Review
An update on biomarkers of heart failure in
hypertensive patients
Anna Gluba a, Agata Bielecka b, Dimitri P. Mikhailidis c, Nathan D. Wong d, Stanley S. Franklin d,
Jacek Rysz a, and Maciej Banach b
Biomarkers should have high sensitivity, specificity,
reproducibility, be cost-effective, and provide incremental
predictive or diagnostic utility over standard risk factors or
tests. Despite numerous studies investigating biomarkers in
heart failure (HF), there are only a few that predict HF in
hypertensive patients. This article summarizes data from
numerous studies concerning possible biomarkers of HF in
hypertensive patients such as: serum uric acid (SUA),
interleukins, monocyte chemoattractant protein one (MCP-
1), cardiotrophin-1 (CT-1), carboxy-terminal propeptide of
procollagen type I (PICP), type I collagen telopeptide (CITP)
and N-terminal propeptide of type III procollagen (PIIINP),
metalloproteinases (MMPs), B-type natriuretic peptide
(BNP) and its derivatives, glycoprotein CA125 and cystatin
C. Early detection of patients of increased risk of
hypertensive heart disease may result in early
implementation of effective preventive strategies.
Therefore, there is need to identify newer biomarkers, if
they can improve risk prediction, identifying patients, in
which earlier or more aggressive intervention will improve
clinical outcomes.
Keywords: biomarkers, blood pressure, diagnosis, heart
failure, hypertension
Abbreviations: BNP, B-type natriuretic peptide; PICP,
carboxy-terminal propeptide of procollagen type I; CT-1,
cardiotrophin-1; CV, cardiovascular; CHF, chronic heart
failure; CAD, coronary artery disease; CRP, C-reactive
protein; CysC, cystatin C; GFR, glomerular filtration rate;
HF, heart failure; IL, interleukin; LV, left ventricular; LDL-C,
low density lipoprotein cholesterol; MMPs,
metalloproteinases; MCP-1, monocyte chemoattractant
protein 1; MPO, myeloperoxidase; NO, nitric oxide; PIIINP,
N-terminal propeptide of type III procollagen; RAA, renin-
angiotensin-aldosterone; SUA, serum uric acid; sICAM-1,
soluble intercellular adhesion molecule-1; SHR,
spontaneously hypertensive rats; TIMP-1, tissue inhibitor of
metalloproteinase-1; TGF, transforming growth factor;
TNF, tumor necrosis factor-a; CITP, type I collagen
telopeptide; XO, xanthine oxidase
INTRODUCTION
B
iomarkers can be valuable diagnostic and prognos-
tic tools. According to the recommendations of
Biomarkers Definitions Working Group (2001), a
Journal of Hypertension
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
biological marker (biomarker) should be: an indicator of
normal biologic processes, pathogenic processes, or
pharmacologic responses to a therapeutic intervention that
can be objectively measured and evaluated, represent a
feature or variable which measures how a patient feels,
functions or survives and substitute for a clinical endpoint
[1,2]. Therefore, the ideal biomarker would have high
sensitivity, specificity and reproducibility. It would also
provide incremental prediction for clinical outcomes and
improved clinical utility over demographic characteristics
and typically performed clinical tests and risk factor assess-
ments. It should also be technically convenient and cost
effective [3]. New biomarkers are continually emerging but
their use may be limited. There have also been attempts to
pool several biomarkers together creating multiple bio-
marker indices to increase their predictive strength.
Although there are numerous studies investigating bio-
markers in heart failure (HF), there are relatively few that
relate these markers to HF in hypertensive patients. This is
vital as hypertension is considered to be one of the main
predictors of HF. Prolonged hypertension has been shown
to cause left ventricular structural remodeling, cardiac
function alterations and chronic heart failure (CHF) [46].
Prognosis in HF is very poor. The average 4-year survival
rate is only about 50%, and in patients with the most
advanced HF 1-year survival rate is only less than 50%
[4]. This prognosis is similar, or worse, than that of
advanced cancer [3,4].
