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Hypertensive left ventricular hypertrophy risk: beyond
adap h
Edwa
The hea
increasi
prolong
addition
myocard
respons
patients
shows t
cardiom
develop
matrix a
myocard
adverse
hyperten
HHD). A
pathoph
to HHD
diagnos
the prog
nti
ard
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Introd
The he
stimuli.
promote
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LVH, p
For ins
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Over th
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Review 17
0263-6352
 � 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
s simply adaptive hypertrophy but as a detrimen-
equence. Second, in terms of myocardial struc-
D is not just a matter of cardiomyocytic hyper-
but of overall remodelling. This report is not
However, as recently reviewed [13], a number of studies
have evidenced that blunting cardiac hypertrophic
response to pressure overload did not result in myocardial
dysfunction or failure. Furthermore, modifications of the
DOI:10.1097/HJH.0b013e328340d787
phic growth [1]. Pathological left ventricular
phy (LVH) is associated with distinct structural
lecular phenotypes from physiological LVH
1) [2,3]. In addition, in contrast to physiological
athological LVH is associated with bad prognosis.
tance, in hypertensive patients, LVH has been
o be a strong, independent predictor of cardio-
events, including heart failure (HF) [4], and
e mortality [5].
e past several years, we and others have published
reports concerning some newer aspects of patho-
V growth in hypertension and a plea calling for a
radigm concerning the pathophysiological view
therapeutic approach to hypertensive heart dis-
HD), defined by the presence of LVH in the
of other causes of LV growth different from
hypertension [6–10]. This view is based on two
s (Fig. 1). First, the response of the cardiomyo-
pressure overload must not be considered any
over
Com
impa
One
respo
is a sl
dimi
tensi
have
recru
ution
level
energ
first s
Anot
to pr
leadi
contr
norm
ht © Lippincott Williams & Wilkins. Unauthorized
ad
nents of the response and potential clinical
ndamental component of the cardiomyocyte
e to pressure overload of the left ventricle (LV)
ing of maximum shortening velocity (Vmax) with a
ion of the heat produced per gram of active
during contraction [11]. Thermodynamic data
ggested that this reduction is due to a decreased
ent of myosin crossbridges. Whereas the dimin-
Vmax is a beneficial event at the cardiomyocyte
llowing the cardiac fiber to contract at a normal
cost, at the LV level the diminution of Vmax is the
that will finally lead to dysfunction/failure [12].
component of the response of the cardiomyocyte
ure overload includes quantitative modifications
to increased cell size, which will multiply the
ile units and, according to Laplace’s law, will
ze wall stress and preserve LV chamber function.
ion, andmyocardial injury can cause its pathologic Response of the cardiomyocyte to pressure
ral activation, consequences associated with hy-
tive cardiomyocytic hypertrop
rd D. Frohlicha, Arantxa Gonza´lezb and
rt is a remarkably adaptive organ, capable of
ng its minute output and overcoming short-term or
ed pressure overload. The structural response, in
to the foregoing functional demands, is that of
ial hypertrophy. Then, why should an adaptive
e increase cardiovascular risk in hypertensive
with left ventricular hypertrophy (LVH)? Evidence
hat the functional performance of hypertrophied
yocytes is impaired, and that additional alterations
in cardiomyocytes themselves, the extracellular
nd the intramyocardial vasculature, leading to
ial remodelling and providing the basis for the
prognosis associated with pathological LVH in
sive patients (i.e., hypertensive heart disease,
s molecular information accumulates, the
ysiological understanding and the clinical approach
are changing. The time has come to develop novel
tic and therapeutic strategies aimed at improving
nosis of HHD on the basis of reversing or even
preve
myoc
Healt
Journa
Keywo
hypert
Abbre
recept
diseas
renin–
aOchsn
Cardio
of Card
Pamplo
Corres
Aplicad
E-mail:
Receiv
Accep
uction
art is capable of growth in response to a variety of
Exercise, pregnancy, and postnatal growth
its physiological adaptive growth, whereas neu-
aime
infor
impo
thera
y
Javier Dı´ezb,c
ng the aforementioned changes in the ventricular
ium. J Hypertens 29:17–26 Q 2010 Wolters Kluwer
Lippincott Williams & Wilkins.
