Biomedical subjects
Publications and source records attributed to J H Chesebro.
This is an extensive review of thrombolysis in myocardial infarction with discussions of the pathophysiology of occlusion, clinical occlusion and rationale for thrombolysis, thrombolytic agents, results of thrombolysis (incidence of reperfusion, left ventricular function, and mortality), complications of thrombolytic therapy, reocclusion, and current recommendations.
The use and type of antithrombotic therapy for patients with cardiac disease are described based on an understanding of the pathophysiologic mechanisms involved, the risk of thromboembolism, and the evidence from prospective and, if necessary, retrospective clinical trials. The indications and intensity of anticoagulant therapy in patients with valvular heart disease and prosthetic valves are first discussed. We recommend that the prothrombin time be reported as a ratio and standardized using the International Normalized Ratio. The pivotal role of platelets and the clotting system in the initiation and progression of atherosclerosis and the acute coronary syndromes is described. There is no evidence to date that antiplatelet therapy is of value in primary prevention or in patients with stable angina, but the value of aspirin in patients with unstable angina was clearly shown in two well-designed studies. Adequate prophylactic therapy to prevent the thrombotic complications of acute myocardial infarction (i.e., venous thrombosis and intracardiac thrombosis) is described, and the available data on the prevention of coronary reocclusion after thrombolysis reviewed. There is now convincing evidence from studies in animals and in patients that vascular injury during aortocoronary vein bypass graft surgery requires antitihrombotic therapy starting before the procedure to minimize acute platelet thrombus deposition and prevent occlusion. Restenosis after arterial angioplasty appears to be related to acute platelet thrombus deposition on the site of deep arterial injury. Therapeutic interventions should probably involve both anticoagulants and platelet inhibitor therapy. Implications derived from recent animal studies are discussed.
Thrombosis is an important pathogenetic factor in acute coronary syndromes, including unstable angina, myocardial infarction and sudden death. In all of these conditions, atherosclerotic plaque fissuring is a key inciting event. Minor injury to the vessel wall brings into play interactions between platelets and the wall. Platelet adhesion and aggregation ensue, modulated by a number of factors and substances. More severe injury to the vessel wall exposes the blood to other thrombogenic substances. Platelet deposition is also affected by rheologic (blood flow) factors at the site of injury, depending on the degree of stenosis and the resulting shear rates. The mechanism of unstable angina appears to be related to these factors in the following sequence: mild stenosis and minor injury with plaque fissuring, platelet responses, labile thrombosis, intermittent ischemia and pain at rest. Vasoconstriction may contribute to the symptoms. Although developing from the same origin, infarction may stem from a greater degree of vessel wall damage resulting in more permanent thrombus. Such considerations provide a focus for preventive strategies, including the optimal use of current inhibitors of platelet adhesion and aggregation and the application of peptide receptor blockers and monoclonal antibodies. Also important is control of rheologic factors by preventing stenosis or correcting it with angioplasty and thrombolytic therapy. Further elucidation of the critical role of thrombosis in coronary syndromes will facilitate progress toward the ultimate goal of primary prevention.
Restenosis after arterial angioplasty appears to be a response to deep arterial injury, which is much more thrombogenic than superficial injury (endothelial denudation). Deep arterial injury exposes collagen, elastin and smooth muscle cells to circulating blood, releases tissue thromboplastin and causes immediate platelet-thrombus deposition as a result of activation of platelets and the clotting system, both of which mutually facilitate activation of the other. Regrowth of endothelium also is protective against platelet deposition. Platelet adherence to collagen, and thus to the arterial wall that is deeply injured, increases with shear rate (related inversely to the fourth power of luminal cross-sectional area and directly to blood flow); thus, the effect of shear rate increases the importance of adequate dilatation at the time of the procedure. Therapy that will reduce acute platelet-thrombus deposition appears to be an important factor for reduction of restenosis. Vasoconstriction occurs experimentally after arterial angioplasty in arterial segments proximal and distal to the dilated segment where there has been no necrosis of smooth muscle cells. The vasoconstriction is directly related to the severity of platelet deposition, can be reduced by reducing platelet deposition with low dose aspirin (1 mg/kg daily) and is probably mediated by vasoconstrictor substances from platelets (thromboxane A2, serotonin and other substances). Platelet-membrane receptor inhibitors to these substances reduce the vasoconstriction but do not reduce platelet deposition. Therapeutic intervention should probably involve both anticoagulation and platelet inhibition. Platelet-membrane receptor inhibition to the fibrinogen receptor, factor VIII-von Willebrand factor or both may be necessary acutely to sufficiently reduce acute platelet-thrombus deposition.
