Videometric analysis of regional left ventricular function before and after aortocoronary artery bypass surgery: correlation of peak rate of myocardial wall thickening with late postoperative graft flows.

The peak rate of systolic wall thickening (pdTw/dt) in regions of the left ventricle was determined by biplane roentgen videometry in 60 patients before and a median of 14 mo after aorto-coronary bypass graft surgery. The left ventricular ejection fraction, stroke volume, and end-diastolic volume and pressure did not change significantly after surgery in the presence of patent or occluded grafts (P greater than 0.05). Statistically significant increases occurred in the peak rate of systolic wall thickening regions supplied by patent bypass grafts, and significant decreases occurred in regions with occluded grafts (P less than 0.01). Of 42 preoperatively hypokinetic regions (pdTw/dt greater than 0 less than 5.0 cm/s) supplied by a patent graft, 30 improved by an average of 2.6 cm/s after operation; 18 returned to normal. Failure of 24 hypokinetic regions to improve to normal was associated with myocardial infarction in 11 or with late postoperative graft blood flows of less than 60 ml/min measured by videodensitometry, in 10. All seven preoperatively akinetic (pdTw/dt=0) or dyskinetic (pdTw/dt less than 0) regions did not improve after the operation despite the fact that, in five of the seven, coronary bypass flows were over 60 ml/min. All eight preoperatively hypokinetic regions supplied by coronary artery graft flows of less than or equal 40 ml/min failed to improve to normal after operation. All nine preoperatively hypokinetic regions supplied by coronary artery graft flows of over 60 ml/min improved to normal after surgery. Late postoperative coronary artery bypass graft flows, the functional status of the myocardium, the status and distribution of the native coronary circulation, and decreased regional function elsewhere in the ventricle must all be considered when regional left ventricular function is interpreted.

Flavone-8-acetic acid (Flavonoid) profoundly reduces platelet-dependent thrombosis and vasoconstriction after deep arterial injury In vivo.

BACKGROUND: Flavone-8-acetic acid (FAA; [Flavonoid]), an adjuvant antitumor drug, inhibits ristocetin-induced aggregation of human platelets. The effect of FAA on platelet-dependent thrombosis was studied in vivo in the porcine carotid artery after deep arterial injury by balloon angioplasty. METHODS AND RESULTS: (111)In-labeled autologous platelet and (125)I-labeled porcine fibrin(ogen) deposition, and the incidence of macroscopic mural thrombosis onto deeply injured artery (tunica media) were compared in 20 pigs (40+/-1 kg [mean+/-SEM], body surface area=1.0+/-0.1 m(2)), randomized to FAA bolus (n=10) of 5.5g/m(2), followed by an infusion at 0.14g. m(-2). min(-1) or placebo (n=10). Vasoconstriction was measured immediately beyond the dilated segment using quantitative angiography. Platelet deposition (x10(6)/cm(2) of carotid artery) was reduced over 12-fold in pigs treated with FAA (13+/-3 versus 164+/-51, P=0.001) compared with placebo. Fibrin(ogen) deposition (x10(12) molecules/cm(2) of carotid artery) did not significantly differ in FAA-treated pigs versus placebo (40+/-8 versus 140+/-69, P=0.08). Large mural thrombi were present in 100% of placebo-treated pigs versus very small thrombi in 40% of FAA-treated pigs (P=0.005). Vasoconstriction was reduced from 46+/-6% in the placebo group to 15+/-3% in the FAA group (P<0.001). Plasma level of FAA before angioplasty was 515+/-23 microgram/mL. The activated partial thromboplastin time was unchanged. The bleeding time was >2SD above the normal mean in 4 of 5 treated pigs (increased from 157+/-29 to 522+/-123 s). CONCLUSIONS: FAA markedly reduced platelet deposition, mural thrombi, and injury-induced vasoconstriction after deep arterial injury, suggesting that a major inhibition of platelet glycoprotein Ibalpha may be beneficial therapy.

Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques: effects of tissue factor pathway inhibitor on plaque thrombogenicity under flow conditions.

