Myocardial blood flow, function, and metabolism in repetitive stunning.

UNLABELLED: Myocardial hibernation refers to a state of persistent left ventricular dysfunction resulting from a chronically reduced blood flow, which is improved or reversed with revascularization. Increased glucose uptake in areas with reduced blood flow at rest on PET has been used successfully to diagnose hibernating myocardium. However, hibernation may represent persistent myocardial stunning resulting from repeated episodes of ischemia and reperfusion rather than from chronic underperfusion. We sought to determine the inter-relationship between blood flow, metabolism, and function in a canine model of repetitive myocardial stunning. METHODS: Ten dogs underwent 4 sequential 5-min intervals of balloon occlusion of the anterior descending or circumflex arteries, each separated by 5 min of reperfusion. Regional blood flow, metabolism, and function were evaluated 3-4 h after reperfusion in all dogs and 24 h and 1 wk after reperfusion in 5 dogs. Regional wall motion was evaluated with echocardiography. Regional blood flow was assessed with radioactive microspheres and by [(13)N]ammonia and PET. Measurements of oxidative metabolism and glucose uptake (during hyperinsulinemic-euglycemic clamping) were derived with [(11)C]-acetate, FDG, and PET. RESULTS: Regional wall motion was severely decreased after the 4 cycles of ischemia, remained impaired 24 h after reperfusion, and normalized after 1 wk. During reflow, blood flow in stunned regions was restored to near-normal levels (0.89 +/- 0.07 versus 0.95 +/- 0.07 mL/g/min, P = 0.023). However, glucose uptake in stunned regions was significantly decreased at 4 h (73% +/- 5% of remote, P < 0.001), remained depressed after 24 h of reflow (83% +/- 4% of remote, P = 0.013), and fully recovered at 1 wk (101% +/- 10% of remote, P = 0.88). Similarly, oxidative metabolism in stunned regions was significantly decreased at 4 h (84% +/- 2% of remote, P < 0.001) and at 24 h (90% +/- 2% of remote, P = 0.005) and recovered to near-normal levels after 1 wk of reperfusion (97% +/- 1% of remote, P = 0.024). The time course of change in postischemic dysfunction correlated with the recovery of oxidative metabolism (r=0.57; P=0.009). CONCLUSION: Myocardium subjected to repetitive stunning showed a prolonged yet reversible reduction in systolic function that was associated with a significant downregulation of glucose and oxidative metabolism despite restoration of normal myocardial blood flow. These findings suggest a unique metabolic adaptation in repetitive stunning that is different from that typically seen in clinical and experimental models of hibernation.

Aqueous oxygen: a highly O2-supersaturated infusate for regional correction of hypoxemia and production of hyperoxemia.

BACKGROUND: High levels of hyperoxemia may have utility in the treatment of regional tissue ischemia, but current methods for its implementation are impractical. A catheter-based method for infusion of O2, dissolved in a crystalloid solution at extremely high concentrations, ie, 1 to 3 mL O2/g (aqueous oxygen [AO]), into blood without bubble nucleation was recently developed for the potential hyperoxemic treatment of regional tissue ischemia. METHODS AND RESULTS: To test the hypotheses that hypoxemia is correctable and that hyperoxemia can be produced locally by AO infusion, normal saline equilibrated with O2 at 3 MPa (30 bar; 1 mL O2/g) was delivered into arterial blood in two different animal models. In 15 New Zealand White rabbits with systemic hypoxemia, AO was infused into the midabdominal aorta at 1 g/min. Mean distal arterial PO2 increased to 236+/-113 and 593+/-114 mm Hg on 1-hour periods of air and O2 breathing, respectively, from a baseline of 70+/-10 mm Hg (P<.01). In contrast, infusion of ordinary normal saline in a control group (n=7) had no effect on arterial PO2. No differences between groups (P>.05) in temporal changes in blood counts and chemistries were identified. In 10 dogs, low coronary blood flow in the circumflex artery was delivered with a roller pump through the central channel of an occluding balloon catheter. Hypoxemic, normoxemic, and AO-induced hyperoxemic blood perfusates (mean PO2, 52+/-4, 111+/-22, and 504+/-72 mm Hg, respectively) were infused for 3-minute periods in a randomized sequence. Short-axis two-dimensional echocardiography demonstrated a significant decrease (P<.05) in left ventricular ejection fraction compared with baseline physiological values with low-flow hypoxemic and normoxemic perfusion but not with low-flow hyperoxemic perfusion. CONCLUSIONS: Intra-arterial AO infusion was effective in these models for regional correction of hypoxemia and production of hyperoxemia.

Effect of ibutilide, a new class III agent, on sustained atrial fibrillation in a canine model of acute ischemia and myocardial dysfunction induced by microembolization.

