Myocardial dysfunction eventuating in systolic and diastolic pump function abnormalities is a consequence of a wide variety of cardiac diseases. The symptoms that develop in this syndrome appear to be related as much to peripheral and neurohormonal mechanisms as to the underlying pathological and cardiac functional abnormality. Relief of symptoms, slowing of the progression of the cardiac functional abnormality, and prolongation of life provide the major agenda for the physician faced with the management of these patients. Judicious use of vasodilators, diuretics, digoxin, dietary therapy, and exercise therapy can relieve symptoms and improve the quality of life in most patients suffering from this syndrome. Recent evidence that vasodilator drugs can prolong life now provides the physician with further justification for routine use of this class of compounds. The eventual solution to the high mortality in this common disease process may be prevention of the development of overt heart failure by more prompt recognition and early treatment of the signs of ventricular dysfunction. This possibility must await the completion of current and proposed clinical trials.

In recent years, there has been a renewed interest in surgical reconstruction of the insufficient mitral valve because of reconfirmation of the limitations of existing prosthetic and bioprosthetic valves. A follow-up study, including late functional data, of 148 patients who underwent mitral valve reconstruction at our institution was combined with a review of the literature to assess the current status of mitral reconstruction. The results indicate that mitral reconstruction by Carpentier techniques is widely applicable, durable, and relatively free of complication. Freedom from late thromboembolic and anticoagulant complications is particularly notable. These factors could prove to justify earlier operative intervention in patients with mitral insufficiency before permanent myocardial damage evolves. As mitral valve reconstruction techniques become more familiar and widely used, mitral reconstruction may become the operative procedure of choice for mitral insufficiency, especially insufficiency due to degenerative disease.

Positron emission tomography offers the possibility of evaluating and quantifying regional myocardial blood flow and metabolism. Used in patients with coronary artery disease, positron emission tomography has demonstrated sustained metabolic activity in regions with reduced blood flow and impaired contractile function, and it thereby enables differentiation between viable myocardium and myocardium that has succumbed to necrosis and scar formation. Viable myocardial regions identified by metabolic rather than functional or blood-flow criteria are frequently observed in patients after an acute coronary event and in patients with stable coronary artery disease. Positron emission tomography reflects either acute myocardial ischemia, "hibernation," as well as "myocardial stunning." Findings from metabolic imaging have proved useful in characterizing more accurately coronary artery disease and its functional consequences. These findings have been found equally useful for clinical management.

Converting-enzyme inhibition, whether teprotide, captopril, or enalapril is used, produces a larger increase in renal blood flow in patients with essential hypertension than in normal subjects when they are on a low-salt diet, a quantitative difference. When studies were performed in individuals on a high-salt diet, normal subjects showed little or no response, whereas a substantial number of patients with essential hypertension displayed an increase in renal blood flow with these agents, a qualitative difference. The individuals that show this potentiated response we now are coming to recognize, have a number of features that suggest a distinct subgroup, the "nonmodulators." Normotensive offspring of hypertensive patients show a directionally similar but smaller renal vascular response to converting-enzyme inhibition. These hypertensive patients also show a blunted natriuresis in response to a sodium loading, which is corrected by converting-enzyme inhibition. Several lines of evidence suggest that the locus of action is intrarenal rather than systemic. Plasma renin activity and plasma angiotensin II concentration are not higher in these subjects, and thus cannot account for their potentiated response to converting-enzyme inhibition. Moreover, the infusion of captopril directly into the renal artery in doses far too low to induce a systemic effect increases renal blood flow specifically in these subjects. They also show a blunted rate of renin suppression after a sodium load, although plasma renin activity falls to the same low level at steady state.(ABSTRACT TRUNCATED AT 250 WORDS)

The presence of the renin-angiotensin system (RAS) in extrarenal tissues, namely the vascular wall and brain tissue, is well established. The availability of effective blocking agents, converting-enzyme inhibitors, has made it possible to further elucidate important functions of the extrarenal RAS. We have found that the angiotensin converting-enzyme inhibitor captopril shifts the limits of cerebral blood flow autoregulation to lower blood pressure levels in normotensive and in spontaneously hypertensive rats. This effect may explain our finding of a remarkable preservation of cerebral blood flow, despite significant blood pressure reduction, in patients with chronic heart failure. We suggest that the effect of angiotensin converting-enzyme inhibition on autoregulation of cerebral blood flow is mediated by a dilatation of larger cerebral arteries, which results from inhibition of the vascular tone normally maintained by locally produced angiotensin II.

The renin-angiotensin system has traditionally been viewed as an endocrine system. Recent data demonstrate that renin and angiotensinogen genes and their products are expressed at many local tissue sites. The concept that multiple tissues synthesize angiotensin has changed our understanding of the physiology of the renin-angiotensin system. These potential autocrine-paracrine systems may be important in the regulation of local tissue functions in addition to the circulating endocrine system. The activity of the tissue system under different conditions can influence the pharmacologic response to inhibitors of the renin-angiotensin system. For example, evidence suggests that tissue angiotensin-converting enzyme (ACE) may be the primary site of action of ACE inhibitors. Consequently, the duration of action of an ACE inhibitor may be more dependent on the duration of tissue ACE inhibition than on the drug's serum half-life. The differential effects of these pharmacologic inhibitors on the tissue renin-angiotensin systems may form the basis of differentiation between the various ACE inhibitors.

