Suppression of the renin-angiotensin system by intravenous digoxin in chronic congestive heart failure

Recent studies have demonstrated that therapy with digitalis preparations may be of inconsistent benefit in the treatment of chronic congestive heart failure. One explanation may be a varying effect on vasoconstrictor hormones, as digoxin has been shown to suppress plasma renin activity in normal and hypertensive persons. Therefore, the effect of short-term digoxin administration on plasma renin activity and plasma aldosterone in six patients with compensated, severe, chronic congestive heart failure was evaluated. Intravenous administration of digoxin (0.50 mg) resulted in a reduction of plasma renin activity from 4.3 ± 0.9 to 2.0 ± 0.9 ng/ml per hour and plasma aldosterone from 34 ± 16 to 14 ± 6 ng/dl (both p < 0.05). Maximal response occurred at three hours after administration, with return to baseline by seven hours. Therefore, evaluation of the role of digitalis in chronic heart failure requires consideration of its direct or indirect effect on angiotensin-mediated vasoconstriction and aldosterone-mediated sodium retention, as well as other neurohormonal mechanisms of vasoconstriction.     

Interrelation of electrolytes and renin-angiotensin system in congestive heart failure

Many of the electrolyte derangements seen in chronic heart failure are related to activation of the renin-angiotensin system. Activation of the system may cause the retention of both sodium and water; the former is primarily related to the release of aldosterone and the latter is related to an angiotensin-mediated increase in thirst and decrease in the excretion of free water. The interaction of these mechanisms may explain why patients with chronic heart failure have higher values for total body sodium but lower values for serum sodium concentration than hypertensive patients or normal subjects. Activation of the renin-angiotensin system may also cause potassium depletion, which is manifest clinically by a decrease in both total body potassium and serum potassium concentration. These electrolyte disturbances may play a role in the development of ventricular arrhythmias. The renin-angiotensin system may also contribute to the development of magnesium deficits. These hormone-electrolyte interactions have important implications in the treatment of patients with heart failure, especially those in whom the renin-angiotensin system is pharmacologically inhibited.     

Role of the renin-angiotensin system in the development of congestive heart failure in the dog as assessed by chronic converting-enzyme blockade

Hormonal factors may be important in the regulation of peripheral vascular resistance (PVR) in congestive heart failure (CHF). The role of the renin-angiotensin system in the development of CHF was studied in 16 unanesthetized dogs. CHF was induced by rapid right ventricular pacing, with and without chronic converting-enzyme inhibition (CEI) by captopril. The hemodynamic changes and the activity of renin, aldosterone, norepinephrine and vasopressin were studied. The control dogs showed a greater decrease in cardiac output and a greater increase of mean pulmonary artery pressure than the captopril-treated group. In the group with CEI, only a small, transient increase in PVR was observed during the development of CHF; in the control group, there was an increase of 94% of basal values. The control group showed a continual increase of renin, aldosterone and norepinephrine. Four control dogs showed an inappropriately high secretion of arginine vasopressin. The increase of sympathetic nervous activity was only insignificantly attenuated by angiotensin II inhibition and was without a considerable influence on PVR except for an early transient increase in vascular tone. In our animal model, the renin-angiotensin system plays an important role in the regulation of PVR in CHF. In this kind of CHF the sympathetic nervous system appears to be of minor importance for the long-term regulation of PVR. Plasma arginine vasopressin levels were increased in control dogs; this increase may contribute to the increased vascular tone.     

Contribution of vasopressin to vasoconstriction in patients with congestive heart failure: comparison with the renin-angiotensin system and the sympathetic nervous system

Ten patients with advanced congestive heart failure were treated with an arginine vasopressin V1 antagonist during hemodynamic monitoring to determine the contribution of vasopressin to vasoconstriction in this disorder. The vasopressin antagonist caused a decrease in systemic vascular resistance in the three patients whose plasma vasopressin was greater than 4.0 pg/ml (average for the group was 2.4 +/- 0.6). Plasma vasopressin concentration correlated with the percent decrease of systemic vascular resistance (r = 0.70, p less than 0.025), serum sodium (r = 0.72, p less than 0.02) and serum creatinine (r = 0.85, p less than 0.005). To compare the relative roles of vasopressin, the renin-angiotensin system and the sympathetic nervous system, these patients also received captopril and phentolamine. Captopril decreased systemic vascular resistance by 20% (p less than 0.05), mostly in patients with high plasma renin activity. Levels of plasma renin activity ranged between 1 and 46 ng/ml per h (average 14.7 +/- 5.7) and correlated with serum sodium (r = 0.77, p less than 0.025), serum creatinine (r = 0.73, p less than 0.025) and right atrial pressure (r = 0.67, p less than 0.05). Phentolamine decreased systemic vascular resistance in all patients (average 34%, p less than 0.01), but the decrease did not correlate with the pretreatment norepinephrine concentration. Norepinephrine levels were elevated in all patients (694 +/- 110 pg/ml) and correlated with baseline stroke volume index (r = 0.75, p less than 0.025) and plasma renin activity (r = 0.67, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

