From Ischemic Conditioning to ‘Hyperconditioning’: Clinical Phenomenon and Basic Science Opportunity

Abstract

Thousands of articles have been published on the topic of ischemic conditioning. Nevertheless, relatively little attention has been given to assessment of conditioning's dose-response characteristics. Specifically, the consequences of multiple conditioning episodes, what we will term "hyperconditioning", have seldom been examined. We propose that hyperconditioning warrants investigation because it; (1) may be of clinical importance, (2) could provide insight into conditioning mechanisms, and (3) might result in development of novel models of human disease. The prevalence of angina pectoris and intermittent claudication is sufficiently high and the potential for daily ischemia-reperfusion episodes sufficiently large that hyperconditioning is a clinically relevant phenomenon. In basic science, attenuation of conditioning-mediated infarct size reduction found in some studies after hyperconditioning offers a possible means to facilitate further discernment of cardioprotective signaling pathways. Moreover, hyperconditioning's impact extends beyond cytoprotection to tissue structural elements. Several studies demonstrate that hyperconditioning produces collagen injury (primarily fiber breakage). Such structural impairment could have adverse clinical consequences; however, in laboratory studies, selective collagen damage could provide the basis for models of cardiac rupture and dilated cardiomyopathy. Accordingly, we propose that hyperconditioning represents the dark, but potentially illuminating, side of ischemic conditioning - a paradigm that merits attention and prospective evaluation.

Remote Ischemic Conditioning

“…Studies where peripheral limb ischemia is the RIC stimulus have mostly employed 3 or 4 episodes of 5 min arm and/or leg ischemia interspersed with 5 min reperfusion periods. However, these are empiric choices, the optimal algorithm has not been identified, and it has been postulated that “hyperconditioning” (i.e., an as-yet undefined, excessive number of conditioning episodes) may be deleterious (33,34). With regard to timing, outcomes of the limited number of head-to-head comparisons revealed no apparent difference in efficacy of RIPC, remote preconditioning, and postconditioning (35,36).…”

The effect of 1 week of repeated ischaemic leg preconditioning on simulated Keirin cycling performance: a randomised trial

“…7 Repeated IPC has been investigated in clinical studies, with local and remote improvements in endothelial function, brachial artery flowmediated dilation and resting skin microcirculation being observed, [8][9][10] although the physiological basis of this 'hyperconditioning' is still to be fully elucidated. 11 Oxidative stress is an integral component of ischaemia/reperfusion, 12 while vasodilation improved tissue oxygenation, 13 14 and inflammatory system modulation 15 is regulated through single or repetitive ischaemic treatment. Neopterin, 7,8-dihydroneopterin, biopterin, 7,8-dihydrobiopterin and tetrahydrobiopterin are heterocyclic pterin compounds metabolised by various cell types whose detection and elevation represent perturbations in oxidative stress, immune system activation and nitric oxide/ catecholamine synthesis.…”

Repeated ischaemic preconditioning: a novel therapeutic intervention and potential underlying mechanisms

“…NO, endothelial progenitor cells and IL-10). However, understanding the potential sustainable effects of repeated IPC is more complicated than simply exploring the early versus late effects of RIPC (Whittaker & Przyklenk, 2014). For example, previous work from Depre et al (2010) found single and repeated RIPC to lead to comparable preconditioning effects, but with marked differences in gene expression.…”

“…For example, previous work from Depre et al (2010) found single and repeated RIPC to lead to comparable preconditioning effects, but with marked differences in gene expression. Furthermore, exposure to a large number of ischaemic episodes may cause local collagen damage, potentially leading to inflammation and fibrosis (Whittaker & Przyklenk, 2014). Future work is required to explore the underlying mechanisms in order to understand the impact of repeated IPC.…”

“…three or four cycles of 5 min ischaemia interspaced with 5 min of reperfusion). Given the potent effects of a single dose of IPC, repeated episodes of IPC may, in theory, provide longer or more potent reduction of ischaemic myocardial damage (Whittaker & Przyklenk, 2014).…”