The effect of ibutilide, a new Class III antiarrhythmic agent, upon acute onset atrial fibrillation was investigated in a closed-chest canine model of acute left ventricular (LV) dysfunction. Twenty-four anesthetized mongrel dogs, mean weight 24.9 +/- 4 kg were subjected to coronary artery microsphere embolization and volume loading, followed by attempted induction of atrial fibrillation (AF) by rapid atrial pacing. Acute ischemic LV dysfunction was successfully induced by embolization in all dogs, and caused significant (P < 0.02) decreases in LV systolic pressure, peak + dp/dt (and -dp/dt), stroke volume, and RR interval; whereas LV end diastolic pressure and QTc significantly increased. Sustained AF (> or = 30 min) was successfully induced in 15 of 24 dogs (62%) and unsustained AF (< 30 min) was induced in the remainder (38%). At 30 minutes after induction of sustained AF, 15 dogs were randomized to intravenous ibutilide (0.15 mg/kg, given as a 0.075 mg/kg bolus, followed by 0.075 mg/kg infusion over 1 hour; n = 7) or placebo (saline; n = 8). There were no statistically significant differences between the ibutilide and the placebo groups with respect to mean LV systolic pressure, LV end diastolic pressure, LV dp/dt, RR interval, or QTc interval during AF prior to infusion. All seven dogs receiving ibutilide converted to sinus rhythm after a median of 3 minutes (range 0.5-26 min), while only three of eight placebo dogs (P < 0.03) converted to sinus rhythm after a median duration of 30 minutes (range 15-60 min) (P < 0.04 for difference in time to conversion).(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental model of chronic global left ventricular dysfunction secondary to left coronary microembolization.

A model of chronic left ventricular dysfunction characterized by left ventricular dilation, elevated filling pressures and histologic changes has been lacking. In this study the use of coronary microsphere embolization-induced ischemia was explored as a method of producing chronic left ventricular dysfunction. Acute ischemic left ventricular dysfunction was induced in 13 mongrel dogs with 50 microns plastic microspheres until the peak positive first derivative of left ventricular pressure (dP/dt) decreased by 25% and the left ventricular end-diastolic pressure increased to greater than or equal to 12 mm Hg. After 8 weeks of observation, hemodynamic and echocardiographic variables were measured in each dog. Acute left ventricular dysfunction resulted in a dilated left ventricle with systolic dysfunction (area ejection fraction 24 +/- 6% vs. 57 +/- 9% initially, p less than 0.01) and elevated left ventricular filling pressures. Isovolumetric relaxation was prolonged and the peak rapid filling/atrial filling velocity and integral ratios were reduced. Eight weeks after embolization, there was an increased left ventricular size (end-diastolic area 15.1 +/- 2.1 cm2 at 8 weeks vs. 13.5 +/- 1.4 cm2 early after microsphere injection, p less than 0.05), unchanged end-systolic area, improved area ejection fraction and increased left ventricular mass. Left ventricular end-diastolic pressure increased and, despite continued abnormal relaxation, the peak rapid filling/atrial filling velocity and integral ratios increased to above baseline values, demonstrating a "restrictive" pattern. Gross and histologic examination revealed diffuse, patchy scarring associated with perivascular fibrosis. Thus, coronary microsphere embolization resulted in a model of chronic moderate left ventricular systolic dysfunction and abnormal diastolic function characterized by a "restrictive" filling pattern.

The systemic and local effects of an intramedullary injection of methylprednisolone acetate in growing rabbits.

Intramedullary injection of methylprednisolone acetate (Depo-Medrol) is successful in the treatment of children with unicameral cysts, but its mechanism of action remains obscure. Using a rabbit model, methylprednisolone was injected into the intramedullary canal of the left proximal tibia. Normal saline was injected into the right proximal tibia as a control. Venous blood samples following injection revealed that corticosteroid was rapidly cleared from bone. Serum methylprednisolone levels rose rapidly, giving a dose-response curve similar to that after an intramuscular injection in humans. Rabbits were killed and analyzed histologically for local changes. There was no fibroblastic proliferation, neovascularization, or other histologic change secondary to injection.

Effect of cervical spinal cord hemisection and hemidiaphragm paralysis on arterial blood gases, pH, and respiratory rate in the adult rat.

We documented the changes that occur in arterial blood gases, pH, and respiratory rate in rats subjected to a C2 spinal cord hemisection which results in paralysis of the ipsilateral hemidiaphragm. The results indicated that rats compensate for hemidiaphragm paralysis by maintaining arterial pO2 through an increased rate of respiration. This observation is of interest because it implies a form of functional recovery from spinal cord injury which has heretofore not been demonstrated.