Effects of diastolic synchronized retroperfusion on regional coronary blood flow in experimental myocardial ischemia

Coronary venous retroperfusion has previously been suggested as a potential mode of treatment of myocardial ischemia. This study was designed to examine the actual changes in regional myocardial blood flow that occur with diastolic synchronized retroperfusion of the coronary sinus. Coronary sinus retroperfusion consisted of (1) diastolic augmentation of delivery of arterial blood into the acutely ischemic myocardium, and (2) systolic facilitation of coronary venous drainage. This was achieved using a gas-actuated electrocardiogram-synchronized retroperfusion pump that propels arterial blood during diastole through an autoinflatable bladder catheter. Hemodynamic data and measurements of ischemic tissue injury (S-T segment mapping) and regional myocardial blood flow (radioactive microsphere technique) were obtained before and after 1 and 2 hours of coronary arterial occlusion. Experiments were performed in 19 open chest dogs: Retroperfusion was instituted after the 1st hour of coronary occlusion and maintained for the subsequent hour in 8 dogs and the results were compared with those obtained in 6 randomly selected untreated dogs. In five additional dogs, the fraction of microspheres escaping myocardial entrapment in either an anterograde or a retrograde direction was determined. In both treated and untreated dogs, changes in hemodynamics, S-T segment mapping and regional myocardial blood flow showed the same trend up to 1 hour of coronary occlusion. Synchronized retroperfusion resulted in a minor but significant decrease in heart rate and an increase in stroke volume. As early as 15 minutes after the start of synchronized retroperfusion, there was a significant decrease in S-T segment elevation (from 5.95 ± 1.01 to 3.09 ± 0.58 mV [mean ± standard error of the mean], p <0.01) that was maintained for the subsequent hour; in the control series, S-T segment elevation was unaffected. After 1 hour of retroperfusion, regional transmural flow increased in the nonischemic zone from 0.84 ± 0.07 to 1.05 ± 0.10 ml/min per g (p <0.05) with an unchanged $\text{endocardial}\text{epicardial}$ flow ratio (1.10 ± 0.04 and 1.11 ± 0.04 before and 1 hour after treatment, respectively). In the ischemic zone, 1 hour of retroperfusion increased transmural flow by 59.3 percent (from 0.32 ± 0.05 to 0.51 ± 0.04 ml/min per g, p <0.05) with a greater increase in endocardial flow (from 0.19 ± 0.02 to 0.35 ± 0.03 ml/min per g, p <0.05) than in epicardial flow (from 0.43 ± 0.05 to 0.59 ± 0.06 ml/min per g, p <0.01) leading to a significant increase in $\text{endocardial}\text{epicardial}$ flow ratio (from 0.46 ± 0.05 to 0.64 ± 0.07, p <0.01).These experimental data show that retroperfused arterial blood reaches the ischemic as well as the nonischemic zones and is favorably redistributed toward the endocardium. Thus, diastolic synchronized retroperfusion is capable of restoring nutritional blood flow to approximately 50 percent of normal control flow. This improvement in myocardial perfusion might be of value in delaying irreversible myocardial ischemia.     

Diastolic retroperfusion of acutely ischemic myocardium.

The effectiveness of coronary venous retroperfusion treatment of an ischemic myocardial segment was assessed by measurements of regional and global myocardial function in 16 dogs. The left anterior descending coronary artery was acutely occluded for 75 minutes. After the first 30 minutes of occlusion, diastolic retroperfusion was instituted for 45 minutes by synchronized pumping of arterial blood from the brachial artery into the anterior interventricular coronary vein. Data collected in the preocclusion control period, during occlusion and the subsequent retroperfusion period included simultaneous measurement os ischemic and border zone myocardial forces, epicardial electrocardiographic S-T segments, intracoronary pressure, coronary blood flow and oxygen pressure (PO2) sampled distal to the site of occlusion. Retroperfusion resulted in significant improvement from the level of regional dysfunction observed after 30 minutes of occlusion: Ischemic zone myocardial force increased 106%, epicardial S-T elevation decreased 46%, normalized peripheral left anterior descending coronary arterial flow increased 50% and distal left anterior descending PO2 decreased 44%. These regional improvements were significant when compared with findings in an untreated series of 12 dogs with 75 minutes occlusion of the left anterior descending coronary artery. Diastolic-augmented coronary venous retroperfusion with arterial blood provided significant but not complete restoration of function in the ischemic segment. Therefore, in the earliest phase of acute myocardial infarction, retroperfusion might represent a useful temporary support to an otherwise inaccessible jeopardized zone of the heart. Regional retroperfusion may constitute an effective emergency procedure, particularly when the occlusive lesions are diffuse and other medical or surgical emergency procedures are inadvisable, unavailable or ineffective.     