BACKGROUND: Plaque disruption and subsequent thrombus formation lead to acute coronary syndromes and progression of atherosclerotic disease. Tissue factor (TF) appears to mediate plaque thrombogenicity. Tissue factor pathway inhibitor (TFPI) is the major physiological inhibitor of TF. This study analyzes the role of TF on thrombogenicity of disrupted human atherosclerotic plaques and the therapeutic possibilities of its specific inhibition. METHODS AND RESULTS: Human atherosclerotic and normal arterial segments were exposed to heparinized blood at flow conditions modeling medium-grade coronary stenosis in the Badimon perfusion chamber. The antithrombotic effects of the specific inhibition of plaque TF was assessed by reduction in the deposition of radiolabeled platelets and fibrin(ogen) and immunohistochemical analysis of perfused arteries. TF activity was inhibited by both recombinant TFPI and a polyclonal antibody against human TF. Human lipid-rich plaques were more thrombogenic than less advanced atherosclerotic plaques. Specific inhibition of TF activity reduced plaque thrombogenicity, inhibiting both platelet and fibrin(ogen) deposition (580 versus 194 plateletsx10(6)/cm2; P<0.01, and 652 versus 172x10(12) molecules of Fg/cm2; P<0.05, respectively) and thrombosis (immunohistochemistry). CONCLUSIONS: This study documents the key role of TF activity in acute arterial thrombosis after atherosclerotic plaque disruption and provides evidence of the benefit of blocking plaque TF activity. Therefore the inhibition of the TF pathway opens a new therapeutic strategy in the prevention of acute coronary thrombosis after plaque disruption.

In vivo magnetic resonance evaluation of atherosclerotic plaques in the human thoracic aorta: a comparison with transesophageal echocardiography.

BACKGROUND: The structure and composition of aortic atherosclerotic plaques are associated with the risk of future cardiovascular events. Magnetic resonance (MR) imaging may allow accurate visualization and characterization of aortic plaques. METHODS AND RESULTS: We developed a noninvasive MR method, free of motion and blood flow artifacts, for submillimeter imaging of the thoracic aortic wall. MR imaging was performed on a clinical MR system in 10 patients with aortic plaques identified by transesophageal echocardiography (TEE). Plaque composition, extent, and size were assessed from T1-, proton density-, and T2- weighted images. Comparison of 25 matched MR and TEE cross-sectional aortic plaque images showed a strong correlation for plaque composition (chi(2) = 43.5, P<0.0001; 80% overall agreement; n = 25) and mean maximum plaque thickness (r = 0.88, n = 25; 4.56+/-0.21 mm by MR and 4.62+/-0.31 mm by TEE). Overall aortic plaque extent as assessed by TEE and MR was also statistically significant (chi(2) = 61.77, P<0.0001; 80% overall agreement; n = 30 regions). CONCLUSIONS: This study demonstrates that noninvasive MR evaluation of the aorta compares well with TEE imaging for the assessment of atherosclerotic plaque thickness, extent, and composition. This MR method may prove useful for the in vivo study of aortic atherosclerosis.

Importance of antithrombin therapy during coronary angioplasty.

Angioplasty procedures with balloons, cutters or lasers all may greatly enlarge the arterial lumen, but luminal diameter may decrease because of mural thrombus in 70% to 80%, smooth muscle proliferation, vasoconstriction or recoil. Thrombin binds to arterial wall matrix and fibrin within a thrombus. Heparin dose-dependently decreases platelet and thrombus deposition but does not eliminate these even at high doses. Specific thrombin inhibition started before angioplasty experimentally prevents mural thrombus and limits platelet deposition to a single layer or less. Experimentally, anticoagulant and antifibrin effects occur at lower antithrombin blood levels and lower activated partial thromboplastin times (1.7 times control). Because platelets are so sensitive to thrombin, the higher level of thrombin inhibition required may occur at a specific level (activated partial thromboplastin time greater than or equal to 2 times control); this is not defined in humans. The duration of therapy is not defined in animals or humans. Thrombus and thrombin may be related to cellular proliferation.

The pathogenesis and prevention of aortocoronary vein bypass graft occlusion and restenosis after arterial angioplasty: role of vascular injury and platelet thrombus deposition.

