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Article Abstract
Background: Ventricular arrhythmias (VAs) in chronic ischemic heart failure (HF) are associated with high mortality and often refractory to beta-blocker treatment, highlighting the need for alternative therapeutic targets.
Objective: This study investigates the role of neuropeptide Y (NPY), a neurotransmitter released during sympathoexcitation, in the pathogenesis of VAs associated with ischemic chronic HF following myocardial infarction (MI).
Methods: Using a mouse model of ischemic chronic HF after coronary ligation, we employed biochemical, electrophysiological, and calcium ion (Ca) imaging analyses to investigate the proarrhythmic mechanisms of NPY.
Results: Immunohistochemical staining revealed a significantly elevated NPY expression in both the MI and border zone, consistent with findings in human autopsy samples. In cardiomyocytes isolated from ischemic HF mice, NPY treatment increased Ca waves at a dose that did not elicit this response in normal heart cardiomyocytes, an effect suppressed by NPY Y1 receptor blocker. Additionally, the NPY treatment elevated the frequency of delayed afterdepolarizations at the membrane potential level. Similarly, NPY-induced VAs that were suppressed by the NPY Y1 receptor blocker in Langendorff-perfused chronic ischemic failed hearts at a concentration that had no effect in normal hearts.
Conclusion: We identified structural and functional changes in NPY within an chronic ischemic HF model, leading to increased arrhythmogenicity through Ca mishandling. Therefore, targeting NPY signaling may offer a novel therapeutic approach for treating VAs in patients with chronic ischemic HF.
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| http://dx.doi.org/10.1016/j.hrthm.2025.08.011 | DOI Listing |
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