Left Ventricular Diastolic Dysfunction
Conditions
Brief summary
The purpose of this research study is to evaluate the effects of cardiac hormone replacement with SQ (subcutaneous or under the skin) injection of BNP (brain natriuretic peptide, a hormone produced by the heart) on the pumping ability of the heart, kidney function and levels of different hormones in the blood in response to an intravenous salt solution.
Detailed description
Prior to initiation of the study, subjects will be stabilized for at least one week on a no added salt diet (120 milliequivalent (mEq) Na/Day) which will be maintained during the study. Participants in this study will be randomized to receive BNP or placebo (an inactive, saline shot). The participant will need to give themselves a shot in their stomach (similar to diabetics giving themselves insulin) twice a day for twelve weeks. The study requires a screening visit to determine eligibility and discuss the study. At this visit a blood draw for heart and liver function and a six minute walk will be done. There will also be two other outpatient visits and two inpatient stays, for 48 hours, in the Clinical Research Unit at St. Marys Hospital. During the two overnight stays, blood and urine samples will be done to get heart and kidney function as well as a research echocardiogram. An acute saline load (0.9% normal saline 1.25 ml/kg/min for 1 hour) will be given and blood and urine samples collected After enrollment, the study lasts for twelve weeks. It is planned to treat 2 subjects with active drug per each placebo subject to improved the precision of between group comparison.
Interventions
DRUGBNP (nesiritide)
DRUGPlacebo
Sponsors
National Institutes of Health (NIH)
Scios, Inc.
National Heart, Lung, and Blood Institute (NHLBI)
National Center for Research Resources (NCRR)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects with 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 and who have not been hospitalized for heart failure
Exclusion criteria
* Myocardial Infarction (MI) 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 central nervous system (CNS) perfusion * Total bilirubin of \> 1.5 mg/dL or other liver enzymes \> 1.5 times the upper limit of normal (mg/dL = milligrams per deciliter) * Serum creatinine of \> 3.0 mg/dL * Serum sodium of \< 125 mEq/dL or \> 160 mEq/dL (milliequivalents per deciliter) * Serum potassium of \< 3.5 mEq/dL or \> 5.0/dL * Serum digoxin level of \> 2.0 ng/ml (nanograms per milliliter) * Systolic pressure of \< 85 mm Hg (millimeters of mercury) * Hemoglobin \< 10 gm/dl (grams per deciliter)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Urinary Sodium Excretion in Response to Saline Load | Baseline, 12 weeks | Renal (or kidney) function was measured by the sodium or salt in the urine, following administration of a pre-specified amount of saline (salt). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Urinary Flow in Response to Saline Load | Baseline, 12 weeks | Urinary flow is a measure of renal (or kidney) function and was measured in milliliters per minute. |
| Change in Glomerular Filtration Rate (GFR) in Response to Saline Load | Baseline, 12 weeks | Renal or kidney function was measured by GFR determined by iothalamate clearance. GFR describes the flow rate of filtered fluid through the kidney measured in milliliters per minute per 1.73 m\^2 of body surface area. A lower GFR means the kidney is not filtering normally. An estimated GFR of less than 60 mg/ml/1.73 m\^2 of body surface area is considered to be impaired kidney function. |
| Left Ventricular (LV) Filling Pressure | Baseline, 12 weeks | LV diastolic function as measured by Doppler echocardiography. E/e' is the ratio of the mitral inflow velocity (E) to the mitral annulus tissue Doppler velocity (e'). A decrease in the ratio indicates a lower filling pressure and improved LV diastolic function. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited at the Mayo Clinic in Rochester, Minnesota.
Pre-assignment details
49 participants signed written informed consent to enroll in the study. Of these 8 were withdrawn prior to randomization for varying reasons.