Effects of hypoxemia on the extent of myocardial necrosis after experimental coronary occlusion

Arterial oxygen tension is variable in patients with acute myocardial infarction, and the effect of hypoxemia on the extent of myocardial necrosis after coronary occlusion has not been defined. In 11 anesthetized open chest dogs the left anterior descending coronary artery or one of its major branches was occluded for 20 minutes, and 10 to 15 epicardial electrocardiographic leads were recorded in the distribution and vicinity of the site of occlusion. Average S-T segment elevation and the number of sites showing S-T segment elevation greater than 2 mv, 15 minutes after occlusion were used as indexes of the severity and extent of ischemic injury. After occlusion with an inspired oxygen concentration of 20 percent these indexes were, respectively, 2.0 ± 0.5 mv (mean ± standard error) and 3.6 ± 0.8 sites; the respective values increased to 3.3 ± 0.5 mv (P < 0.01) and 6.7 ± 0.7 sites (P < 0.01) after occlusion with an inspired oxygen concentration of 10 percent, and arterial partial pressure of oxygen decreased from 92 ± 5 to 45 ± 3 mm Hg. In 23 dogs the occlusion was maintained for 24 hours and the S-T segment elevation 15 minutes after occlusion was compared with myocardial creatlne phosphokinase (CPK) activity and histologic appearance 24 hours later. In control dogs (inspired oxygen concentration of 20 percent) sites with no S-T segment elevation 15 minutes after occlusion showed normal myocardial CPK activity 24 hours later, whereas in sites with S-T segment elevation exceeding 2 mv there was an inverse relation between S-T segment elevation in each site and its myocardial CPK activity 24 hours later. Histologic examination revealed early myocardial necrosis in 98 percent (82 of 84) of sites with S-T segment elevation greater than 2 mv. In experimental dogs (inhaling a 10 percent Oxygen concentration for the first 8 of the 24 hours of occlusion) many sites that showed no S-T segment elevation before hypoxemia was induced exhibited S-T segment elevations 30 minutes later and showed abnormally low CPK activity and histologic evidence of early necrosis. We conclude that after experimental coronary occlusion, hypoxemia is deleterious because it substantially increases myocardial damage.     

Coronary steal-induced increase in myocardial infarct size after pharmacologic coronary vasodilation

This study was performed to determine if maximal coronary arterial vasodilation of nonischemlc areas would produce an increase in myocardial infarct size through a “steal” of collateral flow from an ischemic region. Myocardial infarction was produced by a 2 hour occlusion and reperfusion of the distal left anterior descending coronary artery in anesthetized dogs. Five minutes after occlusion, 7 dogs were given saline solution, and in 12 dogs the coronary vasodilator chromonar (8 mg/kg, intravenously) was administered. Chromonar produced a significant Increase (p < 0.05) in blood flow to nonischemic regions and a concomitant decrease in flow to ischemic areas. Associated with these changes in flow was an elevation in total release and peak plasma creatine kinase compared with values in saline-treated control dogs. Myocardial infarct size determined with nitroblue tetrazolium staining was significantly increased (p < 0.05). These data demonstrate that maximal coronary vasodilation of nonischemic areas can result in an extension of myocardial infarction by a steal of collateral flow away from the ischemic region.     

Effects of ortho-iodo sodium benzoate on acute myocardial ischemia, hemodynamic function, and infarct size after coronary artery occlusion in dogs

Ortho-iodo sodium benzoate (OISB) decreases the affinity of blood for oxygen, thus enhancing potential tissue oxygen delivery. To test the hypothesis that a change in oxygen affinity would ameliorate regional myocardial ischemic injury resulting from occlusion of the left anterior descending (LAD) coronary artery, experiments were carried out in 55 anesthetized dogs which received an intravenous infusion of OISB. In Protocol I studies (n = 9), preocclusion intravenous infusion of OISB (500 mg/kg) reduced epicardial S-T segment elevation 15 minutes after coronary occlusion, while a similar volume of normal saline solution did not affect this index of ischemic damage. In Protocol II experiments, 34 dogs were randomized to either an OISB or saline group, after which the LAD was ligated, the chest closed, and the animal allowed to recover from anesthesia. Myocardial infarction (MI) size was assessed after the animal died or was killed 8 to 24 hours later, and was found to be 29% smaller in dogs receiving OISB. In 6 dogs, blood P50 (the partial oxygen pressure at which hemoglobin is 50% saturated with oxygen) was increased by OISB infusion, confirming that its administration effected a rightward shift in the oxyhemoglobin dissociation curve. Protocol III studies assessed the effects of OISB on cardiac hemodynamic function and acute myocardial ischemic damage when infusion was begun 15 minutes after LAD occlusion: average epicardial S-T segment elevation was not altered by saline solution, but decreased when OISB was infused during the last 15 minutes of myocardial ischemia. Reductions in heart rate, left ventricular dP/dt, and cardiac output were observed in 7 dogs during OISB infusion, but there were no changes in these measurements during coronary occlusion in 5 dogs receiving a constant infusion of saline solution. There were no changes in regional myocardial blood flow (microsphere technique) to either ischemic or nonischemic zones in either the saline control or OISB treatment groups. Thus, both acute myocardial ischemic injury (assessed by epicardial electrocardiographic mapping) and ultimate MI size are reduced when OISB is infused before experimental coronary artery occlusion. OISB also reduces myocardial ischemic injury when its administration is begun 15 minutes after coronary occlusion, while effecting decreases in heart rate, left ventricular contractility, and cardiac output.     

