title: Effects of phosphodiesterase type 5 inhibition on systemic and pulmonary hemodynamics and ventricular function in patients with severe symptomatic aortic stenosis.
abstract: BACKGROUND
  Pressure overload resulting from aortic stenosis causes maladaptive ventricular and vascular remodeling that can lead to pulmonary hypertension, heart failure symptoms, and adverse outcomes. Retarding or reversing this maladaptive remodeling and its unfavorable hemodynamic consequences has the potential to improve morbidity and mortality. Preclinical models of pressure overload have shown that phosphodiesterase type 5 inhibition is beneficial; however, the use of phosphodiesterase type 5 inhibitors in patients with aortic stenosis is controversial because of concerns about vasodilation and hypotension.
  
  
  RESULTS
  We evaluated the safety and hemodynamic response of 20 subjects with severe symptomatic aortic stenosis (mean aortic valve area, 0.7 ± 0.2 cm(2); ejection fraction, 60 ± 14%) who received a single oral dose of sildenafil (40 or 80 mg). Compared with baseline, after 60 minutes, sildenafil reduced systemic (-12%; P<0.001) and pulmonary (-29%; P=0.002) vascular resistance, mean pulmonary artery (-25%; P<0.001) and wedge (-17%; P<0.001) pressures, and increased systemic (13%; P<0.001) and pulmonary (45%; P<0.001) vascular compliance and stroke volume index (8%; P=0.01). These changes were not dose dependent. Sildenafil caused a modest decrease in mean systemic arterial pressure (-11%; P<0.001) but was well tolerated with no episodes of symptomatic hypotension.
  
  
  CONCLUSIONS
  This study shows for the first time that a single dose of a phosphodiesterase type 5 inhibitor is safe and well tolerated in patients with severe aortic stenosis and is associated with improvements in pulmonary and systemic hemodynamics resulting in biventricular unloading. These findings support the need for longer-term studies to evaluate the role of phosphodiesterase type 5 inhibition as adjunctive medical therapy in patients with aortic stenosis.
authors.affiliation: Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. blindman@dom.wustl.edu
authors.forename: Brian R
authors.initials: BR
authors.lastname: Lindman
authors.forename: Alan
authors.initials: A
authors.lastname: Zajarias
authors.forename: José A
authors.initials: JA
authors.lastname: Madrazo
authors.forename: Jay
authors.initials: J
authors.lastname: Shah
authors.forename: Brian F
authors.initials: BF
authors.lastname: Gage
authors.forename: Eric
authors.initials: E
authors.lastname: Novak
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Johnson
authors.forename: Murali M
authors.initials: MM
authors.lastname: Chakinala
authors.forename: Tara A
authors.initials: TA
authors.lastname: Hohn
authors.forename: Mohammed
authors.initials: M
authors.lastname: Saghir
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Mann
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001024:Aortic Valve Stenosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D003187:Compliance / Q000187:drug effects; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D011652:Pulmonary Circulation / Q000187:drug effects*; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects; D012720:Severity of Illness Index; D000068677:Sildenafil Citrate; D013318:Stroke Volume / Q000187:drug effects; D013450:Sulfones / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D014463:Ultrasonography; D014655:Vascular Resistance / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects; D016278:Ventricular Function, Right / Q000187:drug effects
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human