title: Ventricular assist device therapy normalizes inducible nitric oxide synthase expression and reduces cardiomyocyte apoptosis in the failing human heart.
abstract: OBJECTIVE
  We examined the effect of mechanical unloading with ventricular assist device (VAD) therapy on myocardial inducible nitric oxide synthase (iNOS) expression and cardiomyocyte apoptosis in patients with end-stage heart failure (HF).
  
  
  BACKGROUND
  Despite advances in medical therapy, HF continues to be a progressive and ultimately fatal disorder. High levels of iNOS expression are present in the myocardium of failing hearts, suggesting a potential role for iNOS in HF progression.
  
  
  METHODS
  Inducible NOS protein expression was analyzed by Western blotting and cardiomyocyte apoptosis by terminal deoxynucleotidyltransferase dUTP nick end-labeling (TUNEL) in myocardial samples from failing hearts. Included in these analyses were tissues from 9 patients at the time of transplantation (HF-transplant group), 10 patients at the time of VAD insertion (pre-VAD group), and 11 patients undergoing transplant after VAD support (post-VAD group). Seven control samples were obtained at autopsy.
  
  
  RESULTS
  Low or undetectable levels of iNOS were present in controls (0.005 +/- 0.002). The HF-transplant and pre-VAD myocardial specimens exhibited a marked increase in iNOS expression (1.48 +/- 0.34 and 1.29 +/- 0.26, respectively; p < 0.01 for both vs. controls). The increase in iNOS expression was reversed in the post-VAD group (0.36 +/- 0.16; p < 0.01 vs. HF-transplant and pre-VAD groups). The rate of TUNEL-positive cardiomyocytes was high in the pre-VAD group and significantly lower in the post-VAD group (0.64 +/- 0.15% in pre-VAD group and 0.16 +/- 0.07% in post-VAD group; p < 0.01). The iNOS levels correlated significantly with cardiomyocyte apoptosis (r = 0.66, p < 0.01).
  
  
  CONCLUSIONS
  Therapy with VAD normalizes iNOS expression in association with diminished cardiomyocyte apoptosis in the failing heart. Further work is required to define whether a causal relationship exists between iNOS and cardiomyocyte apoptosis.
authors.affiliation: Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111, USA. rpatten@tufts-nemc.org
authors.forename: Richard D
authors.initials: RD
authors.lastname: Patten
authors.forename: David
authors.initials: D
authors.lastname: Denofrio
authors.forename: Mohamad
authors.initials: M
authors.lastname: El-Zaru
authors.forename: Rahul
authors.initials: R
authors.lastname: Kakkar
authors.forename: Jessica
authors.initials: J
authors.lastname: Saunders
authors.forename: Flore
authors.initials: F
authors.lastname: Celestin
authors.forename: Kenneth
authors.initials: K
authors.lastname: Warner
authors.forename: Hassan
authors.initials: H
authors.lastname: Rastegar
authors.forename: Kamal R
authors.initials: KR
authors.lastname: Khabbaz
authors.forename: James E
authors.initials: JE
authors.lastname: Udelson
authors.forename: Marvin A
authors.initials: MA
authors.lastname: Konstam
authors.forename: Richard H
authors.initials: RH
authors.lastname: Karas
mesh_terms: D000328:Adult; D017209:Apoptosis; D015153:Blotting, Western; D016022:Case-Control Studies; D005260:Female; D006333:Heart Failure / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D006353:Heart-Assist Devices; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D012720:Severity of Illness Index
chemical_list: C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II