Contemporary Reviews in Cardiovascular Medicine

The Progression of Hypertensive Heart Disease

Mark H. Drazner, MD, MSc

ypertension remains a major public health problem

associated with considerable morbidity and mortality.
Hypertensive heart disease is a constellation of abnormalities
that includes left ventricular hypertrophy (LVH), systolic and
diastolic dysfunction, and their clinical manifestations including arrhythmias and symptomatic heart failure. The classic
paradigm of hypertensive heart disease is that the left ventricular (LV) wall thickens in response to elevated blood
pressure as a compensatory mechanism to minimize wall
stress. Subsequently, after a series of poorly characterized
events (transition to failure), the left ventricle dilates, and
the LV ejection fraction (EF) declines (defined herein as
dilated cardiac failure).1 The purpose of this review is to
focus on the key steps in the progression of hypertensive
heart disease (Figure 1), highlighting recent advances as well
as some unresolved controversies.

From Hypertension to LVH

What is LVH?
Although an increase in cardiomyocyte size has been offered
to be the sine qua non of LVH,3 in the epidemiological or
clinical setting, it is not feasible to document this abnormality.
Rather, in those settings, LVH is defined as an increase in LV
mass. Criteria to define LVH require using a somewhat arbitrary
threshold to dichotomize a trait that appears to have a continuous
relationship with subsequent risk,4 and an alternative approach is
to define several grades of severity of LVH.5
There is widespread agreement that LVH is an important
intermediate phenotype in the progression of hypertensive
heart disease1 and is associated with adverse outcomes.6
Although LVH can antedate the development of hypertension,7 the progression from hypertension to concentric LVH
(pathway 1, Figure 1) is an important step on the pathway
toward heart failure and will be the focus of this section.
Pathological changes present in patients with hypertensive
LVH include an increase in the size of the cardiomyocyte,
alterations in the extracellular matrix8,9 with accumulation of
fibrosis, and abnormalities of the intramyocardial coronary
vasculature, including medial hypertrophy and perivascular
fibrosis.10 The mechanisms responsible for progression to
hypertrophy include not only a response to the mechanical
stress from elevated blood pressure but also the influences of
neurohormones,11 growth factors, and cytokines.12 Nevertheless, a recent clinical trial demonstrated that tighter control of

systolic blood pressure (target of 130 mm Hg versus

140 mm Hg) was associated with a reduction in the development of LVH on ECG,13 emphasizing the importance of the
pressure load itself.

What Explains the Variability in the Development

and Pattern of LVH?
There is considerable interindividual variability in the increase of LV mass in response to hypertension. For example,
blacks compared with whites have increased LV mass14,15 as
well as more severe diastolic dysfunction.16 In large, wellcharacterized cohort studies, multivariable models adjusted
for known risk factors, including systolic blood pressure,
explained only 50% of the variability of LV mass as assessed
by echocardiography17 and 60% to 68% by cardiac magnetic
resonance imaging.15,18 These data suggest the presence of
other unmeasured risk factors. Because there is strong evidence for heritability of LV mass, including observations
from studies of the general population,19 sibling studies,20 and
recent longitudinal twin studies,21 considerable interest exists
in identifying putative genetic risk factors that modulate LV
mass. These efforts have progressed from candidate gene
association studies22 to genome-wide expression analyses
with the use of microarray data23 and genome-wide association studies24 but remain in their relatively early stages and
have not yet yielded results that have translated into the
clinical arena. It seems likely that multiple variants, each with
modest effect size, will be involved in modulating complex
traits,25 including LV mass.
LV Geometry
LV mass can increase from either wall thickening or chamber
dilation. Wall thickening occurs more commonly in response
to pressure overload, and chamber dilation occurs more
commonly in response to volume overload.1 In an attempt to
categorize these 2 patterns of response, the ratio of the LV
wall thickness to diastolic diameter (relative wall thickness) is measured by echocardiography (Figure 2).28 When
the relative wall thickness is increased (eg, 0.42,5 although
age-variable cutoffs may be necessary29), LVH is classified as
concentric; when the relative wall thickness is not increased,
LVH is classified as eccentric. A third pattern, termed
concentric remodeling, occurs when relative wall thickness,
but not LV mass, is increased. Echocardiographic studies

