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.

HCM is a disorder associated with significant morbidity and mortality and a propensity to cause sudden, often unexpected death. The similarity to the symptom complex of aortic stenosis and the presence of a pressure gradient justified the initial assumption that obstruction was of prime importance in HCM and that relief of obstruction was the focal point of rational therapy. However, it is our belief that the dogma of obstruction has impeded progress in and obscured the understanding of HCM and interpretation of its manifestations. The purpose of this article is to call attention to significant discrepancies in the obstructive concept that have been reinforced as new techniques emerged that have allowed further study of the disease. Since neither the presence of a gradient nor SAM can be justifiably equated with the presence of an obstruction, it is proposed that the appellation "obstruction" be reserved for those cases in which the rate of outflow or the rate or degree of ventricular emptying are demonstrably impeded, as in aortic stenosis. Therapy with beta-adrenergic-receptor and calcium channel-blocking agents have shown promise for alleviating symptoms and possibly prolonging life without systematically or predictably affecting the pressure gradient, probably because of their beneficial effects on ventricular relaxation and diastolic filling. Antiarrhythmic therapy has been effective in reducing mortality. Ideally, prevention or regression of the pathologic hypertrophy should be the major focus of future therapeutic interventions in hypertrophic cardiomyopathy.

The current dispute over the effects of "low" vs "high" doses of aspirin should take into consideration the pharmacokinetics of this drug. In fact, different pharmaceutical formulations of aspirin may deliver little or no aspirin to the systemic blood. This was the case, for instance, in healthy volunteers taking 320 mg of compressed aspirin or 800 mg of enteric-coated aspirin. In all instances thromboxane B2 generation in serum was fully inhibited. Platelet cyclooxygenase might therefore be effectively acetylated by exposure to aspirin in the portal circulation, whereas vascular cyclooxygenase could be spared. Thus aspirin formulations ensuring complete first-pass deacetylation should be sought rather than "low" or "high" doses of unspecified aspirin formulations. Regardless of the type and dose of aspirin administered, salicylate is formed and accumulates in the circulation. It may antagonize the effects of aspirin on cyclooxygenase, at least in acute conditions. As an example, after administration of 1 g of salicylate to healthy volunteers, when plasma levels of the drug were about 75 micrograms/ml, the effect of 40 mg iv aspirin (given 40 min later) on platelet cyclooxygenase and aggregation was significantly diminished. In contrast, in patients undergoing saphenectomy, the same dose of salicylate (1 g) gave plasma drug levels of about 25 micrograms/ml; salicylate was unable to prevent the inhibitory effect on platelets of 40 mg iv aspirin (given 1 hr later) but did act on vascular prostacyclin. Thus the combination of salicylate with aspirin at an appropriate dose and blood level ratio may result in almost complete dissociation of the drug's effect on platelets and vessels in man.(ABSTRACT TRUNCATED AT 250 WORDS)

During the past 15 years coronary artery bypass surgery (CABG) has evolved into a procedure with low operative mortality and morbidity resulting in excellent improvement in lifestyle and improved longevity in some instances. Operative risk factors have been identified. Their significance has changed during this time. Currently, clinical congestive heart failure and emergency operation are the most commonly observed adverse results. Since the patients being operated upon, especially those emergent, are sicker, the improvements in mortality and morbidity with CABG are not due to patient selection, but rather to improvement in preoperative, intraoperative, and postoperative management. The major areas of management that have been responsible for the current status of CABG are myocardial protection, conduit selection and preservation, blood conservation, anesthetic management, pulmonary arterial catheter monitoring, pharmacologic unloading, intraaortic balloon assistance, cardiac assist devices, and arrhythmia control.

Stable angina is the most common form of presentation of ischemic heart disease, being more common in women (65%) than men (37%), while the reverse is true for the prevalence, being present in about 3.5% of men over 55 as opposed to 1.5% of women. The overall 10 year survival for individuals with stable angina at a mean age of 60 years is 58% for men and 68% for women. Prognosis is related to several factors: age, sex, the number of coronary vessels involved, collateral flow, ventricular function, and the extent of myocardium at risk. It is estimated that stable angina of recent onset is associated with single-vessel disease in about 40% of cases. Angina is a clinical diagnosis but, if doubt exists, one should exclude coronary atherosclerosis or spasm by cardiac catheterization and not rely on noninvasive techniques. Therapy for unstable angina or acute infarction receives considerable attention and is reasonably well defined, but such is not the case for stable angina. Conventionally, it consists of secondary prevention and prescription of nitrates, calcium blockers, or beta-blockers. There are several problems: No studies have been performed to assess efficacy in reducing the development of unstable angina. The group of drugs most appropriate for first-line therapy has not been identified. It has not been determined if nitrate tolerance is a major problem. The effect of beta-blockers on prognosis in patients with unstable angina has not been defined. A noninvasive means of identifying high and low risk patients with unstable angina has not been developed.

