A review proposes that neuropeptide Y and sympathetic nerve signaling are central drivers of inherited arrhythmic syndromes, suggesting peptidergic therapies like NPY antagonism as new treatment approaches.
NPY as arrhythmic driverNeuropeptide Y released by sympathetic nerves contributes to both acute arrhythmias and chronic heart remodeling in inherited syndromes, suggesting it as a new therapeutic target
What the researchers found
The review establishes that sympathetic activation is both an acute arrhythmic trigger and a chronic driver of disease progression in inherited arrhythmogenic syndromes. Neuropeptide Y (NPY) and regional cardiac innervation patterns play critical roles in shaping myocardial excitability, tissue remodeling, and arrhythmogenesis.
In CPVT, arrhythmias are triggered by sympathetic stimulation in structurally normal hearts through calcium-handling abnormalities. In ACM, maladaptive autonomic remodeling including neurogenic fibrofatty infiltration creates an amplified arrhythmic substrate. The authors propose NPY antagonism as an emerging peptidergic therapy alongside β-blockade and left cardiac sympathetic denervation.
Why it matters
Sudden cardiac death from inherited arrhythmias is a devastating outcome, particularly in young people. Current treatments (beta-blockers, defibrillators, nerve surgery) are incomplete. Identifying NPY as a treatable mechanism opens a new peptide-based therapeutic avenue that could improve survival in patients with these genetic heart conditions.
How the study worked
This is a narrative review synthesizing current evidence on neurocardiac crosstalk in inherited arrhythmogenic syndromes. The authors analyze CPVT and ACM as representative conditions on a functional-structural continuum, examining the roles of β-adrenergic signaling, neuropeptide Y, and autonomic innervation patterns in disease mechanisms.
What this study cannot tell us
This is a narrative review presenting a conceptual framework rather than new experimental data. NPY antagonism as therapy is described as emerging, with limited clinical evidence currently available. The framework is primarily based on CPVT and ACM; applicability to other arrhythmic syndromes needs validation. The relative contribution of NPY versus other sympathetic mediators is not fully quantified.
How to read the evidence
This is a narrative review presenting an integrated framework based on existing preclinical and clinical evidence. While it synthesizes important mechanistic insights, it does not provide new experimental data, and the proposed NPY-targeted therapies are still largely preclinical.
When this study was published
Published in 2025, this review reflects the latest understanding of neurocardiac signaling in inherited arrhythmias and the emerging role of peptidergic therapies.
The bigger picture
This review reframes inherited arrhythmias from purely cardiac diseases to disorders of integrated neural-cardiac physiology. This paradigm shift has implications beyond arrhythmias — it suggests that neuropeptide signaling may be an underappreciated factor in many cardiac conditions, and that peptidergic therapies could complement traditional cardiac drugs across a wider range of heart diseases.
Questions still open
- Can NPY antagonists reduce arrhythmia risk and sudden cardiac death in patients with inherited arrhythmogenic syndromes?
- Could NPY levels serve as a biomarker for arrhythmic risk stratification in these genetic conditions?
- Does the neurocardiac crosstalk framework apply to acquired arrhythmias as well as inherited ones?
Common questions
What is neuropeptide Y and how does it affect the heart?
Could blocking NPY prevent sudden cardiac death?
Read the original research
The blueprint of neurocardiac crosstalk in arrhythmic syndromes.
American journal of physiology. Cell physiology, 329(4), C1038-C1045
Citation
Zaglia, Tania; Perumal Vanaja, Induja; Guazzo, Anna; Mongillo, Marco. (2025). The blueprint of neurocardiac crosstalk in arrhythmic syndromes.. American journal of physiology. Cell physiology, 329(4), C1038-C1045. https://doi.org/10.1152/ajpcell.00558.2025