Of 2,122 consecutive patients undergoing elective coronary angioplasty from 1982 to 1985, 62% had stable angina pectoris (SAP), and 38% had unstable angina pectoris (UAP). There were differences between the two groups in clinical and morphological factors and in initial and late results of angioplasty. UAP patients were more likely than SAP patients to be smokers and to have had prior myocardial infarctions. Lesions in UAP patients were more severe, longer, more eccentric, more irregular, and more likely to have intracoronary thrombi than were lesions in SAP patients. Coronary angioplasty success was achieved in 84% of UAP and in 88% of SAP patients (p less than 0.05), and complications occurred in 6.7% of UAP and in 4.7% of SAP patients (p less than 0.05). Hospital death rates were low and similar, 0.2% for both groups. Follow-up (mean, 37 months) showed recurrent Canadian Cardiovascular Society (CCVS) class III/IV angina in 30.1% of UAP and in 25.2% of SAP patients (p less than 0.05). There was a return to work in 86% of UAP and in 91% of SAP patients (p less than 0.05). When UAP patients' durations of symptoms were further fractionated, it was found that the earlier angioplasty was performed after onset of angina, the lower was the success rate and the higher the complication rate and incidence of late follow-up untoward events. When coronary angioplasty was performed within 1 week of onset of angina ("early"), success was 79.1%; when angioplasty was performed 2 weeks or more after onset of angina ("later"), success was 86.3%. Major cardiac events occurred in 11.5% in the early group and in 4.8% in the later group (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Rupture of an atherosclerotic plaque associated with partial or complete thrombotic vessel occlusion is fundamental to the development of ischemic coronary syndromes. Plaques that produce only mild-to-moderate angiographic luminal stenosis are frequently those that undergo abrupt disruption, leading to unstable angina or acute myocardial infarction. Plaques with increased lipid content appear more prone to rupture, particularly when the lipid pool is localized eccentrically within the intima. Macrophages appear to play an important role in atherogenesis, perhaps by participating in the uptake and metabolism of lipoproteins, secretion of growth factors, and production of enzymes and toxic metabolites that may facilitate plaque rupture. In addition, the particular composition or configuration of a plaque and the hemodynamic forces to which it is exposed may determine its susceptibility to disruption. Exposure of collagen, lipids, and smooth muscle cells after plaque rupture leads to the activation of platelets and the coagulation cascade system. The resulting thrombus may lead to marked reduction in myocardial perfusion and the development of an unstable coronary syndrome, or it may become organized and incorporated into the diseased vessel, thus contributing to the progression of atherosclerosis. In unstable angina, plaque disruption leads to thrombosis, which is usually labile and results in only a transient reduction in myocardial perfusion. Release of vasoactive substances, arterial spasm, or increases in myocardial oxygen demand may contribute to ischemia. In acute myocardial infarction, plaque disruption results in a more persistent thrombotic vessel occlusion; the extent of necrosis depends on the size of the artery, the duration of occlusion, the presence of collateral flow, and the integrity of the fibrinolytic system. Thrombi that undergo lysis expose a highly thrombogenic surface to the circulating blood, which has the capacity of activating platelets and the coagulation cascade system and may lead to thrombotic reocclusion. Measurements aimed at reversing the process of atherosclerosis via cholesterol reduction and enhanced high density lipoprotein activity are encouraging. Active research is being focused on the development of new antithrombotic tools, such as inhibitors of thrombin, thromboxane, and serotonin receptor antagonists, and monoclonal antibodies aimed at blocking platelet membrane receptors or adhesive proteins. These compounds may prove useful when immediate and potent inhibition of the hemostatic system is desired. Intensive research is still needed in the areas of pathogenesis and therapeutic intervention in atherosclerosis.

