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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The past two decades have witnessed tremendous advances in the pharmacologic therapy of patients with left ventricular dysfunction and chronic heart failure. The pharmacologic repertoire has been and continues to be expanded with newer agents carefully subjected to the rigor of well-designed clinical trials. Treatment has consequently evolved from pathophysiologically guided therapy predicated on older concepts to evidence-guided therapy supported by results of major clinical trials that continue to expand the understanding of the pathophysiology of this complex syndrome. The goals of therapy have ambitiously evolved from the immediate symptomatic relief offered by diuretics; to the short-term hemodynamic improvement in the circulation produced by direct vasodilators; to the intermediate-term improvement in functional capacity and exercise tolerance associated with vasodilators, nitrates, and digoxin; and to the final frontier of long-term improvement in morbidity and survival associated with ACE inhibitor therapy. In addition to the expansion of the understanding of the epidemiology, natural history, and pathophysiology of chronic heart failure, several important lessons in clinical pharmacology have been learned from the clinical trials of the last decade. Many other questions, however, remain unanswered. The role of diuretics, although uncontested in the acute stabilization of congested patients, has yet to be rigorously evaluated in stable patients with chronic left ventricular dysfunction on ACE inhibitors. The long-term effects of nitrates on morbidity and mortality have not yet been established in patients with either ischemic or nonischemic ventricular dysfunction. Vasodilators as a class, and perhaps because they are not a homogeneous class, have had a mixture of successes and failures. There is no evidence that pure vasodilation in and by itself improves survival. There is ample evidence, however, that it improves the circulation and consequently the response to diuretics. This improvement may translate into intermediate-term improvement in functional capacity, but this benefit is seldom sustained. Hemodynamic improvement in the circulation may not always translate into longer-term improvement in morbidity and reduction in mortality. The syndrome of chronic heart failure from systolic left ventricular dysfunction has emerged as a disease of mechanical dysfunction and maladaptation. The maladaptation is a consequence of deleterious effects of compensatory neurohormonal mechanisms: the sympathetic nervous system, renin-angiotensin-aldosterone system, arginine vasopressin, and most likely a host of other mechanisms. The degree of activation of these mechanisms has been established as a marker of prognosis, and the effects of pharmacologic agents on these mechanisms may well determine their long-term effect.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Medical therapy and prognosis in chronic heart failure. Lessons from clinical trials. 779 32

Rapid right ventricular pacing could induce congestive heart failure in conscious dogs with significant increase in plasma concentration of arginine vasopressin (AVP) (from 1.2 +/- 0.2 to 3.4 +/- 0.6 pg/ml). In this experimental model of heart failure, oral administration of the selective AVP V1 receptor antagonist OPC-21268 significantly increased cardiac output and improved renal function without significant changes in serum electrolytes and hormones. Oral administration of the selective AVP V2 receptor antagonist OPC-31260 induced marked water diuresis, which resulted in significant increases in serum sodium concentration, plasma renin activity, and plasma concentration of AVP, although it did not produce hemodynamic improvement. Combined administration of OPC-21268 and OPC-31260 showed supra-additive hemodynamic responses as well as additive renal and metabolic responses, i.e., it showed prolonged decrease in mean arterial pressure and profound increase in cardiac output. These results suggest that AVP plays a significant role in elevation of vascular tone through V1 receptors and plays a major role in retaining free water through V2 receptors in this model of heart failure. Furthermore, combined administration of V1 and V2 receptor antagonists could induce not only metabolic and hormonal responses but also more beneficial hemodynamic responses than those observed following treatment with V1 receptor antagonist alone.
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PMID:Effects of oral AVP receptor antagonists OPC-21268 and OPC-31260 on congestive heart failure in conscious dogs. 781 Jul 24

The present study examines in detail the short-term cardiovascular actions of atrial natriuretic factor (ANF) in sheep with experimental low-output cardiac failure. Five conscious sheep, surgically implanted with a ventricular pacing wire, were paced at 220 beats/min for 14 days. Most clinical symptoms of congestive heart failure (CHF) were apparent after the 14 days, characterized by low cardiac output, high venous pressure, increased total peripheral resistance, increased plasma levels of ANF, noradrenaline, arginine vasopressin and renin, and marked fluid retention. On day 14 of pacing, intravenous infusion of ANF at 100 micrograms/h for 60 min restored cardiac output to prepacing values and reduced both total peripheral resistance and right atrial pressure. These effects were sustained throughout the infusion period. No change was seen in blood pressure, plasma renin, or noradrenaline levels. These hemodynamic changes, produced by short-term infusion of ANF, contrasted with those seen in normal sheep, where there was a fall in cardiac output with increased total peripheral resistance. These changes reflect a return toward normal of the left ventricular function curve. This is the first study to report that ANF improves cardiac function in conscious sheep with CHF, primarily by a vasodilator action to reduce cardiac preload, and suggests that ANF may be useful in treating the hemodynamic effects associated with cardiac failure.
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PMID:Cardiovascular actions of atrial natriuretic factor in sheep with cardiac failure. 782 54

