Does antiplatelet therapy enhance myocardial salvage after coronary reperfusion?

The aim of this study was to test the hypothesis that either the cyclooxygenase inhibitor aspirin or the thromboxane A2 receptor antagonist sulotroban exerts a direct myocardial effect that enhances myocardial salvage afforded by reperfusion. Accordingly, 21 anesthetized dogs underwent suture occlusion of the left anterior descending coronary artery. At 2.5 h after occlusion, all dogs received intravenous streptokinase (20,000 U/kg body weight over 30 min) and were randomized to the following groups: group I (n = 7) received no additional treatment, group II (n = 7) received aspirin (5 mg/kg intravenously) and group III (n = 7) received sulotroban (10 mg/kg followed by 10 mg/kg per h intravenously). At 3 h after occlusion, the dogs underwent coronary reperfusion for the next 3 h. Myocardial infarct size as a percent of the hypoperfused zone was similar among dogs in group I (42 +/- 8%), group II (41 +/- 10%) and group III (45 +/- 11%). The incidence and the extent of myocardial hemorrhage were similar in all three study groups. Infarct size as a percent of the hypoperfused zone was significantly smaller in dogs without hemorrhage irrespective of treatment (35 +/- 9% versus 63 +/- 5%, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Potentiation of coronary vascular platelet adhesion by atrial pacing in the presence of arterial stenosis in dogs.

The effect of atrial pacing on coronary hemodynamics and platelet adhesion was evaluated in 13 dogs. In all 13 dogs, a snare was placed around the circumflex artery and tightened so that distal coronary artery pressure decreased to 60 to 70 mm Hg. In 10 dogs, atrial pacing was instituted at twice the heart rate at rest for 10 minutes. In three dogs, observation was continued for 10 minutes without pacing. In the 10 dogs undergoing pacing, heart rate increased from 90.5 +/- 32.6 to 173.5 +/- 45.8 beats/min. Aortic pressure was unchanged. Distal coronary artery pressure decreased from 70.8 +/- 7.8 to 53.2 +/- 10.0 mm Hg (p less than 0.05) and the pressure gradient across the stenosis increased from 47.6 +/- 12.7 to 61.2 +/- 9.1 mm Hg (p less than 0.05). Stenotic resistance increased from 2.5 +/- 0.8 to 3.6 +/- 2.4 mm Hg/ml X min-1, but coronary flow was unchanged. In all three control dogs, there was no change in coronary dynamics for the 10 minute period. In 8 of the 10 dogs that underwent pacing, platelet deposition was observed at the site of coronary stenosis. In contrast, in the three control dogs there was no platelet deposition. Atrial pacing in the presence of coronary stenosis appears to alter coronary hemodynamics such that there are activation and deposition of platelets at the site of stenosis. This platelet deposition may be transient or could become the nidus for subsequent platelet-related events in the coronary vessel.

Fibrinolytic activity after vessel wall injury.

The goal of this study was to assess fibrinolytic activity after vessel wall injury and to correlate changes in fibrinolytic activity with angiographic and histologic findings. Accordingly, in 18 atherosclerotic rabbits, vessel wall injury was produced by means of iliac artery balloon angioplasty (the injury group), whereas 8 atherosclerotic rabbits served as a control group. In all rabbits from the injury group, deep vessel wall injury was documented by either angiography or histologic study. Plasminogen activator inhibitor-1 activity in plasma increased significantly, from 21.79 +/- 1.29 arbitrary units/ml (AU/ml) at baseline study to 32.05 +/- 1.47 AU/ml at 6 h after vessel wall injury (p less than 0.01), whereas activity remained unchanged throughout the 24-h period in the control group. Plasma levels of tissue plasminogen activator activity were similar in both groups. Intravascular thrombus was found in five of six additional rabbits 6 h after vessel wall injury, that is, at the time of impaired fibrinolytic activity, whereas no thrombus was found in the control group (p less than 0.05). It is concluded that deep vessel wall injury is associated with reduced fibrinolytic activity. In addition to other procoagulant factors, elevated plasminogen activator inhibitor-1 activity may lead to intravascular thrombosis and impaired resolution of thrombus.

Combination therapy for evolving myocardial infarction: intracoronary thrombolysis and percutaneous transluminal angioplasty.