Atherosclerotic plaques are either concentric, producing a fixed degree of obstruction, or eccentric, with retention of an arc of normal vessel wall that allows changes in medial muscle tone to vary the degree of stenosis. Plaques may also either be solid and fibrous or may contain, in addition to fibrous thickening, a pool of extracellular cholesterol. Most subjects with ischemic heart disease have mixtures of all plaque types. The endothelium over established human plaques often shows focal denudation injury, with adhesion of a platelet monolayer not detectable by angiography. Larger thrombi are due either to superficial intimal injury, which is the progression of the endothelial denudation seen over otherwise static and intact plaques, or to deep intimal injury caused by plaque fissuring (rupture). Both forms of intimal injury expose collagen and von Willebrand factor to platelets. In deep injury, tears extend from the lumen into the depths of the intima and often enter a lipid pool; in consequence, thrombus initially forms within the plaque, thereby altering its configuration and expanding its volume. Many fissures will reseal at this stage, but the plaque is larger, and the process is an important cause of episodic sudden plaque growth. A proportion of plaque fissures are associated with the additional formation of a luminal thrombus, which may be either mural or occlusive. In life, transitions between mural and occlusive thrombi and vice versa occur rapidly and frequently. Mural thrombus is associated with distal embolization of platelet masses and, in some cases, is associated with cholesterol from the plaque.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic data on the importance of silent ischemia is lacking. Preliminary reports suggest that ambulatory electrocardiographic monitoring provides additional information not contained in the exercise test, but it is still unclear whether silent ischemia is a marker of subsequent events or is responsible for their development. Recent investigations also suggest that intermittent episodes of ischemia may cause myocardial necrosis. Drugs that are effective in the treatment of angina are also effective in the treatment of silent ischemia, but their value in terms of long-term morbidity and mortality is unclear. Recently, the circadian distribution of silent ischemia has been reported in 150 patients off therapy, in 33 receiving nifedipine, and in 41 receiving atenolol. Most ischemic episodes off therapy occurred between 7:30 AM and 7:30 PM with a peak in the morning and a lesser peak in the evening. Nifedipine did not alter the circadian pattern of ischemic episodes; atenolol abolished the morning peak, the peak incidence of ischemia then occurring in the evening. This circadian distribution of ischemic episodes and the observed changes with treatment resemble the reported circadian variations of acute myocardial infarction and sudden death. Large multicenter studies are now being performed to determine the effects of treatment on silent ischemia and how this treatment may influence outcome. Until such studies have been completed, it is not possible to clearly define the indication for drug therapy in the management of silent ischemia.

In the United States, there may be as many as two million totally asymptomatic men with silent myocardial ischemia due to coronary artery disease. Because detection of such patients is often fortuitous, a rigorous screening protocol has been suggested for high-risk subgroups (i.e., persons with multiple coronary risk factors and/or family histories of premature coronary artery disease). At present, the initial procedure of choice for a screening protocol is the exercise test, followed by radionuclide procedures to differentiate true-positive from false-positive responses if coronary angiography is being considered. Holter monitoring is useful in documenting out-of-hospital ischemic events in asymptomatic patients with documented coronary artery disease. Prognostic studies in patients with and without coronary angiographic data indicate that asymptomatic patients with an ischemic ST-segment depression on exercise tests comprise a high-risk subgroup that has a well-defined morbidity and mortality due to future cardiac events. The angiographic surveys show that the greatest risk is in those individuals with more extensive disease. Treatment in asymptomatic persons requires the use of objective measurements as end points. Several reports have demonstrated the efficacy of beta-blockers, calcium channel blockers, and coronary angioplasty in this population, at least so far as reducing total ischemic activity is concerned. How nonsurgical therapy will affect ultimate prognosis is still unclear. However, surgical therapy in asymptomatic patients with left main coronary artery disease and triple-vessel disease has been reported to improve long-term survival.

Asymptomatic ischemia after myocardial infarction is a common clinical problem. As much as 50% of the postinfarction patient population who have ischemia on exercise testing may have no symptoms at all. In these patients, ischemia detected by either exercise testing or ambulatory electrocardiographic monitoring, with or without symptoms, confers a worse prognosis. The mechanism of silent ischemia in this group of patients may be due to the deprivation of afferent innervations created by critically placed infarctions. The management of these postinfarction patients must be centered on the treatment of ischemia, regardless of symptoms.

