PPG1: Natriuretic Peptide System as Therapy in Human Preclinical Left Ventricle Dysfunction

• Sponsor: Horng Chen (Other)
• Overall Status: Completed
• CT.gov ID: NCT00387621
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), National Center for Research Resources (NCRR) (NIH)
• Enrollment: 58
• Location: 1
• Arms: 2
• Duration (Months): 42
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

In congestive heart failure, cardiac output is low, blood pressure is high, and the body becomes congested with fluid. In normal people, when there is high blood pressure, the heart muscle cells secrete a hormone that excretes sodium and water in the urine, reducing blood pressure. The action of this hormone is called the natriuretic response. The purpose of this study is to determine if nesiritide can improve an impaired natriuretic response in subjects with asymptomatic systolic heart failure or asymptomatic diastolic heart failure.

Condition or Disease	Intervention/Treatment	Phase
Congestive Heart Failure	Drug: Nesiritide; Drug: Placebo; Drug: Saline	Phase 1/Phase 2

Detailed Description

The American Heart Association and the American College of Cardiology define stage B heart failure (HF) as asymptomatic subjects with abnormal heart structure/function. With the advancement of cardiac imaging and biomarkers, abnormal heart structure and function can be detected before the development of symptoms. Stage B HF can represent either diastolic or systolic dysfunction and both are at increased risk of adverse cardiac events and development of symptomatic HF.

The broad objective of this study is to define the integrated cardiorenal response to acute volume expansion (VE) in humans with presystolic dysfunction (PSD), prediastolic dysfunction (PDD), and normal cardiac function. We hypothesized that there is an impaired cardiorenal endocrine response to acute VE in PSD and PDD which is characterized by the lack of appropriate activation of urinary cGMP and urinary sodium excretion. Further, we hypothesized that PSD, PDD, and normal control subjects would respond similarly to exogenous administration B-type natriuretic peptide (BNP).

The natriuretic peptides (NPs) are a family of structurally similar but genetically distinct peptides with vasodilating, natriuretic, renin inhibiting, and lusitropic properties. Acute peptide therapy with brain natriuretic peptide (BNP) infusion has recently been approved by the FDA as a therapeutic strategy for the treatment of acute human decompensated congestive HF. We will determine the effects of acute subcutaneous BNP or placebo administration on the integrated cardiorenal and humoral response to acute sodium load (sodium chloride 0.9% 0.25 ml/kg/min for 1 hour) in three groups of subjects: Group 1 normal controls, Group 2 with PSD, and Group 3 with PDD. Doppler echocardiography and tonometry will be used to measure cardiac and vascular function before and during the sodium load. Renal function studies will assess sodium excretion, renal plasma flow, and glomerular filtration rate at baseline, during, and after the sodium load. Blood will be drawn for humoral analysis including catecholamines, renin, aldosterone, angiotensin II, atrial natriuretic peptide (ANP), BNP, and cyclic guanosine monophosphate (cGMP) at baseline, during, and after the sodium load.

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Basic Science
• Official Title: To Define in Normal Controls, Human Preclinical Systolic Dysfunction (PSD) and Preclinical Diastolic Dysfunction (PDD) the Actions of Acute Subcutaneous Nesiritide (BNP) on the Cardiorenal and Humoral Function and the Integrated Response to Acute Sodium Loading
• Study Start Date: Feb 1, 2006
• Actual Primary Completion Date: Aug 1, 2008
• Actual Study Completion Date: Aug 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Placebo First, then Nesiritide (Arm A) In the first intervention period the subjects received subcutaneous placebo given in the abdomen. After a lead in period of 15 minutes, the acute saline load was administered. There was a 2 week washout period. In the second intervention period, the subjects received subcutaneous nesiritide given in the abdomen. After a lead in period of 15 minutes, the acute saline load was administered.	Drug: Nesiritide; The first 10 subjects in each group will receive a dose of 5 ug/kg and the next ten subjects will receive 10 ug/kg.; Other Names: natrecor human B-type natriuretic peptide (BNP) ; Drug: Placebo; The pharmacy created a placebo subcutaneous injection volume to match the volume of the nesiritide dose.; Drug: Saline; Normal saline 0.9% 0.25 ml/kg/min for 60 minutes
Experimental: Nesiritide First, then Placebo (Arm B) In the first intervention period the subjects received subcutaneous nesiritide given in the abdomen. After a lead in period of 15 minutes, the acute saline load was administered. There was a 2 week washout period. In the second intervention period, the subjects received subcutaneous placebo given in the abdomen. After a lead in period of 15 minutes, the acute saline load was administered.	Drug: Nesiritide; The first 10 subjects in each group will receive a dose of 5 ug/kg and the next ten subjects will receive 10 ug/kg.; Other Names: natrecor human B-type natriuretic peptide (BNP) ; Drug: Placebo; The pharmacy created a placebo subcutaneous injection volume to match the volume of the nesiritide dose.; Drug: Saline; Normal saline 0.9% 0.25 ml/kg/min for 60 minutes

