Natriuretic Peptide System as Therapy in Human Preclinical Left Ventricle Dysfunction

Study Overview
=================
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.

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

Conditions
-----------------
Congestive Heart Failure

Intervention / Treatment
-----------------
* Drug: Nesiritide
* Drug: Placebo
* Drug: Saline


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo First, then Nesiritide (Arm A)<br>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<br>* 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.<br>* Other names: human B-type natriuretic peptide (BNP);Drug: Placebo<br>* The pharmacy created a placebo subcutaneous injection volume to match the volume of the nesiritide dose.<br>Drug: Saline<br>* Normal saline 0.9% 0.25 ml/kg/min for 60 minutes<br>|
| Experimental: Nesiritide First, then Placebo (Arm B)<br>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<br>* 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.<br>* Other names: human B-type natriuretic peptide (BNP);Drug: Placebo<br>* The pharmacy created a placebo subcutaneous injection volume to match the volume of the nesiritide dose.<br>Drug: Saline<br>* Normal saline 0.9% 0.25 ml/kg/min for 60 minutes<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
heart failure, diastolic dysfunction, systolic dysfunction, preclinical, natriuretic peptide, B-type natriuretic peptide, cyclic guanosine monophosphate