Nitroprusside therapy in acute and chronic coronary heart disease

To elucidate the effects of nitroprusside on the relations between systemic pressure, coronary blood flow and regional myocardial ischemia, dogs were subjected to constriction of the proximal left anterior descending (LAD) artery to induce ischemia determined by intramyocardial S-T segments and intramyocardial mass spectrometric oxygen tension (PO₂) and carbon dioxide tension (PCO₂). Nitroprusside was infused to incrementally lower mean blood pressure from 137 to 62 mm Hg. A decrease in mean blood pressure to 87 mm Hg lowered (p < 0.05) intramyocardial S-T segment elevations and diminished left ventricular filling pressure, but it did not alter (p > 0.05) poststenotic flow in the LAD artery, intramyocardial PCO₂ and PO₂, and cardiac oxygen uptake. With a further decrease in systemic arterial blood pressure below normal, S-T segments rose, LAD artery flow decreased, intramyocardial PCO₂ increased and intramyocardial PO₂ decreased. In addition, 12 patients with acute anterior infarction had 35-lead S-T segment maps before and after a 10 minute infusion of nitroprusside. Heart rate was unchanged, left ventricular pressure decreased from 139/19 to 115/11 mm Hg (p < 0.01), cardiac index was maintained, S-T segment sum was lowered from 42 to 29 mm (p < 0.001) and mean S-T segment elevation declined from 1.6 to 1.2 mm/lead (p < 0.001). Thus, modest nitroprusside-induced reduction in blood pressure has beneficial effects on multiple indices of experimental and clinical regional ischemia. In contrast, a further decrease in blood pressure below normal lowers poststenotic coronary blood flow and thereby ischemia worsens.     

Antiarrhythmic and hemodynamic effects of calcium channel blocking agents during coronary arterial reperfusion: Comparative effects of verapamil and nifedipine

To determine the comparative actions of the calcium channel blocking agents verapamil and nifedipine on coronary flow and ventricular arrhythmias during myocardial reperfusion, 24 open chest dogs underwent proximal occlusion of the left anterior descending coronary artery. Regional myocardial blood flow (ml/mln per 100 g) was quantltated by microspheres (strontium [⁸⁵Sr]and cerium [¹⁴¹Ce]) 20 minutes after coronary occlusion and 10 minutes after reperfusion. Dogs were randomly assigned to one of three groups 20 minutes after coronary occlusion: (1) control group (n = 8); (2) dogs given intravenous verapamil (n = 8), 0.2 mg/kg body weight in 5 minutes followed by an infusion of 0.01 mg/kg per min; or (3) dogs given nifedipine (n = 8), 100 μg/kg in 5 minutes followed by an infusion of 3 μg/kg per min. Ten minutes after reperfusion, transmural regional myocardial blood flow in the ischemic zone was unchanged by verapamil and nifedipine (p = not significant [NS]versus control value). The endocardial/epicardial ratio in the hyperemlc zone tended to be lowered by the calcium blocking agents compared with that observed in control animals. Coronary resistance during reperfusion was similar (p = NS) in animals treated with verapamil and nifedipine.Ventricular tachycardia or fibrillation occurred in six dogs In the control group (tachycardia in three and fibrillation in three). Among dogs given verapamil, none had ventricular tachycardia and one of eight had ventricular fibrillation (p <0.05 versus control value). Four of the eight dogs given nifedipine, had ventricular tachycardia (two dogs) or fibrillation (two dogs) (p = NS versus control and verapamil values). Thus, verapamil and nifedipine had similar effects on central and coronary hemodynamics during myocardial reperfusion. However, verapamil, in contrast to nifedipine, decreased reperfusion ventricular arrhythmias. These data suggest that despite similar calcium channel blocking actions, verapamil and nifedipine possess different antiarrhythmic effects.     

