Symptoms of dyspnea and fatigue limit effort tolerance in patients with chronic cardiac failure. These symptoms may be consequent to an abnormal cardiocirculatory response to the increased O2 demand that accompanies exercise as manifested by: reduced ability to augment cardiac output in response to increased left ventricular filling pressure, inadequate vasodilatory response in exercising limbs, the onset of lactate production by muscle at relatively low levels of work, and increased work of breathing that accompanies pulmonary venous hypertension and abnormal compliance of the lung secondary to left ventricular dysfunction. The clinical experience with new positive inotropic agents in the long-term treatment of patients with chronic cardiac failure is accumulating rapidly. Attention has focused on the ability of these agents to improve exercise performance, particularly their ability to increase the aerobic capacity. The experience to date suggest that beta-adrenergic receptor agonists offer little advantage in this regard while causing ventricular arrhythmias. On the other hand, the phosphodiesterase inhibitors, MDL 17,043 and MDL 19,205, and the bipyridine derivatives, amrinone and milrinone, may improve exercise performance in many patients and exert a sustained effect during long-term therapy. Placebo-controlled, randomized trials will need to be performed, however, to determine the ultimate efficacy and safety of these agents. The most meaningful results for analysis will be obtained when objective parameters of exercise performance, such as aerobic capacity and anaerobic threshold, are monitored that are free of patient or physician bias.

Coronary angiography has proved beyond doubt that complete coronary occlusion is the rule in the very early hours of infarction. The 60% to 80% rate of coronary recanalization after thrombolytic therapy has proved that thrombosis is a major component of the occlusion at the time when the procedure is performed a few hours after the onset of symptoms. However, the trigger for coronary thrombosis and the causes of failure of thrombolytic therapy are still a matter of speculation. The relatively rare occurrence of acute coronary occlusion in the life of an individual with even severe coronary disease can be explained on the basis of the necessity of either extremely powerful isolated stimuli, which only occurs rarely, or the casual simultaneous presence in one coronary arterial segment of multiple unfavorable events, such as plaque fissuring, enhanced reactivity of coronary smooth muscle to constrictor stimuli and displacement of the thrombotic-thrombolytic equilibrium toward thrombosis. Coronary artery constriction possibly caused by vasoconstrictor substances released by thrombus, represents the potential element of a vicious cycle causing persistent coronary occlusion and reocclusion when reflow occurs with thrombolysis.

To study the prevention of occlusion of aortocoronary-artery bypass grafts, we conducted a prospective, randomized, double-blind trial comparing long-term administration of dipyridamole (begun 2 days before operation) plus aspirin (begun 7 hr after operation) with placebo in 407 patients. Results at 1 month and at 1 year showed a reduction in the rate of graft occlusion in patients receiving dipyridamole and aspirin. On the basis of our clinical trial and our experimental studies in dogs and pigs, we describe four consecutive phases of aortocoronary artery bypass vein-graft disease: an early postoperative phase of platelet thrombotic occlusion, which is significantly prevented by platelet inhibitor therapy when started in the perioperative period; in addition, occlusion rates are presently decreasing, perhaps related to better surgical and technical experience; an intermediate phase of platelet-related intimal hyperplasia, within the first postoperative year, which is not prevented with platelet inhibitor therapy; a late phase of occlusion, toward the end of the first postoperative year, in which intimal hyperplasia or complicating platelet thrombi superimposed on the intimal hyperplasia may contribute to occlusion; platelet inhibitor therapy is of significant benefit in the prevention of this thrombotic type of occlusion; a phase of atherosclerotic disease, after the first postoperative year, in which the role of platelets and of platelet inhibitor therapy is under investigation.

Aspirin has been convincingly shown to reduce stroke and death in men with transient ischemic attacks (it may possibly be beneficial to women also), myocardial infarction and death in patients with unstable angina, thromboembolic complications associated with artificial heart valves in patients receiving oral anticoagulants (although gastrointestinal bleeding is prohibitive with this combination), and thrombotic occlusion of silicone rubber arteriovenous cannulae in uremic patients undergoing hemodialysis. In addition, aspirin may possibly decrease occlusion of saphenous vein aortocoronary grafts and venous thrombosis in men after hip replacement, although these reports require confirmation. Aspirin is ineffective in the secondary prevention of stroke and has unproven benefit in the secondary prevention of myocardial infarction. Dipyridamole in combination with oral anticoagulation decreases the thromboembolic complications associated with mechanical heart valves. The combination of aspirin and dipyridamole prevents both early and late occlusion of saphenous vein aortocoronary bypass grafts and protects renal function in patients with membranoproliferative glomerulonephritis. The relative importance of combining aspirin and dipyridamole compared with either agent used singly remains to be established. Sulfinpyrazone reduces the thrombotic occlusion of arteriovenous cannulae and early occlusion of saphenous vein aortocoronary grafts. The reported benefit in the secondary prevention of myocardial infarction is controversial.

