Phosphodiesterase-5 (PDE-5) Inhibition in Heart Transplant Recipients

Background and Significance In the United States, heart failure is an epidemic affecting
5,700,000 people, of which an estimated 100,000 to 200,000 suffer from end-stage heart
failure. Cardiac transplantation has emerged as the definitive therapy for patients with
end-stage heart failure.

Cardiac allograft vasculopathy (CAV) is the major limitation to longevity after heart
transplant (HTx) and currently there are no effective treatments. It affects up to 45% of
transplant recipients by year four post transplantation and is detectable on intravascular
ultrasound in up to 75% at one year. Attempts to prevent cardiac allograft vasculopathy by
modifying traditional risk factors such as dyslipidemia and hypertension have resulted in
only modest improvements in outcomes after transplant. The efficacy of these preventive
measures have been limited by the multifactorial nature of the process and the influence of
nontraditional, less well-defined risk factors such as immune response, mode of brain death
of the donor, and cytomegalovirus infection.

Both traditional and non-traditional risk factors do share a common final pathway, which is
endothelial injury and subsequent endothelial dysfunction.

Endothelial dysfunction has been well described as a precursor to cardiac allograft
vasculopathy in cardiac transplant recipients. While endothelial dysfunction is an integral
part of the development of CAV and one of the earliest manifestations, it has not yet been
demonstrated that targeting endothelial dysfunction delays or prevents the onset of cardiac
allograft vasculopathy. Thus this study seeks to determine whether short-term sildenafil,
when administered during the first 3 years after transplant, improves endothelial function
in heart transplant recipients and thereby could prevent or delay cardiac allograft
vasculopathy (CAV).

Rationale for using sildenafil Sildenafil has been demonstrated to dilate epicardial
coronary arteries in patients with coronary artery disease and in those with normal coronary
arteries who have risk factors for CAD and has been demonstrated to improve endothelial
function in a variety of cardiovascular diseases including pulmonary hypertension and heart
failure. By inhibiting PDE-5, an enzyme that metabolizes cyclic guanosine monophosphate
(c-GMP), sildenafil enhances c-GMP-mediated relaxation and inhibits proliferation of
vascular smooth-muscle cells. Inhibition of PDE-5 receptors with sildenafil appears to
selectively improve endothelial function of the epicardial arteries; and in patients with
severe CAD, sildenafil has been shown to improve coronary flow reserve. Based on these
properties, we hypothesize that PDE-5 inhibition will improve endothelial function in
transplant recipients and delay or prevent the onset of vasculopathy

Study Objectives

To determine the effect of Sildenafil on endothelial function in cardiac transplant
recipients by:

1. Measuring the change in radial artery elasticity in HTx recipients before and after
Sildenafil therapy.

2. Measuring change in number of endothelial progenitor cells before and after Sildenafil
therapy

Study Design Overview of Study Design This is a randomized, double-blind, placebo-controlled
16 week crossover designed pilot study to evaluate the effect of oral sildenafil 20mg t.i.d,
on small artery elasticity (SAE) and endothelial cells in heart transplant recipients.

Subjects will have pre-randomization and post treatment measurements of peripheral artery
elasticity and endothelial progenitor cells Visits will occur at 0, 4, 8, 12 and 16 weeks. A
graphic presentation of the study is shown below.

Inclusion Criteria:

- Subject provided written informed consent

- Subject is 18 years old or Older

- Subject is a cardiac transplant recipient between 6 months - 5 years prior to week 0

Exclusion Criteria:

- Multi-organ transplant

- Been re-transplanted

- A contraindication to taking sildenafil

- Currently taking a PDE-5 inhibitor

- Mean arterial pressure < 65 mmHg

- A Left ventricular outflow obstruction

- A history or active retinitis pigmentosa

- Major surgery within 3 months of week 0

- Active infections to exclude are (CMV infection, febrile illness and Bacterial
illness) within 3 months of week 0

- Acute rejection (grade 3A or greater) within 3 months of week 0

- Chronic kidney disease stage 4 (GFR<30 mL/min/1.73 m2) or acute renal failure

- Unstable cardiac disease, including myocardial infarction, stroke, or life-
threatening arrhythmia within 6 months of week 0