Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study
Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study
Currently, aortic stenosis (AS) is considered a "surgical disease" with no medical therapy
 available to improve any clinical outcomes, including symptoms, time to surgery, or long-term
 survival. Thus far, randomized studies involving statins have not been promising with respect
 to slowing progressive valve stenosis. Beyond the valve, two common consequences of aortic
 stenosis are hypertrophic remodeling of the left ventricle (LV) and pulmonary venous
 hypertension; each of these has been associated with worse heart failure symptoms, increased
 operative mortality, and worse long-term outcomes. Whether altering LV structural
 abnormalities, improving LV function, and/or reducing pulmonary artery pressures with medical
 therapy would improve clinical outcomes in patients with AS has not been tested. Animal
 models of pressure overload have demonstrated that phosphodiesterase type 5 (PDE5) inhibition
 influences nitric oxide (NO) - cyclic guanosine monophosphate (cGMP) signaling in the LV and
 favorably impacts LV structure and function, but this has not been tested in humans with AS.
 Studies in humans with left-sided heart failure and pulmonary venous hypertension have shown
 that PDE5 inhibition improves functional capacity and quality of life, but patients with AS
 were not included in those studies. The investigators hypothesize that PDE5 inhibition with
 tadalafil will have a favorable impact on LV structure and function as well as pulmonary
 artery pressures. In this pilot study, the investigators anticipate that short-term
 administration of tadalafil to patients with AS will be safe and well-tolerated.
Subjects with moderately severe to severe aortic stenosis (AS), left ventricular hypertrophy
 (LVH), diastolic dysfunction, preserved ejection fraction, and no planned aortic valve
 replacement over the next 6 months will be eligible for this randomized, double-blind,
 placebo-controlled, pilot study. There will be a diabetic cohort (n=32) and non-diabetic
 cohort (n=24); each cohort will be randomized 1:1 to tadalafil vs. placebo. During a baseline
 study visit, the following will be obtained: clinical data, 6 minute walk, quality of life
 questionnaire, blood draw, and an echocardiogram. A 3-day run-in will occur to initially
 assess tolerability and compliance. If the drug is tolerated during this run-in period,
 participants will be randomized. An MRI will also be performed during this randomization
 visit. Follow-up study visits and testing will occur at 6 and 12 weeks and 6 months.
Inclusion Criteria:

 -  Patients with moderate to severe aortic stenosis (AVA < 1.5 cm2)

 -  Left ventricular hypertrophy

 -  Diastolic dysfunction as evidenced by tissue Doppler e' (average of septal and
 lateral) ≤ 7 cm/s

 -  EF ≥ 50%

 -  None or minimal symptoms related to aortic stenosis (NYHA ≤ 2)

 -  The subject and treating physician are not planning on a valve replacement procedure
 to occur during the next 6 months

 -  Ambulatory

 -  Normal sinus rhythm

 -  18 years of age and older

 -  Able and willing to comply with all the requirements for the study

 Exclusion Criteria:

 -  Need for ongoing nitrate medications

 -  SBP < 110mmHg or MAP < 75mmHg

 -  Moderately severe or severe mitral regurgitation

 -  Moderately severe or severe aortic regurgitation

 -  Contraindication to MRI

 -  Creatinine clearance < 30 mL/min

 -  Cirrhosis

 -  Pulmonary fibrosis

 -  Increased risk of priapism

 -  Retinal or optic nerve problems or unexplained visual disturbance

 -  If a subject requires ongoing use of an alpha antagonist typically used for benign
 prostatic hyperplasia (BPH) (prazosin, terazosin, doxazosin, or tamsulosin), SBP < 120
 mmHg or MAP < 80 mmHg is excluded

 -  Need for ongoing use of a potent CYP3A inhibitor or inducer (ritonavir, ketoconazole,
 itraconazole, rifampin)

 -  Current or recent (≤ 30 days) acute coronary syndrome

 -  O2 sat < 90% on room air

 -  Females that are pregnant or believe they may be pregnant

 -  Any condition which the PI determines will place the subject at increased risk or is
 likely to yield unreliable data

 -  Unwilling to provide informed consent