Ventricular assist device therapy normalizes inducible nitric oxide synthase expression and reduces cardiomyocyte apoptosis in the failing human heart.
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.
Patten
Richard D
RD
Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111, USA. rpatten@tufts-nemc.org
Denofrio
David
D
El-Zaru
Mohamad
M
Kakkar
Rahul
R
Saunders
Jessica
J
Celestin
Flore
F
Warner
Kenneth
K
Rastegar
Hassan
H
Khabbaz
Kamal R
KR
Udelson
James E
JE
Konstam
Marvin A
MA
Karas
Richard H
RH
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
C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II