Extended Follow-Up of Patients With Heart Failure Receiving Autonomic Regulation Therapy in the ANTHEM-HF Study

Premchand, Rajendra Kumar; Sharma, Kamal; Mittal, Sanjay; Monteiro, Rufino; Dixit, Satyajit; Libbus, Imad; DiCarlo, Lorenzo A.; Ardell, Jeffrey L.; Rector, Thomas S.; Amurthur, Badri; KenKnight, Bruce H.; Anand, Inder S.

doi:10.1016/j.cardfail.2015.11.002

Cited by 100 publications

(96 citation statements)

References 8 publications

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“…Patient baseline characteristics have been previously published . Briefly, 87% (51 of 59) were male, and average age was 52 ± 12 (mean ±SD) years.…”

Section: Resultsmentioning

confidence: 99%

Acute Autonomic Engagement Assessed by Heart Rate Dynamics During Vagus Nerve Stimulation in Patients With Heart Failure in the ANTHEM‐HF Trial

Nearing

Libbus

Amurthur

et al. 2016

Cardiovasc electrophysiol

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Acute Heart Rate Dynamics During VNS. Background: Chronic vagus nerve stimulation (VNS) applied to produce biomimetic levels of parasympathetic activation is feasible, well tolerated, safe, improves left ventricular ejection fraction, NYHA class, heart rate variability, and baroreflex function, and reduces T-wave alternans (TWA) in patients with chronic heart failure. However, the acute effects of VNS on beat-to-beat heart rate dynamics have not been systematically characterized in humans. Methods and Results:We evaluated acute effects of VNS on R-R-interval dynamics during the VNS titration period in patients (n = 59) enrolled in ANTHEM-HF trial by quantifying effects during continuous cyclic VNS (14-seconds on-time, 66-seconds off-time) adjusted to the maximum tolerable dose without excessive (<4 bpm) bradycardia during the 10-week titration period. VNS elicited an immediate change in heart rate that was correlated to VNS current amplitude, pulse width, and frequency. Heart rate decreased more in the 28 patients with right-sided stimulation (-2.22 ± 0.13 bpm) than in the 31 patients with leftsided stimulation (-0.60 ± 0.08 bpm, P < 0.001). The linear correlation between stimulus intensity and lengthening of the R-R interval was stronger among the 28 patients with right-sided VNS implantation (r = 0.88, P < 0.0001) than among the 31 patients with left-sided VNS implantation (r = 0.49, P < 0.002). In all patients, the heart rate change elicited by VNS was significantly greater than the change during the same timing intervals in 10 randomly selected patients without stimulation (+0.08 ± 0.06 bpm, P < 0.001).Conclusion: Instantaneous heart rate change during therapeutic levels of VNS in patients with heart failure indicates consistent modulation of the autonomic nervous system for both left-and right-sided

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“…Patient baseline characteristics have been previously published . Briefly, 87% (51 of 59) were male, and average age was 52 ± 12 (mean ±SD) years.…”

Section: Resultsmentioning

confidence: 99%

Acute Autonomic Engagement Assessed by Heart Rate Dynamics During Vagus Nerve Stimulation in Patients With Heart Failure in the ANTHEM‐HF Trial

Nearing

Libbus

Amurthur

et al. 2016

Cardiovasc electrophysiol

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“…; De Ferrari, ; Premchand et al . , ) have indicated improvements in ejection fraction and decreases in cardiac size with VNS, the third study reporting neutral effects (Zannad et al . ).…”

Section: Structural and Functional Organization Of The Cardiac Nervoumentioning

confidence: 99%

“…Preliminary data from these trials likewise indicated that therapeutic levels of VNS can be delivered from either the right or left vagus (Premchand et al . , ). To date, two of three reported trials (De Ferrari et al .…”

Section: Structural and Functional Organization Of The Cardiac Nervoumentioning

confidence: 99%

Translational neurocardiology: preclinical models and cardioneural integrative aspects

