J. Kevin Drury

Myocardial contrast two-dimensional echocardiography: Experimental examination at different coronary flow levels

Regional myocardial echo contrast appearance-disappearance after intracoronary contrast agent injection was examined with computerized two-dimensional contrast echocardiography in eight open chest dogs during successive variation of the coronary blood supply. A new sonication method applied to dextrose 50% produced an echo contrast agent with a microbubble size of 12 +/- 6 mu (mean +/- standard deviation), and 1 cc of this agent was injected into a coronary artery during the echocardiographic study of the left ventricle. Left anterior descending or circumflex coronary artery flow, measured by electromagnetic flowmeter, was successively reduced up to 90% with an extravascular hydraulic occluder, or else increased 40 to 60% through intravenous dipyridamole infusion (7 to 10 micrograms/kg per min). The corresponding myocardial echo time-intensity curves were analyzed for each of 12 segments of a midventricular short-axis cross section. Several potential indexes of myocardial perfusion were derived: peak echo contrast intensity, time from echo contrast appearance to peak intensity, half-life of echo contrast decay phase (T 1/2) and total duration of contrast appearance-disappearance. Except for peak intensity, all of these indexes provided significant (p less than 0.05) differentiation between control coronary flow (66 +/- 17 ml/min) and greater than 50% flow reductions (26 +/- 6 ml/min) or hyperemia (115 +/- 17 ml/min). Half-life values were 5.2 +/- 0.3 seconds for the control state, 9 +/- 2 seconds for the reduced coronary flow and 2 +/- 2 seconds for dipyridamole hyperemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Synchronized diastolic coronary venous retroperfusion: Results of a preclinical safety and efficacy study

The safety and efficacy of a new clinical synchronized diastolic retroperfusion mechanical pump and autoinflatable balloon catheter was studied in 10 dogs during and after 6 hours of left anterior descending coronary artery occlusion. Eight other dogs served as the untreated control group. Infarct size measured by triphenyltetrazolium chloride, and expressed as a percent of area at risk, was significantly reduced by retroperfusion treatment (19 +/- 18 versus 58 +/- 36, p less than 0.01). Morphologic examination of the coronary sinus and cardiac veins did not demonstrate evidence of damage from synchronized retroperfusion. There was also no evidence of excess myocardial edema in either the jeopardized ischemic or normally perfused zones. There was no evidence of significant red cell hemolysis or platelet destruction from the treatment. Thus, it appears that synchronized diastolic retroperfusion is a safe and effective treatment of acute myocardial ischemia in experimental animals and warrants clinical testing.

Pharmacokinetic analysis of coronary venous retroinfusion: A comparison with anterograde coronary artery drug administration using metoprolol as a tracer☆

Plasma and myocardial tissue concentrations of metoprolol were studied in ischemic and nonischemic areas of 22 pigs after 90 (n = 19) and 16 (n = 3) min of left anterior descending coronary artery occlusion. Group A (n = 6) received simultaneous intravenous metoprolol (0.2 mg/kg body weight) and tritium-labeled (3H)-metoprolol (0.2 mg/kg) retrogradely into the coronary vein. In group B (n = 5), metoprolol and 3H-metoprolol were administered in the same way, but at half the volume to study the influence of derived coronary venous pressure on the myocardial concentration of drug. In group C (n = 3), metoprolol was given retrogradely and saline solution was infused into the left anterior descending artery before induced death to wash out metoprolol from the coronary veins. To rule out a possible influence of the development of myocardial necrosis on drug distribution, metoprolol was retroinfused after 1 min of arterial occlusion in three pigs (group D). In group E (n = 5), metoprolol (0.2 mg/kg) was infused anterogradely into the left anterior descending artery. Peak plasma concentration was significantly higher after intravenous infusion of metoprolol (1,188 +/- 503 nmol/liter) than after coronary venous infusion (417 +/- 155 nmol/liter; p less than 0.001). In groups A and B, the nonischemic myocardial concentration of metoprolol was 250 to 300 pmol/g, whether the drug was infused intravenously or into the coronary vein. Coronary venous retroinfusion, however, resulted in a substantial accumulation of metoprolol in the ischemic myocardium. In group A pigs, subendocardial myocardial concentration was 16,800 +/- 7,774, mid-myocardial 39,590 +/- 18,043 and subepicardial 57,143 +/- 29,030 pmol/g (mean +/- SE). The ischemic myocardial concentration in pigs from group B was somewhat less pronounced, probably secondary to a lower coronary venous pressure (15 +/- 3 mm Hg) with the lower volume of infusion (6.1 +/- 0.3 ml) in group B compared with 32 +/- 5 mm Hg with a 14 +/- 1 ml infusion in group A. Coronary artery anterograde administration resulted in myocardial ischemic and nonischemic zone drug concentrations similar to those observed after retroinfusion into the coronary vein. With both modes of administration, there was a transmyocardial gradient from a somewhat lower drug concentration in the subendocardium, toward an increasing level in the mid-myocardium, to the highest concentration in the subepicardial zone of the ischemic myocardium. Coronary venous retroinfusion resulted in pronounced drug accumulation in the ischemic myocardium. The derived coronary venous pressure during infusion influenced the concentration of drug.(ABSTRACT TRUNCATED AT 400 WORDS)

