Age- and Gender-Related Differences in Ischemia/Reperfusion Injury and Cardioprotection: Effects of Diazoxide

Abstract

Background-Recent studies have demonstrated that aging is associated with reduced tolerance to ischemia and that the aged (not senescent) female heart has greater susceptibility to ischemia as compared with the aged male heart. Previously, we have shown that ischemia can be modulated with cardioplegia in the male heart; however, efficacy in the female heart was unknown.

Age- and Gender-Related Differences in Mitochondrial Oxygen Consumption and Calcium With Cardioplegia and Diazoxide

“…We also demonstrated that the effects of global ischemia were partially ameliorated by cardioplegia ± diazoxide, but this cardioprotection was significantly decreased in the aged compared with the mature heart and significantly decreased in the aged female compared with the aged male rabbit heart [2]. These animal studies are consistent with human studies indicating that women have a significantly greater risk potential compared with men and worse outcomes after cardiac surgery [3,4].…”

“…All rabbits were anesthetized with pentobarbital sodium (Nembutal, 100 mg/kg; Abbott Laboratories, North Chicago, IL), and heparin (200 U/kg) was given intravenously through the marginal ear vein [1,2,10]. Langendorff perfusion was performed as previously described [1,2,10].…”

“…Our model was chosen because previous studies in animal models have shown that age-related ischemic intolerance develops well before senescence, being primarily evident by middle age [2,6,7]. It has been demonstrated in animal models that there is an apparent nadir in ischemic tolerance in middle-aged to aged hearts, with a subsequent modest improvement with senescence [6,7].…”

Histidine-Tryptophan-Ketoglutarate or Celsior: Which Is More Suitable for Cold Preservation for Cardiac Grafts From Older Donors?

“…Because the use of organs from older donors is a major concern in transplantation, our approaches aiming to determine more effective and secure myocardial preservation solutions for older donors will advance transplantation medicine and could have substantial clinical impact. We and others have shown that aging is related to reduced tolerance to myocardial ischemia and postischemic functional recovery and infarct size is affected by age [25]. Hearts from older donors are associated with increased myocardial stunning, decreased recovery of hemodynamic and high-energy phosphates, and greater overall tissue damage after ischemic insult [26].…”

Estrogen, NFκB, and the Heat Shock Response

“…Ovariectomy also negates cardioprotection in an I/R model of injury, and exogenous E2 treatment can restore protection (23). However, there are some studies that show no benefit of E2 in I/R injury (24,25). The discrepancies in protection could be due to species differences (rat versus dog and rabbit) or differences in estrogen treatment or cycle stage.…”