Ambulatory electrocardiographic monitoring now makes it possible to document silent ischemic type ST segment changes that are seen in patients who suffer from stable angina and that often occur during periods of modest physical activity and mental arousal. These observations suggest that ischemic episodes occur as a consequence of a relatively complicated interplay of changes in oxygen supply and demand. Furthermore, silent ischemia displays a circadian variation with the greatest frequency in the morning, a pattern similar to that noted for the onset of acute myocardial infarction and the occurrence of sudden death. Ischemic episodes, whether symptomatic or silent, carry a serious prognosis in subsets of patients with coronary artery disease; therefore, prophylactic treatment may be desirable. Ideally this should be based on an understanding of the pathophysiological processes involved and should also be directed at the other coronary artery risk factors of the patients. The effects of beta-blockers, which reduce the duration and frequency of silent ischemic episodes, is well described. The effect is most pronounced in the morning, when the frequency of ischemia is highest, and the mechanism of action seems mainly mediated through a reduction in myocardial oxygen demand. beta-Blockers have shown effectiveness in both effort-induced angina and mixed angina, and increased anti-ischemic potency may be achieved by combination therapy with a calcium antagonist. Abrupt withdrawal of beta-blockers is associated with a rebound increase in ischemic activity, which is mainly silent. Further studies are needed to determine whether improved control of silent ischemia reduces the risk of adverse cardiac outcomes.

Relatively few observational (i.e., nonexperimental) studies have been conducted to examine the role of antihypertensive drug therapy in the primary prevention of coronary heart disease. To draw valid conclusions from experimental or observational studies, internal validity should be ensured. In particular, similarity of "extraneous" effects, of information, and of prognosis between the treatment groups compared in a particular study is needed. Because allocation of participants to antihypertensive drug therapy in observational studies is nonrandomized by definition, special efforts should be made to achieve comparability of prognosis, that is, to avoid "confounding by indication." Follow-up and case-control studies, the two main types of observational studies, also offer certain advantages over randomized clinical trials, particularly when different classes of drugs are compared. Although few valid observational studies on the efficacy of drug therapy for hypertension in the primary prevention of first coronary events have been published, the available data suggest that beta-blockers might confer greater protection than other drug regimens. However, more evidence is needed to confirm these findings. It is concluded that observational studies could play an increasing role in the assessment of the role of antihypertensive therapy in the primary prevention of coronary heart disease when the inherent potentials and pitfalls of these studies are appreciated.

The roles of fibrinolysis, fibrinogen, and plasminogen activator inhibitor-1 in the development of coronary heart disease are reviewed, and possible effects of long-term treatment with beta-blockade are discussed. Decreased fibrinolysis is associated with coronary artery disease, and coronary thrombus formation is the most frequent event precipitating myocardial infarction. Recently, it has also been shown that high levels of fibrinogen and plasminogen activator inhibitor-1 are predictors for myocardial infarction. Because beta-blockers are used to treat hypertension, angina, and myocardial infarction, it is important to determine the impact of beta-blockers on fibrinolysis. Several factors influence fibrinolysis. Some forms of stress and epinephrine infusions increase fibrinolysis, probably by stimulating beta 2-adrenoceptors. Nonselective beta-blockers may adversely affect this process, whereas beta 1-selective antagonists and those with intrinsic sympathomimetic activity may not. Since prostacyclin synthesis is correlated to increased fibrinolytic activity and since beta-blockers may moderate stress-induced reductions in prostacyclin formation, beta-blockers may have the potential to exert a beneficial effect on fibrinolysis in chronic stress situations. The net effect of beta-blockade is not easily predicted and probably depends on the nature of the stress (whether it is acute or chronic), the status of the patient, and the selectivity of the beta-blocker. Nevertheless, it remains a possibility that beta-blockers may exert a positive therapeutic effect in relation to coronary thrombosis by an action on fibrinolytic mechanisms.

