Cardiovascular Research (2009) 81, 509–518

doi:10.1093/cvr/cvn235
Review

Biochemical markers of myocardial remodelling

in hypertensive heart disease
Arantxa González1, Begoña López1, Susana Ravassa1, Javier Beaumont1, Teresa Arias1,
Nerea Hermida1, Amaia Zudaire1, and Javier Dı́ez1,2*
1
Division of Cardiovascular Sciences, Centre of Applied Medical Research, University of Navarra, Pamplona, Spain; and
2
Department of Cardiology and Cardiovascular Surgery, University Clinic, University of Navarra, Pamplona, Spain
Received 27 June 2008; revised 11 August 2008; accepted 28 August 2008; online publish-ahead-of-print 1 September 2008

Time for primary review: 39 days

KEYWORDS The intricate mechanisms responsible for the structural remodelling of the myocardium that facilitates
Biochemical markers; the evolution to heart failure in hypertensive patients, namely in those with left ventricular hypertro-
Hypertension; phy, requires from clinicians the utilization of a multibiomarker approach for short-term and long-term
Cardiotrophin-1; stratification as well as prognostication of patients. Biochemical markers may also help to identify
Annexin A5; patients with no clinical evidence of hypertensive heart disease, and provide information about the
PICP; need for more aggressive therapy during different stages of the disease, and potentially provide valu-
Metalloproteinase-1; able biochemical data for the specialist. Although there is a continuous and complex interplay
Tissue inhibitor of between biochemical and imaging markers, perhaps their use will also have the potential to modify

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metalloproteinases-1
the medical management of patients with hypertensive heart disease and therapeutic decision-
making by tailoring a targeted therapy according to the predominant mechanism of myocardial
remodelling. This article will review in brief the most relevant information on a panel of circulating
molecules that may accomplish the criteria required to be considered as biochemical markers of the
cardiomyocyte and non-cardiomyocyte structural changes that occur in the hypertensive myocardium.

1. Introduction
Hypertensive heart disease (HHD), here defined by the pre-
sence of left ventricular hypertrophy (LVH) in the absence of
a cause other than arterial hypertension, has been long con-
sidered as one of the most common aetiological conditions
predisposing to heart failure (HF). In fact, although hyper-
tension increases the risk for developing HF,1 LVH itself is
an independent risk factor for HF.1,2 Furthermore, in spite
of the continuous progress of antihypertensive strategies
over the years, the incidence of HF in hypertensive patients
with LVH remains high and comparable with that of major
cardiovascular events, such as stroke.3
HHD is characterized by complex changes in myocardial
structure (e.g. enhanced cardiomyocyte growth, excessive
cardiomyocyte apoptosis, accumulation of interstitial and
perivascular collagen fibres, disruption of endomysial and
perimysial collagen network) that induce the remodelling
of the myocardium, and ultimately, deteriorate left ventri-
cular function and facilitate the development of HF.4 Hyper-
tensive myocardial remodelling is the consequence of a
* Corresponding author: Área de Ciencias Cardiovasculares, Edificio CIMA,
Av. Pio XII, 55, 31008 Pamplona, Spain. Tel: þ34 948 194700; fax: þ34
948 194716.
E-mail address: jadimar@unav.es
number of pathological processes mediated by mechanical,
neurohormonal, and cytokine routes, occurring in the cardi-
omyocyte and the non-cardiomyocyte compartments of the
myocardium.5
The identification of biomarkers of potential usefulness
for the clinical handling of cardiac diseases evolving to
HF has been a prolific field in the last years. Biomarkers
either determined in the circulation as biochemical
markers or detected in the heart by imaging technologies,
can be defined as alterations in the constituents of tissues
or body fluids that can be applicable in at least five clinical
areas: screening, diagnosis, prognostication, prediction of
disease recurrence, and therapeutic monitoring. The inves-
tigation of novel circulating biochemical markers of myocar-
dial remodelling in HHD has been accelerating at a
remarkable pace, but it has also deluged the clinical and
research communities with candidate molecules, very few
of which are likely to survive the test of time as useful clini-
cal tools.6,7 In this regard, it is the opinion of the authors
that for a circulating molecule to be considered a biochemi-
cal marker of myocardial remodelling it must fulfil several
criteria. First of all, there must be a relationship between
its expression in the myocardium and its blood concen-
tration; secondly, there has to be a positive gradient from
its concentration in coronary sinus blood towards its

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2008.
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510
concentration in peripheral vein blood, proving its main
cardiac origin; thirdly, there must be an association of its
concentration in blood with the cardiac structural and/or
functional parameters reflecting the hallmarks of the myo-
cardial changes under study; finally, its levels should vary
in parallel with the changes in the above parameters
induced by pharmacological treatment. On the other hand,
its method of determination must be easy (i.e. ELISA),
reproducible and low cost, and the biochemical marker
must have a good sensitivity and specificity to detect the
pathology under study.
In this conceptual framework, recent studies performed in
our laboratory and by other groups with small populations of
hypertensive patients in which other cardiac conditions
different from HHD were carefully excluded, have allowed
to identify a panel of circulating molecules that fulfil the
above criteria. This paper reviews and summarizes recent
literature on these biochemical markers.
2. Biochemical markers related
to the cardiomyocyte
2.1 Cardiotrophin-1 and cardiomyocyte
hypertrophy
2.1.1 Fundamental aspects
LVH is the first compensatory mechanism that the haemo-
dynamically overloaded myocardium employs to maintain
normal function of the left ventricle in conditions of sys-
temic arterial hypertension. At the cellular level, the
growth of cardiomyocytes is the main determinant of LVH,
and it is accepted now that it represents the cell response
to both mechanical stretch and activation of humoral
growth factors due to pressure overload.8
Cardiotrophin-1 (CT-1) is a cytokine member of the
interleukin-6 (IL-6) superfamily, produced by cardiomyo-
cytes and cardiac fibroblasts in situations of biomechanical
stress and under exposure to humoral factors such as angio-
tensin II (Figure 1).9,10 Once secreted, it interacts with its
Figure 1 Schematic representation of the production and actions of cardiotrophin-1 (CT-1) and annexin A5 (AnxA5) in the hypertensive myocardium.
A. González et al.
receptor, the heterodimer formed by gp130 and the leukae-
mia inhibitory factor receptor, activating different signalling
pathways leading to cardiomyocyte growth and dysfunc-
tion.11 In vitro experiments have demonstrated that CT-1
induces an exaggerated growth response in cardiomyocytes
from adult spontaneously hypertensive rats (SHR) when
compared with those from adult Wistar rats.12 Recently,
Zolk et al.13 reported in heart tissues reconstituted from
rat cardiomyocytes that long-term exposure to CT-1
depressed basal force of contraction and the inotropic
response to Ca2þ and isoprenaline. In addition, CT-1 down-
regulated expression of calsequestrin, a protein involved
in Ca2þ handling, and prevented the formation of longitu-
dinally oriented bundles of cardiomyocytes, both changes
might contribute to ineffective force generation.