Coronary venous retroinfusion of procainamide: A new approach for the management of spontaneous and inducible sustained ventricular tachycardia during myocardial infarction

The efficacy of retrograde coronary venous delivery of procainamide for the management of spontaneous and inducible sustained ventricular tachycardia was evaluated and compared with systemic intravenous procainamide administration in 22 conscious dogs with permanent left anterior descending coronary artery occlusion. Selective retrograde injection of procainamide was achieved through an autoinflatable balloon catheter placed in the great cardiac vein, with the tip positioned in the vicinity of the site of left anterior descending coronary occlusion. Great cardiac vein retroinfusion of procainamide was significantly (p less than 0.05) more effective than systemic intravenous injection against spontaneous ventricular tachycardia 1 day after coronary artery occlusion (13 dogs) and against electrically induced sustained ventricular tachycardia in the 3 to 12 day postocclusion period (9 dogs). Significantly lower doses of procainamide were used with retroinfusion as compared with systemic administration, that is, 19.6 +/- 8.8 versus 35 +/- 0 mg/kg body weight during spontaneous tachycardia and 13.4 +/- 4.1 versus 32.1 +/- 2 mg/kg during induced tachycardia (p less than 0.01). Retroinfusion of saline solution through the great cardiac vein had no effect on either type of tachycardia. Myocardial tissue procainamide levels measured in infarcted and ischemic zones of the left anterior ventricular wall were 9 to 100 times higher after great cardiac vein retroinfusion than after systemic injection. Great cardiac vein dye injection studies demonstrated a preferential distribution in left ventricular regions supplied by the occluded coronary artery. It is concluded that regional coronary venous procainamide retroinfusion in dogs with myocardial infarction is more effective than systemic intravenous injection against both spontaneous and inducible sustained ventricular tachycardia. The greater efficacy of great cardiac vein treatment appears to be primarily related to selectively increased delivery of procainamide to ischemic myocardial sites.

Synchronized coronary venous retroperfusion for support and salvage of ischemic myocardium during elective and failed angioplasty