Derangements of myocardial metabolism preceding onset of ventricular fibrillation after coronary occlusion

To determine alterations in myocardial metabolism and and hemodynamics that occur within the first 30 minutes after coronary arterial occlusion, before the onset of ventricular fibrillation, measurements were compared in two series of dogs. Series A, 90 dogs that did not manifest ventricular fibrillation after coronary occlusion, were considered a control group. Series B consisted of 28 dogs that had ventricular fibrillation within 30 minutes after occlusion. All had similar comprehensive measurements completed preceding the onset of ventricular fibrillation. The animals in series B (subseuqnt fibrillation) had significantly higher heart rates before and after coronary occlusion. In this series cardiac metabolism of the occluded segment judged by transmyocardial lactate extraction, potassium balance, sodium/potassium ratio and blood pH because grossly more abnormal after coronary occlusion than in series A. In 5 animals whose measurements were obtained within 5 minutes of the onset of ventricular fibrillation, a sudden massive lactate production, potassium loss and increased acidosis of the occluded portion supervened minutes before the onset of the fatal arrhythmia. Animals with ventricular fibrillation had higher intracoronary S-T segment elevation that persisted until the onset of ventricular fibrillation. Measurements of abnormal hemodynamic function (left ventricular end-diastolic pressure, peak systolic pressure and first derivative of left ventricular pressure [DP/dt]) were not associated with an increased incidence of ventricular fibrillation. The study indicates that animals that manifest ventricular fibrillation within 30 minutes after coronary occlusion have higher preocclusion heart rates, a more severe metabolic disorder of the coronary occluded segment and more persistent intracoronary S-T segment elevation compared with animals that do not manifest ventricular fibrillation.     

Diastolic synchronized retroperfusion versus reperfusion: effects on regional left ventricular function and myocardial blood flow during acute coronary occlusion in dogs

The effects of 170 minutes of diastolic synchronized retroperfusion of the coronary sinus with arterial blood during 180 minutes of coronary artery occlusion on regional myocardial contractility (ultrasonic crystals) and blood flow (microspheres) were investigated in open-chest dogs. These effects were compared with those of 180 minutes of coronary occlusion and those of 170 minutes of anterograde reperfusion after 10 minutes of coronary occlusion in separate groups of dogs. Retroperfusion was able to almost restore transmural blood flow in the moderately ischemic zones and to increase it back to 47% of its preocclusion value in the severely ischemic zones with, in both zones, a favorable redistribution of flow toward the endocardium. Simultaneously, retroperfusion significantly improved segment length shortening in the moderately ischemic zones and significantly reduced the extent of paradoxical bulging in the severely ischemic zones. These partial recoveries in regional contractility and blood flow during retroperfusion were intermediate between those induced by 170 minutes of anterograde reperfusion and those of 180 minutes of coronary artery occlusion. Thus, in the presence of coronary artery occlusion, retroperfusion appears to exert a beneficial effect by improving both regional perfusion and function in the ischemic zones and may be proposed as a medical circulatory support to the jeopardized myocardium.     

Intermittent coronary sinus occlusion after coronary arterial ligation results in venous retroperfusion

Coronary sinus occlusion retards necrosis of ischemic myocardium. To test the hypothesis that coronary sinus occlusion induces retrograde venoarterial flow, the coronary arteriovenous pressure gradient and the coronary arterial oxygen saturation were measured distal to a left anterior descending coronary artery ligature in dogs. In parallel, we constructed a mathematical model of known coronary physiology to characterize pressure and flow patterns during coronary sinus occlusion. In dogs, coronary sinus occlusion produced a systolic pressure gradient between the coronary artery and the coronary sinus of -20 +/- 9 mm Hg (higher venous pressure, p less than 0.0001) and a positive diastolic gradient of 3 +/- 5 mm Hg (lower venous pressure p less than 0.01). An average reduction in the oxygen saturation in the ligated coronary artery of 20 +/- 13% was also observed (p less than 0.005) consequent to admixture of venous (desaturated) blood. By graded inflation of the coronary sinus balloon, it was demonstrated that desaturation of arterial blood typically occurs above a coronary sinus systolic pressure of 40-50 mm Hg. The mathematical model indicates the possibility of venoarterial pressure gradients and reversal of flow at the microcirculatory level during coronary sinus occlusion. These studies provide evidence that retrograde flow into the ischemic zone occurs in association with intermittent coronary sinus occlusion. Thus, alternating flow over the ischemic territory may be the mechanism of myocardial salvage during intermittent coronary sinus occlusion.     