From the Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas.
Correspondence to Dr Mark Drazner, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9047. E-mail
Mark.Drazner@utsouthwestern.edu
(Circulation. 2011;123:327-334.)
2011 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org

DOI: 10.1161/CIRCULATIONAHA.108.845792

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Table 1. Factors Influencing LV Geometry in
Hypertensive Patients
Pressure load: severity, duration, rapidity of onset
Volume load
Demographic factors: age, race/ethnicity, gender
Concomitant medical conditions: coronary artery disease, diabetes mellitus,
obesity, valvular heart disease
Neurohormonal milieu
Alterations of the extracellular matrix
Genetic factors

Figure 1. The 7 pathways in the progression from hypertension

to heart failure. Hypertension progresses to concentric (thickwalled) LVH (cLVH; pathway 1). The direct pathway from hypertension to dilated cardiac failure (increased LV volume with
reduced LVEF) can occur without (pathway 2) or with (pathway
3) an interval myocardial infarction (MI). Concentric hypertrophy
progresses to dilated cardiac failure (transition to failure) most
commonly via an interval myocardial infarction (pathway 4).
Recent data suggest that it is not common for concentric hypertrophy to progress to dilated cardiac failure without interval
myocardial infarction (pathway 5). Patients with concentric LVH
can develop symptomatic heart failure with a preserved LVEF
(pathway 6), and patients with dilated cardiac failure can
develop symptomatic heart failure with reduced LVEF (pathway
7). The influences of other important modulators of the progression of hypertensive heart disease, including obesity, diabetes
mellitus, age, environmental exposures, and genetic factors, are
not shown to simplify the diagram. A thicker arrow depicts a
more common pathway compared with a thinner arrow.
Adapted from Drazner.2 Copyright 2005 , the American Heart
Association.

have demonstrated that hypertensive patients can have any of

these patterns of LV geometry.26,28
Why Do Some Patients With Hypertension Develop
Concentric Hypertrophy and Others Eccentric Hypertrophy?
It remains uncertain why some hypertensive patients develop
concentric hypertrophy and others eccentric hypertrophy
(Table 1). The joint influences of volume overload, pressure
overload, and contractile dysfunction have been empha-

Figure 2. Classification of LV geometry based on LV mass and

relative wall thickness (the ratio of LV wall thickness to diastolic
dimension).28 Depicted schematically are cross sections of the
left ventricle. The striped area represents LV wall thickness, and
the area of the inner circle represents LV volume. Adapted from
Sehgal and Drazner26 (copyright 2007, Elsevier) and Khouri et
al27 (copyright 2010, the American Heart Assocaition).

sized.28,30,31 Undoubtedly, some of the apparent variability of

the hypertrophic response among hypertensive patients will
be attributable to unappreciated differences in the pressure
load itself, whether it be the severity, duration, or rate of
increase of the blood pressure.32 Subjects with concentric
versus eccentric hypertrophy have been shown to have higher
systolic blood pressures and total peripheral resistance.28
Additionally, ambulatory blood pressure is a better correlate
of LV mass than single office blood pressure measurements,33
and those with concentric compared with eccentric hypertrophy had significantly higher ambulatory blood pressure even
when the office blood pressure was not dramatically different
between the 2 groups.34
Demographic factors can also modulate the manner in
which the left ventricle responds to an elevation in blood
pressure. Blacks compared with whites appear to be
predisposed to a concentric hypertrophic response,14,15,26
although it is uncertain whether this represents an effect
independent of blood pressure.35 In isolated systolic hypertension, women were more likely to develop concentric
LVH, and men were more likely to develop eccentric
LVH.36 Increasing age has also been associated with a
concentric as opposed to eccentric hypertrophic response
in hypertension as assessed by echocardiography37 and, in
a large cohort of adults free of clinical cardiovascular
disease, by cardiac magnetic resonance imaging.38
Other medical conditions common in hypertensive subjects, such as diabetes mellitus, obesity, and coronary artery
disease, can also affect the pattern of hypertrophic response.
In the Losartan Intervention For End Point Reduction in
Hypertension Study, coronary artery disease was associated
with an increased LV diastolic dimension and a higher
prevalence of eccentric LVH.39 Diabetes mellitus has been
associated with a concentric hypertrophic response, as measured by increased relative wall thickness,37,40 whereas obesity, characterized as a volume-overload state, has been
associated predominantly with eccentric hypertrophy.41,42
However, others have reported discordant data, with diabetes
mellitus being associated with eccentric remodeling43 and
obesity with increased relative wall thickness.44 Furthermore,
the impact of body composition (fat-free versus fat mass) on
LV geometry in hypertensive subjects has not been explored
fully. Additional work is needed to further delineate the
impact of obesity and diabetes mellitus on LV geometry in
hypertension.