Hypertension 2011, 29:17–26
: arterial hypertension, hypertensive heart disease, left ventricular
y, myocardial hypertrophy, myocardial remodelling
ions: ACE, angiotensin converting enzyme; AR, angiotensin
As, fatty acids; HF, heart failure; HHD, hypertensive heart
V, left ventricular; LVH, left ventricular hypertrophy; RAS,
iotensin system
linic Foundation, New Orleans, Louisiana, USA, bDivision of
ular Sciences, Centre of Applied Medical Research and cDepartment
gy and Cardiovascular Surgery, University Clinic, University of Navarra,
Spain
dence to Javier Dı´ez, MD, PhD, Centro de Investigacio´n Me´dica
v. Pı´o XII, 55, 31008 Pamplona, Spain
mar@unav.es
30 July 2010 Revised 14 September 2010
21 September 2010
o provide a systematic review of all the published
tion on HHD but to give insight on these two
nt aspects of HHD, with emphasis on its potential
utic impact.
 reproduction of this article is prohibited.
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rather complex rope structure of the LV and the pro-
gressive
to the p
purely b
An addi
which o
substrat
hydrate
oxidatio
that of
mitate a
FAs yields far more ATP (�129) than glucose (�36) [17].
rdi
ise
9].
tio
ap
ca
eve
dow
to
bo
A
18 Journal of Hypertension 2011, Vol 29 No 1
Table 1 Differences between physiological and pathological manifestations of left ventricular hypertrophy
Physiological Pathological
Conditions Pregnancy Pressure overload
Postnatal growth Volume overload
Regular physical activity Direct myocardial injury
Stimuli Peptidic growth factors Physical stretch
Neurohumoral agents
Cardiomyocyte changes
Receptor RTK GPCR
Signalling pathway PI3K-Akt Gaq/PLC
Calcium homeostasis Preserved Disturbed
Fetal gene expression Relatively normal Usually upregulated
Apoptosis Normal Stimulated
Noncardiomyocyte changes
Extracellular matrix Normal Fibrosis
Intramyocardial vessels Normal Arteriolar remodelling
Capillary rarefaction
Clinical aspects
Cardiac function Normal or enhanced Depressed over time
Association with HF No Yes
Incidence of arrhythmia Normal Increased
Coronary flow reserve Normal or increased Reduced
Association with increased mortality No Yes
Complete regression Usually Not usually
GPCR, G-protein-coupled receptor; HF, heart failure; PI3K-Akt, phosphatidylinositol 30-kinase-Akt; PLC, phospholipase C; RTK, receptor tyrosine kinase. Adapted from [3].
Fig. 1
Pathophy
echocard
increase in fiber parallelism may also contribute
roblem and can create a myocardial dysfunction
ased on anatomy [14].
tional component of the cardiomyocyte response
ccurs during pressure overload involves a shift in
e oxidation from fatty acids (FAs) toward carbo-
s [15,16]. Although in terms of oxygen cost, the
n of glucose is more efficient (ATP/0� 3.1) than
FAs (ATP/0� 2.8), in absolute terms, with pal-
s an example, the oxidation of one molecule of
Acco
prom
[18,1
oxida
an in
phiedand
that
recep
meta
in F
t © Lippincott Williams & Wilkins. Unauthorized 
siological view of the two phases of hypertensive heart disease (as discrimi
iographic left ventricular hypertrophy, LVH). CV, cardiovascular.
ngly, the hypertrophied heart is an energy-com-
d organ, with a diminished ATP production
On the other hand, a sustained decline in FA
n (in the face of unaltered FA uptake) may cause
propriate accumulation of lipids in the hypertro-
rdiomyocyte resulting in contractile dysfunction,
ntually cell death [20]. Some studies suggest
nregulation of peroxisome proliferator-activated
r alpha (a nuclear receptor that regulates lipid
lism by increasing transcription of genes involved
oxidation) contributes to the alterations of FA
reproduction of this article is prohibited.
nated by the presence of either electrocardiographic or
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oxidation in pathological cardiomyocytic hypertrophy
[15,21].
Pathwa
Essenti
sion of
from [2
(1) Glo
(a)
(b)
(c)
(2) Re-
adu
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
(i)
(j)
(3) Rep
life:
(a) Cal
(SE
(b) Ear
(c) a-M
(d) b1
(e) Mu
(f) My
Activati
synthesis o
increased c
altered ene
studies have
load both
stimulate th
pholipase C
molecules in
(i.e., Ca2þ/c
(i.e., protei
kinases ER
factors (
expressions
hypertrophy
Transcr
Nkx2.5
c-fos, c-
in the ac
signallin
evidenc
of class
derepre
factor of activated T-cells and MEF-2 [28], downregula-
and loss of function of some microRNAs (i.e., 1 and
and upregulation and gain of function of other
RNAs (i.e., 208) resulting in enhanced transcription
number of mRNAs [29] also play a role in the
ation of cardiomyocyte fetal gene program during
ure overload.