In studies performed in vivo it has been reported that CT-1
expression is abnormally high in the hypertrophied left ven-
tricle of SHR.12,14,15 In addition, it has been reported that
the myocardial expression of CT-1 is higher in aged SHR
with HF than in adult SHR without HF.16 Altogether, the
experimental data support the notion that an excessive pro-
duction of CT-1 by cardiac cells in response to biomechanical
stress associated with increased blood pressure might, in
turn, be involved in the hypertrophy and dysfunction of
the cardiomyocyte in hypertension (Figure 1).
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2.1.2 Plasma CT-1 in hypertensive patients
In studies performed in humans, it has been reported that
plasma CT-1 concentration shows a positive gradient from
coronary sinus blood towards aortic blood.17 On the other
hand, it has been shown that plasma concentration of CT-1
is directly correlated with the myocardial expression of
CT-1.18 Collectively, these findings suggest that, in the
human the heart secretes CT-1 via the coronary sinus into
the peripheral circulation, and that the concentration of cir-
culating CT-1 is a reliable index of cardiac CT-1.
Plasma CT-1 concentration has been found to be increased
in hypertensive patients as a whole group when compared
with normotensive subjects.19,20 Additionally, it has been
Biochemical markers in hypertension 511

reported that plasma CT-1 is higher in patients with LVH than 2.2 Annexin A5 and cardiomyocyte apoptosis
in patients without LVH,19 and in patients with HF than in
2.2.1 Fundamental aspects
patients with LVH (Figure 2A).18 It is interesting to point
Exaggerated stimulation of cardiomyocyte apoptosis is one
out that 31% of hypertensive patients without LVH already
of the cellular characteristics of the hypertrophied left ven-
exhibited concentrations of CT-1 abnormally elevated
tricle in arterial hypertension.24 Cardiomyocyte apoptosis
(above the upper normal limit measured in the normoten-
may be involved in the deterioration of left ventricular func-
sive control population),19 suggesting that CT-1 increases
tion and development of HF through several mechanisms,
early during the evolution of arterial hypertension.
including loss of cardiomyocytes due to cell death, compro-
Plasma CT-1 concentration is correlated with left ventricular
mise of oxidative phosphorylation and ATP production due to
mass index (LVMI) in hypertensive patients (Figure 2B).18,19,21
the loss of mitochondrial cytochrome c into the cytosol, and
Furthermore, an association has been found between antihy-
progressive contractile dysfunction of viable cardiomyocytes
pertensive treatment-induced decrease of plasma CT-1 and
related to enzymes involved in the apoptotic process.24
reduction of LVMI in patients with LVH.21 The lack of association
Annexin A5 (AnxA5) is a 32–35 kDa Ca2þ-binding protein
of LVMI with plasma IL-6,21 another member of the IL-6 super-
that becomes upregulated in response to different apoptotic
family of cytokines, reinforces the specificity of the association
stimuli acting on cardiomyocytes and other cardiac cells
of CT-1 with LVH and suggests that plasma CT-1 may be a poten-
(Figure 1).25–27 In addition, recent data suggest that an
tial biochemical marker for assessment of LVH in hypertension.
excess of intracellular AnxA5 will, in turn, contribute to
This is supported by the finding that it presents an acceptable
apoptosis of cardiomyocytes, likely through alterations in
sensitivity (70%) and specificity (75%) to detect LVH, as
cellular Ca2þ handling and mitochondrial metabolism.27,28 It
assessed by echocardiography, in hypertensive patients.19
is likely that AnxA5 released to the extracellular space will
Plasma CT-1 concentration has been measured also in hyper-
reach the blood via cardiac lymph and/or venous drainage.
tensive patients in whom left ventricular mass exceeds indi-
An abnormal increase of myocardial AnxA5 protein has
vidual needs to compensate haemodynamic load imposed by
been reported in the heart of guinea pigs made hypertensive
increased blood pressure and thus present inappropriate left
by stenosis of the abdominal aorta and in which LVH and left
ventricular mass, defined by a ratio of observed/predicted
ventricular dysfunction developed.29 Although the immuno-
left ventricular mass .135%.22 Plasma CT-1 concentration
histochemical study showed intense staining for AnxA5 at

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has been found to be higher in patients with inappropriate
the level of both cardiomyocytes and the interstitium in
left ventricular mass than in patients with appropriate left
hypertensive animals, AnxA5 was seen just within cardio-
ventricular mass.23 In addition, plasma CT-1 is directly corre-
myocytes in normotensive sham-operated animals. Of inter-
lated with the ratio of observed/predicted left ventricular
est, annexins A2 and A6 did not show this pattern of
mass in all patients. After treatment, plasma CT-1 decreases
interstitial accumulation in the left ventricle of hyperten-
and increases in patients in whom inappropriate left ventricu-
sive animals.
lar mass regresses and persists, respectively, despite a similar
The expression of AnxA5 has been shown to be also abnor-
reduction of blood pressure in the two subgroups of patients.
mally increased in the myocardium of hypertensive patients
Interestingly, abnormally high plasma CT-1 concentration is
with LVH exhibiting increased cardiomyocyte apoptosis,
associated with reduced fractional shortening and altered
namely in those with HF.30 The excess of myocardial AnxA5
relaxation in patients with inappropriate left ventricular
was associated with impairment of systolic function in HF
mass, suggesting that the cytokine can be one of the non-
patients.30 In comparison to normotensive subjects and
haemodynamic factors involved in both excessive growth
patients without LVH, AnxA5 was highly expressed in cardio-
and functional deterioration of the left ventricle in these
myocytes and the interstitium of both patients with LVH and
patients.
patients with HF. Upregulation and translocation from
Altogether, these findings support the notion that
cardiomyocytes to interstitial tissue of AnxA5, but not of
plasma CT-1 may be a potential biochemical marker of the
other annexin isoforms, has also been reported in the myo-
development, progression, and regression of cardiomyocyte-
cardium of patients with end-stage HF of non-hypertensive
dependent LVH in hypertensive patients.
origin.31,32 Collectively, the available data suggest that

Figure 2 (A) Changes in the circulating concentration of cardiotrophin-1 (CT-1) in hypertensive patients when compared with normotensive subjects. (B) Associ-
ation between CT-1 and left ventricular mass index (LVMI) in normotensive subjects and hypertensive patients. NT, normotensive subjects; HT, hypertensive
patients without left ventricular hypertrophy; LVH, hypertensive patients with left ventricular hypertrophy; HF, hypertensive patients with heart failure.
Results are shown as mean+SE. Adapted from González et al.,18 López et al.,19 and González et al.21
512
increased production of AnxA5 by the hypertensive myocar-
dium might contribute to further cardiomyocyte apoptosis
and dysfunction (Figure 1).
