Sympathetic nociceptive afferent signaling drives the chronic structural and functional autonomic remodeling after myocardial infarction

TL;DR

This study shows that nerve signals from the heart after a heart attack cause harmful changes in the autonomic nervous system, increasing the risk of dangerous heart rhythms.

Contribution

The study identifies sympathetic nociceptive afferents as a causal driver of autonomic remodeling and arrhythmia risk after myocardial infarction.

Findings

Epidural RTX improved vagal tone and reduced inflammation and glial activation after MI.

RTX treatment decreased the inducibility of ventricular arrhythmias in infarcted animals.

Afferent ablation after chronic MI acutely restored vagal function and reduced arrhythmia risk.

Abstract

After myocardial infarction (MI), pathological autonomic remodeling, including vagal dysfunction and sympathoexcitation, occurs and predisposes to ventricular arrhythmias (VT/VF). The underlying factors that drive this remodeling, including the observed neuroinflammation and glial activation, remain unknown. We hypothesized that sympathetic nociceptive afferents underlie this remodeling post-MI. Epidural resiniferatoxin (RTX, to ablate sympathetic cardiac afferent neurons) vs. saline was administered in pigs prior to MI and autonomic and electrophysiological effects assessed four to six weeks post-infarction. Acute effects of afferent ablation after chronic MI were also assessed in a separate group of animals. Baroreflex sensitivity and vagal tone, as measured by parasympathetic neuronal activity and cardiac nociceptive responses, were improved in infarcted animals which received epidural RTX prior to MI. These animals also demonstrated reduced spinal cord inflammation and glial activation, downregulation of circulating stress and inflammatory pathways, and stabilization of electrophysiological parameters, with reduced VT/VF-inducibility. Epidural RTX after chronic MI also acutely restored vagal function and decreased VT/VF. These data suggest that cardiac spinal nociceptive afferents directly contribute to VT/VF susceptibility and MI-induced autonomic remodeling, including oxidative stress, inflammation, glial activation, and reduced vagal function, providing novel insights into the causal role of these afferents in driving sympathovagal imbalance after MI.