Regional left ventricular (LV) function was assessed using serial biplane orthogonal LV angiograms recorded before and after reperfusion therapy for acute myocardial infarction (AMI) in 24 patients. Improvement in regional LV function was seen in only 5 patients after reperfusion therapy when only the right anterior oblique view was analyzed; improvement in regional wall motion was seen in 14 when biplane views were analyzed. Biplane analysis was particularly important in the 12 patients with right coronary artery occlusion, among whom the right anterior oblique view showed improvement in only 1 patient but the left anterior oblique view showed improvement in 6 patients (p less than 0.05). Biplane analysis is more sensitive than monoplane right anterior oblique analysis alone for detecting improvement in LV function after reperfusion therapy for AMI. However, both views are complementary, adding information about regional function not revealed by either view alone.
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Although aggregating platelets can release potent vasoactive substances in vitro, the importance of platelets in mediating naturally occurring or provoked spasm in vivo is not clear. To investigate the possible role of platelets in arterial spasm following arterial injury induced by angioplasty, quantitative platelet deposition of the dilated arterial segment and the degree of vasoconstriction (average percent diameter narrowing just proximal and distal to the dilated segment) produced during angioplasty of the common carotid arteries were studied in 42 heparinized normal pigs that were killed immediately after the angioplasty procedure. Angiographic films of the carotid arteries were taken before and after the dilatation to assess the vasoconstriction. Vasoconstriction was greater (40% vs 19%, p less than .002) when platelet deposition (X 10(6)/cm2) was in excess of 10, and the severity of vasoconstriction in vivo had a close positive exponential correlation (r = .77, p less than .001) with extent of platelet deposition in 24 untreated pigs. Platelet deposition and vasoconstriction were greater with severe arterial wall injury than with mild injury (58.8 versus 6.9, p less than .0001; 37% vs 21%, p less than .001, respectively). After severe injury in 18 pigs pretreated with 1 mg/kg/day aspirin, platelet deposition decreased (from 58.8 to 19.6, p less than .02) and vasoconstriction decreased (from 37% to 21%, p less than .003) relative to control. After mild injury, platelet deposition and vasoconstriction were mild and unchanged by aspirin. Thus, local vasoconstriction is influenced by the degree of platelet deposition.(ABSTRACT TRUNCATED AT 250 WORDS)
Intravenous administration of 80 mg of recombinant tissue plasminogen activator (rt-PA, 40, 20, and 20 mg in successive hours) and streptokinase (SK, 1.5 million units over 1 hr) was compared in a double-blind, randomized trial in 290 patients with evolving acute myocardial infarction. These patients entered the trial within 7 hr of the onset of symptoms and underwent baseline coronary arteriography before thrombolytic therapy was instituted. Ninety minutes after the start of thrombolytic therapy, occluded infarct-related arteries had opened in 62% of 113 patients in the rt-PA and 31% of 119 patients in the SK group (p less than .001). Twice as many occluded infarct-related arteries opened after rt-PA compared with SK at the time of each of seven angiograms obtained during the first 90 min after commencing thrombolytic therapy. Regardless of the time from onset of symptoms to treatment, more arteries were opened after rt-PA than SK. The reduction in circulating fibrinogen and plasminogen and the increase in circulating fibrin split products at 3 and 24 hr were significantly less in patients treated with rt-PA than in those treated with SK (p less than .001). The occurrence of bleeding events, administration of blood transfusions, and reocclusion of the infarct-related artery was comparable in the two groups. Thus, in patients with acute myocardial infarction, rt-PA elicited reperfusion in twice as many occluded infarct-related arteries as compared with SK at each of seven serial observations during the first 90 min after onset of treatment.