There is evidence that aspirin is partially effective in the prophylaxis of various vasoocclusive disorders. This article reviews pharmacologic opportunities for improvement over and above the therapeutic effect of aspirin. It is concluded that several rational possibilities merit consideration, in particular, the use of combinations of drugs that affect the thrombotic process at different points. Such strategies will ultimately require validation by clinical trial.

Nonsteroidal anti-inflammatory drugs and sulfinpyrazone compete dose-dependently with arachidonate for binding to platelet cyclooxygenase. Such a process closely follows systemic plasma drug concentrations and is reversible as a function of drug elimination. Peak inhibition and extent of its reversibility at 24 hr varies consistently with individual pharmacokinetic profile. Inhibition of platelet cyclooxygenase activity by these agents is associated with variable effects on prostaglandin (PG) synthesis in the gastric mucosa and the kidney. Aspirin acetylates platelet cyclooxygenase and permanently inhibits thromboxane (TX) A2 production in a dose-dependent fashion when single doses of 0.1 to 2.0 mg/kg are given. Acetylation of the enzyme by low-dose aspirin is cumulative on repeated dosing. The fractional dose of aspirin necessary to achieve a given level of acetylation by virtue of cumulative effects approximately equals the fractional daily platelet turnover. Serum TXB2 measurements obtained during long-term dosing with 0.11, 0.22, and 0.44 mg/kg aspirin in four healthy subjects could be fitted by a theoretical model assuming identical acetylation of platelet (irreversible) and megakaryocyte (reversible) cyclooxygenase. For a given dose within this range, both the rate at which cumulative acetylation occurs and its maximal extent largely depend upon the rate of platelet turnover. Continuous administration of low-dose aspirin (20 to 40 mg/day) has no statistically significant effect on urinary excretion of either 6-keto-PGF1 alpha or 2,3-dinor-6-keto-PGF1 alpha, i.e., indexes of renal and extrarenal PGI2 biosynthesis in vivo. Whether a selective sparing of extraplatelet cyclooxygenase activity by low-dose aspirin will result in increased antithrombotic efficacy, fewer toxic reactions, or both remains to be established in prospective clinical trials.

Myocardial thallium-201 (201Tl) scintigraphy or radionuclide angiography performed in conjunction with exercise stress testing can provide clinically useful information regarding the functional significance of underlying coronary artery stenoses in patients with known or suspected coronary artery disease. Knowledge of type, location, and extent of myocardial 201Tl perfusion abnormalities or the severity of exercise-induced global and regional dysfunction has prognostic value. Risk stratification can be undertaken with either radionuclide technique by consideration of the magnitude of the ischemic response and may assist in the selection of patients for coronary artery bypass graft surgery (CABG). In patients with coronary artery disease, delayed 201Tl redistribution observed on exercise or dipyridamole 201Tl scintigraphy, particularly when present in multiple vascular regions and associated with increased lung 201Tl uptake, has been shown to be predictive of an adverse outcome, whereas patients with chest pain and a normal exercise 201Tl scintigram have a good prognosis with medical treatment. Similarly, a marked fall in the radionuclide ejection fraction from rest to exercise has been found to correlate with high-risk anatomic disease. In one published nonrandomized study, patients with coronary artery disease who demonstrated an abnormal ejection fraction response to exercise preoperatively had a better survival with CABG than with medical therapy. Another important application of radionuclide imaging in patients being considered for CABG (particularly those with a depressed resting left ventricular ejection fraction) is the determination of myocardial viability and potential for improved blood flow and enhanced regional function after revascularization. There are certain limitations of exercise 201Tl scintigraphy and radionuclide angiography that can be reduced by improved methods of quantitation of perfusion and function and further development of tomographic imaging approaches.

