Long Term Model for Evaluation of Myocardial Metabolic Recovery following Global Ischemia

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Abstract
Myocardial ATP levels remain depressed following significant periods of ischemia (Isc) despite reperfusion (Rpf). Neither the rate of in vivo ATP return following global Isc nor the factors which influence recovery have been defined. In order to determine the time course to complete the return of ATP levels and evaluate methods of enhancing recovery of ATP levels, we have devised a chronic canine model of global Isc. In this model serial ventricular biopsies can be taken in the awake animal over several days without reoperation which allows an investigation of the recovery of the myocardium following a uniform global insult to be performed. Recovery of ATP levels has been shown to depend, at least in part, on the availability of precursors and the activity of the ATP regenerating enzymes. Because complete recovery of ATP levels takes days, short term (hours) models have limitations. Previous attempts at enhancing ATP recovery,following Isc have been only partially successful because either the degree of depression was not great or the period of observation was short, resulting in incomplete return. To identify the best precursor choice, we previously measured the activity of the AMP regenerating enzymes, adenosine kinase (AdK) (adenosine → AMP) and adenine phosphoribosyl transferase (APRT) (adenine → AMP). Because APRT activity was 20 fold higher than AdK with similar Km values for substrates, it appeared that adenine (A) is preferred to adenosine for AMP regeneration in the dog’s myocardium. The formation of 5-phosphoribosyl 1-pyrophosphate (PRPP) may also be rate limiting and, therefore, the effect of ribose (R) on ATP recovery was also evaluated. Recovery of ATP levels was assessed in three groups: (1) normal saline (NS), (2) A (20 mM) in normal saline (A/NS) or (3) A with R (80 mM) in normal saline (A/R) were infused (1.0 ml/min) into the right atrium of dogs for 48 hours following Isc. In all groups, ATP levels fell to between 46–60% of pre-Isc levels during Isc. In the NS dogs, ATP levels continued to fall slightly to 46% pre-Isc levels during the first four hours of Rpf after Isc. By 24 hours no appreciable recovery had occurred and the measured ATP was only 51% of the pre-Isc value. Even by seven days, ATP had not returned fully, and by extrapolation, complete recovery required 9.9±1.4 days. Treated dogs showed, however, that ATP recovery could be significantly enhanced. In the A/NS treated group, the ATP levels rebounded to 69% of pre-Isc values during the first four hours of Rpf following Isc but recovery leveled off during the next 20 hours. Recovery in the A/R treated group rose to 60% of pre-Isc values after four hours of Rpf and continued to improve thereafter. Recovery was virtually complete by 24 hours (96%). The calculated mean recovery rate for the first 24 hours in each group: (NS) 0.04±0.33 nmoles/mg wet wt/day, (A/NS) 0.41±0.55 nmoles/mg wet wt/day and (A/R) 2.44±0.38 nmoles/mg wet wt/day. Our results reveal that (1) This long term model allows serial myocardial sampling in the awake state for investigation of recovery from Isc. (2) ATP recovery following a significant global Isc insult is slow. (3) Precursor availability is an important limiting factor in recovery. (4) Recovery time can be greatly shortened with ATP precursor infusion even when started after Isc. (5) Although A alone initially enhanced ATP recovery, the addition of R provided a more rapid complete return suggesting PRPP formation is also rate limiting.