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Drazner
Variation in neurohormonal activation in hypertension is
another putative factor influencing the development of either
concentric or eccentric hypertrophy. Differences in plasma
renin activity are widespread in hypertensive subjects,45,46
and some investigators equate high- versus low-renin states
with concentric versus eccentric hypertrophy, respectively.47
Patients with eccentric hypertrophy have been shown to have
low plasma renin activity.48 Other neurohormones, including
angiotensin II and aldosterone, have also been associated with
LV geometry in small cross-sectional studies.49 51 However,
the Framingham Offspring Study recently reported that an
increased aldosterone-to-renin ratio was associated with both
concentric and eccentric hypertrophy in multivariable models.52 Their sample was by far the largest to date (n2119),
and these data question whether variability in the renin-angiotensin-aldosterone axis will be a key factor in the predilection to develop increased LV wall thickness versus ventricular dilation in hypertension.
Alterations in the extracellular matrix are suspected to be
critical mediators in the development of LV chamber dilation.
In a study of hypertensive subjects with heart failure in which
coronary artery disease was excluded by angiography, endomyocardial biopsy of the right ventricular septum was performed in16 subjects with dilated cardiac failure and 23 with
a preserved LVEF.53 Those with dilated cardiac failure had a
lower amount of collagen surrounding the cardiomyocytes, a
higher amount of perivascular and scar-related collagen, and
a higher ratio of matrix metalloproteinase-1 to tissue inhibitor
of matrix metalloproteinase-1, highlighting the importance of
alterations of the extracellular matrix in leading to LV
dilation.
As with LV mass (see above), there likely will be genetic
influences discovered that affect the pattern of the hypertrophic response (wall thickening or dilation).2,21,24,54 In a canine
model of aortic constriction, dogs that had a higher baseline
indexed LV mass and lower systolic wall stress before
placement of the aortic band had a larger increase in LV mass
and preservation of cardiac function compared with dogs with
baseline lower LV mass and higher systolic wall stress.55
Similarly, approximately one half of rats who underwent
suprarenal aortic banding remodeled concentrically and one
half eccentrically at 20 weeks.56 These data suggest that
intrinsic factors, possibly genetic, that are operative before
exposure to injury can modulate the hypertrophic response.
This hypothesis is supported by the murine model of transverse aortic constriction, in which the background mouse
strain influenced whether concentric or eccentric hypertrophy
developed.57 Potential molecular pathways affecting the ability of the ventricle to tolerate pressure overload have been
delineated.58,59 In total, these data suggest that genetic factors
may influence the response to pressure overload and, specifically, whether concentric or eccentric hypertrophy develops.

Regression of LV Mass
The pathway from hypertension to concentric LVH is not
unidirectional. With pharmacological control of blood pressure, LV mass decreases60 and is associated with reduced risk
of clinical events including cardiovascular death, myocardial
infarction, and stroke.61 However, whether a strategy tailored

From Hypertension to LVH and Heart Failure

329

Table 2. Challenges to the Classic Paradigm of the

Progression of Hypertensive Heart Disease
In animal models of pressure overload, concentric LVH can be blocked and
dilated cardiac failure does not develop.
In humans, concentric LVH does not commonly progress to dilated cardiac
failure in the absence of myocardial infarction.
Some hypertensive subjects develop dilated cardiac failure without
antecedent concentric LVH and without clinical evidence of myocardial
infarction.

to reduction of LV mass provides additional clinical benefit

compared with blood pressure controlled to conventional
targets is uncertain.