Numerous studies [710] revealed that echocardiograph-
ically confirmed left ventricular hypertrophy (LVH) is a
powerful, predictive independent risk factor of future car-
diovascular (CV) morbidity and mortality in patients with
uncomplicated essential hypertension [1113]. According
to Koren et al. [8] LVH and age are the best independent
Journal of Hypertension 2012, 30:16811689
a
Department of Nephrology, Hypertension and Family Medicine, bDepartment of
Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz,
Poland, cDepartment of Clinical Biochemistry, Royal Free Campus, University College
London Medical School, University College London (UCL), London, UK and dDepart-
Department of Medicine, University of CA, Irvine, California, USA
Correspondence to Maciej Banach, MD, PhD, FAHA, FESC; FASA, FRSPH, Head,
Department of Hypertension, WAM University Hospital in Lodz, Medical University of
Lodz, Poland. Zeromskiego 113; 90549 Lodz, Poland. Tel: +48 42 639 37 71; fax:
+48 42 639 37 82; e-mail: maciejbanach@aol.co.uk
Received 25 December 2011 Revised 14 April 2012 Accepted 4 June 2012
J Hypertens 30:16811689 2012 Wolters Kluwer Health | Lippincott Williams &
Wilkins.
DOI:10.1097/HJH.0b013e3283569a9c
www.jhypertension.com 1681
Gluba et al.
predictors of CV events or CV death in patients with
hypertension. These data underline the importance of
introducing optimal early treatment of hypertension and
symptomatic treatment of HF in its early stages in order to
prevent the progression towards advanced disease. Quan-
titative assessment of risk in hypertensive patients must
include the search for subclinical organ damage, as under-
lined in the recent guidelines of the European Society of
Hypertension (ESH) [14]. In clinical practice, patients with
well controlled hypertension may report exercise limitation
and/or stenocardial pain, which is not reflected by a normal
standard resting echocardiograph. Often there are no signs
of coronary artery disease (CAD) on an electrocardio-
graphic stress test with no change in epicardial coronary
vessels on coronary angiography [14,15]. Therefore, it is
important to establish a panel of diagnostic tests in patients
with hypertension to enable the early detection of abnor-
malities before the occurrence of symptoms and thus allow
the implementation of optimal treatment.
The biomarkers presented in the article were selected
on the basis of the most recent data suggesting their
potentially utility in diagnosis of left ventricular dysfunction
in patients with hypertension, on their novelty and pre-
dictable properties.
SEARCH STRATEGY
We searched using electronic databases [MEDLINE (1966
December 2011), EMBASE and SCOPUS (1965 December
2011), DARE (1966 December 2011)]. Additionally,
abstracts from national and international CV meetings were
searched. When necessary, the relevant authors were con-
tacted to obtain further data. The main data search terms
were: biomarker(s), blood pressure (BP), diagnosis, HF,
hypertension and marker(s).
SERUM URIC ACID
Hyperuricaemia is an independent prognostic marker for
mortality and morbidity in chronic and acute heart failure
(AHF) [1618]. Twenty-five to forty percent of patients with
untreated hypertension and more than 80% of patients with
malignant hypertension have high SUA levels [19,20]. Kur-
ata et al. [11] demonstrated that in male hypertensive
patients echocardiographic left ventricular mass positively
significantly correlated with SUA levels. When these
patients were classified on the basis of their pattern of left
ventricular geometry, it turned out that the highest SUA
levels were observed in patients with concentric hyper-
trophy [11]. Epidemiological studies that revealed the
association between SUA and CV risk [20,21], came as
something of a surprise as SUA is a powerful antioxidant.
SUA protects against free radical damage by reacting with a
variety of oxidants and prevents both the formation of
peroxynitrite and the inactivation of the nitric oxide
(NO) by superoxide anions [20]. It has been suggested that
SUA, which acts as an antioxidant under normal physio-
logical conditions, in atherosclerotic state exerts deleterious
effects which include: endothelial dysfunction, prolifer-
ation of vascular smooth muscle cells, increases in platelet
adhesiveness, oxidation of low-density lipoprotein
1682 www.jhypertension.com
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cholesterol (LDL-C) and lipid peroxidation [20,22]. Among
patients with CHF, SUA concentrations are also associated
with greater activity of superoxide dismutase and endo-
thelium-dependent vasodilatation [23]. Both LVH and elev-
ated SUA in hypertensive patients may indicate preclinical
CV disease, which could potentially be reversed using
effective therapeutic interventions [24,25]. In the Losartan
Intervention For Endpoint reduction in hypertension (LIFE)
study SUA as a time-varying covariate was significantly
associated with increased risk of the composite endpoint
of (P < 0.0001) [25]. In women, the baseline SUA concen-
tration was strongly related to the composite endpoint,
even after adjustment for other CV risk factors [25]. How-
ever, in men, there was only a weak association when
established risk factors were considered separately [25].
