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(Circulation. 1996;94:3184-3189.)
© 1996 American Heart Association, Inc.

Articles

Hemodynamic and Renal Excretory Effects of Human Brain Natriuretic Peptide Infusion in Patients With Congestive Heart Failure

A Double-Blind, Placebo-Controlled, Randomized Crossover Trial

Lee S. Marcus, MD; Douglas Hart, MD; Milton Packer, MD; Madeline Yushak, RN; Norma Medina, RN; Robert S. Danziger, MD; Daniel F. Heitjan, PhD; Stuart D. Katz, MD

Columbia Presbyterian Medical Center, Department of Medicine, Divisions of Circulatory Physiology and Cardiology, Columbia University College of Physicians and Surgeons, New York, NY, and the Columbia University School of Public Health, Division of Biostatistics, New York, NY.

Correspondence to Stuart D. Katz, MD, Columbia Presbyterian Medical Center, Division of Circulatory Physiology, Room MHB5-435, 177 Fort Washington Ave, New York, NY 10032. E-mail sdk8@columbia.edu.

	Abstract

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Background The pharmacological effects of infusion of human brain natriuretic peptide (hBNP) in patients with severe congestive heart failure have not been characterized previously.

Methods and Results Twenty patients with severe congestive heart failure were randomized in a double-blind, placebo-controlled, crossover trial to receive incremental 90-minute infusions of hBNP (0.003, 0.01, 0.03, and 0.1 µg/kg per minute) or placebo on 2 consecutive days. At the highest completed dose of the hBNP, mean pulmonary artery pressure decreased from 38.3±1.6 to 25.9±1.7 mm Hg; mean pulmonary capillary wedge pressure decreased from 25.1±1.1 to 13.2±1.3 mm Hg; mean right atrial pressure decreased from 10.9±1 to 4.8±1.0 mm Hg; mean arterial pressure decreased from 85.2±2.0 to 74.9±1.7 mm Hg; and cardiac index increased from 2.0±0.1 to 2.5±0.1 L/min per square meter (all P<.01 versus placebo). Urine volume and urine sodium excretion increased significantly during hBNP infusion when compared with placebo infusion (90±38 versus 67±27 mL/h and 2.6±2.4 versus 1.4±1.2 mEq/h, respectively, both P<.05 versus placebo), whereas creatinine clearance and urinary potassium excretion did not change.

Conclusions Infusion of incremental doses of hBNP is associated with favorable hemodynamic and natriuretic effects in patients with severe congestive heart failure. (Circulation. 1996;94:3184-3189.)

Key Words: heart failure • natriuretic peptides • hemodynamics • pharmacology • drugs

	Introduction

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Brain natriuretic peptide (BNP) is a 32–amino acid protein with vasodilating, natriuretic, and diuretic properties that was originally isolated from porcine brain but subsequently found to be secreted in humans primarily by the heart.^{1 2 3} Plasma concentrations of BNP are increased in patients with chronic congestive heart failure and are closely correlated with several clinical and hemodynamic parameters of disease severity.^{2 4}

Brain natriuretic peptide shares substantial structural homology with atrial natriuretic peptide (ANP).^{1 5 6} However, the primary sites of synthesis, receptor affinities, and clearance mechanisms of these two peptides are different.^{2 4 5} It has been suggested that ANP and BNP function as a dual cardiac natriuretic peptide system with distinct physiological, pathophysiological, and pharmacological properties.^{2 7} Previous studies have demonstrated that the pharmacological effects of ANP infusion are attenuated in heart failure, particularly in patients with the most advanced disease.^{8 9 10 11 12} In contrast, in a previous study in 7 patients with mild to moderate heart failure, the vasodilatory and renal excretory effects of BNP infusion were comparable to those observed in normal subjects.¹³ Whether the effects of BNP infusion are attenuated in patients with more severe congestive heart failure is unknown. Accordingly, the current study was undertaken to determine the acute hemodynamic and renal excretory effects of an infusion of graded doses of human brain natriuretic peptide (hBNP) in patients with severe congestive heart failure in a placebo-controlled, double-blind, crossover trial.

