Subcutaneous Injection of Human Brain Natriuretic Peptide (BNP), Natrecor (Nesiritide), to Improve Kidney and Hormonal Function of People With Abnormal Function of the Heart

Condition(s) targeted: Congestive Heart Failure

Intervention: Human BNP Natrecor (nesiritide) (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Mayo Clinic

Official(s) and/or principal investigator(s):
Horng H. Chen, M.D., Principal Investigator, Affiliation: Mayo Clinic

To determine if you are eligible for this study you will have the following blood tests done as part of the screening procedures: blood count, kidney and liver blood test. If you are in Group of 40, you will complete a 6-minute walk test. You will be instructed to follow a no-added-salt diet for 1-3 weeks before the study and for the whole duration of the study. Diet instructions will be given to you and you will collect your urine for 24 hours before the active study day. You will need to avoid strenuous exercise and abstain from smoking, alcohol, and caffeine for 3 days prior to the study days. You will remain on your regular medications. If your urine collection shows that there is too much salt, you will need to continue the diet for one more week and another urine collection will be done. You will need to come to the General Clinical Research Center (GCRC) at St. Marys Hospital the evening before the study day, between 5: 00 p. m. and 6: 00 p. m. The next morning, two catheters (small plastic tubes) will be placed in your arm vein, one for giving fluids and one for sampling blood. You will be given an injection of two substances, iothalamate and para-amino-hippurate (PAH), that will allow the investigators to measure and record the function of your kidneys. You will be asked to drink water to be sure that your urine flow is adequate, and to empty your bladder every 30 minutes. If you are not able to go to the bathroom every half hour, a urinary catheter will be used if you agree to its use. Each time you empty your bladder, an ultrasound of your bladder will be done to see if you emptied completely. Blood pressure will be measured frequently and your heart rate will be monitored. The collection periods will consist of obtaining samples of urine and blood to measure hormone levels. You will also have an echocardiogram and tonometry (ultrasound exam of your heart and blood vessels) performed. At the completion of the three 30-minute collection periods, by the flip of a coin you will receive either BNP or placebo (salt solution) injected subcutaneously into the stomach wall. Neither you nor the study doctor will know which subcutaneous (SQ) injection you received. Immediately after that, the investigators will infuse salt solution through the catheter in the vein for 1 hour. During that hour, we will continue to collect blood and urine every 30 minutes. You will spend about 24 hours in the GCRC. After 2 weeks, you will return to the GCRC and have the study repeated, and this time you will receive the other SQ injection which you did not receive the first time. Natrecor has been approved by the US Food and Drug Administration (FDA) to be given intravenously for the management of acute heart failure. For the whole study, the total amount of blood drawn from you will be about a 3/4cup (250 mls). You will be in the study for 1-3 months.

Official title: To Define in Normal Controls, Human PSD and PDD the Actions of Acute SQ BNP on the Cardiorenal and Humoral Function and the Integrated Response to Acute Sodium Loading

Study design: Basic Science, Randomized, Double Blind (Subject, Caregiver, Investigator), Crossover Assignment, Pharmacodynamics Study

Primary outcome: To define in normal controls, human PSD, PDD, the actions of acute SQ BNP on the cardiorenal and humoral function and the integrated response to acute sodium loading dose

Secondary outcome:

Subjects with PSD, PDD, acute SQ BNP administration will result in improved renal response to acute sodium loading with an increase in urinary sodium excretion, urine flow, glomerular filtration rate, effective renal plasma flow as compared to placebo

Subjects with PSD,PDD, acute SQ BNP administration will result in improved humoral response to acute sodium loading with greater suppression of plasma renin activity, plasma angiotensin II, plasma aldosterone, plasma catecholamines as compared to placebo

Subjects with PSD and PDD, acute SQ BNP will respond to acute sodium loading by increased cardiac output, improved diastolic filling, less of an increase in filling pressures and improved cardiac response compared to controls.

Detailed description: The broad objective of this project is to advance our understanding of the integrative biology of the natriuretic peptide system (NPS) in the regulation of ventricular, renal, and humoral function in human preclinical left ventricular dysfunction, and to evaluate chronic peptide therapy with BNP as an effective strategy in preclinical ventricular dysfunction. Specifically, we will focus on human preclinical left ventricular systolic dysfunction (PSD) and human preclinical left ventricular diastolic dysfunction (PDD). Our studies recognize that the number of persons with congestive heart failure (CHF) continues to rise, and despite recent advances in the treatment of overt symptomatic CHF, mortality and morbidity remain high, and the potential for retarding progression to terminal CHF is limited. Studies have established that 40-50% of incident CHF cases are due primarily to abnormal diastolic function. The need to understand the biology and to identify effective therapy for preclinical left ventricular dysfunction is now a priority in efforts to delay the progression of CHF. The importance of recognizing and treating preclinical left ventricular dysfunction has been likened to well-recognized strategies in the field of oncology, where an emphasis on recognition and treatment of preclinical disease has been adapted. 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 CHF. We will determine the effects of acute SQ 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. Collection of blood at baseline, during, and after sodium load to store for future DNA/Protein analysis.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

1. Group 1(normal controls)- will consist of 20 subjects with :

- an ejection fraction of greater 50%

- normal Doppler diastolic function with no clinical signs or symptoms

- history of cardiovascular and renal disease

- they have never been on any cardiovascular medications

2. Group 2(PSD)- will consist of 20 subjects with:

- an ejection fraction of less than 40% with no clinical signs or symptoms of

congestive heart failure

- a minimal distance on 6-minute walk of > 450 meters

The subjects will all be on stable doses of ACE inhibitor for two weeks prior to the active study date. Therapy with other vasodilators, beta-receptor antagonists, digoxin and antiarrhythmic medications will be allowed, however, all medications must be at stable doses two weeks prior to the study date.

3. Group 3 (PDD)- will consist of 20 subjects with:

- an ejection fraction of greater than 50% with moderate or severe diastolic

dysfunction as assessed by Doppler echocardiography

- who do not have any signs or symptoms of congestive heart failure (see Core B for

classification of diastolic dysfunction)

- a minimal distance on 6-minute walk of > 450 meters

The subjects will be allowed to take whatever cardiovascular medications they have been prescribed previously; however, the doses must be stable for two weeks prior to the actual study date.

Mayo Clinic, Rochester, Minnesota 55905, United States; Recruiting
Sherry Benike, Phone: 507-266-3629, Email: benike.sherry@mayo.edu
Horng H. Chen, M.D., Principal Investigator

Starting date: February 2006
Ending date: July 2011
Last updated: September 10, 2008