What does this research mean for the field?

High-dose beta blocker therapy is insufficient to fully block the electrophysiological effects of sympathetic activation, which are partially mediated by neuropeptide Y (NPY) and can be mitigated by NPY Y1 receptor antagonism. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This study aims to evaluate the impact of high-dose beta blockers on ventricular electrophysiological effects and the role of neuropeptide Y in a porcine model.

June 4, 2020JCI InsightOpen Access

Cardiac sympathetic activation circumvents high-dose beta blocker therapy in part through release of neuropeptide Y

Q: What is the clinical evidence from this study?

Study design: Other. Population: Sympathetic activation and ventricular arrhythmias (n=28). Intervention: BIBO 3304 (NPY Y1 receptor antagonist) + Propranolol vs. Propranolol alone (1.0 mg/kg). Primary outcome: BSS-induced shortening of global ventricular corrected activation recovery interval (ARIc) (p=<0.01).

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Key result

Adjuvant NPY Y1 receptor blockade with BIBO 3304 significantly reduced sympathoexcitation-induced ventricular ARIc shortening by 11 ms compared to high-dose propranolol alone in a porcine model.

Why the study?

Many patients experience VT despite maximal beta blocker doses, potentially due to sympathetic cotransmitters such as neuropeptide Y.

Does NPY Y1 receptor antagonism with BIBO 3304 reduce residual electrophysiological effects of sympathetic activation in a porcine model treated with high-dose propranolol?

Population

Porcine model undergoing stellate ganglia stimulation

Comparison

High-dose propranolol with vs without adjuvant NPY Y1 receptor antagonist BIBO 3304

Design

Animal experimental study

Authors

JHJonathan D. HoangCalifornia Institute of Technology SSSiamak SalavatianUniversity of Pittsburgh NYNaoko YamaguchiNew York University

Discussion

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Implication

May attenuate residual sympathetic effects beyond beta-blockade in pigs; leaves open translation to human VT prevention.

Key Points

This study aims to evaluate the impact of high-dose beta blockers on ventricular electrophysiological effects and the role of neuropeptide Y in a porcine model.
Conducted a porcine model experiment with high-dose propranolol (1.0 mg/kg) and assessed ventricular electrophysiological responses through stellate ganglia stimulation.
Measured cardiac neuropeptide Y release at varying sympathetic stimulation frequencies (4, 10, and 20 Hz).
Administered the NPY Y1 receptor antagonist BIBO 3304 to evaluate its effects on residual electrophysiological changes.
High-dose propranolol did not completely block the electrophysiological effects of sympathoexcitation, persisting with a shortened activation recovery interval (ARI).
Increased neuropeptide Y release was noted at higher stimulation frequencies, suggesting its mediating role in residual effects.
BIBO 3304 reduced these electrophysiological effects and improved inotropy, indicating potential for adjuvant therapy.

Structured PICO

Does NPY Y1 receptor antagonism with BIBO 3304 reduce residual electrophysiological effects of sympathetic activation in a porcine model treated with high-dose propranolol?

Population

28 Yorkshire pigs (Sus scrofa), 3.6 ± 0.1 months old, undergoing bilateral stellate ganglion stimulation (BSS) to induce sympathetic activation.

Intervention

Intravenous propranolol at high doses (0.5 mg/kg and 1.0 mg/kg) with or without adjuvant NPY Y1 receptor antagonist BIBO 3304 (0.2 mg/kg + 0.4 mg/kg/h).

Comparator

Baseline (no stimulation), sympathetic stimulation without pharmacological blockade, and high-dose propranolol alone.

Outcome

Ventricular activation recovery interval (ARIc), a surrogate of action potential duration (APD).surrogate

Main Result

Absolute Event Rate: 8% vs 19%

p-value: p=<0.01

High-dose beta-blocker therapy is insufficient to fully block the electrophysiological effects of sympathetic activation, which are partly mediated by neuropeptide Y and can be mitigated by Y1 receptor blockade.

Limitations

Evaluated effects acutely; chronic effects remain to be investigated.
General anesthesia with isoflurane may blunt autonomic responses.
Atropine administration to prevent reflex bradycardia may have led to underestimation of NPY effects via other receptors.
Did not correct for HR changes with pacing due to known effects of cardiac pacing on exacerbating sympathoexcitation.
Ventricular stimulation was not performed to evaluate VT inducibility.

Cite This Study

Hoang et al. (2020) studied Sympathetic activation and ventricular arrhythmias (n=28). BIBO 3304 (NPY Y1 receptor antagonist) + Propranolol vs. Propranolol alone (1.0 mg/kg) was evaluated on BSS-induced shortening of global ventricular corrected activation recovery interval (ARIc) (p=<0.01). Adjuvant NPY Y1 receptor blockade with BIBO 3304 significantly reduced sympathoexcitation-induced ventricular ARIc shortening by 11 ms compared to high-dose propranolol alone in a porcine model.

synapsesocial.com/papers/6a1c79e14defe5c851c3d596 https://doi.org/10.1172/jci.insight.135519

Topics

Ventricular arrhythmias

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Cardiac sympathetic activation circumvents high-dose beta blocker therapy in part through release of neuropeptide Y

Discussion

Member takes

Implication

Key Points

Structured PICO

Main Result

Limitations

Cite This Study

Topics

Cardiac sympathetic activation circumvents high-dose beta blocker therapy in part through release of neuropeptide Y

Discussion

Member takes

Implication

Key Points

Structured PICO

Main Result

Limitations

Cite This Study

Also Consider

Topics

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