Left ventricular function and neurohormonal status in patients with heart failure remaining symptomatic during therapy with angiotensin-converting enzyme inhibitors were assessed, and the effects of dopaminergic receptor stimulation in this setting were determined. Neurohormonal and left ventricular function (radionuclide angiography) data were obtained in 19 patients with symptomatic ischemic heart failure. Measurements were repeated after 4 to 6 weeks of therapy with the dopamine agonist ibopamine (100 mg, 3 times/day) or placebo administered in a double-blind, randomized, parallel group design. At baseline, despite therapy with enalapril, the angiotensin II levels (mean 39.4 pg/ml; p < 0.01 vs controls) were significantly increased, as were plasma norepinephrine (497 +/- 240 pg/ml; p < 0.01 vs controls), endothelin-1, atrial natriuretic peptide and arginine vasopressin. Moreover, in comparison with pretreatment values, left ventricular ejection fraction had decreased substantially (-9.1%) in patients with plasma norepinephrine > or = 600 pg/ml, but not in those with lower values of norepinephrine. With ibopamine, plasma norepinephrine decreased from 516 +/- 241 to 391 +/- 208 pg/ml (n = 8; p < 0.025 vs placebo), whereas it increased with placebo. In conclusion, the neurohormonal control provided by an angiotensin-converting enzyme inhibitor is reduced in a large subset of patients during prolonged therapy; ibopamine appears to be a potentially useful drug to improve neurohormonal control in this setting.
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PMID:Progression of left ventricular dysfunction secondary to coronary artery disease, sustained neurohormonal activation and effects of ibopamine therapy during long-term therapy with angiotensin-converting enzyme inhibitor. 790 64

Neuroendocrine activation, which begins early after myocardial injury, participates significantly in the pathogenesis of acute myocardial infarction and its complications. Plasma concentrations of catecholamines, arginine vasopressin and atrial natriuretic factor were highest on admission. Activation of the renin-angiotensin-aldosterone system reached its peak after 72 hours. In patients with acute myocardial infarction and heart failure the neuroendocrine activation was more intensively expressed. This study presents clinical consequences of neuroendocrine activation. Its relation to ventricular remodeling, as a potentially maladaptive mechanism is especially discussed. Angiotensin-converting-enzyme inhibitors influence favourably both neuro-endocrine activation and ventricular remodeling after myocardial infarction. At present 7 ongoing extensive multicenter trials are to determine if such a therapy would lead to a better survival and attenuate the progressive deterioration of heart function after myocardial infarction. (Fig. 2, Ref. 24.)
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PMID:[Neurohumoral activation and remodeling after acute myocardial infarct and the effect of angiotensin-converting enzyme inhibitors]. 810 88

Our earlier work showed that stress had progressively more serious consequences in a hamster model of congestive heart failure as the magnitude of heart failure worsened. Based on that study, we hypothesized that the intensity of the stressor used might play an important part in determining this outcome as well as in influencing coronary reactivity to arginine vasopressin (AVP). Cardiomyopathic (2.5, 6.5, and 10 months) hamsters (CMHs) were stressed with a 2-hr period of supine immobilization for five consecutive days. Stressor intensity was increased by exposing the hamsters to progressively longer periods at 4 degrees C: the low stress group was never put in the cold; the moderate stress group was exposed to cold for 1 hr, and the high stress group for 2 hr. CMHs were anesthetized and sacrificed 5 days after stress, and their hearts were perfused using a modified Langendorff system. Maximum +/- dP/dt, developed pressure, ventricular relaxation time, (T), and coronary vascular resistance (CVR) were recorded, and CVR was also measured following coronary infusion of AVP. Stressor intensity had no effect on cardiac mechanics in 2.5-month CMHs. In 6.5-month CMHs, only the high-intensity stressor impaired ventricular mechanics (decreased maximum +/- dP/dt and developed pressure, increased T; P < 0.05), while low and moderate stress produced no effects. In 10-month CMHs, stress at all intensities exacerbated ventricular dysfunction (decreased maximum +/- dP/dt and developed pressure; P < 0.05). These results support our first hypothesis that stressor intensity interacts multiplicatively with severity of the underlying disease to influence the course of heart failure. However, our second hypothesis was not supported, because stress-regardless of intensity-affected reactivity of the coronary vasculature to AVP only in 2.5-month CMHs. A further test of the relation of stressor intensity and coronary vascular reactivity requires study of additional groups of CMHs during the period of their disease characterized by coronary vasospasm.
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PMID:The role of stressor intensity in influencing the course of heart disease in cardiomyopathic hamsters. 867 70

