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.

The alpha-adrenergic component of the sympathetic nervous system plays a major role in the pathophysiology, clinical manifestations, and natural history of human congestive heart failure. While the augmentation of alpha-adrenergic tone (through the neuronal release of norepinephrine) is a valuable mechanism to maintain adequate systemic blood pressure and perfusion of vital organs in states of circulatory collapse, stimulation of alpha-adrenergic receptors produces detrimental hemodynamic effects in congestive heart failure. These undesirable effects result from alpha-mediated vasoconstriction and consist of excessive elevation of right and left ventricular filling pressures and pulmonary and systemic vascular resistances. The enhancement of alpha-adrenergic tone preferentially reduces blood flow to the hepatosplanchnic circulation. Many of the hemodynamic responses that are seen after activation of the renin-angiotensin system are related to the ability of angiotensin II to amplify the actions of the alpha-adrenergic system. Stimulation of myocardial alpha-adrenergic receptors in most species elicits a modest positive inotropic effect, but the presence and importance of this property in the human heart remains controversial. Chronic stimulation of myocardial alpha-adrenergic receptors may result in the hypertrophy of cardiomyocytes and may also contribute to the development of catecholamine-induced cardiomyopathy. Acute blockade of the heightened alpha-adrenergic tone in congestive heart failure (e.g., with first doses of prazosin) results in favorable hemodynamic effects, but repeated dosing leads to pharmacological tolerance. Consequently, the long-term administration of alpha-adrenergic blocking agents in human heart failure has not been accompanied by an improvement in clinical status, exercise capacity, or survival.(ABSTRACT TRUNCATED AT 250 WORDS)

The functional importance of abnormalities in the myocardial beta-adrenergic receptor (BAR) pathway of patients with congestive heart failure (CHF) is not known. To address this issue, the inotropic, chronotropic, and lusitropic responses to BAR stimulation were studied in patients with CHF and in patients without cardiac disease. To evaluate inotropic responsiveness, dobutamine was infused directly into the left main coronary artery. The maximum inotropic response, as assessed by measurement of left ventricular +dP/dt, was markedly reduced in patients with CHF; however, the concentration-response curve for the effect of dobutamine was not shifted relative to that of normal subjects. The magnitude of the impairment in the inotropic response to intracoronary dobutamine was inversely related to resting plasma norepinephrine. Although there was no relation between resting plasma norepinephrine and any measure of hemodynamic function, the improvement in pump function that occurred with intracoronary dobutamine resulted in a rapid decrease in plasma norepinephrine. Preinfusion of the phosphodiesterase inhibitor, milrinone, into the coronary artery resulted in a significant increase in the response to intracoronary dobutamine. To evaluate chronotropic responsiveness, the heart rate responses to a graded infusion of isoproterenol and during maximal exercise on a cycle ergometer were determined. The isoproterenol dose causing a 25 beat/min increase in heart rate (ISO25) was significantly higher in patients with CHF than in normal subjects. Likewise, the heart rate at peak exercise was significantly reduced in patients with CHF, despite similar levels of plasma norepinephrine at peak exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Congestive heart failure is associated with blunted cardiac adrenergic responsiveness, clinically manifested by diminished chronotropic, inotropic, and lusitropic responses to beta-adrenergic stimulation. Recent advances in our understanding of the multiple components of the beta-adrenergic receptor complex and of the mechanisms by which these components interact with each other have led to insights beyond the mere evaluation of beta-receptors to account for adrenergic hyporesponsiveness in congestive heart failure. In addition to a reduction in beta-adrenergic receptors, the failing heart appears to show key abnormalities in the guanine nucleotide-binding proteins that link the beta-receptor to its biochemical effector. A reduction in the stimulatory protein and in the extent to which the stimulatory protein is linked to the beta-receptor are demonstrable in peripheral circulating lymphocytes and in cardiac tissue. These abnormalities are at least partially reversible.

beta-Adrenergic pathways in the human ventricular myocardium mediate the powerful positive inotropic effects of released neurotransmitters (norepinephrine) and circulating hormones (epinephrine) and the response to therapeutically administered beta-agonists. Two genetically and pharmacologically distinct receptors, beta 1 and beta 2, mediate the contractile effects of catecholamines in a similar manner. The biologic signal produced by the occupancy of beta-adrenergic receptors by catecholamine agonists is transduced, amplified, and regulated by a family of guanine nucleotide-binding proteins (G proteins), which serve both stimulatory and inhibitory functions. Although the major biochemical effector of beta-adrenergic receptors is the enzyme protein--coupled directly to ion channels that regulate inotropic and electrophysiological effects. In human ventricular myocardium, heart failure produces changes in the beta-adrenergic receptor pathways that have the collective effect of reducing the degree of inotropic stimulation that may be produced by a given amount of beta-agonist. These changes include downregulation of beta 1-adrenergic receptors, uncoupling of beta 2-adrenergic receptors, and an increase in the functional activity of the inhibitory G protein. These effects in turn are probably caused by exposure to increased amounts of neurotransmitter resulting from a complex series of changes in the cardiac sympathetic nervous system. Finally, the components of the beta-receptor-G protein system may be both acutely and chronically modulated by certain kinds of pharmacological therapy. These observations underscore the importance of the adrenergic nervous system in heart failure, and they create the potential for the development of new interventional strategies designed to alter the natural history of heart muscle disease and heart failure.

The existence of two dopamine receptor subtypes (DA1 and DA2) has been firmly established. Activation of DA1 receptors is associated with vasodilation, primarily in the renal, mesenteric, cerebral, and coronary arterial beds, and a natriuresis. DA2 receptors located on postganglionic sympathetic nerves and sympathetic ganglia mediate a decrease in the release of norepinephrine from sympathetic nerve terminals. The DA receptor activity of dopamine (which activates beta 1- and alpha-adrenoceptors as well as DA receptors) plays a prominent role in determining the beneficial hemodynamic responses to this drug in patients with heart failure. As a result, recent research efforts have been directed toward the development of dopamine analogues, which are orally effective and exhibit more selective agonist activity at DA receptors. Limited clinical experience in heart failure is now available for analogues with different spectra of receptor activity than dopamine, including selective DA1 and DA2 agonists. A review of these data is presented with an attempt to define the clinical relevance of the DA receptor-agonist properties of the compounds. Although the results of early clinical studies with some of these first-generation dopamine congeners are encouraging, analysis of ongoing large-scale placebo-controlled trials will provide valuable insight into their utility as therapeutic agents for patients with heart failure.