Vascular injury during aortocoronary vein bypass graft surgery and arterial angioplasty initiates platelet thrombus deposition and mandates antithrombotic therapy, starting before the procedures to maximize protection against occlusion. This has been shown in studies in animals and in patients undergoing aortocoronary vein bypass graft operation where dipyridamole therapy was started before the operation, heparin was given intraoperatively and combined dipyridamole and aspirin therapy was started 7 hours after operation and markedly reduced vein graft occlusion in patients with grafts at both high and low risk for occlusion without increasing bleeding. Other alternative regimens, particularly preoperative dipyridamole followed postoperatively with aspirin alone, offer a promising future. Therapy should be continued for at least 1 year and perhaps indefinitely. Control of coronary risk factors appears important for long-term therapy to try to retard the atherosclerotic and occlusive process that leads to approximately 50% vein graft attrition by 10 years after operation. The possible role of cod liver oil and internal mammary artery bypass is discussed. Arterial angioplasty appears to cause deep arterial injury that activates both platelets and the coagulation system. These potentiate each other to form macroscopic mural thrombus within 1 hour in more than 90% of arteries that manifested deep arterial injury in pigs. Acute platelet thrombus deposition was retarded but not eliminated by only certain platelet-inhibitor agents. Implications for ongoing trials, current empiric therapy and future therapy are discussed.

Antithrombotic therapy in patients with valvular heart disease and prosthetic heart valves.

Indications and the type of antithrombotic therapy for the prevention of thromboembolism in patients with valvular heart disease, mechanical prosthetic heart valves and bioprosthetic heart valves are discussed. The evidence for these clinical recommendations is described and graded into five levels. The indications for anticoagulation in patients with valvular heart disease are chronic or paroxysmal atrial fibrillation, sinus rhythm with a very large left atrium, severe left ventricular dysfunction or presence of heart failure or a history of previous thromboembolism. Anticoagulant therapy is administered to prolong the prothrombin time to 1.5 to 2.0 times control, using rabbit brain thromboplastin (standardized international normalized ratio = 3.0 to 4.5). Risk factors for thromboembolism in patients with prosthetic heart valves are discussed. Because intracardiac thrombus formation may start during and continues early after operation, restarting heparin therapy 6 hours after operation and continuing it for the duration of the hospitalization is advised. For mechanical prosthetic heart valves, oral anticoagulation as outlined plus dipyridamole is advised indefinitely. Platelet inhibitor therapy alone is insufficient. For bioprosthetic heart valves, heparin is followed by oral anticoagulation as outlined for 3 months after mitral or aortic valve replacement and indefinitely after mitral valve replacement if there is atrial fibrillation or a very large left atrium; aspirin may be recommended indefinitely after aortic valve replacement. Antithrombotic therapy is also considered for four special situations: noncardiac surgery, prosthetic valve endocarditis, anticoagulation after a thromboembolic event, and antithrombotic therapy during pregnancy.

Role of platelets and thrombosis in coronary atherosclerotic disease and sudden death.

During the last decade, significant advances have been made in the understanding of the pathogenesis of coronary atherosclerotic disease. Two facts are important: 1) the early and some of the advanced coronary atherosclerotic lesions progress very slowly, probably by means of a complex stepwise biologic process with one of the steps being an interaction between platelets and the arterial wall; the process can be favored by the so-called risk factors of atherosclerotic disease, and 2) some of the advanced coronary atherosclerotic lesions progress very rapidly, probably by means of complicating anatomic events, one of which is related to a thrombogenic process. From a clinical point of view, technologic improvements, such as serial coronary arteriography, reperfusion during the acute coronary artery syndromes, postmortem coronary arteriography, and methods for serial histopathologic and histochemical studies, have brought to light the clinical importance of the processes of plaque rupture, dissecting hemorrhage and, most important, thrombosis. These complicated processes appear to be of paramount importance in the pathogenesis of some of the acute coronary syndromes including unstable angina, myocardial infarction and sudden coronary death. Antithrombotic and platelet inhibitor therapy is under investigation and appears promising in some of these patient subsets.

Thrombosis and embolism from cardiac chambers and infected valves.