Nonsurgical coronary reperfusion for evolving myocardial infarction is a promising new technique for the salvage of jeopardized myocardium. Successful reperfusion can be established by intracoronary infusion of streptokinase in approximately 75 percent of patients within the first 6 hours of transmural infarction [1.2]. Following recanalization, most patients are left with high grade fixed coronary stenoses which are potential sites for recurrent thrombus formation. Since the underlying site for coronary thrombosis is still present, reocclusion may occur. Indeed, early experience suggests that recurrence of thrombosis is not uncommon [3.4]. Therapy for evolving myocardial infarction should, in some patients, involve not only thrombolysis, but also an attack on the fixed coronary lesion. We describe a patient wit evolving myocardial infarction who was treated successfully with combination therapy consisting of intracoronary streptokinase followed by percutaneous transluminal coronary angioplasty [5].

Beneficial effects of ibuprofen in pacing-induced myocardial ischemia.

Lysosomal membrane instability and platelet activation are both associated with acute myocardial ischemia. The effect of ibuprofen on cathepsin D as a marker of lysosomal membrane "leakiness" and thromboxane B2 as a marker of platelet activation was evaluated in 44 patients with angina pectoris. Samples of blood analyzed for cathepsin D, thromboxane B2, and lactate were withdrawn from the coronary sinus and brachial artery before and after pacing to 140 beats/min for 4 minutes. Myocardial ischemia was assessed by determination of transmyocardial lactate extraction or production. Ibuprofen (800 mg) or placebo was administered orally 2 hours before cardiac catheterization. Patients were classified into 4 groups on the basis of administration of placebo or ibuprofen and the presence or absence of myocardial ischemia as determined by demonstration of lactate extraction or production after atrial pacing. In patients with lactate extraction, no significant efflux of cathepsin D or thromboxane B2 occurred after pacing. In patients with lactate production given placebo, a 64 +/- 25% increase in the thromboxane B2 level and a 113 +/- 37% increase in cathepsin D activities occurred in the coronary sinus effluent sampled after pacing. In contrast, in patients with comparable coronary artery disease and comparable lactate production who were given ibuprofen, no release of thromboxane B2 (p = 0.05 compared with patients given placebo) or cathepsin D (p less than 0.01 compared with patients given placebo) occurred after pacing-induced ischemia. These findings suggest that ibuprofen stabilizes membranes and prevents platelet-activated release of thromboxane A2 in pacing-induced myocardial ischemia.

Improved survival after coronary bypass surgery in patients with poor left ventricular function: role of intraaortic balloon counterpulsation.

The operative mortality rate of aortocoronary bypass surgery in 23 patients with poor left ventricular function (ejection fraction 0.30 or less) operated on in 1973-74 was 34.7 percent. The incidence rate of operative myocardial infarction was 30.4 percent. In an attempt to improve survival, intraaortic balloon counterpulsation was used therafter in 25 similar patients. Counterpulsation was instituted preoperatively and continued intra- and postoperatively for 2 to 5 days. Preoperative studies revealed an "unloading" effect of the left ventricle, with significant reductions of systolic arterial blood pressure, end-diastolic pulmonary arterial pressure and end-diastolic left ventricular volume and pressure. Metabolic improvement was demonstrated by the lesser production of myocardial lactate after pacing-induced tachycardia when the ventricle was balloon-assisted. Intraoperatively, blood flow through the vein graft was found to increase with counterpulsation. The rate of operative myocardial infarction was reduced to 4 percent and the mortality rate to 8 percent. In patients who have sustained a significant loss of functioning myocardium, the beneficial hemodynamic and metabolic effects of intraaortic balloon counterpulsation appear to prevent furhter, possibly critical, myocardial damage in the perioperative period.

Comparison of coronary angiographic findings during the first six hours of non-Q-wave and Q-wave myocardial infarction.

The angiographic features of non-Q-wave acute myocardial infarction (AMI) soon after symptom onset have not been previously reported. Accordingly, this study reviewed the coronary angiographic findings of 86 patients with AMI studied within 6 hours of symptom onset: 58 had Q-wave and 28 had non-Q-wave AMI. Patients with Q-wave and non-Q-wave AMI were comparable in terms of clinical characteristics, frequency of 1-vessel disease, and infarct-related artery location. Thrombus was observed in 49 patients (84%) with Q-wave AMI versus 12 (43%) with non-Q-wave AMI (p = 0.0002). Whereas complete occlusion of the infarct-related artery was present in 53 patients (91%) with Q-wave AMI, total coronary occlusion was present in only 11 (39%) with non-Q-wave AMI (p = 0.0001). Collaterals to occluded infarct arteries were seen in 10 patients (19%) with Q-wave AMI versus 5 (45%) with non-Q-wave AMI (p = 0.06). Residual perfusion of the infarct artery by either anterograde or collateral flow was typical of patients with non-Q-wave AMI (22 of 28, 79%) but was uncommon in those with Q-wave AMI (15 of 58, 26%) (p = 0.0001). Thus, coronary angiography performed within 6 hours of symptom onset demonstrates important differences between Q-wave and non-Q-wave AMI. Non-Q-wave AMI is characterized by partial perfusion of the infarct-related artery by either anterograde or collateral flow, and a lower incidence of thrombus than Q-wave AMI.(ABSTRACT TRUNCATED AT 250 WORDS)

Lisinopril for severe congestive heart failure.

