Treatment of unstable angina: role of antithrombotic therapy.
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Angina, Unstable↗
Biomedical subjects
J H Chesebro
Publications and source records attributed to J H Chesebro.
Lone atrial fibrillation in elderly persons: a marker for cardiovascular risk.
BACKGROUND: The risk of stroke in persons aged 60 years and younger with lone atrial fibrillation (LAF) is no greater than in the general population. The effect of older age on the risk of stroke in persons with LAF is less well established. PARTICIPANTS AND METHODS: The risk of stroke in persons with LAF and without substantial comorbidities was examined in a population-based study at a single institution in Olmsted County, Minnesota, and compared with that in an age- and sex-matched population. The mean age was 74 years (range, 61-97 years). The median duration of follow-up was 9.6 years until death or last follow-up. RESULTS: Of 55 patients, 26 had 31 cardiovascular events during follow-up, occurring a median of 5.1 years after diagnosis (range, 0.7-18 years). Of 11 cerebrovascular events, 6 were transient ischemic attacks and 5 were strokes. The event rates (percentage per person-year) were 0.9% for stroke, 1.1% for transient cerebral ischemia, and 2.6% for myocardial infarction, for a total cardiovascular event rate of 5.0% per person-year. The corresponding rates for the age- and sex-matched control group were 0.2%, 0%, and 1.1%, for a total of 1.3% per person-year. The incidence of total cardiovascular events was significantly greater (P< .01) in those with LAF, although there was no difference in survival. CONCLUSION: Lone atrial fibrillation occurring after age 60 years is a risk marker for a substantial increase in cardiovascular events that warrants consideration for antithrombotic therapy.
Aged↗
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.
Animals↗
Management strategies in unstable coronary artery disease--current problems and future directions. The UCAD Council.
Unstable coronary artery disease continues to pose a major challenge to clinicians. The advent of new therapies, such as percutaneous transluminal coronary angioplasty, low-molecular-weight heparins, and glycoprotein IIb/IIIa inhibitors, provides new management options for this indication but also raises new questions with regard to optimal management. Prospective randomized trials with well-defined, long-term outcome measures and a means of identifying which patients will derive most benefit from each treatment, together with a means of rapid and clear dissemination of study results and implications, are required in order to advance the management of unstable coronary artery disease.
Angina, Unstable↗
Antiplatelet therapy in the prevention of ischemic vascular events: literature review and evidence-based guidelines for drug selection.
BACKGROUND: New antiplatelet drugs are being developed and many clinical trials evaluating the benefits of antiplatelet drugs for the secondary prevention of ischemic events in patients with atherosclerotic vascular disease have been performed. HYPOTHESIS: An updated systematic review and evidence-based guidelines for the appropriate selection of antiplatelet drugs may be beneficial to physicians and healthcare organizations attempting to create or update current clinical practice guidelines or clinical pathways aimed at caring for these patients. METHODS: (1) A systematic review of the recent literature on the relative efficacy and safety of aspirin, ticlopidine, and clopidogrel was undertaken; (2) an evidence-based, expert panel approach using a modified Delphi technique to create explicit guidelines for prescribing antiplatelet therapy was instituted; and (3) the recommendations of an expert panel were summarized. RESULTS: Consensus guidelines were developed for the utilization of aspirin, ticlopidine, or clopidogrel for the prevention of ischemic events in patients with manifestations of atherosclerotic vascular disease (prior myocardial infarction, prior ischemic stroke, or established peripheral arterial disease) who are at increased risk for recurrent ischemic events. Based on efficacy and safety, clopidogrel was recommended as the drug of choice for patients with established peripheral arterial disease; aspirin or clopidogrel should be considered in patients with prior myocardial infarction (with clopidogrel favored for patients who have had a recurrent event while on aspirin or in whom aspirin is contraindicated); aspirin or clopidogrel should be considered as first-line treatment in patients with prior ischemic (nonhemorrhagic) stroke--however, clopidogrel is the favored drug in patients in whom other antiplatelet drugs are either contraindicated or who have had recurrent events while on therapy. CONCLUSIONS: Myocardial infarction, ischemic stroke, and peripheral arterial disease are all clinical manifestations of the same underlying disease process (atherosclerosis), with thrombus formation on the disrupted atherosclerotic plaque (atherothrombosis) being a common precipitating factor of ischemic events in patients suffering from these disorders. An evidence-based approach was used to develop a practice guideline, based on available published evidence, for the appropriate utilization of antiplatelet agents (aspirin, ticlopidine, or clopidogrel). These guidelines may be of use to multidisciplinary teams wishing to create or update clinical guidelines or clinical pathways which address the care of patients with atherosclerotic vascular disease. New antiplatelet agents such as clopidogrel may be more effective and associated with lower risk of selected adverse effects (such as gastrointestinal distress, gastrointestinal hemorrhage, and neutropenia) than those previously used to prevent thrombus formation in the setting of atherosclerotic arterial disease. Combination antiplatelet therapy is being evaluated as an option for those patients who experience recurrent events on a single antiplatelet agent.
