The effects of 1 hour of mild and moderate reductions in coronary blood flow on myocardial high-energy phosphate levels were evaluated. Thirty anesthetized pigs were instrumented with left anterior descending arterial and venous catheters, crystals for instantaneous wall thickness, and a fluid-filled occluder. Measurement of myocardial blood flow was performed with microspheres, and a series of myocardial biopsies also was performed. In 10 pigs, overall coronary blood flow was lowered by 22%, with a fall in subendocardial-to-subepicardial flow ratio from 1.11 to 0.54 and in wall thickening from 33% to 15%. Subendocardial flow fell 48%. Coronary blood flow and thickening were constant during 1 hour of ischemia. Phosphocreatine (mumol/g wet wt) in the subendocardial third of the ischemic zone fell from 7.6 to 3.8 at 5 minutes of ischemia (p less than 0.005 versus control) and returned to normal (7.9) at 60 minutes (p = NS), despite ongoing ischemia. Subendocardial ATP (mumol/g wet wt) fell slowly from 4.3 and leveled off at 2.1 at 60 minutes of ischemia (p less than 0.001 versus control). Similar regeneration of phosphocreatine was found in seven additional pigs, with a 43% transmural reduction in coronary blood flow and a 66% reduction in subendocardial flow. No significant changes in ATP and phosphocreatine were noted in two different control groups (n = 13 pigs). The regeneration of phosphocreatine despite ongoing ischemia and low ATP levels was not related to changes in myocardial oxygen demand or consumption, or in regional function during the period of ischemia. This may reflect 1) a successful downregulation of the energy needs of the ischemic myocardium to maintain cell viability, or 2) a metabolic abnormality in the ability of the cells to produce ATP primarily or by use of phosphocreatine.

We studied the effects of rapid atrial pacing during the final 10 minutes of a 70-minute, 31% reduction in coronary blood flow in anesthetized swine to understand the significance of apparent metabolic improvements during the initial 60 minutes of segmental ischemia. Within 5-10 minutes of ischemia, subendocardial phosphocreatine (PCr) and ATP were depleted to 47% and 63% of control, respectively; lactate accumulated within the subendocardium to 300% of control; and net arteriovenous lactate production occurred. Despite continued ischemia and no significant changes in the external determinants of myocardial oxygen consumption, by 60 minutes subendocardial PCr and lactate contents returned to near control levels and there was net arteriovenous lactate consumption. Ischemic left ventricular wall thickening and ATP levels remained depressed throughout the experiment. Atrial pacing during the final 10 minutes of ischemia again resulted in depletion of PCr and lactate production. Since the myocardium was capable of hydrolyzing PCr in response to atrial pacing at 60 minutes of ischemia, we conclude it was capable of hydrolyzing PCr during the period of constant ischemia when instead it was accumulating PCr. We propose the ischemic myocardium downregulates regional energy requirements below blood flow-limited rates of energy production during ischemia. This appears to be an active adaptation to ischemia and not a result of passive damage or cellular injury.

To determine if endogenous (ENDG) vasodilation was maximum during myocardial ischemia, left anterior descending (LAD) mean pressure (P) was reduced for 20 min in 13 swine. At LAD P of 45 mmHg (LAD P45) flow fell during ENDG = 25 but rose to 44 ml/min during adenosine (AD) infusion (P less than 0.01). Flow increased to subendocardium (ENDG 0.65 vs. AD 1.04 ml X min-1 X g-1) and to subepicardium (ENDG 0.99 vs. AD 1.83 ml X min-1 X g-1; P less than 0.05). No significant change occurred in myocardial O2 consumption (MVO2; ENDG 2.91 vs. AD 3.18 ml X min-1 X g-1), lactate extraction (ENDG = -5 vs. AD-1%), and wall thickening (WTh; ENDG + 16 vs. AD + 17%). At LAD P35, flow during ENDG was 12 but rose to 19 ml/min during AD (P less than 0.01). Flow increased to subendocardium (ENDG 0.24 vs. AD 0.46 ml X min-1 X g-1; P less than 0.02) and subepicardium (ENDG 0.51 vs. AD 0.87 ml X min-1 X g-1; P less than 0.01). No significant change occurred in MVo2 (ENDG 1.38 vs. AD 1.59 ml/min), lactate extraction (ENDG -38 vs. AD -22%), WTh (ENDG -1 vs. AD + 1%). Thus endogenous vasodilation reserve was not used fully during ischemia. AD increased flow but did not improve abnormalities in myocardial function or metabolism.

Metabolic markers of ischemia such as ratio of phosphocreatine to ATP, ATP content, lactate content, and lactate production were blunted during this protocol of gradually worsening ischemia. Thus, contractile abnormalities of mild ischemia can develop with minimal metabolic evidence of ischemia. The downregulation of myocardial energy requirements can almost keep pace with the gradual decline in coronary blood flow.

To explore the relation between myocardial and vascular injury in the generation of the no-reflow phenomenon, the pressure-flow relation during maximal vasodilation after coronary artery reperfusion was studied in the open-chest porcine model. During both endogenous and maximal vasodilation with intracoronary adenosine, pressure-flow (P/Q) plots were constructed before and after 20-minute (n = 9) or 40-minute (n = 17) circumflex artery occlusions. Decreases in circumflex vascular bed conductance were represented by downward shifts in P/Q plot regression lines. No significant change occurred in P/Q line slope or pressure at zero flow 30 minutes after release of the 20-minute occlusion, and no infarction was found. After release of the 40-minute occlusion, a small but insignificant decrease in P/Q line slope occurred during endogenous vasodilation. However, during maximal vasodilation, a significant (p<0.01) decrease in P/Q line slope was present during reperfusion compared with preocclusion corresponding to a decrease in vasodilatory reserve (P/Q line slope = 1.52 + 0.14 ml/min/mm Hg preocclusion vs. 1.03+±0.13 at 15 minutes reperfusion). Pretreatment with aspirin did not prevent this decrease in vascular conductance during maximal vasodilation. Total circumflex, as well as subendocardial, midmyocardial, and subepicardial blood flows, was measured with radioactive microspheres. There was a good correlation between the extent of infarction measured by triphenyltetrazolium chloride staining and the decrease in vascular conductance during maximal vasodilation for all three myocardial layers as well as for the total circumflex vascular bed. Hence, the degree of no-reflow correlates closely with the extent of infarction during maximal vasodilation (but not during endogenous vasodilation) and is not altered by aspirin therapy. (Circulation 1988;78:462-472)