Lisinopril, a new converting enzyme inhibitor, was studied hemodynamically in 55 patients. The response to 2.5-, 5- and 10-mg doses showed significant increases in cardiac index and significant reductions in pulmonary artery wedge, right atrial, pulmonary arterial and systemic arterial pressures, as well as in systemic vascular resistance. Significant changes in most parameters were present at 24 hours. A dose-response relation for most parameters was noted. Over a 3-month period, 47 patients were followed up, with improvement in functional capacity and symptomatic status. Metabolic parameters did not change over time, although 26% showed evidence of reversible renal dysfunction. Only 3 patients (6.4%) required discontinuation because of adverse effects. A subgroup of patients reassessed at 3 months demonstrated maintenance of hemodynamic effects. The present study demonstrates that (1) the hemodynamic effects of lisinopril are of relatively long duration; (2) within certain limits, a dose-response relation can be defined; and (3) the drug has an acceptable long-term tolerability profile.

Spectrum of coronary arterial spasm. Clinical, angiographic and myocardial metabolic experience in 29 cases.

A relationship of coronary arterial spasm to variant angina pectoris, subendocardial ischemia, major ventricular arrhythmias and myocardial infarction has been demonstrated. In 29 patients, spasm was angiographically observed in normal-appearing coronary arteries (7 patients) as well as superimposed on various degrees of coronary atherosclerotic obstruction (22 patients). All patients experienced an atypical anginal syndrome;16 patients also experienced typical exertional angina. Coronary spasm appeared to be a major contributory factor in eight occurrences of myocardial infarction and in 11 incidents of ventricular tachycardia, ventricular fibrillation and heart block. Coronary spasm in the 29 cases was distributed in the following fashion: left main trunk, 6 cases; right main trunk, 12 cases; proximal left anterior descending artery, 13 cases; proximal circumflex artery, 1 case; distal left anterior descending artery, 1 case; and distal circumflex artery, 2 cases. In 5 cases coronary spasm was noted at multiple sites.

Early experience with minimally invasive direct coronary artery bypass grafting with the internal thoracic artery.

OBJECTIVE: Minimally invasive direct coronary artery bypass is performed under direct vision without sternotomy or cardiopulmonary bypass. The technique can be used in both primary and reoperative cases by employing the internal thoracic artery to perform arterial revascularization of the anterior surface of the heart. METHODS: Patients were selected who had significant coronary artery disease limited to 1 or 2 coronary distributions on the anterior surface of the heart. Coronary target vessels were grafted with the internal thoracic artery through a small anterior thoracotomy. After partial heparinization the anastomosis was facilitated by local coronary occlusion and handheld stabilization. RESULTS: Between August 1994 and July 1997, 162 patients underwent minimally invasive direct coronary artery bypass grafting with the internal thoracic artery. The left and right internal thoracic arteries were used for grafting of the left anterior descending artery in 142 patients (88%), the proximal right coronary artery in 7 patients (4%), existing saphenous vein grafts in 5 patients (3%), and diagonal branches in 2 patients (1%). Sequential grafting with the left internal thoracic artery was performed in 2 patients (1%) and bilateral internal thoracic artery grafting was performed in 4 patients (3%). Eight patients (4.9%) died within 30 days after the operation, 3 of cardiac causes. Seven additional patients died during the follow-up period. Nine patients (5.6%) required reintervention for graft stenosis or occlusion during follow-up. Of 141 patients seen 2 or more weeks after the operation, 135 (96%) had resolution of their anginal symptoms at a mean follow-up of 12 months (range 0-31 months). CONCLUSIONS: Anterior minimally invasive direct coronary artery bypass grafting with the internal thoracic artery avoids the risks of repeated sternotomy, aortic manipulation, and cardiopulmonary bypass. There was a low rate of reintervention, and patients had excellent resolution of anginal symptoms. Postoperative length of stay was comparatively short, and continued follow-up will be essential to evaluate long-term graft patency and patient survival.

