Human Cardiac Ischemia-Reperfusion Injury: Blunted Stress Response with Age

Abstract

Background & Aim: Autophagy is a cytoprotective recycling mechanism, capable of digesting dysfunctional cellular components, and this process is associated with pro-survival outcomes. Autophagy may decline in the aging myocardium, thereby contributing to cardiac dysfunction. However, it remains to be established how autophagy responds to ischemia-reperfusion stress with age. Methods: Samples from the right atrium were collected from young (≤50 years; n=5) and aged (≥70 years; n=11) patients prior to and immediately following cardioplegic arrest during coronary artery bypass grafting (CABG) surgery, a model of human ischemia-reperfusion injury. Results: Mitochondrial content did not differ between the age groups, however a 32% reduction in UQCRC2 (0.74 vs 0.53, effect of age, p=0.03) was seen with age, indicating possible compositional disruptions. In response to IR, VDAC (0.75 vs 1.05, p=0.03) and COX-I protein (0.63 vs 1.10, p=0.03) was over expressed in young, but not in aged patients. Reductions in Parkin (0.95 vs 0.49, interaction effect, p=0.04) and NIX (0.60 vs 0.21, p=0.004) protein expression with age suggest an impairment in mitochondrial recycling, which may lead to an accumulation of dysfunctional mitochondria. Following IR, our data suggest that in the young cohort, autophagy is reduced as a Beclin-1 decreased by 63% (0.95 vs 0.36, p=0.001) and no changes were observed in either p62 or LC3-II:I ratio. Conclusion: Our data demonstrate a blunted cardiac mitochondrial response to ischemia with age, accompanied by a possible impairment in mitophagy. These findings support an age-associated inability of the atrial myocardium to mount appropriate adaptive responses to stress.

Aging as a risk factor for cardiac surgery: Blunted ischemic‐reperfusion stress response?

“…analyzed right atrial samples from young (≤50 years) and aged (≥70 years) patients just before and immediately after cardioplegic arrest during CABG surgery, a model of human I/R injury. 15 These authors observed a decline in mitochondrial content in aged myocardium. In response to I/R challenge, the mitochondrial marker COX-I was upregulated in young, but not aged patients.…”

“…In this issue of Journal of Cardiac Surgery, Oliveira et al analyzed right atrial samples from young (≤50 years) and aged (≥70 years) patients just before and immediately after cardioplegic arrest during CABG surgery, a model of human I/R injury 15 . These authors observed a decline in mitochondrial content in aged myocardium.…”