2.2.2 Plasma AnxA5 in hypertensive patients
Several findings support the potential usefulness of
measurement of plasma AnxA5 concentration to assess myo-
cardial AnxA5 abundance in humans.30 First, the finding that
there is a gradient of the plasma concentration of AnxA5
from the coronary blood to the peripheral blood suggests
that this protein is released from the heart through the coro-
nary sinus. Secondly, the highly significant correlation
observed between plasma concentration of AnxA5 in antecu-
bital vein blood and coronary sinus blood suggests that the
heart is, among other organs, an important source of circu-
lating AnxA5. Thirdly, the direct correlations found between
plasma and myocardial AnxA5 suggest that circulating AnxA5
may be a representative index of myocardial AnxA5 in these
patients. It is important to mention that the above findings
were reported in hypertensive patients free of coronary
artery disease after angiographic examination, thus the
potential origin of AnxA5 from coronary atherosclerotic
plaques was excluded.33
It has been reported that although plasma concentration
of AnxA5 was normal in patients without LVH, it was abnor-
mally high in patients with LVH (Figure 3A).30 In addition,
plasma AnxA5 concentration was higher in patients with
HF than in patients with LVH (Figure 3A). Interestingly,
plasma AnxA5 was directly correlated with left ventricular
end-diastolic diameter and inversely correlated with ejec-
tion fraction in the whole group of patients (Figure 3B).30
Therefore, these clinical findings support the notion that
plasma AnxA5 may be useful as a biochemical marker of
apoptosis-related cardiomyocyte dysfunction in hyperten-
sive patients.
3. Biochemical markers related
to the collagen matrix
3.1 Carboxy-terminal propeptide of procollagen
type I and myocardial fibrosis
3.1.1 Fundamental aspects
An exaggerated accumulation of collagen fibres, namely of
type I, within the myocardial interstitium and surrounding
intramural coronary arteries and arterioles has been
Figure 3 (A) Changes in the circulating concentration of annexin A5 (AnxA5) in hypertensive patients when compared with normotensive subjects. (B) Associ-
ation between AnxA5 and left ventricular ejection fraction (LVEF) in normotensive subjects and hypertensive patients. NT, normotensive subjects; HT, hyperten-
sive patients without left ventricular hypertrophy; LVH, hypertensive patients with left ventricular hypertrophy; HF, hypertensive patients with heart failure.
Results are shown as mean+SE. Adapted from Ravassa et al.30
A. González et al.
consistently found in a number of studies performed in post-
mortem human hearts and endomyocardial human biopsies
in patients with HHD.34 Myocardial fibrosis increases pro-
gressively in HHD, being higher in patients with LVH than
in patients without LVH and normotensive subjects, and
higher in patients with HF than in patients with LVH. Hyper-
tensive myocardial fibrosis is related to the predominance of
an exaggerated synthesis over an unchanged degradation of
collagen molecules, as a consequence of a number of pro-
cesses, mediated by mechanical and humoral mechanisms.35
The increase in collagen content increases myocardial stiff-
ness and promotes the onset of abnormalities in diastolic
function, as well as in the regulation of coronary reserve
and electrical activity in the hypertensive heart.34
An emerging experimental and clinical experience holds
promise for the determination of various serum peptides
derived from the metabolism of collagen type I in arterial
hypertension. More specifically, the serum concentration of
the carboxy-terminal propeptide of procollagen type I or
PICP (a peptide that is cleaved from procollagen type
I during the extracellular synthesis of fibril-forming collagen
type I by the enzyme procollagen type I carboxy-terminal
proteinase or PCPase, and which is released into the blood
stream with a stoichiometric ratio of 1:1) (Figure 4) has
been shown to be associated with the volume of myocardial
tissue occupied by collagen fibres in both SHR with LVH,36
and hypertensive patients with LVH.37,38 In addition, serum
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PICP concentration has been found to be associated with
the activation of the enzyme PCPase in the myocardium of
patients with HHD.39
3.1.2 Serum carboxy-terminal propeptide of procollagen
type I in hypertensive patients
Recently, we reported that the concentration of PICP was
significantly higher in blood from the coronary sinus than
in blood from the antecubital vein in patients with HHD,
but not in normotensive subjects.40 In addition, PICP
measured in blood from the antecubital vein was associated
with PICP measured in blood from the coronary sinus
and with the amount of collagen fibres present in the
myocardium. It is important to remark that none of these
findings has been reported for other collagen-derived
peptides than can also be measured in blood (i.e. the
amino-terminal propeptide of procollagen type I, and the
carboxy-terminal and the amino-terminal propeptides of
Biochemical markers in hypertension 513

Figure 4 Schematic representation of the different steps involved in the synthesis and degradation of collagen type I in the hypertensive myocardium. PICP,
carboxy-terminal propeptide of procollagen type I; PINP, amino-terminal propeptide of procollagen type I; MMP-1, matrix metalloproteinase-1; TIMP-1, tissue
inhibitor of matrix metalloproteinases-1; active MMP-1, MMP-1 not bound to TIMP-1.

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Figure 5 (A) Changes in the serum concentration of carboxy-terminal propeptide of procollagen type I (PICP) in hypertensive patients when compared with
normotensive subjects. (B) Parallel increases in the values of serum PICP and left ventricular stiffness constant (KLV) in hypertensive patients with heart
failure compared with hypertensives patients without heart failure. NT, normotensive subjects; HT, hypertensive patients without left ventricular hypertrophy;
LVH, hypertensive patients with left ventricular hypertrophy; HF, hypertensive patients with heart failure. Results are shown as mean+SE. Adapted from
Querejeta et al.,40 Dı́ez et al.,41 López et al.,43 and Müller-Brunotte et al.46

procollagen type III). Therefore, the available findings
suggest that just circulating PICP is a reliable index of the
extent and severity of fibrosis in the human hypertensive
myocardium.
We37–44 and others45–48 have reported that serum PICP
concentration is elevated in hypertensive patients when
compared with normotensive subjects. Interestingly, higher
serum PICP concentrations have been found in patients
with HF when compared with patients with LVH
(Figure 5A).40,48 However, no significant differences in
serum PICP have been found between patients with and
without LVH (Figure 5A).40,46,48 These findings indicate
that PICP may be useful to assess the severity of myocardial
fibrosis in HHD. In this regard, studies performed by our
group have determined that PICP presents 75% sensitivity
and 78% specificity to detect severe myocardial fibrosis in
hypertensive patients with LVH.37
It has also been shown that the variation in serum PICP
concentration induced by treatment is associated with par-
allel changes in the amount of myocardial fibrosis in
treated hypertensive patients. In fact, the values of PICP
and the volume of myocardial tissue occupied by collagen
fibres decrease in parallel in patients with LVH treated
with losartan,38,41 and in patients with HF treated with tor-
asemide.39,43 On the contrary, no changes in either serum
PICP concentration or myocardial collagen content were
observed in patients with LVH treated with amlodipine,38,41
and patients with HF treated with furosemide.39,43
An association has been reported between the serum con-
centrations of PICP and transforming growth factor-beta
(TGF-b) in patients with HHD before and after antihyperten-
sive treatment.44 Because TGF-b has been shown to upregu-
late PCPase expression and to stimulate its activity,49 it is
tempting to speculate that serum PICP may reflect the
514
myocardial profibrotic activity of the cytokine in patients
with HHD.
