rates in response to RVP were also greater in RTX-treated animals, as was the SGN network activity in response to cardiac stressors. These data suggest that elimination of cardiac nociceptive afferents reorganizes the central-peripheral nervous system interaction to enhance cardiac sympathetic outflow. NEW & NOTEWORTHY Our work demonstrates a role for cardiac vanilloid receptor-1-expressing afferents in reflex processing of cardiovascular stress. Current understanding suggests that elimination of vanilloid receptor-1 afferents would decrease reflex cardiac sympathetic outflow. We found, paradoxically, that sympathetic outflow to the heart is instead enhanced at baseline and during cardiac stress.
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http://dx.doi.org/10.1152/ajpheart.00593.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008140PMC
May 2018

Autonomic regulation therapy to enhance myocardial function in heart failure patients: the ANTHEM-HFpEF study.

ESC Heart Fail 2018 02 28;5(1):95-100. Epub 2017 Dec 28.

Minneapolis VA Health Care System, University of Minnesota, Cardiology 111 C, One Veterans Drive, Minneapolis, MN, 55417, USA.

Background: Approximately half of the patients presenting with new-onset heart failure (HF) have HF with preserved left ventricular ejection fraction (HFpEF) and HF with mid-range left ventricular ejection fraction (HFmrEF). These patients have neurohormonal activation like that of HF with reduced ejection fraction; however, beta-blockers and angiotensin-converting enzyme inhibitors have not been shown to improve their outcomes, and current treatment for these patients is symptom based and empiric. Sympathoinhibition using parasympathetic stimulation has been shown to improve central and peripheral aspects of the cardiac nervous system, reflex control, induce myocyte cardioprotection, and can lead to regression of left ventricular hypertrophy. Beneficial effects of autonomic regulation therapy (ART) using vagus nerve stimulation (VNS) have also been observed in several animal models of HFpEF, suggesting a potential role for ART in patients with this disease.

Methods: The Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Patients with Heart Failure and Preserved Ejection Fraction (ANTHEM-HFpEF) study is designed to evaluate the feasibility, tolerability, and safety of ART using right cervical VNS in patients with chronic, stable HFpEF and HFmrEF. Patients with symptomatic HF and HFpEF or HFmrEF fulfilling the enrolment criteria will receive chronic ART with a subcutaneous VNS system attached to the right cervical vagus nerve. Safety parameters will be continuously monitored, and cardiac function and HF symptoms will be assessed every 3 months during a post-titration follow-up period of at least 12 months.

Conclusions: The ANTHEM-HFpEF study is likely to provide valuable information intended to expand our understanding of the potential role of ART in patients with chronic symptomatic HFpEF and HFmrEF.
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http://dx.doi.org/10.1002/ehf2.12241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793957PMC
February 2018

Inflammation, oxidative stress, and glial cell activation characterize stellate ganglia from humans with electrical storm.

JCI Insight 2017 09 21;2(18). Epub 2017 Sep 21.

UCLA Cardiac Arrhythmia Center and.

Background: Neuronal remodeling in human heart disease is not well understood.

Methods: Stellate ganglia from patients with cardiomyopathy (CMY) and refractory ventricular arrhythmias undergoing cardiac sympathetic denervation (n = 8), and from organ donors with normal hearts (n = 8) collected at the time of organ procurement were compared. Clinical data on all subjects were reviewed. Electron microscopy (EM), histologic, and immunohistochemical assessments of neurotransmitter profiles, glial activation and distribution, and lipofuscin deposition, a marker of oxidative stress, were quantified.

Results: In CMY specimens, lipofuscin deposits were larger, and present in more neurons (26.3% ± 6.3% vs. 16.7% ± 7.6%, P < 0.043), than age-matched controls. EM analysis revealed extensive mitochondrial degeneration in CMY specimens. T cell (CD3+) infiltration was identified in 60% of the CMY samples, with one case having large inflammatory nodules, while none were identified in controls. Myeloperoxidase-immunoreactive neutrophils were also identified at parenchymal sites distinct from inflammatory foci in CMY ganglia, but not in controls. The adrenergic phenotype of pathologic samples revealed a decrease in tyrosine hydroxylase staining intensity compared with controls. Evaluation of cholinergic phenotype by staining for the vesicular acetylcholine transporter revealed a low but comparable number of cholinergic neurons in ganglia from both groups and demonstrated that preganglionic cholinergic innervation was maintained in CMY ganglia. S100 staining (a glial cell marker) demonstrated no differences in glial distribution and relationship to neurons; however, glial activation demonstrated by glial fibrillary acidic protein (GFAP) staining was substantially increased in pathologic specimens compared with controls.

Conclusions: Stellate ganglia from patients with CMY and arrhythmias demonstrate inflammation, neurochemical remodeling, oxidative stress, and satellite glial cell activation. These changes likely contribute to excessive and dysfunctional efferent sympathetic tone, and provide a rationale for sympathectomy as a treatment for arrhythmias in this population.

Funding: This work was made possible by support from NIH grants HL125730 to OAA, GM107949 to DBH, and HL084261 and OT2OD023848 to KS.
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http://dx.doi.org/10.1172/jci.insight.94715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621921PMC
September 2017

Thoracic spinal cord and cervical vagosympathetic neuromodulation obtund nodose sensory transduction of myocardial ischemia.