Regional myocardial blood flow and left ventricular diastolic properties in pacing-induced ischemia

The relation between left ventricular diastolic abnormalities and myocardial blood flow during ischemia was studied in eight open chest dogs with critical stenoses of the proximal left anterior descending and circumflex coronary arteries. The heart was paced at 1.7 times the heart rate at rest for 3 min. In dogs with coronary stenoses, left ventricular end-diastolic pressure increased from 8 +/- 1 to 14 +/- 2 mm Hg during pacing tachycardia (p less than 0.01) and 16 +/- 3 mm Hg (p less than 0.01) after pacing, with increased end-diastolic and end-systolic segment lengths in the ischemic regions. Left ventricular diastolic pressure-segment length relations for ischemic regions shifted upward during and after pacing tachycardia in dogs with coronary stenoses, indicating decreased regional diastolic distensibility. In dogs without coronary stenoses, the left ventricular diastolic pressure-segment length relation was unaltered. Pacing tachycardia without coronary stenoses induced an increase in anterograde coronary blood flow (assessed by flow meter) in both the left anterior descending and circumflex coronary arteries, and a decrease in regional vascular resistance. In dogs with coronary stenoses, regional vascular resistance before pacing was decreased by 18%; myocardial blood flow (assessed by microspheres) was unchanged in both the left anterior descending and circumflex coronary artery territories. During pacing tachycardia with coronary stenoses, regional coronary vascular resistance did not decrease further; subendocardial myocardial blood flow distal to the left anterior descending coronary artery stenosis decreased (from 1.03 +/- 0.07 to 0.67 +/- 0.12 ml/min per g, p less than 0.01), as did subendocardial to subepicardial blood flow ratio (from 1.04 +/- 0.09 to 0.42 +/- 0.08, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of intraaortic balloon counterpulsation on regional myocardial blood flow and oxygen consumption in the presence of coronary artery stenosis: Observations in an awake animal model

The mechanism by which intraaortic balloon pumping ameliorates myocardial ischemia in patients with unstable angina pectoris is uncertain. Accordingly, the following study was performed to determine the effect of intraaortic balloon pumping on regional myocardial blood flow and myocardial oxygen consumption (MVO₂) distal to severe coronary artery stenosis. Nine closed chest conscious pigs were instrumented with a 7.5 mm long plastic stenosis which reduced vessel diameter by 82%. Measurements of hemodynamics, regional myocardial blood flow (microsphere technique) and MVO₂ were made (1) before intraaortic balloon pumping, (2) at the end of 15 to 20 minutes of intraaortic balloon pumping, and (3) 20 minutes after its discontinuation.Control endocardial blood flow (ml · min^{? 1} · g^{? 1}) distal to the stenosis (1.04 ± 0.20, mean ± 1 standard deviation [SD]) was less than endocardial flow in myocardium perfused by the unobstructed circumflex coronary artery (1.67 ± 0 0.77, p < 0.01). Likewise, control distal zone epicardial flow (1.16 ± 0.36) was reduced in comparison with control circumflex zone epicardial flow (1.48 ± 0.60, p < 0.01In response to intraaortic balloon pumping rate-pressure product declined versus control (10,300 ± 2,090 [SD] mm Hg · min^{? 1} to 9,110 ± 2,010, p < 0.005), whereas aortic mean diastolic pressure (mm Hg) increased versus control (109.0 ± 9.9 to 121.0 ± 13.8, p < 0.01). Distal coronary mean diastolic pressure did not change in response to intraaortic balloon pumping (61.9 ± 13.0 to 68.7 ± 16.5, p = NS). Likewise, endocardial blood flow (ml · min^{? 1} · ^{? 1}) distal to the stenosis did not change during intraaortic balloon pumping (1.00 ± 0.24) versus control (1.04 ± 0.20). In contrast, during intraaortic balloon pumping epicardial blood flow distal to the stenosis declined versus control (1.16 ± 0.36 to 1.01 ± 0.27, p < 0.05). Regional MVO₂ (ml · min^{? 1} · 100 g^{? 1}) distal to the stenosis also decreased versus control in response to intraaortic balloon pumping (12.90 ± 3.55 to 10.30 ± 2.52, p < 0.05). Furthermore, regional MVO₂ correlated well (r = 0.74, p < 0.002) with rate-pressure product.Thus, intraaortic balloon pumping reduces myocardial oxygen demand but does not improve blood flow distal to a severe coronary stenosis; (2) blood flow distal to a severe stenosis may fail to increase with intraaortic balloon pumping because (A) distal coronary mean diastolic pressure may not increase, and (B) blood vessels distal to the stenosis tend to autoregulate in response to a decline in myocardial oxygen demand; and (3) intraaortic balloon pumping ameliorates myocardial ischemia in patients with unstable angina pectoris primarily by reducing oxygen demand rather than by increasing oxygen supply.     

