Our objective is to establish that the cardiac peptide BNP is a novel and efficacious therapy for human acute myocardial infarction (AMI) to preserve myocardial structure and function. This highly translational research takes advantage of the cardioprotective and renal enhancing properties of this small and endogenous peptide in protecting the heart from injury and promoting cardiac repair. Our broad unifying hypothesis is that the endogenous natriuretic peptide (NP) system mediates cardiorenal protection and that therapeutic enhancement in experimental and human AMI with exogenous BNP will preserve myocardial structure and function while maintaining renal function. This strategy is based on the biology of BNP that enhances renal function, mediates coronary vasodilatation, reduces myocardial oxygen consumption, suppresses aldosterone release, retards adrenergic activation, induces vascular regeneration, inhibits cardiac fibroblast collagen synthesis and has anti-apoptotic properties. First, we will utilize a murine model of partial proANP gene disruption (Nppa+/-) that has clinical relevance to the recently reported human polymorphism (C664G) that is reported to be characterized by a distruption of the ANP promoter with reduced circulating ANP and risk for ventricular remodeling in human hypertension. This novel genetically altered model has normal cardiac phenotype but demonstrates an exaggerated ventricular hypertrophic and fibrotic response to AMI. In this model with AMI and in wild type (WT) mice we seek to establish cardiorenal protection with 5 days of BNP based therapy. Second, we will extend our research to human AMI investigating the cardiorenal protective properties of 72 hours of BNP therapy initiated at the time of revascularization compared to conventional therapy to preserve myocardial and renal function.
Our Specific Aims are as follows:
Aim 1 : To characterize myocardial structure and function, humoral function and renal function in WT and Nppa+/- mice after AMI;
Aim 2 : To characterize myocardial structure and function, humoral function and renal function in WT and Nppa+/- mice after AMI in the presence of BNP therapy;
and Aim 3 : To characterize myocardial structure and function, humoral function and renal function in human AMI in the presence and absence of BNP therapy. For the public, this research may enhance long-term survival after a heart attack. The use of a hormone made in the heart and given at the time of heart attack may help the heart protect and repair itself.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083231-04
Application #
7669135
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Sopko, George
Project Start
2006-08-01
Project End
2010-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$508,284
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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