cardial structure in hypertensive heart
ase
ges in myocardial composition and potential
al impact
ies performed during the last two decades have
nced that beyond cardiomyocytic hypertrophy,
lex
fo
ult
me
1].
id
m
s cl
pe
tu
ic
lop
ar
ur
ntr
er
en
on
to
ase
ve
cte
asi
as
sio
ge
oti
niz
ase
Risk of left ventricular hypertrophy Frohlich et al. 19
2
ard
vasc
extra
card
who
oron
myc, NFkB, and NFAT have been implicated
tivation of cardiac genes in response to the above
g pathways [26,27]. In addition, the available
e supports that phosphorylation and inactivation
II histone deacetylases (HDACs), subsequent
ssion of transcription factors including nuclear
At the
At the
At the
CFR, c
iption
, my
ht 
associated with pathological cardiomyocytic
.
factors including GATA4, GATA6, Csx/
ocyte enhancer factor-2 (MEF-2), c-jun,
myoc
At the
© L
i.e., a
f the proteins necessary to bring about
ardiomyocyte size and adjustment to the
rgy demands of these larger cells. Recent
revealed that in conditions of pressure over-
neurohumoral factors and physical stretch
e Gaq heterotrimeric G protein and phos-
leading to activation of several signalling
cluding: calcium (Ca2þ)-dependent proteins
almodulin and calcineurin); protein kinases
n kinase C and mitogen-activated protein
K, JNK and p38) [24]; and intracrine growth
ngiotensin II) [25] that result in altered gene
wave
refle
incre
decre
perfu
Exag
prom
recog
incre
Table
on of
cium ATPase of sarcoplasmic reticulum
RCA2).
ly transient Kþ current, ItO.
yosin heavy chain.
subunit of the adrenergic receptor.
scarinic receptors.
oglobin.
the fetal gene program allows coordinated
deve
coron
mia d
unco
furth
frequ
vasoc
due
incre
ys mediating the response
al for the above three responses is the re-expres-
the cardiomyocyte fetal gene program (adapted
2,23]):
bal increase in gene expression:
Collagen.
Contractile proteins.
Transmembrane ionic channels.
expression of genes not directly expressed in
lts:
b-Myosin heavy chain (in rodents).
Lactate dehydrogenase M subunits.
B subunit of creatine kinase.
Neuronal nitric oxide synthase.
Caveolin.
Natriuretic peptides.
Genes of the apoptotic pathway.
Naþ,Kþ-ATPase a3-subunit.
Embryonic myosin light chain.
IVS3A form of calcium channel.
ression of genes not expressed during the fetal
tion
133),
micro
of a
activ
press
Myo
dise
Chan
clinic
Stud
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that
detri
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ippincott Williams & Wilkins. Unauthorized
changes in myocardial composition are respon-
r the structural remodelling of the myocardium
imately develops in HHD and has a profound
ntal impact on overall cardiac function (Table 2)
Gene expression profiling (microarray) studies
entified gene cluster expression profiles (i.e.,
ation, tissue reparation, apoptotic, and oxidative
usters) that may be involved in the development
rtensive myocardial remodelling [32,33].
ral changes (i.e., inward eutrophic or hyper-
arteriolar remodelling and capillary rarefaction)
inmyocardialmicrocirculation thereby reducing
y flow reserve and causing subendocardial ische-
ing conditions of high metabolic demand such as
olled hypertension and tachycardia [34]. This is
aggravated by vascular functional alterations
tly present in hypertension such as coronary
striction secondary to endothelial dysfunction
reduced nitric oxide availability [35], and
d arterial stiffness that accelerates aortic pulse
locity and facilitates earlier return of the wave
d at the iliac bifurcation in systole, thereby
ng LV afterload and central pulse pressure and
ing central diastolic blood pressure and coronary
n [36].
rated deposition of collagen types I and III fibers
ng interstitial and perivascular fibrosis is a well-
ed lesion in HHD [37]. The interstitial fibrosis
s myocardial stiffness facilitating LV diastolic
Structural components and pathophysiological impact of
ial remodelling in hypertensive heart disease
Structural component
Pathophysiological
impact
ular level Arteriolar changes Reduced CFR
Capillary rarefaction Reduced CFR
cellular matrix level Interstitial fibrosis Diastolic dysfunction
Arrhythmias
Perivascular fibrosis Reduced CFR
iomyocyte level Increased apoptosis Systolic dysfunction
Increased autophagy Systolic dysfunction
le myocardial level Global remodelling LV dys-synchrony
ary flow reserve; LV, left ventricular. Adapted from [9,30].
 reproduction of this article is prohibited.