Changes in ischemic blood flow distribution and dynamic severity of a coronary stenosis induced by beta blockade in the canine heart

The effects of equipotent beta 1-receptor-blocking doses of propranolol, metoprolol and sotalol on distal coronary pressure, stenosis resistance and regional myocardial blood flow (endo/epi) were studied in anesthetized dogs with a severe noncircumferential stenosis of the left circumflex coronary artery. No significant differences between the three beta blockers were observed for overall hemodynamics and regional myocardial blood flow. After drug treatment, subendocardial blood flow (0.47 +/- 0.05 to 0.78 +/- 0.05 ml/min/g) and endo/epi (0.67 +/-0.04 to 1.18 +/- 0.04) increased significantly (p less than 0.05) in the ischemic region. These changes were associated with a marked increase in distal coronary perfusion pressure and a decrease in heart rate. Resistance across the stenosis decreased significantly (p less than 0.05) after beta-receptor blockade (3.2 +/- 0.3 to 1.4 +/- 0.2 units). Atrial pacing to control heart rate only partially attenuated these changes. These results suggest that a favorable redistribution of ischemic blood flow after beta blockade is the result of an increase in distal diastolic pressure-time index and an autoregulation-induced increase in distal bed vascular resistance due to a decrease in myocardial oxygen demand associated with beta blockade. The latter effect also resulted in a decrease in the dynamic severity of a proximal coronary stenosis.     

Effect of the kallikrein inhibitor aprotinin on myocardial ischemic injury after coronary occlusion in the dog.

The effect of administration of aprotinin (a kallikrein inhibitor) on the extent and severity of acute myocardial ischemic injury, subsequent necrosis and collateral blood flow was studied in 55 dogs after acute coronary occlusion. Two 20 minute occlusions of the left anterior coronary artery were performed in eight dogs and epicardial electrograms were recorded from 10 to 14 sites. The sum of S-T segment elevations (σST) 15 minutes after the occlusion without drug administration was 38.7 ± 7.0 mv (mean ± standard error of the mean). Before the second occlusion aprotinin was administered and σST decreased to 22.6 ± 5.6 mv (P < 0.01). Similarly, the number of sites exhibiting S-T segment elevations of more than 2 mv (NST) decreased from 6.4 ± 0.8 after the first occlusion to 4.2 ± 1.2 (P < 0.01) after the occlusion following aprotinin administration. The effect of aprotinin on myocardial necrosis administered 30 minutes after coronary occlusion was established by means of the relation between epicardial S-T segment elevation 15 minutes after coronary occlusion and myocardial creatine kinase (CK) activity and histologic appearance at the same sites 24 hours later. In the control group the relation was: log CK = −0.059S-T + 1.53 (no. = 92 specimens, r = 0.74); in the treated group it was: log CK = —0.036S-T + 1.54 (no. = 60 specimens, r = 0.79). These slopes differed (P < 0.001), indicating that aprotinin prevented myocardial CK depletion. In the control group all sites exhibiting S-T elevations of more than 2 mv 15 minutes after occlusion showed early signs of myocardial infarction 24 hours later when examined by light microscopy. In contrast, in dogs that received aprotinin, only 66 percent of sites with abnormally elevated S-T segments showed abnormal histologic features, indicating that administration of the drug led to preservation of structural integrity in many sites. Similarly, significantly deeper Q waves evolved in the control than in the treated group: ΔQ (6 hours) = 0.82 S-T (15 min) + 0.86 (no. = 9 dogs, r = 0.76) and in the treated group: ΔQ (6 hours) = 0.46S-T (15 min) + 0.72 (no. = 10 dogs, r = 0.64) (P < 0.02). Regional myocardial blood flow decreased from 15 minutes to 6 hours after occlusion in both the control and treated groups. However, the decrease was less in the treated than in the control group (37 versus 16 percent and the distribution of flow endocardialepicardial ratio was significantly better with aprotinin. Thus, it is concluded that aprotinin diminishes myocardial damage after acute coronary occlusion.     