	Methods

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Patient Population
Twenty patients (17 men and 3 women; mean age, 57±2 years) with congestive heart failure of at least 2 months' duration participated in the study. The mean left ventricular ejection fraction was 0.20, determined by either two-dimensional echocardiography or radionuclide angiography. The etiology of left ventricular dysfunction was idiopathic dilated cardiomyopathy in 11 patients, coronary artery disease in 7 patients, and surgically corrected valvular disease in 2 patients. According to the criteria of the New York Heart Association, 2 patients were in functional class II, 16 patients were in functional class III, and 2 patients were in functional class IV. The mean peak oxygen uptake, determined during symptom-limited, graded treadmill exercise testing, was 14.5 mL/kg per minute. Six patients had chronic atrial fibrillation. All patients were receiving chronic treatment with digoxin and a loop diuretic. All patients were also taking vasodilating agents, either alone or in combination: ACE inhibitors in 18 patients, long-acting nitrates in 9 patients, and hydralazine in 3 patients. Subjects with pulmonary capillary wedge pressure <15 mm Hg, recent myocardial infarction (within 3 months), unstable angina (within 2 weeks), heart failure caused by uncorrected valvular pathology, or acute myocarditis were excluded from the study. The study protocol was approved by the institutional review board at Columbia Presbyterian Medical Center. All patients gave written informed consent before entry into the study.

Hemodynamic Measurements
Right heart catheterization was performed to measure thermodilution cardiac output, intracardiac and pulmonary pressures, and derived hemodynamic variables with procedures and formulas that have been published in detail elsewhere.¹⁴

Study Protocol
The study commenced in the morning on the day after placement of the right heart catheter. Hydralazine and long-acting nitrate preparations were discontinued 48 hours before entry into the study. Digoxin, diuretics, and ACE inhibitors (captopril in 10 patients, enalapril in 7 patients, lisinopril in 1 patient) were given in the evening, 12 hours before administration of study drug on each day of the trial. This regimen was chosen to avoid prolonged withdrawal of background medical therapy over the 48-hour period of the study in patients with severe heart failure and yet minimize the direct effect of background therapy on resting hemodynamics during study drug infusion. Patients received a 2-g sodium diet throughout the study.

All hemodynamic measurements were performed in a quiet, temperature-controlled room while the patient rested supine in a fasting state. Before drug administration on each day of the study, hemodynamic measurements were repeated at 15-minute intervals 2 or 3 times until two sequential measurements varied <10%. Twenty-two patients were screened for the study; 2 were excluded because the initial pulmonary capillary wedge pressure was <15 mm Hg.

After stable resting hemodynamic measurements were established, patients were randomized in a double-blind fashion to receive 6-hour infusions of hBNP and placebo in a randomized, crossover trial design, on 2 consecutive days. Four incremental doses of synthetic human BNP (32–amino acid peptide, Scios Nova) or matching placebo was administered as sequential 90-minute infusions: 0.003, 0.01, 0.03, and 0.1 µg/kg per minute. Hemodynamic measurements were recorded at 90-minute intervals at the completion of each incremental dose of study drug.

The study protocol was modified to eliminate the highest dose of study drug after an adverse event (prolonged symptomatic hypotension) was observed in the 14th enrolled patient. Thus, the last 6 patients enrolled in the study did not receive the highest dose of study drug.

Urine was collected at 12-hour intervals overnight before each study drug infusion and after initiation of study drug infusion on each study day for analysis of urine volume and urinary sodium, potassium, and creatinine concentrations. Blood was obtained for measurement of serum BNP concentration before and at the completion of the study drug infusion on each day of the study. Blood was obtained for measurement of serum cGMP concentrations at the completion of the study drug infusion on each day of the study. Plasma BNP and cGMP concentrations were determined by radioimmunoassay (Biomedical Technologies). Serum sodium and potassium concentrations, blood urea nitrogen, serum creatinine concentration, and complete blood counts were determined 1 hour after the cessation of study drug infusion on each day of the study by standard clinical laboratory methods.