Outcome Measures

Primary Outcome Measures

1. Change in Natriuresis (Urinary Sodium Excretion) in Control Subjects at 60 Minutes After Volume Expansion Compared to Baseline in Response to Placebo Treatment [baseline and 60 minutes]

   Value at 60 minutes minus value at baseline.

2. Placebo Pre-Treatment Urinary Sodium Excretion After Volume Expansion (UnaV) [Baseline, 30 min, 60 min]

   Subjects received subcutaneous placebo in the abdomen. After 15 minutes, the acute saline load (volume expansion, VE) was administered. Subjects were asked to empty bladder spontaneously every 30 min (if unable to void every 30 min, a urinary catheter was placed). Adequate bladder emptying was insured by ultrasonography. UNaV was collected at baseline (immediately before VE) and at 30 and 60 min after initiation of VE.

3. Placebo Pre-Treatment Urinary cGMP Excretion After Volume Expansion (UcGMPV) [Baseline, 30 min, 60 min]

   Subjects received subcutaneous placebo in the abdomen. After 15 minutes, the acute saline load (volume expansion, VE) was administered. Subjects were asked to empty bladder spontaneously every 30 min (if unable to void every 30 min, a urinary catheter was placed). Adequate bladder emptying was insured by ultrasonography. UcGMPV was collected at baseline (immediately before VE) and at 30 and 60 min after initiation of VE.

4. Nesiritide Pre-Treatment Urinary Sodium Excretion After Volume Expansion (UNaV) [Baseline, 30 min, 60 min]

   Subjects received subcutaneous Nesiritide in the abdomen. After 15 minutes, the acute saline load (volume expansion, VE) was administered. Subjects were asked to empty bladder spontaneously every 30 min (if unable to void every 30 min, a urinary catheter was placed). Adequate bladder emptying was insured by ultrasonography. UNaV was collected at baseline (immediately before VE) and at 30 and 60 min after initiation of VE.

5. Nesiritide Pre-Treatment Urinary cGMP Excretion After Volume Expansion (UcGMPV) [Baseline, 30 min, 60 min]

   Subjects received subcutaneous Nesiritide in the abdomen. After 15 minutes, the acute saline load (volume expansion, VE) was administered. Subjects were asked to empty bladder spontaneously every 30 min (if unable to void every 30 min, a urinary catheter was placed). Adequate bladder emptying was insured by ultrasonography. UcGMPV was collected at baseline (immediately before VE) and at 30 and 60 min after initiation of VE.

Secondary Outcome Measures

1. Change in Urinary Cyclic Guanosine Monophosphate (cGMP) in Control Subjects at 60 Minutes After Volume Expansion Compared to Baseline in Response to Placebo Treatment [baseline and 60 minutes]

   Value at 60 minutes minus value at baseline

2. Change in Natriuresis (Urinary Sodium Excretion) at 30 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment [30 minutes]

   Value of natriuresis at 30 min on nesiritide treatment minus value of natriuresis at 30 min on placebo treatment (per subject group). The baseline was not involved in this calculation.

3. Change in Natriuresis (Urinary Sodium Excretion) at 60 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment [60 minutes]

   Value of natriuresis at 60 min on nesiritide treatment minus value of natriuresis at 60 min on placebo treatment (per subject group). The baseline was not involved in this calculation.

4. Change in Urinary Cyclic Guanosine Monophosphate (cGMP) at 30 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment [30 minutes]

   Value of cGMP at 30 min on nesiritide treatment minus value of cGMP at 30 min on placebo treatment (per subject group). The baseline was not involved in this calculation.