Algorithms↗
Hirudin reduces tissue factor expression in neointima after balloon injury in rabbit femoral and porcine coronary arteries.
BACKGROUND: Tissue factor (TF) is a transmembrane glycoprotein that, after binding to factor VII/VIIa, initiates the extrinsic coagulation pathway, resulting in thrombin generation and its sequelae. Thrombin has been shown to induce TF mRNA in endothelium, monocytes, and smooth muscle cells, further perpetuating the thrombogenic cycle. This study was designed to determine the effect of specific inhibition of thrombin by recombinant hirudin (r-hirudin) on TF distribution after balloon angioplasty in the cholesterol-fed rabbit femoral artery and porcine coronary artery models. METHODS AND RESULTS: Thirty-five femoral arteries from 32 cholesterol-fed New Zealand White rabbits and 84 coronary arteries from 55 Yorkshire-Albino swine were studied by use of a recently developed in situ method of TF localization based on digoxigenin labeling of recombinant factor VIIa (Dig-VIIa), with correlative studies of TF immunoreactivity by use of anti-rabbit (AP-1) or anti-human (sTF) antibodies. At sites of balloon angioplasty in rabbit femoral or pig coronary arteries (double or single injury), TF-antibody and Dig-VIIa staining were noted in association with endothelial cells, smooth muscle cells, and foam cells and within the fibrous tissue matrix primarily of the adventitia and neointima. Staining was significantly greater after balloon angioplasty than in vessels that had not undergone angioplasty but was similar after single and double balloon injury. Animals treated with r-hirudin (rabbits, 1 mg/kg bolus plus 2-hour infusion; pigs, 1 mg/kg bolus plus 0.7 mg x kg(-1) x d(-1) infusion for 14 days with implantable pump) had diminished TF-antibody and Dig-VIIa staining 28 days after balloon angioplasty compared with controls (bolus heparin only). This effect was more prominent on the neointima and was more striking in the porcine than the rabbit model. CONCLUSIONS: TF expression, persistent 1 month after balloon angioplasty in rabbit femoral arteries and porcine coronary arteries, is attenuated by specific thrombin inhibition with hirudin. These results suggest that thrombin inhibition, in addition to its effect on acute thrombus formation and its effect on luminal narrowing by plaque in experimental animals, may result in a prolonged reduction in thrombogenicity of the restenotic plaque through this effect on TF expression.
Angioplasty, Balloon↗
Platelet glycoprotein IIb/IIIa receptor blockade in unstable coronary disease.
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Angina, Unstable↗
Dissolution of mural thrombus by specific thrombin inhibition with r-hirudin: comparison with heparin and aspirin.
BACKGROUND: The presence of residual mural thrombus may predispose to recurrent thrombotic events in acute coronary syndromes. The purpose of this study was to evaluate the effects of antithrombotic and antiplatelet agents on a preformed, fresh mural thrombus during growth of thrombus. METHODS AND RESULTS: A fresh mural thrombus was formed by perfusing severely injured arterial wall with porcine blood for 5 minutes at a shear rate of 1690 s(-1). Thrombus formation was measured by morphometric analysis (mm2/mm). The average size of a mural thrombus formed in 5 minutes was 0.14+/-0.03 mm2/mm. Progression of thrombus growth within 10 minutes triggered by the preformed thrombus was evaluated in pigs treated with r-hirudin (1 mg/kg per hour i.v.) as a probe for thrombin, high-dose heparin (250 IU/kg per hour i.v.), moderate-dose heparin (100 IU/kg per hour), moderate-dose heparin (100 IU/kg per hour) plus aspirin, aspirin alone (5 mg/kg i.v.), and placebo. Hirudin was associated with a significant decrease (48%) of mural thrombus area and significantly reduced growth of thrombus (0.07+/-0.01), even compared with the highest dose of heparin (0.15+/-0.03), although at lower levels of anticoagulation. Inhibition of growth of thrombus with heparin was dose dependent, showing an inverse correlation of thrombus area with mean plasma heparin concentrations (r=.77, P=.0001). Thrombus size was unchanged by aspirin (0.29+/-0.07) compared with controls (0.28+/-0.07). CONCLUSIONS: Direct inhibition of thrombin activity with r-hirudin completely inhibits growth of thrombus, causes dissolution of a preexisting mural thrombus, and is more effective at lower levels of anticoagulation than the highest dose of heparin at shear rates typical of a moderate coronary stenosis.