Data Analysis
Measured and derived hemodynamic variables on each study day were compared by fitting mixed linear models in SAS Proc Mixed (SAS version 6.09, SAS Institute, Inc). All results are stated as mean±SEM as estimated under the model. Since such models assume normality, preliminary tests for normality of each variable were executed (SAS Proc Univariate). These analyses suggested that all variables were normally distributed with the exception of pulmonary vascular resistance (PVR). PVR was positively skewed and became approximately normal when transformed to the inverse scale (ipvr=-1/pvr). For each variable analyzed, the data were fit in a full model that included main effects and interactions of treatment (BNP or placebo), dose level (baseline, 0.003, 0.01, 0.03, and 0.1 µg/kg per minute), and randomization treatment order (BNP-placebo or placebo-BNP), with random effects of subject and day. Hypotheses concerning model parameters were tested by Wald tests with an approximate F null distribution. To assess the effect of treatment order (carryover effects), the full model was compared with a reduced model that included only treatment, dose, and the treatment-by-dose interaction. Since comparisons of the full and reduced models were not significant at the 0.1 level for any of the variables, the final mixed linear model was reestimated to include only treatment, dose, and the treatment-by-dose interaction. The F test of the treatment-by-dose interaction is the main test of a treatment effect. Dose-response effects were separately analyzed for hBNP and placebo treatment by estimated contrasts comparing each dose of hBNP or placebo with the next higher dose. A separate analysis to determine the maximal effect of hBNP and placebo at the highest completed dose was also performed with Student's t test for paired observations. Renal excretory parameters, laboratory data, and serum BNP, and cGMP concentrations determined on each study day were compared with Student's t test for paired observations. For all variables, differences between hBNP and placebo were considered statistically significant if the two-tailed probability value was <.05.

	Results

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Of the 20 patients who entered the study, 11 received all four doses of both study drugs. Eight patients did not receive the highest dose (0.1 µg/kg per minute) of study drug; 2 because of an adverse event during study drug infusion and 6 because the protocol was modified to exclude the highest dose of study drug after an adverse event was observed in the 14th enrolled patient. One patient (No. 14) did not receive placebo infusion because of early withdrawal from the study, when an adverse event was observed after completion of hBNP infusion on the first study day. The first study day data from this patient were excluded from the analysis.

Systemic Hemodynamics
All systemic hemodynamic parameters were similar before study drug infusion on each study day (Table 1). Mean pulmonary artery pressure, pulmonary capillary wedge pressure, mean right atrial pressure, and mean systemic arterial pressure decreased significantly during hBNP infusion when compared with placebo infusion (Fig 1, A through D). At the highest completed dose of the hBNP infusion, mean pulmonary artery pressure decreased from baseline by 32%; mean pulmonary capillary wedge pressure decreased from baseline by 47%; mean right atrial pressure decreased from baseline by 56%; and mean arterial pressure decreased from baseline by 12% (Table 1, all P<.01 versus baseline and versus placebo). Cardiac index significantly increased during infusion of hBNP at the two highest doses when compared with placebo (Fig 1E). At the highest completed dose, cardiac index increased from baseline by 25% (Table 1, P<.01 versus baseline and versus placebo). Heart rate decreased slightly but significantly during infusion of hBNP at a dose of 0.01 µg/kg per minute when compared with placebo and increased slightly but not significantly at a dose of 0.1 µg/kg per minute when compared with placebo (Fig 1F and Table 1). The observed mean changes in heart rate during study drug infusions were small (10 min^-1) and of uncertain clinical significance. Pulmonary vascular resistance and systemic vascular resistance decreased significantly during infusion of hBNP when compared with placebo (Table 1). Stroke volume increased significantly during infusion of hBNP when compared with placebo (Table 1). A significant dose-response relationship was observed for all systemic hemodynamic variables during infusion of hBNP but not placebo.

