Natriuretic Peptide System as Therapy in Human Preclinical Left Ventricle Dysfunction

NCT ID: NCT00387621

Last Updated: 2012-05-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 58 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-02-28
• Study Completion Date: 2009-08-31

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.

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.

Conditions

Congestive Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Nesiritide

Intervention Type: DRUG

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.

Placebo

Intervention Type: DRUG

The pharmacy created a placebo subcutaneous injection volume to match the volume of the nesiritide dose.

Saline

Intervention Type: DRUG

Normal saline 0.9% 0.25 ml/kg/min for 60 minutes

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.

Group Type: EXPERIMENTAL

Nesiritide

Intervention Type: DRUG

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.

Placebo

Intervention Type: DRUG

The pharmacy created a placebo subcutaneous injection volume to match the volume of the nesiritide dose.

Saline

Intervention Type: DRUG

Normal saline 0.9% 0.25 ml/kg/min for 60 minutes

Interventions

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.

Intervention Type: DRUG

Placebo

The pharmacy created a placebo subcutaneous injection volume to match the volume of the nesiritide dose.

Intervention Type: DRUG

Saline

Normal saline 0.9% 0.25 ml/kg/min for 60 minutes

Intervention Type: DRUG

Other Intervention Names

natrecor; human B-type natriuretic peptide (BNP)

Eligibility Criteria

Inclusion Criteria

• 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.

• 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.

• 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

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

National Center for Research Resources (NCRR)

NIH

Sponsor Role: collaborator

Horng Chen

OTHER

Sponsor Role: lead

Responsible Party

Horng Chen

MD, Professor of Medicine

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Horng H. Chen, M.D.

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

Locations

Mayo Clinic

Rochester, Minnesota, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 22051332 (View on PubMed)

Other Identifiers

P01HL076611

Identifier Type: NIH

Identifier Source: secondary_id

View Link

R01HL084155

Identifier Type: NIH

Identifier Source: secondary_id

View Link

UL1RR024150

Identifier Type: NIH

Identifier Source: secondary_id

View Link

05-004027

Identifier Type: -

Identifier Source: org_study_id

NCT00818974

Identifier Type: -

Identifier Source: nct_alias