Platelets-isolated or in conjunction with leukocytes-interact with vessel walls in many experimental and human diseases. Several mediators are held responsible for platelet activation and interaction with leukocytes, among which PAF-acether (platelet-activating factor) is a prime candidate. This phospholipid mediator is released by most inflammatory cells, including neutrophils, by isolated organs such as kidney and heart, is a potent platelet and neutrophil agonist, and exerts major vasoactive properties. Its biosynthesis involves a two-step enzymatic process yielding the active molecule from the membrane alkyl-ether choline-containing phospholipids. The first step implicates a phospholipase A2 that hydrolyzes a long-chain fatty acid (which can be arachidonic acid) from membrane phospholipids, leaving the intermediate compound lyso PAF-acether, a PAF-acether precursor that is acetylated by an acetyltransferase in a second step. It can also result from deacetylation of PAF-acether by an acetylhydrolase. PAF-acether release might explain the intervention of platelets in diseases such as glomerulonephritis and allergic vasculitis, in which the involvement of neutrophils and platelets is frequently noted. The end result of these complex sets of cell-to-cell interactions is the release of most known inflammatory mediators, influencing vascular permeability, cell infiltration, and smooth muscle contraction. Nevertheless, direct evidence for the implication of these rather well-defined cellular and molecular interactions in human pathologic states remains to be obtained.

Release of platelet-derived growth factor (PDGF) from platelets has been postulated to stimulate at least some of the cell proliferation seen at sites of tissue damage, both beneficially (wound healing) and perniciously (during formation of atherosclerotic lesions). Two other growth factors have been localized to the platelet: epidermal growth factor and transforming growth factor. These factors may function synergistically with PDGF in promoting smooth muscle cell proliferation in the injured vessel wall. PDGF-like molecules (PDGF-c) that bind to the PDGF receptor and are at least partially recognized by antiserum against PDGF may also be synthesized by vessel wall cells themselves under certain circumstances. Arterial endothelial cells secrete several mitogens, one of which is a PDGF-c. Release is greatly stimulated by exposure of the cells to physiologic concentrations of thrombin. Also, aortic smooth muscle cells from 2-week-old rats secrete mitogenic levels of PDGF-c. In this case, PDGF-c accounts for all the mitogenic activity in conditioned medium (when assayed on 3T3 cells). Smooth muscle cells obtained from adult rat aortae secrete 150-fold less PDGF-c. In a third example, when adult rat carotid arteries are damaged with a balloon catheter, smooth muscle cells migrate into the intima of the artery and proliferate. By 2 weeks, the number of smooth muscle cells in the artery has doubled. When these intimal smooth muscle cells are cultured, they are found to secrete PDGF-c. These findings suggest that activation of endogenous synthesis of PDGF-c may contribute to the smooth muscle cell proliferation seen in response to vascular injury.

Accumulating experimental and clinical evidence indicates that a time for reappraisal of therapeutic modalities designed to inhibit the eicosanoid pathway as it may affect vascular disease may be approaching. Pharmacologic agents originally used were chosen because they were capable of suppressing platelet functions such as aggregation, release, and adhesion. The goals of clinical trials were to evaluate medications that would prevent or reduce platelet accumulation in critically located blood vessels of the heart, brain, and extremities and on vascular prostheses. Evaluation of results of therapeutic trials has been difficult and this is superimposed on less-than-complete knowledge of the basic pharmacology of the drugs that have been used. Participation of neutrophils and possibly macrophages in the thrombotic process is now well recognized on morphologic grounds. Because different cell types such as platelets, neutrophils, and endothelial cells have been shown to interact biochemically by sharing precursors and intermediates of the eicosanoid pathway, the pharmacologic approach to inhibition of vascular disease may require reevaluation. Neutrophils appear to lack a cyclooxygenase pathway but serve as a source of the lipoxygenase product leukotriene B4 (LTB4). Actions of LTB4 include neutrophil aggregation, adhesion of neutrophils to endothelial cells, chemotaxis, chemokinesis, and plasma exudation. We have demonstrated in vitro that released free arachidonic acid from aspirin-treated platelets can serve as a source of neutrophil LTB4. Leukotrienes C4, D4, and E4 are agonists for various functions of vascular endothelium and smooth muscle. Most pharmacologic agents used in the treatment of vascular diseases inhibit the cyclooxygenase pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

This statement is an update of the 1970 Inter-Society Commission for Heart Disease Resources ( ICHD ) report, "Primary Prevention of the Atherosclerotic Diseases." The charge to the Study Group was to assess relevant new data and, where the evidence is less than definitive, to formulate conclusions and recommendations based on best judgment. Current developments are reviewed, and issues raised in response to the earlier recommendations are considered. Recommendations are intended to serve as a guide for individual behavior, physician practice, and the formulation of public health policy.