In a number of cardiac conditions (acute myocardial infarction, chronic left ventricular aneurysm, dilated cardiomyopathy, infective endocarditis and atrial fibrillation in the absence of valvular disease), the risk of embolism gives cause for concern. Although anticoagulation with warfarin (Coumadin)-derivatives has been shown to be effective in some of these situations, there is no evidence regarding the role of antiplatelet agents. The common factor in the thromboembolic potential of acute myocardial infarction, chronic left ventricular aneurysm and dilated cardiomyopathy is mural thrombus. This can be detected by two-dimensional echocardiography and indium-111 platelet scintigraphy. Although of value in elucidating the natural history of mural thrombus, in most cases, management is not substantially aided by these investigations. In patients with extensive myocardial infarction, particularly anterior infarction, moderate intensity anticoagulation started soon after hospital admission reduces the rate of embolism. After 8 to 12 weeks, embolic risk is low so that anticoagulants can usually be discontinued. Patients with chronic left ventricular aneurysm have a low incidence of embolism; anticoagulation is, therefore, inappropriate. Dilated cardiomyopathy is associated with a high risk of embolism; moderate intensity anticoagulation may be advisable in many such cases. Little information is available regarding the incidence of thromboembolism or the role of antithrombotic therapy in the patient with a diffusely dilated left ventricle due to ischemic heart disease. In native valve infective endocarditis, the risk of hemorrhage is high, and the efficacy of conventional anticoagulants unclear; thus, anticoagulation should not be instituted for the cardiac condition as such. However, in prosthetic valve endocarditis, the risk of embolism seems to be very high, and anticoagulant therapy should be continued, but with great care because there is a substantial risk of cerebral hemorrhage. Atrial fibrillation in patients with valvular heart disease is dealt with in a previous review. Patients with nonvalvular atrial fibrillation are at varying risk of embolism, depending on the etiology of the arrhythmia; trials of antithrombotic therapy are needed for the various subsets of patients. In most elderly patients, the etiology is not known, and their stroke risk is high. The risk of embolism in younger patients with idiopathic atrial fibrillation is so low as to make any antithrombotic therapy unnecessary.(ABSTRACT TRUNCATED AT 400 WORDS)

Exogenous prostacyclin decreases vasoconstriction but not platelet thrombus deposition after arterial injury.

OBJECTIVES: The aim of this study was to examine the in vivo effects of increasing doses of prostacyclin (PGI2) on arterial vasoconstriction, platelet deposition and their interrelation after balloon injury of porcine carotid arteries. BACKGROUND: Extensive platelet deposition and localized vasoconstriction occur acutely after arterial injury in vivo. The platelet deposition and vasoconstriction are directly correlated, and previous studies suggest that platelets may mediate the vasoconstrictive response. However, it is unclear whether vasoconstriction contributes to platelet deposition. METHODS: Seven pigs received an intravenous infusion of PGI2 at 10 ng/kg per min (PGI2 10), 8 pigs at 50 ng/kg per min (PGI2 50) and 4 pigs at 500 ng/kg per min (PGI2 500); 24 pigs with saline infusion served as a control group. RESULTS: Vasoconstriction immediately proximal and distal to the balloon-dilated carotid arterial segment where selective endothelial injury occurred was directly related to indium-111-labeled platelet deposition within the dilated segment in both control pigs and PGI2-treated pigs. However, this relation was such that for any given level of platelet deposition relative to control, PGI2 decreased vasoconstriction in a dose-related manner. None of the treatments (PGI2 10, 50 or 500) decreased quantitative 111In-labeled platelet deposition or the proportion of deeply injured arteries with mural thrombus (91%, 70% or 75%, respectively, p = NS) compared with values in control pigs (81%). Thus, vasoconstriction was directly related to platelet deposition in control and PGI2-treated animals, but vasodilation alone did not decrease platelet deposition. CONCLUSIONS: Intravenous infusion of PGI2 significantly decreases vasoconstriction but not platelet deposition or mural thrombosis after arterial injury by balloon dilation. It is therefore unlikely that vasoconstriction mediates platelet deposition in this model. At hemodynamically tolerated doses, PGI2 infusion probably will not prevent the thrombotic complications associated with angioplasty.

Antithrombotic therapy after myocardial reperfusion in acute myocardial infarction.

The problem of post-thrombolytic reocclusion can be approached in several ways. 1) Better thrombolytic agents with longer duration of effects and more powerful properties aimed at enhanced clot lysis and anticoagulation are under study. 2) The combination of high dose heparin and low dose aspirin is proposed for all patients with an acute myocardial infarction treated with thrombolytic agents. 3) Peptide inhibitors of thrombin and monoclonal antibodies against platelet glycoprotein receptors and adhesive macromolecules are potentially effective inhibitors of platelet aggregation and thrombus formation during or after thrombolytic therapy.

The role of platelets, thrombin and hyperplasia in restenosis after coronary angioplasty.