The emerging recognition of the existence and potential biological significance of local tissue renin-angiotensin systems in a number of organs has fostered interest in a possible intrinsic cardiac renin-angiotensin system. Evidence for such a system was first provided by biochemical measurements of components of the renin-angiotensin system in cardiac tissue. It has recently been demonstrated that the genes coding for renin and angiotensinogen are expressed in all regions of the heart, an essential prerequisite for the postulated intracardiac biosynthesis of these proteins. Moreover, we have shown the presence of a functional and physiologically active pathway for the conversion of angiotensin I to angiotensin II in the beating mammalian heart. This conversion appears to be catalyzed by a specific cardiac converting enzyme that is susceptible to systemically administered converting-enzyme inhibitors. Evidence for the physiologic importance of the cardiac renin-angiotensin system comes from experimental data as well as indirect clinical evidence. The potent coronary vasoconstrictor properties of angiotensin II underscore its possible significance in myocardial ischemia and ischemic heart disease, in particular when viewed in the context of selective local activation. The long-known positive inotropic effects of angiotensin II are based on its direct myotropic properties and on its facilitatory effects on sympathetic neurotransmission and may be of added significance in metabolically compromised states. We have recently demonstrated that locally generated angiotensin may be a dominant etiologic factor in the pathogenesis of reperfusion arrhythmias. In addition, we have found experimental evidence for a deleterious effect of angiotensin II on myocardial metabolism in the setting of regional myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent findings suggest that the local renin-angiotensin systems, locally generated catecholamines, and possibly other locally generated peptides interact in a complex fashion to regulate the cellular biology of the myocardium, the vascular wall, and other tissues. New evidence indicates that the components of the renin-angiotensin system are synthesized in cardiovascular tissues, that the synthesis of these components can be modulated by pharmacologic agents, and that angiotensin II, the effector protein of the renin system, appears to be capable of producing hypertrophy or hyperplasia in specific tissues. In addition, recent studies suggest the participation of enhanced proto-oncogene transcriptional activity in the development of hyperplasia and hypertrophy in cardiovascular tissue. Taken together, these data raise the possibility that angiotensin and perhaps other components of the renin system can be viewed as locally active growth factors capable of acting in a fashion similar to that associated with cytokines in other systems.

Despite a dramatic fall in renal blood flow, glomerular filtration rate is usually preserved in patients with congestive heart failure until the terminal stages of the disease. This maintenance of renal function appears to be achieved in part by the synthesis of two vasoactive factors within the kidney--angiotensin II and prostaglandins--which are rapidly released whenever renal perfusion is compromised or sympathetic nerve traffic to the kidneys is increased. Although these two hormonal systems exert opposite effects on systemic and renal blood flow and sodium and water excretion, both act to preserve glomerular filtration rate: prostaglandins by a vasodilator action exerted primarily on the afferent arteriole and angiotensin II by a vasoconstrictor effect on the efferent arteriole. Consequently, when the synthesis of these hormones is experimentally blocked, renal function deteriorates, especially in subjects with marked renal hypoperfusion and sodium depletion; these two factors interact to determine the importance of intrarenal hormonal release in the modulation of renal function. Clinically, four specific factors have been identified that predispose patients with heart failure to the development of functional renal insufficiency after treatment with converting-enzyme or cyclo-oxygenase inhibitors: (1) marked renal hypoperfusion, (2) vigorous diuretic therapy, (3) diabetes mellitus, and (4) intensity of hormonal inhibition within the kidney. This last risk factor may provide the basis for differentiating among enzyme-inhibitory drugs and suggests that renal insufficiency in low-output states may be minimized by the development of therapeutic agents that block hormonal synthesis selectively at sites that are critical to the disease process but spare the homeostatic tissue-based enzyme systems that exist within the kidney.

The angiotensin converting-enzyme inhibitors available so far are active-site directed inhibitors. They utilize all the critical binding interactions of the substrate and convert the catalytic interaction with the zinc atom into an effective binding interaction. Three chemical classes of angiotensin converting-enzyme inhibitors have been introduced into clinical use, the sulfhydryl-containing inhibitors such as captopril and its analogs and prodrugs, carboxyalkyldipeptides such as enalapril and its analogs, and phosphorus-containing inhibitors such as fosinopril and the phosphonate SQ 29,852. Within each of the three groups of inhibitors significant differences in molecular weight and polarities can be observed. These differences have a significant influence in the routes of elmination and tissue distribution of these inhibitors. Tissue distribution and intrinsic potency will determine the magnitude of angiotensin converting-enzyme inhibition at the tissue level, which could play a critical role in the clinical utilization of these inhibitors. The sulfhydryl-containing inhibitors such as captopril undergo a metabolic process significantly different from that of the other two classes. They can interact with endogenous sulfhydryl-containing compounds like glutathione and proteins, to form reversible disulfides, which can serve as depot forms of the drug. Also, because of their redox properties they might function as recyclable free radical scavengers.

The existence of a brain renin-angiotensin system (RAS) as one of various tissue RASs is now firmly established. Angiotensin-containing pathways within brain areas involved in central blood pressure regulation have been described. Evidence from biochemical, neurophysiologic, pharmacologic, and most recently, molecular genetic studies indicate that the brain RAS is regulated independently of the hormonal RAS and may contribute to blood pressure control and body fluid homeostasis. In addition, circulating angiotensin II can exert some of its action through stimulation of brain angiotensin receptors accessible from the blood. In experimental animal preparations of hypertension, especially in spontaneously hypertensive rats, an overactive brain RAS may be one of the factors involved in pathogenesis and maintenance of hypertension. In spontaneously hypertensive rats, inhibitors of the angiotensin II-generating converting enzyme (CE) have been shown to lower blood pressure by a central action when applied to the brain and to inhibit brain CE when applied systemically. The pathogenetic mechanisms underlying a particular cardiovascular disease and the characteristics of the CE inhibitor used (e.g., its lipid solubility governing penetration into tissue) may determine the degree to which CE inhibition within a given organ, such as the brain, contributes to the action of these drugs.