Both the Veterans Administration Cooperative Study and the European Coronary Surgery Study have provided only brief accounts of graft patency rates in their surgically treated patients. In the Veterans Administration Cooperative Study, at an average of 1 year after operation, 69% of the grafts were patent among 208 patients; 88% of patients had at least one patent graft, and 58% had all grafts patent. In the European Coronary Surgery Study, angiographic examination of the grafts was performed within 9 months of operation in 84 patients, and showed a patency rate of 90%; in 223 patients, the examination was performed at between 9 and 18 months, and showed a 77% patency rate. In the Coronary Artery Surgery Study (CASS), graft patency rates were evaluated within 60 days of operation in 129 patients, a median of 18 months after operation in 121 patients, and a median of 5 years after operation in 197 patients. Cumulative vein graft patency (per distal anastomosis) was 90% early, 82% at 18 months, and 82% at 5 years. At least one graft anastomosis was patent early in 97% of patients, at 18 months in 96% of patients, and at 5 years in 97% of patients; all graft anastomoses were patent early in 81% of patients, at 18 months in 70% of patients, and at 5 years in 67% of patients. The incidence of vein graft stenosis of 50% or more was 10% at 18 months and 8% at 5 years after operation. The excellent results reported in CASS were associated with marked improvement in quality of life and excellent survival 5 years after operation in surgically treated patients, as previously reported.(ABSTRACT TRUNCATED AT 250 WORDS)

On the basis of our recent experimental studies in dogs and pigs and a prospective clinical study in 407 patients, we describe four consecutive phases of aortocoronary artery bypass vein-graft disease. We focus on the role of platelets in its pathogenesis and of platelet inhibitor drugs in its prevention: (1) an early postoperative phase of platelet thrombotic occlusion, which is significantly prevented by platelet inhibitor therapy when started in the perioperative period; (2) an intermediate phase of platelet-related intimal hyperplasia, within the first postoperative year, which is not prevented with platelet inhibitor therapy; (3) a late phase of occlusion, towards the end of the first postoperative year, in which intimal hyperplasia or complicating platelet thrombi superimposed on the intimal hyperplasia may contribute to occlusion--platelet inhibitor therapy is of significant benefit in the prevention of the thrombotic type of occlusion; (4) a phase of atherosclerotic disease, after the first postoperative year, in which the role of platelets and of platelet inhibitor therapy is under investigation. Vein graft disease and occlusion rates vary widely according to time after operation and risk factors of occlusion. Currently, it appears that occlusion rates are decreasing, perhaps related to better surgical and technical experience.

Repeat coronary artery bypass grafting (CABG) accounts for approximately 5% of all myocardial revascularization procedures in the United States annually; it is estimated that nearly 7000 reoperations will be performed in 1984. Angiographic indications for repeat CABG include primary bypass graft obstruction, progressive coronary arteriosclerosis, and combined graft failure and new coronary artery disease. Saphenous vein obstruction secondary to arteriosclerosis occurs in more than half the bypass grafts at 10 years after CABG. Successful aortocoronary reoperation is dependent on careful attention to special surgical technical considerations such as chest reentry, cardiopulmonary bypass management and myocardial preservation, primary graft handling and identification of the target coronary vessel, choice of available bypass conduits, completeness of revascularization, and hemostasis and blood conservation. Operative mortality for repeat CABG is approximately twice that for an initial aortocoronary bypass procedure. Overall operative morbidity is not significantly different for primary and subsequent myocardial revascularization. Five-year survival after repeat aortocoronary surgery is approximately 90% and compares favorably with survival rates after initial CABG. However, symptomatic relief of angina pectoris is not as effective after a repeat myocardial revascularization as it was after the first CABG; only half the patients are angina-free 5 years after reoperation. As with primary revascularization, long-term graft patency rates after coronary reoperation are superior for the internal artery as compared with the saphenous vein.

This is a review of relative indications and contraindications for the selection of patients for coronary arteriography. Patients with angina pectoris at rest ("unstable" angina pectoris) and after low levels of effort despite a good medical regimen, those with chest pain that cannot be distinguished from angina pectoris at low or moderate levels of effort with or without abnormal 201Tl perfusion scans or radionuclide ventriculograms during stress, and those with suspected significant left main coronary arterial stenosis based on exercise testing should undergo coronary arteriography. In addition, coronary arteriography is usually an important part of the clinical evaluation of the patient with unexplained and clinically important congestive heart failure, recent myocardial infarction treated with thrombolytic therapy, a mechanical complication of myocardial infarction requiring cardiac surgery, including a large ventricular septal defect, hemodynamically important mitral insufficiency, or a large ventricular aneurysm leading to heart failure, hemodynamically important valvular, subvalvular, or supravalvular heart disease in whom corrective surgery is contemplated, suspected anomalous origin or communication of a major coronary artery, and sudden death syndrome unrelated to acute myocardial infarction.

