Aortic Stenosis and PhosphodiEsterase iNhibition With Aortic Valve Replacement (ASPEN-AVR): A Pilot Study
Aortic Stenosis and PhosphodiEsterase iNhibition With Aortic Valve Replacement (ASPEN-AVR): 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 PDE5 inhibition influences NO-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 upregulate NO-cGMP signaling, reduce
 oxidative stress, and have a favorable impact on LV structure and function as well as
 pulmonary artery pressures and quality of life. In this pilot study, the investigators
 anticipate that short-term administration of tadalafil to patients with AS will be safe and
 well-tolerated.
Patients with severe symptomatic AS who will undergo elective aortic valve replacement will
 be eligible for this randomized, double-blind, placebo-controlled, pilot study. Prior to
 randomization, subjects will have testing including: 6 minute walk, quality of life
 questionnaire, blood draw, and an echocardiogram. If an initial monitored dose of tadalafil
 is tolerated, participants will be randomized 2:1 to tadalafil vs. placebo. After 4 weeks on
 drug or placebo, subjects will have the same baseline testing repeated. At the time of aortic
 valve replacement surgery, the aortic valve and a small piece of LV myocardium will be taken
 for several analyses.
Inclusion Criteria:

 -  Patients with severe aortic stenosis (AVA < 1.0 cm2)

 -  Left ventricular hypertrophy

 -  EF ≥ 45%

 -  NYHA functional class ≥ 2

 -  Ambulatory (able to perform a 6 minute walk test)

 -  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

 -  Creatinine clearance < 30 mL/min

 -  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)

 -  Cirrhosis

 -  Pulmonary fibrosis

 -  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