The relationship of the sympathetic nervous system and the renin-angiotensin system in congestive heart failure

Congestive heart failure is a complex clinical syndrome characterized by circulatory and metabolic abnormalities. It has been apparent for more than 25 years that the sympathetic nervous system and the renin-angiotensin-aldosterone system are markedly activated in the late stages of heart failure. These two systems interact to facilitate sympathetic drive and promote salt and water retention. Circumstantial evidence is now accumulating to indicate that excessive sympathetic drive and angiotensin II activity may contribute to the pathophysiology of heart failure. These observations suggest that a dual strategy of modulating sympathetic nervous system activity to the heart while blocking angiotensin II activity may provide a rational therapeutic approach to the treatment of heart failure. Xamoterol, a beta 1 partial agonist, may enhance myocardial contractile force in the steady state, while acting to inhibit excessive sympathetic drive during exercise or severe heart failure. The concomitant use of a converting-enzyme inhibitor would be expected to blunt the detrimental effects of excessive angiotensin II activity. Modulation of adrenergic drive coupled with inhibition of marked angiotensin II activity may be potentially more effective in the treatment of congestive heart failure than either strategy used alone.     

Potential role of the tissue renin-angiotensin system in the pathophysiology of congestive heart failure

The circulating renin-angiotensin system (RAS) plays an important role in the maintenance of cardiovascular homeostasis. It has recently been demonstrated that endogenous RAS exist in target tissues that are important in cardiovascular regulation. This article reviews the multiple effects of angiotensin II in target tissues, the evidence for the presence of functional tissue RAS and the data that suggest a role for these tissue RAS in the pathophysiology of heart failure. Activation of circulating neurohormones is predictive of worsened survival in heart failure; however, cardiac and renal tissue RAS activities are also increased in the compensated stage of heart failure, when plasma renin-angiotensin activity is normal. It is hypothesized that the plasma RAS maintains circulatory homeostasis during acute cardiac decompensation, while changes in tissue RAS contribute to homeostatic responses during chronic sustained cardiac impairment. This concept of different functions of circulating and tissue RAS in the pathophysiology of heart failure may have important pharmacologic implications.     

The renin-angiotensin system in heart failure

The renin-angiotensin aldosterone system does appear to have a central role in the haemodynamic and metabolic response to declining ventricular function. Human heart failure usually occurs in the setting of preceding disease, which may itself influence the underlying activity of the system. Studies of the renin-angiotensin system after myocardial infarction are in agreement with animal models, that transient activation of the renin-angiotensin system occurs. This may be sustained if the cardiac insult is severe and especially if diuretic therapy is initiated. In those patients in whom the insult is less severe, activity of the renin-angiotensin system wanes. The finding that patients with stable untreated heart failure do not have markedly activated renin-angiotensin systems is not surprising, but correction of the plasma and extracellular volume (for instance with a diuretic) will result in reappearance of activation of these systems. Since the introduction of angiotensin-converting enzyme inhibitors, several new peptides have been discovered (atrial natriuretic peptide, endothelin etc.) that have important effects on cardiovascular function. New potential therapeutic agents with actions on neuroendocrine systems, such as the atrial peptidase inhibitors, angiotensin-II receptor antagonists and renin inhibitors, are on the horizon. Such exciting new discoveries will give as much insight into the pathophysiology of heart failure as the angiotensin-converting enzyme inhibitors have done.     

