Brain Natriuretic Peptide (Nesiritide) in the Treatment of Heart Failure

Over the last decade brain natriuretic peptide (BNP) emerged as a cardiac hormone of clinical interest in diagnosis, prognosis and treatment of patients with Heart Failure (HF). The diagnostic potential of BNP is now well established both in patients with suspected HF as well as in patients with asymptomatic left ventricular systolic dysfunction. The prognostic information obtained from BNP levels in HF and acute myocardial infarction patients seems even more promising. Nesiritide is a synthetic peptide, homologous to endogenous BNP. It is a balanced vasodilator with diuretic and natriuretic properties. It decreases the elevated levels of neurohormones resulting from activation of the sympathetic and renin‐aldosterone systems in HF. The results of clinical trials involving more than 2000 patients with decompensated HF are now available. In these trials nesiritide was administered by single or repeated bolus injections, as well as by sustained infusions. Nesiritide has been shown to produce a potent, dose‐related vasodilator effect that is rapid in onset and sustained during infusion. Balanced vasodilation is reflected by decreases in systemic vascular resistance, pulmonary artery wedge pressure and right atrial pressure. No tachyphylaxis has been observed in these trials. Efficacy of nesiritide in the treatment of decompensated HF has been demonstrated. Trials comparing nesiritide with conventional treatment of decompensated HF showed that nesiritide compares favorably to standard agents. The safety profile has been excellent with a dose‐dependent hypotension as the major side effect. Ventricular arrhythmia was not more frequent in patients treated with nesiritide than with placebo. Thus, nesiritide appears to be useful as a first‐line agent in the treatment of patients with decompensated HF.     

A review of the renal and neurohormonal effects of B-type natriuretic peptide

Adverse neurohormonal activation is an essential component in the pathogenesis of acute decompensated congestive heart failure (CHF). Consequently, blunting this activation is an important therapeutic goal. B-type natriuretic peptide (BNP) is a counterregulatory hormone produced by the ventricles in response to pressure and volume load. Endogenous BNP levels are significantly elevated in patients with acute CHF, but these levels are frequently inadequate to overcome the excess neurohormonal activation present in this condition. Infusion of nesiritide, a recombinant form of endogenous human BNP, increases circulating BNP levels by several-fold, augmenting the counterregulatory effects of this hormone. Clinical trials demonstrate that in patients with acute decompensated CHF, nesiritide produces arterial and venous vasodilation, reducing both preload and afterload; blunts adverse neurohormones, including renin, aldosterone, norepinephrine, and endothelin-1; and improves renal hemodynamics and tubular function. As a result, nesiritide quickly reduces clinical symptoms and improves mortality in patients with acute CHF.     

The clinical role of natriuretic peptides--importance of BNP and NT-proBNP. Implications in heart failure and acute coronary syndrome.

Natriuretic peptides are increasingly used as biomarkers for several clinical entities. An overview of the clinical applications of brain natriuretic peptide (BNP) and N-terminal brain natriuretic peptide (NT-proBNP) is presented. These neurohormones are used for diagnosis, monitoring and predicting prognosis in patients with chronic heart failure. The indications extend to risk stratification and prognosis of acute coronary syndromes and prognosis of acute pulmonary embolism. An appraisal of the influence of beta-blockers and other drugs in the measurement of natriuretic peptides is performed. The clinical effectiveness of treatment with the cardiac hormone nesiritide (human B-type natriuretic peptide) in heart failure is assessed.     