On the other hand, serum PICP concentration has been
found to be directly correlated with LVMI in hypertensive
patients.42,46 In addition, the increase of serum PICP paral-
lels the increase of left ventricular stiffness constant in
patients developing HF (Figure 5B),41 suggesting that the
compromise of diastolic function, likely secondary to an
exaggerated accumulation of collagen type I fibres within
the myocardium, may play a determinant role in the devel-
opment of HF in patients with HHD.
Collectively, these findings suggest that PICP provides
indirect diagnostic and therapeutic information regarding
the extent of collagen type I-dependent myocardial fibrosis
and the ability of pharmacological therapy to reduce it in
hypertensive patients.
3.2 Matrix metalloproteinase-1/tissue inhibitor
of metalloproteinases-1 balance and collagen
network disruption
3.2.1 Fundamental aspects
The collagen network (collagen associated with groups of
cardiomyocytes or perimysium, and collagen which surrounds
and interconnects individual cardiomyocytes or endomysium)
is responsible for providing the supportive scaffolding for car-
diomyocytes, but also serves to integrate the individual con-
tractions of these cells and provide a coordinated delivery of
force (pressure) to the left ventricular chamber for expulsion
of blood.50 Therefore, the loss or disruption of this collagen
network may compromise systolic function by three mechan-
isms.51,52 The first implies discontinuities in the mysial matrix
that provides support, geometric alignment, and coordi-
nation of adjacent cardiomyocyte fascicle contraction. The
second involves the loss of the normal collagen matrix-
basement membrane-integrin connections that contribute
to the synchrony and synergy of sarcomeres during the con-
tractile process. The third is related to sliding displacements
(slippage) of cardiomyocytes leading to a decrease in the
number of muscular layers in the ventricular wall and left
ventricular dilatation, which in turn impairs the working con-
ditions of the left ventricular myocardium.
The interaction between the enzyme matrix metallo-
proteinase-1 (MMP-1) or collagenase that initiates the
degradation of collagen fibres within the heart, and its
inhibitor tissue inhibitor of metalloproteinases-1 (TIMP-1)
Figure 6 (A) Changes in the values of the serum ratio of matrix metalloproteinase-1 to tissue inhibitor of matrix metalloproteinases-1 (MMP-1: TIMP-1) in hyper-
tensive patients when compared with normotensive subjects. (B) Parallel increases in the values of serum MMP-1: TIMP-1 and left ventricular end-diastolic
volume (LVEDV) in hypertensive patients with systolic heart failure compared with hypertensive patients with diastolic heart failure. NT, normotensive subjects;
HT, hypertensive patients without left ventricular hypertrophy; LVH, hypertensive patients with left ventricular hypertrophy; HF, hypertensive patients with
heart failure. Results are shown as mean+SE. Adapted from López et al.56 and Laviades et al.57
A. González et al.
is of critical relevance in the maintenance of the integrity
of the collagen network (Figure 4). A clear cause-and-effect
relationship between excessive myocardial MMP-1 activity,
increased mysial collagen degradation, and progression to
systolic HF has been shown experimentally through the use
of transgenic models and the use of pharmacological MMP
activators.53,54 In addition, experimental evidence has
been provided showing that following chronic neurohor-
monal activation, increased synthesis and release of MMPs
into the local extracellular matrix of the cardiomyocyte
occurs,55 which in turn could contribute to endomysial and
perimysial collagen degradation and disruption.
In this context, we have reported recently that the
volume of myocardial tissue occupied by perimysial and
endomysial collagen was lower in hypertensive patients
with HF and depressed ejection fraction (systolic HF), than
in hypertensive patients with HF and preserved ejection
fraction (diastolic HF) and normotensive subjects.56 Of
interest, the interstitial and perivascular accumulation
of collagen fibres was abnormally high in the two groups of
patients. Thus, myocardial fibrosis may coexist with disrup-
tion of the mysial collagen network in hypertensive patients
with systolic HF. The MMP-1 expression was increased in the
myocardium of systolic HF patients compared with diastolic
HF patients and normotensive subjects. In particular, cardio-
myocyte MMP-1 expression was higher in systolic HF patients
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than in the other two groups of subjects. No differences in
myocardial expression of TIMP-1 were observed among the
three groups of subjects. These findings suggest that exces-
sive MMP-1 dependent degradation of mysial collagen may
be related to the compromise of systolic function in HF
hypertensive patients.
3.2.2 Serum matrix metalloproteinase-1 and tissue
inhibitor of metalloproteinases-1 ratio in hypertensive
patients
The higher concentrations of MMP-1 and TIMP-1 in blood
from the coronary sinus blood vs. blood from the antecubital
vein blood, found in hypertensive patients but not in
normotensive subjects, and the correlations between their
antecubital vein and coronary sinus concentrations,56
suggest that circulating MMP-1 and TIMP-1 detected in HF
hypertensive patients may be of cardiac origin and that
the serum MMP-1:TIMP-1 ratio may be useful as an index
of the MMP-1/TIMP-1 balance within the myocardium.
Biochemical markers in hypertension
As shown in Figure 6A, although the serum MMP-1:TIMP-1
ratio is abnormally increased in patients with HF, it is abnor-
mally decreased in both patients without LVH and patients
with LVH.56,57 Furthermore, this ratio is higher in hyperten-
sive patients with systolic HF than in patients with diastolic
HF.56 In addition, the increase in serum MMP-1:TIMP-1 ratio
is associated with the decrease in ejection fraction and
with the increase in left ventricular end-diastolic volume
in patients with systolic HF compared with patients with
diastolic HF (Figure 6B).56 Therefore, the determination of
MMP-1 and TIMP-1 in serum might be a useful biochemical
marker of alterations in the perimysial and endomysial col-
lagen network involved in systolic deterioration and geo-
metric dilatation of the left ventricular chamber in
hypertensive patients with HF.
4. Future directions
4.1 Clinical integration
The pivotal criterion with regards to the potential clinical
value of a candidate biochemical marker for a given
disease is the consistency and strength of the association
between the biochemical marker and the outcome of the
disease, and the extent to which it is an improvement on
(either adding to or replacing) established tools [e.g. brain
natriuretic peptides (BNPs)].
