• To define in human PSD the actions of chronic administration of SQ BNP on left ventricular, renal, and humoral function and on the integrated response to acute sodium loading [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  

• Chronic peptide therapy with SQ BNP in subjects with PSD will reverse left ventricular remodeling as compared to placebo as evident by reduced left atrium volume, improved diastolic relaxation, decreased E/e ratio, reduction of plasma procollagen [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  
• Chronic peptide therapy with SQ BNP in subjects with PSD will improve renal function by increased sodium excretion, GFR, and effective renal plasma flow in response to acute sodium loading as compared to the response of placebo-treated subjects. [ Time Frame: 5 ] [ Designated as safety issue: No ]
  
• 4. Chronic peptide therapy with SQ BNP in subjects with PSD will improve humoral function with suppression of the renin-angiotensin-aldosterone system, cardiotrophin I, endothelin I and catecholamines as compared to placebo. [ Time Frame: 5 ] [ Designated as safety issue: No ]
  

The following are done for screening procedures to determine if patients are eligible for this study: blood count, kidney and liver blood test. Patients will complete a 6-minute walk test. Patients 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 the patient and the patient will collect his/her urine for 24 hours before the active study day. Patients will need to avoid strenuous exercise and abstain from smoking, alcohol, and caffeine for 3 days prior to the study days. Patients will remain on their regular medications. If the patient's urine collection shows that there is too much salt, the patient will need to continue the diet for one more week and another urine collection will be done. Participants will need to come to the General Clinical Research Center (GCRC) at St. Mary's Hospital the evening before the first kidney study day, between 5:00 - 6:00 p.m. The next morning, two catheters (small plastic tubes) will be placed in the patient's arm vein, one for giving fluids and one for sampling blood. Patients will be given an injection of two substances, iothalamate and para-amino-hippurate (PAH), which will allow the researchers to measure and record the function of the kidneys. Patients will be asked to drink water to be sure that urine flow is adequate, and to empty their bladder every 30 minutes. If patients are not able to go to the bathroom every half-hour, a urinary catheter will be used if the patient agrees to its use. Each time patients empty their bladder, an ultrasound of their bladder will be done to see if it is emptied completely. Blood pressure will be measured frequently and heart rate will be monitored. The collection periods will consist of obtaining samples of urine and blood to measure hormone levels. During the testing period mentioned above, patients will have an echocardiogram and tonometry (ultrasound examination of the heart and blood vessels) done to determine heart function. At the completion of the three 30-minute collection periods, the researchers will infuse salt solution through the catheter in the vein for 1 hour. During that hour, the researchers will continue to collect blood and urine every 30 minutes. Then, by computerized selection process, the patient will be assigned to the BNP or placebo (inactive medication) group. For every 2 patients assigned to the BNP group, one patient will be assigned to the placebo group. Neither the patient nor the study doctor will know which group patients are assigned to. Patients will then be instructed on the proper technique for preparing the BNP or placebo and injecting it subcutaneously (in the fat tissue) into the stomach wall. Thereafter, both blood pressure and heart rate will continue to be monitored for the next 4 hours. Patients will self administer the 2nd dose of subcutaneous BNP or placebo 12 hours after the 1st dose and will be supervised to ensure that proper technique is used. Once again, after the 2nd dose, both blood pressure and heart rate will be monitored every 20 minutes for 4 hours. This monitoring may interrupt the patient's sleep. The third dose will be self administered under supervision 12 hours after the 2nd dose and both blood pressure and heart rate will be monitored every 20 minutes for 4 hours. Patients will spend a total of approximately 48 hours in the GCRC. Patients will then be dismissed with instructions and a kit containing enough supplies for six weeks of subcutaneous administration. Patients will give themselves the subcutaneous injection twice a day for 12 weeks. Patients will return in one week to have a blood test to ensure that their electrolytes are okay and will also undergo a physical exam. Patients will also have access to a 24-hour phone number should they have any questions or develop any side effects. Patients will receive a weekly phone call to check on how they are doing. After six weeks, patients will return to the GCRC for an outpatient visit where a repeat blood draw for tests to assess safety and measurements of hormones will occur. Patients will also do a 24-hour urine collection the day before the return visit.

Patients will be dismissed with instructions and supplies enough for another six weeks of injections under the skin. At the end of the twelve-week study period, patients will again be admitted to the GCRC the afternoon before the second kidney study day. Echocardiography, kidney function and blood tests will be carried out in the same manner as the baseline study. Patients will also do a 24-hour urine collection the day before the return visit. Baseline renal clearances and clearances during 1-hour saline infusion will be obtained. There will be no subcutaneous injections during this end study. Patients will spend one day in the GCRC for this visit. Patients will receive a six month follow up phone call to ask if they have been hospitalized and to inquire about their health status. For the whole study, the total amount of blood drawn from the patient will be a little over 1 cup (325 mls).

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, ANP, BNP and cGMP at baseline, during and after the sodium load. Collection of blood at baseline, during and after sodium load will be stored for future DNA/protein analysis.