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dysfunction and diastolic HF [38], as well as electrical
heterog
to ventr
vascular
vessels,
reserve
complex
by fibro
broblast
transfor
may be
local infi
exocyto
and pro
Apoptos
mally st
when H
Apoptos
tractile
ways: in
tion of
product
tractile
aggrava
lization
activate
phagy e
provoke
All toge
myocard
electrica
tion cou
mechan
chrony
detrime
metabo
dys-syn
patients
but with
QRS du
Mechan
Myocar
the resp
myocyti
and neu
nation o
common
recently
(MRTF
rohumo
respons
been sh
promoti
broblast
by activ
Other recently identified systemic factors should be
d to the local remodelling process, all of which
de
din
nce
d
se
ase
ase
8].
I le
nts
rte
[59
nd
gro
my
nce
en
ne
be
ten
ure
-su
ll
suc
ved
o
s
ten
nt
ion
ela
t. H
obs
ard
[62
id
gen
icu
lly,
ini
stri
tru
th
s
py
ion
o a
te
g
it
pa
c f
nt
th
20 Journal of Hypertension 2011, Vol 29 No 1
eneity of the myocardium, which predisposes it
icular dysrhythmias [39]. On the contrary, peri-
fibrosis reduces wall distensibility of intramural
thus contributing to reduced coronary flow
[40]. Interstitial fibrosis may be the result of
alterations that control collagen metabolism
blasts and by fibroblasts differentiated to myofi-
s under the influence of profibrotic factors such as
ming growth factor-b [41]. Perivascular fibrosis
the reparative response of fibroblasts produced by
ltration by inflammatory cellsdue to endothelial
sis and adhesion induced by pro-inflammatory
fibrotic factors such as aldosterone [42].
is of cardiac cells (i.e. cardiomyocytes) is abnor-
imulated in hypertensive LVH [43,44], especially
F with depressed ejection fraction develops [45].
is may contribute to the loss of effective con-
mass and function in HHD through two path-
ducing cardiomyocytic death or impairing func-
cellular organelles (i.e. reducing mitochondrial
ion of ATP and/or enhancing proteolysis of con-
apparatus) in viable cells [46]. This is further
ted by autophagia, a process of cellular canniba-
serving to maintain cellular homeostasis that is
d during LVH [47]. However, excessive auto-
liminates essential cellular elements and possibly
s cellular death.
ther, the above structural changes present in
ial remodelling may conspire to produce delayed
l activation and/or impaired excitation–contrac-
pling which result in a dispersion of regional
ical activation causing intraventricular dys-syn-
[48]. In turn, mechanical dys-synchrony also has
ntal effects on regional myocardial perfusion,
lism and electrophysiology [49]. Of interest, LV
chrony has been reported in hypertensive
with LVH and subclinical diastolic dysfunction,
out overt HF or conduction abnormalities (i.e.,
ration <120ms) [50,51].
isms of myocardial remodelling
dial remodelling is a complex process driven by
onses of the cardiomyocytic and the noncardio-
c components of the heart to dynamic mechanical
rohumoral stimuli [52,53]. Because of the coordi-
f these responses it is likely that they recognize
mediators. In this regard, it has been reported
that myocardin-related transcription factor
)-A mediates both mechanical stretch- and neu-
ral stimulation-induced gene and hypertrophic
es in cardiomyocytes [54]. Furthermore, it has
own that MRTF-A plays also a critical role in
ng the conversion of cardiac fibroblasts to myofi-
s in response to mechanical and humoral factors
ating a fibrotic gene program [55].
adde
add
inclu
insta
been
gluco
incre
incre
sis [5
sin I
patie
hype
trols
Beyo
back
ence
varia
indep
of ge
have
angio
natri
three
as we
tion
invol
the m
phism
angio
accou
posit
der-r
offse
and
myoc
men
are w
estro
ventr
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conta
indu
the s
as in
organ
thera
addit
rise t
diabe
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rats w
The
nami
opme
grow
t © Lippincott Williams & Wilkins. Unauthorized 
leterious elements to myocardial remodelling
g senescence, obesity, and diabetes. For
, elevation of intracellular angiotensin II has
emonstrated in cardiac cells exposed to high-
[56,57]. In addition, diabetic rat hearts exhibited
d intracellular angiotensin II, which resulted in
d cardiomyocyte apoptosis and myocardial fibro-
Interestingly, myocardial intracellular angioten-
vels were reported to be increased three-fold in
with diabetes and an additional two-fold in
nsive patients with diabetes compared with con-
].