Animals↗
Prolonged thrombin inhibition reduces restenosis after balloon angioplasty in porcine coronary arteries.
BACKGROUND: Arterial injury after percutaneous transluminal coronary angioplasty (PTCA) triggers acute thrombus formation and thrombin generation. Hirudin, a potent and direct thrombin inhibitor, prevents thrombus formation after arterial injury. Two large clinical trials showed marked reduction in acute clinical events but no long-term benefits in reducing restenosis during short-term administration of thrombin inhibitors. Our hypothesis is that adequate, maintained thrombin inhibition, by inhibiting all the thrombin-dependent mechanisms, will reduce neointima formation after PTCA. METHODS AND RESULTS: Thirty-six pigs received three different regimens of hirudin: bolus (1 mg/kg), short-term (bolus + 0.7 mg/kg per day for 2 days), and long-term (bolus + 0.7 mg/kg per day for 14 days). The results on neointima formation at 4 weeks after coronary angioplasty were compared with the control group (100 IU heparin/kg bolus). Hirudin was continuously administered for 2 weeks through an infusion pump. In vivo thrombin generation was persistently increased up to 2 weeks after angioplasty. Inhibition of thrombin activity for 14 days reduced luminal narrowing by 40% (58+/-3% versus 35+/-3%; P<.001). No differences were observed among the bolus and short-term hirudin groups and the control group. CONCLUSIONS: Our results indicate that there is a continued, marked thrombin generation that lasts for at least 2 weeks after PTCA. Administration of r-hirudin for 2 weeks significantly reduces neointima formation after PTCA. This observation, if extrapolated to humans, could explain the lack of effect on restenosis observed in the clinical trials with antithrombin agents despite the clear benefits on reducing acute thrombotic complications after PTCA. Therefore an adequate and prolonged administration of thrombin inhibitors is needed to "passivate" the thrombogenic substrate (disrupted arterial wall) and achieve full benefit of this therapeutic approach.
Angioplasty, Balloon, Coronary↗
Different response to balloon angioplasty of carotid and coronary arteries: effects on acute platelet deposition and intimal thickening.
PTCA is a well-established intervention to reduce the severity of atherosclerotic coronary stenosis. Its primary success rate is seriously handicapped by the high incidence of late restenosis. Given the clinical and social importance of this proliferative process, new strategies are needed to prevent or reduce restenosis. Several animal models as well as different arteries have been used to study neointimal proliferation after arterial injury. A number of agents have shown to reduce neointimal proliferation after arterial injury in the carotids and iliac arteries of rodent models. Unfortunately, these results have not been replicated in humans. We have compared the acute and late response to vascular injury of the carotid and coronary arteries in the pig. Arterial injury was induced by performing balloon angioplasty of the carotid (elastic) and coronary (muscular) arteries in swine. Acute platelet-thrombus formation was evaluated by quantitation of Indium-labeled platelets deposited on the injured segments 1 h after procedure. Measurement of intimal area was performed by morphometry of the most stenotic cross-section at 28 days after balloon angioplasty. Platelet deposition after mild and severe injury in carotids (4 +/- 1 and 56 +/- 13 x 10(6) platelets/cm2, respectively) and coronaries (15 +/- 5 and 141 +/- 20 x 10(6) platelets/cm2, respectively) are significantly greater in deep, than in mild injury (P < 0.005), and significantly greater in coronary than in carotid arteries after deep injury (P < 0.05). Likewise, late neointima formation was significantly greater (P < 0.05) after mild and severe injury in coronary (17 +/- 0.5 and 56 +/- 2%, respectively) than in carotid arteries (5 +/- 0.5 and 12 +/- 1%, respectively). Acute platelet-thrombus formation and late neointimal thickening are modulated by the degree of injury induced during the interventions; and after disruption of the internal elastic lamina, coronary arteries always had significantly more acute thrombus and neointimal thickening. This study emphasizes the importance of the animal species, the type of injury and the artery chosen for studies on restenosis post interventions.