Consequences of reperfusion after coronary occlusion. Effects on hemodynamic and regional myocardial metabolic function

Hemodynamic and regional metabolic measurements were obtained in seven closed chest dogs during a control period, 3 hours of coronary occlusion and 5 hours of reperfusion. Reperfusion resulted in intermittent ectopic arrhythmias in five dogs and severe shock in two. It usually caused increases in heart rate, coronary sinus flow and maximal isovolumetric rate of rise in left ventricular pressure (dP/dt), which were associated with a decrease in systemic pressure, left ventricular end-diastolic pressure, systemic vascular resistance and stroke work. A transitory increase in cardiac output occurred. Global myocardial oxygen consumption, which was reduced during occlusion, increased with reperfusion. Reperfusion induced abnormal lactate metabolism and myocardial potassium loss in the previously occluded area and often in the nonoccluded segment as well. Histopathologic changes of accelerated necrosis, reactive hyperemia and hemorrhage were often noted after reperfusion.These studies indicate that reperfusion after 3 hours of occlusion caused serious abnormalities in hemodynamic states, metabolic function and morphologic features of the heart.     

Coronary steal: Its role in detrimental effect of isoproterenol after acute coronary occlusion in dogs

Using epicardial electrograms others have established that infusion of isoproterenol increases myocardial injury after acute coronary occlusion. To define the contribution of alterations in collateral blood flow to this increased ischemia, isoproterenol was administered to 10 dogs. After pretreatment with practolol in doses that successfully block inotropic but not vascular effects of beta adrenergic stimulants, intracoronary isoproterenol continued to enhance the magnitude of S-T segment elevation in ischemic areas. Thus, vasodilation induced by isoproterenol appears to divert flow from the ischemic area. To test this hypothesis, intracoronary adenosine was given to cause coronary vasodilation without enhancing inotropy. S-T segment elevation at ischemic and adjacent sites was significantly increased. Neither agent had systemic effects, but each increased coronary blood flow while concomitantly decreasing collateral flow as evidenced by a reduction in retrograde coronary flow and peripheral coronary pressure. In addition, adenosine significantly diminished the rate of xenon-133 clearance from the ischemic myocardium. Thus, isoproterenol, in addition to its positive inotropic effect, increases myocardial injury by its vascular action. Collateral blood flow to acutely ischemic myocardium is diminished by the production of a coronary steal. Intravenously administered isoproterenol additionally diminishes collateral flow by decreasing coronary perfusion pressure. It is postulated that any agent that causes either a primary or secondary coronary vasodilation may cause a coronary steal and subsequently enhance myocardial injury.     

Reduction of infarct size induced by pressure-controlled intermittent coronary sinus occlusion

The effect of pressure-controlled intermittent coronary sinus (CS) occlusion on myocardial infarction (MI) size was evaluated. A device for this purpose was developed that consisted of a balloon catheter and pump system that produced controlled, intermittent occlusion of the CS and used CS pressure as a feedback to determine the duration of occlusion. It was hypothesized that proper selection of occlusion and nonocclusion times would both facilitate improved retrograde flow to ischemic areas and allow for more complete venous washout of metabolites. In 13 treated dogs and 12 control dogs before treatment, myocardium at risk of MI was estimated by injection of technetium-labeled microspheres. Intermittent CS occlusion was then begun, 15 minutes after coronary artery occlusion, and continued until termination of the experiment 6 hours later. Postmortem determination of infarct size was performed using the triphenyltetrazolium chloride staining technique. Intermittent CS occlusion begun 15 minutes after coronary artery occlusion and continued for 6 hours resulted in a 45% average reduction in MI size (p <0.001). During CS occlusion, the sinus systolic mean pressure increased from 10 to 44 mm Hg, while the distal coronary artery mean pressure increased by an average of 36% (from 22 to 30 mm Hg, p <0.05). These results suggest intermittent occlusion may be an effective treatment for evolving MI. This therapy, used alone or combined with other therapies (e.g., administration of pharmacologic agents), appears to have great clinical potential.     

Effect of myocardial contraction on systolic coronary resistance in conscious dogs

We studied the effect of cardiac contraction on systolic coronary resistance under the conditions of maximally dilated coronary resistance vessels in six conscious dogs. Subendocardial segment length in areas supplied by the left circumflex coronary artery, left ventricular pressure and left circumflex coronary artery flow were simultaneously measured. At 5 sec after release of the first 2 min of left circumflex coronary artery occlusion, diastolic coronary blood flow revealed its peak value in association with markedly depressed regional contractile function. With collateral development induced by repeated 2 min left circumflex coronary artery occlusions, segmental dysfunction during occlusion and early reperfusion was progressively attenuated. Before and after collateral development, diastolic coronary resistance at 5 sec of reperfusion remained unchanged, but systolic coronary resistance increased by 41% secondary to restoration of regional myocardial shortening. In each animal, normalized regional shortening correlated well with changes in systolic coronary resistance. The fraction of systolic coronary resistance due to active regional myocardial contraction was 52%. These studies demonstrate that when coronary vasomotor tone is abolished, regional myocardial contraction impedes the coronary systolic flow in proportion to the extent of shortening.     