hemodynamic and humoral factors, the genetic
und, gender, and lifestyle factors may also influ-
ocardial composition in HHD. Up to 60% of the
of LV mass may be due to genetic factors
dent of blood pressure. An increasing number
s that contribute to the development of HHD
en described, including members of the renin–
sin–aldosterone system, the type A human
tic peptide receptor gene, the G-protein b
bunit gene affecting the Naþ–Hþ exchanger,
as genes related to cardiac contractility and func-
h as the myosin-binding protein C and genes
in the b-adrenergic system [8,60]. Among them,
st robustly associated with LVH are polymor-
of genes that encode components of the renin–
sin–aldosterone system [61]. Taking into
that men and women have different body com-
, when normalized for lean body mass, the gen-
ted differences in LV mass are almost completely
owever, experimental studies and postmortem
ervational clinical studies have suggested that
ial remodelling is more benign in women than
]. These differences between men and women
ely held to be related to sex hormones such as
, although the molecular effects of estrogen on
lar tissue still remain incompletely understood.
several studies have demonstrated that a diet
ng a surfeit in salt content (so very common in
al societies) is associated with an exacerbation of
ctural and functional alterations in the LV, as well
e kidneys, that promote failure of these vital
[63–65]. Hopefully, wiser correction by diet
will prevent these severe consequences. In
, it has been shown that Western diets giving
metabolic syndrome phenotype (obesity, type 2
s, dyslipidemia) also exacerbate myocardial remo-
changes in experimental genetic hypertensive
h LVH [66,67].
thophysiological relevance of these nonhemody-
actors is that they may be involved in the devel-
of inappropriate LVmass, which is defined as the
of the LV exceeding the individual needs to
reproduction of this article is prohibited.
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compensate hemodynamic load imposed by increased
blood p
seems
adverse
sically d
Poten
Optimiz
During
mine w
LVH c
Indeed,
sive dru
differen
and ang
calcium
[70,71].
reductio
reduced
the dec
risk wh
arterial
Interven
(LIFE)
of the
greater
eral blo
associat
addition
[74]. T
control’
ties of t
(i.e., a
remode
properti
evidenc
and mo
patients
phically
blood p
reduced
extent
contrary
Ongoin
Ramipr
Telmisa
iNtolera
CEND)
LVH w
Neverth
lack of
antihyp
be due
pliance.
still per
mass de
the avai
AR blockers must be the core of antiremodelling strat-
, the time has come to optimize and redirect the
py
the
ty
h t
y o
ort
, w
of
lin
an
HF
em
ard
ep
e-d
orm
bri
efo
rm
em
V
nd,
blo
ed
ac
2],
f
ed
lity
ock
act
ed
ito
an
iso
5].
ac
b
ten
me
h t
ing
al
iren
er
iat
d,
ad
ut
ard
spi
sis
ion
Risk of left ventricular hypertrophy Frohlich et al. 21
ressure [52]. Importantly, inappropriate LV mass
to be associated with cardiac dysfunction and
cardiovascular prognosis independently of clas-
efined LVH [68,69].
tial therapeutical impact
ation of available therapies
recent decades, efforts have been made to deter-
hether the increased LV mass associated with
ould be reversed by antihypertensive therapy.
each and every class of available antihyperten-
gs has been shown to diminish LV mass with
t efficacy [angiotensin receptor (AR) blockers
iotensin converting enzyme (ACE) inhibitors>
antagonists>diuretics and beta-blockers]
Subsequently, several studies have demonstrated
n of cardiovascular risk associated with the
LV mass [72], although they did not disassociate
reased LV mass from the clear cut reduction in
ich also could be attributable to the decreased
pressure [73]. Nevertheless, in the Losartan
tion For Endpoint reduction in hypertension
study, the observed clinical benefit with blockers
renin–angiotensin system (RAS) tended to be
than that expected from the decrease in periph-
od pressure (i.e., the regression of LVH was
ed with lower rates of clinical end points,
al to the effects of blood pressure lowering)
hese potential effects ‘beyond blood pressure
are perhaps accounted for by protective proper-
hese drugs that affect subclinical organ damage
ngiotensin-II-mediated LVH and myocardial
lling) or intermediate end points, such as arterial
es or central blood pressure, for which there is
e that they are related to cardiovascular mortality
rbidity [75]. In this regard, it has been shown in
with essential hypertension and echocardiogra-
assessed LVH that, despite similar peripheral
ressure control, chronic treatment with losartan
LV mass and myocardial fibrosis to a greater
than treatment with amlodipine [76]. On the
, a recent posthoc analysis of data from the large
gTelmisartan Alone and in combination with
il Global Endpoint Trial (ONTARGET) and
rtan Randomized Assessment Study in ACE
nt subjects with cardiovascular Disease (TRAS-
trials has shown that a decreased prevalence of
as not translated into a prognostic benefit [77].
