title: Isosorbide Dinitrate, With or Without Hydralazine, Does Not Reduce Wave Reflections, Left Ventricular Hypertrophy, or Myocardial Fibrosis in Patients With Heart Failure With Preserved Ejection Fraction.
abstract: Wave reflections, which are increased in patients with heart failure with preserved ejection fraction, impair diastolic function and promote pathologic myocardial remodeling. Organic nitrates reduce wave reflections acutely, but whether this is sustained chronically or affected by hydralazine coadministration is unknown.
  
  
  
  We randomized 44 patients with heart failure with preserved ejection fraction in a double-blinded fashion to isosorbide dinitrate (ISDN; n=13), ISDN+hydralazine (ISDN+hydral; n=15), or placebo (n=16) for 6 months. The primary end point was the change in reflection magnitude (RM; assessed with arterial tonometry and Doppler echocardiography). Secondary end points included change in left ventricular mass and fibrosis, measured with cardiac magnetic resonance imaging, and the 6-minute walk distance. ISDN reduced aortic characteristic impedance (mean baseline=0.15 [95% CI, 0.14-0.17], 3 months=0.11 [95% CI, 0.10-0.13], 6 months=0.10 [95% CI, 0.08-0.12] mm Hg/mL per second;P=0.003) and forward wave amplitude (Pf, mean baseline=54.8 [95% CI, 47.6-62.0], 3 months=42.2 [95% CI, 33.2-51.3]; 6 months=37.0 [95% CI, 27.2-46.8] mm Hg,P=0.04), but had no effect on RM (P=0.64), left ventricular mass (P=0.33), or fibrosis (P=0.63). ISDN+hydral increased RM (mean baseline=0.39 [95% CI, 0.35-0.43]; 3 months=0.31 [95% CI, 0.25-0.36]; 6 months=0.44 [95% CI, 0.37-0.51],P=0.03), reduced 6-minute walk distance (mean baseline=343.3 [95% CI, 319.2-367.4]; 6 months=277.0 [95% CI, 242.7-311.4] meters,P=0.022), and increased native myocardial T1 (mean baseline=1016.2 [95% CI, 1002.7-1029.7]; 6 months=1054.5 [95% CI, 1036.5-1072.3],P=0.021). A high proportion of patients experienced adverse events with active therapy (ISDN=61.5%, ISDN+hydral=60.0%; placebo=12.5%;P=0.007).
  
  
  
  ISDN, with or without hydralazine, does not exert beneficial effects on RM, left ventricular remodeling, or submaximal exercise and is poorly tolerated. ISDN+hydral appears to have deleterious effects on RM, myocardial remodeling, and submaximal exercise. Our findings do not support the routine use of these vasodilators in patients with heart failure with preserved ejection fraction.
  
  
  
  URL: www.clinicaltrials.gov. Unique identifier: NCT01516346.
authors.affiliation: Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.
authors.forename: Payman
authors.initials: P
authors.lastname: Zamani
authors.affiliation: Department of Radiology, Philadelphia Veterans' Affairs Medical Center, Philadelphia, PA.
authors.forename: Scott
authors.initials: S
authors.lastname: Akers
authors.affiliation: Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.
authors.forename: Haideliza
authors.initials: H
authors.lastname: Soto-Calderon
authors.affiliation: Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Beraun
authors.affiliation: Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.
authors.forename: Maheswara R
authors.initials: MR
authors.lastname: Koppula
authors.affiliation: Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.
authors.forename: Swapna
authors.initials: S
authors.lastname: Varakantam
authors.affiliation: Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.
authors.forename: Deepa
authors.initials: D
authors.lastname: Rawat
authors.affiliation: Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.
authors.forename: Prithvi
authors.initials: P
authors.lastname: Shiva-Kumar
authors.affiliation: Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.|Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Haines
authors.affiliation: Office of Nursing Research, School of Nursing, University of Pennsylvania, Philadelphia, PA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Chittams
authors.affiliation: Division of Nephrology/Hypertension, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Townsend
authors.affiliation: Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Walter R
authors.initials: WR
authors.lastname: Witschey
authors.affiliation: Biofluid, Tissue, and Solid Mechanics for Medical Applications, IBiTech, iMinds Medical IT, Ghent University, Ghent, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Segers
authors.affiliation: Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA julio.chirinos@uphs.upenn.edu.
authors.forename: Julio A
authors.initials: JA
authors.lastname: Chirinos
mesh_terms: D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D015150:Echocardiography, Doppler; D005260:Female; D005355:Fibrosis / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000503:physiopathology; D006801:Humans; D006830:Hydralazine / Q000008:administration & dosage*; D017379:Hypertrophy, Left Ventricular / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D007548:Isosorbide Dinitrate / Q000008:administration & dosage*; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology*; D010865:Pilot Projects; D013318:Stroke Volume / Q000502:physiology*; D014665:Vasodilator Agents / Q000008:administration & dosage; D016277:Ventricular Function, Left / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D014665:Vasodilator Agents; D006830:Hydralazine; D007548:Isosorbide Dinitrate
keywords: heart failure; hemodynamics; magnetic resonance imaging; remodeling heart failure; vascular biology; vascular stiffness; vasodilators