Platelet function can be assessed by various techniques in vitro or in vivo, but methodological problems in the field are considerable. By use of the conventional in vitro technique (Born aggregometry), it has been shown that sympathoadrenal activation in vivo (e.g., mental stress, epinephrine infusions, exercise, and surgical stress) may result in either enhanced or reduced platelet aggregability in vitro. In vivo measures of platelet function (platelet counts, size distribution, and aggregability, as reflected by filtragometry ex vivo) more consistently indicate platelet activation during stress. Platelet-specific proteins in plasma are less readily affected by stress. Elevations of circulating epinephrine do not seem to explain proaggregatory effects of stress. Aggregatory responses to epinephrine may be enhanced by propranolol in vitro, because of unopposed alpha 2-stimulation (beta 2-stimulation attenuates aggregation). Other in vitro effects of beta-blockade seem to be related to nonspecific effects at very high concentrations. Studies of the effects of beta-blockade in vivo have yielded conflicting data. Some studies suggest that beta 2-blockade may reduce platelet cAMP and enhance aggregability in vitro; other studies show that propranolol attenuates platelet aggregability, particularly in patients with ischemic heart disease. There is, however, a need for well-conducted studies assessing platelet function in vivo during beta-blockade to evaluate whether platelet responses contribute to favorable effects of beta-blockade in unstable angina, for example, or after myocardial infarction. Methodological developments are needed to better understand platelet function in vivo in humans. Available data suggest that stress enhances and beta-blockade reduces platelet function. This may influence thrombus formation in the short term and atherosclerosis in the long term.

Results from several studies suggest that beta-adrenoceptor blockade causes increased biosynthesis of the vasodilator prostanoid prostacyclin in the arterial wall. This effect may contribute to the clinical effects of beta-blockers in hypertension and coronary heart disease. Studies in hypertensive patients and in animals indicate that the arterial pressure reduction after beta-blockade is related to the associated increase of prostacyclin biosynthesis, regarding both magnitude and time of onset of effect. Some observations suggest that the effects of beta-blockers in myocardial ischemia may in part be due to an improvement of coronary blood flow caused by increased prostacyclin biosynthesis.

Coronary artery disease is the most serious complication of hypertension; therefore, the treatment of hypertension should be directed toward reducing the mortality from this disease. Since the majority of deaths occurring in post-myocardial infarction patients and hypertensive patients are sudden, the key objective is coronary artery disease treatment that will reduce the risk of sudden death. Several pharmacological interventions have been tested to determine whether they reduce the risk of sudden death. So far, only treatment with beta-adrenoceptor antagonists has been proven effective. Since most sudden cardiac deaths are due to ventricular fibrillation, an antifibrillatory effect on beta-adrenoceptor blockade has been invoked and demonstrated in clinical as well as animal experimental studies. Apart from an antifibrillatory effect, other effects of beta-blockade may also be involved. In the present review, different effects of beta-blockers that may contribute to the observed beneficial effects are discussed. The reduction in the risk of sudden death during active beta-adrenoceptor blockade reported in clinical studies is probably related to the summation of different effects, since cardiovascular drugs with a more limited mode of action (i.e., pure anti-ischemic effect or pure antiarrhythmic effect) have not shown similar impressive results.

Clinical and epidemiological investigations provide evidence that psychosocial factors influence the development of coronary heart disease and underlying atherosclerosis, an association that appears to be independent of the effects of other coronary disease risk factors. It has been hypothesized that sympathoadrenal medullary activation mediates behavioral influences on coronary disease, perhaps by potentiation of atherogenesis. This article summarizes four recent studies of the effects of psychosocial stress and sympathetic arousal on atherogenesis in cynomolgus monkeys (Macaca fascicularis) and rabbits. It is reported that socially dominant male monkeys, when fed an atherogenic diet and subjected to periodic social disruption, developed markedly worsened coronary atherosclerosis in comparison with subordinate monkeys; this effect may have been sympathetically mediated, as it was inhibited in similarly aggressive monkeys treated with a beta-adrenergic blocking agent. Studies using chow-fed rabbits demonstrated that exposure to chloralose anesthesia (an agent that provokes profound sympathetic activation) induced endothelial injury (indicated by intracellular accumulation of immunoglobulin G in the aortic endothelium) and abnormal (increased) platelet accumulation. The further observation that these effects were inhibited under beta-adrenoceptor blockade implicates sympathoadrenomedullary arousal in the initiation of atherogenesis. Additionally, sympathetically mediated endothelial damage and increased platelet accumulation occurred preferentially at circumostial sites in the rabbits, a finding consistent with the hypothesis that the hemodynamic concomitants of sympathetic activation contribute to atherogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

The accumulation of lipoproteins and lipids associated with the progression of atherosclerotic lesions appears to be a sequential process involving interactions with the intimal extracellular matrix and, subsequently, with cells. Apolipoprotein B-containing lipoproteins appear first to be retained and modified focally by proteoglycans of the extracellular matrix. The association with the extracellular matrix may lead to further modifications. In vitro resident macrophages take up the modified apolipoprotein B lipoproteins via a nonsaturable mechanism that may contribute to their transformation into foam cells characteristic of the atherosclerotic lesion. The affinity of low density lipoprotein (LDL) for arterial proteoglycans in vitro is related to the charge and triglyceride content. Small, triglyceride-poor, cholesterol-rich particles interact more efficiently with proteoglycans and are taken up faster by cultured macrophages than larger triglyceride-rich ones. beta-Blockers increase the relative triglyceride content of circulating LDL, and in vitro this LDL has a lower affinity for arterial proteoglycans. These results suggest that some of the experimental antiatherogenic actions of beta-blockers may be related to a reduced LDL affinity for extracellular intima components associated with the small changes induced by the drugs in the lipoprotein structure. Hypothetically, this reduced affinity could diminish the focal accumulation of LDL in lesion-prone sites.

In this article, the issues involved in the measurements of quality of life in clinical trials of cardiovascular drugs are discussed with emphasis on beta-blocker treatment. The extensive documentation available for beta-blockers makes it possible to evaluate different aspects of this class of drugs. Generally, beta-blockers have been shown to be safe with a low frequency of serious side effects. However, results of different studies have shown that this class of drugs affects various aspects of well-being and psychomotor tests both negatively and positively. Adverse effects often associated with beta-blockers are the subjective symptoms that are considered to be related to the central nervous system. Today there is increasing evidence that these can be quantitatively as well as qualitatively reduced by using beta-blockers in a low dose and avoiding high plasma peak concentrations. Considering effects on well-being and psychomotor tests, there seems to be no clinical difference between hydrophilic and lipophilic beta-blockers, when administered in comparable therapeutic dosages, whereas beta 1-selective blockers in clinically relevant doses seem to produce fewer and less severe adverse effects than nonselective blockers. Compared with other classes of cardiovascular drugs, there is no clear evidence of differences in well-being between selective beta-blockers and angiotensin converting enzyme inhibitors or calcium antagonists.

By the mid 1960s a beneficial effect of post-myocardial infarction treatment with beta-blockade had been proposed. However, it was not until 1981 that large clinical trials clearly demonstrated a beneficial effect both in terms of reduction in mortality and morbidity. Today treatment with beta-blockers both in the acute phase of acute myocardial infarction as well as in the stable post-myocardial infarction patient is well established. In this review article, different aspects of early and late treatment with beta-adrenoceptor blockers are discussed. The cardioprotective effects of beta-blockers on mortality and morbidity should not be considered class effects valid for all beta-blockers. Pooled data have clearly demonstrated that beta-blockers with intrinsic sympathomimetic activity have less marked effects. Impressive effects on mortality and morbidity have been obtained with propranolol, timolol, and metoprolol, which are noncardioselective as well as more beta 1-selective (metoprolol), but they are all lacking intrinsic sympathomimetic activity and, furthermore, have a relatively high degree of lipophilicity. It is clear that acute beta-adrenoceptor blockade in suspected acute myocardial infarction reduces mortality and morbidity as well as complications such as chest pain and ventricular arrhythmias during the acute phase. In post-myocardial infarction treatment, it is clear that both mortality and morbidity are reduced. Reports from extended follow-ups after termination of initial double-blind beta-blocker studies in postinfarction patients indicate that withdrawal of the active treatment may increase mortality after cessation of treatment. This is observed despite measures having been taken to avoid so-called acute withdrawal phenomena.(ABSTRACT TRUNCATED AT 250 WORDS)