Losartan significantly attenuated the increase in SUA, which
was associated with a reduction in the risk of the primary
composite endpoint by 29% (P 0.004) [25]. The LIFE study
revealed for the first time, that reduction of SUA had
beneficial effects on hypertension treatment outcome
[25]. The Samuelsson et al. [26] study was another one that
demonstrated that hyperuricemia can predict HF among
those with preexisting hypertension [26]. However, accord-
ing to Ekundayo et al. [27], the association between hyper-
uricemia and coexisting HF was significant only in patients
without hypertension [hazard ratio 1.31; 95% confidence
interval (CI): 1.031.66; P 0.03] [27].
Several mechanisms have been proposed to explain how
SUA affects CV risk. It has been suggested that SUA values
may reflect a decreased glomerular filtration rate (GFR) and
thus be a marker of CV risk [25]. However, following the
adjustment for renal function indices, SUA remained a
predictor of CV events in the LIFE study suggesting a
different mechanism [25]. High levels of SUA, in humans,
positively correlate with plasma renin activity in hyper-
tensive patients [28], which suggests that adverse effects
of SUA on the CV system could be mediated by renin
angiotensinaldosterone (RAA) system activation [25,28].
Hyperuricemia-induced HF may be also associated with
increased SUA production probably due to increased levels
of xanthine oxidase (XO) substrate and an upregulation of,
and increase in XO activity [17,19]. The inhibition of XO
enzyme by allopurinol exerts beneficial effects in terms of
improved peripheral vasodilator capacity, systemic blood
flow and clinical outcomes [29,30].
SUA can produce additional adverse effects on the CV
system and can mediate the immune response [17,19,31].
Hyperuricemia in patients with HF is associated with higher
levels of serum markers of inflammation [C-reactive protein
(CRP), interleukin (IL)-6, and neutrophil count] [32], and
higher levels of markers of endothelial activation [soluble
intercellular adhesion molecule-1 (sICAM-1)], and raised
inflammatory markers [IL-6, tumor necrosis factor (TNF)-a,
and its receptors] [18,25,29,3346] (Table 1).
INTERLEUKINS AND MONOCYTE
CHEMOATTRACTANT PROTEIN-1
Various inflammatory biomarkers serve as predictors of
long-term outcomes in patients with acute and chronic
HF [47]. Elevations in inflammatory markers, not observed
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 An update on biomarkers of heart failure in hypertensive patients

TABLE 1. Summary of biomarker utility in the prediction of heart failure in hypertensive patients
Biomarker name Biomarker utility
SUA Independent prognostic marker of mortality and morbidity
in chronic and acute HF. Best survival is observed in
patients with normal SUA.
Baseline SUA significantly associated with increased
CV events.
ILs and MPC-1 Significantly elevated IL-6, MCP1 and IL-8 levels in
hypertensive patients with symptoms of HF.
Cardiotrophin-1 Independent association between progressive increase of
plasma CT-1 and progressive LV growth and dysfunction
in hypertensive patients.
Plasma cardiotrophin-1 directly and inversely correlated
with LV mass index and EF.
Plasma CT-1 a good diagnostic tool for HF with 95%
sensitivity and 82.5% specificity.
Cardiotrophin-1 higher in patients with severe LVH than in
patients with mild to moderate LVH; Direct correlations
between CT-1 and maximal LV wall thickness.
PICP, CITP and PIIINP Plasma PIIINP level significantly increases in NYHA classes III
and IV; CITP level increases and PIP/CITP ratio is decreased
in the NYHA IV hypertensive patients.