Silent myocardial ischemia is increasingly recognized as a common phenomenon in a variety of populations with coronary artery disease. In patients with angina pectoris, this condition has been recognized during either exercise stress testing or ambulatory monitoring when ischemic-type ST-segment shifts occur without symptoms. Although more information is clearly needed, available data suggest an important independent relation between ambulant ischemia, most of which is silent, and adverse outcome. Other studies show that currently available antianginal agents can prevent or modify symptomatic as well as silent ischemic episodes. Several reports indicate that when these agents are prescribed to control symptomatic ischemic episodes, silent ischemia may continue to occur. Yet, when antianginal drugs are used either alone or in combination in those with recurrent silent ischemia, both the frequency and duration of the silent ischemic episodes are greatly reduced. To date, however, no data are yet available on the impact on outcome of a strategy directed at detecting and treating silent ischemia. Until this information is available, more attention should be focused on identifying and adequately controlling ischemia rather than on simply managing chest pain.

During myocardial ischemia, malignant arrhythmias and acceleration of cell damage may be induced by sympathetic overstimulation of the heart. This stimulation is due to excessive concentrations of catecholamines within the underperfused myocardium, in combination with enhanced myocyte sensitivity to adrenergic stimuli. Various mechanisms may account for local accumulation of catecholamines in the extracellular space of the ischemic but still viable myocardium. In early myocardial infarction, plasma noradrenaline and adrenaline concentrations are enhanced, reflecting increased activity of the whole sympathetic nervous system, rather than local activity in the heart. In uncomplicated infarction, these concentrations are only five times the normal levels at rest, and there are no convincing data that these mildly increased levels of plasma catecholamines directly induce a major deterioration of myocardial function during the ischemic process. Of more importance is the reflex increase in cardiac sympathetic nerve activity that is induced by pain, anxiety, and a fall in cardiac output or arterial blood pressure and that is accompanied by local exocytotic release of noradrenaline from sympathetic nerve endings of the heart. Excessive accumulation of the neurotransmitter, however, is prevented by at least three mechanisms: 1) Released noradrenaline is rapidly removed so long as neuronal catecholamine reuptake is functional. 2) Adenosine accumulating in the ischemic myocardium effectively suppresses exocytotic noradrenaline release by stimulating presynaptic A1-adenosine receptors. 3) Exocytotic catecholamine release ceases when the sympathetic neurons become depleted of adenosine triphosphate since this release mechanism requires high-energy phosphates. However, with progression of ischemia (i.e., greater than 10 minutes), the myocardium is no longer protected against excess adrenergic stimulation since local metabolic release mechanisms become increasingly important. This release, which is independent of both central sympathetic activation and extracellular calcium, occurs in two steps. First, catecholamines escape from their storage vesicles and accumulate in the cytoplasm of the neuron. In the second, rate-limiting step, noradrenaline is transported across the axolemma from the cytoplasm to the interstitial space via the neuronal uptake carrier in reverse of its normal transport direction. As a consequence of this nonexocytotic local metabolic release, extracellular noradrenaline reaches 100-1,000 times its normal plasma concentrations within 30 minutes of ischemia. Concentrations of this magnitude are capable of producing myocardial necrosis, even in the nonischemic heart, and may play an important role in the pathogenesis of ventricular fibrillation in early ischemia.

Prompt reperfusion of the ischemic myocardium by the successful use of thrombolytic agents in the setting of acute myocardial infarction has substantially reduced mortality among patients judged eligible for their use. This approach has revolutionized the management of acute infarction patients worldwide. Such therapy, however, is associated with increased rates of reinfarction and postinfarction angina that have been attributed to the underlying residual atherosclerotic lesion. The expectation that coronary angioplasty would provide the logical solution to this clinical problem has been considerably lowered by the results of a number of prospective randomized clinical trials. These findings, coupled with the realization that as many as 50% of patients suffering acute infarctions will not safely qualify for the use of thrombolytic agents, present compelling reasons to more accurately investigate the role of primary angioplasty and bypass surgery as a means of effecting reperfusion therapy in the setting of acute infarction.