It is evident that the practice of cardiac catheterization has undergone, and continues to undergo, marked change. Most prominent are the recent very rapid proliferation of catheterization laboratories in general and the development of newer types of catheterization laboratory. No uniform definitions exist for these newer laboratories, so meaningful communication is difficult. The new settings are of particular concern because their location, mobility, organization, and ownership raise questions about the quality of patient care. Most difficult to address are the questions about patient safety and physician conflict of interest. There are no objective data in peer-reviewed literature to support the reported safety and cost savings of these newer settings. Through deliberations, surveys, interviews, and correspondence with the cardiology community embraced by the ACC and the AHA, the task force generally found that in freestanding catheterization laboratories, access to emergency hospitalization may be delayed, and appropriate oversight may be lacking. Additionally, opportunities for self-referral may be fostered and the perception of commercialism and entrepreneurial excess in practice created. All of these problems must be avoided. The growth and development of some freestanding facilities, particularly the mobile laboratories, do not seem to have been driven by an increased need in remote communities or for temporary support but rather almost exclusively by a desire to capture market share. Accordingly, a series of definitions, guidelines, and recommendations for the laboratories as well as for patient selection has been developed. The consensus was that a very restrictive and cautious attitude to the newer settings is appropriate at this time. The justification for development or expansion of cardiac catheterization services must be patient need. Documentation of this need must be based on objective estimates of the number of patients with known or suspected cardiac disease who meet generally accepted indications for laboratory study. Concerns about the lack of data from prospective clinical trials of patient safety in such a group necessitate a very cautious attitude toward any new catheterization services, in particular those without in-house cardiac surgical support. In view of the lack of appropriately controlled safety and need data for hospital-based, mobile, or freestanding laboratories operating without on-site (accessible by gurney) cardiac surgery facilities, the task force reaffirms the position that further development of these services cannot be endorsed at this time. In addition, there is reason for major concern that such proliferation in catheterization services may contribute to increasing costs and troubling ethical questions.

The interim results of the Cardiac Arrhythmia Suppression Trial requires physicians to use a higher threshold for employing antiarrhythmic agents in the treatment of benign or potentially lethal ventricular arrhythmias. Many have managed patients by switching to the traditional class I quinidine despite its known proarrhythmic tendency.

This meta-analysis was performed to determine the efficacy of digoxin, verapamil, and beta-adrenoceptor blockers as prophylaxis against supraventricular arrhythmias (SVAs) after coronary artery bypass graft surgery (CABG). Randomized control trials were included if the electrocardiographic monitoring technique was clearly defined and extended through at least the first 3 postoperative days. Twenty-four of 69 identified studies were included in the final analysis. A summary odds ratio (OR) of the likelihood of developing SVAs after CABG in the treatment versus control groups was calculated. The pooled mean ventricular rate during SVA in patients who developed such an arrhythmia was also calculated. Neither digoxin nor verapamil reduced the likelihood of SVAs after CABG (digoxin: OR = 0.97, 95% confidence interval [CI] = 0.62-1.49; verapamil: OR = 0.91, CI = 0.57-1.46). The likelihood of developing an SVA in patients treated with beta-blockers was markedly decreased compared with controls (OR = 0.28, CI = 0.21-0.36). The pooled ventricular rate when SVAs did occur was significantly lower in each of the treatment groups. Prophylactic beta-adrenoceptor blockers had a protective effect against the development of SVAs in a select population of patients undergoing CABG. No such beneficial effect was demonstrated for digoxin or verapamil. All three classes of agents reduced the ventricular rate in patients who developed the arrhythmia, although the ventricular rate reduction was not clinically optimal.