To determine the safety and efficacy of synchronized coronary venous retroperfusion during brief periods of ischemia, 30 patients undergoing angioplasty of the left anterior descending coronary artery were studied. Each patient underwent a minimum of two angioplasty balloon inflations. Alternate dilations were supported with retroperfusion; the unsupported inflations served as the control inflations. Synchronized retroperfusion was performed by pumping autologous femoral artery blood by means of an electrocardiogram-triggered retroperfusion pump into the great cardiac vein through a triple lumen 8.5F balloon-tipped retroperfusion catheter inserted percutaneously from the right internal jugular vein. Clinical symptoms, hemodynamics and two-dimensional echocardiographic wall motion abnormalities were analyzed. Retroperfusion was associated with a lower angina severity score (0.8 +/- 1 vs. 1.2 +/- 1) and delay in onset of angina (53 +/- 31 vs. 37 +/- 14 s; p less than 0.05) compared with the control inflations. The magnitude of ST segment change was 0.11 +/- 0.14 mV with retroperfusion and 0.16 +/- 0.17 mV without treatment (p less than 0.05). The severity of left ventricular wall motion abnormality was also significantly (p less than 0.01) reduced with retroperfusion compared with control (0.7 +/- 1.4 [hypokinesia] vs. -0.3 +/- 1.6 [dyskinesia]). There were no significant changes in hemodynamics, except in mean coronary venous pressure, which increased from 8 +/- 3 mm Hg at baseline to 13 +/- 6 mm Hg with retroperfusion. Four patients required prolonged retroperfusion for treatment of angioplasty-induced complications. The mean retroperfusion duration in these patients was 4 +/- 2 h (range 2 to 7). In the three patients who underwent emergency bypass surgery, the coronary sinus was directly visualized during surgery and found to be without significant injury. There were no major complications. Minor adverse effects were transient atrial fibrillation (n = 2), jugular venous catheter insertion site hematomas (n = 4) and atrial wall staining (n = 1), all of which subsided spontaneously. Thus, retroperfusion significantly reduced and delayed the onset of coronary angioplasty-induced myocardial ischemia and provided effective supportive therapy for failed and complicated angioplasty.

Enhanced myocardial washout and retrograde blood delivery with synchronized retroperfusion during acute myocardial ischemia

The effects of synchronized coronary venous retroperfusion of arterial blood on myocardial washout were studied with digital subtraction angiography in 10 closed chest dogs during balloon occlusion of the proximal left anterior descending coronary artery. The center lumen of the intracoronary balloon catheter was used for sequential injections of 1 ml (meglumine diatrizoate) Renografin-76, and contrast washout rate was determined by videodensitometry in myocardial regions subserved by the left anterior descending coronary artery. Before coronary artery occlusion, washout rate was 22.4 +/- 2.7 min-1 (mean +/- SEM). Five minutes after occlusion, and immediately before synchronized retroperfusion, washout rate dropped sharply to 2.0 +/- 0.7 min-1. Twenty-five minutes after occlusion, with 50 ml/min synchronized retroperfusion treatment applied for 5 minutes, washout rate was 5.0 +/- 1.5 min-1. Thus, synchronized retroperfusion significantly (p less than 0.05) accelerated contrast disappearance over that during presynchronized retroperfusion ischemia. To determine the effects of synchronized retroperfusion on retrograde delivery to the ischemic myocardium, monastral blue dye was retroinfused through the system into the great cardiac vein before the dog was killed. Transverse heart slices were then studied by light microscopy, and regional intravascular dye content was scored from 0 to 3 (0 = no dye, 3 = maximal dye). After great cardiac vein synchronized retroperfusion, blue dye content in capillaries of ischemic anterior and nonischemic posterior aspects of the left ventricle was 2.3 +/- 0.5 versus 0.7 +/- 0.3, respectively (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Synchronized coronary venous tetroperfusion: Prompt improvement of left ventricular function in experimental myocardial ischemia

The effect of synchronized coronary venous retroperfusion of arterial blood on cardiac function after experimental coronary occlusion was examined by two-dimensional echocardiography. In 18 closed chest anesthetized dogs, the proximal left anterior descending coronary artery was occluded for 6 hours with an intracoronary balloon catheter. Eight of these animals served as untreated controls. Ten were treated with synchronized retroperfusion initiated 30 minutes after occlusion, and treatment was interrupted for 5 minutes at 1 hour after occlusion for study of the rapidity of retroperfusion response. Quantitative echographic analysis yielded global ejection fraction and regional indexes of contraction in a low left ventricular short-axis section, including segmental systolic area change, systolic wall thickening and end-diastolic wall thickness. At 6 hours after occlusion, ejection fraction had decreased from 50.7 +/- 4.9% to 28.1 +/- 7.7% (mean +/- standard deviation) in control dogs, but was significantly (p less than 0.01) less depressed in treated dogs (from 55.9 +/- 5.2 to 41.8 +/- 9.3%). The ischemic zone fractional area change at 30 minutes of occlusion exhibited a marked depression in both groups, after which the dysfunction persisted in the control dogs, but was largely reversed with retroperfusion from 6.0 +/- 6.5 to 35.9 +/- 15.9% at 6 hours of occlusion (p less than 0.01). Brief interruption of retroperfusion 1 hour after occlusion reduced ischemic zone fractional area change from 33.0 +/- 14.9 to 12.2 +/- 9.5% (p less than 0.01). This depression was promptly reversed to 33.6 +/- 12.2% when retroperfusion was resumed. Segmental wall thickening followed a similar trend.(ABSTRACT TRUNCATED AT 250 WORDS)

