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.
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.
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.
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.
•Chronic VNS is associated with improvement in cardiac function and HF symptoms.•The ANTHEM-HF study evaluated VNS in HF patients with 42 months of follow-up.•There were no device-related SAEs or malfunctions during extended follow-up.•There was significant improvement in cardiac function and HF symptoms at 42 months.•This therapy is being further evaluated in a randomized, controlled, pivotal study.
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.
Cardiac injury, such as myocardial infarction (MI), leads to neurohormonal activation and autonomic remodeling, resulting in reflexive sympathoexcitation and parasympathetic dysfunction, which ...further contribute to progression of disease. The purpose of this study was to determine whether chronic cervical vagal nerve stimulation (VNS) influences MI‐associated changes in cardiac sympathetic function. Yucatan minipigs were divided into control (n=6), chronic MI (n=7), and chronic MI + chronic VNS (n=8) groups. VNS therapy was delivered to the right cervical vagus nerve and systematically titrated to an optimal intensity based on heart rate dynamics (5Hz, 2.1±0.3mA, 250μs, 17.5% duty cycle) using telemetry in the conscious state. Chronic MI was created using percutaneous embolization of the left anterior descending coronary artery with polystyrene beads under fluoroscopy (Figure 1A). VNS therapy was started 2 days following MI, and the animals maintained for 6‐8 weeks. At terminal study, we evaluated hemodynamic responses to graded bilateral sympathetic chain stimulation (BSS). Left ventricular (LV) strips encompassing regions of scar, border zone, and normal myocardium were fixed in 10% formalin, embedded in paraffin, sectioned, and studied using Masson's trichrome stain (Figure 1B‐C). Structural changes at the peri‐infarct area were scored (0‐3) for myocyte morphology and presence of hypertrophy or myocytolysis. Animals with MI alone exhibited spontaneous ventricular arrhythmias, including two that experienced sudden cardiac death (Figure 1D). At terminal study, there were no significant differences in baseline systolic function among groups. Moderate (4Hz) and high (10Hz) intensity BSS increased LV contractility (dp/dtmax) in all groups (Figure 2A‐B); however, evoked changes were significantly reduced in the chronic MI compared to control or MI + VNS groups. While control animals displayed evidence of contractile reserve at 10Hz vs 4Hz (1297±266 mmHg/s, p=0.03), chronic MI animals did not (631.9±264 mmHg/s, p=0.11), which was improved with chronic VNS therapy (1027±160.6 mmHg/s, p<0.01, Figure 2C). Chronic VNS therapy also significantly reduced MI‐associated structural remodeling in the peri‐infarct area, including the degree of myocytolysis and dysmorphic myocytes (structural abnormality index 0.6±0.2 vs 1.8±0.2, p<0.01). Our findings suggest that chronic VNS ameliorates sympathetic functional remodeling following myocardial infarction and improves cardiac mechanical performance in response to simulated stress. Furthermore, chronic VNS reduces pathologic myocardial remodeling at the peri‐infarct zone, potentially stabilizing the resultant ventricular scar.
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.
The influence of cardiac sympathetic innervation on electrical activation in normal and chronically infarcted ventricular myocardium is not understood. Yorkshire pigs with normal hearts (NL,
= 12) or ...anterior myocardial infarction (MI,
= 9) underwent high-resolution mapping of the anteroapical left ventricle at baseline and during left and right stellate ganglion stimulation (LSGS and RSGS, respectively). Conduction velocity (CV), activation times (ATs), and directionality of propagation were measured. Myocardial fiber orientation was determined using diffusion tensor imaging and histology. Longitudinal CV (CV
) was increased by RSGS (0.98 ± 0.11 vs. 1.2 ± 0.14m/s,
< 0.001) but not transverse CV (CV
). This increase was abrogated by β-adrenergic receptor and gap junction (GJ) blockade. Neither CV
nor CV
was increased by LSGS. In the peri-infarct region, both RSGS and LSGS shortened ARIs in sinus rhythm (423 ± 37 vs. 322 ± 30 ms,
< 0.001, and 423 ± 36 vs. 398 ± 36 ms,
= 0.035, respectively) and altered activation patterns in all animals. CV, as estimated by mean ATs, increased in a directionally dependent manner by RSGS (14.6 ± 1.2 vs. 17.3 ± 1.6 ms,
= 0.015), associated with GJ lateralization. RSGS and LSGS inhomogeneously modulated AT and induced relative or absolute functional activation delay in parts of the mapped regions in 75 and 67%, respectively, in MI animals, and in 0 and 15%, respectively, in control animals (
< 0.001 for both). In conclusion, sympathoexcitation increases CV in normal myocardium and modulates activation propagation in peri-infarcted ventricular myocardium. These data demonstrate functional control of arrhythmogenic peri-infarct substrates by sympathetic nerves and in part explain the temporal nature of arrhythmogenesis.
This study demonstrates regional control of conduction velocity in normal hearts by sympathetic nerves. In infarcted hearts, however, not only is modulation of propagation heterogeneous, some regions showed paradoxical conduction slowing. Sympathoexcitation altered propagation in all infarcted hearts studied, and we describe the temporal arrhythmogenic potential of these findings.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/sympathetic-nerves-and-cardiac-propagation/.
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.
Autonomic dysfunction contributes to induction of ventricular tachyarrhythmia (VT).
To determine the efficacy of charge-balanced direct current (CBDC), applied to the T1-T2 segment of the ...paravertebral sympathetic chain, on VT inducibility post-myocardial infarction (MI).
In a porcine model, CBDC was applied in acute animals (n = 7) to optimize stimulation parameters for sympathetic blockade and in chronic MI animals (n = 7) to evaluate the potential for VTs. Chronic MI was induced by microsphere embolization of the left anterior descending coronary artery. At termination, in anesthetized animals and following thoracotomy, an epicardial sock array was placed over both ventricles and a quadripolar carousel electrode positioned underlying the right T1-T2 paravertebral chain. In acute animals, the efficacy of CBDC carousel (CBDCC) block was assessed by evaluating cardiac function during T2 paravertebral ganglion stimulation with and without CBDCC. In chronic MI animals, VT inducibility was assessed by extrasystolic (S1-S2) stimulations at baseline and under >66% CBDCC blockade of T2-evoked sympathoexcitation.
CBDCC demonstrated a current-dependent and reversible block without impacting basal cardiac function. VT was induced at baseline in all chronic MI animals. One animal died after baseline induction. Of the 6 remaining animals, only 1 was reinducible with simultaneous CBDCC application (P < .002 from baseline). The ventricular effective refractory period (VERP) was prolonged with CBDCC (323 ± 26 ms) compared to baseline (271 ± 32 ms) (P < .05).
Axonal block of the T1-T2 paravertebral chain with CBDCC reduced VT in a chronic MI model. CBDCC prolonged VERP, without altering baseline cardiac function, resulting in improved electrical stability.
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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