Natriuretic Peptide System as Therapy in Human Preclinical LV Dysfunction

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. The Specific Aims of this application are as follows: 1) Define in normal controls, human PSD and PDD the actions of acute SQ BNP on the integrated ventricular, renal and humoral response to acute sodium loading. 2) Define in human PSD the actions of chronic administration of SQ BNP on ventricular, renal and humoral function and the integrated response to acute sodium loading. 3) To define in human PDD the actions of chronic administration of SQ BNP on the ventricular, renal and humoral function and the integrated response to acute sodium loading. Studies will be will be performed in the General Clinical Research Center (GCRC) at St Mary's Hospital, Mayo Clinic, Rochester. This project will advance our understanding of the integrated cardiorenal and humoral physiology of preclinical left ventricular dysfunction and defines the efficacy of chronic peptide therapy with BNP.