Among the numerous mechanisms proposed for myocardial stunning, three appear to be more plausible: 1) generation of oxygen radicals, 2) calcium overload, and 3) excitation-contraction uncoupling. First, the evidence for a pathogenetic role of oxygen-derived free radicals in myocardial stunning is overwhelming. In the setting of a single 15-minute coronary occlusion, mitigation of stunning by antioxidants has been reproducibly observed by several independent laboratories. Similar protection has been recently demonstrated in the conscious animal, that is, in the most physiological experimental preparation available. Furthermore, generation of free radicals in the stunned myocardium has been directly demonstrated by spin trapping techniques, and attenuation of free radical generation has been repeatedly shown to result in attenuation of contractile dysfunction. Numerous observations suggest that oxyradicals also contribute to stunning in other settings: after global ischemia in vitro, after global ischemia during cardioplegic arrest in vivo, and after multiple brief episodes of regional ischemia in vivo. Compelling evidence indicates that the critical free radical damage occurs in the initial moments of reflow, so that myocardial stunning can be viewed as a sublethal form of oxyradical-mediated "reperfusion injury." Second, there is also considerable evidence that a transient calcium overload during early reperfusion contributes to postischemic dysfunction in vitro; however, the importance of this mechanism in vivo remains to be defined. Third, inadequate release of calcium by the sarcoplasmic reticulum, with consequent excitation-contraction uncoupling, may occur after multiple brief episodes of regional ischemia, but its role in other forms of postischemic dysfunction has not been explored. It is probable that multiple mechanisms contribute to the pathogenesis of myocardial stunning. The three hypotheses outlined above are not mutually exclusive and in fact may represent different steps of the same pathophysiological cascade. Thus, generation of oxyradicals may cause sarcoplasmic reticulum dysfunction, and both of these processes may lead to calcium overload, which in turn could exacerbate the damage initiated by oxygen species. The concepts discussed in this review should provide not only a conceptual framework for further investigation of the pathophysiology of reversible ischemia-reperfusion injury but also a rationale for developing clinically applicable interventions designed to prevent postischemic ventricular dysfunction.

Acute myocardial ischemia leads to a gradual increase in beta-adrenergic receptors at the cell surface. This increase occurs rapidly after onset of global ischemia (15 minutes) and persists even after prolonged periods of global ischemia. This alteration can be observed both in vivo and in vitro in isolated perfused hearts. Several groups have previously shown that ischemia induces a local release of endogenous catecholamines. Here, we show that these endogenous catecholamines are sufficiently high to induce receptor desensitization with internalization of beta-adrenergic receptors in normal hearts. In acute myocardial ischemia, however, agonist-promoted internalization and functional uncoupling of beta-adrenergic receptors is abolished. Consequently, the balance of internalization and externalization of receptors is shifted toward an increase in functionally coupled receptors at the cell surface. Similarly, but inconsistently, the density of alpha 1-adrenergic receptors in the plasma membrane is increased in acute myocardial ischemia. In regard to function, the increase of coupled beta-adrenergic receptors leads to an augmented responsiveness of the adenylyl cyclase system to beta-adrenergic stimulation. This receptor-specific sensitization is superimposed by a transient increase of total adenylyl cyclase activity in the very early phase of global ischemia (0-20 minutes). The enhanced activity of adenylyl cyclase to direct stimulation is tightly associated with the partially purified enzyme, suggesting a covalent modification of the enzyme molecule. However, after prolonged periods (greater than 30 minutes) of global ischemia, the ischemia-induced enzyme-specific sensitization is displaced by a general reduction in enzyme activity, both in vivo and in vitro. The persistent sensitization at the receptor level then meets an unresponsive adenylyl cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)

