Impaired natriuretic and renal endocrine response to acute volume expansion in pre-clinical systolic and diastolic dysfunction

Abstract

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.

Figure 1. Urinary Sodium Excretion After Volume Expansion

Urinary sodium excretion in normal control, pre-clinical systolic dysfunction (PSD), and pre-clinical diastolic dysfunction (PDD) subjects at baseline (black bars), 30 min after volume expansion (white bars), and 60 min after volume expansion (gray bars). *p < 0.05 versus baseline as measured by t test using a Bonferroni correction for multiple comparisons.

Figure 2. Urinary cGMP Excretion After Volume Expansion

Urinary cyclic guanosine monophosphate (cGMP) excretion (A) and change in urinary cGMP excretion from baseline (B) in normal control subjects (normals), PSD subjects, and PDD subjects at baseline (black bars), 30 min after volume expansion (white bars), and 60 min after VE (gray bars). *p < 0.05, †p = 0.06, §p = 0.08 versus baseline as measured by t test using a Bonferroni correction for multiple comparisons. ‡The p value represents comparison of change from baseline to VE between groups as measured by 1-way analysis of variance. Abbreviations as in Figure 1.

Figure 3. Urinary Sodium Excretion After Volume Expansion With BNP Pre-Treatment

Urinary sodium excretion in (A) normal control subjects, (B) PSD subjects, and (C) PDD subjects at baseline, 30 min after volume expansion, and 60 min after volume expansion, after placebo (open bars) or subcutaneous B-type natriuretic peptide (SQ BNP) (solid bars) administration. *p < 0.05, ‡p = 0.07 versus baseline, and †p < 0.05 versus placebo as measured by t test using a Bonferroni correc- tion for multiple comparisons. Abbreviations as in Figure 1.

Figure 4. Urinary cGMP Excretion After Volume Expansion With BNP Pre-Treatment

Urinary cyclic guanosine monophosphate (cGMP) excretion in (A) normal control subjects, (B) PSD subjects, and (C) PDD subjects at baseline, 30 min after volume expansion, and 60 min after volume expansion, after placebo (open bars) or subcutaneous B-type natriuretic peptide (SQ BNP) (solid bars) administration. *p < 0.05, ‡p = 0.06, §p = 0.08 versus baseline, and †p < 0.05 versus placebo as measured by t test using a Bonferroni correction for multiple comparisons. Abbreviations as in Figure 1.