View this table: [in this window] [in a new window]   Table 1. Systemic Hemodynamic Parameters Before and at the Highest Completed Dose During Infusion of hBNP and Placebo in 19 Patients With Severe Congestive Heart Failure

View larger version (26K): [in this window] [in a new window]   Figure 1. Effects of human brain natriuretic peptide (hBNP) and placebo infusion on (A) mean pulmonary artery pressure (PAP), (B) mean pulmonary capillary wedge pressure (PCWP), (C) mean right atrial pressure, (D) mean arterial pressure, (E) cardiac index, and (F) heart rate in 19 patients with severe congestive heart failure. Mean values±SEM before and during 90-minute infusions of 4 doses of hBNP () and placebo () are shown. Stated probability values refer to comparison of treatment by dose curves for placebo versus hBNP infusion.

Renal Excretory Effects
Urinary rate, urinary sodium excretion, urinary potassium excretion, and creatinine clearance were similar in the 12-hour periods before each study drug infusion (Table 2). Urinary rate and urinary sodium excretion increased significantly during hBNP infusion when compared with placebo infusion (90±38 versus 67±27 mL/h and 2.6±2.4 versus 1.4±1.2 mEq/h, respectively, both P<.05; Fig 2, A and B). Urinary potassium excretion and creatinine clearance did not change during hBNP infusion when compared with placebo infusion (Fig 2, C and D).

View this table: [in this window] [in a new window]   Table 2. Baseline Urinary Excretion Data Before Infusion of hBNP or Placebo

View larger version (20K): [in this window] [in a new window]   Figure 2. Effects of human brain natriuretic peptide (hBNP) and placebo infusion on (A) urinary sodium excretion, (B) urinary volume, (C) urinary potassium excretion, and (D) creatinine clearance in 19 patients with severe congestive heart failure. Mean values±SEM from urine collected during infusion of 4 doses of hBNP and placebo are shown. *P<.05 vs placebo; **P<.01 vs placebo.

Laboratory Effects
Plasma BNP concentrations were slightly greater before study drug infusion on the day before infusion of hBNP when compared with placebo (684±150 versus 623±157 pg/mL, respectively, P=.02). Plasma BNP levels were significantly greater during hBNP infusion when compared with placebo (12912±954 versus 585±139 pg/mL, P<.01). Plasma concentrations of cGMP were significantly greater during infusion of hBNP when compared with placebo (41.6±7.1 versus 6.3±1.3 pmol/mL, P<.01). Hematocrit significantly increased after hBNP infusion when compared with placebo infusion (40.9±5.7 versus 38.8±4.7%, respectively, P<.01). No differences between hBNP and placebo infusions were observed with respect to serum sodium or potassium concentrations, blood urea nitrogen, or serum creatinine concentration.

Adverse Effects
Transient symptomatic hypotension was observed in 6 patients either during or shortly after (within 60 minutes) completion of hBNP infusion. Symptoms of lightheadedness accompanied by transient decreases in systolic blood pressure occurred in 2 patients receiving 0.03 µg/kg per minute of hBNP and 4 patients receiving 0.1 µg/kg per minute of hBNP. In 5 of the 6 patients, symptoms resolved within 15 minutes, either spontaneously after discontinuation of study drug (n=2) or in response to infusion of normal saline solution (n=3). In 1 patient (No. 14), the episode of hypotension was prolonged and associated with sinus bradycardia unresponsive to administration of atropine. This patient required administration of dopamine in addition to normal saline solution for 6 hours after cessation of study drug before the episode of symptomatic hypotension resolved. This adverse event occurred after completion of hBNP infusion on the first study day and resulted in early withdrawal from the study.

	Discussion

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The current data demonstrate that short-term infusion of graded doses of hBNP is associated with favorable hemodynamic effects (decreased cardiac filling pressures, increased cardiac index) and favorable renal excretory effects (diuresis and natriuresis) in patients with severe congestive heart failure.

