Study objective – The aim of the study was to assess the contribution of adenine nucleotide depletion to postischaemic myocardial dysfunction (“stunned” myocardium).

Design – Isolated perfused hearts release purine catabolites even in the absence of ischaemia, and undergo spontaneous reduction of adenine nucleotide pool. A comparison was therefore made between mechanical function, purine release and tissue adenine nucleotides in working rat hearts reperfused after short term ischaemia or subjected to prolonged perfusion (up to 180 min).

Experimental material – 49 Sprague-Dawley rats of 250-300 g body weight were used. The animals were anaesthetised and the hearts quickly excised and perfused with the working heart technique.

Measurements and main results – Reperfusion after 10 min ischaemia provided a good model of “stunned” myocardium: aortic flow and minute work decreased by 15(SEM 2)% and 20(3)%, no enzyme leakage was observed, and the adenine nucleotide pool decreased by 3.5(0.4) μmol·g−1. During prolonged perfusion no change was observed in any haemodynamic variable until the adenine nucleotide pool was depleted by over 8.5 μmol·g−1. Adenylate energy charge and the phospho-creatine-creatine pool were unchanged in all cases.

Conclusions – Depletion of adenine nucleotides does not account for contractile dysfunction in our model of “stunned” myocardium.

Adenine nucleotide depletion and contractile dysfunction in the "stunned" myocardium.

Background: After hypoxia-ischaemia and successful resuscitation, cerebral energy metabolism transiently recovers to the normal level (latent phase); after a variable period of time this phase is followed by secondary energy failure (SEF) in those subjects with an adverse outcome. A better understanding of the regional evolution of SEF may enhance the application of future neuroprotective strategies. Aims: The aim of this thesis was to determine associations between the insult severity, regional SEF evolution, and subsequent histo-pathological brain injury using magnetic resonance biomarkers. Methods: An established piglet model of neonatal encephalopathy was used. 1. Twenty-nine piglets were studied either normothermic or hypothermic (35°C or 33°C during 2-26 hours after hypoxia-ischaemia). 31-phosphorus magnetic resonance spectroscopy (31P MRS) was serially acquired; the brain was assessed histo-pathologically after 48 hours. 2. Global 31P MRS, and maps of apparent diffusion coefficient (ADC) and transverse relaxation time (T2) were serially obtained in 3 control and 18 asphyxiated piglets. Histo-pathological brain injury and MR biomarkers were compared at time periods of 16-48 hours after hypoxia-ischaemia. Results: 1. Severe acute insult, short latent phase, severe SEF and profound histo-pathological brain injury were associated between each other. 2. Transient recovery in phosphocreatine (PCr) higher than its baseline was indicative of absent subsequent evolution of SEF, whereas sub-baseline PCr recovery was suggestive of severe SEF. 3. Global 31P MRS biomarkers and regional ADC obtained just prior to termination and up to 18-24 hours before termination predicted histo-pathological brain injury; the predictive value was optimal for global PCr/ inorganic phosphate (Pi), followed by global PCr/exchangeable high-energy phosphate pool (EPP), Pi/EPP and regional ADC. Conclusions: Although 31P MRS was more accurate, regional ADC predicted subsequent brain injury up to 18 hours in advance of termination. Regional ADC can be used as a sensitive early marker for subsequent tissue injury when 31P MRS is not available.

Temporal and spatial evolution of cerebral injury in the piglet asphyxia model : a comparative study of serial magnetic resonance biomarkers and histopathology

Following hypoxia-ischaemia (HI), an early biomarker of insult severity is desirable to target neuroprotective therapies to patients most likely to benefit; currently there are no biomarkers within the ‘latent phase’ period before the establishment of secondary energy failure. Brief transient phosphocreatine (PCr) recovery overshoot (measured absolutely or relative to nucleotide triphosphate, NTP) following HI has been observed in cardiac and skeletal muscle; its significance however is unclear. To investigate cerebral PCr recovery levels after HI in relation to (i) baseline metabolism, (ii) insult severity, (iii) energy metabolism at recovery and (iv) subsequent metabolic derangement, cerebral NTP, PCr and inorganic phosphate (relative to the exchangeable high-energy phosphate pool) were measured serially in an in vivo model of perinatal asphyxial encephalopathy using phosphorus-31 magnetic resonance spectroscopy. Measures were compared either in all piglets or between 3 subgroups with no ( n = 5, favourable outcome), moderate ( n = 8, intermediate outcome) or severe ( n = 5, unfavourable outcome) secondary energy failure at 24 h after HI. Maximum NTP, PCr and inorganic phosphate recoveries were observed 2–8 h after HI. Following resuscitation, in subjects with favourable outcome PCr recovered to higher than its baseline level (overshoot); in subjects with unfavourable outcome maximum PCr recovery was lower than baseline and lower than in subjects with favourable and intermediate outcomes. Recovery PCr correlated linearly and negatively with both acute insult severity and baseline PCr/NTP. These results suggest that recovery metabolism 2–8 h after HI may provide an early biomarker of injury severity. PCr recovery overshoot in the developing brain may indicate a protective response to HI leading to cell recovery, survival and protection against subsequent stress. In addition, baseline cerebral metabolism (PCr/NTP) may identify vulnerable infants prior to invasive surgery.

/pdf/supra-and-sub-baseline-phosphocreatine-recovery-in-1b0y7yxr1f.pdf

Supra- and sub-baseline phosphocreatine recovery in developing brain after transient hypoxia-ischaemia: relation to baseline energetics, insult severity and outcome.

We investigated whether there is a relationship between the prolonged dysfunction after myocardial ischaemia and the postischaemic phosphocreatine overshoot phenomenon. In 16 open-chest rats 3 periods of 4 minutes of oxygen deficiency were performed and basal haemodynamic variables and the myocardial oxygen demand were determined during the recovery period. At the end of the 20 minutes recovery period, left ventricular pressure, dp/dtmax, ejection fraction, and myocardial oxygen demand were completely recovered. High energy phosphate levels, however, were still altered. The sum of adeninenucleotides was decreased to 78 ± 4% of control (\( (\overline x \pm \)SEM, p<0.05) . The level of phosphocreatine was markedly elevated to 162 ± 14 (\( (\overline x \pm \) SEM). The persistence of the phosphocreatine overshoot phenomenon, while basal function was already normalized, indicates that a reduced function and thus a reduced energy demand of the contractile apparatus are not the cause of the phosphocreatine overshoot. We found no close relationship between high energy levels and basal function or oxygen demand in myocardium after mild oxygen deficiency.

Phosphocreatine and adeninenucleotides in postasphyxial hearts with normal basal function and normal oxygen demand

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Phosphocreatine and adeninenucleotides in postasphyxial hearts with normal basal function and normal oxygen demand