Aging attenuates the protective effect of ischemic preconditioning against endothelial ischemia-reperfusion injury in humans

Abstract

Reperfusion is mandatory after ischemia but also triggers ischemia-reperfusion (I/R) injury. Ischemic preconditioning (IPC) can limit endothelial I/R injury. Nonetheless, translation of IPC to the clinical arena is often disappointing. Since application of IPC typically relates to older patients, efficacy of IPC may be attenuated with aging. Our objective was to examine the impact of advanced age on the ability of IPC to protect against endothelial dysfunction due to I/R injury. We included 15 healthy young (20-25 yr) and 15 older (68-77 yr) men. We examined brachial artery endothelial function using flow-mediated dilation (FMD) before and after arm I/R (induced by inflation of an upper-arm blood pressure cuff for 20 min and 15 min of reperfusion). In a randomized order, I/R was preceded by IPC or a control intervention consisting of three cycles of 5 min upper-arm cuff inflation to 220 or 20 mmHg, respectively. As a result, in young men, FMD decreased significantly after I/R (6.4 ± 2.7 to 4.4 ± 2.5%). This decrease was not present when I/R was preceded by IPC (5.9 ± 2.3 to 5.6 ± 2.5%). IPC-induced protection appeared to be significantly reduced in the elderly patients (P = 0.04). Although FMD decreased after I/R in older men (3.5 ± 1.7 to 2.5 ± 1.0%), IPC could not prevent this (3.7 ± 2.1 to 2.2 ± 1.1%). In conclusion, this study is the first to observe in humans in vivo that older age is associated with an abolished effect of IPC to protect against endothelial dysfunction after I/R in the brachial artery. This provides a possible explanation for the problematic translation of strategies that reduce I/R injury from preclinical work to the clinical arena.

Acute exercise increases resistance to oxidative stress in young but not older adults

“…Therefore, these lower levels of SOD activity following acute exercise in older adults, compared to young, could help explain the lack of protection from exercise against the oxidative challenge. These data are supported in rat and human models where aging attenuates the benefits of different forms of ischemic preconditioning against an I/R injury (Fenton et al 2000;van den Munckhof et al 2013).…”

“…Similarly, preconditioning with blood pressure cuff at 200 mmHg did not alter the response of flow-mediated dilation of the brachial artery in older adults, whereas in young adults, there was a significant difference in endothelial function with preconditioning (van den Munckhof et al 2013). Reasons for this increased rate of mortality and lack of preconditioning in older adults is not well understood; however, specific interest in cardiac protection has been placed on heat shock proteins, nitric oxide, and antioxidant enzymes (specifically SOD) due to cardiac protective properties and to further assess the mechanisms of age-associated decrease in the ability to handle I/R injury (Hamilton et al 2001;Lennon et al 2004;Starnes and Taylor 2007).…”

“…What is not known is whether these acute responses to exercise provide a sustained protection to subsequent oxidative stressors, especially those that are not produced by exercise. In addition, data from animal studies show that aging is associated with reduced ability to translate stress signals such as acute exercise or ischemic preconditioning (induced brief periods of ischemia prior to ischemic event) into improved protection (Fenton et al 2000;McArdle et al 2002;van den Munckhof et al 2013). The goal of this study was to investigate whether resistance to oxidative stress was increased by preceding acute exercise and to examine the effect of aging on this response.…”

HORMESIS: A Fundamental Concept with Widespread Biological and Biomedical Applications

“…In 1996, Abete et al [48] reported that the preconditioning hormetic dose response became profoundly diminished in elderly rats. This striking observation was confirmed and extended to other biological models and to humans via clinical as well as epidemiological studies [49]. It was also extended to biological systems beyond the initial work in cardiovascular systems.…”

Sympathetic nervous response to ischemia-reperfusion injury in humans is altered with remote ischemic preconditioning

“…Hence, we cannot determine whether an older population at high cardiovascular risk may show comparable sympathetic buffering response to RIPC following an ischemic injury. This issue was raised in a previous study showing that older age is associated with an abolished effect of RIPC to protect against endothelial dysfunction after IR in the brachial artery (34). In addition, older age and increased cardiovascular risk are typically associated with altered sympathetic nervous function at rest and during physiological challenges (14).…”