title: Losartan ameliorates "upstream" pulmonary vein vasculopathy in a piglet model of pulmonary vein stenosis.
abstract: OBJECTIVE
  Pulmonary vein stenosis (PVS) is a relentless disease with a poor prognosis. Although surgical repair can effectively treat "downstream" (near left atrial junction) PVS, residual "upstream" (deep in lung parenchyma) PVS commonly dictates long-term survival. Our initial studies revealed an association between PVS and transforming growth factor-β signaling, which led us to investigate the effect of losartan on upstream pulmonary vein vasculopathy in a piglet model of PVS.
  
  
  METHODS
  Neonatal Yorkshire piglets underwent sham surgical banding (sham, n = 6), staged bilateral pulmonary vein banding of all pulmonary veins except the right middle pulmonary vein (banded, n = 6), and staged pulmonary vein banding with losartan treatment (losartan, 1 mg/kg/d, n = 7). After 7 weeks, the hemodynamic data were obtained and the piglets killed.
  
  
  RESULTS
  Pulmonary vein banding (compared with sham) was associated with continuous turbulent flow in banded pulmonary veins, pulmonary hypertension (pulmonary artery/systemic blood pressure ratio 0.51 ± 0.06 vs 0.23 ± 0.02, P < .001), and diffuse pulmonary vein intimal hyperplasia in the upstream pulmonary veins (P < .001). Losartan administration decreased the pulmonary artery/systemic blood pressure ratios compared with those in the banded piglets (0.36 ± 0.08 vs 0.51 ± 0.06, P = .007) but it remained greater than those in the sham group (P = .001). Losartan was also associated with diminished pulmonary vein intimal hyperplasia compared with that in the banded piglets (P < .001) but still remained more than that in the sham group (P = .035). Pulmonary vein banding reduced vascular endothelial-cadherin expression, indicative of diminished endothelial integrity, which was restored with losartan.
  
  
  CONCLUSIONS
  Losartan treatment improved PVS-associated pulmonary hypertension and intimal hyperplasia and might be a beneficial prophylactic therapy for patients at high risk of developing PVS after pulmonary vein surgery.
authors.affiliation: Division of Cardiovascular Surgery, Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jiaquan
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Division of Cardiovascular Surgery, Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Haruki
authors.initials: H
authors.lastname: Ide
authors.affiliation: Division of Cardiovascular Surgery, Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Yaqin Yana
authors.initials: YY
authors.lastname: Fu
authors.affiliation: Division of Cardiovascular Surgery, Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Anouk-Martine
authors.initials: AM
authors.lastname: Teichert
authors.affiliation: Division of Cardiovascular Surgery, Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kato
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada; Toronto General Research Institute, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.affiliation: Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Maynes
authors.affiliation: Division of Cardiovascular Surgery, Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: John G
authors.initials: JG
authors.lastname: Coles
authors.affiliation: Division of Cardiovascular Surgery, Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada. Electronic address: christopher.caldarone@sickkids.ca.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Caldarone
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D006965:Hyperplasia; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology*; D058426:Neointima; D011667:Pulmonary Veins / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011668:Pulmonary Veno-Occlusive Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013552:Swine; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000099152:Cadherin 5
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D015703:Antigens, CD; D015820:Cadherins; D019808:Losartan; D000099152:Cadherin 5