The three major randomized studies of medical vs surgical therapy in patients with coronary artery disease have had a major impact in the management of patients with this disease. For the most part, these multicenter trials have provided concordant information regarding the influence of surgery on survival in asymptomatic or mildly symptomatic patients. It has been demonstrated that coronary artery bypass surgery improves survival in patients with stenosis of the left main coronary artery. Bypass surgery probably should be performed in most patients with this lesion, although studies have identified low-risk subgroups in whom surgery may not improve survival. There are also concordant data that survival is not enhanced by surgery in mildly symptomatic patients with either one- or two-vessel disease. The important discrepancies regarding the role of surgery in three-vessel disease have been resolved to a major extent. Long-term follow-up studies in the Veterans Administration Cooperative Study and the Coronary Artery Surgery Study (CASS) demonstrate improved survival with surgical management in patients with three-vessel disease and left ventricular dysfunction. The remaining controversy regards management of patients with three-vessel disease and normal left ventricular function; this may be resolved by studies indicating that inducible left ventricular ischemia in patients with three-vessel disease and preserved left ventricular function at rest identifies patients at higher risk during medical management. Different proportions of such patients entered into the multicenter studies may explain the discordant results in three-vessel disease and normal left ventricular function reported by the European trial and CASS.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial ischemia is an important determinant of survival in patients with coronary artery disease (CAD) and it may be silent. Coronary bypass surgery (CBS) is more effective than medical treatment in the relief of myocardial ischemia, anginal pain, and of events that are related to myocardial ischemia such as episodes of angina and left ventricular dysfunction caused by ischemia. Patients with chronic, stable angina assigned to CBS have an improved survival if they have left main CAD, three-vessel CAD with normal or impaired left ventricular function, proximal left anterior descending CAD that is part of two-vessel CAD, or two- or 3-vessel CAD with a positive exercise test for ischemia. In other respects, patients assigned to medical therapy fare as well as or better than those assigned to surgical therapy. Many issues that cause concern with regard to the randomized trials were considered in detail. The greatest problems are biostatistical tenets, small numbers of patients randomized in many of the subgroups, physician bias before and after randomization, crossovers, and inappropriate conclusions and unjustified extrapolations of the results. Timely, detailed, and comprehensive publication of the methods and results of these clinical trials is necessary. Meticulous, detailed, and critical reading of all of the published data is urged.

Selective inhibitors of thromboxane synthase have two theoretical advantages over inhibitors of the cyclooxygenase enzyme as potential antithrombotic compounds. First, they do not prevent formation of prostacyclin, a platelet-inhibitory, vasodilator compound, coincident with inhibiting thromboxane biosynthesis. Second, the prostaglandin endoperoxide substrate that accumulates in the platelet in the presence of thromboxane synthase inhibition may be donated to endothelial prostacyclin synthase at the site of platelet-vascular interactions (endoperoxide "steal"). Selective inhibition of thromboxane biosynthesis coincident with enhanced prostacyclin formation in vivo has been observed after administration of these compounds to man. Despite these attractive features and the efficacy of these compounds in diverse short-term animal preparations of thrombosis, investigations of their efficacy in human disease have proven disappointing. This may reflect on the importance of thromboxane A2 in the diseases that have been investigated. Alternatively, the lack of drug efficacy may have resulted from either incomplete suppression of thromboxane biosynthesis and/or substitution for the biological effects of thromboxane A2 by prostaglandin endoperoxides during long-term dosing studies. Given that selective inhibition of thromboxane formation can be approached with aspirin, the particular value of these compounds is dependent on enhancing prostacyclin formation. Aspirin inhibits thromboxane-dependent platelet activation, but many platelet agonists are likely to act in concert in vivo and prostacyclin inhibits platelet aggregation induced by both thromboxane-dependent and thromboxane-independent mechanisms. To test the hypothesis that thromboxane synthase inhibitors are efficacious in human disease, compounds of longer duration of action are required. Combination with antagonists of the prostaglandin/thromboxane A2 receptor may be necessary to reveal their full beneficial action.