Remote ischemic conditioning: from experimental observation to clinical application: report from the 8th Biennial Hatter Cardiovascular Institute Workshop

Abstract

In 1993, Przyklenk and colleagues made the intriguing experimental observation that 'brief ischemia in one vascular bed also protects remote, virgin myocardium from subsequent sustained coronary artery occlusion' and that this effect'... may be mediated by factor(s) activated, produced, or transported throughout the heart during brief ischemia/reperfusion'. This seminal study laid the foundation for the discovery of 'remote ischemic conditioning' (RIC), a phenomenon in which the heart is protected from the detrimental effects of acute ischemia/reperfusion injury (IRI), by applying cycles of brief ischemia and reperfusion to an organ or tissue remote from the heart. The concept of RIC quickly evolved to extend beyond the heart, encompassing inter-organ protection against acute IRI. The crucial discovery that the protective RIC stimulus could be applied non-invasively, by simply inflating and deflating a blood pressure cuff placed on the upper arm to induce cycles of brief ischemia and reperfusion, has facilitated the translation of RIC into the clinical setting. Despite intensive investigation over the last 20 years, the underlying mechanisms continue to elude researchers. In the 8th Biennial Hatter Cardiovascular Institute Workshop, recent developments in the field of RIC were discussed with a focus on new insights into the underlying mechanisms, the diversity of non-cardiac protection, new clinical applications, and large outcome studies. The scientific advances made in this field of research highlight the journey that RIC has made from being an intriguing experimental observation to a clinical application with patient benefit.

Fig. 1

Connecting the limb to the heart in RIC. This figure shows the potential interplay between the neural pathway (green solid lines) and humoral pathway (broken red lines) in mediating RIC cardioprotection. Cycles of brief upper limb ischemia/reperfusion induced by inflation/deflation of a cuff placed on the upper arm produce the local release of autacoids, which then activate local sensory afferent neurons. One experimental study has shown the involvement of the neuronal activity in the brainstem dorsal motor vagal nucleus (DMVN) in RIC cardioprotection—this provides parasympathetic innervation of the left ventricle and other internal organs. A circulating blood-borne cardioprotective factor(s) is produced in response to the RIC stimulus downstream of the local sensory afferent neurons in the upper limb, but the actual source for its release is not currently known. Potential sites of release of the cardioprotective factor(s) include: (1) from the conditioned limb itself, (2) from the central nervous system (brainstem), (3) from pre-/post-ganglionic parasympathetic nerve endings within the heart (broken green lines); and (4) from a non-conditioned remote organ/tissue receiving parasympathetic innervation