Nesiritide for the treatment of decompensated heart failure

Nesiritide (human recombinant B-type natriuretic peptide) binds to receptors in the vasculature, kidney, and other organs to mimic the actions of endogenous natriuretic peptides. Intravenous infusion of nesiritide has been studied in more than 1,700 patients with acute decompensated heart failure (HF). Nesiritide causes potent, dose-related vasodilation that is rapid in onset and sustained for the duration of drug infusion. There is balanced arterial and venous dilation as reflected by decreases in systemic vascular resistance, systemic arterial pressure, pulmonary capillary wedge pressure, right atrial pressure, and mean pulmonary arterial pressure. Vasodilation occurs without a change in heart rate and is associated with increases in stroke volume and cardiac output. Nesiritide may promote diuresis because of a direct natriuretic action, increased cardiac output, and/or decreased aldosterone levels. In patients hospitalized for decompensated HF, nesiritide improves symptoms and is well tolerated. The major adverse effect is dose-related hypotension. Nesiritide is thus an attractive new vasodilator that should be valuable in the treatment of patients hospitalized for acute decompensated HF.     

Subcutaneous administration of the cardiac hormone BNP in symptomatic human heart failure

BACKGROUND: Brain natriuretic peptide (BNP) is a cardiac hormone with vasodilating, natriuretic, renin-angiotensin-aldosterone-inhibiting and lusitropic properties. We have demonstrated that acute subcutaneous (SQ) administration of BNP in experimental congestive heart failure results in elevation of plasma BNP and its second messenger 3',5'-cyclic guanosine monophosphate (cGMP) with natriuresis and reduction in cardiac filling pressures. Furthermore, chronic subcutaneous BNP in experimental congestive heart failure also resulted in increases in cardiac output and decreases in pulmonary capillary wedge pressure and systemic vascular resistance. METHODS: The objective of the current study was to assess the safety and efficacy of repeated doses of subcutaneous human BNP, nesiritide, a recombinant form of human BNP (Scios Inc, Fremont, CA) in human subjects with New York Heart Association class II-III congestive heart failure. We defined the cardiorenal and humoral responses to subcutaneous BNP (nesiritide) administered every 12 hours with a total of 5 doses over 72 hours in a single-blind placebo-controlled design (n=8). The mean dose of nesiritide was 10 microg/kg every 12 hours. RESULTS: Initial saline placebo resulted in no change in any measured parameters (P<.05 versus baseline). With the first dose of BNP (nesiritide), cardiac output increased (4.8+/-0.4 to 6.4+/-0.5 L/min) and systolic blood pressure decreased (125+/-5 to 104+/-3 mm Hg) without a change in heart rate. Plasma BNP (167+/-115 to 830+/-470 pg/mL), cGMP (4+/-2 to 14+/-4 pmol/mL), and urinary cGMP excretion (3900+/-930 to 10,600+/-5000 pmol/min) increased with natriuresis and diuresis. Both plasma renin activity and plasma aldosterone decreased. These favorable biologic responses were observed with the fifth dose 72 hours after the initial dose. All the subjects tolerated the study well without any adverse events except for 1 subject who had a vasovagal episode during micturition after receiving the fifth dose on day 3. CONCLUSION: We conclude that subcutaneous administration of BNP (nesiritide) represents a novel and efficacious therapeutic strategy in human congestive heart failure to deliver BNP, a cardiac hormone which possesses unique cardiorenal and neurohumoral properties.     

Rationale and Design of a Randomized,Double-Blind,Placebo-Controlled Clinical Trial to Evaluate the Efficacy of B-Type Natriuretic Peptide for the Preservation of Left Ventricular Function After Anterior Myocardial Infarction

BackgroundB-type natriuretic peptide (BNP) is a hormone with pleiotropic cardioprotective properties. Previously in our non–placebo-controlled non-blinded pilot study (BELIEVE) in human ST-segment-elevation anterior acute myocardial infarction (AMI), a 72-hour intravenous (IV) infusion of recombinant human BNP (nesiritide) at a dose of 0.006 μg kg⁻¹ min⁻¹ suppressed plasma aldosterone, reduced cardiac dilatation, and improved left ventricular (LV) ejection fraction (LVEF) at 1 month compared with baseline.Methods and DesignThe BELIEVE II study is a phase II, randomized, double-blind, placebo-controlled, single-center clinical trial to assess the efficacy of 72-hour IV infusion of nesiritide therapy (0.006 μg kg⁻¹ min⁻¹) in humans with first-time ST-segment-elevation anterior AMI and successful reperfusion, in preventing adverse LV remodeling and preserving LV function. A total of 60 patients will be randomized to placebo or nesiritide therapy. The primary efficacy end point is LV end-systolic and end-diastolic dimensions determined by multiple gated acquisition scan between placebo and nesiritide groups at 30 days; secondary end points include 30-day LVEF, diastolic function, infarct size, LV mass, and combined total mortality and heart failure hospitalization.ConclusionsThis will be the first randomized, double-blind, placebo-controlled clinical trial to assess the clinical efficacy of nesiritide in human ST-segment-elevation anterior AMI.     