Angiotensin converting enzyme (ACE) inhibition undoubtedly has become the cornerstone of heart failure treatment. Useful in each stage, it should possibly be considered first-line treatment in many patients with mild heart failure in whom fluid retention is not clearly present. Careful consideration of the optimal dose for the individual is important. Until further data are available concerning the efficacy and tolerability of high and low doses, the clinician should consider the target doses used in large controlled heart failure trials. Even under optimal dosing conditions, it is likely that ACE inhibition may not suffice in completely modulating the extensive neurohormonal stimulation extant in heart failure. In part this may result from a breakthrough of the ACE inhibitor effect as well as from activation of hormones and peptides that may not be affected by ACE inhibition. Also, a substantial proportion of patients may not tolerate sufficient ACE inhibition. Alternative or additional therapy aimed at modulating neurohormonal activation concerns interference with other parts of the renin angiotensin system, such as angiotensin II receptor and aldosterone receptor antagonism. Sympathetic activity and catecholamine levels may decrease with dopaminergic D2 agonists and, possibly, beta-blockade; in the latter, this may be confined to patients with pre-existing sympathetic over-activation. Increasing circulating levels of atrial natriuretic peptide via neutral endopeptidase inhibition may offer an alternative way to increase diuresis and natriuresis without neuroendocrine stimulation. Novel possibilities that have not yet been tested sufficiently in patients with heart failure include endothelin receptor antagonism, arginine vasopressin antagonism, and renin inhibition. Finally, digitalis glycosides may be considered neurohormonal modulators in addition to being positive inotropes. Heart failure is a complex condition that involves many organs and systems besides the heart. Polypharmacy tailored to the individual is mandatory. It is thus necessary to investigate approaches to the modulation of neurohormonal activation beyond ACE inhibition.
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PMID:Neurohormonal modulation in heart failure: ACE inhibition and beyond. 868 65

The goal of this study was to test the hypothesis that chronic myocardial infarction potentiates agonist-induced constrictor responses of rat skeletal muscle arterioles in vivo. Eight weeks after we performed coronary artery ligation or sham (control) surgery, the spinotrapezius muscle was prepared for direct visualization of the microcirculation. Diameter of third-order arterioles (40.7 +/- 0.5 microns) to topical suffusion of angiotensin II (ANG II; 0.1-10 nM), arginine vasopressin (AVP; 0.1-10 nM), endothelin-1 (ET-1; 1.0-100 pM), and the thromboxane analog U-46619 (1.0-100 nM) was measured in both groups. Myocardial-infarcted rats exhibited enhanced arteriolar constrictor responses to ANG II and AVP compared with the responses in controls. In contrast, ET-1- and U-46619-induced constrictor responses were similar in control and myocardial-infarcted rats. Additional experiments explored the impact of NG-monomethyl-L-arginine (L-NMMA; 0.1 mM) on arteriolar reactivity. In control animals, L-NMMA potentiated ANG II- and AVP-induced vasoconstriction, achieving values similar to those observed in myocardial-infarcted rats. L-NMMA did not alter vasoconstrictor responses in rats with chronic myocardial infarction. These observations suggest that enhanced agonist-induced vasoconstriction during heart failure may reflect a loss of nitric oxide-mediated modulation of arteriolar tone.
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PMID:Enhanced constrictor responses of skeletal muscle arterioles during chronic myocardial infarction. 932 43

The hormone arginine vasopressin (AVP) contributes to water retention and vasoconstriction in congestive heart failure (CHF) through effects at the V2 and V1a receptors, respectively. The effect of long-term V2 receptor (V2R) blockade using OPC-31260 was assessed in a rat model of postinfarction-induced CHF. Rats underwent coronary artery ligation or sham operation and were treated for 6 mo with oral OPC-31260 (10 mg . kg-1 . day-1) or vehicle. CHF was characterized by left ventricular remodeling and impaired systolic function, increased cardiac and lung weight, and elevated plasma atrial natriuretic peptide; plasma AVP and plasma renin activity were not increased. Chronic V2R blockade increased urine volume (P < 0.01) and decreased urine osmolality (P < 0.01) but had no natriuretic effects. V2R blockade did not activate the renin-angiotensin system but increased plasma AVP in CHF (P < 0.01). V2R blockade did not influence cardiac remodeling, cardiac function, or survival. These results suggest that AVP plays a major role in water retention through the renal V2R in a rat model of CHF. V2R blockade using OPC-31260 may represent an alternative to standard diuretic therapy in the management of water retention that characterizes heart failure.
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PMID:Long-term effects of nonpeptide vasopressin V2 antagonist OPC-31260 in heart failure in the rat. 968 11

Traditionally, the pathophysiology of heart failure was viewed as a derangement in hemodynamic factors. Impairment in cardiac function resulted in decreased cardiac output and end-organ hypoperfusion triggering compensatory increases in heart rate, blood pressure and cardiac contractility. While initially beneficial, these mechanisms placed additional stress on the failing heart. Unfortunately, pharmacologic therapies that restored hemodynamic balance failed to halt disease progression. The activation of neurohormonal responses, including those of the renin-angiotensin-aldosterone system, the sympathetic nervous system and the arginine vasopressin system, has been implicated in the progression of heart disease. In acute heart failure, their effects help to restore cardiovascular homeostasis. However, the chronic stimulation of these systems eventually leads to worsening left ventricular function. Drug treatments that activate neurohormonal systems may have long-term clinically deleterious outcomes, and therefore new pharmacological therapies for cardiovascular disease must take into account the interaction between neurohormonal activation and hemodynamic factors.
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PMID:Neurohormonal activation in the treatment of congestive heart failure: basis for new treatments? 969 63


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