CITP may be useful in screening for severe myocardial
fibrosis in patients with hypertension.
MMPs Haplotype of MMP-2 modulates left ventricular remodeling
in hypertensive patients.
MMPs Significant elevations of MMP2 and MMP9 levels are seen
together with HF symptoms. Patients with HF-PEF had
significant elevations in MMP2 and MMP9 in comparison
to those with AH.
Elevated MMP9/TIMP1 ratios are associated with left atrial
remodeling in patients with more advanced hypertensive
heart disease.
BNP and derivatives BNP levels may identify hypertensive patients who are
likely to have progressive cardiac hypertrophy.
N-terminal pro-brain natriuretic peptide is independently
associated with LV mass index especially with eccentric
hypertrophy.
In elderly hypertensive patients with left ventricular
hypertrophy elevated BNP is associated with a higher
incidence of cardiovascular events at follow-up.
CysC Elevated CysC level is an independent risk factor for
increased mortality in elderly patients with HF.
Detailed data and level of significance Ref.
SUA (400 mmol/l) (at 12 months, 93%) in comparison [18]
to patients with UA 401600 mmol/l (87%, RR 1.76
[1.112.78]), patients with SUA 601800 mmol/l
(54%, RR 6.27 [3.7310.54]), and patients with
UA > 800 mmol/l (17%, RR 18.53 [9.1837.42]).
(HR) 1.024 (95% CI 1.0171.032) per 10 mmol/l, [25]
P < 0.0001
[37]
P < 0.001 [38]
r 0.416, P < 0.001 r 0.263, P < 0.01 [38]
[39]
P 0.02; s 0.284, P 0.001 [40]
[41]
78% specificity and 75% sensitivity for predicting [42]
severe fibrosis with RR 4.80 (95% CI, 1.1919.30).
[43]
AH 1.5 ng/ml (1.3 : 2.1) vs. HF-PEF 2.0 (1.3 : 3.2) for [37]
MMP-2 (P < 0.001) and AH 96 ng/ml (40 : 205) vs.
HF-PEF 233 (67 : 642) (P < 0.001). Values are
presented as median (10th: 90th percentile).
[37]
Left ventricular mid-wall systolic function decreases [45]
significantly at follow-up in patients with elevated
BNP levels (P < 0.05 vs. baseline), only initial
plasma BNP is significantly (P < 0.01) associated
with subsequent left ventricular hypertrophy.
(b  SE 0.07  0.01 pg/ml; P < 0.0001). [45]
The highest correlation between BNP and incident [44]
cardiovascular events (risk ratio 1.011; P 0.0011).
Each standard deviation increase in CysC (0.35 mg/l) [46]
is associated with a 31% greater adjusted mortality
risk (95% CI 2043%, P < 0.001).

AH, asymptomatic hypertension; BNP, brain natriuretic peptide; CITP, carboxy-terminal telopeptide of collagen type 1; CT-1, cardiotrophon-1; CV, cardiovascular; CysC, cystatin C; HF,
heart failure; HF-PEF, heart failure with preserved ejection fraction; IL, interleukin; LV, left ventricle; MMPs, metalloproteinases; MPC-1, monocyte chemoattractant protein-1; NYHA,
New York Heart Association; PICP, procollagen I carboxy-terminal propeptide; PIIINP, procollagen type III n-peptide; SUA, serum uric acid; TIMP-1, tissue inhibitor of metalloproteinase 1;
b  SE, standardized beta-coefficient (per 1 SD increase in the levels of biomarker).

in isolated hypertension, become evident in the presence of
target organ damage [37,48,49]. Collier et al. [37] reported
significantly elevated IL-6, MCP-1 and IL-8 levels in hyper-
tensive patients with symptoms of HF. IL-6 level seemed to
be associated with cardiomyocyte hypoxic stress, target
organ damage and an increase in major adverse CV event
rate [37,50]. Release of MCP-1 results in macrophage infil-
tration of cardiac myocytes, induction of transforming
growth factor (TGF) b as well as the development of
reactive fibrosis and diastolic dysfunction [37,51]. IL-4 has
been suggested as another marker of HF. It is an anti-
inflammatory cytokine and inhibits the production of
inflammatory cytokines as well as activating the synthesis
of collagen type I and III [52]. Rosello-Llet E et al. [52]
observed higher concentrations of IL-4 and N-terminal
propeptide of type III procollagen (PIIINP) in patients with
hypertensive cardiomyopathy. Moreover, they noted a sig-
nificant positive correlation between IL-4 and PIIINP in
patients with CHF, especially those with hypertensive
cardiomyopathy (r 0.7, P < 0.01) [52]. This was probably
due to an increased profibrotic activity in these patients
[52,53].