Coronary angioplasty has become a successful and widely used treatment for patients with coronary artery disease since its first clinical application in 1977. The primary success rate has improved despite the increase in procedure and case complexity. However, acute reocclusion and late restenosis, which constitute the most important problems after successful angioplasty, continue to occur in about 5% and 35% of patients within 3 to 6 months, respectively. Angioscopic and pathologic observations have suggested that a multifactorial pathophysiologic process accounts for acute reocclusion, involving marked thrombosis, intimal dissection, medial and subintimal hemorrhage, vascular recoil and vasocontriction. In contrast, chronic restenosis involves the development of fibrocellular intimal hyperplasia within a milieu created by vascular injury, platelet activation, thrombin generation and the release of mitogens. Although current pharmacologic approaches, which involve antithrombotic and anticoagulant therapy, have been largely ineffective in eliminating acute reocclusion and chronic restenosis, recent advances in the research in thrombosis, platelet receptors and smooth muscle growth regulation have allowed new therapeutic options to be tested in the experimental setting, with subsequent potential clinical applications in patients.

Deep arterial injury during experimental angioplasty: relation to a positive indium-111-labeled platelet scintigram, quantitative platelet deposition and mural thrombosis.

Although it is not clear why coronary occlusion and restenosis occur after successful coronary angioplasty, factors related to the procedure may influence early and late results. The possible adverse effects of a medial tear documented histologically and produced during balloon angioplasty of the common carotid arteries were studied in 30 fully heparinized (100 U/kg body weight) normal pigs. Scanning electron microscopy showed endothelial denudation and extensive platelet deposition in all dilated arterial segments. Visible macroscopic mural thrombus was present within an hour of the procedure in 29 (91%) of the 32 arteries that had a medial tear documented by histologic study; the tear produced an indium-111-labeled platelet deposition of 116.4 +/- 26.5 X 10(6)/cm2 (mean +/- SE) and total thrombotic occlusion in 2 arteries (4%). None of the 24 arteries without a medial tear had a thrombus, and the mean platelet deposition in that group was 7.0 +/- 0.5 X 10(6)/cm2 (p less than 0.0008). In 12 pigs scanned with a gamma camera, visible thrombus was associated with platelet deposition in excess of 20 X 10(6)/cm2 in 12 arteries, 9 of which had a positive indium-111-labeled platelet scintigram. Thus, arterial angioplasty causes deep arterial injury, which appears to be a major cause of mural thrombosis, heavy platelet deposition, a positive indium-111-labeled platelet scintigram and acute arterial occlusion. A positive indium-111-labeled platelet scintigram was always associated with macroscopic thrombus of at least 20 > 10(6) platelets/cm2 and underlying deep arterial injury.

Role of antithrombotic therapy in unstable angina, myocardial infarction and sudden death.

The role of platelets and the clotting system in the initiation and progression of atherosclerosis has received significant attention. Most importantly, platelets and thrombosis play a pivotal role in the pathogenesis of the acute coronary syndromes of unstable angina, myocardial infarction and sudden death. In each stage of the development of coronary artery disease, from the early symptomatic stage through the growing lesion and finally to the complicated plaque that results in the precipitation of the acute coronary syndromes, platelets and the clotting system serve as a common link among them. Antithrombotic therapy aimed at halting the progression of these syndromes, preventing their occurrence or even reversing them (such as in the early stages of acute myocardial infarction), has provided exciting new modalities to treat these disorders. The use of aspirin in unstable angina in two well designed studies has clearly shown a reduction in fatal as well as nonfatal cardiac events compared with control groups not treated with aspirin. Although demonstration of a benefit of anticoagulant and antiplatelet therapy is difficult owing to a low event rate of thrombotic events (low sensitivity) and other nonthrombotic fatal events (low specificity) after myocardial infarction, pooled results have shown a favorable effect with their use. The usefulness of thrombolytic therapy in the early stages of acute myocardial infarction depends on the timing of initiation of therapy, the severity of the residual stenosis and possible use of agents that protect the ischemic myocardium. Other potential therapies for the acute coronary syndromes are also suggested. Further studies are in progress to establish the clinical benefits of antithrombotic agents in acute coronary syndromes.

Platelet inhibitor agents in cardiovascular disease: an update.