From LVH to Dilated Cardiac Failure and to

Clinical Heart Failure
From Concentric LVH to Dilated Cardiac Failure
The classic paradigm of the cardiac structural and functional
changes in hypertensive heart disease is that hypertension
leads to concentric hypertrophy (pathway 1, Figure 1), which
then (transition to failure) is followed by dilated cardiac
failure (pathways 4 and 5, Figure 1), commonly referred to as
a burned-out left ventricle. This transition to failure was
described in principle by Meerson62 50 years ago on the
basis of a series of experiments that imposed aortic constriction in rabbits and dogs and continues to be an accepted
paradigm today.58 However, recent data have challenged 3 of
the classic tenets of this paradigm (Table 2).
Challenges to the Classic Paradigm of Hypertensive
Heart Disease
Classic Tenet 1: Concentric LVH Is Necessary to Avoid
Dilated Cardiac Failure
In the 1970s, the concept that LVH, manifest as increased
wall thickness, was compensatory in pressure overload to
reduce wall stress, thereby allowing preservation of LVEF,
was supported by animal models of ascending aortic constriction63 and studies of patients with aortic stenosis.64 However,
this compensatory, and thus beneficial, aspect of LVH was
not consistent with epidemiological data that showed that
LVH was associated with adverse clinical outcomes.6 Furthermore, animal models of aortic constriction have now
demonstrated that prevention of LVH does not lead to dilated
cardiac failure in the setting of pressure overload.65 67 Specifically, blockade of calcineurin either pharmacologically
with cyclosporine66 or via transgenic overexpression of
myocyte-enriched calcineurin-interacting protein-1 (an endogenous inhibitor of calcineurin)67 attenuated the increase in
LV mass after aortic banding but did not lead to ventricular
dilation or decline in fractional shortening. Similarly, inhibition of concentric hypertrophy in 2 other transgenic mouse
models (1 in which Gq-mediated signaling was inhibited and
1 in which the dopamine -hydroxylase gene was disrupted,
blocking production of endogenous norepinephrine and epinephrine) was not associated with ventricular dilation or
reduced fractional shortening despite elevated wall stress.65
These data from animal studies suggest that inhibition of
concentric LVH is a potential therapeutic target in pressure-

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January 25, 2011

overload states such as hypertension,68 a hypothesis that

awaits testing in humans.
Classic Tenet 2: Concentric LVH Is a Common Precursor
to Dilated Cardiac Failure in the Absence of
Myocardial Infarction
Several lines of evidence support the concept that concentric
LVH commonly precedes dilated cardiac failure in patients
with hypertension. First, the findings of Meerson62 have been
duplicated in numerous animal models, including the spontaneously hypertensive rat69 and transgenic models of pathological hypertrophy including calcineurin overexpression.70
Second, hypertension is a major risk factor for the development of clinical heart failure.71 Third, progression from
concentric LVH to dilated cardiac failure has been demonstrated in humans with aortic stenosis72 and hypertrophic
cardiomyopathy.73 Fourth, LVEF overestimates cardiac contractility in the setting of concentric hypertrophy.74 Indeed,
more sophisticated measures assessing LV midwall shortening and peak systolic midwall circumferential strain document abnormalities in systolic function in patients with
concentric LVH despite a normal LVEF,7577 suggesting that
the process of developing dilated cardiac failure has begun.
However, there are important caveats when one considers
the aforementioned data.2,78 It is not known how well the
natural history in animal models or patients with aortic
stenosis or hypertrophic cardiomyopathy faithfully recapitulates that of human hypertensive disease. Although hypertension is associated with the development of clinical heart
failure, the percentage that is associated with a reduced or
preserved LVEF is uncertain. Finally, although concentric
LVH is associated with subtle abnormalities in systolic
function, it is not known whether such patients subsequently
develop ventricular dilation.
Another important consideration is the role of myocardial
infarction in the progression from hypertension to dilated
cardiac failure (pathways 3 and 4, Figure 1). LVH is
associated with incident coronary heart disease, including
myocardial infarction.79 Although the mechanisms linking
LVH and myocardial infarction remain obscure, LVH has
been associated with subclinical atherosclerosis as assessed
by coronary artery calcium as well as inflammation.80 Moreover, in a study in which serial cardiac catheterizations were
performed, plaque rupture was more common among patients
with LVH.81 A hypertensive patient with (pathway 4) or
without (pathway 3) concentric LVH who sustains a large
myocardial infarction will be at risk for developing dilated
cardiac failure. The key unresolved question is whether
concentric hypertrophy is a common precursor to dilated
cardiac failure in the absence of interval myocardial infarction in hypertensive patients (pathway 5).
Over the last 5 years, several studies have provided data to
address this question. In a retrospective study of 159 subjects
(77% black; mean age, 56 years) who had concentric LVH, a
normal LVEF, and a follow-up echocardiogram performed
for clinical indications at least 1 year after the baseline
echocardiogram, only 18% developed a reduced LVEF after
a median follow-up of 4 years.82 Furthermore, this transition occurred after an interval myocardial infarction in 41%

