Post-infarct therapies that prevent ventricular arrhythmias are limited. Prior work suggested that ablating TRPV1-expressing cardiac sensory afferents at the time of acute MI can improve remodeling, but the effect of targeting these afferents during the subacute period after a completed MI was unknown. The investigators tested whether selective depletion of cardiac TRPV1 afferents during the subacute post-MI window mitigates structural, electrophysiologic, and neuro-cardiac axis remodeling and thereby suppresses ventricular arrhythmias.
The study used Yorkshire pigs that underwent either sham surgery or creation of an anterior myocardial infarction. Two weeks after MI, animals were randomized to receive percutaneous epicardial administration of resiniferatoxin (RTX) for cardiac-selective TRPV1 afferent depletion or vehicle. Terminal studies were performed four weeks after treatment to evaluate outcomes across structural, electrophysiologic, neurochemical, histologic, and transcriptomic domains.
A percutaneous epicardial approach delivered RTX to target cardiac sensory afferents expressing TRPV1. RTX is a potent TRPV1 agonist used here to selectively deplete TRPV1-expressing afferent fibers within the heart. The control group received vehicle via the same delivery route.
Ablation of cardiac TRPV1 afferents after RTX administration was confirmed functionally: responses to TRPV1 agonists were blunted in RTX-treated animals relative to controls, demonstrating effective depletion of TRPV1-mediated signaling in the heart.
Compared with vehicle-treated MI animals, RTX-treated pigs exhibited improved left ventricular function and a reduction in left ventricular end-diastolic diameter. These findings indicate that selective cardiac TRPV1 afferent ablation during the subacute phase alters structural remodeling and preserves ventricular performance.
In vivo electrophysiologic testing showed that RTX-treated animals had suppressed inducibility of ventricular tachycardia and ventricular fibrillation (VT/VF) relative to vehicle-treated MI animals. This reduction in arrhythmia inducibility suggests a functional antiarrhythmic effect associated with TRPV1 afferent depletion in the subacute post-MI period.
Endocardial electroanatomic mapping revealed improved electrophysiologic substrate correlates in RTX-treated hearts, including fewer deceleration zones and fewer late potentials, which are electrophysiologic features commonly associated with arrhythmogenic scar. Epicardial multielectrode mapping demonstrated reduced electrophysiologic heterogeneity within the scar border zone after RTX treatment, consistent with a more homogeneous conduction environment less favorable to reentry.
Real-time sensing of adrenergic neurotransmitters during sympathoexcitation showed that RTX treatment normalized the release of catecholaminergic mediators, specifically noradrenaline and neuropeptide Y. These data indicate that TRPV1 afferent depletion modulates neurochemical responses to sympathetic activation after MI.
Histologic analysis of the myocardium and associated neural tissues demonstrated that RTX treatment attenuated scar border zone myocardial fibrosis and reduced sympathetic nerve sprouting. Additionally, RTX suppressed T cell infiltration within cardiac sensory ganglia. These structural and cellular changes in both the heart and its sensory neural elements are aligned with the observed functional benefits.
Bulk RNA sequencing of stellate ganglia from treated animals revealed downregulation of adrenergic genes after RTX-mediated TRPV1 afferent depletion. This transcriptomic signal supports a broader attenuation of adrenergic drive within the neuro-cardiac axis following targeted ablation of cardiac sensory afferents.
In this preclinical porcine model, percutaneous epicardial RTX-mediated depletion of cardiac TRPV1 afferents performed in the subacute period after completed MI altered disease trajectory by mitigating structural remodeling, improving left ventricular function, reducing electrophysiologic heterogeneity, normalizing adrenergic neurotransmitter release, and lowering VT/VF inducibility. The combined histologic and transcriptomic findings point to reduced fibrosis, less sympathetic sprouting, and attenuated adrenergic gene expression as potential mechanisms.
The authors propose that targeting cardiac TRPV1 afferents during the subacute post-MI window may represent a promising therapeutic strategy to reduce post-infarct ventricular arrhythmias.
Note on scope and reporting
This article is a preprint and has not been peer-reviewed. The abstract provides study design, major outcomes, and mechanistic observations; specific quantitative metrics, sample sizes, detailed statistical results, and long-term follow-up data were not reported in the abstract and thus are not included here.