All thrombolytic agents convert plasminogen to plasmin, either directly, as in the case of urokinase, saruplase, and alteplase, or indirectly, as in the case of streptokinase. In the majority of recent clinical trials with streptokinase, a high-dose (0.7-1.5 million units), brief-duration (30-90 minutes) drug regimen has been used. After a mean interval of 4.2 hours from onset of chest pain to intravenous infusion of streptokinase, repeat angiography performed 60-90 minutes after the start of thrombolytic treatment gave a reperfusion rate of 43%; the corresponding figures for anistreplase, saruplase, and alteplase are 56%, 67%, and 69%. The patency rates obtained in similar studies with the same end point are 56% for streptokinase, 77% for anistreplase, 62% for urokinase, 71% for saruplase, and 75% for alteplase. The in-hospital mortality in randomized trials (six large studies in a total of 31,713 randomized patients) with intravenous high-dose streptokinase decreased from 12.0% in the control group to 9.47% in the streptokinase group. In a mortality study involving 1,258 patients randomized to intravenous anistreplase or placebo, the 30-day mortality was reduced by 47%, from 12.2% to 6.4%. In a large trial in which 5,011 patients were randomized to alteplase or placebo, the 30-day mortality was 7.2% compared with 9.8% in controls, a reduction of 27% by alteplase. In another trial, 721 patients were randomized to placebo or alteplase; all patients received acetylsalicylic acid and intravenous heparin. The 14-day mortality was only 2.8% in the alteplase group, 51% less than that in the control group. It is most important that the favorable impact on hospital survival be maintained at 1 year for any thrombolytic drug. Large-scale trials directly comparing mortality after alteplase, streptokinase, or anistreplase are being performed or are in the planning phase. The risk of bleeding exists with any thrombolytic agent; intracranial bleeding is the most serious risk. In a large trial in 5,011 patients with acute myocardial infarction, stroke occurred in 1.1% of alteplase-treated patients compared with 1.0% in placebo-treated controls. Haunting problems are residual stenosis of the coronary artery and reocclusion. Urgent angioplasty does not seem to be the right answer; more effective antithrombotic strategies have yet to be developed.

High plasma cholesterol concentration is an important coronary heart disease risk factor, particularly in subjects less than 50 years old. Cholesterol is transported mainly by low (LDLs) and high (HDLs) density lipoproteins. High plasma levels of HDL and its apolipoprotein (A-I) are associated with low coronary heart disease risk, and the reverse is true for LDL and its apolipoprotein (B). Plasma levels of very low density lipoproteins (VLDLs) are probably not an independent risk factor, and the situation for plasma triglycerides is unclear. beta-Blockers have no significant effects on plasma concentrations of either total or LDL cholesterol, but HDL plasma concentration is reduced by about 10%, particularly by nonselective beta-blockers. Plasma triglyceride and VLDL concentrations are both raised by beta-blockade. Despite these plasma lipid changes, beta-blockers, by decreasing myocardial oxygen requirements, exhibit marked anti-ischemic properties. beta-Blockers without intrinsic sympathomimetic activity effect a 30% decrease in death from myocardial infarction (MI) in the years after an acute MI. Primary prevention of MI by beta-blockade in hypertensive persons has been well debated and probably exists (although to a lesser extent than secondary prevention) in men, particularly for nonsmokers (for nonselective beta-blockers), and despite any plasma lipid changes. beta-Blockade can inhibit the preatheromatous and atheromatous changes induced by catecholamines in the coronary arteries of animals. beta-blockers may also reduce or slow the following processes: 1) endothelial permeability to lipoproteins; 2) acylcholesterol acyltransferase activity within the arterial wall, thereby preventing cholesterol esterification and deposition in foam cells; 3) LDL precipitation with arterial wall proteoglycans; 4) calcium influx into atheromatous areas; 5) preatheromatous increased endothelial turnover; 6) heart rate; 7) blood velocity and flow disturbances; 8) atheromatous plaque rupture and consequent coronary thrombosis; and 9) platelet activity. Thus, beta-blockers may inhibit atheromatous plaque formation and reduce the likelihood of plaque beta-blockers may inhibit atheromatous plaque formation and reduce the likelihood of plaque rupture, clot formation, and coronary thrombosis.

