Tadalafil and Nesiritide as Therapy in Pre-clinical Heart Failure
Condition: Congestive Heart Failure
MeSH terms: Heart Failure
Study type: Interventional
Phase: Phase 1/Phase 2

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.
    

Intervention name(s): Nesiritide; Tadalafil; Placebo; Saline load
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 10 ug/kg; 5 mg; The pharmacy will create a placebo subcutaneous injection volume to match the volume of Nesiritide dose.; Normal saline 0.9% 0.25 ml/kg/min for 60 minutes
Other intervention name(s): Cialis; Adcira
Intervention MeSH terms: Natriuretic Peptide, Brain; Tadalafil
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention