NCT01544998

Tadalafil and Nesiritide as Therapy in Pre-clinical Heart Failure

To Define the Role of PDEV in Mediating the Decreased GFR and Attenuated Renal Sodium and cGMP Excretory Response to Acute Saline Volume Expansion in PSD and PDD With Renal Dysfunction.

• Status: Completed
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 43 (actual)
• Sponsor: Mayo Clinic · Academic / Other
• Sex: All
• Age: 21 Years – 90 Years
• Healthy volunteers: Not accepted

Summary

This study is being done to determine the effects of subcutaneous (under the skin) injection of human B-type natriuretic factor (BNP), Natrecor (nesiritide), a hormone produced by the heart, in combination with Tadalafil on: * The pumping function of the heart * Kidney function * Hormonal function (levels of different hormones in your blood) in persons with lower pumping function of their heart.

Detailed description

In the American Heart Association/American College of Cardiology classification of heart failure (HF), stage B is defined as patients with abnormal heart structure/function (systolic or diastolic dysfunction) without symptoms. This concept of preclinical HF is based on the fact that abnormal heart structure/function can be detected by complementary methods before the development of symptoms. Patients with those abnormalities may progress to heart failure and are at increased risk of adverse cardiac events. Preclinical systolic dysfunction (PSD) is the initial compensated phase of left ventricular systolic dysfunction without symptoms of HF. We have established that diastolic dysfunction is common in the general population being present in approximately 25% of the population over age 45, the majority of whom are asymptomatic i.e., preclinical diastolic dysfunction (PDD). Cyclic guanosine monophosphate (cGMP) is the second messenger of the natriuretic peptide system (NPS) and the nitric oxide system (NO) and plays an important role in the preservation of myocardial, vascular, and renal function. Hence, disruption of this signal transduction process may contribute to the development of cardiorenal dysfunction. Type V phosphodiesterase (PDEV) metabolizes cGMP and is abundant in the kidney, vasculature, and has been recently reported in the heart. We and others have demonstrated that renal PDEV is up-regulated in experimental HF and may lead to the attenuation of renal cGMP generation in response to both endogenous and exogenous BNP, thus serving as a mechanism for renal resistance to BNP. Furthermore, in experimental overt HF, 10 days of PDEV inhibition treatment resulted in reduction of left ventricular (LV) mass, increased LV fractional shortening and cardiac output but did not improve renal function. However, chronic PDEV inhibition did enhance the renal actions of exogenous BNP, specifically improving glomerular filtration rate (GFR) and renal cGMP generation. PDEV inhibitors are FDA approved for erectile dysfunction and pulmonary hypertension.

Conditions

• Congestive Heart Failure

Interventions

Type	Name	Description
DRUG	Nesiritide	10 ug/kg
DRUG	Tadalafil	5 mg
DRUG	Placebo	The pharmacy will create a placebo subcutaneous injection volume to match the volume of Nesiritide dose.
DRUG	Saline load	Normal saline 0.9% 0.25 ml/kg/min for 60 minutes

Timeline

• Start date: 2012-02-01
• Primary completion: 2013-08-01
• Completion: 2014-08-01
• First posted: 2012-03-06
• Last updated: 2018-03-22
• Results posted: 2015-03-04

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study