Initial experience with MIDCAB grafting using the gastroepiploic artery.

BACKGROUND: Minimally invasive direct coronary artery bypass grafting with the gastroepiploic artery can be used in primary operations and reoperations to revascularize the inferior or anterior surface of the heart. METHODS: Patients who had symptomatic coronary artery disease limited to a single coronary distribution were selected. Coronary targets were grafted with the pedicled gastroepiploic artery through a small midline epigastric incision. Patients were followed with scheduled outpatient clinic visits, Doppler examination, and selective recatheterization. RESULTS: Between May 1995 and November 1997, 74 patients underwent gastroepiploic artery minimally invasive direct coronary artery bypass grafting; 33 (45%) had a primary operation and 41 (55%), a reoperation. Grafting was performed to the distal right coronary artery (n = 38), the posterior descending artery (n = 28), or the distal left anterior descending coronary artery (n = 8). There were six deaths (8%) within 30 days after operation. Twenty patients (28%) underwent recatheterization; there were two graft occlusions, two graft stenoses, and five anastomotic stenoses. Of 60 patients seen 2 or more weeks after operation, 53 (88%) had resolution of anginal symptoms at a mean follow-up of 10.9 months (range, 0 to 30 months). CONCLUSIONS: Inferior minimally invasive direct coronary artery bypass grafting with the gastroepiploic artery avoids the risks of repeat sternotomy, aortic manipulation, and cardiopulmonary bypass. Patency rates, however, were lower than expected, and there is significant morbidity and mortality associated with high-risk patients undergoing the procedure. Continued follow-up is essential to evaluate long-term graft patency and patient survival.

Assessing the impact of cerebral injury after cardiac surgery: will determining the mechanism reduce this injury?

BACKGROUND: Central nervous system dysfunction continues to produce significant morbidity and associated mortality in patients undergoing cardiac surgery. Using a closed-chest canine cardiopulmonary bypass model, dogs underwent 2 h of hypothermic circulatory arrest (HCA) at 18 degrees C, followed by resuscitation and recovery for 3 days. Animals were assessed functionally by a species-specific behavioral scale, histologically for patterns of selective neuronal necrosis, biochemically by analysis of microdialysis effluent, and by receptor autoradiography for N-methyl-D-aspartate (NMDA) glutamate receptor subtype expression. RESULTS: Using a selective NMDA (glutamate) receptor antagonist (MK801) and an AMPA antagonist (NBQX), glutamate excitotoxicity in the development of HCA-induced brain injury was documented and validated. A microdialysis technique was employed to evaluate the role of nitric oxide (NO) in neuronal cell death. Arginine plus oxygen is converted to NO plus citrulline (CIT) by the action of NO synthase (nNOS). CIT recovery in the cerebrospinal fluid and from canine cortical homogenates increased during HCA and reperfusion. These studies demonstrated that neurotoxicity after HCA involves a significant and early induction of nNOS expression, and neuronal processes leading to widespread augmentation of NO production in the brain. To further investigate the production of excitatory amino acids in the brain, we hypothesized the following scenario: HCA--> increased glutamate, increased aspartate, increased glycine--> increased intracellular Ca2+--> increased NO + CIT. Using the same animal preparation, we demonstrated that HCA caused increased intracerebral glutamate and aspartate that persists up to 20 h post-HCA. HCA also resulted in CIT (NO) production, causing a continued and delayed neurologic injury. Confirmatory evidence of the role of NO was demonstrated by a further experiment using a specific nNOS inhibitor, 7-nitroindazole. Animals underwent 2 h of HCA, and then were evaluated both physiologically and for NO production. 7-Nitroindazole reduced CIT (NO) production by 58.4 +/- 28.3%. In addition, dogs treated with this drug had superior neurologic function compared with untreated HCA controls. CONCLUSIONS: These experiments have documented the role of glutamate excitotoxicity in neurologic injury and have implicated NO as a significant neurotoxin causing necrosis and apoptosis. Continued research into the pathophysiologic mechanisms involved in cerebral injury will eventually yield a safe and reliable neuroprotectant strategy. Specific interventional agents will include glutamate receptor antagonists and specific neuronal NO synthase inhibitors.

Hemodynamics of human arterial stenoses.