Nesiritide in congestive heart failure associated with acute coronary syndromes: a pilot study of safety and efficacy

BACKGROUND: To compare the safety and efficacy of nesiritide versus intravenous nitroglycerin (NTG) in patients with acute coronary syndromes enrolled in the Vasodilation in the Management of Acute Congestive heart failure trial.Methods and results Retrospective review of Vasodilation in the Management of Acute Congestive heart failure trial data for heart failure associated with prospectively diagnosed acute coronary syndromes. Sixty-one patients were included; 34 received nesiritide and 27 received NTG. Pulmonary capillary wedge pressure was measured in right heart-catheterized patients (11 nesiritide, 9 NTG). Death at 6 months occurred in 2 nesiritide and 5 NTG patients (P>.2). Hypotension occurred in 4 nesiritide and 3 NTG patients (P>.6). At 24 hours, pulmonary capillary wedge pressure improvements persisted (P=.001) in the nesiritide group, whereas the NTG group had returned to baseline (P>.1). In non-right heart-catheterized patients, 24-hour dyspnea scores were at least moderately improved in all nesiritide and 71% of NTG (P=.031). At least minimal dyspnea improvement was seen in 100% of nesiritide versus 71% of NTG patients (P>.3), and 6-hour global clinical scores were at least moderately better in 75% of nesiritide versus 32% of NTG (P=.031). In non-right heart-catheterized patients, there were no 30-day readmissions with nesiritide versus 17% with NTG (P>.2). CONCLUSIONS: Nesiritide is as safe as NTG in heart failure patients with acute coronary syndromes.     

"Diastolic" heart failure and pulsed pressure

Cardiac failure is the leading cause of hospital admission after 65 years of age. Several studies have confirmed the frequency of cardiac failure with normal systolic function ("diastolic" cardiac failure) in the elderly (nearly half the cases). The cause is commonly isolated systolic hypertension. The pulsed pressure depends on ventricular ejection, arterial rigidity and the precocity of reflected pulse waves. In the elderly, the pulse pressure is a powerful predictive factor for mortality and adverse cardiovascular events (acute coronary syndromes, cardiac failure and cerebrovascular accidents). Patients with isolated systolic hypertension or an increased pulsed pressure usually have left ventricular hypertrophy or concentric remodelling, abnormal relaxation, alteration of hypertrophied myocytes with increased myocardial oxygen consumption and subendocardial ischaemia, especially when the coronary reserve is reduced. The decrease of the diastolic blood pressure reduces the presence of coronary perfusion. Moreover, an increase in the pulsed pressure predisposes to coronary atherosclerosis. These patients are very symptomatic on exercise because they do not have a reserve of preload and easily develop acute pulmonary oedema after a volume overload (increased salt intake, postoperative rehydratation). A recent study showed that the left ventricular ejection fraction was preserved during acute pulmonary oedema of hypertensive patients. The diagnosis of "diastolic" cardiac failure is often suspected by elimination (clinical signs of cardiac failure with a normal left ventricular ejection fraction), and echographers have proposed many criteria to detect abnormal relaxation, filling or distensibility of the left ventricle. Mortality would seem to be half that of systolic cardiac failure. Treatment should normalise the hypertension, ischaemia, tachycardia, and maintain or reestablish sinus rhythm, but it remains empirical.     