To study the effect of dietary supplementation with fish oil on endothelium-dependent responses, Yorkshire pigs were maintained on a normal diet or on a low (0.6 ml/kg/day) or a high (1.0 ml/kg/day) dose of cod-liver oil for 4 weeks. Endothelium-dependent responses were examined in vitro in rings of proximal left anterior descending coronary arteries taken from control and treated animals studied in parallel. Endothelium-dependent relaxations in response to bradykinin, serotonin, adenosine diphosphate, and thrombin were facilitated in arteries from treated but not in those from control animals, whereas the relaxations in response to A23187 were unaltered. The facilitated relaxations were not altered by indomethacin but significantly inhibited by methylene blue. Aggregating platelets from control and treated pigs induced comparable, facilitated endothelium-dependent relaxations in rings taken from treated pigs. The platelet-induced contractions were significantly reduced in rings with endothelium taken from treated pigs, and they were comparable in rings without endothelium in both groups. Aggregating platelets from control and treated pigs released comparable amounts of serotonin and thromboxane A2. Endothelium-dependent relaxations induced by arachidonic acid and eicosapentaenoic acid were unaltered, whereas transient endothelium-dependent contractions induced by arachidonic acid were significantly reduced by the treatment with cod-liver oil. Relaxations to sodium nitroprusside or isoproterenol,and contractions to potassium chloride or serotonin were not different in rings without endothelium from control or treated pigs. These results indicate that dietary supplementation with cod-liver oil facilitates endothelium-dependent relaxations and inhibits endothelium-dependent contractions in porcine coronary arteries.
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There is now considerable evidence to suggest that some aspects of early lesion formation and later lesion growth are a reaction to injury. Hemodynamic factors are important in determining the site of injury and may produce injury directly. Injury can lead to atherogenesis in animal models as well as in humans. Superficial injury exposes the subendothelium, allowing platelet adhesion, which at high shear rates is dependent on vWF. Platelet adhesion and degranulation release PDGF, which stimulates smooth muscle cell proliferation, synthetic functions, and vasoconstriction. LDL stimulates smooth muscle cell growth as well as damages endothelium in some experimental systems. Thus, a link is provided between platelet and lipid involvement in atherosclerosis. Direct evidence for a role of platelets in atherogenesis comes from studies in which animals were treated to reduce platelet number or function or in which platelet function is genetically impaired (pigs with von Willebrand's disease). In these models, reduced platelet function is associated with less atherosclerosis. Deeper injury exposes collagen, with subsequent platelet aggregation, thrombin and fibrin generation. The role of reduced production of PGI2 and fibrinolytic agents following severe damage is unknown. Deep injury to the vessel occurs during plaque fissuring, the pathologic process underlying most cases of myocardial infarction, unstable angina, and some cases of sudden death. Angioplasty produces amelioration of many patients' symptoms and is safe. However, acute occlusion occurs occasionally, and restenosis in the first year occurs in some 30 percent of patients treated. Angioplasty damages the arterial wall, with endothelial denudation and intimal and medial splitting. Why does this, and plaque injury, by stimulating platelet deposition, not produce more restenosis? Changes in arterial anatomy are likely to be important: the increase in vessel diameter and in blood flow produce conditions less favorable for thrombotic or arteriosclerotic restenosis.