Platelets interact with the coagulation and fibrinolytic systems in the maintenance of hemostasis. However, these physiologic mechanisms may become pathologic, requiring prevention and treatment. In this review, the following clinical developments are analyzed: 1) the role of platelets in thrombogenesis; 2) the pharmacology of platelet inhibitory agents; and, most important, 3) the results of recent randomized trials of platelet inhibitor agents in different cardiovascular disorders. Aspirin reduces mortality and infarction rates in unstable angina and significantly decreases vascular mortality in acute myocardial infarction. Platelet inhibitors decrease mortality and recurrent cardiovascular events in the chronic phase after myocardial infarction. They also decrease vein graft occlusion rates after coronary bypass surgery. Although platelet inhibitors are beneficial in preventing acute vessel occlusion during coronary angioplasty, they are ineffective in preventing chronic restenosis. Antiplatelet agents, combined with warfarin, reduce thromboembolic events in patients with a mechanical prosthesis. Platelet inhibitors are also effective in secondary prevention of vascular events in patients with cerebrovascular disease. Finally, the use of aspirin for primary prevention of cardiovascular disease is still evolving, particularly in individuals at high risk. In conclusion, platelet inhibitors are effective in patients with a variety of cardiovascular disorders. The best studied, most inexpensive and least toxic agent is aspirin at a daily dose of 160 to 325 mg. Studies using new platelet inhibitor agents with different mechanisms of action are currently underway.

Intracellular calcium transients in human working myocardium as detected with aequorin.

The calcium transients associated with contraction in human working myocardium were recorded by use of the bioluminescent protein, aequorin, a substance that emits light when it combines with calcium ion (Ca++). Small amounts of aequorin were microinjected into superficial cells of human atrial and ventricular muscle obtained from tissue routinely excised and discarded at the time of cardiac surgery. Light output, an index of intracellular Ca++, and isometric tension development were recorded at 37.5 degrees C at 1 to 5 second intervals of stimulation. Light increases much more quickly than tension and decreases toward basal levels by the time that peak tension is reached. The configuration and time course of the aequorin signal in human myocardium and its responses to inotropic interventions are similar to those recorded in lower mammalian species. The calcium transient appears to be dominated by the release and uptake of Ca++ from intracellular stores under all conditions studied. These results indicate that aequorin is a useful tool for studying the effects of drugs and disease states on cardiac excitation-contraction coupling in human beings as well as in lower animals.

Syndromes of accelerated atherosclerosis: role of vascular injury and smooth muscle cell proliferation.

Vascular injury represents a critical initiating event in the pathogenesis of various vascular diseases, including atherosclerosis. This review discusses 1) the current understanding and a new pathologic classification of vascular injury; 2) the resultant cellular pathophysiologic responses, specifically, lipid accumulation, platelet aggregation, thrombus formation and smooth muscle cell proliferation; 3) the role of vascular injury in the pathogenesis of spontaneous and accelerated atherosclerosis; and 4) emerging therapeutic approaches in preventing these vascular diseases. The process of type I vascular injury (nondenuding functional injury) followed by lipid accumulation, monocyte and platelet adhesion, smooth muscle cell proliferation and resultant plaque formation represents the prevalent view of the early stages of spontaneous atherogenesis. The syndromes of accelerated atherosclerosis (namely, heart transplant atherosclerosis, coronary vein graft disease and restenosis after percutaneous transluminal coronary angioplasty) appear to share etiologic mechanisms with spontaneous atherosclerosis by means of the "response to injury" hypothesis. However, type II and type III vascular injury (denuding endothelial and intimal injury with or without medial damage) followed by thrombus and its organization by smooth muscle cell proliferation and subsequent fibrosis appear to be responsible for the vascular process. This accelerated and premature occlusive process accounts for significant morbidity and mortality in patients with these conditions. Better understanding of the nature of vascular injury and its pathophysiologic responses in these clinical situations may aid in developing therapeutic strategies for preventing these vascular diseases.

Mismatch of left ventricular function and infarct size demonstrated by technetium-99m isonitrile imaging after reperfusion therapy for acute myocardial infarction: identification of myocardial stunning and hyperkinesia.

