Douglas H. Israel

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.

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.

Adjunctive thrombolytic therapy during angioplasty for ischemic rest angina. Results of the TAUSA Trial. TAUSA Investigators. Thrombolysis and Angioplasty in Unstable Angina trial.

BACKGROUND Acute closure is increased after angioplasty in unstable angina, and adjunctive intracoronary thrombolytic therapy has been used successfully to increase angiographic success. The role of prophylactic thrombolytic therapy during angioplasty in unstable angina is unknown. METHODS AND RESULTS Four hundred sixty-nine patients with ischemic rest pain with or without a recent (< 1 month) infarction were randomized in double-blind fashion to intracoronary urokinase or placebo. Randomization was carried out in two sequential phases. In phase I, 257 patients were randomized to 250,000 U of urokinase or placebo given in divided doses at the time of angioplasty. In phase II, 212 patients were randomized to 500,000 U of urokinase or placebo in divided doses. All patients were pretreated with aspirin, and activated clotting times were followed to maintain them at > 300 seconds during angioplasty. Angiographic end points of thrombus after angioplasty were insignificantly decreased by urokinase (30 [13.8%] versus 41 [18.0%] with placebo; P = NS). Acute closure, on the other hand, was increased with urokinase (23 [10.2%] versus 10 [4.3%] with placebo; P < .02). The difference in acute closure between urokinase and placebo was more striking at the higher dose of urokinase (P < .04) than in phase I at the lower urokinase dose (P = NS). Adverse in-hospital clinical end points (ischemia, infarction, or emergency coronary artery bypass surgery) were also increased with urokinase versus placebo (30 [12.9%] versus 15 [6.3%], respectively; P < .02). Angiographic and clinical end points were worse with urokinase in unstable angina without recent infarction than with angioplasty after a recent infarction. CONCLUSIONS Adjunctive urokinase given prophylactically during angioplasty for ischemic rest angina as administered in this trial is associated with adverse angiographic and clinical events. These detrimental effects may be related to hemorrhagic dissection, lack of intimal sealing, or procoagulant or platelet-activating effects of urokinase.

Clinical, angiographic, and procedural determinants of major and minor coronary dissection during angioplasty.

Angiographic evidence of coronary dissection after angioplasty is found in 25% to 30% of cases. Although patients are usually asymptomatic, in a small percentage angioplasty-induced coronary dissection results in luminal impairment and ischemic complications. The present study was undertaken to identify factors responsible for a predisposition to coronary dissection after angioplasty and to determine whether major and minor dissections share the same underlying risk factors. Clinical records and angiograms from 363 patients with 489 lesions were retrospectively graded for the presence and severity of dissection and complications. Both major and minor angiographic dissections were noted in 30.3%, and in 8.8% they were major. On multivariate analysis the most significant correlates of any dissection included a balloon-to-artery ratio > 1.1 (p = 0.0001), calcification (p = 0.003), presence of other lesions in the angioplasty vessel (p = 0.018), and lesion length (p = 0.02). However, in a multivariate model there were no variables that could predict whether a dissection would be major or minor. Only the mean total number of inflations was significantly different, but this was likely the result rather than the cause of dissection. Thus a number of variables can predict the occurrence of angiographic coronary dissection after angioplasty. Major dissections constitute a small fraction of the total number but are difficult to predict differentially.

Thrombin generation in human coronary arteries after percutaneous transluminal balloon angioplasty

OBJECTIVES The aim of this study was to investigate the relation between coronary atherosclerotic plaque injury and activation of the coagulation cascade. BACKGROUND Thrombus formation after atherosclerotic plaque disruption has been implicated in the pathogenesis of atherosclerosis, unstable angina and myocardial infarction. METHODS Biochemical markers of thrombin generation (prothrombin fragment F1+2) and thrombin activity (fibrinopeptide A) were measured in coronary blood before, during and immediately after percutaneous transluminal coronary angioplasty. After demonstrating that blood withdrawal through an angioplasty catheter does not artifactually elevate the plasma levels of these markers in patients after heparinization, coronary artery samples were collected proximal and distal to the lesion before and distal to the lesion after balloon inflation in 26 patients. RESULTS Plasma levels of F1+2 measured proximal to the lesion before angioplasty (median 0.47 nmol/liter, 95% confidence interval [CI] 0.40 to 0.50) were significantly elevated after angioplasty (median 0.55 nmol/liter, 95% CI 0.46 to 0.72, p = 0.001). In contrast, plasma fibrinopeptide A levels measured proximal to the lesion before angioplasty (median 2.0 ng/ml, 95% CI 1.3 to 2.2) were similar to those measured after angioplasty (median 1.8 ng/ml, 95% CI 1.3 to 3.0, p = NS). After we defined a normal range of interassay variability on the basis of values obtained from samples drawn proximal and distal to the lesion before angioplasty, seven patients (27%) had a significant increase in F1+2 plasma levels. A significant increase in plasma fibrinopeptide A occurred in five of these seven patients. Lesions with dissection, filling defects or haziness on postangioplasty angiography were associated with more thrombin generation than lesions without these features. CONCLUSIONS Markers of thrombin generation and activity can be collected safely and assayed accurately in heparinized blood withdrawn through an angioplasty catheter. Balloon dilation of coronary stenoses increases thrombin generation and activity within the coronary artery in a substantial subgroup of patients undergoing angioplasty.