Administration of hBNP caused vasodilation in both the arterial and venous circulations, as evidenced by substantial decreases in mean systemic arterial pressure, mean pulmonary artery pressure, pulmonary capillary wedge pressure, and right atrial pressure during hBNP infusion. The balanced vasodilatory effects of hBNP are in accord with previous studies of the acute vascular effects of BNP in isolated vascular preparations and previous hemodynamic studies in normal human subjects.^{15 16 17} The direct vascular action of hBNP probably is mediated by activation of the guanylyl cyclase–coupled natriuretic peptide receptor-A (NPR-A) on the membrane surface of vascular smooth muscle cells.^{15 18} Decreased cardiac filling pressures also may be partly attributable to other known actions of natriuretic peptides, ie, inhibition of activation of the renin-angiotensin system, inhibition of sympathetic neurotransmission, reduction in intravascular volume through natriuresis and diuresis, and reduction in intravascular volume secondary to changes in capillary permeability.^{5 6} The decrease in cardiac filling pressures during infusion of hBNP in the current study population was accompanied by an increase in resting cardiac index. Since hBNP is not known to exert direct positive inotropic effects, the increase in cardiac index observed in the current study probably can be attributed to favorable changes in ventricular loading conditions and/or preload-related reduction in mitral regurgitant volume.^{19 20} The current hemodynamic findings are comparable to those reported in an uncontrolled trial of the acute hemodynamic effects of hBNP in 7 patients with mild to moderate heart failure.¹³ In this small trial, baseline hemodynamic dysfunction was less severe than that of the current study population, as evidenced by a baseline pulmonary capillary wedge pressure of 21 mm Hg and resting cardiac index of 2.4 L/min per square meter. A 30-minute infusion of hBNP (0.1 µg/kg per minute) decreased pulmonary capillary wedge pressure by 33% to 14 mm Hg and increased resting cardiac index by 33% to 3.2 L/min per square meter. In contrast to the findings of the current trial, mean arterial pressure did not change during hBNP infusion.

Administration of hBNP enhanced renal excretory function in the study population, as evidenced by significant increases in urine volume and urinary sodium excretion during hBNP infusion when compared with placebo infusion. Despite a substantial decrease in renal arterial perfusion pressure, creatinine clearance did not change during administration of hBNP. These findings are consistent with previous studies that suggest the renal excretory effects of hBNP are related to changes in both glomerular hemodynamics and tubular function.^{21 22} The natriuretic and diuretic effects of BNP probably are attributable to its direct actions on the guanylyl cyclase–coupled natriuretic peptide receptors in the kidneys, suppression of serum aldosterone production through activation of natriuretic peptide receptors in the adrenal glands, and possibly inhibition of renal sympathetic stimulation.^{18 21 23} Although serum aldosterone concentrations were not measured in this study, the absence of change in urinary potassium excretion in response to the increased natriuresis during hBNP infusion is consistent with diminished aldosterone effects. The increases in urinary volume and urine sodium excretion observed in the current study are less than those reported in a previous uncontrolled trial of 7 patients with mild to moderate congestive heart failure. In this previous trial, urine sodium excretion increased nearly 10-fold during a 30-minute infusion of hBNP at a dose of 0.1 µg/kg per minute.¹³ The smaller, nearly 2-fold increase in sodium excretion observed during hBNP infusion in the current study may be related to differences in severity of disease and/or study design. The urinary sodium excretion during placebo infusion in this study population (1.4 mEq/h) was much lower than the preinfusion values reported in the previous trial (4.5 mEq/h), a finding that is consistent with more advanced heart failure in the current study population. In addition, urine was collected for 12 hours during infusion of a wide range of doses of hBNP and thus may have underestimated the renal excretory effects of the higher doses of hBNP administered in the current study.