Raised levels of hsCRP and myeloperoxidase (MPO)
have been suggested as markers of HF in hypertensive
patients [47]. Although a lack of significant correlation
between log-transformed hsCRP and MPO were observed,
combined analysis of these two parameters revealed a six-
fold increased risk of HF (95% CI: 2.416.8; P < 0.01) when
both markers were elevated [47]. According to the authors,
concurrent hsCRP and MPO measurements may be of
distinct and complementary prognostic value in patients
with chronic systolic HF [47,54] (Table 1).

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Gluba et al.
CARDIOTROPHIN-1
It has been hypothesized that a chronic rise in CT-1 levels
may be associated with a progression to HF in patients with
hypertension [38]. CT-1, which is a member of the IL-6
superfamily of cytokines, was originally considered to
affect cardiomyocyte hypertrophy and survival [38,55,56].
It exerts its cellular actions via the heterodimer comprising
the glycoprotein 130 (gp130) and the leukemia inhibitory
factor receptor b (LIFR) [57]. It has been observed that
ventricular CT-1 mRNA correlates with LVH what suggests
that CT-1 plays an important role in the structural remodel-
ing of heart [58]. The hypertrophy of the left ventricle (LV) is
a compensatory mechanism, which helps the hemodynami-
cally overloaded myocardium to maintain normal left ven-
tricular function in systemic arterial hypertension [59,60].
Adaptive growth of cardiomyocytes in LVH is a result of cell
response to mechanical stretch as well as the activation of
pressure overload-induced humoral growth factors [59,60].
Experimental studies revealed that CT-1 may contribute to
cardiomyocyte hypertrophy and left ventricular growth in
spontaneously hypertensive rats (SHR) [61]. However,
according to some other studies CT-1 is unlikely to play
a mechanistic role in the development and maintenance of
LVH in rats [57,6264].
The study of Lopez et al. [38] confirmed the independent
association between progressive increase of plasma CT-1
and progressive left ventricular growth and dysfunction in
hypertensive patients. They observed the decrease in
plasma CT-1 level in patients with never-treated hyperten-
sion after the implementation of appropriate treatment
which resulted in left ventricular mass regression. However,
the increase of CT-1 was observed in patients with unal-
tered left ventricular mass despite a similar reduction of BP
in these two groups of patients. These results suggest that
increased level of CT-1 may contribute to inappropriate left
ventricular growth in hypertensive patients [38,64,65,66].
Also, CT-1 levels have been shown to be increased in the
myocardium and plasma of hypertensive patients with HF
compared with those without HF [38,67]. Raised CT-1
plasma levels have been associated with the progression
of HF in patients with hypertension [68]. CT-1 plasma levels
progressively increased (P < 0.001) along with the pro-
gression of HF stages in hypertensive patients [68]. Plasma
CT-1 was directly correlated with LV mass index (LVMI)
(r 0.416, P < 0.001) and inversely correlated with left
ventricular ejection fraction (LVEF) (r 0.263, P < 0.01)
[68]. According to Lopez et al. [38] increased plasma levels
of CT-1 observed in stage C HF in hypertensive patients may
mirror cardiac overspilling of this cytokine and that the
mineralocorticoid pathway may be involved in CT-1 over-
production. The latter hypothesis has been supported by
preliminary data from animal study, which demonstrated
that aldosterone induced CT-1 expression in isolated rat
cardiomyocytes via genomic (transcriptional) and nonge-
nomic (nontranscriptional) signaling mechanisms [69]. It
was also suggested that an excess of CT-1 might contribute
to HF via gp130 receptor downregulation and subsequent
gp130-mediated survival pathway inhibition [38,67]. On
the contrary, it was demonstrated that excessive CT-1
signaling was efficiently attenuated by negative feedback
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mechanisms, which included gp130 receptor internaliz-
ation and degradation and induction of intrinsic suppressor
of cytokine signaling (SOCS) proteins, such as SOCS-3 [70].