Acute Disease↗
Atherothrombosis: mechanisms and clinical therapeutic approaches.
Eroded or disrupted atherosclerotic plaques act as a substrate for thrombosis, leading to ischemic coronary artery and cerebrovascular disease. Plaques vary greatly in composition, size, and the degree of stenosis they cause. Plaques can be categorized based on these features, which helps to estimate the likelihood of rupture and subsequent thrombosis. Vascular plaques often begin at regions with low and oscillatory shear forces that cause chronic minimal endothelial damage or dysfunction. Lipoproteins enter the vessel wall, promoting the recruitment of monocytes, which imbibe lipids and become foam cells. Smooth muscle cells invade these early plaques, producing connective tissue fibrils that form a fibrous cap over the lipid center; rupture of this cap is an important cause of thrombosis. Passive plaque disruption occurs when physical forces cause cap rupture; active disruption occurs when the cap is attacked by macrophages and proteolytic enzymes. Tissue factor is one of many factors within plaque that stimulates thrombosis.
Acute Disease↗
Guidelines for management of left-sided prosthetic valve thrombosis: a role for thrombolytic therapy. Consensus Conference on Prosthetic Valve Thrombosis.
OBJECTIVES: We sought to form a consensus recommendation for management of prosthetic valve thrombosis (PVT) from previous case and uncontrolled reports from a consensus of international specialists. BACKGROUND: PVT and thromboembolism relate to inadequate anticoagulation and valve type and location. PVT is suspected by history (dyspnea) and auscultation (muffled valve sounds or new murmurs) and confirmed by Doppler echocardiography showing a marked valve gradient. METHODS: A consensus conference was held to recommend management of left-sided PVT. RESULTS: Transesophageal Doppler echocardiography is used to visualize abnormal leaflet motion and the size, location and mobility of thrombus. Thrombolysis is used for high risk surgical candidates with left-sided PVT (New York Heart Association functional class III or IV) because cerebral thromboembolism may occur in 12% of patients. Duration of thrombolysis depends on resolution of pressure gradients and valve areas to near normal by Doppler echocardiography performed every few hours. Lysis is stopped after 72 or 24 h if there is no hemodynamic improvement (operation indicated). Heparin infusion with frequent measurement of activated partial thromboplastin time (aPTT) begins when aPTT is more than twice control levels and can be converted to warfarin (international normalized ratio [INR] 2.5 to 3.5) plus aspirin (81 to 100 mg/day). Patients in functional class I or II have lower surgical mortality, and those with large immobile thrombi on the prosthetic valve or left atrium have responded to endogenous lysis with combined subcutaneous heparin every 12 h (aPTT 55 to 80 s) plus warfarin (INR 2.5 to 3.5) for 1 to 6 months. Operation is advised for nonresponders or patients with mobile thrombi. CONCLUSIONS: Thrombolysis, followed by heparin, warfarin and aspirin, is advised for high risk surgical candidates with left-sided PVT.
Aortic Valve↗
Direct thrombin inhibition superior to heparin during and after thrombolysis: dose, duration, and drug.
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Animals↗
Mechanisms determining course and outcome of diabetic patients who have had acute myocardial infarction.
PURPOSE: To review the pathogenic mechanism that lead to the poor prognosis of diabetic patients after myocardial infarction and to determine the efficacy of current interventions for myocardial infarction in these patients. DATA SOURCES: Search of the MEDLINE database from 1985 to 1995, using the keywords diabetes, myocardial infarction, and cardiomyopathy, and a search of the reference citations of relevant articles. STUDY SELECTION: Experimental and clinical studies on myocardial infarction in diabetic patients and basic research studies relevant to this topic. DATA SYNTHESIS: The excess in-hospital mortality of diabetic patients results primarily from an increased incidence of congestive heart failure. Several combined mechanisms reduce the compensatory ability of the noninfarcted myocardium; such mechanisms include preexisting congestive heart failure caused by diabetic cardiomyopathy, severe coronary artery disease, decreased vasodilatory reserve of epicardial and resistance arteries, and possibly abnormal metabolism of myocardial substrate. Late mortality results from increased reinfarction rates caused by the diffuse nature of the atherosclerotic disease and hypercoagulable state. Platelet hyperactivity, reduced fibrinolytic capacity, increased concentrations of hemostatic proteins, and endothelial dysfunction promote thrombosis at the site of plaque rupture. Autonomic neuropathy predisposes patients to ventricular arrhythmias. Thrombolytic agents, aspirin, beta-blockers, and angiotensin-converting enzyme inhibitors are effective in patients with diabetes. CONCLUSIONS: In the thrombolytic era, mortality rates of diabetic patients who have had acute myocardial infarction remain 1.5 to 2 times higher than those in nondiabetic patients. This increased mortality rate is caused by diverse mechanisms that affect myocardial function and blood supply and by the tendency toward thrombosis in diabetic patients. Current therapies for myocardial infarction are effective in these patients. Improved metabolic control may also decrease mortality rates.