of patients. In 3042 participants of the Cardiovascular Health

Study with a normal LVEF, 8.7% developed a low LVEF
after 5-years of follow-up.83 Although increased LV mass
was an independent risk factor for that transition, it was
eccentric but not concentric hypertrophy that was associated
with this outcome.83 In total, these data suggest that concentric hypertrophy does not commonly progress to dilated
cardiac failure after 5 to 7 years of follow-up in the absence
of interval myocardial infarction (ie, pathway 5 is not
common). Large prospective studies with serial assessment
of ventricular structure and function over 5 to 10 years or
longer are necessary.2
Classic Tenet 3: In the Absence of Myocardial Infarction,
Hypertension Does Not Lead Directly to Dilated Cardiac
Failure Without Antecedent Concentric Hypertrophy
The classic paradigm of the progression of hypertensive heart
disease is that hypertension does not lead to dilated cardiac
failure unless there is interval myocardial infarction84 or a
preceding phase of concentric hypertrophy1 (ie, hypertension
does not lead directly to a dilated ventricular chamber)
(pathway 2, Figure 1). However, this may not be accurate.2
First, echocardiographic studies have found that eccentric
hypertrophy is at least as common as concentric hypertrophy
in many hypertensive populations,26,28 the caveat being that it
is not known whether such patients had antecedent concentric
LVH. Second, blacks who commonly have a nonischemic
cardiomyopathy attributed to hypertension have heart failure
onset at a relatively young age,85 making it less likely that
they had progressed from concentric hypertrophy to a burnedout dilated cardiomyopathy during a long latent period. Third,
in the Coronary Artery Risk Development in Young Adults
study, although LVH was associated with incident heart
failure 15 years later (80% of which occurred with dilated
cardiomyopathy or LVEF 50%),86 the predisposing LVH
was in an eccentric and not concentric pattern.87 In aggregate,
these data raise the possibility that hypertensive patients can
progress directly to dilated cardiac failure without antecedent
concentric hypertrophy (pathway 2). If so, it will be important
to determine whether patients who progress along this pathway have a defect in the ability to develop LV wall thickening
(which would be contrary to the conclusions of the animal
studies discussed above in the section about classic tenet 1) or
rather a predisposition to develop LV dilation perhaps due to
an underlying abnormality in the extracellular matrix.
Overall, further work is needed to determine how frequently hypertensive patients progress directly to LV dilation
(pathway 2) or concentric LVH (pathway 1). Because the
transition between the 2 appears uncommon in the absence of
interval injury (pathway 5), identifying factors that predispose patients to develop either LV dilation or wall thickening
will have implications for predicting the risk of subsequently
developing heart failure with a reduced or preserved LVEF,
respectively.