5. Change in Urinary Cyclic Guanosine Monophosphate (cGMP) at 60 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment [60 minutes]

   Value of cGMP at 60 min on nesiritide treatment minus value of cGMP at 60 min on placebo treatment (per subject group). The baseline was not involved in this calculation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion criteria for normal control group:

• ejection fraction of greater 50%

• normal Doppler diastolic function with no clinical signs or symptoms

• history of cardiovascular and renal disease

• no prior use of any cardiovascular medications.

Inclusion criteria for pre-systolic dysfunction group:

• ejection fraction of less than 40% with no clinical signs or symptoms of congestive heart failure

• ability to perform a 6-minute walk of > 450 meters

• if subjects are not able to walk 450 meters due to pain in hips and knees and not fatigue or shortness of breath, then they will still qualify for the study

• subjects will all be on stable doses of ACE inhibitor for two weeks prior to the active study date

• previously prescribed cardiovascular medications are allowed, however, all medications must be at stable doses two weeks prior to the study date.

Inclusion criteria for pre-diastolic dysfunction group:

• ejection fraction of greater than 50% with moderate or severe diastolic dysfunction as assessed by Doppler echocardiography

• no signs or symptoms of congestive heart failure

• ability to perform a 6-minute walk of > 450 meters

• if subjects are not able to walk 450 meters due to pain in hips and knees and not fatigue or shortness of breath, then they will still qualify for the study

• previously prescribed cardiovascular medications are allowed, however, all medications must be at stable doses two weeks prior to the study date.

Exclusion criteria for all groups:

• myocardial infarction within 3 months of screening

• unstable angina within 14 days of screening, or any evidence of myocardial ischemia

• significant valvular stenosis, hypertrophic, restrictive or obstructive cardiomyopathy, constrictive pericarditis, primary pulmonary hypertension, or biopsy proven active myocarditis

• severe congenital heart diseases

• sustained ventricular tachycardia or ventricular fibrillation within 14 days of screening

• second or third degree heart block without a permanent cardiac pacemaker

• stroke within 3 months of screening, or other evidence of significantly compromised CNS perfusion

• total bilirubin of > 1.5 mg/dL or other liver enzymes >1.5 times the upper limit of normal

• serum creatinine of > 3.0 mg/dL

• serum sodium of < 125 mEq/dL or > 160 mEq/dL

• serum potassium of < 3.5 mEq/dL or > 5.0 mEq/dL

• serum digoxin level of > 2.0 ng/ml

• systolic pressure of < 85 mmHg

• hemoglobin < 10 gm/dl

• other acute or chronic medical conditions or laboratory abnormality which may increase the risks associated with study participation or may interfere with interpretation of the data

• received an investigational drug within 1 month prior to dosing

• patients with an allergy to iodine

• in the opinion of the investigator, is unlikely to comply with the study protocol or is unsuitable for any reason.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Horng Chen
• National Heart, Lung, and Blood Institute (NHLBI)
• National Center for Research Resources (NCRR)

Investigators

• Principal Investigator: Horng H. Chen, M.D., Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

• McKie PM, Schirger JA, Costello-Boerrigter LC, Benike SL, Harstad LK, Bailey KR, Hodge DO, Redfield MM, Simari RD, Burnett JC Jr, Chen HH. Impaired natriuretic and renal endocrine response to acute volume expansion in pre-clinical systolic and diastolic dysfunction. J Am Coll Cardiol. 2011 Nov 8;58(20):2095-103. doi: 10.1016/j.jacc.2011.07.042.

• Responsible Party: Horng Chen, MD, Professor of Medicine, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00387621
• Other Study ID Numbers: 05-004027; P01HL076611; R01HL084155; UL1RR024150; NCT00818974
• First Posted: Oct 13, 2006
• Last Update Posted: May 17, 2012
• Last Verified: Apr 1, 2012

• Keywords provided by Horng Chen, MD, Professor of Medicine, Mayo Clinic: heart failure; diastolic dysfunction; systolic dysfunction; preclinical; natriuretic peptide; B-type natriuretic peptide; cyclic guanosine monophosphate
• Additional relevant MeSH terms: Heart Failure; Natriuretic Peptide, Brain

Study Results

Participant Flow

Recruitment Details	The study took place between February 2006 and August 2009. All subjects were consented and were seen at the Mayo Clinic in Rochester, MN.
Pre-assignment Detail	63 participants were enrolled in the study, but 5 participants were excluded because they did not meet inclusion criteria. Participants included normal controls, Preclinical Systolic Dysfunction, and Preclinical Diastolic Dysfunction subjects, who were randomized into Placebo First, then Nesiritide (Arm A) and Nesiritide First, then Placebo (Arm B)