Alpha 2-receptor-mediated vasoconstriction in patients with congestive heart failure

alpha 2-Adrenoceptors exist postsynaptically to subserve vasoconstriction and presynaptically to modulate norepinephrine release into the synaptic cleft. Because adrenoceptors may down-regulate in response to chronic stimulation, we investigated the activity of alpha 2-receptor-mediated vasoconstriction in patients with congestive heart failure, who had increased levels of plasma norepinephrine. We used the isolated forearm model and intra-arterial infusions of subsystemic doses of yohimbine, a specific alpha 2-blocker, in 11 patients with heart failure and in 15 normal subjects. Yohimbine produced a dose-related increase in forearm blood flow and decrease in forearm vascular resistance. These findings were consistent with a direct vasodilator effect mediated by blockade of the postsynaptic alpha 2-vascular receptor. Furthermore, the vasodilator responses in patients with heart failure were similar to the normal subjects in terms of the percent increase in forearm blood flow, the dose-response relation, and the fractional response to hyperemia and phentolamine; thus, alpha 2-receptor-mediated vasoconstriction is neither enhanced nor down-regulated in heart failure. In addition, in patients with heart failure and in normal subjects, yohimbine produced an increase in the forearm venous norepinephrine concentration, consistent with an inhibition of the presynaptic alpha 2-receptor resulting in an augmented release of norepinephrine into the synaptic cleft. Thus, these data suggest that the postsynaptic alpha 2-receptor is an important mediator of vasoconstriction in patients with heart failure. Despite chronic elevations in plasma norepinephrine in patients with heart failure, alpha 2-receptor mechanisms subserving vasoconstriction and inhibition of norepinephrine release into the synaptic cleft are still functional in heart failure.     

Role of nitrates in congestive heart failure

The systemic vasoconstriction that is characteristic of patients with congestive heart failure involves arteriolar constriction, reduction in arterial compliance and reduction in venous capacitance, all of which contribute to the increased impedance and increased preload that aggravate the hemodynamic abnormality. Nitrates are effective in increasing arterial compliance and venous capacitance and thus have a favorable acute hemodynamic effect in heart failure. Long-term studies suggest that this favorable effect is maintained in response to high dose oral isosorbide dinitrate therapy and that it is associated with relief of symptoms and improved exercise tolerance. When combined with hydralazine, isosorbide dinitrate therapy has been shown in the Veterans Administration study to prolong survival in patients with class II and III congestive heart failure. Therefore, long-term nitrate therapy appears to have an important potential in patients with heart failure. It may now be appropriate to use nitrates not only to relieve symptoms, but also to improve long-term outlook in this syndrome.     

The role of the central nervous system in chronic congestive heart failure

Even though congestive heart failure is extremely common, the mechanisms responsible for the clinical manifestations remain a puzzle. The central and autonomic (sympathetic) nervous systems are responsible for a large part of the clinical manifestations. The role of the nervous system in CHF is discussed briefly. It is evident that there are many gaps in knowledge that remain concerning the role of the central, peripheral, and autonomic nervous systems in congestive heart failure. The peripheral vascular constriction, increase in venous tone and pressure, tachycardia, sweating, dermal pallor, and tension and anxiety in patients with CHF reflect generalized sympathetic nervous system activity and the influence of the central and autonomic nervous systems on the clinical syndrome of CHF.     

Role of systemic and pulmonary hemodynamics in genesis pleural effusion in congestive heart failure

We tried to make an estimate of how pleural effusion occur in congestive heart failure, using right atrial pressure (RA) and pulmonary arterial wedge pressure (PAW) as variables. We calculated the following equation by quoting the data in the past. RA greater than -0.02 x PAW + 13.3. We speculated that when this relationship is satisfied, pleural effusion will appear. We also studied the patients with severe congestive heart failure, dividing them into 2 groups, ie the pleural effusion group (EF) and pulmonary edema group (ED). Compared with ED, EF has a significantly higher RA (RA = 6.1 +/- 1.33 mmHg in EF and 13.3 +/- 2.21 mmHg in ED, mean +/- SE, p less than 0.02) and a significantly lower cardiac index (3.17 +/- 0.26 l/min/m2 vs 2.23 +/- 0.16 l/min/m2, mean +/- SE, p less than 0.01). Therefore, we thought that it was adequate to treat RA and PAW as independent variables. These equations appear to be useful in predicting the development of pleural effusion that's based in the plots of our patients on RA-PAW plane and their relationship to our equations.     