In this conceptual framework, the studies here reviewed
have set the stage for larger on-going trials wherein
biochemical markers of myocardial remodelling could
prove to be definitively useful per se and when compared
with BNPs for the following aspects. First, early detection
of hypertensive patients at risk of developing LVH
(e.g. patients with high plasma levels of CT-1); secondly,
identification of hypertensive patients with LVH prone to
evolve to HF (e.g. patients with increased serum levels of
PICP); and thirdly, identification of hypertensive patients
with HF that will exhibit progressive deterioration of
cardiac pump performance (e.g. patients with enhanced
plasma AnxA5 and/or serum MMP-1:TIMP-1 ratio). Some of
these trials are currently ongoing. For instance, preliminary
data show that plasma CT-1 measurement provides
additional prognostic information to that of BNP and that
combined levels of CT-1 and BNP are more accurate at pre-
dicting mortality in patients with CHF than either marker
alone.58
Similarly, the potential usefulness of these biochemical
markers in other cardiac conditions different from HHD
Table 1 Reported data on biochemical markers of myocardial remodelling in cardiac diseases different from hypertensive heart disease
Cardiac disease Increase in plasma Increase in plasma
CT-1 AnxA5
Ischaemic heart disease 59–61 64,65
Dilated cardiomyopathy 62
Hypertrophic
cardiomyopathy
Diabetic cardiomyopathy
Aortic stenosis 63 64
CT-1, cardiotrophin-1; AnxA5, annexin A5; PICP, carboxy-terminal propeptide of procollagen type I; MMP-1:TIMP-1, ratio of matrix metalloproteinase-1 to
tissue inhibitor of metalloproteinases-1.
515
needs also to be investigated. Up to now, several promising
findings have been reported (Table 1).
4.2 Combination of biochemical
and imaging markers
Although circulating biochemical markers may offer the
advantage of availability, relative easy of collection and
storage, and lower cost, they may not prove as sensitive
as imaging markers in the detection or assessment of
disease. On the other hand, imaging technologies can
assess disease in human clinical trials with a high degree
of sensitivity and specificity but may be limited by technical
difficulty, availability, and cost. In this context, the combi-
nation of some of the biochemical markers here considered
and imaging markers have inherent advantages.
For example, an association between alterations in echor-
eflectivity, namely diminution in the cyclic variation of back-
scatter signal, and increase in fibrous tissue was shown in the
heart of hypertensive patients.77,78 Interestingly, an associ-
ation has been found between diminished cyclic variation of
backscatter and increased serum concentration of PICP in
hypertensive patients.47,79 In magnetic resonance imaging
studies, it has been shown that late gadolinium enhancement
has strong correlation with histologically assessed myocardial
fibrosis in patients with arrhythmogenic right ventricular car-
diomyopathy80 and hypertrophic cardiomyopathy.81 On the
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other hand, (99m)Tc-labelled AnxA5 has been successfully
used for the non-invasive detection of myocardial apoptosis
in patients with HF of non-hypertensive origin.82
4.3 Targeted therapy
A role might exist for biochemical markers in the monitoring
of therapy and tailoring of management for individuals. In
particular, the combination of biomarkers with clinical
phenotypes and genetic information can lead to a more
precise diagnosis and therapy on an individual basis. For
instance, based on various lines of evidence suggesting
that systemically and/or locally produced angiotensin II
may participate in the development of myocardial fibrosis
in HHD via activation of AT1 receptors, we investigated the
potential interaction of the A1166C polymorphism of the
AT1 receptor gene with PICP in patients with the clinical
phenotype of HHD.83 In the study, patients were studied
before and 1 year after treatment with either the AT1 recep-
tor blocker losartan or the beta-blocker atenolol. Baseline
PICP and LV chamber stiffness were significantly increased
in AA hypertensives compared with AC/CC hypertensives.
Increase in serum Increase in serum MMP-1:TIMP-1
PICP ratio
66–70 75,76
71 71
72,73
74
516
Table 2 New candidates for biochemical markers of
myocardial remodelling under investigation
Molecules related to cardiomyocyte injury
IL-6, IGF-1, LIF, oncostatin M, neuregulin
FAS, FAS-l, TNFa
Myosin light chain-1, H-FABP
Soluble ST2
Molecules related to extracellular matrix alteration
Osteopontin, thrombospondin
TGF-ß, CTGF
MMP-2, MMP-9, TIMP-4
Molecules related to inflammation and oxidative stress
IL-1a, MCP-1
MPO, SOD, nitrotyrosin, 8-OH-2deoxyguanosine
Molecules related to neurohormonal activation
Adrenomedullin, urodilatin
Neuropeptide Y
Soluble EGF receptor
Other molecules
CA 125
Urocortin
Soluble TNF receptor-1
Cystatin C
Confounding factors were similar in the two subgroups of
hypertensives. Administration of losartan was associated
with significant reduction in PICP and left ventricular
chamber stiffness in AA hypertensives but not AC/CC hyper-
tensives. Treatment with atenolol did not change these
two parameters in either subgroup of hypertensives. Blood
pressure was reduced to the same extent in the four sub-
groups with treatment. If these results were confirmed by
larger, prospective, double-blind studies, the combination
of the genotype of the A1166C polymorphism of the AT1
receptor gene with serum PICP levels could be a useful indi-
cator for antihypertensive drug strategy aimed to reduce
cardiac fibrosis and stiffness in patients with HHD.
4.4 Search of new biochemical markers of interest
The development of new biochemical markers of myocardial
remodelling can be thought of as consisting of two comp-
lementary approaches: the ‘knowledge-based’ and the
‘unbiased’. The knowledge-based approach relies on a direct
understanding of the biological mechanisms that underlie
the process of myocardial remodelling and its evolution to
HF. It may comprise designing assays for attractive new candi-
date molecules informed by the biology of the remodelling
process. In this regard, a number of candidates currently
under clinical investigation are presented in Table 2.
Proteomic analysis provides a unique opportunity to
perform the unbiased approach to identify new candidate
biomarkers for the diagnosis, staging, and tracking of HF.
Analysis of ventricular proteomic changes during the initial
inception, development, and progression to HF revealed
large-scale pattern differences.84 In terms of plasma, the
protein candidates are also consistent with the efforts of
the Human Proteomic Organisation (HUPO) to analyse the
human plasma subproteome systematically. Initial analysis
identified families of proteins involved in inflammation, sig-
nalling, growth and differentiation, cytoskeletal, channel/
receptors, and extracellular matrix turnover processes.85
A. González et al.
5. Conclusions
Large epidemiological and clinical studies will be required to
assess the cost-effectiveness of biochemical markers of
hypertensive myocardial remodelling here reviewed. Those
biochemical markers that perform well and cost-effectively
in the testing of rapid ‘rule out’ or ‘rule in’ strategies and
those that help to triage patients into low- and high-risk
treatment strategies will be integrated into clinical
decision-making protocols for hypertensive patients. In
addition, those biochemical markers of myocardial remodel-
ling that facilitate choice of the most appropriate drug and
that enable titration of drug dose to maximize therapeutic
anti-remodelling effects are likely to be attractive to clini-
cians attending hypertensive patients.
Funding
Part of this work was supported by the Network of Excel-
lence on Integrated Genomics, Clinical Research and Care
in Hypertension, Ingenious HyperCare, financed by the
European Commission (contract no. LSHM-CT-2006-037093).