Arm/Group Title	Placebo First, Then Nesiritide (Arm A)	Nesiritide First, Then Placebo (Arm B)
Arm/Group Description	In the first intervention period the subjects received subcutaneous placebo given in the abdomen. After a lead in period of 15 minutes, the acute saline load was administered. There was a 2 week washout period. In the second intervention period, the subjects received subcutaneous nesiritide given in the abdomen. After a lead in period of 15 minutes, the acute saline load was administered.	In the first intervention period the subjects received subcutaneous nesiritide given in the abdomen. After a lead in period of 15 minutes, the acute saline load was administered. There was a 2 week washout period. In the second intervention period, the subjects received subcutaneous placebo given in the abdomen. After a lead in period of 15 minutes, the acute saline load was administered.
Period Title: First Intervention
STARTED	29	29
COMPLETED	29	29
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	29	29
COMPLETED	29	29
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	29	29
COMPLETED	29	29
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Control Group (Normals)	Preclinical Systolic Dysfunction Group (PSD)	Preclinical Diastolic Dysfunction Group (PDD)	Total
Arm/Group Description	Healthy volunteers without heart disease	Participants with ejection fraction <40% and no heart failure symptoms	Participants with an ejection fraction of > 50% and no heart failure symptoms	Total of all reporting groups
Overall Participants	20	20	18	58
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37 (11)	65 (12)	72 (7)	57.5 (18.4)
Sex: Female, Male (Count of Participants)
Female	17 85%	2 10%	9 50%	28 48.3%
Male	3 15%	18 90%	9 50%	30 51.7%
Region of Enrollment (participants) [Number]
United States	20 100%	20 100%	18 100%	58 100%
Creatinine (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	0.9 (0.1)	1.1 (0.2)	1.1 (0.3)	1.0 (0.2)
Blood Urea Nitrogen (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	11 (5)	21 (10)	23 (6)	18.2 (8.6)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	25 (4)	31 (5)	30 (5)	28.5 (5.1)

Outcome Measures

1. Primary Outcome

Title	Change in Natriuresis (Urinary Sodium Excretion) in Control Subjects at 60 Minutes After Volume Expansion Compared to Baseline in Response to Placebo Treatment
Description	Value at 60 minutes minus value at baseline.
Time Frame	baseline and 60 minutes

Outcome Measure Data

Analysis Population Description

per protocol

Arm/Group Title	Control Group
Arm/Group Description	Healthy volunteers without heart disease. Prior to initiation of study, subjects drank water and emptied their bladders to reach an equilibrium, then baseline urine samples were collected. After these samples were collected, all subjects were randomized into Placebo First, then Nesiritide (Arm A) or Nesiritide First, then Placebo (Arm B).
Measure Participants	20
Mean (Standard Error) [mEq/min]	87.19 (22.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	t-test, 1 sided
	Comments	With Bonferroni correction for multiple comparisons

2. Secondary Outcome

Title	Change in Urinary Cyclic Guanosine Monophosphate (cGMP) in Control Subjects at 60 Minutes After Volume Expansion Compared to Baseline in Response to Placebo Treatment
Description	Value at 60 minutes minus value at baseline
Time Frame	baseline and 60 minutes

Outcome Measure Data

Analysis Population Description

intention to treat (ITT)

Arm/Group Title	Control Group
Arm/Group Description	Healthy volunteers without heart disease. Prior to initiation of study, subjects drank water and emptied their bladders to reach an equilibrium, then baseline urine samples were collected. After these samples were collected, all subjects were randomized into Placebo First, then Nesiritide (Arm A) and Nesiritide First, then Placebo (Arm B).
Measure Participants	20
Mean (Standard Error) [pmol/min]	98.23 (34.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	rank-sum test
	Comments	Rank-sum test was used due to non-normality of data with Bonferroni correction for multiple comparisons

3. Secondary Outcome

Title	Change in Natriuresis (Urinary Sodium Excretion) at 30 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment
Description	Value of natriuresis at 30 min on nesiritide treatment minus value of natriuresis at 30 min on placebo treatment (per subject group). The baseline was not involved in this calculation.
Time Frame	30 minutes

Outcome Measure Data

Analysis Population Description

intention to treat (ITT)

