Effects of Chimeric Natriuretic Peptide Versus Placebo in Stable Heart Failure and Moderate Renal Dysfunction

The overall aim is to conduct a human physiologic study to assess the renal and neurohumoral effects of CD-NP vs placebo in older subjects with stable chronic systolic heart failure and moderate renal dysfunction.

The investigators will evaluate the renal and neurohumoral effects of dual receptor (NPR-A and NPR-B) activation with CD-NP. This is a clinically relevant patient population who is at increased risk of developing diuretic resistance during the treatment of HF exacerbations.

Eligibility Criteria:
Inclusion Criteria:

* Male and non-pregnant female with stable chronic HF of primary cardiac etiology, resting left ventricular ejection fraction (LVEF) ≤ 40 % documented within the last 2 years.
* Moderate renal dysfunction with creatinine clearance of 30-60 ml.min-1.1.73m-2, as calculated by Cockcroft-Gault formula24 and adjusted for body surface area within the past year or at screening, or requirement for dialysis.
* Be willing to provide informed consent.

Exclusion Criteria:

* Known allergy or other adverse reactions to exogenous natriuretic peptides (CD-NP or its components, nesiritide, other natriuretic peptides, or related compounds).
* Women who are pregnant, or breast-feeding, on hormonal contraceptives or hormone replacement therapy. (Women should be in the post-menopausal state, defined as the absence of menses for ≥ 1 year and serum follicle-stimulating hormone ≥ 20 IU/L; or should be previously sterilized defined as bilateral tubal occlusion for ≥ 6 months, bilateral oophorectomy, or complete hysterectomy)
* Having received nesiritide for within 7 days prior to prior to entry into the study.
* Having received any investigational drug or device within 30 days prior to entry into the study.
* Clinically unstable patients (e.g. systolic blood pressure \< 90 mmHg, ongoing requirement for vasopressors or mechanical circulatory support, or mechanical ventilation).
* Recent hospitalization for decompensated HF or recent defibrillation for cardiac resuscitation within 30 days prior to randomization.
* Prior organ transplantation, being on a waiting list for organ transplantation, or ongoing requirement for long-term vasoactive support.
* Prior requirement for dialysis or ultrafiltration
* Active urinary tract infection
* Patients with guarded prognosis who are unlikely to derive meaningful benefit from CD-NP.
* Use of sulfonamides, non-steroidal anti-inflammatory drugs, probenecid, or other drugs that are known to alter renal function within one week of the first dose of CD-NP or placebo.
* Presence of cardiac lesions or comorbidities that may contraindicate the use of natriuretic peptides, such as clinically significant cardiac valvular stenosis, hypertrophic cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis, primary pulmonary hypertension, or uncorrected congenital heart disease that contraindicates the use of vasodilators.
* History of blood pressure \> 190/115 mmHg or unexplained syncope within the past 3 months.
* Symptomatic carotid artery disease, known critical carotid stenosis, or stroke within the past 3 months
* Clinically significant renal artery stenosis
* Baseline hemoglobin \< 10.0 g/dl.
* Serum sodium \< 130 mEq/L, potassium \< 3.6 mEq/L, or magnesium \< 1.7 mEq/L.
* Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at least 5 times the upper limit of normal or bilirubin at least 3 times the upper limit of normal
* History of alcohol abuse within the past 6 months.
* Consumption of a phosphodiesterase-5 inhibitor (sildenafil, vardenafil, or tadalafil) within 72 hours of receiving CD-NP or placebo.
* Inability to communicate effectively with study personnel.
* BMI \>38