According to the study of Liao et al. [39] plasma CT-1 is a
good diagnostic tool for HF with a sensitivity and specificity
of 95 and 82.5%, respectively.
CT-1 has lower specificity than N-terminal pro-B-type
natriuretic peptide (NT-proBNP), but is more sensitive in
detecting stage C HF in hypertensive patients [38]. How-
ever, it seems that simultaneous determination of serum
NT-proBNP and plasma CT-1 may increase the ability to
detect stage C HF among hypertensive patients. Increased
CT-1 was found to be associated with echocardiographi-
cally assessed left ventricular growth and dysfunction
whereas increased NT-proBNP was related to reduced
GFR [38,40] (Table 1).
FIBROSIS BIOMARKERS
Inflammatory fibrosis present in myocarditis and CHF is
characterized by fibroblastic overproduction and depo-
sition of collagen [50,51]. A cross-sectional study [41] dem-
onstrated that the progressive deterioration of cardiac
function in hypertensive patients with HF was associated
with changes in the level of serological markers of fibrosis.
The level of plasma PIIINP was significantly increased in
New York Heart Association (NYHA) classes III and IV as
well as in the upper LVMI tertile in hypertensive patients
indicating enhanced collagens synthesis [41]. It was also
observed that levels of type I collagen telopeptide (CITP)
were increased whereas procollagen type I (PIP) /CITP
ratio was decreased, all of which might imply that collagen I
catabolism was the predominant process [41]. However, the
change in levels of the serological markers of collagen
synthesis and degradation was not observed in NYHA
classes I and II [41]. This might be explained by an over-
lapping effect of other factors influencing extracellular
matrix turnover, especially metalloproteinases (MMPs)
and their tissue inhibitors [41]. The serum carboxy-terminal
propeptide of procollagen type I (PICP) has been suggested
as a biomarker of collagen type 1 synthesis [42]. Altered
levels of serum PICP and plasma tissue inhibitor of metal-
loproteinase-1 (TIMP-1) have been demonstrated in hyper-
tensive patients with HF with normal ejection fraction
(HFNEF) [51,71,72,73].
HF with a preserved ejection fraction has been associ-
ated with a significant increase in the collagen III synthesis
marker PIIINP and the collagen I degradation marker CITP
levels [37,50]. According to Querejeta et al. [42,73] the
circulating terminal peptides PIP and PIIINP were cleaved
off during synthesis of collagen type I and III. Also, CITP
formed during collagen I degradation may be useful in
screening for severe myocardial fibrosis in patients with
hypertension [73]. However, Plaksej et al. [41] were unable
to replicate these findings and could not demonstrate a
relationship between PIP and myocardial fibrosis develop-
ment. Moreover, it was [41] noted that relative increase in
the collagen type 3/type 1 ratio was connected with a
progressive decline in cardiac longitudinal function in
patients with advancing hypertensive HF. Increased colla-
gen type I and type III accumulation within the myocardial
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 An update on biomarkers of heart failure in hypertensive patients
interstitium was associated with increased synthesis and
unaltered or decreased degradation [41]. This resulted from
prolonged stimulation from chronic pressure overload and
other factors such as angiotensin II, aldosterone, endothe-
lin-1, insulin-like growth factor-1 or tissue growth factor-b.
There may also have been a genetic predisposition to
collagen deposition [41,74,75]. Collagen accumulation
facilitates abnormalities of cardiac diastolic function as well
as contractile impairment [41,74,75]. Aggravation of hyper-
tensive HF may lead to global LV systolic dysfunction with a
reduction in LVEF [41,76,77] (Table 1).
