ABSTRACT: The pattern of metabolic reprogramming in chronic
hypoxia shares similarities with that following
myocardial infarction or
hypertrophy; however, the response of the chronically hypoxic heart to subsequent acute injury, and the role of metabolism is not well understood. Here, we determined the myocardial tolerance of the chronically hypoxic heart to subsequent acute injury, and hypothesised that activation of a key regulator of myocardial metabolism, the
pyruvate dehydrogenase complex (PDC), could improve hypoxic tolerance. Mouse hearts, perfused in Langendorff mode, were exposed to 30 min of
hypoxia, and lost 80% of pre-hypoxic function (P = 0.001), with only 51% recovery of pre-hypoxic function with 30 min of reoxygenation (P = 0.046). Activation of the PDC with infusion of 1 mm dichloroacetate (DCA) during
hypoxia and reoxygenation did not alter function. Acute hypoxic tolerance was assessed in hearts of mice housed in
hypoxia for 3 weeks. Chronic
hypoxia reduced cardiac tolerance to subsequent acute
hypoxia, with recovery of function 22% of pre-acute hypoxic levels vs. 39% in normoxic control hearts (P = 0.012). DCA feeding in chronic
hypoxia (per os, 70 mg kg-1 day-1 ) doubled cardiac
acetylcarnitine content, and this fell following acute
hypoxia. This
acetylcarnitine use maintained cardiac
ATP and
glycogen content during acute
hypoxia, with hypoxic tolerance normalised. In summary, chronic
hypoxia renders the heart more susceptible to acute hypoxic injury, which can be improved by activation of the PDC and pooling of
acetylcarnitine. This is the first study showing functional improvement of the chronically hypoxic heart with activation of the PDC, and offers therapeutic potential in
cardiac disease with a hypoxic component.