Clinical applications of B-type natriuretic peptide levels in the care of cardiovascular patients

B-type natriuretic peptide (BNP), is a cardiac neurohormone, and is released as prepro BNP and then enzymatically cleaved to the N-terminal-proBNP and BNP upon ventricular myocyte stretch. Blood measurements of BNP have been used to identify patients with heart failure (HF). The BNP assay is currently used in diagnosis, prognosis, screening, and response to treatment for patients with HF. In general, a BNP level below 100 pg/mL excludes acutely decompensated HF and levels > 500 pg/ml indicate decompensation. There are supportive data for using BNP to guide both inpatient and outpatient HF diagnosis and treatment. When BNP is elevated in acute coronary syndromes, pulmonary embolism, and sepsis, it implies that subclinical left ventricular dysfunction is present and a higher mortality rate can be expected. Elevated BNP levels before cardiac surgery are associated with higher rates of atrial fibrillation and death. After bypass surgery, as left ventricular function improves, the BNP level can be expected to fall. Lastly, in patients with aortic stenosis, aortic regurgitation, and mitral regurgitation, BNP elevates and is associated or may precede the development of symptoms and possibly can serve as a trigger for additional evaluation or intervention.     

脑钠素在心血管疾病中的变化及意义

脑钠素是一种神经激素 ,主要在心室容量及压力增高的情况下分泌 ,可作为充血性心力衰竭的诊断、严重程度评估以及预后的重要标志物 ,对于急性冠状动脉综合征 ( ACS)的危险分层及死亡预测有重要价值。     

Effects of intravenous nesiritide on pulmonary vascular hemodynamics in pulmonary hypertension

BACKGROUND: Nesiritide is effective in the treatment of decompensated heart failure (HF). We evaluated the acute hemodynamic effects of nesiritide, a recombinant B-type natriuretic peptide, in patients with HF and pulmonary hypertension (PH). METHODS AND RESULTS: Twenty patients with HF and PH (mean pulmonary arterial [PA] pressure >25 mm Hg) were enrolled: 10 with postpulmonary capillary wedge (PCW) >15 mm Hg and 10 with precapillary PH (PCW) < or =15. The pulmonary and systemic hemodynamics were determined by right heart catheterization at baseline and at 15 and 30 minutes after an intravenous nesiritide infusion (2 mcg/kg bolus and 0.01 mcg.kg.min). For the patients with postcapillary PH, the mean left ventricular ejection fraction was 28 +/- 15%. After the 30-minute nesiritide infusion, right atrial (RA) pressure decreased 48% (P < .0001), mean PA pressure decreased 29% (P < .0001), PCW pressure decreased 40% (P < .0001), cardiac index (CI) increased 35% (P = .009), pulmonary vascular resistance index (PVRI) decreased 35% (P = .01), and arteriovenous oxygen difference (AVDO(2)) decreased 27% (P = .0003). For precapillary PH patients, there was no change in RA, PA, or PCW pressure, nor any change in CI, PVRI, or AVDO(2). CONCLUSIONS: Nesiritide acutely and significantly reduced PA pressure, PVRI, and biventricular filling pressures in patients with postcapillary PH. However, for patients with precapillary PH, nesiritide had no significant acute hemodynamic effect on the pulmonary hemodynamics. The lack of acute beneficial effects of nesiritide in patients with advanced precapillary PH may be related to their relatively fixed remodeling of the pulmonary vasculature.     