Auton Neurosci 2017 12 18;208:57-65. Epub 2017 Aug 18.

UCLA Neurocardiology Research Program of Excellence, Los Angeles, CA, United States; UCLA Cardiac Arrhythmia Center, Los Angeles, CA, United States. Electronic address:

Background: Autonomic regulation therapy involving either vagus nerve stimulation (VNS) or spinal cord stimulation (SCS) represents emerging bioelectronic therapies for heart disease. The objective of this study was to determine if VNS and/or SCS modulate primary cardiac afferent sensory transduction of the ischemic myocardium.

Methods: Using extracellular recordings in 19 anesthetized canines, of 88 neurons evaluated, 36 ventricular-related nodose ganglia sensory neurons were identified by their functional activity responses to epicardial touch, chemical activation of their sensory neurites (epicardial veratridine) and great vessel (descending aorta or inferior vena cava) occlusion. Neural responses to 1min left anterior descending (LAD) coronary artery occlusion (CAO) were then evaluated. These interventions were then studied following either: i) SCS [T1-T3 spinal level; 50Hz, 90% motor threshold] or ii) cervical VNS [15-20Hz; 1.2× threshold].

Results: LAD occlusion activated 66% of identified nodose ventricular sensory neurons (0.33±0.08-0.79±0.20Hz; baseline to CAO; p<0.002). Basal activity of cardiac-related nodose neurons was differentially reduced by VNS (0.31±0.11 to 0.05±0.02Hz; p<0.05) as compared to SCS (0.36±0.12 to 0.28±0.14, p=0.59), with their activity response to transient LAD CAO being suppressed by either SCS (0.85±0.39-0.11±0.04Hz; p<0.03) or VNS (0.75±0.27-0.12±0.05Hz; p<0.04). VNS did not alter evoked neural responses of cardiac-related nodose neurons to great vessel occlusion.

Conclusions: Both VNS and SCS obtund ventricular ischemia induced enhancement of nodose afferent neuronal inputs to the medulla.
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http://dx.doi.org/10.1016/j.autneu.2017.08.005DOI Listing
December 2017

Defining the neural fulcrum for chronic vagus nerve stimulation: implications for integrated cardiac control.

J Physiol 2017 11 30;595(22):6887-6903. Epub 2017 Sep 30.

UCLA Neurocardiology Research Center of Excellence and UCLA Cardiac Arrhythmia Center, Los Angeles, Los Angeles, CA, USA.

Key Points: The evoked cardiac response to bipolar cervical vagus nerve stimulation (VNS) reflects a dynamic interaction between afferent mediated decreases in central parasympathetic drive and suppressive effects evoked by direct stimulation of parasympathetic efferent axons to the heart. The neural fulcrum is defined as the operating point, based on frequency-amplitude-pulse width, where a null heart rate response is reproducibly evoked during the on-phase of VNS. Cardiac control, based on the principal of the neural fulcrum, can be elicited from either vagus. Beta-receptor blockade does not alter the tachycardia phase to low intensity VNS, but can increase the bradycardia to higher intensity VNS. While muscarinic cholinergic blockade prevented the VNS-induced bradycardia, clinically relevant doses of ACE inhibitors, beta-blockade and the funny channel blocker ivabradine did not alter the VNS chronotropic response. While there are qualitative differences in VNS heart control between awake and anaesthetized states, the physiological expression of the neural fulcrum is maintained.

Abstract: Vagus nerve stimulation (VNS) is an emerging therapy for treatment of chronic heart failure and remains a standard of therapy in patients with treatment-resistant epilepsy. The objective of this work was to characterize heart rate (HR) responses (HRRs) during the active phase of chronic VNS over a wide range of stimulation parameters in order to define optimal protocols for bidirectional bioelectronic control of the heart. In normal canines, bipolar electrodes were chronically implanted on the cervical vagosympathetic trunk bilaterally with anode cephalad to cathode (n = 8, 'cardiac' configuration) or with electrode positions reversed (n = 8, 'epilepsy' configuration). In awake state, HRRs were determined for each combination of pulse frequency (2-20 Hz), intensity (0-3.5 mA) and pulse widths (130-750 μs) over 14 months. At low intensities and higher frequency VNS, HR increased during the VNS active phase owing to afferent modulation of parasympathetic central drive. When functional effects of afferent and efferent fibre activation were balanced, a null HRR was evoked (defined as 'neural fulcrum') during which HRR ≈ 0. As intensity increased further, HR was reduced during the active phase of VNS. While qualitatively similar, VNS delivered in the epilepsy configuration resulted in more pronounced HR acceleration and reduced HR deceleration during VNS. At termination, under anaesthesia, transection of the vagi rostral to the stimulation site eliminated the augmenting response to VNS and enhanced the parasympathetic efferent-mediated suppressing effect on electrical and mechanical function of the heart. In conclusion, VNS activates central then peripheral aspects of the cardiac nervous system. VNS control over cardiac function is maintained during chronic therapy.
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http://dx.doi.org/10.1113/JP274678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685838PMC
November 2017
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