| Summary: | Acute myocardial infarction (AMI) is the leading cause of death and disability worldwide. Timely reperfusion is the standard of care and results in decreased infarct size, improving patient survival and prognosis. However, 25% of patients proceed to develop heart failure (HF) after myocardial infarction (MI) and 50% of these will die within five years. Since the size of the infarct is the major predictor of the outcome, including the development of HF, therapies to improve myocardial salvage have great potential. Over the past three decades, a number of stimuli have been discovered that activate endogenous cardioprotective pathways. In ischemic preconditioning (IPC) and ischemic postconditioning, ischemia within the heart initiates the protection. Brief reversible episodes of ischemia in vascular beds remote from the heart can also trigger cardioprotection when applied before, during, or immediately after myocardial ischemia—known as remote ischemic pre-, per-, and post-conditioning, respectively. Although the mechanism of remote ischemic preconditioning (RIPC) has not yet been fully elucidated, many mechanistic components are shared with IPC. The discovery of RIPC led to research into the use of remote non-ischemic stimuli including nerve stimulation (spinal and vagal), and electroacupuncture (EA). We discovered and, with others, have elucidated mechanistic aspects of a non-ischemic phenomenon we termed remote preconditioning of trauma (RPCT). RPCT operates via neural stimulation of skin sensory nerves and has similarities and differences to nerve stimulation and EA conducted at acupoints. We show herein that RPCT can be mimicked using electrical stimulation of the abdominal midline (EA-like treatment) and that this modality of activating cardioprotection is powerful as both a preconditioning and a postconditioning stimulus (when applied at reperfusion). Investigations of these cardioprotective phenomena have led to a more integrative understanding of mechanisms related to cardioprotection, and in the last five to ten years, it has become clear that the mechanisms are similar, whether induced by ischemic or non-ischemic stimuli. Taking together much of the data in the literature, we propose that all of these cardioprotective “conditioning” phenomena represent activation from different entry points of a cardiac conditioning network that converges upon specific mediators and effectors of myocardial cell survival, including NF-кB, Stat3/5, protein kinase C, bradykinin, and the mitoKATP channel. Nervous system pathways may represent a novel mechanism for initiating conditioning of the heart and other organs. IPC and RIPC have proven difficult to translate clinically, as they have associated risks and cannot be used in some patients. Because of this, the use of neural and nociceptive stimuli is emerging as a potential non-ischemic and non-traumatic means to initiate cardiac conditioning. Clinical relevance is underscored by the demonstration of postconditioning with one of these modalities, supporting the conclusion that the development of pharmaceuticals and electroceuticals for this purpose is an area ripe for clinical development.
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