First ultra-short-acting beta-adrenergic blocking agent: Its effect on size and segmental wall dynamics of reperfused myocardial infarcts in dogs

Beta-adrenergic blocking agents have an established role in the treatment of myocardial ischemia, but precipitation of cardiac failure or bronchospasm may restrict their use in some patients with acute myocardial infarction or in those undergoing coronary bypass surgery. ASL-8052 is a new cardioselective ultra-short-acting beta blocker which allows abolition of beta blockade within 16 minutes on termination of an intravenous infusion. An investigation was made of the effect of ASL-8052 on myocardial infarct size, regional myocardial wall function, and hemodynamic features during a 3-hour experimental occlusion of the left anterior descending coronary artery followed by 3 hours of reperfusion in dogs.

Twenty-two dogs (10 control, 12 treated) were instrumented for the measurement of left ventricular (LV) pressure, the first derivative of left ventricular pressure (LV dP/dt), systolic and diastolic aortic pressure, and heart rate. Two pairs of ultrasonic crystals were inserted into a nonischemic segment and an ischemic marginal zone segment to obtain percent segment shortening. The area of necrosis was determined by tetrazolium staining and expressed as a percentage of the in vivo area at risk obtained by autoradiography. Dogs in the control group received saline solution; in treated dogs, a continuous infusion of ASL-8052 was begun 15 minutes after occlusion with a dose “titrated” to reduce the heart rate by approximately 20% (100 to 150 μg/kg/min). After 3 hours of reperfusion, the amount of myocardial tissue necrosis, as a function of the in vivo area at risk, was significantly lower in ASL-8052-treated (48 ± 7%) than in control (73 ± 6%) dogs (p < 0.025). Upon reperfusion, segment shortening decreased in control dogs from −3.3 ± 1.1% after 3 hours of occlusion to −6.3 ± 1.9% (p < 0.05) 2 hours after reperfusion (that is, systolic bulging increased). This functional deterioration upon reperfusion did not occur in treated dogs. During the occlusion period, infusion of ASL-8052 caused a decrease in heart rate of 22 ± 3% (p < 0.001) and in LV dP/dt by 22 ± 4% (p < 0.05). Upon reperfusion, control dogs had an increase in heart rate of 26 ± 1% (p < 0.05). In treated dogs, heart rate did not change. Hence, infarct size, reperfusion tachycardia, and myocardial wall asynergy were reduced in ASL-8052-treated dogs. A potential advantage of this agent is that its short duration of action would allow rapid reversal of beta blockade if adverse effects developed.     

Comparative effects of calcium-channel blocking agents on left ventricular function during acute ischemia in dogs with and without congestive heart failure

To examine the relative potencies of verapamil, nifedipine and diltiazem on left ventricular (LV) function under ischemic conditions, 20 conscious closed-chest dogs that had partial occlusion of their circumflex coronary arteries were studied. Myocardial blood flow was measured by microspheres, LV function by radionuclide angiography. Drug effects were compared at doses causing equal decreases in mean arterial pressure (MAP) and in coronary vascular resistance of the nonischemic zone. Global ejection fraction (EF) and EF of the ischemic region were significantly decreased by verapamil (p less than 0.002) and increased by nifedipine (p less than 0.001); diltiazem caused no significant changes. Verapamil significantly increased peak diastolic filling rate (p less than 0.001); nifedipine also increased diastolic filling rate but only at doses that markedly decreased MAP and coronary vascular resistance. Diltiazem was not significantly different from placebo. For doses causing an equal decrease in MAP, verapamil decreased heart rate (p less than 0.001), and diltiazem and nifedipine increased heart rate (p less than 0.05). Myocardial ischemic zone flow remained unchanged during placebo, verapamil, diltiazem or nifedipine infusion. To study the influence of heart failure on the hemodynamic effects of the calcium-channel blocking agents, 6 foxhounds underwent total occlusions of the left anterior descending coronary artery, resulting in myocardial infarction, volume loading to increase left atrial pressure and partial occlusion of the circumflex coronary artery. Verapamil depressed global left ventricular ejection fraction and increased left atrial pressure to as high as 40 to 45 mm Hg. In contrast, nifedipine decreased left atrial pressure and increased global EF.(ABSTRACT TRUNCATED AT 250 WORDS)