Interpretation of B-type natriuretic peptide in cardiac disease and other comorbid conditions

B-Type natriuretic peptide (BNP) is elevated in states of increased ventricular wall stress. BNP is most commonly used to rule out congestive heart failure (CHF) in dyspneic patients. BNP levels are influenced by age, gender and, to a surprisingly large extent, by body mass index (BMI). In addition, it can be elevated in a wide variety of clinical settings with or without CHF. BNP is elevated in other cardiac disease states such as the acute coronary syndromes, diastolic dysfunction, atrial fibrillation (AF), amyloidosis, restrictive cardiomyopathy (RCM), and valvular heart disease. BNP is elevated in non-cardiac diseases such as pulmonary hypertension, chronic obstructive pulmonary disease, pulmonary embolism, and renal failure. BNP is also elevated in the setting of critical illness such as in acute decompensated CHF (ADHF) and sepsis. This variation across clinical settings has significant implications given the increasing frequency with which BNP testing is being performed. It is important for clinicians to understand how to appropriately interpret BNP in light of the comorbidities of individual patients to maximize its clinical utility. We will review the molecular biology and physiology of natriuretic peptides as well as the relevant literature on the utilization of BNP in CHF as well as in other important clinical situations, conditions that are commonly associated with CHF and or dyspnea.     

Clinical trials update from the American College of Cardiology 2007: ALPHA, EVEREST, FUSION II, VALIDD, PARR-2, REMODEL, SPICE, COURAGE, COACH, REMADHE, pro-BNP for the evaluation of dyspnoea and THIS-diet

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the American College of Cardiology meeting in March 2007. Unpublished reports should be considered as preliminary data, as analyses may change in the final publication. The ALPHA study suggested that patients with heart failure (HF) due to idiopathic dilated cardiomyopathy who have a negative T-wave alternans test have a good prognosis and are unlikely to benefit from ICD therapy. EVEREST provides some evidence of short-term symptom benefit of tolvaptan in patients with acute decompensated HF but no clinically important long-term benefit. FUSION II failed to show a benefit of nesiritide in patients with chronic decompensated HF. Reducing blood pressure in hypertensive patients improved diastolic dysfunction in VALIDD. Eplerenone did not improve left ventricular remodelling in mild to moderate chronic HF. Selecting HF patients for revascularisation using FDG-PET imaging did not significantly improve outcome. Crataegus extract added to standard HF therapy did not reduce morbidity or mortality in SPICE. The COURAGE study, conducted in patients without HF or major cardiac dysfunction, showed that PCI did not reduce cardiac morbidity or mortality and can be safely deferred in patients with stable coronary disease on optimal medical therapy. The COACH study failed to show that HF nurse-intervention could reduce hospitalisations but did show trends to lower mortality, especially amongst patients with reduced ejection fraction; however, the smaller REMADHE study suggested striking benefits on morbidity and mortality. A large study of BNP provided additional information on its ability to distinguish cardiac and pulmonary breathlessness. The importance of dietary intervention in post-MI patients was highlighted by the findings of THIS-diet study.     

Acute heart failure: a novel approach to its pathogenesis and treatment

Acute heart failure (HF) is one of the most common syndromes in emergency medicine, however, its exact pathogenesis has remained largely unknown. Based on clinical and hemodynamic data we have sub-divided acute HF into four syndromes: cardiogenic shock, pulmonary edema, hypertensive crisis and exacerbated HF. Cardiogenic shock is caused by a severe reduction in cardiac power which is not met by an adequate increase in peripheral vascular resistance leading to significant decrease in blood pressure and end organ perfusion. Hence the treatment of cardiogenic shock should be directed at improving cardiac performance (by optimizing filling pressure, intra-aortic balloon pump and immediate revascularization) and administration of peripheral vasoconstrictors. The other acute HF syndromes (pulmonary edema, HTN crisis and exacerbated HF) are caused by a combination of progressive excessive vasoconstriction superimposed on reduced left ventricular functional reserve. The impaired cardiac power and extreme vasoconstriction induce a vicious cycle of afterload mismatch resulting in a dramatic reduction of CO and elevated left ventricular end diastolic pressure, which is transferred backwards to the pulmonary capillaries yielding pulmonary edema. Therefore, the immediate treatment of these acute HF syndromes should be based on the administration of strong, fast-acting intravenous vasodilators such as nitrates or nitroprusside. After initial stabilization, therapy should be directed at reducing recurrent episodes of acute HF, by prevention of repeated episodes of excessive vasoconstriction along with efforts to optimize cardiac function.     

