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Cardiac TRPV1‐Afferent Signaling Promotes Arrhythmogenic Ventricular Remodeling after Myocardial Infarction
Author(s) -
Yoshie Koji,
Rajendran Pradeep A.,
Massoud Louis,
Mistry Janki,
Swid M. Amer,
Wu Xiaohui A.,
Sallam Tamer A.,
Zhang Rui,
Goldhaber Joshua I.,
Salavatian Siamak A.,
Ajijola Olujimi A.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06830
Subject(s) - trpv1 , resiniferatoxin , medicine , endocrinology , cardiology , chemistry , neuroscience , transient receptor potential channel , biology , receptor
Chronic sympathoexcitation is implicated in ventricular arrhythmogenesis (VAs) following myocardial infarction (MI), but the critical neural pathways involved are not well understood. Cardiac adrenergic function is partly regulated by sympathetic afferent reflexes, transduced by spinal afferent fibers expressing the TRPV1 channel. The role of chronic TRPV1 afferent signaling in VAs is not known. We hypothesized that persistent TRPV1 afferent neurotransmission promotes VAs after MI. Using epicardial Resiniferatoxin (RTX) to deplete cardiac TRPV1‐expressing fibers, we dissected the role of this neural circuit in VAs after chronic MI in a porcine model. We examined the underlying mechanisms using molecular approaches, immunohistochemistry, in vitro and in vivo cardiac electrophysiology, and simultaneous cardio‐neural mapping. Epicardial RTX depleted cardiac TRPV1 afferent fibers and abolished functional responses to TRPV1 agonists. Ventricular tachycardia/fibrillation (VT/VF) was readily inducible in MI subjects by programmed electrical stimulation or cesium chloride administration, however, TRPV1 afferent depletion prevented VT/VF induced by either method. Mechanistically, TRPV1 afferent depletion neither altered cardiomyocyte action potentials and calcium transients; nor the expression of ion channels and calcium handling proteins. However, it attenuated fibrosis and mitigated electrical instability in the scar‐border zone. In vivo recordings of cardiovascular‐related stellate ganglion neurons (SGNs) revealed that MI enhances SGN function and disrupts integrated neural processing. Depleting TRPV1 afferents normalized these processes. Taken together, these data indicate that after MI, TRPV1 afferent‐induced adrenergic dysfunction promotes fibrosis, adverse cardiac remodeling, and worsens border zone electrical heterogeneity, resulting in electrically unstable ventricular myocardium. We propose targeting TRPV1‐expressing afferent to reduce VT/VF following MI. Support or Funding Information NIH/NHLBI DP2 OD024323‐01