Acute severe myocardial ischemia and evolving myocardial infarction cause neural stimulation, increased levels of circulating catecholamines, and release of catecholamines from storage depots in the left ventricle, with consequent exposure of injured myocardial cells to relatively high concentrations of catecholamines during the transitional period in which myocyte injury becomes progressively more severe. beta-Adrenergic receptor numbers may be increased in the ischemic myocardium within 15-35 minutes of coronary artery occlusion and are associated with intact or enhanced coupling with the adenylate cyclase enzyme and elevated levels of cyclic adenosine monophosphate (AMP); their stimulation may mediate ventricular fibrillation. The administration of beta-adrenergic blockers before or within the first few minutes after coronary artery occlusion prevents or attenuates the development of ventricular fibrillation. beta-Receptor numbers are increased in the ischemic myocardium at 60 minutes of coronary artery occlusion but are uncoupled from the adenylate cyclase enzyme at the level of the G protein and/or catalytic unit. However, with reperfusion after 60 minutes of coronary artery occlusion, the increase in ischemic-region beta-adrenergic receptor numbers persists, and adenylate cyclase responsiveness to beta-receptor stimulation is restored. If a catecholamine is administered, increases in cyclic AMP and activated phosphorylase occur in ischemic-reperfused myocardium. These data indicate that beta-adrenergic mechanisms may play an important role in arrhythmogenesis and may contribute to myocyte injury during severe and intense myocardial ischemia and evolving myocardial infarction.

In recent years, several large randomized trials have clarified the role of various interventions in acute myocardial infarction. There is clear evidence that thrombolytic therapy, aspirin, and beta-blockers reduce mortality. Both aspirin and beta-blockers also reduce reinfarction and stroke. Of the thrombolytic agents, comparative trials have established that tissue plasminogen activator and streptokinase have similar effects on mortality, morbidity, and left ventricular function. There appears to be an increased risk of cerebral hemorrhage with tissue plasminogen activator. The benefits of heparin in conjunction with aspirin and a thrombolytic agent are unclear and, at best, are likely to be modest. Heparin increases the risk of hemorrhagic complications twofold. Although trials of vasodilators conducted before the widespread use of thrombolytic therapy and aspirin have been promising, newer trials are needed to evaluate their effects among patients receiving these agents. The aggregate of all trials of the routine use of calcium antagonists or antiarrhythmic agents indicates that these agents do not improve survival.

Sympathetic cardiac stimulation is a major extrinsic compensatory mechanism that maintains or augments systolic and diastolic ventricular function during physiological stress or pathological conditions. In particular, catecholamines may selectively improve diastolic function by reducing myofilament calcium sensitivity, accelerating sequestration of calcium into the sarcoplasmic reticulum, and increasing the rate of actin-myosin cross-bridge turnover. These subcellular mechanisms, unique to inotropic agents that increase myocyte cyclic adenosine monophosphate, result in an increased rate and extent of ventricular relaxation and diastolic filling and a decrease in cardiac filling pressures. Despite these potentially favorable biochemical and mechanical actions, a number of limitations and theoretical concerns remain to be addressed before catecholamine therapy is widely administered to patients with congestive heart failure and diastolic dysfunction.

The sympathetic nervous system contributes importantly to the clinical expression and, perhaps, to the course of myocardial failure. The failing heart exhibits both anatomic and functional defects in its sympathetic innervation and adrenergic receptor function. The nature of these abnormalities is at least partially dependent on the etiology of the underlying myocardial injury. Both efferent cardiac sympathetic tone and circulating catecholamines are elevated during the later stages of most forms of heart failure. This increase is not merely a reflex compensatory response but is also a reflection of defects in parasympathetic function, baroreceptor afferent nerve traffic, and regulation of sympathetic tone within the central nervous system through a serotonergic pathway. Prolonged stimulation of the heart may exhaust myocardial stores of norepinephrine and may lead to the destruction of sympathetic nerve terminals. Importantly, these abnormalities of autonomic function are distributed nonuniformly across the myocardium. Such heterogeneity can have profound effects on the temporal coordination of myocardial contraction and relaxation as well as the duration and configuration of the cardiac action potential and, thus, may contribute to both the mechanical and electrophysiological derangements seen in the failing heart. Therapy that makes sympathetic responses more uniform may improve the temporal coordination of excitation and contraction between innervated and denervated segments. This hypothesis might explain why both sympathetic agonists and antagonists may improve cardiac function since both types of drugs can restore the uniformity of neural stimulation.