Effect of Intermittent Hypoxia on Ischemia-reperfusion Injury in Healthy Individuals

The objective of the present study is to determine whether intermittent hypoxia protects against ischemia-reperfusion injury in young and older healthy individuals. The investigators hypothesize that intermittent hypoxia will attenuate the reduction in flow-mediated dilation following ischemia-reperfusion injury.

Ischemic heart disease represents the most common form of cardiovascular disease and the main cause of mortality in the United States. Ischemic heart disease originates from an inadequate blood supply to the coronary arteries. While immediate reperfusion of the tissues represents the first-line treatment for ischemia, restoration of blood flow causes further damage to the endothelial cells lining the blood vessels. Indeed, severe endothelial dysfunction occurs paradoxically during the initial period of reperfusion, partly due to oxidative stress caused by a burst of reactive oxygen species formation and a reduction in nitric oxide bioavailability. Ischemia-reperfusion injury represents the endothelial damage caused by the combined effects of ischemia and reperfusion. Myocardial ischemia-reperfusion injury induces coronary endothelial dysfunction, which in turn promotes myocardial infarction. Thus, interventions designed to attenuate the effect of ischemia-reperfusion injury are urgently needed to prevent myocardial injury in patients with ischemic heart disease. The endothelial function of the brachial artery strongly correlates with coronary artery endothelial function. Accordingly, measures of brachial artery function such as flow-mediated dilation can act as a surrogate of coronary artery endothelial function. Flow-mediated dilation, an indicator of nitric oxide-dependent endothelial function, represents the dilation of the brachial artery following increases in blood flow and shear stress induced by a transient period of ischemia. A standard model of ischemia-reperfusion injury consists of occluding blood flow to the arm for a period of 20 minutes. This prolonged forearm occlusion causes a reduction in flow-mediated dilation ranging from 30 to 50% for at least 30 minutes after reperfusion in young individuals. Local ischemic preconditioning offers protection against ischemia-reperfusion injury. Ischemic preconditioning consists of exposing an individual to repeated brief periods of ischemia, induced by inflating a cuff on the upper arm, before an ischemia-reperfusion injury. Ischemic preconditioning (3 cycles of 5-minute ischemia followed by 5 minutes of reperfusion) applied immediately before ischemia-reperfusion injury prevents the reduction in flow-mediated dilation in healthy individuals, suggesting that ischemic preconditioning could be protective in patients with acute ischemia about to undergo therapeutic reperfusion. The protection provided by ischemic preconditioning appears to depend on the activation of adenosine triphosphate-sensitive potassium channel. Therefore, ischemic preconditioning attenuates the impaired endothelial-dependent dilation from subsequent, prolonged ischemia-reperfusion injury in humans. Intermittent hypoxia represents a potential systemic strategy to prevent the reduction in flow-mediated dilation following ischemia-reperfusion injury. Intermittently breathing mildly hypoxic air stimulates an endothelium-dependent dilation and prevents endothelial dysfunction through the production of reactive oxygen species and an increase in nitric oxide bioavailability. Short periods of intermittent hypoxia in animal models induces ischemic preconditioning and protect the heart from subsequent infarction. Indeed, intermittent hypoxia conditioning consisting of 5-8 cycles/day for 5-10 min/cycle at a fraction of inspired oxygen of 9.5-10% interspersed with 4 min normoxia over a period of 20 days protected the endothelium-dependent dilation of coronary and systemic arteries in rats through activation of free-radical processes. Moreover, intermittent hypoxia consisting of 5 cycles of 6-minutes of hypoxia at an oxygen concentration of 6% interspersed with 6 minutes of exposure to room air over 1 hour significantly reduced infarct size in hearts from mice when performed 24 hours before ischemia-reperfusion injury, in association with hypoxia-inducible factor expression. Intermittent hypoxia may therefore induce protection via a systemic response representing a distinct mechanism from the local protective response induced by brief ischemic preconditioning. Healthy aging results in a greater decrease in flow-mediated dilation following blood flow occlusion. Indeed, decreases in flow-mediated dilation ranging from 50 to 68% were observed in middle-aged men, due to further oxidative stress and reduced nitric oxide bioavailability. While ischemic preconditioning prevented the decrease in flow-mediated dilation in young healthy individuals, the preventive effect of ischemic preconditioning against ischemia-reperfusion injury was abolished in older individuals. However, ischemic preconditioning significantly attenuated the decrease in flow-mediated dilation in older patients with atherosclerosis.

The intermittent hypoxia protocol will consist of three 4-minute hypoxic cycles (arterial oxygen saturation of 80%) interspersed with 4-minute normoxic cycles.

The intermittent normoxia protocol will consist of three 4-minute normoxic cycles (compressed air) interspersed with 4-minute normoxic cycles (room air).

The intermittent hypoxia protocol will consist of three 4-minute hypoxic cycles (arterial oxygen saturation of 80%) interspersed with 4-minute normoxic cycles.

The intermittent normoxia protocol will consist of three 4-minute normoxic cycles (compressed air) interspersed with 4-minute normoxic cycles (room air).

Change in endothelial-dependent vasodilation of the brachial artery will be assessed by flow-mediated dilation using an ultrasound machine

Inclusion Criteria: Men and women aged 18 to 80 years old Exclusion Criteria: Have high blood pressure (above 130/80 mmHg) Are smokers Are pregnant Have a history of cardiovascular disease, diabetes or lung disease Are taking medication affecting the cardiovascular system Carpal tunnel syndrome

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