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.

Recently completed controlled clinical trials suggest that the functional status and natural history of patients with chronic heart failure can be modified by drugs that enhance or interfere with the effects of the sympathetic nervous system. Long-term treatment with beta-receptor agonists can produce clinical benefits in some patients by improving left ventricular diastolic function, even if tolerance develops to the effects of these drugs on cardiac output and left ventricular ejection fraction. beta-Receptor stimulation, however, may also provoke ventricular arrhythmias by a direct effect on the failing heart or by promoting the development of hypokalemia. Similarly, long-term treatment with beta-receptor antagonists may improve left ventricular systolic performance, ameliorate symptoms, and reduce mortality in chronic heart failure. beta-Receptor blockade, however, may lead to worsening heart failure by interfering with the positive inotropic or the peripheral vasodilator actions of endogenous catecholamines. It is noteworthy that many of the benefits of beta-adrenergic agonists and antagonists seem to be mediated by the effects of these drugs on the beta 1-receptor, whereas many of the deleterious responses to treatment appear to be related to the interaction of these agents with the beta 2-receptor. These observations support the concept that beta 1-receptors are the principal mediators of cardiac sympathetic nerve activity in states of circulatory stress, are most likely to be altered by the abnormal pathophysiological conditions of chronic heart failure, and consequently, provide a rational target for the development of novel therapeutic agents.

beta-Adrenergic agonists and other agents that increase cellular levels of cyclic adenosine monophosphate (cyclic AMP) exert complex actions on myocardial cell function that enhance both the force of contraction and the rate of relaxation. At the same time that cyclic AMP increases the amount of activator Ca2+ released at the onset of systole, which increases contractility, this intracellular messenger accelerates the removal of activator Ca2+ from the cytosol by the sarcoplasmic reticulum, which promotes relaxation. Cyclic AMP also increases Ca2+ sensitivity of the sarcoplasmic reticular Ca2+ pump and desensitizes contractile proteins to Ca2+, both of which favor relaxation. Thus, the lusitropic effects of cyclic AMP, which allow the heart to remove increased amounts of activator Ca2+ from the cytosol, occur simultaneously with cyclic AMP's inotropic effects. This interplay between inotropic and lusitropic effects allows beta-adrenergic agonists to increase myocardial contractility while accelerating relaxation, a combination of effects that allows the ventricles to fill during the agonist-induced tachycardia.

The sympathetic nervous system (SNS) is activated in patients with heart failure. Hemodynamic and metabolic abnormalities probably serve as the afferent stimulus for this response. This chronic activation is accompanied by an attenuation of reflex responsiveness to unloading of the central baroreceptors and mechanoreceptors. Loss of the buffering capacity of these afferent receptors may contribute to the sustained SNS stimulation. The renin-angiotensin system is uncoupled from the SNS, probably because the intrarenal mechanisms subserving renin release are preserved. Chronic activation of the SNS may contribute to disturbed hemodynamics as well as to long-term structural changes that may influence the natural history of the syndrome. A relation between plasma norepinephrine and mortality raises the possibility of a direct adverse effect of SNS activation on survival. Therapeutic approaches to inhibit the SNS include agents that block receptors, enhance the response to baroreceptor loading, inhibit presynaptic norepinephrine release, or act centrally to inhibit sympathetic outflow. The benefit-to-risk ratio for each of these possible interventions needs to be assessed in controlled long-term trials.

Activation of the sympathetic nervous system is an important factor in the genesis of ventricular arrhythmias in patients with impaired ventricular function. Such patients have an appropriate substrate that is capable of generating rhythm abnormalities, which may be related to enhanced automaticity, triggered automaticity, and reentrant mechanisms; all three mechanisms are markedly potentiated by the action of catecholamines. Additionally, the sympathetic nervous system can provoke the development of hypokalemia and ischemia (which can independently lead to the occurrence of rhythm disturbances), and catecholamines may negate the beneficial electrophysiological actions of antiarrhythmic drugs. A substantial amount of experimental data implicates the sympathetic nervous system as a potent stimulus for ventricular tachyarrhythmias and sudden cardiac death, especially in the setting of myocardial ischemia. Two important mechanisms that have been identified include 1) enhanced sympathetic outflow from the central nervous system and 2) nonuniform myocardial denervation resulting in beta-receptor up-regulation and catecholamine hypersensitivity in the infarct zone. Disruption of sympathetic neural innervation of the heart and the use of beta-blocking agents may reduce the occurrence of sudden death and improve survival in animal models of arrhythmias and in some subsets of patients, including those with the long QT syndrome, a recent myocardial infarction, and perhaps those with a cardiomyopathy. The mechanism of this beneficial effect remains to be defined.

Studies of the coronary circulation have divided vascular resistances into three large components: large vessels, small resistance vessels, and veins. Studies of the epicardial microcirculation in the beating heart using stroboscopic illumination have suggested that resistance is more precisely controlled in different segments of the circulation. Measurements of coronary pressure in different sized arteries and arterioles have indicated that under normal conditions, 45-50% of total coronary vascular resistance resides in vessels larger than 100 microns. This distribution of vascular resistance can be altered in a nonuniform manner by a variety of physiological (autoregulation, increases in myocardial oxygen consumption, sympathetic stimulation) and pharmacological stimuli (norepinephrine, papaverine, dipyridamole, serotonin, vasopressin, nitroglycerin, adenosine, and endothelin). Studies of exchange of macromolecules in the microcirculation using fluorescent-labeled dextrans have also identified the size of the small pore (35-50 A) in coronary microvessels that can be altered by myocardial ischemia. Studies of the coronary microcirculation have demonstrated that the control of vascular resistance is extremely complex, and mechanisms responsible for these heterogeneous responses need further examination.