eless, it should be taken into account that the
improved prognosis associated with traditional
ertensive treatment in large clinical trials might
in part to insufficient doses and reduced com-
In any case, an unacceptably high residual risk
sists in treated hypertensive patients in whom LV
creased with treatment [78]. Therefore, although
lable evidence supports that ACE inhibitors and
egies
thera
cing
quali
whic
abilit
supp
First
sion
cross
mass
with
toras
stand
per-d
lysin
the f
III fi
Ther
confi
toras
and L
Seco
RAS
yield
cardi
[81,8
II. In
block
inabi
to bl
and
sider
inhib
mech
perox
[84,8
cardi
block
angio
treat
whic
think
clinic
alisk
block
assoc
Thir
block
attrib
myoc
with
analy
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ht © Lippincott Williams & Wilkins. Unauthorized
of hypertensive LVH, not just in terms of redu-
quantity of LV mass, but also to restore the
of myocardial composition. Some examples in
he addition of other drugs may potentiate the
f therapies interfering with the RAS may further
this view.
e have recently reported that myocardial expres-
the active form of lysyl oxidase (LOX), collagen
king and the amount of fibrosis, as well as LV
d stiffness was decreased in hypertensive patients
after chronic treatment with the loop diuretic
ide, but not with furosemide, in addition to
HF therapy [79]. The enzyme LOX is a cop-
endent extracellular enzyme that catalyzes
erived crosslinks in collagen, thus promoting
ation and crosslinking of collagen types I and
ls and their subsequent tissue deposition [80].
re, although further studies are required to
these preliminary data, the possibility exists that
ide may be useful to prevent myocardial fibrosis
dysfunction in patients with HHD.
as recently reviewed, clinical trials comparing
ckers with other antihypertensive regimens have
new perspectives on the role for angiotensin II in
pathology beyond blood pressure reduction
for instance, the role for intracellular angiotensin
act, intracellular angiotensin II actions are not
by all ACE inhibitors or AR blockers, due to an
of each of these drugs either to enter the cell or
alternative pathways of angiotensin II synthesis
ions [57,58,83]. Additionally, it should be con-
that maybe part of the clinical benefits of RAS
r therapy might be related to non-RAS-mediated
isms, such as the kallikrein–kinin system and/or
me proliferator-activated receptor-g activation
A more specific and complete inhibitor of the
RAS, such as a renin inhibitor, with the ability to
oth extracellular and intracellular generation of
sin II [57,58], may provide a more effective
nt of HHD in conditions such as diabetes in
he intracellular RAS is stimulated. This line of
is partially supported by experimental [58] and
[86] findings showing that the renin inhibitor
adds benefit to an ACE inhibitor or an AR
reducing LV myocardial fibrosis in hypertension
ed with diabetes.
some beneficial effects of aldosterone receptor
e in hypertensive patients have been, in part,
ed to a blood pressure independent reduction in
ial fibrosis [87]. In patients with LVH, treatment
ronolactone decreased LV fibrosis as assessed by
of ultrasonic radiofrequency signals [88]. In
, in patients with essential hypertension, the
 reproduction of this article is prohibited.
thais
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22 Journal of Hypertension 2011, Vol 29 No 1
Fig. 2
Time cour elli
(as discrim phi
is a biom en
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simply co 96]
of low-dose spironolactone to an ACE inhibitor
owed by a greater decrease in LV mass and in a
arker of collagen type III synthesis (i.e., procol-
pe III aminoterminal peptide) than with ACE
n alone, despite the absence of fall in blood
in response to the spironolactone [89]. Similar
on LV mass were found after the addition of
actone to the AR blocker candesartan in hyper-
patients with concentric LVH [90]. Combination
with eplerenone and enalapril caused a larger
n in LV mass than either treatment alone [91].
er, it has been recently published that addition of
one to standard pharmacological treatment in
with HF and preserved ejection fraction pre-
a progressive increase in procollagen type III
rminal peptide [92]. The failure of ACE inhi-
achieve full regression of LV mass might in part
ution
ician
and b
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mech
bioch
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clinic
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[95,9
se changes of the three major circulating biomarkers of myocardial remod
inated by the presence of either electrocardiographic or echocardiogra
arker of cardiomyocyte apoptosis; the C-terminal propeptide of procollag
hin-1 (CT-1) is a biomarker of cardiomyocyte hypertrophy. The figure co
nfigured based upon data previously published in references [95] and [
t © Lippincott Williams & Wilkins. Unauthorized 
ed by the phenomenon of aldosterone escape, as
s did not decrease in patients with aldosterone
n ACE inhibition as opposed to a decline in LV
patients without aldosterone escape [93].
