Tadalafil and Nesiritide as Therapy in Pre-clinical Heart Failure

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.

Inclusion Criteria:

Group 1 (PSD)

- an ejection fraction of less than 45% with no clinical signs or symptoms of congestive
heart failure;

- a minimal distance on 6-minute walk of >450 meters

- calculated creatinine clearance of equal or less than 90 ml/min and greater than 30
ml/min, using the Modification of Diet in Renal Disease (MDRD) formula assessed within
the past 24 months. If the creatinine clearance is > 24 months a creatinine test can
be drawn at screen/enrollment visit.

- A 6-minute walk distance of 450 meters

Group 2 (PDD)

- ejection fraction of greater than 50% with moderate or severe diastolic dysfunction as
assessed by Doppler echocardiography,

- who do not have any signs or symptoms of congestive heart failure

- minimal distance on 6-minute walk of >450 meters

- calculated creatinine clearance of equal or less than 90 ml/min and greater than 30
ml/min

Exclusion Criteria:

- Current or anticipated future need for nitrate therapy

- Systolic blood pressure < 90 mmHg or > 180 mm Hg

- Diastolic blood pressure < 40 mmHg or > 100 mmHg

- Resting heart rate (HR) > 100 bpm

- Patients taking alpha antagonists or cytochrome P450 3A4 inhibitors (ketoconazole,
itraconazole, erythromycin, saquinavir, cimetidine or serum protease inhibitors for
HIV).

- Patients with retinitis pigmentosa, previous diagnosis of nonischemic optic
neuropathy, untreated proliferative retinopathy or unexplained visual disturbance

- Patients with sickle cell anemia, multiple myeloma, leukemia or penile deformities
placing them at risk for priapism (angulation, cavernosal fibrosis or Peyronie's
disease)

- Contraindication to nesiritide.

- Patients with an allergy to iodine.

- Valve disease (> moderate aortic or mitral stenosis; > moderate aortic or mitral
regurgitation)

- Hypertrophic cardiomyopathy

- Infiltrative or inflammatory myocardial disease (amyloid, sarcoid)

- Pericardial disease

- Have experienced a myocardial infarction or unstable angina, or have undergone
percutaneous transluminal coronary angiography (PTCA) or coronary artery bypass
grafting (CABG) within 60 days prior to consent, or requires either PTCA or CABG at
the time of consent

- Severe congenital heart diseases

- Sustained ventricular tachycardia or ventricular fibrillation within 14 days of
screening

- Second or third degree heart block without a permanent cardiac pacemaker

- Stroke within 3 months of screening or other evidence of significantly compromised
central nervous system (CNS) perfusion

- Patients with severe liver disease (AST > 3x normal, alkaline or bilirubin > 2x
normal)

- Serum sodium of < 125 milliequivalents (mEq)/dL or > 150 mEq/dL

- Serum potassium of < 3.2 mEq/dL or > 5.7 mEq/dL

- Prior diagnosis of intrinsic renal diseases including renal artery stenosis of > 50%

- Peritoneal or hemodialysis within 90 days or anticipation that dialysis or
ultrafiltration of any form will be required during the study period

- Less than 21 years of age

- Pregnant or nursing women.

- Women of child bearing potential who do not have a negative pregnancy test at study
entry and who are not using effective contraception