Chronic hypoxia induces adaptive metabolic changes in neonatal myocardium

Abstract

The effect of chronic hypoxia on neonatal myocardial metabolism remains undefined. With a new neonatal piglet model, we determined changes in myocardial metabolism during global ischemia after chronic hypoxia. Five-day-old piglets (N = 30) were randomly assigned to two groups and exposed to an atmosphere of 8% oxygen or to room air for 28 days before they were killed. Left ventricular myocardium was then analyzed at control and at 15-minute intervals during 60 minutes of global normothermic ischemia to determine high-energy phosphate levels, glycogen stores, and lactate accumulation. Time to peak ischemic myocardial contracture was measured with intramyocardial needle-tipped Millar catheters as a marker of the onset of irreversible ischemic injury. Results showed an initially greater level of myocardial adenosine triphosphate in the hypoxic group (27 +/- 1.2 vs 19 +/- 1.8 micromol/gm dry wt, p = 0.001) and a delay in adenosine triphosphate depletion during 60 minutes of global ischemia compared with the control group. Initial energy charge ratios (1/2 adenosine diphosphate + adenosine triphosphate/adenosine monophosphate + adenosine diphosphate + adenosine triphosphate) were also greater in the hypoxic group (0.96 +/- 0.01 vs 0.81 +/- 0.04, p = 0.01) and remained so throughout global ischemia. Initial glycogen stores were greater in the hypoxic group (273 +/- 13.3 vs 215 +/- 14.7 micromol/gm dry weight, p = 0.02) when compared with the control group. Lactate levels in the hypoxic group were initially higher (19.1 +/- 6.4 vs 8.9 +/- 3.1 micromol/gm dry weight, p = 0.001) compared with control levels and remained elevated throughout 60 minutes of ischemia. Time to peak ischemic contracture was prolonged in the hypoxic group (69.5 +/- 1.8 vs 48.9 +/- 1.4 minutes, p = 0.001) compared with the controls group. These data show that chronic hypoxia results in significant myocardial metabolic adaptive changes, which in turn result in an improved tolerance to severe normothermic ischemia. These beneficial effects are associated with elevated baseline glycogen storage levels and an accelerated rate of anaerobic glycolysis during ischemia.

Balance between hypertrophic and hypoxic stimulus in caspase-3 activation during rat heart development

“…However, it must be noted that in vivo, while until day 4 of life the balance between these two opposite pathways was maintained, at day 8 of life the apoptotic stimulus overcomes the hypertrophic status, determining elimination of redundant and stressed cells, as elsewhere suggested (Wang et al 1998, Chae et al 2001.Thus, this evidence confirms that both postnatal cardiac remodelling and hypoxic response result from changes in molecular mechanisms mediating apoptosis and proliferation (Fernandez et al 2001). Furthermore, chronic hypoxia, as previously reported in rabbit developing heart (Baker et al 1995) induces rat myocardial metabolic changes, so determining a sort of early 'adaptive' response similar to the one physiologically occurring during the early phases of life and aging (Plunkett et al 1996, Cataldi et al 2004.…”

Intermittent Hypobaric Hypoxia Promotes Atherosclerotic Plaque Instability in ApoE-Deficient Mice

“…Taken together, the effects on plaque instability may mostly be attributed to hypobaric conditions. Chronic hypoxia induces adaptive metabolic changes in several different types of cells (Lodi et al, 2011;Plunkett et al, 1996). We found that exposure to IHH significantly decreased body weights of mice but did not affect the food intake of mice.…”

Adaptation to Chronic Hypoxia Confers Tolerance to Subsequent Myocardial Ischemia by Increased Nitric Oxide Production

“…Recently a non‐surgical model of chronic hypoxia has been described in the pig where hypoxic conditions ( F I O 2 = 0.08 ) are created 5 days after birth. 27 The piglets are then raised to 28 days of age prior to study. However, the piglet model is relatively expensive and hypoxic conditions are not imposed from birth.…”