METALLOPROTEINASES
It has been suggested that in hypertensive heart disease
TIMPs are increased and MMPs are decreased [78,79]. This is
associated with decreased collagen degradation and
increased collagen accumulation [6]. Experimental and
clinical studies have shown that hypertensive heart disease
can result in increased fibrillar collagen content, altered
fibrillar collagen geometry, and an increased collagen I to
III isotype ratio [6,80,81]. The expression of MMP-2 and
MMP-9 changes during hypertensive heart disease
suggesting that their activation contributes to cardiac
remodeling [6,82]. According to data from numerous stud-
ies, levels of MMP-2 gradually increase after the onset of an
acute myocardial infarction [83,84]. Serum concentration of
MMP-9 decreases for several days after acute myocardial
infarction and then gradually increases [84,85]. Ahmed et al.
[6] demonstrated that decreased MMP-2 and increased
MMP-9 levels may contribute to the structural and func-
tional heart changes seen in hypertensive heart disease.
Significant elevations of MMP2 and MMP9 levels in the
presence of symptoms of HF were also observed by Collier
et al. [37]. According to these and other authors [37,43]
elevated MMP9/TIMP1 ratios are specifically associated
with LV remodeling in patients with more advanced hyper-
tensive heart disease (Table 1).
BNPAND ITS DERIVATIVES
Biomarkers such as natriuretic peptides [43,86,87] and
tumor marker antigen carbohydrate 125 (CA125) [88,89]
have been suggested to be useful in determining the
severity of disease and prognosis of clinical outcomes in
patients with AHF [90].
BNP, a neurohormone synthesized in ventricular myo-
cardium, is released into the circulation in response to
ventricular dilatation and pressure overload [91,92]. The
plasma level of BNP is considered to be a powerful marker
for cardiac dysfunction and a useful prognostic indicator in
patients with critical CV diseases [44]. What is more, some
studies indicated that BNP can be even useful in healthy
asymptomatic patients. Freitag et al. [93] evaluated the
relations of plasma BNP to longitudinal BP tracking and
incidence of hypertension in 1801 nonhypertensive Fra-
mingham Heart Study participants. On follow-up 4 years
from baseline, progression of BP category was observed in
36.2% of men and 33.1% of women, and hypertension
developed in 16.4% of men and 15.5% of women. In
multivariable models adjusting for known risk factors,
Journal of Hypertension
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elevated plasma BNP level was associated with increased
risk of BP progression in men [odds ratio (OR) of 1.15 for
trend across categories, P 0.046] but not in women
(P 0.82) [93]. Melander et al. [94] and Fradley et al. [95]
also observed the potential usefulness of NT-pro-BNP in the
prediction of CV events in people without CV disease.
Suzuki et al. [45] reported that BNP can be used in
screening to identify patients with hypertension and pro-
gressive LVH. Another study of Suzuki et al. [44] demon-
strated that BNP was an important risk marker for incident
CV events in patients with hypertension. Age and LVH have
an additive effect on BNP level. This may decrease the
usefulness of this peptide as a risk marker for hypertensive
CV events [44,45]. According to the Suzuki study, age had a
greater influence on BNP level in hypertensive patients with
LVH than those without LVH [44]. In addition, multivariate
Cox proportional hazard regression analysis showed that in
elderly hypertensive patients with LVH elevated BNP was
associated with a higher incidence of CV events at follow up
[44]. The recent study conducted on 1193 black hyper-
tensive patients confirmed that NT-proBNP was independ-
ently associated with LVMI especially with eccentric
hypertrophy (P < 0.0001) [96]. The same study suggested
other potentially useful biomarkers of HF in hypertensive
patients, including mid-regional pro-atrial natriuretic
peptide (P < 0.0001), mid-regional pro-adrenomedullin
(P 0.0006), C-terminal pro-endothelin (P 0.0009), and
osteoprotegerin (P 0.0005), however, their utility should
be confirmed in large population studies [96] (Table 1).