Acute occlusion and restenosis of the dilated coronary segment remain serious unsolved complications that can occur after coronary angioplasty. Acute occlusion is seen in approximately 3-5% of patients and restenosis in 13-47% of patients undergoing this procedure. While the causes of these complications are incompletely understood, platelets and their interactions with the vessel wall appear to be important. The mechanism of stenosis dilatation involves a splitting or tearing of the atherosclerotic plaque as well as desquamation of the endothelial layer of the vessel wall. Therefore, superficial as well as deep arterial injury occurs as a result of angioplasty. Acute occlusion and restenosis appear to be the biological response to this injury. Following even subtle injury to the endothelial layer, platelets adhere to the vessel wall and become activated, releasing substances such as platelet derived growth factor which stimulates intimal hyperplasia and re-growth of the atherosclerotic plaque. Deeper injury results in increased platelet deposition and mural thrombus formation. Rheologic factors including oscillatory shear forces and high local shear rates resulting from residual stenosis and intimal dissection further promote platelet activation and thrombus formation. Both the rheologic factors and the thrombogenic properties of the vessel wall and circulating blood promote restenosis and acute occlusion. Studies using animal models have demonstrated that platelet inhibitor drugs used in addition to heparin can reduce the amount of platelet deposition at the time of angioplasty, and may have a favorable effect on the occurrence of acute occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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The ability of radionuclide variables obtained at rest and at peak exercise to discriminate the number of stenosed (greater than or equal to 70% luminal diameter narrowing) major coronary arteries was evaluated in 296 patients undergoing supine exercise radionuclide ventriculography. Stepwise linear discriminant analysis of the data from the first 200 patients identified a significant (p less than 0.001) discriminatory combination. Application of this function to the remaining 96 patients provided correct classification of arteriographically determined zero, one, two, and three stenosed arteries in 59%, 18%, 14%, and 60% of cases, respectively. The discriminant function classified minimal stenoses (zero or one artery) and multivessel stenoses (two or three arteries) correctly by arteriography in two thirds of cases in each group. Arteriographic presence of three stenoses was unlikely in those classified as having no stenosis, and absence of stenosis was rare in those classified as having three stenoses. Exercise radionuclide ventriculography is most helpful in identifying minimal and multivessel coronary disease rather than number of stenosed major coronary arteries.
Early patency and late patency have consistently been better with single internal mammary artery grafts than with saphenous vein conduits. To determine the efficacy of these two types of grafts in sequential anastomoses, we performed sequential anastomoses of the left internal mammary artery to the left anterior descending and diagonal coronary arteries in 40 patients and compared the results with those in 58 patients who received sequential saphenous vein grafts. Treatment with dipyridamole (starting 48 hours before operation) and aspirin (added 7 hours after operation) was given to the 40 patients with internal mammary artery grafts and to 32 of the 58 patients in the saphenous vein group. After the bypass procedure, mean blood flows were as follows: 68 ml/min in patients with internal mammary artery grafts, 73 ml/min in patients who received saphenous vein grafts and a placebo, and 99 ml/min in those who received saphenous vein grafts, aspirin, and dipyridamole. Early patency of sequential internal mammary artery grafts to the diagonal and left anterior descending coronary arteries was comparable to that of sequential saphenous vein grafts. Because a substantial late reduction in patency has been noted in sequential saphenous vein grafts, sequential internal mammary artery grafts may be the preferred conduit for coronary artery revascularization.
We studied mean platelet survival times in healthy volunteers with use of [51Cr]disodium chromate, 111In-oxine (in a solution of acid-citrate-dextrose [ACD] and saline), and 111In-tropolone (in ACD-plasma) as markers. Differences found between the 51Cr and 111In labels probably can be attributed to a variation in localization of the label on the cell and of renal handling of the free label after release. The mean platelet survival time with 51Cr was slightly longer than the survival time with both indium labels and showed a sex difference not seen with 111In-oxine. Protein-bound plasma 51Cr was lower than plasma 111In and remained constant throughout the study. Plasma 111In increased with time. For survival time calculations, no correction for free 51Cr is necessary, but correction should routinely be performed when 111In markers are used. Both 111In markers gave similar results with respect to platelet survival time. The somewhat more elaborate plasma labeling procedure with tropolone shows no measurable advantage over the original 111In-oxine method. 111In-tropolone labeling takes less time and maintains platelets in the physiologic environment of plasma during incubation. Biodistribution studies show no difference between the two 111In markers.
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.
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.