The broad objective of this new application is to advance our understanding of the pathophysiological mechanisms of human Cardiorenal Syndrome (CRS) with a specific emphasis upon the biological interaction between diuretic therapy, the renin-angiotensin-aldosterone-system (RAAS) and cyclic 3_- 5_-guanosine monophosphate (cGMP) pathway. Renal dysfunction is a common and progressive complication of chronic heart failure (CHF) and despite growing recognition of the frequent presentation of combined cardiac and renal dysfunction, or CRS, its underlying pathophysiology is not well understood, with a lack of consensus as to its appropriate management. The CRS can be classified into 2 broad categories: 1) patients with compensated CHF and impaired renal function;and 2) patients with decompensated CHF and worsening renal function. Diuretics are effective and necessary to relieve congestion in CHF however recent reports have suggested potential deleterious effects on the progression of CHF. We demonstrated that angiotensin II receptor (AT1) blockade prevented the detrimental renal effects of diuretics. Cyclic GMP (cGMP) is the second messenger of both the natriuretic peptide (NP) system and the nitric oxide system (NO). Both of these humoral systems are important in balancing the vasocontricting and sodium retaining hormones such as the angiotensin II to preserve renal function in CHF. To address these issues related to human CRS, we will pursue human studies taking advantage of the extensive clinical facilities, patient populations and our NIH funded General Clinical Research Center (GCRC) at the Mayo Clinic, which makes our proposed research highly feasible and of significant clinical importance.
Our Specific Aims are as follows:
Aim 1 : To define the effects of decreasing the furosemide dose on cardiorenal and humoral function in humans with compensated CHF and renal dysfunction and also in humans with compensated CHF without renal dysfunction. Secondly, to define the humoral activation in both groups..
Aim 2 : Define in humans with compensated CHF and renal dysfunction, the modulating actions of chronic AT1 receptor blockade on cardiorenal and humoral function as compared to increased ACE inhibition.
Aim 3 : Define in hospitalized decompensated CHF patients with CRS, the renal actions of low dose intravenous infusion of BNP in the presence and absence of acute PDE V inhibition in improving renal function.

Public Health Relevance

Chronic heart failure is a major health problem in the US and despite recent advances in the treatment, the outcome remains poor, especially in those patients with renal failure as well. This research should aid in addressing this health challenge.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL084155-04
Application #
8279189
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Adhikari, Bishow B
Project Start
2009-07-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$354,920
Indirect Cost
$107,420
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Wan, Siu-Hin; McKie, Paul M; Schirger, John A et al. (2016) Chronic Peptide Therapy With B-Type Natriuretic Peptide in Patients With Pre-Clinical Diastolic Dysfunction (Stage B Heart Failure). JACC Heart Fail 4:539-47
Patel, Pratik A; Scott, Christopher G; Rodeheffer, Richard J et al. (2016) The Natural History of Patients With Isolated Metabolic Syndrome. Mayo Clin Proc 91:623-33
Wan, Siu-Hin; Stevens, Susanna R; Borlaug, Barry A et al. (2016) Differential Response to Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Reduced or Preserved Ejection Fraction: Results From the ROSE AHF Trial (Renal Optimization Strategies Evaluation in Acute Heart Failure). Circ Heart Fail 9:
McKie, Paul M; Schirger, John A; Benike, Sherry L et al. (2016) Chronic subcutaneous brain natriuretic peptide therapy in asymptomatic systolic heart failure. Eur J Heart Fail 18:433-41
Wan, Siu-Hin; Vogel, Mark W; Chen, Horng H (2014) Pre-clinical diastolic dysfunction. J Am Coll Cardiol 63:407-16
Jain, Amit K; Chen, Horng H (2014) ROSE-AHF and lessons learned. Curr Heart Fail Rep 11:260-5
Dandamudi, Sanjay; Slusser, Joshua; Mahoney, Douglas W et al. (2014) The prevalence of diabetic cardiomyopathy: a population-based study in Olmsted County, Minnesota. J Card Fail 20:304-9
McKie, Paul M; Schirger, John A; Benike, Sherry L et al. (2014) The effects of dose reduction of furosemide on glomerular filtration rate in stable systolic heart failure. JACC Heart Fail 2:675-7
Chen, Horng H; Anstrom, Kevin J; Givertz, Michael M et al. (2013) Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA 310:2533-43
Chen, Horng H; Glockner, James F; Schirger, John A et al. (2012) Novel protein therapeutics for systolic heart failure: chronic subcutaneous B-type natriuretic peptide. J Am Coll Cardiol 60:2305-12

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