TY - JOUR
T1 - Impaired natriuretic and renal endocrine response to acute volume expansion in pre-clinical systolic and diastolic dysfunction
AU - McKie, Paul M.
AU - Schirger, John A.
AU - Costello-Boerrigter, Lisa C.
AU - Benike, Sherry L.
AU - Harstad, Lynn K.
AU - Bailey, Kent R.
AU - Hodge, David O.
AU - Redfield, Margaret M.
AU - Simari, Robert D.
AU - Burnett, John C.
AU - Chen, Horng H.
N1 - Funding Information:
This research was supported by grants from the National Institutes of Health PO1 HL 76611 , R01 HL 84155 , and NIH/NCRR CTSA Grant Number UL1 RR024150 . Subcutaneous B-type natriuretic peptide was provided by Scios (Mountain View, California) at no cost to the authors; company representatives had no role in the design of the trial, access to the data, or input into the manuscript. Dr. Simari has received research funding and royalties from Anexon, Inc. and is the inventor of related technology. Dr. Chen has received research grants from Scios Inc., Niles Therapeutics, and Anexon; and through Mayo Clinic has patented and licensed designer natriuretic peptides other than BNP. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
PY - 2011/11/8
Y1 - 2011/11/8
N2 - Objectives: We hypothesized an impaired renal endocrine and natriuretic response to volume expansion (VE) in humans with pre-clinical systolic dysfunction (PSD) and pre-clinical diastolic dysfunction (PDD). We further hypothesized that exogenous B-type natriuretic peptide (BNP) could rescue an impaired natriuretic response in PSD and PDD. Background: Recent reports suggest that in early systolic heart failure (HF), there is an impaired natriuretic response to acute VE. Methods: PSD was defined as left ventricular ejection fraction <40% without HF symptoms. PDD was defined as ejection fraction >50%, moderate to severe diastolic dysfunction by Doppler criteria, and no HF symptoms. A double-blinded, placebo-controlled, crossover study was employed to determine the renal response to VE (0.25 ml/kg/min of normal saline for 60 min) in the presence and absence of exogenous BNP. Twenty healthy control subjects, 20 PSD subjects, and 18 PDD subjects participated. Results: In healthy control subjects, urinary cyclic guanosine monophosphate (cGMP) and natriuresis increased after VE. In contrast, among PSD and PDD subjects, there was a paradoxical decrease in urinary cGMP and attenuated natriuresis. Pre-treatment with subcutaneous BNP resulted in similar increases in both urinary cGMP and natriuresis among healthy normal, PSD, and PDD subjects. Conclusions: In PSD and PDD, there is impaired renal cGMP activation, which contributes to impaired natriuresis in response to VE. Impaired activation of urinary cGMP and reduced natriuresis may contribute to volume overload and the progression of HF among PSD and PDD subjects. Importantly, the impaired renal excretory response to VE is rescued by exogenous BNP in PSD and PDD.
AB - Objectives: We hypothesized an impaired renal endocrine and natriuretic response to volume expansion (VE) in humans with pre-clinical systolic dysfunction (PSD) and pre-clinical diastolic dysfunction (PDD). We further hypothesized that exogenous B-type natriuretic peptide (BNP) could rescue an impaired natriuretic response in PSD and PDD. Background: Recent reports suggest that in early systolic heart failure (HF), there is an impaired natriuretic response to acute VE. Methods: PSD was defined as left ventricular ejection fraction <40% without HF symptoms. PDD was defined as ejection fraction >50%, moderate to severe diastolic dysfunction by Doppler criteria, and no HF symptoms. A double-blinded, placebo-controlled, crossover study was employed to determine the renal response to VE (0.25 ml/kg/min of normal saline for 60 min) in the presence and absence of exogenous BNP. Twenty healthy control subjects, 20 PSD subjects, and 18 PDD subjects participated. Results: In healthy control subjects, urinary cyclic guanosine monophosphate (cGMP) and natriuresis increased after VE. In contrast, among PSD and PDD subjects, there was a paradoxical decrease in urinary cGMP and attenuated natriuresis. Pre-treatment with subcutaneous BNP resulted in similar increases in both urinary cGMP and natriuresis among healthy normal, PSD, and PDD subjects. Conclusions: In PSD and PDD, there is impaired renal cGMP activation, which contributes to impaired natriuresis in response to VE. Impaired activation of urinary cGMP and reduced natriuresis may contribute to volume overload and the progression of HF among PSD and PDD subjects. Importantly, the impaired renal excretory response to VE is rescued by exogenous BNP in PSD and PDD.
KW - B-type natriuretic peptide
KW - cyclic guanosine monophosphate
KW - diastolic dysfunction
KW - heart failure
KW - natriuretic peptide
KW - pre-clinical
KW - systolic dysfunction
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U2 - 10.1016/j.jacc.2011.07.042
DO - 10.1016/j.jacc.2011.07.042
M3 - Article
C2 - 22051332
AN - SCOPUS:80155188415
SN - 0735-1097
VL - 58
SP - 2095
EP - 2103
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 20
ER -