We assessed the hemodynamic and geometric changes in compliant, human arterial stenoses in response to manipulation of vascular tone, perfusion pressure and distal resistance. Coronary and popliteal arteries were harvested from human cadavers shortly after death. Following incubation for several hours to permit recovery of physiologic energy stores and ion gradients, the vessels were attached to a perfusion apparatus and perfusion pressure (PP), distal pressure (DP), and flow (F) were recorded as perfusion pressure and distal resistance (DR) were varied. The experiments were then repeated in the presence of a vasoconstrictor (100 mM KCl). Orthogonal arteriograms were performed at maximums of vasoconstriction and vasodilation. Stenotic resistance (SR) was calculated as (PP-DP)F. Minimum cross-sectional area was determined by computer assisted analysis of the arteriograms. Stenosed vessels with normal wall segments at the stenosis responded to vasoconstriction with a large stenotic resistance increase (111 +/- 15%; P less than 0.05) and a flow decrease averaging 39.3 +/- 6.2% (P less than 0.05). In addition, decreased perfusion pressure also increased stenotic resistance significantly (P less than 0.05). Stenotic resistance changes were of sufficient magnitude to be both statistically significant and clinically important. These results confirm the existence of dynamic arterial stenoses in humans and further support the assertion that dynamic stenotic severity changes elicited by manipulation of proximal and distal vascular tone and pressure are of sufficient magnitude to create acute ischemia. This information may apply to clinical situations in which compliant stenoses and acute ischemia coexist.

Reoperative MIDCAB grafting: 3-year clinical experience.

OBJECTIVE: Minimally invasive direct coronary artery bypass (MIDCAB) is performed under direct vision without sternotomy or cardiopulmonary bypass. The technique is used in reoperative patients through various incisions to revascularize one or two areas of the heart. The internal mammary artery, gastroepiploic artery, radial artery, or saphenous vein are used as graft conduits. METHODS: Anterior coronary targets are grafted with the internal mammary artery via a small anterior thoracotomy. Inferior coronary targets are grafted with the gastroepiploic artery via a small midline epigastric incision. Lateral coronary targets are grafted with radial artery or saphenous vein via a posterior thoracotomy. After partial heparinization, the anastomosis is facilitated by local coronary occlusion and stabilization. Graft follow-up consists of outpatient Doppler examination and selective recatheterization. RESULTS: Between January 1994 and August 1997, 81 patients underwent reoperative MIDCAB grafting. Twenty-one patients (25.9%) had internal mammary grafting, 39 (48.2%) had gastroepiploic grafting, and 21 (25.9%) had lateral grafting with radial artery or saphenous vein. There were nine early deaths (four cardiac, five non-cardiac), five late deaths (three cardiac, two non-cardiac), and nine myocardial infarctions in remaining patients. Sixteen patients underwent recatheterization; there were one graft occlusion, two graft stenoses, and eight anastomotic stenoses. Mean postoperative length of stay was 3.8 days. Ninety percent (55/61) of patients are free of symptoms at a mean follow-up of 7.8 months (range 0-39). CONCLUSIONS: Reoperative MIDCAB grafting avoids the risks of resternotomy, aortic manipulation, and cardiopulmonary bypass. The techniques yield an early patency rate of 94%, which includes eight patients who had postoperative catheter-based interventions. Reoperative MIDCAB grafting had lower rates of supraventricular arrhythmia and transfusion when compared with conventional coronary artery bypass grafting, but did not offer an advantage for mortality, stroke or myocardial infarction. This 3-year experience suggests that while reoperative MIDCAB grafting can effectively revascularize focal areas of the heart, patients should be carefully selected to minimize operative risk.

Lactate metabolism as a prognostic index in unstable angina.

Fifty patients evaluated because of unstable angina were followed up for a mean period of 63.7 months. Analysis of transmyocardial lactate metabolism was performed in all patients in addition to coronary angiography and ventriculography. All patients had at least one coronary lesion of great than 75%. Although technically feasible, aortocoronary bypass surgery was not performed on initial hospitalization and all patients were treated medically. Patients were divided into two groups on the basis of lactate metabolism; group A lactate production great than 15%, group B lactate production less than 15% or lactate extraction. There was no difference in left ventricular end-diastolic pressure or ejection fraction between the two groups. A coronary score index was higher in group A than group B (5.45 +/- 2.2 vs 3.13 +/- 1.2) (p less than 0.05). The incidence of myocardial infarction was higher in group A than group B in hospital (44.4% vs. 4.3%, p less than 0.05), and long term (70.3% vs. 17.3%, p less than 0.05). Mortality was higher in group A than group B in hospital (25.9% vs. 0%, p less than 0.05) and long term (66.7% vs. 13%, p less than 0.05). Analysis of lactate metabolism thus provides a prognostic index in unstable angina which complements information obtained by coronary angiography and ventriculography.