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

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

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.

Study Overview

• Status: Completed
• Conditions: Congestive Heart Failure
• Intervention / Treatment: Drug: Nesiritide; Drug: Placebo; Drug: Saline

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 Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Natriuresis (Urinary Sodium Excretion) in Control Subjects at 60 Minutes After Volume Expansion Compared to Baseline in Response to Placebo Treatment	Value at 60 minutes minus value at baseline.	baseline and 60 minutes
Placebo Pre-Treatment Urinary Sodium Excretion After Volume Expansion (UnaV)	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.	Baseline, 30 min, 60 min
Placebo Pre-Treatment Urinary cGMP Excretion After Volume Expansion (UcGMPV)	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.	Baseline, 30 min, 60 min
Nesiritide Pre-Treatment Urinary Sodium Excretion After Volume Expansion (UNaV)	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.	Baseline, 30 min, 60 min
Nesiritide Pre-Treatment Urinary cGMP Excretion After Volume Expansion (UcGMPV)	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.	Baseline, 30 min, 60 min

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Urinary Cyclic Guanosine Monophosphate (cGMP) in Control Subjects at 60 Minutes After Volume Expansion Compared to Baseline in Response to Placebo Treatment	Value at 60 minutes minus value at baseline	baseline and 60 minutes
Change in Natriuresis (Urinary Sodium Excretion) at 30 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment	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.	30 minutes
Change in Natriuresis (Urinary Sodium Excretion) at 60 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment	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.	60 minutes
Change in Urinary Cyclic Guanosine Monophosphate (cGMP) at 30 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment	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.	30 minutes
Change in Urinary Cyclic Guanosine Monophosphate (cGMP) at 60 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment	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.	60 minutes

Collaborators and Investigators

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

Publications and helpful links

General 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.

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start: February 1, 2006
• Primary Completion (Actual): August 1, 2008
• Study Completion (Actual): August 1, 2009

Study Registration Dates

• First Submitted: October 12, 2006
• First Submitted That Met QC Criteria: October 12, 2006
• First Posted (Estimate): October 13, 2006

Study Record Updates

• Last Update Posted (Estimate): May 17, 2012
• Last Update Submitted That Met QC Criteria: April 18, 2012
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Keywords: heart failure; diastolic dysfunction; cyclic guanosine monophosphate; natriuretic peptide; B-type natriuretic peptide; preclinical; systolic dysfunction
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Natriuretic Agents; Natriuretic Peptide, Brain
• Other Study ID Numbers: 05-004027; P01HL076611 (U.S. NIH Grant/Contract); UL1RR024150 (U.S. NIH Grant/Contract); R01HL084155 (U.S. NIH Grant/Contract)