Myocardial infarction (MI) predisposes patients to ventricular tachycardia/fibrillation (VT/VF) and sudden
cardiac death. After MI, alterations within the cardiac sympathetic nervous system (SNS) have been tightly
linked to VT/VF. These alterations include inflammation, structural and functional remodeling within the stellate
ganglion, and heterogeneous remodeling of intramyocardial sympathetic nerves in the scar-border zone.
These result in enhanced and dysfunctional cardiac sympathetic neurotransmission that lead to VT/VF.
Although spinal afferent signaling is enhanced after MI, the arrhythmogenic potential of spinal afferents (via
maladaptive interactions with cardiac sympathetic nerves) has not been explored. Based on novel data from
our group, the goal of this proposal is to test the hypothesis that chronic enhanced cardiac afferent signaling is
the primary driver of sympathetic neural remodeling and dysfunction that causes VT/VF.
Pilot studies from our group using epicardial resiniferatoxin (RTX) to deplete cardiac TRPV1 afferents in
porcine support the rationale that persistent afferent signaling (beyond the acute ischemic phase) plays a
central role in shaping the neural and cardiac substrates that lead to VAs. We will test our hypotheses using
novel tools from a multidisciplinary team of investigators in 3 aims, in porcine with MI. In aim 1, we will
determine whether post-MI structural, neuroinflammatory, and functional neuronal remodeling within stellate
ganglia are caused by persistent TRPV1 afferent signaling. In aim 2, we will determine whether persistent
cardiac TRPV1 activation amplifies intramyocardial neurotransmitter release to increase VT/VF risk. This will
be accomplished using simultaneous cardiac electrophysiologic mapping and real time in vivo detection of
intramyocardial Norepinephrine and neuropeptide Y levels. We will determine whether TRPV1 afferent
depletion attenuates arrhythmogenicity by normalizing neurotransmitter release patterns. In aim 3, we will
define the optimal site of RTX delivery for clinical management of VT/VF [Epicardial vs. Stellate Ganglion vs.
Epidural application]. This will guide clinical translation of afferent neuromodulation. The results of this proposal
may shift how arrhythmogenesis is approached after MI, and guide the development of new therapies that
prevent altered afferent signaling after MI to fill a major clinical gap.