title: Everolimus prevents coronary microvasculopathy in heart transplant recipients with normal coronary angiograms: an anatomo-functional study.
abstract: BACKGROUND
  Coronary allograft vasculopathy (CAV) involves both epicardial vessels and coronary microcirculation. Little is known about the effect of everolimus on coronary microvasculopathy in heart transplantation (HT). The aim of our study was to assess the pathological substrate of coronary flow reserve (CFR) impairment in HT patients and the effect of everolimus on microvascular remodeling and CFR.
  
  
  METHODS
  We studied 28 HT patients with normal coronary angiograms (25 male, age at HT 54±10 years). Immunosuppressive regimen consisted of cyclosporine and everolimus (10 patients) or mycophenolate mophetil (18 patients). They were evaluated with digital microscopy for morphometric analysis of fibrosis and microvascular remodeling. Coronary flow velocity in the left anterior descending coronary artery was detected using transthoracic Doppler echocardiography at rest and during adenosine infusion. CFR was the ratio of hyperaemic diastolic flow velocity (DFV) to resting DFV. A CFR≤2.5 was considered abnormal and sign of coronary microvascular dysfunction.
  
  
  RESULTS
  In patients with CFR≤2.5 the thickness of the tunica media of intramyocardial arterioles was greater than in patients with CFR>2.5 (39±2 vs 17±3 μm; P=.02). Microvascular remodeling was significantly higher in patients with CFR≤2.5 (72.7±2.4 vs 50.4±8.4%; P<.007). Capillary density and fibrosis were comparable between groups (157.2±42.4 vs 175.7±42.4 capillaries/mm2; P=.3; and 6.8±5 vs 8.3±4.9%; P=.4, respectively). The thickness of the tunica media of intramyocardial arterioles was lower in patients whose therapy included everolimus (15±2 vs 32±4 μm, P=.03) and CFR was higher (3.2±0.5 vs 2.8±0.9; P=.03).
  
  
  CONCLUSIONS
  The pathological substrate of reduced CFR in HT patients seems to be a hypertrophic remodeling of coronary arterioles. Everolimus appears to prevent such microvascular remodeling and preserve coronary flow reserve.
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy. Electronic address: francesco.tona@unipd.it.
authors.forename: F
authors.initials: F
authors.lastname: Tona
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Fedrigo
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Famoso
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Previato
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Tellatin
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Vecchiati
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Bellu
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy.
authors.forename: M P
authors.initials: MP
authors.lastname: Marra
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Feltrin
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Gerosa
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Thiene
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Iliceto
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Angelini
mesh_terms: D003326:Coronary Circulation; D000068338:Everolimus; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D011446:Prospective Studies; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017540:Tunica Media / Q000000981:diagnostic imaging; D014463:Ultrasonography; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus