Effect of Intermittent Hypoxia on Ischemia-reperfusion Injury in Healthy Individuals
Condition: Intermittent Hypoxia
MeSH terms: Reperfusion Injury; Ischemia; Hypoxia
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Intermittent hypoxia; Intermittent normoxia
Intervention type(s): Behavioral; Behavioral
Intervention description(s): 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).
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Prevention