Cardioprotection via the skin; Nociceptor-Induced Conditioning Against Cardiac MI, in the NIC of time.

Timely reperfusion is still the most effective approach to limit infarct size in man. Despite advances in care and reduction in door-to-balloon times, nearly 25% of pa-tients develop heart failure post-MI, with its attendant morbidity and mortality. We pre-viously showed that cardioprotection results from a skin incision through the umbilicus in a murine model of myocardial infarction. In this study, we show that an electrical stimulus (ES) or topical capsaicin applied to the skin in the same region induces signif-icantly reduced infarct size in a murine model. We define this class of phenomena as nociceptor-induced conditioning (NIC), based upon peripheral nerve mechanism of initiation. We show that NIC is effective both as a pre- and a post-conditioning remote stimulus, reducing infarct size by 86 and 80 percent, respectively. NIC is induced via activation of skin C-fiber nerves. Interestingly, the skin region that activates NIC is lim-ited to the anterior of the T9-10 vertebral region of the abdomen. Cardioprotection after NIC requires the integrity of the spinal cord from the region of stimulation to the thoracic vertebral region but does not require that the cord be intact in the cervical region. Thus, we show that NIC is a reflex and not a CNS-mediated effect. The mechanism involves bradykinin 2 receptor (BK2R) activity and activation of PKC, specifically, PKC-α. The similarity of the neuroanatomy and conservation of the effectors of cardioprotection supports that NIC may be translatable to man as a non-traumatic and practical adjunct therapy against ischemic disease.