Loss of Preconditioning by Attenuated Activation of Myocardial ATP-Sensitive Potassium Channels in Elderly Patients Undergoing Coronary Angioplasty

Abstract

Background-The ischemic preconditioning response among elderly patients is known to be lower than in adult patients.Since mitochondrial ATP-sensitive potassium (K ATP ) channels exert preconditioning effects, we undertook this study to determine whether this attenuated activation of K ATP channels influences the reduced responsiveness of elderly patients to ischemic preconditioning. Methods and Results-Fifty-six patients undergoing angioplasty for a major epicardial coronary artery were randomly allocated to either an ischemic preconditioning group, a nicorandil (an agonist of K ATP channels) group, or a glibenclamide (an antagonist of K ATP channels), group based on their age: adult groups (nϭ26; age, Յ55 years; mean age, 45Ϯ5 years) and elderly groups (nϭ30; age, Ն65 years; mean age, 71Ϯ3 years). Ischemic preconditioning with a 120-second coronary occlusion significantly lowered the ischemic burden assessed by ST-segment shift, chest pain score, and myocardial lactate extraction ratios in the adult group. This did not occur in the elderly group. The impaired preconditioning responsiveness in the elderly patients was reversed by nicorandil administration or an ischemic period lengthened to 180 seconds. However, nicorandil-induced cardioprotection was abolished by administering glibenclamide in both the adult and elderly groups. Conclusions-The present study demonstrates that preconditioning significantly enhances the tolerance of the heart to subsequent ischemia in adults but not in senescent patients. Since prolonged ischemia and nicorandil are able to mimic preconditioning and can reverse impaired responsiveness, impaired preconditioning of the aged heart appears to be due to an attenuated activation of K ATP channels.

Exercise improves postischemic function in aging hearts

“…Cardiac function working heart with equal preload, afterload, and heart rate, the enhanced cardioprotection after exercise preconditioning was due to adaptations within the ventricle. Although several reports indicate that aging attenuates or abolishes the improved tolerance to I/R after ischemic preconditioning (1,2,12,20,24,29), those studies focused on the "early" stage of preconditioning, which does not require protein synthesis and lasts only 2-3 h after the preconditioning stimulus (5,19). In this regard, Abete et al (1) reported that a 6-wk swimming program restored the effectiveness of ischemic preconditioning in aged Wistar rats.…”

“…For example, several studies conclude that HSP70 expression after heat stress is impaired in the heart of aged animals (for a review, see Ref. 30), and the cardioprotective benefits induced by ischemic preconditioning are attenuated or abolished with age (2,12,20,24,29). Thus the purpose of this study was to determine the effect of age on exercise-induced protection against I/R and on changes in cardioprotective proteins.…”

Impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxide-dependent increase in nuclear Sirt1

“…In addition, several experimental and clinical investigations have addressed the issue of whether IPC occurs in aged hearts (1,2,28,40,46). The efficacy of IPC has been reported to be decreased or lost in senescent patients (2,28) and in aged animals (1,40).…”

“…Hearts from senescent animals are more susceptible to ischemia than those from young animals (7,20,45). Recently, a number of investigators have demonstrated that the cardioprotective effect of ischemic preconditioning (IPC) is impaired in aged animals (1,2,28,40,46). Aging also loses the cardioprotection afforded by postconditioning (8).…”

Ischemic preconditioning of the liver: A few perspectives from the bench to bedside translation

“…38 Mechanistic explanations for the loss of IPC efficacy with increasing age include decreased norepinephrine release in older hearts, 50 decreased connexin 43 and ability to generate adenosine triphosphate (ATP) in mitochondria, decreased gap junctions 51 and impaired activation of the ATP-sensitive potassium (K ATP ) channels. 52 Therefore, it is possible that the decreased efficacy of IPC of the liver in clinical trials could partly arise from enrollment of a significant proportion of elderly subjects/donors. For example, in our recent trial of IPC in DDLT, 46% of the donors were aged Ն50 years.…”