GLYCOPROTEIN CA125
Glycoprotein CA125 is synthesized by epithelial serosal
cells in response to fluid accumulation [97,98] and proin-
flammatory stimulation [99]. Increased antigen carbo-
hydrate 125 level is associated with higher NYHA class
and signs of fluid congestion [98,100,101]. Raised levels
of glycoprotein CA125 has been shown to directly correlate
with pulmonary artery wedge and right atrial pressures
[88,89,102] and inversely correlates with the deceleration
time of early filling on transmitral Doppler [89,90]. Nunez
et al. [90] found that a raised CA125 was associated with an
increased 6-month mortality. As CA125 and BNP reflect
different pathophysiological mechanisms for the pro-
gression of HF and that fluctuations of both biomarkers
have been observed in response to treatment, it has been
suggested that the measurement of both their levels after
initial treatment for AHF could provide a better tool for risk
stratification [90]. By combining BNP and CA125 levels in
nonselected hospitalized patients with AHF, three sub-
groups were defined according to 6-month mortality risk:
low (both biomarkers levels were below the cut-off points),
intermediate (only one biomarker level was elevated), and
high risk (both biomarkers levels were elevated). Of note,
patients with hypertension accounted for up to 83.9% of
those in the studied groups [90] (Table 1).
CYSTATIN C
It is also noteworthy that the role of CysC in hypertensive
patients, as renal impairment, which may appear very early
www.jhypertension.com 1685
Gluba et al.
in this group of patients, also reflects the degree of HF [103].
CysC is a protein from the family of cysteine proteinase
inhibitors and consists of 120 amino acids [104]. It is the
product of a gene that is expressed in all nucleated cells of
the body. With a low molecular weight and a high iso-
electric point, it easily undergoes glomerular filtration [46].
In the proximal tubule it is absorbed and then catabolized,
and therefore it does not return to circulation [46]. As the
concentration of CysC in the urine is low, the clearance of
CysC cannot be determined by urinary analysis. However,
its concentration in plasma correlates with GFR [46,104].
CysC concentration is not dependent on muscle mass, BMI
or sex and increases with age [46].
There is increasing evidence that CysC can be used to
detect kidney disease at earlier stages than plasma crea-
tinine [46,104]. This may facilitate screening in the elderly,
patients with diabetes, hypertension or CV diseases. Even
minor renal dysfunction adversely affects the prognosis of
patients with CV diseases. As well as traditional coronary
heart disease risk factors such as hypertension, impaired
glucose and lipid metabolism, hyperhomocysteinemia,
endothelial dysfunction or inflammation (CRP, fibrinogen,
IL-6) are more prevalent in patients with renal failure [46].
Studies enrolling patients with HF have shown that accom-
panying renal failure is a bad prognostic factor [46]. What is
more important renal impairment also reflects the degree of
HF and contributes to its progression [46,105]. Elevated
CysC level is an independent risk factor for increased
mortality in elderly patients with HF [46,106]. Microalbu-
minuria is the first sign of the kidney damage caused by
hypertension [107]. It indicates that there are structural
changes in the CV system along with retinopathy and left
ventricular hypertrophy [46,106,107]. A positive correlation
between CysC, microalbuminuria and left ventricular mass
indicator has been reported [46]. From this, CysC may
become an additional marker of organ damage in hyper-
tension (Table 1).
CONCLUSION
Early detection of patients at increased risk of hypertensive
heart disease may help facilitate earlier implementation of
effective preventive strategies such as more attentive BP
monitoring and other risk factor control [37,108,109]. More-
over, high-risk individuals may be the most suitable can-
didates for interventional trials which are assessing novel
drugs aimed at the prevention of HF. Currently, the known
biomarkers for HF in hypertensive patients are relatively
limited. There is a need for a widespread search for new
markers with high sensitivity, specificity, reproducibility
and low biovariability, which are independent of demo-
graphic characteristics.
ACKNOWLEDGEMENTS
Conflicts of interest
The authors have not received any payments in connection
with the preparation of this review. No medical or phar-
maceutical company was involved with the preparation of
this article.
Conflict of Interest Disclosures: None.
1686 www.jhypertension.com
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Reviewers Summary Evaluation biomarkers in predicting heart failure in patients with

Reviewer 2
The article is a comprehensive review of the use of bio-
markers to predict heart failure in patients with hyperten-
sion. The article points out the limitations of these
hypertension. The authors underline the need to identify
newer biomarkers to improve prediction of developing
heart failure in hypertensive patients thus reducing clinical
outcomes by earlier or more aggressive intervention.

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