Ardell

Andresen

Armour

et al. 2016

The Journal of Physiology

144

178

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Neuronal elements distributed throughout the cardiac nervous system, from the level of the insular cortex to the intrinsic cardiac nervous system, are in constant communication with one another to ensure that cardiac output matches the dynamic process of regional blood flow demand. Neural elements in their various 'levels' become differentially recruited in the transduction of sensory inputs arising from the heart, major vessels, other visceral organs and somatic structures to optimize neuronal coordination of regional cardiac function. This White Paper will review the relevant aspects of the structural and functional organization for autonomic control of the heart in normal conditions, how these systems remodel/adapt during cardiac disease, and finally how such knowledge can be leveraged in the evolving realm of autonomic regulation therapy for cardiac therapeutics.

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“…The current FDA-approved protocol requires general anesthesia for about 1 h of surgery needed to implant a pulse generator, run subcutaneous wires, and place the stimulation lead around either the left or right cervical vagus nerve. The left vagus nerve is stimulated for treatment of epilepsy and depression because it is thought to have less influence on cardiac rate than the right vagus nerve (Howland, 2014), but stimulation of either right or left vagus nerve appears to be safe and effective in patients with chronic heart failure (Premchand et al, 2014; Premchand et al, 2016). Stimulation of the vagus is phasic ( e.g.…”

Section: Clinical Studies and Trialsmentioning

confidence: 99%

Cholinergic modulation of the immune system presents new approaches for treating inflammation

Hoover

2017

Pharmacology & Therapeutics

240

169

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The nervous system and immune system have broad and overlapping distributions in the body, and interactions of these ubiquitous systems are central to the field of neuroimmunology. Over the past two decades, there has been explosive growth in our understanding of neuroanatomical, cellular, and molecular mechanisms that mediate central modulation of immune functions through the autonomic nervous system. A major catalyst for growth in this field was the discovery that vagal nerve stimulation (VNS) caused a prominent attenuation of the systemic inflammatory response evoked by endotoxin in experimental animals. This effect was mediated by acetylcholine (ACh) stimulation of nicotinic receptors on splenic macrophages. Hence, the circuit was dubbed the “cholinergic anti-inflammatory pathway”. Subsequent work identified the α7 nicotinic ACh receptor (α7nAChR) as the crucial target for attenuation of pro-inflammatory cytokine release from macrophages and dendritic cells. Further investigation made the important discovery that cholinergic T cells within the spleen and not cholinergic nerve cells were the source of ACh that stimulated α7 receptors on splenic macrophages. Given the important role that inflammation plays in numerous disease processes, cholinergic anti-inflammatory mechanisms are under intensive investigation from a basic science perspective and in translational studies of animal models of diseases such as inflammatory bowel disease and rheumatoid arthritis. This basic work has already fostered several clinical trials examining the efficacy of VNS and cholinergic therapeutics in human inflammatory diseases. This review provides an overview of basic and translational aspects of the cholinergic anti-inflammatory response and relevant pharmacology of drugs acting at the α7nAChR.

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Extended Follow-Up of Patients With Heart Failure Receiving Autonomic Regulation Therapy in the ANTHEM-HF Study

Abstract: Chronic open-loop ART via left- or right-sided VNS continued to be feasible and well-tolerated in patients with HF with reduced EF. Improvements in cardiac function and HF symptoms seen after 6 months of ART were maintained at 12 months.

Cited by 100 publications

References 8 publications

Acute Autonomic Engagement Assessed by Heart Rate Dynamics During Vagus Nerve Stimulation in Patients With Heart Failure in the ANTHEM‐HF Trial

Acute Autonomic Engagement Assessed by Heart Rate Dynamics During Vagus Nerve Stimulation in Patients With Heart Failure in the ANTHEM‐HF Trial

Translational neurocardiology: preclinical models and cardioneural integrative aspects

Cholinergic modulation of the immune system presents new approaches for treating inflammation

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