title: 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.
authors.affiliation: Department of Physiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Inge
authors.initials: I
authors.lastname: van den Munckhof
authors.forename: Niels
authors.initials: N
authors.lastname: Riksen
authors.forename: Joost P H
authors.initials: JP
authors.lastname: Seeger
authors.forename: Tim H
authors.initials: TH
authors.lastname: Schreuder
authors.forename: George F
authors.initials: GF
authors.lastname: Borm
authors.forename: Thijs M H
authors.initials: TM
authors.lastname: Eijsvogels
authors.forename: Maria T E
authors.initials: MT
authors.lastname: Hopman
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Rongen
authors.forename: Dick H J
authors.initials: DH
authors.lastname: Thijssen
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D001794:Blood Pressure; D001916:Brachial Artery / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D014664:Vasodilation
keywords: cardiovascular disease; endothelial function; flow-mediated dilation; ischemia