Acknowledgements
The initiatives and clinical support of Dr Ramón Querejeta are
Downloaded from by guest on February 2, 2016
acknowledged, as well as the technical contribution of Sonia
Martı́nez, Marı́a González, and Laura Martı́nez.
Conflict of interest: none declared.
References
1. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from
hypertension to congestive heart failure. JAMA 1996;275:1557–1562.
2. Kannel WB, Levy D, Cupples LA. Left ventricular hypertrophy and risk of
cardiac failure: insights from the Framingham Study. J Cardiovasc
Pharmacol 1987;10(Suppl. 6):S135–S140.
3. Tocci G, Sciarretta S, Volpe M. Development of heart failure in recent
hypertension trials. J Hypertens 2008;26:1477–1486.
4. Dı́ez J, González A, López B, Querejeta R. Mechanisms of disease: patho-
logic structural remodelling is more than adaptive hypertrophy in hyper-
tensive heart disease. Nat Clin Pract Cardiovasc Med 2005;2:209–216.
5. Swynghedauw B. Molecular mechanisms of myocardial remodelling.
Physiol Rev 1999;79:215–262.
6. Vasan RS. Biomarkers of cardiovascular disease: molecular basis and prac-
tical considerations. Circulation 2006;113:2335–2362.
7. Morrow DA, de Lemos JA. Benchmarks for the assessment of novel cardi-
ovascular biomarkers. Circulation 2007;115:949–952.
8. Sadoshima J, Izumo S. The cellular and molecular response of cardiac
myocytes to mechanical stress. Annu Rev Physiol 1997;59:551–571.
9. Kuwahara K, Saito Y, Harada M, Ishikawa M, Ogawa E, Miyamoto Y et al.
Involvement of cardiotrophin-1 in cardiac myocyte-nonmyocyte inter-
actions during hypertrophy of rat cardiac myocytes in vitro. Circulation
1999;100:1116–1124.
10. Sano M, Fukuda K, Kodama H, Takahashi T, Kato T, Kahuno D et al.
Interleukin-6 family of cytokines causes angiotensin II-induced delayed
STAT3 activation. Biochem Biophys Res Commun 2000;269:798–802.
11. Pennica D, Wood WI, Chien KR. Cardiotrophin-1: a multifunctional cyto-
kine that signals via LIF receptor-gp 130 dependent pathways. Cytokine
Growth Factor Rev 1996;7:81–91.
12. López N, Dı́ez J, Fortuño MA. Differential hypertrophic effects of
cardiotrophin-1 on adult cardiomyocytes from normotensive and spon-
taneously hypertensive rats. J Mol Cell Cardiol 2006;41:902–913.
13. Zolk O, Engmann S, Münzel F, Krajcik R. Chronic cardiotrophin-1 stimu-
lation impairs contractile function in reconstituted heart tissue. Am J
Physiol Endocrinol Metab 2005;288:E1214–E1221.
14. Ishikawa M, Saito Y, Miyamoto Y, Kuwahara K, Ogawa E, Nakagawa O et al.
cDNA cloning of cardiotrophin-1 (CT-1): augmented expression of CT-1
Biochemical markers in hypertension
gene in ventricle of genetically hypertensive rats. Biochem Biophys Res
Commun 1996;219:377–381.
15. Ishikawa M, Saito Y, Miyamoto Y, Harada M, Kuwahara K, Ogawa E et al.
A heart-specific increase in cardiotrophin-1 gene expression precedes
the establishment of ventricular hypertrophy in genetically hypertensive
rats. J Hypertens 1999;17:807–816.
16. López N, Varo N, Dı́ez J, Fortuño MA. Loss of myocardial LIF receptor in
experimental heart failure reduces cardiotrophin-1 cytoprotection. A
role for neurohumoral agonists? Cardiovasc Res 2007;75:536–545.
17. Asai S, Saito Y, Kuwahara K, Mizuno Y, Yoshimura M, Higashikubo C et al.
The heart is a source of circulating cardiotrophin-1 in humans. Biochem
Biophys Res Commun 2000;279:320–323.
18. González A, Ravassa S, Loperena I, López B, Beaumont J, Querejeta R
et al. Association of depressed cardiac gp130-mediated antiapoptotic
pathways with stimulated cardiomyocyte apoptosis in hypertensive
patients with heart failure. J Hypertens 2007;25:2148–2157.
19. López B, González A, Lasarte JJ, Sarobe P, Borrás F, Dı́az A et al. Is plasma
cardiotrophin-1 a marker of hypertensive heart disease? J Hypertens
2005;23:625–632.
20. Pemberton CJ, Raudsepp SD, Yandle TG, Cameron VA, Richards AM.
Plasma cardiotrophin-1 is elevated in human hypertension and stimulated
by ventricular stretch. Cardiovasc Res 2005;68:109–117.
21. González A, López B, Martı́n-Raymondi D, Lozano E, Varo N, Barba J et al.
Usefulness of plasma cardiotrophin-1 in assessment of left ventricular
hypertrophy regression in hypertensive patients. J Hypertens 2005;23:
2297–2304.
22. de Simone G, Devereux RB, Kimball TR, Mureddu GF, Roman MJ,
Contaldo F et al. Interaction between body size and cardiac workload
influence on left ventricular mass during body growth and adulthood.
Hypertension 1998;31:1077–1082.
23. López B, Castellano JM, González A, Barba J, Dı́ez J. Association of
increased plasma cardiotrophin-1 with inappropriate left ventricular
mass in essential hypertension. Hypertension 2007;50:977–983.
24. González A, Fortuño MA, Querejeta R, Ravassa S, López B, López N et al.
Cardiomyocyte apoptosis in hypertensive cardiomyopathy. Cardiovasc
Res 2003;59:549–562.
25. Wang W, Xu J, Kirsch T. Annexin-mediated Ca2þ influx regulates growth
plate chondrocyte maturation and apoptosis. J Biol Chem 2003;278:
3762–3769.
26. Konishi Y, Sato H, Tanaka T. Anisomycin superinduces annexin V mRNA
expression through the ERK1/2 but not the p38 MAP kinase pathway.
Biochem Biophys Res Commun 2004;313:977–983.
27. Monceau V, Belikova Y, Kratassiouk G, Charue D, Camors E, Communal C
et al. Externalization of endogenous annexin A5 participates in apoptosis
of rat cardiomyocytes. Cardiovasc Res 2004;64:496–506.
28. Camors E, Monceau V, Charlemagne D. Annexins and Ca2þ handling in the
heart. Cardiovasc Res 2005;65:793–802.
29. Trouvé P, Legot S, Bélikova I, Marotte F, Bénévolensky D, Russo-Marie F
et al. Localization and quantitation of cardiac annexins II, V, and VI in
hypertensive guinea pigs. Am J Physiol 1999;276:H1159–H1166.