Arm/Group Title	Control	PSD-Preclinical Systolic Dysfunction	PDD-Preclinical Diastolic Dysfunction
Arm/Group Description	Healthy volunteers without heart disease. Prior to initiation of study, subjects drank water and emptied their bladders to reach an equilibrium, then baseline urine samples were collected. After these samples were collected, all subjects were randomized into Placebo First, then Nesiritide (Arm A) or Nesiritide First, then Placebo (Arm B).	Participants with ejection fraction <40% and no heart failure symptoms. Prior to initiation of study, subjects drank water and emptied their bladders to reach an equilibrium, then baseline urine samples were collected. After these samples were collected, all subjects were randomized into Placebo First, then Nesiritide (Arm A) or Nesiritide First, then Placebo (Arm B).	Participants with an ejection fraction of > 50% and no heart failure symptoms. Prior to initiation of study, subjects drank water and emptied their bladders to reach an equilibrium, then baseline urine samples were collected. After these samples were collected, all subjects were randomized into Placebo First, then Nesiritide (Arm A) or Nesiritide First, then Placebo (Arm B).
Measure Participants	20	20	18
Mean (Standard Error) [mEq/min]	440.93 (76.67)	261.07 (101.60)	242.82 (68.58)

4. Secondary Outcome

Title	Change in Natriuresis (Urinary Sodium Excretion) at 60 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment
Description	Value of natriuresis at 60 min on nesiritide treatment minus value of natriuresis at 60 min on placebo treatment (per subject group). The baseline was not involved in this calculation.
Time Frame	60 minutes

Outcome Measure Data

Analysis Population Description

intention to treat (ITT)

Arm/Group Title	Control	PSD-Preclinical Systolic Dysfunction	PDD-Preclinical Diastolic Dysfunction
Arm/Group Description	Healthy volunteers without heart disease. Prior to initiation of study, subjects drank water and emptied their bladders to reach an equilibrium, then baseline urine samples were collected. After these samples were collected, all subjects were randomized into Placebo First, then Nesiritide (Arm A) or Nesiritide First, then Placebo (Arm B).	Participants with ejection fraction <40% and no heart failure symptoms. Prior to initiation of study, subjects drank water and emptied their bladders to reach an equilibrium, then baseline urine samples were collected. After these samples were collected, all subjects were randomized into Placebo First, then Nesiritide (Arm A) or Nesiritide First, then Placebo (Arm B).	Participants with an ejection fraction of > 50% and no heart failure symptoms. Prior to initiation of study, subjects drank water and emptied their bladders to reach an equilibrium, then baseline urine samples were collected. After these samples were collected, all subjects were randomized into Placebo First, then Nesiritide (Arm A) or Nesiritide First, then Placebo (Arm B).
Measure Participants	20	20	18
Mean (Standard Error) [mEq/min]	183.83 (60.60)	226.89 (101.72)	41.55 (46.07)

5. Secondary Outcome

Title	Change in Urinary Cyclic Guanosine Monophosphate (cGMP) at 30 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment
Description	Value of cGMP at 30 min on nesiritide treatment minus value of cGMP at 30 min on placebo treatment (per subject group). The baseline was not involved in this calculation.
Time Frame	30 minutes

Outcome Measure Data

Analysis Population Description

intention to treat (ITT)

Arm/Group Title	Control	PSD-Preclinical Systolic Dysfunction	PDD-Preclinical Diastolic Dysfunction
Arm/Group Description	Healthy volunteers without heart disease. Prior to initiation of study, subjects drank water and emptied their bladders to reach an equilibrium, then baseline urine samples were collected. After these samples were collected, all subjects were randomized into Placebo First, then Nesiritide (Arm A) or Nesiritide First, then Placebo (Arm B).	Participants with ejection fraction <40% and no heart failure symptoms. Prior to initiation of study, subjects drank water and emptied their bladders to reach an equilibrium, then baseline urine samples were collected. After these samples were collected, all subjects were randomized into Placebo First, then Nesiritide (Arm A) or Nesiritide First, then Placebo (Arm B).	Participants with an ejection fraction of > 50% and no heart failure symptoms. Prior to initiation of study, subjects drank water and emptied their bladders to reach an equilibrium, then baseline urine samples were collected. After these samples were collected, all subjects were randomized into Placebo First, then Nesiritide (Arm A) or Nesiritide First, then Placebo (Arm B).
Measure Participants	20	20	18
Mean (Standard Error) [pmol/min]	244.69 (59.09)	255.31 (59.60)	353.37 (155.65)