the calcium antagonist amlodipine may possess
ptotic properties. In the in-vitro setting of dox-
-induced cardiomyocyte apoptosis, this agent
ted several hallmarks of the activated apoptotic
including mitochondrial release of cytochrome c,
n of caspase-3, and phosphatidylserine mem-
xposure, on all of which nifedipine had no effects
lodipine has, within the dihydropiridine rings,
rogen atoms which may quench reactive oxygen
thus explaining that mitochondrial oxidative
are reduced in doxorubicin-treated cardiomyo-
posed to amlodipine [94].
ricate mechanisms responsible for the structural
lling of the myocardium that facilitates the evol-
the C-te
lating b
cantly m
than in a
pressure
Explora
Recent
new tar
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HHD.
HHD b
tricular
(1) Stra
pha
(a)
(b)
HF in patients with HHD, requires from clin-
e utilization of a multibiomarker (i.e., imaging
chemical) approach to modify the medical man-
t of patients with HHD and therapeutic decision-
by tailoring a targeted pharmacological anti-
nsive therapy according to the predominant
ism of myocardial remodelling. In particular,
ical markers reflecting alterations in the different
ents involved in the development of LVH (i.e.,
yocyte hypertrophy, myocardial fibrosis, cardio-
apoptosis) may help to identify patients with no
evidence of HHD, but alterations in the histo-
components involved in LVH, and provide infor-
about the need for more aggressive therapy during
t stages of the disease, and potentially provide
biochemical data for the specialist (reviewed in
(Fig. 2). For instance, the serum concentration of
ng described in the two phases of hypertensive heart disease
c left ventricular hypertrophy, LVH). Annexin A5 (AnxA5)
type I (PICP) is a biomarker of myocardial fibrosis; and
ins original figure art not previously published elsewhere, but
.
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propeptide of procollagen type I, a circu-
r of myocardial fibrosis, decreased signifi-
ypertensive patients treated with losartanine-treated patients, despite similar blood
ion in both groups [76].
ew therapeutic targets and strategies
from experimental studies have provided
lunt or even reverse pathological cardi-
rtrophy and myocardial remodelling in
lowing are the newer strategies to treat
eduction of blood pressure and left ven-
apted from [9,97]):
o optimize the use of the available
gical agents:
rugs with clinically proven antiremodel-
cts.
rugs able to block the intracellular RAS.
Copyright 
(c) Use of drugs to restore ventricular synchrony.
(2) Strategies to blunt or reverse pathological cardio-
myo
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(b)
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Risk of left ventricular hypertrophy Frohlich et al. 23
© L
etabolic rescue in order to increase energy
the remodelled myocardium [110]. In this
s been reported recently that dichloroacetate,
LVH
we s
in th
with
ion of its synthesis [108] or inhibition of its
ress-mediated degradation [109] have been
improve the balance between muscle growth
y) and nutrient supply (capillary density) in
hypertensive LVH. Of special interest is the
the a
temp
arise
the r
prese
07], or increased nitric oxide availability cacio
factor
linositol 30-kinase-Akt signalling [105] and
ith growth hormone [106] that have been
hen LV dysfunction or failure was present.
, experimental treatments promoting coron-
nesis via induction of vascular endothelial
[1
inher
musc
unde
fibro
Migh
cyte growth:
Genetic manipulation.
Pharmacological intervention.
tegies to induce physiological cardiomyocyte
th:
Physical exercise.
Administration of growth hormone or insulin-like
growth factor-1.
tegies to repair myocardial remodelling:
Facilitation of intramural perfusion.
Reduction of myocardial fibrosis.
Inhibition of cardiomyocyte apoptosis.
Correction of metabolic derangements.