Cardiomyopathies↗
Tissue factor modulates the thrombogenicity of human atherosclerotic plaques.
BACKGROUND: The thrombogenicity of a disrupted atherosclerotic lesion is dependent on the nature and extent of the plaque components exposed to flowing blood together with local rheology and a variety of systemic factors. We previously reported on the different thrombogenicity of the various types of human atherosclerotic lesions when exposed to flowing blood in a well-characterized perfusion system. This study examines the role of tissue factor in the thrombogenicity of different types of atherosclerotic plaques and their components. METHODS AND RESULTS: Fifty human arterial segments (5 foam cell-rich, 9 collagen-rich, and 10 lipid-rich atherosclerotic lesions and 26 normal, nonatherosclerotic segments) were exposed to heparinized blood at high shear rate conditions in the Badimon perfusion chamber. The thrombogenicity of the arterial specimens was assessed by 111In-labeled platelets. After perfusion, specimens were stained for tissue factor by use of an in situ binding assay for factor VIIa. Tissue factor in specimens was semiquantitatively assessed on a scale of 0 to 3. Platelet deposition on the lipid-rich atheromatous core was significantly higher than on all other substrates (P = .0002). The lipid-rich core also exhibited the most intense tissue factor staining (3 +/- 0.1 arbitrary units) compared with other arterial components. Comparison of all specimens showed a positive correlation between quantitative platelet deposition and tissue factor staining score (r = .35, P < .01). CONCLUSIONS: Our results show that tissue factor is present in lipid-rich human atherosclerotic plaques and suggest that it is an important determinant of the thrombogenicity of human atherosclerotic lesions after spontaneous or mechanical plaque disruption.
Animals↗
Directions for improvement of substitute heart valves: National Heart, Lung, and Blood Institute's Working Group report on heart valves.
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Equipment Design↗
Thrombosis triggered by severe arterial lesions is inhibited by oral administration of a glycoprotein IIb/IIIa antagonist.
Platelet aggregation and thrombosis play an important role in the onset of acute coronary events. Regardless of the stimulus for activation, platelet thrombus formation is ultimately regulated through the IIb/IIIa receptor complex. The effects of oral administration of xemilofiban, a non-peptide mimetic of the RGDF sequence of the IIb/IIIa receptor complex, on thrombus formation were evaluated in a canine model. Xemilofiban significantly reduced platelet deposition on severely damaged arterial wall. Platelet deposition was reduced at both low (13 +/- 1 from 56 +/- 18 x 10(6) platelets cm-2; P < 0.05) and high (23 +/- 2 from 111 +/- 21 x 10(6) platelets cm-2; P < 0.01) shear rates. Platelet deposition was reduced to a monolayer as seen by electron microscopy (platelet-vessel wall interaction). Therefore, the availability of an orally active IIb/IIIa antagonist for chronic use may have significant value in preventing thrombus formation in those clinical situations associated with severe arterial injury, such as atherosclerotic plaque disruption.
Administration, Oral↗
Pathogenesis of thrombosis in coronary artery disease.
Arterial thrombosis in the acute coronary syndromes is precipitated by plaque disruption. This occurs in lesions with a large lipid core, a thin fibrous cap, macrophages infiltrating the fibrous cap, and a lipid core with a high tissue-factor content. This results in acute platelet deposition and rapid growth of mural thrombus which unfavorably influences the rheology of blood flow to produce more thrombus, and propagates additional thrombosis by the high thrombogenicity of the mural thrombus overlying the disrupted culprit arterial lesion. Acute therapy in the hospital and subacute therapy beyond the hospital phase for as long as 1.5-3 months with aspirin plus anticoagulation, such as low-molecular-weight heparin, or oral anticoagulation, reduces thrombotic occlusion, myocardial infarction, death, and need for coronary revascularization.
Coronary Disease↗