30. Ravassa S, González A, López B, Beaumont J, Querejeta R, Larman M
et al. Upregulation of myocardial Annexin A5 in hypertensive heart
disease: association with systolic dysfunction. Eur Heart J 2007;28:
2785–2791.
31. Benevolensky D, Belikova Y, Mohammadzadeh R, Trouvé P, Marotte F,
Russo-Marie F et al. Expression and localization of the annexins II, V,
and VI in myocardium from patients with end-stage heart failure. Lab
Invest 2000;80:123–133.
32. Song G, Campos B, Wagoner LE, Dedman JR, Walsh RA. Altered cardiac
annexin mRNA and protein levels in the left ventricle of patients with
end-stage heart failure. J Mol Cell Cardiol 1998;30:443–451.
33. Laufer EM, Reutelingsperger CP, Narula J, Hofstra L. Annexin A5: an
imaging biomarker of cardiovascular risk. Basic Res Cardiol 2008;103:
95–104.
34. Weber KT. Fibrosis and hypertensive heart disease. Curr Opin Cardiol
2000;15:264–272.
35. Dı́ez J. Mechanisms of cardiac fibrosis in hypertension. J Clin Hypertens
2007;9:546–550.
36. Dı́ez J, Panizo A, Gil MJ, Monreal I, Hernandez M, Pardo Mindan J. Serum
markers of collagen type I metabolism in spontaneously hypertensive
rats: relation to myocardial fibrosis. Circulation 1996;93:1026–1032.
37. Querejeta R, Varo N, López B, Larman M, Artiñano E, Etayo JC et al.
Serum carboxy-terminal propeptide procollagen type I is a marker of
myocardial fibrosis in hypertensive heart disease. Circulation 2000;
101:1729–1735.
517
38. López B, Querejeta R, Varo N, González A, Larman M, Martı́nez Ubago JL
et al. Usefulness of serum carboxy-terminal propeptide of procollagen
type I in assessment of the cardioreparative ability of antihypertensive
treatment in hypertensive patients. Circulation 2001;104:286–291.
39. López B, González A, Beaumont J, Querejeta R, Larman M, Dı́ez J. Identi-
fication of a potential cardiac antifibrotic mechanism of torasemide in
patients with chronic heart failure. J Am Coll Cardiol 2007;50:859–867.
40. Querejeta R, López B, González A, Sanchez E, Larman M, Martinez
Ubago JL et al. Increased collagen type I synthesis in patients with
heart failure of hypertensive origin. Relation to myocardial fibrosis.
Circulation 2004;110:1263–1268.
41. Dı́ez J, Querejeta R, López B, González A, Larman M, Martı́nez Ubago JL.
Losartan-dependent regression of myocardial fibrosis and improvement
of left ventricular chamber stiffness in hypertensive patients. Circulation
2002;105:2512–2517.
42. Dı́ez J, Laviades C, Mayor G, Gil MJ, Monreal I. Increased serum concen-
trations of procollagen peptides in essential hypertension. Relation to
cardiac alterations. Circulation 1995;91:1450–1456.
43. López B, Querejeta R, González A, Sánchez E, Larman M, Dı́ez J. Effects
of loop diuretics on myocardial fibrosis and collagen type I turnover in
chronic heart failure. J Am Coll Cardiol 2004;43:2028–2035.
44. Laviades C, Varo N, Dı́ez J. Transforming growth factor beta in hyperten-
sives with cardio-renal damage. Hypertension 2000;36:517–522.
45. McNulty, Mahmud A, Spiers P, Feely J. Collagen type-I degradation is
related to arterial stiffness in hypertensive and normotensive subjects.
J Hum Hypertens 2006;20:867–873.
46. Müller-Brunotte R, Kahan T, López B, Edner M, González A, Dı́ez J et al.
Myocardial fibrosis and diastolic dysfunction in patients with hiperten-
sión: results from Swedish Irbesartan Left Ventricular Hypertrophy Inves-
tigation versus Atenolol (SILVHIA). J Hypertens 2007;25:1958–1966.
47. Ling YH, Shiau YC, Yen RF, Lin LC, Wu CC, Ho YL et al. The relation
between myocardial cyclic variations of integrated backscatter and
Downloaded from by guest on February 2, 2016
serum concentrations of procollagen propeptides in hypertensives
patients. Ultrasound Med Biol 2004;30:885–891.
48. Martos R, Baugh J, Ledwige M, ÓLoughlin C, Conlon C, Patle A et al. Evi-
dence of increased myocardial collagen turnover linked to diastolic dys-
function. Circulation 2007;115:888–895.
49. Lee S, Solow-Cordero DE, Kessler E, Takahara K, Greenspan DS.
Transforming growth factor-b regulation of bone morphogenetic
protein-1/procollagen C-proteinase and related proteins in fibrogenic
cells and keratinocytes. J Biol Chem 1997;272:19059–19066.
50. Weber KT, Sun Y, Tyagi SC, Cleutjens JP. Collagen network of the myocar-
dium: function, structural remodelling and regulatory mechanisms. J Mol
Cell Cardiol 1994;26:279–292.
51. Janicki JS, Brower GL. The role of myocardial fibrillar collagen in ventri-
cular remodelling and function. J Card Fail 2002;8(suppl.):S319–S325.
52. Linzbach AJ. Hypertrophy, hyperplasia and structural dilatation of the
human heart. Adv Cardiol 1976;18:1–14.
53. Baicu CF, Stroud JD, Livesay VA, Hapke E, Holder J, Spinale FG et al.
Changes in extracellular collagen matrix alter myocardial systolic per-
formance. Am J Physiol Heart Circ Physiol 2003;284:H122–H132.
54. Kim HE, Dalal SS, Young E, Legato MJ, Weisfeldt ML, D’Armiento J. Disrup-
tion of the myocardial extracellular matrix leads to cardiac dysfunction.
J Clin Invest 2000;106:857–866.
55. Coker ML, Doscher MA, Thomas CV, Galis ZS, Spinale FG. Matrix metallo-
proteinase synthesis and expression in isolated LV myocyte preparations.
Am J Physiol Heart Circ Physiol 1999;277:H777–H787.
56. López B, González A, Querejeta R, Larman M, Dı́ez J. Alterations in the
pattern of collagen deposition may contribute to the deterioration of sys-
tolic function in hypertensive patients with heart failure. J Am Coll
Cardiol 2006;48:89–96.
57. Laviades C, Varo N, Fernández J, Mayor G, Gil MJ, Monreal I et al.
Abnormalities of the extracellular degradation of collagen type I in essen-
tial hypertension. Circulation 1998;98:535–540.
58. Tsutamoto T, Asai S, Tanaka T, Sakai H, Nishiyama K, Fujii M et al. Plasma
level of cardiotrophin-1 as a prognostic predictor in patients with chronic
heart failure. Eur J Heart Fail 2007;9:1032–1037.
59. Talwar S, Squire IB, Downie PF, Davies JE, Ng LL. Plasma N terminal pro-
brain natriuretic peptide and cardiotrophin 1 are raised in unstable
angina. Heart 2000;84:421–424.