Cell therapy-based interventions.
tioned above [13], preclinical studies have shown
nting cardiomyocyte growth in pressure overload
ible by genetic manipulations and/or special
cological interventions without compromising
ile ventricular performance. More direct inter-
s that regulate the fetal gene program such as
n of class II HDACs [98], or reduction of micro-
8 expression [99] also may prevent pathological
yocyte growth. These studies have uncovered a
l new target of therapy: the hypertrophic pheno-
elf. This strategy is based on the controversial
hat suppressing pathological hypertrophy (either
etic manipulations or pharmacological actions)
the key to impeding progression of HF [97].
s some experimental evidence provides support
therapeutic targeting of the hypertrophic process
.g., IP3 receptor) [100], other findings suggest that
olecules may be common mediators for the
t aspects involved in myocardial remodelling
ophy, fibrosis, and cardiomyocyte apoptosis) con-
new therapeutic targets to be either inhibited
lcium- or calmodulin-dependent protein kinase
] or stimulated (e.g., ACE2) [102].
rategies have focused on activation of physiologic
by means of exercise [103,104], stimulation of
factor (i.e., insulin-like growth factor-1)-triggered
nuate
incre
phos
salt-s
Fina
myofi
to pr
cardi
ment
arrhy
heart
diom
strate
It m
precl
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addit
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that
drug
mate
hype
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HHD
Con
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to de
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cardi
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ippincott Williams & Wilkins. Unauthorized
the transition from LVH to HF associated with
d energy reserves, activation of the pentose
te pathway, and reduced oxidative stress in Dahl
sitive rats fed a high-salt diet [111].
in addition to their involvement in fibrosis,
oblasts have been recently discovered in vitro
ote arrhythmogenesis by direct modification of
yocyte electrophysiology following establish-
heterocellular electrical coupling [112]. If similar
ogenic mechanisms may be operational in intact
myofibroblasts might emerge as a novel noncar-
cyte target for cell therapy-based antiarrhythmic
s in HHD.
be remarked that the challenge in translating
cal observations into clinical therapeutic strat-
lates to clinical studies that are designed in
to established therapeutic options (e.g., pharma-
l agents to treat arterial hypertension and HF).
trategies may contrast with experimental studies
e tested novel interventions without established
imens. Therefore, animal studies may overesti-
e effect of potential novel treatment strategies on
phy, remodelling and dysfunction of the LV,
established pharmacological therapies may act,
via identical or similar signalling pathways [113].
eless, preclinical studies provide essential infor-
for identifying potential novel targets, and their
l drawbacks, and are required for developing
linical treatment strategies to prevent or reverse
sion
ical burden of HHD is great as is the opportunity
lop studies that focus on specific molecular and
processes that may be specifically targeted to
ize the detrimental prognosis associated with
his problem does not exclusively relate to the
yocytic hypertrophy process, but also to the
lling of the myocardium and the pathological
omena that coincide with the development of
other words, the thrust of our message is that the
t risk of LVH is not primarily due to the increased
r mass of the ventricular chamber but to its
ing fundamental elements, namely ischemia,
apoptosis and other yet to be elucidated [9].
lockade of these aspects be therapeutically effi-
in HHD beyond reduction of LV mass? Although
er to this question remains to be determined, it is
g to speculate that at least some benefit could
m the restoration of cardiomyocyte function and
air of myocardial structure. This is, then, the
status of the exciting story about the risk of
arterial hypertension. And, from this lesson,
est an analogy to Churchill’s admonition early
econd World War: ‘Now this is not the end. It is
 reproduction of this article is prohibited.
Copyrigh
not even the beginning of the end. But it is, perhaps, the
end of the beginning’ (Sir Winston Churchill Speech in
Novem
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19 Lamb HJ, Beyerbacht HP, van der Laarse A, Stoel BC, Doornbos J, van
der Wall EE, de Roos A. Diastolic dysfunction in hypertensive heart
dise
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inter24 Journal of Hypertension 2011, Vol 29 No 1
ber 1942).
wledgements
rk was partially funded through the UTE-FIMA
tive project, the Red Tema´tica de Investigacio´n
tiva en Enfermedades Cardiovasculares
VA) (grant RD06/0014/0008) and a FIS project
2234) from the Instituto de Salud Carlos III,
of Science and Innovation, Spain, and the Euro-
nion (InGenious HyperCare, grant LSHM-CT-
7093).
re no conflicts of interest.
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26 Journal of Hypertension 2011, Vol 29 No 1
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reproduction of this article is prohibited.
	Hypertensive left ventricular hypertrophy risk: beyond adaptive cardiomyocytic™hypertrophy
	Introduction
	Response of the cardiomyocyte to pressure overload
	Components of the response and potential clinical impact
	Pathways mediating the response
	Myocardial structure in hypertensive heart disease
	Changes in myocardial composition and potential clinical impact
	Mechanisms of myocardial remodelling
	Potential therapeutical impact
	Optimization of available therapies
	Exploration of new therapeutic targets and strategies
	Conclusion
	Acknowledgements
	References