Chronic Peptide Therapy With B-Type Natriuretic Peptide in Patients With Pre-Clinical Diastolic Dysfunction (Stage B Heart Failure)

Abstract

Objective Our objective is to determine in patients with preclinical diastolic dysfunction (PDD), if there is development of tachyphylaxis to enhancement of cardiorenal response to acute volume loading (AVL) with B-type natriuretic peptide (BNP) after 12-week, twice-daily subcutaneous BNP administration. Background PDD is characterized by normal systolic function, moderate or severe diastolic dysfunction but no symptoms of heart failure (HF). Impairment in cardiorenal endocrine response to stress by AVL exists in PDD and is corrected by acute administration of subcutaneous BNP. Methods Double-blinded, placebo controlled proof-of-concept study to compare 12 weeks of twice daily subcutaneous BNP 10 ug/kg (n=24) versus placebo (n=12) in PDD. Subjects underwent two study visits: baseline and after 12 weeks. At each study visit, echocardiography, renal, and neurohumoral assessments were performed before and after intravascular AVL. Results Among those with PDD, there was a statistically significant improvement in diastolic function after 12 weeks of BNP as measured by a decrease in Doppler E/e’ ratio (p = 0.004) and improvement of diastolic dysfunction grade (p = 0.008). After 12 weeks there was a statistically significantly greater sodium excretion, urine flow, and urinary cGMP excretion to AVL (all p < 0.001), as well as a trend towards greater glomerular filtration rate (p = 0.050) in the BNP group as compared to the placebo group. Conclusion In subjects with PDD, chronic BNP administration resulted in sustained improvement in diastolic function without development of tachyphylaxis to the enhancement of cardiorenal response to volume expansion with BNP.

Atrial remodelling in heart failure: recent developments and relevance for heart failure with preserved ejection fraction

“…Beta‐blockade with metoprolol increases plasma BNP levels in HFrEF 64. BNP given subcutaneously can improve the haemodynamic response to acute volume load in patients with HFpEF,65 corroborating a relative deficit of natriuretic peptides. Likewise, increasing natriuretic peptide availability by neprilysin inhibition with simultaneous angiotensin II receptor blockade and neprilysin inhibition has been shown to be beneficial (see below ‘Atrial Reverse Remodeling with Therapy’).…”

A Human Study to Evaluate Safety, Tolerability, and Cyclic GMP Activating Properties of Cenderitide in Subjects With Stable Chronic Heart Failure

“…as is used for insulin. Such a delivery strategy is supported by our success with chronic delivery of BNP in patients with HF . Finally, based on what we have learned in studies of Cenderitide in normal humans, in which cGMP was activated with natriuresis and in cultured human cardiac fibroblasts in which Cenderitide suppressed collagen gene expression greater than either BNP or CNP, one could make an informed assessment that a definitive trial in humans with HF to show renal enhancing and antifibrotic actions would be of 3‐month duration, with s.q.…”

“…Plasma and urinary cGMP and plasma CNP to determine Cenderitide immunoreactivity were performed with previously reported methods . Angiotensin II and aldosterone were measured as previously reported …”

Divergent effects of a designer natriuretic peptide CD-NP in the regulation of adipose tissue and metabolism

“…Other human studies with cenderitide are still recruiting or are ongoing, but so far there is no study involving obese patients. Recently completed studies of 12 weeks of subcutaneously delivered BNP to patients with symptomatic and asymptomatic heart failure have been reported [79] , [80] , [81] . Compared to controls, treated subjects exhibited cGMP activation and improved cardiovascular and renal function.…”