Quantitation of perfusion defect size using tomographic imaging with technetium-99m-hexakis-2-methoxy isobutyl isonitrile was performed at the time of hospital discharge in 32 patients with a first myocardial infarction who underwent successful coronary reperfusion within 8 h of the onset of chest pain. Reperfusion was accomplished with thrombolysis or primary coronary angioplasty. Radionuclide angiography was performed at discharge and 6 weeks later. There was a close correlation between perfusion defect size and values for ejection fraction and regional wall motion both at discharge (r = -0.80 and -0.75, respectively) and 6 weeks later (r = -0.81 and -0.81, respectively). There was no overall group difference in ejection fraction between the value at discharge and at 6 weeks; however, five patients had a significant increase (greater than or equal to 0.08) and six had a significant decrease (greater than or equal to 0.08) in ejection fraction. In patients with a significant increase at 6 weeks, ejection fraction was significantly lower at discharge than the value predicted from perfusion defect size (0.37 +/- 0.09 measured versus 0.47 +/- 0.13 predicted, p less than 0.05) and it improved at 6 weeks to near predicted values (0.51 +/- 0.07). In patients with a significant decrease at 6 weeks, ejection fraction was significantly higher at discharge than the value predicted from perfusion defect size (0.60 +/- 0.10 measured versus 0.50 +/- 0.10 predicted, p less than 0.05) and it decreased at 6 weeks to near predicted levels (0.51 +/- 0.09). Left ventricular ejection fraction at the time of hospital discharge is a potentially misleading index of the efficacy of reperfusion therapy for myocardial infarction. In a significant minority (34%) of patients this index does not accurately reflect perfusion defect size, apparently because of the effects of myocardial stunning and compensatory hyperkinesia.

Systemic embolism in chronic left ventricular aneurysm: incidence and the role of anticoagulation.

The incidence and prevention of systemic embolism in patients with chronic left ventricular aneurysm have been controversial. This retrospective study investigated the incidence of clinically evident embolic events and the effect of oral anticoagulation in patients with unequivocal angiographically defined left ventricular aneurysm. Between 1971 and 1979, 76 patients met the ventriculographic criteria and received initial medical management. The median interval from myocardial infarction to ventriculography was 11 months (range 1 month to 16 years) and subsequent median follow-up time was 5 years. Twenty patients receiving anticoagulant therapy were followed up for a total of 40 patient-years and 69 patients not on anticoagulant therapy were followed up for a total of 288 patient-years; 13 patients were included in both subsets. Twenty-eight patients died during follow-up and the 3 and 5 year survival rates were 75 and 61%, respectively. Only one patient not receiving anticoagulant therapy had a clinical embolic event, resulting in an incidence of 0.35 per 100 patient-years. Therefore, in the absence of other predisposing conditions, the extremely low incidence of systemic emboli in these patients with chronic (first documented at least 1 month after myocardial infarction) left ventricular aneurysm does not justify the use of long-term oral anticoagulant therapy.

Inhibition of tissue factor reduces thrombus formation and intimal hyperplasia after porcine coronary angioplasty.

OBJECTIVES: We investigated the in vivo effects of tissue factor (TF) inhibition with recombinant tissue factor pathway inhibitor (rTFPI) on acute thrombus formation and intimal hyperplasia and the in vitro effects on smooth muscle cell migration and proliferation. BACKGROUND: Inhibition of TF with TFPI has been shown to reduce intimal hyperplasia in experimental models. However, its effects after coronary angioplasty and the cellular mechanisms involved have not been investigated. METHODS: Twenty-three swine underwent multivessel coronary angioplasty. Fifteen (n = 25 arteries) were euthanized at 72 h to assess thrombus formation and eight (n = 24 arteries) at 28 days to assess intimal hyperplasia. Animals in the 72-h time point received: 1) human rTFPI (0.5 mg bolus plus 25 microg/kg/min continuous infusion for 3 days) plus heparin (150 IU/kg intravenous bolus) plus acetyl salicylic acid (ASA) (325 mg/day); 2) rTFPI regimen plus ASA and 3) heparin (150 IU/kg intravenous bolus) plus ASA. RESULTS: On histology the control group had evidence of mural thrombus (area 0.8+/-0.4 mm2). Treatment with TFPI plus heparin abolished thrombus formation (mean area: 0.0+/-0.0 mm2, p < 0.05) but was associated with prolonged activated partial thromboplastin time and extravascular hemorrhage. Recombinant TFPI alone inhibited thrombosis without bleeding complications (mean area: 0.03+/-0.02 mm2, p < 0.05 vs. control). Animals in the 28-day time point received continuous intravenous infusion of rTFPI or control solution for 14 days. Tissue factor pathway inhibitor reduced neointimal formation with mean intimal area of 1.2+/-0.3 mm2 versus 3.2+/-0.4 mm2 in the control group; p < 0.01. Recombinant TFPI had no effect on human aortic smooth muscle cell growth but inhibited platelet-derived growth factor BB-induced migration. CONCLUSIONS: Inhibition of TF with rTFPI can prevent acute thrombosis and intimal hyperplasia after injury. Tissue factor plasma inhibitor may prove useful as an adjunct to intracoronary interventions.