60. Talwar S, Squire IB, O’Brien RJ, Downie PF, Davies JE, Ng LL. Plasma
cardiotrophin-1 following acute myocardial infarction: relationship with
left ventricular systolic dysfunction. Clin Sci (Lond) 2002;102:9–14.
61. Khan SQ, Kelly D, Quinn P, Davies JE, Ng LL. Cardiotrophin-1 predicts
death or heart failure following acute myocardial infarction. J Card
Fail 2006;12:635–640.
518
62. Tsutamoto T, Wada A, Maeda K, Mabuchi N, Hayashi M, Tsutsui T et al.
Relationship between plasma level of cardiotrophin-1 and left ventricular
mass index in patients with dilated cardiomyopathy. J Am Coll Cardiol
2001;38:1485–1490.
63. Talwar S, Downie PF, Squire IB, Davies JE, Barnett DB, Ng LL. Plasma
N-terminal pro BNP and cardiotrophin-1 are elevated in aortic stenosis.
Eur J Heart Fail 2001;3:15–19.
64. Kaneko N, Matsuda R, Hosoda S, Kajita T, Ohta Y. Measurement of plasma
annexin V by ELISA in the early detection of acute myocardial infarction.
Clin Chim Acta 1996;251:65–80.
65. Matsuda R, Kaneko N, Kikuchi M, Chiwaki F, Toda M, Ieiri T et al. Clinical
significance of measurement of plasma annexin V concentration of
patients in the emergency room. Resuscitation 2003;57:171–177.
66. Takino T, Nakamura M, Hiramori K. Circulating levels of carboxyterminal
propeptide of type I procollagen and left ventricular remodelling after
myocardial infarction. Cardiology 1999;91:81–86.
67. Poulsen SH, Høst NB, Egstrup K. Long-term changes in collagen formation
expressed by serum carboxyterminal propeptide of type-I procollagen
and relation to left ventricular function after acute myocardial infarc-
tion. Cardiology 2001;96:45–50.
68. Cerisano G, Pucci PD, Sulla A, Tommasi M, Raspanti S, Santoro GM et al.
Relation between plasma brain natriuretic peptide, serum indexes of
collagen type I turnover, and left ventricular remodelling after reper-
fused acute myocardial infarction. Am J Cardiol 2007;99:651–656.
69. McGavigan AD, Maxwell PR, Dunn FG. Serological evidence of altered col-
lagen homeostasis reflects early ventricular remodelling following acute
myocardial infarction. Int J Cardiol 2006;111:267–274.
70. Murakami T, Kusachi S, Murakami M, Sano I, Uesugi T, Hirami R et al.
Time-dependent changes of serum carboxy-terminal peptide of type I
procollagen and carboxy-terminal telopeptide of type I collagen concen-
trations in patients with acute myocardial infarction after successful
reperfusion: correlation with left ventricular volume indices. Clin Chem
1998;44:2453–2461.
71. Schwartzkopff B, Fassbach M, Pelzer B, Brehm M, Strauer BE. Elevated
serum markers of collagen degradation in patients with mild to moderate
dilated cardiomyopathy. Eur J Heart Fail 2002;4:439–444.
72. Fassbach M, Schwartzkopff B. Elevated serum markers for collagen
synthesis in patients with hypertrophic cardiomyopathy and diastolic
dysfunction. Z Kardiol 2005;94:328–335.
73. Lombardi R, Betocchi S, Losi MA, Tocchetti CG, Aversa M, Miranda M et al.
Myocardial collagen turnover in hypertrophic cardiomyopathy. Circula-
tion 2003;108:1455–1460.
A. González et al.
74. Ihm SH, Youn HJ, Shin DI, Jang SW, Park CS, Kim PJ et al. Serum carboxy-
terminal propeptide of type I procollagen (PIP) is a marker of diastolic
dysfunction in patients with early type 2 diabetes mellitus. Int J
Cardiol 2007;122:e36–e38.
75. Papadopoulos DP, Moyssakis I, Makris TK, Poulakou M, Stavroulakis G,
Perrea D et al. Clinical significance of matrix metalloproteinases activity
in acute myocardial infarction. Eur Cytokine Netw 2005;16:152–160.
76. Ueshima K, Shibata M, Suzuki T, Endo S, Hiramori K. Extracellular matrix
disturbances in acute myocardial infarction: relation between disease
severity and matrix metalloproteinase-1, and effects of magnesium pre-
treatment on reperfusion injury. Magnes Res 2003;16:120–126.
77. Picano E, Pelosi G, Marzilli M, Lattanzi F, Benassi A, Landini L et al. In vivo
quantitative ultrasonic evaluation of myocardial fibrosis in humans.
Circulation 1990;81:58–64.
78. Ciulla M, Paliotti R, Hess DB, Tjahja E, Campbell SE, Magrini F et al. Echo-
cardiographic patterns of myocardial fibrosis in hypertensive patients:
Endomyocardial biopsy versus ultrasonic tissue characterization. J Am
Soc Echocardiogr 1997;10:657–664.
79. Maceira AM, Barba J, Varo N, Beloqui O, Dı́ez J. Ultrasonic backscatter
and serum marker of cardiac fibrosis in hypertensives. Hypertension
2002;39:923–928.
80. Tandri H, Saranathan M, Rodriguez ER, Martinez C, Bomma C, Nasir K
et al. Noninvasive detection of myocardial fibrosis in arrhythmogenic
right ventricular cardiomyopathy using delayed-enhancement magnetic
resonance imaging. J Am Coll Cardiol 2005;45:98–103.
81. Moon JC, Reed E, Sheppard MN, Elkington AG, Ho SY, Burke M et al. The
histologic basis of late gadolinium enhancement cardiovascular magnetic
resonance in hypertrophic cardiomyopathy. J Am Coll Cardiol 2004;43:
2260–2264.
82. Kietselaer BL, Reutelingsperger CP, Boersma HH, Heidendal GA, Liem IH,
Crijns HJ et al. Noninvasive detection of programmed cell loss with
99mTc-labeled annexin A5 in heart failure. J Nucl Med 2007;48:562–567.
Downloaded from by guest on February 2, 2016
83. Dı́ez J, Laviades C, Orbe J, Zalba G, López B, González A et al. The
A1166C polymorphism of the AT1 receptor gene is associated with col-
lagen type I synthesis and myocardial stiffness in hypertensives.
J Hypertens 2003;21:2085–2092.
84. Arab S, Gramolini AO, Ping P, Kislinger T, Stanley B, van Eyk J et al. Car-
diovascular proteomics: tools to develop novel biomarkers and potential
applications. J Am Coll Cardiol 2006;48:1733–1741.
85. Berhane BT, Zong C, Liem DA, Huang A, Le S, Edmondson RD et al.
Cardiovascular-related proteins identified in human plasma by the
HUPO Plasma Proteome Project pilot phase. Proteomics 2005;5:
3520–3530.