6. Secondary Outcome

Title	Change in Urinary Cyclic Guanosine Monophosphate (cGMP) at 60 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment
Description	Value of cGMP at 60 min on nesiritide treatment minus value of cGMP at 60 min on placebo treatment (per subject group). The baseline was not involved in this calculation.
Time Frame	60 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	PSD-Preclinical Systolic Dysfunction	PDD-Preclinical Diastolic Dysfunction
Arm/Group Description	Healthy volunteers without heart disease. Prior to initiation of study, subjects drank water and emptied their bladders to reach an equilibrium, then baseline urine samples were collected. After these samples were collected, all subjects were randomized into Placebo First, then Nesiritide (Arm A) or Nesiritide First, then Placebo (Arm B).	Participants with ejection fraction <40% and no heart failure symptoms. Prior to initiation of study, subjects drank water and emptied their bladders to reach an equilibrium, then baseline urine samples were collected. After these samples were collected, all subjects were randomized into Placebo First, then Nesiritide (Arm A) or Nesiritide First, then Placebo (Arm B).	Participants with an ejection fraction of > 50% and no heart failure symptoms. Prior to initiation of study, subjects drank water and emptied their bladders to reach an equilibrium, then baseline urine samples were collected. After these samples were collected, all subjects were randomized into Placebo First, then Nesiritide (Arm A) or Nesiritide First, then Placebo (Arm B).
Measure Participants	20	20	18
Mean (Standard Error) [pmol/min]	303.32 (71.21)	384.62 (120.47)	335.29 (90.48)

7. Primary Outcome

Title	Placebo Pre-Treatment Urinary Sodium Excretion After Volume Expansion (UnaV)
Description	Subjects received subcutaneous placebo in the abdomen. After 15 minutes, the acute saline load (volume expansion, VE) was administered. Subjects were asked to empty bladder spontaneously every 30 min (if unable to void every 30 min, a urinary catheter was placed). Adequate bladder emptying was insured by ultrasonography. UNaV was collected at baseline (immediately before VE) and at 30 and 60 min after initiation of VE.
Time Frame	Baseline, 30 min, 60 min

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control Group (Normals)	Preclinical Systolic Dysfunction Group (PSD)	Preclinical Diastolic Dysfunction Group (PDD)
Arm/Group Description	Healthy volunteers without heart disease	Participants with ejection fraction <40% and no heart failure symptoms	Participants with an ejection fraction of > 50% and no heart failure symptoms
Measure Participants	20	20	18
Urinary Sodium Excretion (Baseline/Pre-treatment)	186.6 (67.3)	255.4 (189.2)	202.1 (137.5)
Urinary Sodium Excretion at 30 min	197.4 (80.8)	221.0 (118.6)	187.9 (110.3)
Urinary Sodium Excretion at 60 min	211.8 (89.5)	231.1 (130.8)	205.0 (130.5)

8. Primary Outcome

Title	Placebo Pre-Treatment Urinary cGMP Excretion After Volume Expansion (UcGMPV)
Description	Subjects received subcutaneous placebo in the abdomen. After 15 minutes, the acute saline load (volume expansion, VE) was administered. Subjects were asked to empty bladder spontaneously every 30 min (if unable to void every 30 min, a urinary catheter was placed). Adequate bladder emptying was insured by ultrasonography. UcGMPV was collected at baseline (immediately before VE) and at 30 and 60 min after initiation of VE.
Time Frame	Baseline, 30 min, 60 min

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control Group (Normals)	Preclinical Systolic Dysfunction Group (PSD)	Preclinical Diastolic Dysfunction Group (PDD)
Arm/Group Description	Healthy volunteers without heart disease	Participants with ejection fraction <40% and no heart failure symptoms	Participants with an ejection fraction of > 50% and no heart failure symptoms
Measure Participants	20	20	18
Urinary cGMP Excretion (Baseline/Pre-treatment)	97.8 (124.8)	219.5 (188.1)	245.8 (198.7)
Urinary cGMP Excretion at 30 min	154.9 (141.7)	133.3 (109.9)	134.4 (114.4)
Urinary cGMP Excretion at 60 min	196.0 (182.6)	134.1 (97.7)	139.7 (118.6)

