Background There is increasing evidence that alterations in nitric oxi
de synthesis are of pathophysiological importance in heart failure. A
number of studies have shown altered nitric oxide production by the en
dothelial constitutive isoform of nitric oxide synthase (NOS), but the
re is very little information on the role of the inducible isoform. Me
thods and Results We analyzed inducible NOS (iNOS) expression in ventr
icular myocardium taken from 11 control subjects (who had died suddenl
y from noncardiac causes), from 10 donor hearts before implantation, a
nd from 51 patients with heart failure (24 with dilated cardiomyopathy
[DCM], 17 with ischemic heart disease [IHD], and 10 with valvular hea
rt disease [VHD]). Reverse transcription-polymerase chain reaction was
used to confirm the presence of intact mRNA and to detect expression
of iNOS and atrial natriuretic peptide (ANP). ANP was used as a molecu
lar phenotypic marker of ventricular failure. iNOS was expressed in 36
of 51 biopsies (71%) from patients with heart failure and in none of
the control patients (P<.0001). iNOS expression could also be detected
in 50% of the donor hearts. All samples that expressed iNOS also expr
essed ANP. iNOS gene expression occurred in 67% of patients with DCM,
59% of patients with IHD, and 100% of patients with VHD. To determine
whether iNOS protein was expressed in failing ventricles, immunohistoc
hemistry was performed on three donor hearts and nine failing hearts w
ith iNOS mRNA expression. Staining for iNOS was almost undetectable in
the donor myocardium and in control sections, but all failing hearts
showed diffuse cytoplasmic staining in cardiac myocytes. Expression of
iNOS could be observed in all four chambers. Western blot analysis wi
th the same primary antibody showed a specific positive band for iNOS
protein in the heart failure specimens; minimal iNOS protein expressio
n was seen in donor heart samples. Conclusions iNOS expression occurs
in failing human cardiac myocytes and may be involved in the pathophys
iology of DCM, IHD, and VHD.