血浆脑钠肽在急性冠状动脉综合征中的临床应用进展

脑钠肽是主要由心室肌细胞分泌的一种心脏神经激素,是心功能不全时机体的代偿机制之一。近年来研究表明,心肌缺血同样能够引起脑钠肽水平的升高,血浆脑钠肽与急性冠脉综合征的关系已经引起人们的关注。脑钠肽与NYHA分级和左室射血分数间存在较好的相关性,可作为预测急性冠脉综合征心室重塑、冠脉病变程度的有效指标,是急性冠脉综合征的独立预后因子,并作为高敏C反应蛋白、肌酸激酶同工酶和肌钙蛋白I等生化指标的有益补充,为急性冠脉综合征提供有价值的辅助诊断。     

Safety and efficacy of nesiritide in pediatric heart failure

BackgroundWe hypothesized that recombinant B-type natriuretic peptide (BNP) (nesiritide) could improve urine output and neurohormonal markers of heart failure without worsening renal function in pediatric patients.Methods and ResultsWe analyzed our experience involving 140 nesiritide infusions in 63 consecutive children. Serum levels of BNP and electrolytes were measured before and after therapy. Dosing was begun at 0.01 mcg·kg·min without a bolus and titrated to a maximum of 0.03 mcg·kg·min, in 0.005-mcg·kg·min increments. Blood pressure, heart rate, and heart rhythm were monitored. In a substudy, 20 patients with decompensated cardiomyopathy-related heart failure received 72 hours of nesiritide with prospective assessment of aldosterone, norepinephrine, plasma renin, and endothelin-1 levels before and after therapy. The heart rate decreased significantly (P = .001). Urine output increased significantly on Days 1 and 3 (P ≤ .001 and .004, respectively). The mean serum creatinine level decreased from 1.135 to 1.007 mg/dL (P ≤ .001). In the substudy, aldosterone levels decreased from 37.5 ± 57.1 to 20.5 ± 41.9 ng/dL (P = .005). Plasma renin, norepinephrine, and endothelin-1 levels decreased nonsignificantly. Two infusions were discontinued because of hypotension.ConclusionsNesiritide safely treated decompensated heart failure in children. Increased urine output reflected improving renal function. Improved neurohormonal markers were seen after 72 hours of therapy, and complications were uncommon.     

Effects of captopril in acute and chronic heart failure. Correlations with plasma levels of noradrenaline, renin, and aldosterone

The angiotensin-converting enzyme inhibitor, captopril, was given to 19 patients with severe heart failure. Seven patients had acute myocardial infarction and the remainder had chronic myocardial damage caused by ischaemia or valvular disease. Cardiac filling pressures were raised in all, the pulmonary capillary "wedge" pressure being 17 mmHg or more. Captopril, 50 mg orally, raised stroke volume and cardiac output, and reduced heart rate, cardiac filling pressures, systemic arterial pressure, and the plasma concentrations of aldosterone and noradrenaline. These changes were attended by clinical improvement. Decrements in cardiac filling pressures, systemic arterial pressure, and total peripheral resistance were positively correlated with pretreatment plasma renin. Long-term treatment with captopril was offered to 14 patients. Four patients with severe coronary disease died suddenly after initial clinical improvement. In nine patients haemodynamic measurements were repeated after three months. The results showed sustained effects on cardiac output and filling pressures but there was no loss of body weight. The haemodynamic effects were at least as good as with previous vasodilators. The fall in systemic arterial pressure, however, was greater with captopril. Captopril may become a valuable adjunct to the treatment of acute and chronic heart failure, but more information about its effect on coronary blood flow is required.     

Effects of captopril in acute and chronic heart failure. Correlations with plasma levels of noradrenaline, renin, and aldosterone.