9. Primary Outcome

Title	Nesiritide Pre-Treatment Urinary Sodium Excretion After Volume Expansion (UNaV)
Description	Subjects received subcutaneous Nesiritide in the abdomen. After 15 minutes, the acute saline load (volume expansion, VE) was administered. Subjects were asked to empty bladder spontaneously every 30 min (if unable to void every 30 min, a urinary catheter was placed). Adequate bladder emptying was insured by ultrasonography. UNaV was collected at baseline (immediately before VE) and at 30 and 60 min after initiation of VE.
Time Frame	Baseline, 30 min, 60 min

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control Group (Normals)	Preclinical Systolic Dysfunction Group (PSD)	Preclinical Diastolic Dysfunction Group (PDD)
Arm/Group Description	Healthy volunteers without heart disease	Participants with ejection fraction <40% and no heart failure symptoms	Participants with an ejection fraction of > 50% and no heart failure symptoms
Measure Participants	20	20	18
Urinary Sodium Excretion (Baseline/Pre-treatment)	183.9 (58.1)	232.6 (166.7)	219.1 (201.7)
Urinary Sodium Excretion at 30 min	393.4 (143.4)	314.7 (225.3)	303.2 (185.0)
Urinary Sodium Excretion at 60 min	650.1 (337.9)	469.4 (458.9)	464.8 (272.7)

10. Primary Outcome

Title	Nesiritide Pre-Treatment Urinary cGMP Excretion After Volume Expansion (UcGMPV)
Description	Subjects received subcutaneous Nesiritide in the abdomen. After 15 minutes, the acute saline load (volume expansion, VE) was administered. Subjects were asked to empty bladder spontaneously every 30 min (if unable to void every 30 min, a urinary catheter was placed). Adequate bladder emptying was insured by ultrasonography. UcGMPV was collected at baseline (immediately before VE) and at 30 and 60 min after initiation of VE.
Time Frame	Baseline, 30 min, 60 min

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control Group (Normals)	Preclinical Systolic Dysfunction Group (PSD)	Preclinical Diastolic Dysfunction Group (PDD)
Arm/Group Description	Healthy volunteers without heart disease	Participants with ejection fraction <40% and no heart failure symptoms	Participants with an ejection fraction of > 50% and no heart failure symptoms
Measure Participants	20	20	18
Urinary cGMP Excretion (Baseline/Pretreatment)	130.8 (145.9)	192.2 (157.3)	258.0 (176.2)
Urinary cGMP Excretion at 30 min	399.6 (252.6)	388.6 (276.7)	487.8 (634.0)
Urinary cGMP Excretion at 60 min	508.4 (382.3)	518.7 (578.3)	475.0 (347.2)

Adverse Events

Time Frame	Participants were followed for adverse events from the time of randomization until the completion of the second visit, approximately two months.
Arm/Group Title	Placebo		Nesiritide
Arm/Group Description	The pharmacy created a placebo subcutaneous injection volume to match the volume of the nesiritide dose. As this was a cross over study, all participants received placebo and nesiritide.		The first 10 subjects in each group received a dose of 5 ug/kg and the next 10 subjects received a dose of 10 ug/kg. As this was a cross over study, all participants received placebo and nesiritide.
All Cause Mortality
	Placebo		Nesiritide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Nesiritide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/58 (0%)		1/58 (1.7%)
Psychiatric disorders
Panic Attack	0/58 (0%)	0	1/58 (1.7%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Nesiritide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/58 (8.6%)		6/58 (10.3%)
Cardiac disorders
re-stenosis	0/58 (0%)	0	1/58 (1.7%)	1
heart palpatations	0/58 (0%)	0	1/58 (1.7%)	1
afibrillation	1/58 (1.7%)	1	0/58 (0%)	0
atypical chest pain	1/58 (1.7%)	1	0/58 (0%)	0
hypotension	0/58 (0%)	0	2/58 (3.4%)	2
Gastrointestinal disorders
diarrhea	2/58 (3.4%)	2	0/58 (0%)	0
esophageal reflux	1/58 (1.7%)	1	0/58 (0%)	0
Musculoskeletal and connective tissue disorders
muscle fatigue	0/58 (0%)	0	1/58 (1.7%)	1
Renal and urinary disorders
urinary urgency	0/58 (0%)	0	1/58 (1.7%)	1

Limitations/Caveats

Different baseline characteristics of the three groups of subjects Did not define a mechanism for the impaired renal cGMP activation Future studies needed to determine effects of chronic nesiritide therapy in preclinical HF.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.