Captopril therapy in chronic congestive heart failure

Acute and chronic effects of captopril (C) were studied in 14 patients (12 males, 2 females; mean age 56 +/- 15 years) with chronic congestive heart failure (CCHF) refractory to digitalis and diuretics. All patients underwent hemodynamic evaluation before and after increasing doses of C (6.25-100 mg). Nine patients were evaluated during long term therapy by means of clinical examination, exercise testing, chest-X-ray and echocardiography. After C the following acute haemodynamic changes were observed. Mean right atrial pressure: -25% (p less than 0.01), left ventricular filling pressure: -22% (p less than 0.01), mean systemic arterial pressure: -15% (p less than 0.01), systemic vascular resistance: -31% (p less than 0.01), cardiac index: +36% (p less than 0.01). Of the 9 patients who were evaluated during long term C treatment, 7 (group A, mean follow up 6.4 +/- 4.2 months) improved in 1 or 2 NYHA functional classes and showed an increased exercise tolerance during the first 3-6 months of therapy. In this period, however, two sudden deaths and one drop-out were observed. Moreover, after the seventh month two patients of this group deteriorated clinically. Two patients (group B) developed a progressively weight gain during the first 15 days of C treatment. In the majority of our patients with refractory CCHF, captopril improves cardiac performance in the acute phase and in the first 3-6 months of therapy. Controlled studies and longer follow up are needed to understand better the long term effects of C in CCHF patients.     

Deactivation of the sympathetic nervous system in patients with chronic congestive heart failure

In this article, we review the basic biology, signal transduction pathways, and clinical pharmacology associated with cardiac β-adrenergic receptors (β-ARs) in the context of the use of β-blocking agents in patients with chronic congestive heart failure. Adrenergic receptors, particularly the β-AR subtypes (β₁-AR and β₂-AR), are known to play a critical role in the modulation of cardiac function, providing for both "adaptive" and "maladaptive" compensatory changes. In the context of exercise or self-preservation, the adrenergic nervous system, acting via β-ARs permits an appropriately rapid, highly-dynamic increase in cardiac function. Conversely, in individuals with chronic congestive heart failure, the sustained, heightened activation of adrenergic nervous system, as manifested by increases in circulating catecholamines, results in downregulation and desensitization of myocardial β-ARs, and potentially, significant myocardial damage. A number of recent clinical trials have demonstrated a marked mortality benefit from using β-blocking agents such as metoprolol and carvedilol in patients with heart failure. The pharmacologic properties of several of these drugs and some of the specifics of their usefulness and limitations are discussed herein.     

Role of beta blockers in congestive heart failure

Prolonged activation of the adrenergic nervous system has adverse consequences on the cardiovascular system in patients with congestive heart failure. Beta adrenergic receptor-blocker therapy modifies these deleterious effects. Beta blockers have been shown to improve myocardial function and survival when used in conjunction with conventional treatment with diuretics, angiotensin-converting enzyme inhibitors, and digoxin. Beta blocker therapy in mild-to-moderate heart failure should not be delayed because it causes some reversal of both neurohormonal compensatory mechanisms and the deleterious myocardial remodeling process. This paper reviews the beneficial effects of beta adrenergic receptor-blocker therapy on the pathophysiology, symptoms, left ventricular function, morbidity, and mortality in patients with congestive heart failure. (c)2000 by CHF, Inc.     

慢性充血性心衰患者下丘脑-垂体-甲状腺轴的变化

目的:研究慢性充血性心衰患者甲状腺激素变化与下丘脑-垂体轴系统的关系。方法:应用放射免疫法测定28例慢性充血性心衰(CHF)患者及14例健康人血清甲状腺激素浓度(T_3、T_4、FT_3、FT_4、rT_3),促甲状腺激素(TSH)浓度和促甲状腺激素释放激素(TRH)浓度。结果:(1)CHF组:T_3、FT_3、FT_4较对照组显著下降(P<0.05～<0.01);(2)随心衰加重,T_3、FT_3浓度减少,rT_3浓度增加,在心衰各组间有显著性差异,而T_4、FT_4、TSH、TRH水平在心衰各组间无显著性差异。结论:在充血性心衰时,下丘脑-垂体-甲状腺轴系统调节失衡。T_3、rT_3的改变可作为判断CHF严重程度的指标。     

Management of chronic congestive heart failure in children

Opinion statement The medical management of congestive heart failure involves manipulating myocardial contractility and loading conditions to achieve optimal performance. Medication may be used to counteract potentially deleterious neurohumoral changes that are associated with congestive heart failure. When appropriate, the correction of the underlying cardiac defect by surgery or catheter intervention is usually the most effective treatment for congestive heart failure in children.