Serum BNP concentration was increased in the current study population before study drug infusion when compared with previous reports in normal subjects.^{13 16 17} During administration of hBNP, serum concentrations increased roughly 20-fold. Increased serum BNP concentrations were accompanied by significant increases in plasma cGMP concentrations. This finding is consistent with previous reports in patients with heart failure and experimental studies that suggest that the pharmacological effects of hBNP infusion are mediated by activation of membrane-bound guanylate cyclase.^{5 13 15 18} However, since baseline cGMP concentrations were not determined before study drug infusions, it is possible that increased cGMP during hBNP infusion was related to carryover or other time-dependent factors. Despite increased serum concentrations of endogenous natriuretic peptides in patients with congestive heart failure, the clinical syndrome is characterized by avid sodium retention and increased systemic vascular resistance. Decreased responsiveness to endogenous natriuretic peptides may be related to downregulation of the main guanylyl cyclase–coupled receptor (NPR-A), post–receptor uncoupling in the effector tissues, activation of counterregulatory vasoconstrictor and antinatriuretic neurohormones, and/or increased peptide degradation.^{24 25 26 27 28} These same mechanisms may contribute to a reduction in the effects of exogenous natriuretic peptides when administered in pharmacological doses. Indeed, previous studies of ANP infusion in patients with congestive heart failure have demonstrated variable but largely attenuated hemodynamic and renal excretory effects, particularly in patients with most advanced heart failure.^{8 9 10 11 12}

In contrast to the previous reports of ANP infusion in heart failure, the current findings demonstrate potent vasodilating effects of exogenously administered hBNP in patients with severe congestive heart failure. Differences in the pharmacological effects of exogenous ANP and BNP in heart failure may be attributable to different receptor binding affinities and/or different rates of hydrolysis by neutral endopeptidase.^{2 3 4 5 29} However, comparison of the current results with data from previous studies of ANP infusion in patients with congestive heart failure is confounded by several important differences in study design. First, in most studies of ANP infusion, patients were not receiving background ACE inhibition therapy. Since angiotensin II enhances cGMP degradation by stimulation of a calcium-dependent cGMP phosphodiesterase, ACE inhibition may enhance the physiological and pharmacological effects of natriuretic peptides.^{30 31} Second, some previous ANP infusion studies may not have achieved steady-state plasma levels secondary to inadequate lengths of infusion (30 minutes) and thereby underestimated the full magnitude of the hemodynamic and renal effects. Last, since most previous studies with ANP did not administer the full human ANP peptide chain, it is possible that the pharmacological effects of synthetic ANP analogues may have been less than the endogenous peptide hormone.

While hBNP infusion was generally well tolerated, the highest dose of hBNP administered in the current study (0.1 µg/kg per minute) was associated with transient episodes of symptomatic hypotension. In a single patient, the hypotensive episode was prolonged, associated with inappropriate bradycardia, and unresponsive to administration of atropine and normal saline solution. Prolonged hypotensive episodes also have been reported after infusion of ANP in normal subjects and patients with congestive heart failure.^{8 32} Natriuretic peptide–induced episodes of prolonged hypotension appear to be idiosyncratic because the duration of the hypotensive episode appears to greatly exceed the expected duration of the pharmacological effects predicted from pharmacokinetic data.^{5 6} The inappropriate bradycardia suggests that the hypotensive episode may be partly attributed to the effects of hBNP on the autonomic nervous system. Natriuretic peptides attenuate the heart rate response to hypotension in experimental studies and in normal humans. The autonomic effects of natriuretic peptides appear to be mediated by both inhibition of sympathetic-mediated reduction in parasympathetic neurotransmission and central inhibition of sympathetic neurotransmission.^{33 34} This mechanism of hypotension may not be specific to natriuretic peptides as nitroglycerin, another cGMP-dependent vasodilating agent, is also rarely associated with episodes of bradycardia and hypotension.³⁵

Conclusions
Short-term infusion of hBNP exerts significant favorable hemodynamic and renal excretory effects in patients with severe chronic congestive heart failure. Additional studies are needed to characterize the hemodynamic, renal, and neurohormonal effects of longer-duration infusions of hBNP in patients with congestive heart failure.

	Acknowledgments

 
This study was supported in part by National Institutes of Health grant 5-M01-RR00645, Division of Research Resources, General Clinical Research Centers Program.

Received May 9, 1996; revision received July 24, 1996; accepted July 31, 1996.

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