Differences in infarct size with lidocaine as compared with bretylium tosylate in acute myocardial ischemia and reperfusion in pigs

Summary: The effects of the antiarrhythmic drugs lidocaine and bretylium tosylate on myocardial necrosis were studied in anesthetized pigs subjected to 60-min coronary occlusion followed by 3-h reperfusion. Group A (n = 7) received lidocaine (average dose × SD = 1,828 × 515 mg) before and during coronary occlusion and after reperfusion; the other series (group B, n = 7) received bretylium tosylate (3,457 × 1,323 mg). Infarct size was 16.3 × 14.7% in the lidocaine group as compared with 68.6 × 12.6% (p < 0.01) in the bretylium group. In vitro release of superoxide anion from porcine granulocytes was studied using the lucigenin-dependent chemiluminescence technique. Lidocaine significantly reduced the peak chemiluminescence response to zymosan from 3.34 × 0.44 without lidocaine to 2.23 × 0.46 (p < 0.01) and 1.06 × 0.17 mV (p < 0.001), with lidocaine concentrations of 20 and 200 μg/ml, respectively. Bretylium had no effect on the chemiluminescence response. Adherence of porcine granulocytes to plastic was also reduced from 332 × 32 cells/mm2 (no lidocaine) to 247 × 35 and 206 × 26 cells/mm2 with lidocaine concentrations of 20 and 200 μg/ml, respectively (p < 0.001). Bretylium had no significant effect. Eight additional bretylium-treated pigs received either rabbit antiporcine granulocyte serum (group C, n = 4) to reduce circulating granulocytes or nonimmune serum (group D, n = 4). Infarct size in the granulocyte-depleted pigs was 26.6 × 5.6% as compared with 51.4 × 5.5% in pigs that received nonimmune serum (p < 0.01). Smaller infarct size with lidocaine as compared with bretylium tosylate therapy is associated with decreased adherence of granulocytes to vascular endothelium in the ischemic myocardium and inhibition of superoxide anion release.

Purification and properties of porcine polymorphonuclear cells

A method for the rapid separation of highly purified populations of porcine polymorphonuclear cells from whole blood is described. Porcine blood, anti-coagulated with EDTA, was layered over a discontinuous Percoll gradient (62.5% and 75%) and then centrifuged at 400 X g for 25 min. This results in the formation of a band of cells at the interface of the two Percoll layers which is greater than 99% granulocytes (93.8 +/- 1.8% neutrophils and 5.3 +/- 1.8% eosinophils) with a 77% recovery. The mononuclear cells remain above the 62.5% Percoll layer, and most erythrocytes pellet to the bottom of the tube. The isolated porcine granulocytes were found to respond to opsonized zymosan, phorbol myristate acetate (20 ng/ml), and the calcium ionophore A23187 (10(-5) M) in chemiluminescence assays with kinetics similar to those of human granulocytes. The porcine cells did not respond to the chemotactic peptide N-formyl-methionyl-leucyl-phenalanine (FMLP; 10(-6) M) unlike the human granulocytes which display a very rapid response to FMLP. Both porcine and human granulocytes readily changed shape by elongating and developing pseudopods when exposed to zymosan-activated serum, but only human granulocytes changed on exposure to FMLP. Thus, porcine granulocytes may be rapidly isolated on discontinuous Percoll gradients with little mononuclear cell contamination. Porcine and human PMN have similar oxidative and chemotactic responses, but porcine PMN differ from human granulocytes in the inability of porcine granulocytes to respond to FMLP.