Sherry L. Benike

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.

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

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.

The effects of dose reduction of furosemide on glomerular filtration rate in stable systolic heart failure.

Loop diuretics are effective and necessary to improve hemodynamics and relieve congestion in subjects with systolic heart failure (HF) and fluid overload. In contrast, in compensated/noncongested patients with left ventricular systolic dysfunction, reports suggest negative consequences of chronic

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

Cenderitide is a novel designer natriuretic peptide (NP) composed of C‐type natriuretic peptide (CNP) fused to the C‐terminus of Dendroaspis natriuretic peptide (DNP). Cenderitide was engineered to coactivate the two NP receptors, particulate guanylyl cyclase (pGC)‐A and ‐B. The rationale for its design was to achieve the renal‐enhancing and antifibrotic properties of dual receptor activation, but without clinically significant hypotension. Here we report the first clinical trial on the safety, tolerability, and cyclic guanosine monophosphate (cGMP) activating properties of Cenderitide in subjects with stable heart failure (HF). Four‐hour infusion of Cenderitide was safe, well‐tolerated, and significantly increased plasma cGMP levels and urinary cGMP excretion without adverse effects with no change in blood pressure. Thus, Cenderitide has a favorable safety profile and expected pharmacological effects in stable human HF. Our results support further investigations of Cenderitide in HF as a potential future cGMP‐enhancing therapeutic strategy.

INTRARENAL RENIN ANGIOTENSIN SYSTEM ACTIVATION: PATHOPHYSIOLOGIC AND THERAPEUTIC IMPLICATIONS IN ACUTE DECOMPENSATED HEART FAILURE

Introduction: The Renin Angiotensin System (RAS) plays a pivotal role in mediating Cardiorenal Syndrome in acute decompensated heart failure (ADHF) and is one of the most targeted pathways in the treatment of HF. Human Angiotensinogen (AGT) is the precursor for all angiotensin (ANG) isoforms,