Chronic subcutaneous brain natriuretic peptide therapy in asymptomatic systolic heart failure.

AIMS: We have previously reported that asymptomatic systolic heart failure (HF) is characterized by an impaired renal response to volume expansion due to lack of activation of urinary cGMP which is corrected by subcutaneous (SQ) BNP. In the current study, we sought to define the cardiorenal response to intravascular volume expansion after 12 weeks of SQ BNP therapy. METHODS AND RESULTS: We utilized a double-blinded, placebo-controlled study to compare 12 weeks of twice-daily SQ BNP 10 µg/kg (n = 22) or placebo (n = 12) in asymptomatic systolic HF. Subjects underwent two study visits: baseline and after 12 weeks of therapy. At each study visit, echocardiography, renal, and neurohumoral assessments were performed before and after intravascular volume expansion. The primary endpoint was change in urinary sodium excretion in response to volume expansion at 12 weeks, and we observed a greater increase in urinary sodium excretion [166 (77, 290) vs. 15 (-39, 72) mEq/min; P = 0.02] with SQ BNP treatment vs. placebo. Secondary endpoints included change in urine flow and glomerular filtration rate (GFR) in response to volume expansion at 12 weeks. We observed a significant increase in urine flow (P < 0.01) and trend for differential response in GFR (P = 0.08) with SQ BNP treatment vs. placebo. CONCLUSION: Among patients with asymptomatic systolic HF, twice-daily SQ BNP therapy improved the cardiorenal response to volume expansion at 12-week follow-up. Further studies are warranted to determine if these beneficial physiological observations with chronic natriuretic peptide administration translate into a delay in the progression to symptomatic HF.

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

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.

Local renal delivery of a natriuretic peptide a renal-enhancing strategy for B-type natriuretic peptide in overt experimental heart failure.

OBJECTIVES: The purpose of this study was to test the hypothesis that local renal delivery of B-type natriuretic peptide (BNP) will overcome renal resistance to BNP without systemic hypotension. BACKGROUND: BNP has vasodilating, natriuretic, and renin-inhibiting properties. In overt heart failure (HF), there is development of renal resistance to BNP. METHODS: We defined the cardiorenal and humoral effects of systemic (n = 6) or local renal (n = 7) administration of canine BNP (0.01 microg/kg/min) in 2 separate groups of dogs with pacing-induced subacute overt HF complicated by renal dysfunction. We used a commercially available small (3.1-F) bifurcated renal catheter (FlowMedica Inc., Fremont, California) for direct bilateral infusion of BNP into both renal arteries. RESULTS: With systemic BNP at this clinically used dose (without the bolus), urine flow increased, but there was only a trend for an increase in urinary sodium excretion and glomerular filtration rate (GFR). In contrast, local renal delivery of BNP resulted in significant diuresis and natriuresis and an increase in GFR. These diuretic and natriuretic responses were greater with local renal BNP compared with systemic BNP, and were associated with increased delivery of BNP to the renal tubules as evident by a greater urinary BNP excretion resulting in a decrease in distal reabsorption of sodium. Importantly, local renal BNP did not result in a significant decrease in mean arterial pressure that was observed with systemic BNP. CONCLUSIONS: We conclude that local renal BNP delivery is a novel strategy that may overcome renal assistance to BNP in overt HF by increasing local delivery of BNP to the renal tubules.