The angiotensin-converting enzyme inhibitor, captopril, was given to 19 patients with severe heart failure. Seven patients had acute myocardial infarction and the remainder had chronic myocardial damage caused by ischaemia or valvular disease. Cardiac filling pressures were raised in all, the pulmonary capillary "wedge" pressure being 17 mmHg or more. Captopril, 50 mg orally, raised stroke volume and cardiac output, and reduced heart rate, cardiac filling pressures, systemic arterial pressure, and the plasma concentrations of aldosterone and noradrenaline. These changes were attended by clinical improvement. Decrements in cardiac filling pressures, systemic arterial pressure, and total peripheral resistance were positively correlated with pretreatment plasma renin. Long-term treatment with captopril was offered to 14 patients. Four patients with severe coronary disease died suddenly after initial clinical improvement. In nine patients haemodynamic measurements were repeated after three months. The results showed sustained effects on cardiac output and filling pressures but there was no loss of body weight. The haemodynamic effects were at least as good as with previous vasodilators. The fall in systemic arterial pressure, however, was greater with captopril. Captopril may become a valuable adjunct to the treatment of acute and chronic heart failure, but more information about its effect on coronary blood flow is required.     

Spironolactone preserves cardiac norepinephrine reuptake in salt-sensitive Dahl rats

An impairment of cardiac norepinephrine (NE) reuptake via the neuronal NE transporter (NET) enhances the effects of increased cardiac NE release in heart failure patients. Increasing evidence suggests that aldosterone and endothelins promote sympathetic overstimulation of failing hearts. Salt-sensitive Dahl rats (DS) fed a high-salt diet developed arterial hypertension and diastolic heart failure as well as elevated plasma levels of endothelin-1 and NE. Cardiac NE reuptake and NET-binding sites, as assessed by clearance of bolus-injected [(3)H]NE in isolated perfused rat hearts and [(3)H]mazindol binding, were reduced. Treatment of DS with the mineralocorticoid receptor antagonist spironolactone preserved the plasma levels of endothelin-1 and NE, cardiac NE reuptake, and myocardial NET density. Moreover, the ventricular function and survival of spironolactone-treated DS were significantly improved compared with untreated DS. The alpha(1)-inhibitor prazosin decreased blood pressure in DS similar to spironolactone treatment, but did not normalize the plasma levels of endothelin-1 and NE, NE reuptake, or ventricular function. In a heart failure-independent model, Wistar rats that were infused with aldosterone and fed a high-salt diet developed impaired cardiac NE reuptake. Treatment of these rats with the endothelin A receptor antagonist darusentan attenuated the impairment of NE reuptake. In conclusion, spironolactone preserves NET-dependent cardiac NE reuptake in salt-dependent heart failure. Evidence is provided that aldosterone inhibits NET function through an interaction with the endothelin system. Selective antagonism of the mineralocorticoid and/or the endothelin A receptor might represent therapeutic principles to prevent cardiac sympathetic overactivity in salt-dependent heart failure.     

Clinical applications of brain natriuretic peptide testing]

Natriuretic peptide hormones are a family of vasoactive peptides with many favorable physiological properties and have emerged as useful markers in cardiovascular disease. In particular, brain natriuretic peptide (BNP) is a cardiac neurohormone secreted by the cardiac ventricles as a response to ventricular volume expansion, pressure overload and resultant increased wall tension, directly correlated with both left ventricular filling and pulmonary wedge pressure. It is nowadays considered an important diagnostic tool, adding information to clinical judgment in the evaluation of patients with acute dyspnea, and a useful guide to the treatment of chronic heart failure. Moreover, the prognostic value of BNP has been established in several studies, both in postmyocardial infarction patients with asymptomatic left ventricular dysfunction and in patients with overt heart failure. Furthermore it has been shown that BNP could also predict sudden death and offer an additive and easily obtainable tool for risk stratification of patients with chronic heart failure. This paper summarizes the current evidence concerning the use of this peptide in a variety of clinical scenarios.