From LVH to Clinical Heart Failure

It is now well recognized that clinical heart failure can occur
either in the setting of reduced LVEF (pathway 7, Figure 1)
or preserved LVEF (pathway 6).88 The progression of asymptomatic LV dysfunction to clinical heart failure (pathway 7)

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Drazner
has been reviewed recently.89 Thus, this review will focus on
the progression from concentric LVH to symptomatic heart
failure with a normal LVEF (pathway 6, Figure 1).
One factor that appears to be associated with the development of heart failure in those with LVH and a normal LVEF
is a progressive change in the extracellular matrix. In an
elderly canine model of hypertension, exogenous mineralocorticoid (deoxycorticosterone acetate) administration was
associated with progressive cardiac fibrosis and increased LV
stiffness,90 suggesting that mineralocorticoid receptor activation may be important in this progression. Others have
demonstrated a shift in serum levels of matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases with
progression in the continuum of hypertensive heart disease.91
Higher tissue inhibitor of matrix metalloproteinase-1 levels,
which are associated with increased collagen accumulation,
were observed in patients with LVH and clinical heart failure
compared with patients with hypertension and LVH but no
clinical heart failure. In a study of 85 hypertensive patients,
serum levels of matrix metalloproteinase-2 and -9 and amino
peptide of procollagen type 3 were independent predictors of
identifying those with heart failure with a preserved LVEF,
and matrix metalloproteinase-2 had a better diagnostic utility
than B-type natriuretic peptide for this purpose.92 Together,
these studies suggest that progressive changes in the extracellular matrix may be responsible for the transition from
LVH to symptomatic heart failure with a preserved LVEF.
Another key component in the development of clinical
heart failure with a preserved LVEF appears to be elevation
in LV filling pressures. Data from implantable hemodynamic
monitors demonstrate that such filling pressures appear elevated in both the chronically compensated and acutely decompensated state of heart failure with preserved LVEF.93
Consistent with this hypothesis are echocardiographic data
that demonstrate an enlarged left atrium in patients with heart
failure and preserved LVEF94,95 as well as elevated pulmonary artery pressures, which are themselves correlated with
LV filling pressures.96

Conclusion
Hypertensive heart disease encompasses a broad spectrum
including asymptomatic LVH (either a concentric or an
eccentric pattern) and clinical heart failure (with either a
preserved or a reduced LVEF). There is considerable interindividual variability in the progression from hypertension to
LVH in both the magnitude of the increase in LV mass and its
geometric pattern (ventricular dilation or wall thickening).
Some of these differences are likely attributable to differences in the pressure load (which may not be discernable by
office measurements of blood pressure), concomitant medical
conditions, and the underlying neurohormonal milieu. However, these differences in LV geometry also suggest the
likelihood of operative genetic influences that are only
beginning to be uncovered. The classic paradigm of the
progression from hypertension to concentric hypertrophy and
then dilated cardiac failure has been established in animal
models, but recent data have challenged several of its components. First, in animal models of pressure overload, concentric hypertrophy, which normalizes wall stress, is not

From Hypertension to LVH and Heart Failure

331

obligatory to prevent dilated cardiac failure, raising the

possibility that targeted therapy of the hypertrophic pathway
may be a potential means to prevent hypertensive heart
disease. Second, the progression from concentric hypertrophy
to dilated cardiac failure in the absence of interval myocardial
infarction may not be a common pathway. Third, patients
with hypertension may progress directly to dilated cardiac
failure in the absence of myocardial infarction or antecedent
concentric hypertrophy. The frequency of this occurrence and
its triggers remain to be defined but are important to uncover
in order to determine why some hypertensive subjects develop LV dilation and others concentric LVH. Finally, the
mechanisms for the progression from asymptomatic concentric LVH to clinical heart failure with a preserved LVEF are
just now being unraveled. Presently, this transition appears to
be associated with progressive adverse remodeling of the
extracellular matrix and increase in LV filling pressures.
Further advances in our understanding of the risk factors for
progression along each of these pathways will undoubtedly
help to accomplish the goal of reducing the burden of heart
failure.

Acknowledgments
I appreciate the assistance of Dr James de Lemos for his critical
review of this manuscript.

Sources of Funding
Dr Drazner was supported by the James M. Wooten Chair in
Cardiology.

Disclosures
None.

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KEY WORDS: heart failure

hypertension

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hypertrophy

remodeling

The Progression of Hypertensive Heart Disease

Mark H. Drazner
Circulation. 2011;123:327-334
doi: 10.1161/CIRCULATIONAHA.108.845792
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