Cardiotrophin-1 has been shown to be profibrogenic in experimental models. The aim of this study was to
analyze whether cardiotrophin-1 is associated with left ventricular end-diastolic stress and myocardial fibrosis
in hypertensive patients with heart failure. Endomyocardial biopsies from patients (n=31) and necropsies from 7
control subjects were studied. Myocardial cardiotrophin-1 protein and mRNA and the fraction of myocardial volume
occupied by collagen were increased in patients compared with controls (
P
<0.001). Cardiotrophin-1 overexpression in
patients was localized in cardiomyocytes. Cardiotrophin-1 protein was correlated with collagen type I and III mRNAs
(
r
=0.653,
P
<0.001;
r
=0.541,
P
<0.01) and proteins (
r
=0.588,
P
<0.001;
r
=0.556,
P
<0.005) in all subjects and with left
ventricular end-diastolic wall stress (
r
=0.450;
P
<0.05) in patients. Plasma cardiotrophin-1 and N-terminal pro-brain
natriuretic peptide and serum biomarkers of myocardial fibrosis (carboxy-terminal propeptide of procollagen type I
and amino-terminal propeptide of procollagen type III) were increased (
P
<0.001) in patients compared with controls.
Plasma cardiotrophin-1 was correlated with N-terminal pro-brain natriuretic peptide (
r
=0.386;
P
<0.005), carboxy-
terminal propeptide of procollagen type I (
r
=0.550;
P
<0.001), and amino-terminal propeptide of procollagen type III
(
r
=0.267;
P
<0.05) in all subjects. In vitro, cardiotrophin-1 stimulated the differentiation of human cardiac fibroblast to
myofibroblasts (
P
<0.05) and the expression of procollagen type I (
P
<0.05) and III (
P
<0.01) mRNAs. These findings
show that an excess of cardiotrophin-1 is associated with increased collagen in the myocardium of hypertensive patients
with heart failure. It is proposed that exaggerated cardiomyocyte production of cardiotrophin-1 in response to increased
left ventricular end-diastolic stress may contribute to fibrosis through stimulation of fibroblasts in heart failure of
hypertensive origi