Baseline elevation and reduction in cardiac electrical instability assessed by quantitative T-wave alternans in patients with drug-resistant epilepsy treated with vagus nerve stimulation in the AspireSR E-36 trial

Verrier, Richard L.; Nearing, Bruce D.; Olin, Bryan; Boon, Paul; Schachter, Steven C.

doi:10.1016/j.yebeh.2016.06.016

Cited by 57 publications

(46 citation statements)

References 40 publications

(45 reference statements)

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“…It is well known that the sympathetic neurotransmitter NE evokes chronotropic and hypertensive effects, and seizure-induced enhancement of sympathetic drive is a risk factor for cardiac SUDEP (Schomer et al, 2014; Verrier et al, 2016). Thus, we evaluated the effects of atomoxetine on heart rate and systemic blood pressures, surrogates for cardiovascular function.…”

Section: Discussionmentioning

confidence: 99%

The effect of atomoxetine, a selective norepinephrine reuptake inhibitor, on respiratory arrest and cardiorespiratory function in the DBA/1 mouse model of SUDEP

et al. 2017

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Sudden unexpected death in epilepsy (SUDEP) is a significant public health burden. The mechanisms of SUDEP are elusive, although cardiorespiratory dysfunction is a likely contributor. Clinical and animal studies indicate that seizure-induced respiratory arrest (S-IRA) is the primary event leading to death in many SUDEP cases. Our prior studies demonstrated that intraperitoneal (IP) injection of atomoxetine, a norepinephrine reuptake inhibitor (NRI) widely used to treat attention deficit hyperactivity disorder, suppresses S-IRA in DBA/1 mice. In the current study, we injected atomoxetine intracerebroventricularly (ICV) and measured its effect on S-IRA in DBA/1 mice to determine its central effects. Additionally, to test our hypothesis that atomoxetine reduces S-IRA via altering cardiorespiratory function, we examined the effect of atomoxetine on respiratory and cardiac function using non-invasive plethysmography and ECG in anesthetized DBA/1 mice, and on blood pressure and heart rate using a tail-cuff system in conscious DBA/1 mice. ICV administration of atomoxetine at 200–250 nmol significantly reduced S-IRA evoked by acoustic stimulation in DBA/1 mice, consistent with a central atomoxetine effect on S-IRA. Peripheral atomoxetine administration at a dosage that reduces S-IRA (15 mg/kg, IP) slightly increased basal ventilation and the ventilatory response to 7% CO2, but exerted no effect on heart rate in anesthetized DBA/1 mice. IP injection of atomoxetine produced no effect on the heart rate and blood pressures in conscious mice. These data suggest that atomoxetine suppresses S-IRA through direct effects on the CNS and potentially through enhanced lung ventilation in DBA/1 mice.

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Section: Discussionmentioning

confidence: 99%

The effect of atomoxetine, a selective norepinephrine reuptake inhibitor, on respiratory arrest and cardiorespiratory function in the DBA/1 mouse model of SUDEP

et al. 2017

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“…demonstrated in the ANTHEM‐HF trial that chronic low‐level VNS in patients with symptomatic heart failure resulted in improvement in cardiac electrical instability, as reflected by reduced TWA levels, suppression of NSVT, and increase in baroreceptor sensitivity . Furthermore, patients with drug‐refractory epilepsy, who are known to be at elevated risk for sudden unexpected death in epilepsy patients (SUDEP) and who exhibit markedly elevated levels of TWA, have been shown to be highly responsive to VNS therapy . In an elegant series of experiments, chronic low‐level VNS has been shown capable of reducing susceptibility to AF, a finding paradoxical to the contemporary view that elevated parasympathetic activity predisposes to AF …”

Section: Discussionmentioning

confidence: 99%

“…11 Furthermore, patients with drug-refractory epilepsy, who are known to be at elevated risk for sudden unexpected death in epilepsy patients (SUDEP) and who exhibit markedly elevated levels of TWA, have been shown to be highly responsive to VNS therapy. 24,25 In an elegant series of experiments, chronic low-level VNS has been shown capable of reducing susceptibility to AF, 7-9 a finding paradoxical to the contemporary view that elevated parasympathetic activity predisposes to AF. 10 While the exact mechanisms whereby low-level VNS operates are unclear, a number of plausible and intriguing mechanisms have been explored experimentally and discussed in detail.…”

Section: Previous Studiesmentioning

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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“…34,35 As well, therapeutic application of vagal nerve stimulation (VNS) is associated with a reduction in T-wave alternans, a measure of cardiac instability, making VNS an attractive candidate to reduce SUDEP risk; however, the effects of VNS on HRV have not yet been thoroughly studied, and a clear reduction in SUDEP incidence post-VNS implantation has not been shown. 36,37 In the future, clinicians may use sequential HRV measurements to assess whether a patient's SUDEP risk had changed on a given treatment. Changes in HRV could be an additional clinically relevant outcome measure when assessing the efficacy of new therapies.…”

Section: Future Directionsmentioning

confidence: 99%

Heart rate variability in epilepsy: A potential biomarker of sudden unexpected death in epilepsy risk

et al. 2018

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These findings suggest that autonomic dysfunction is associated with SUDEP risk in patients with epilepsy due to sodium channel mutations. The relationship of HRV to SUDEP merits further study; HRV may eventually have potential as a biomarker of SUDEP risk, which would allow for more informed counseling of patients and families, and also serve as a useful outcome measure for research aimed at developing therapies and interventions to reduce SUDEP risk.

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Baseline elevation and reduction in cardiac electrical instability assessed by quantitative T-wave alternans in patients with drug-resistant epilepsy treated with vagus nerve stimulation in the AspireSR E-36 trial

Abstract: These findings suggest significant interictal cardiac electrical instability in this population of patients with drug-resistant epilepsy and suggest that VNS may be a novel approach to reducing risk.

Cited by 57 publications

References 40 publications

The effect of atomoxetine, a selective norepinephrine reuptake inhibitor, on respiratory arrest and cardiorespiratory function in the DBA/1 mouse model of SUDEP

The effect of atomoxetine, a selective norepinephrine reuptake inhibitor, on respiratory arrest and cardiorespiratory function in the DBA/1 mouse model of SUDEP

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

Heart rate variability in epilepsy: A potential biomarker of sudden unexpected death in epilepsy risk

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