TRPV1-cardiac afferent ablation after completed myocardial infarction prevents arrhythmogenic remodeling

Therapies to prevent ventricular arrhythmias after completed myocardial infarction (MI) remain limited. Although TRPV1 afferent ablation at acute MI improves cardiac remodeling, the effect of delayed subacute targeting remains unknown.

We investigated whether ablating cardiac TRPV1 afferents during the subacute post-MI window mitigates structural, electrophysiological, and neuro-cardiac axis remodeling to suppress ventricular arrhythmias.

Yorkshire pigs underwent sham surgery or anterior MI creation. Two weeks post-MI, animals were randomized to percutaneous epicardial resiniferatoxin (RTX, for cardiac-selective TRPV1 afferent depletion) or vehicle administration. Four weeks later, terminal studies assessed the effects of RTX on cardiac structure and function, ventricular arrhythmogenesis, and neuro-cardiac axis remodeling using in vivo electrophysiologic mapping, real-time neurotransmitter sensing, immunohistochemistry, and transcriptomic profiling.

Cardiac TRPV1 afferent depletion was confirmed by blunted responses to TRPV1 agonists. RTX-treated animals exhibited improved left ventricular function, reduced end-diastolic diameter, and suppressed ventricular tachycardia/fibrillation (VT/VF) inducibility. Endocardial electroanatomic mapping revealed improved VT/VF electrophysiologic correlates in RTX-treated animals, including fewer deceleration zones and late potentials. Epicardial multielectrode mapping demonstrated reduced electrophysiologic heterogeneity in the scar border zone. Real-time release of adrenergic neurotransmitters (noradrenaline and neuropeptide Y) was normalized during sympathoexcitation in RTX-treated animals. Histologically, RTX treatment attenuated scar border zone myocardial fibrosis and sympathetic nerve sprouting, while suppressing T cell infiltration in cardiac sensory ganglia. Bulk RNA-sequencing of stellate ganglia revealed downregulation of adrenergic genes.

Cardiac TRPV1 afferent ablation post-completed MI alters disease trajectory by mitigating structural, functional, and neuro-cardiac axis remodeling. Targeting cardiac TRPV1 afferents represents a promising subacute post-MI therapeutic strategy.

Therapies to prevent ventricular arrhythmias following completed myocardial infarction (MI) remain limited, and the impact of targeting cardiac TRPV1 afferents during the subacute phase is unknown. We evaluated whether epicardial resiniferatoxin (RTX) administration two weeks post-MI in swine mitigates structural, electrophysiological, and neuro-cardiac remodeling to suppress ventricular arrhythmogenesis. Four weeks post-treatment, RTX-treated animals exhibited improved left ventricular function, reduced chamber dilation, and suppressed ventricular tachycardia/fibrillation (VT/VF) inducibility compared with controls. Electroanatomic and multielectrode mapping revealed fewer deceleration zones, smaller late potential areas, and reduced repolarization heterogeneity in the scar border zone. Real-time neurotransmitter sensing demonstrated normalized adrenergic release during sympathoexcitation. Histological and transcriptomic profiling showed that RTX attenuated border-zone fibrosis, decreased sympathetic nerve sprouting, suppressed sensory ganglion T-cell infiltration, and downregulated stellate ganglion adrenergic gene expression. Cardiac TRPV1 afferent ablation during the subacute post-MI window alters disease trajectory by mitigating structural and autonomic remodeling, representing a promising disease-modifying therapeutic strategy.