Angioplasty of complex lesions in ischemic rest angina: Results of the Thrombolysis and Angioplasty in Unstable Angina (TAUSA) Trial

OBJECTIVES This study sought to analyze the role of complex lesion morphology on the acute results of angioplasty. BACKGROUND Acute complications of angioplasty are higher in unstable than in stable angina. The unstable culprit lesion is usually complex, indicative of plaque disruption and thrombus formation. Previous nonrandomized studies have shown that the presence of intracoronary thombus increases morbidity after coronary angioplasty. The role of complex morphology in coronary angioplasty outcome was studied in a prespecified subgroup analysis of a large multicenter coronary angioplasty trial. METHODS The results of coronary angioplasty from the Thrombolysis and Angioplasty in Unstable Angina (TAUSA) trial were analyzed. This large trial randomized 469 patients in double-blinded manner to receive either intracoronary urokinase or placebo during coronary angioplasty of the culprit lesion in ischemic rest angina with or without recent infarction. The study presented here analyzes in detail the results of coronary angioplasty in complex versus simple lesions in the urokinase and placebo groups. Complex lesions were defined before angioplasty by a core laboratory as having one or more of the following: irregular borders, overhanging edges, ulcerations or intraluminal filling defects proximal or distal to the lesion. RESULTS Of the 469 patients, 458 had identifiable culprit lesions, of which 245 were complex and 213 were simple. Complex lesions were associated with a higher abrupt closure rate than simple lesions (10.6% vs. 3.3%, respectively, p < 0.003). Patients with complex lesions also had higher recurrent in-hospital angina (p < 0.02) and emergent bypass surgery (p < 0.02). Further analysis of complex lesions revealed that abrupt closure was particularly high in the urokinase group (15.0% vs 5.9% for the placebo group, p < 0.03), and most abrupt closures were thrombotic. Composite clinical end points were also significantly higher with complex lesions and urokinase. In the placebo group, complex lesions had a higher abrupt closure rate as well as postcoronary angioplasty filling defects, but clinical end points were not significantly different. CONCLUSIONS Complex lesions before coronary angioplasty increase acute complication rates after coronary angioplasty. Urokinase as administered in the TAUSA trial had significant adverse effects, especially in complex lesions. However, even in the placebo arm, complex lesions were associated with higher complication rates than simple lesions. Newer antithrombotic measures that particularly target the platelet may eventually decrease complication rates in these lesions.

Fish oils in the prevention of atherosclerosis

The hypothesis that oils derived from the flesh of fish and marine mammals inhibit the atherosclerotic process is critically reviewed. Populations consuming a diet rich in fish have low rates of coronary heart disease. Dietary fish oil is associated with changes in serum lipids, prostaglandin and leukotriene metabolism, enhanced endothelial function and effects on growth factors released from platelets, leukocytes and endothelial cells. Dietary fish oil supplementation has been associated with inhibition of atherosclerosis experimentally induced by dietary hyperlipidemia and balloon injury. Results of studies of the use of fish oil to inhibit postangioplasty restenosis in human subjects have been inconclusive.

Dynamic coronary ostial obstruction due to papillary fibroelastoma leading to myocardial ischemia and infarction

Abstract Papillary fibroelastoma is an uncommon cardiac tumor rarely diagnosed during life. Although most are incidental findings at autopsy, a small number of cases have been associated with cardiac symptoms that include angina, embolism and sudden death. We describe a case of papillary fibroelastoma detected angiographically and shown to cause coronary obstruction and myocardial ischemia.

Clinical, angiographic and anatomic findings in acute severe ischemic mitral regurgitation

Severe mitral regurgitation (MR) due to coronary artery disease unfavorably alters prognosis for medical therapy and is also associated with increased surgical mortality. In this report, the clinical, angiographic and pathoanatomic findings in 50 consecutive patients with severe ischemic MR were characterized. Forty-two patients (84%) either presented with acute myocardial infarction or a well-documented prior infarction. Eleven patients (22%) were in cardiogenic shock at the time of catheterization. Forty patients (80%) had greater than 70% stenosis of the right and left circumflex coronary arteries with or without left anterior descending coronary artery stenosis. Segmental asynergy of the left ventricular wall was present in 48 patients (96%) and involved the inferior wall in 43 (86%). Mean ejection fraction for the group was 51 +/- 7%. A total of 15 patients had direct inspection of the mitral valve apparatus at surgery or autopsy. Posteromedial papillary muscle involvement was found in 14 patients, fibrosis or necrosis in 10 and rupture in 4, with anterolateral papillary muscle rupture in 1 patient. Thus, acute severe ischemic MR is usually associated with significant narrowing of both right and left circumflex coronary arteries, and posteromedial papillary muscle involvement.

Excimer laser-facilitated balloon angioplasty of a nondilatable lesion☆

Preliminary clinical experience with excimer laser coronary angioplasty shows that it is a safe and effective means of achieving nonsurgical coronary revascularization in selected patients but specific indications for its use are as yet undefined. In the present report a specific indication is proposed for the use of the excimer laser: to facilitate balloon inflation in a rigid stenosis that fails to dilate despite high balloon inflation pressures.