Participants by arm
| Arm | Count |
|---|---|
| BNP (Nesiritide) BNP 10 micrograms/Kg twice per day given subcutaneously for 12 weeks | 24 |
| Placebo Saline solution given subcutaneously twice per day for 12 weeks (packaged to match active comparator) | 12 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Amyloidosis on study echo-exclusionary | 0 | 1 |
| Overall Study | Cognitive Memory problems on study day | 1 | 0 |
| Overall Study | Unable to self-administer shots | 1 | 0 |
| Overall Study | Venous access failed during study day | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | BNP (Nesiritide) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 17 Participants | 25 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 7 Participants | 11 Participants |
| Age, Continuous | 69.6 years STANDARD_DEVIATION 10.9 | 68.8 years STANDARD_DEVIATION 8.1 | 69.1 years STANDARD_DEVIATION 9 |
| Region of Enrollment United States | 12 participants | 24 participants | 36 participants |
| Sex: Female, Male Female | 7 Participants | 9 Participants | 16 Participants |
| Sex: Female, Male Male | 5 Participants | 15 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 24 | 3 / 12 |
| serious Total, serious adverse events | 0 / 24 | 0 / 12 |
Outcome results
Primary
Change in Urinary Sodium Excretion in Response to Saline Load
Renal (or kidney) function was measured by the sodium or salt in the urine, following administration of a pre-specified amount of saline (salt).
Time frame: Baseline, 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BNP (Nesiritide) | Change in Urinary Sodium Excretion in Response to Saline Load | 381.6 mEq/minute | Standard Deviation 450.8 |
| Placebo | Change in Urinary Sodium Excretion in Response to Saline Load | -10.5 mEq/minute | Standard Deviation 90.1 |
p-value: <0.001t-test, 2 sided
Secondary
Change in Glomerular Filtration Rate (GFR) in Response to Saline Load
Renal or kidney function was measured by GFR determined by iothalamate clearance. GFR describes the flow rate of filtered fluid through the kidney measured in milliliters per minute per 1.73 m\^2 of body surface area. A lower GFR means the kidney is not filtering normally. An estimated GFR of less than 60 mg/ml/1.73 m\^2 of body surface area is considered to be impaired kidney function.
Time frame: Baseline, 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BNP (Nesiritide) | Change in Glomerular Filtration Rate (GFR) in Response to Saline Load | 6.8 ml/min/1.73 m^2 body surface area | Standard Deviation 19.3 |
| Placebo | Change in Glomerular Filtration Rate (GFR) in Response to Saline Load | 4.4 ml/min/1.73 m^2 body surface area | Standard Deviation 27.3 |
p-value: 0.05t-test, 2 sided
Secondary
Change in Urinary Flow in Response to Saline Load
Urinary flow is a measure of renal (or kidney) function and was measured in milliliters per minute.
Time frame: Baseline, 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BNP (Nesiritide) | Change in Urinary Flow in Response to Saline Load | 4.2 ml/minute | Standard Deviation 5.4 |
| Placebo | Change in Urinary Flow in Response to Saline Load | -1.0 ml/minute | Standard Deviation 2.1 |
p-value: <0.001t-test, 2 sided
Secondary
Left Ventricular (LV) Filling Pressure
LV diastolic function as measured by Doppler echocardiography. E/e' is the ratio of the mitral inflow velocity (E) to the mitral annulus tissue Doppler velocity (e'). A decrease in the ratio indicates a lower filling pressure and improved LV diastolic function.
Time frame: Baseline, 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BNP (Nesiritide) | Left Ventricular (LV) Filling Pressure | Baseline LV Filling Pressure | 14.9 E/e' | Standard Deviation 4.1 |
| BNP (Nesiritide) | Left Ventricular (LV) Filling Pressure | 12 Week LV Filling Pressure | 12.6 E/e' | Standard Deviation 3.5 |
| Placebo | Left Ventricular (LV) Filling Pressure | Baseline LV Filling Pressure | 14.9 E/e' | Standard Deviation 4.5 |
| Placebo | Left Ventricular (LV) Filling Pressure | 12 Week LV Filling Pressure | 14.0 E/e' | Standard Deviation 5.1 |
Comparison: Mean LV filling pressure was compared from baseline to 12 weeks within the Placebo group.p-value: 0.43t-test, 2 sided
Comparison: Mean LV filling pressure was compared from baseline to 12 weeks within the BNP group.p-value: 0.004t-test, 2 sided