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642 Original article

Compensatory or inappropriat

e left ventricular mass indifferent models of left ventricular pressure overload:comparison between patients with aortic stenosis andarterial hypertensionGian Francesco Mureddua, Giovanni Cioffib, Carlo Stefenellib, AlessandroBoccanellia and Giovanni de Simonec

Background Aortic valve stenosis and arterial hypertension

(AH) are two models of left ventricular (LV) pressure

overload, which commonly induce increase in LV mass.

Prevalence and predictors of excess of LV mass

(inappropriate LVM) has been recently investigated in AH

patients. Whether or not this phenomenon also exists in

patients with aortic valve stenosis has to be defined.

Objective To evaluate prevalence of and factors associated

with inappropriate LVM as a response to overload in aortic

valve stenosis compared to AH patients.

Design and methods One hundred patients with aortic

valve stenosis (mean valve area 0.67 W 0.18 cm2/m2) were

studied by Doppler echocardiography and compared to 200

patients with AH. Inappropriate LVM was diagnosed when

the measured LV mass exceeded by 28% the expected

value predicted from height2.7, sex and stroke work.

Results Prevalence of inappropriate LVM was similar in

aortic valve stenosis (n: 24 U 24%) and AH patients (n:

55 U 27.5%). Aortic valve stenosis had greater LVM (203 W 57

vs. 182 W 53 g, P U 0.001), more concentric LV geometry,

lower midwall shortening and higher left atrial systolic force

than AH. In both study groups, high LV mass, concentric LV

geometry and reduced systolic function emerged as

independent correlates of inappropriate LV mass.

opyright © Lippincott Williams & Wilkins. Unautho

0263-6352 � 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

Conclusion Although LV and left atrial geometric

adaptation in aortic valve stenosis is different from AH,

reflecting a near-pure pressure overload, aortic valve

stenosis patients have a prevalence of inappropriately high

LVM which is similar to those with AH. Geometric and

functional characteristics of inappropriate LVM do not differ

in aortic valve stenosis and AH, despite the different loading

conditions. J Hypertens 27:642–649 Q 2009 Wolters Kluwer

Health | Lippincott Williams & Wilkins.

Journal of Hypertension 2009, 27:642–649

Keywords: aortic stenosis, arterial hypertension, cardiac load, ventriculargeometry, ventricular hypertrophy, ventricular mass

Abbreviations: AH, Arterial hypertension; AS, Aortic stenosis; LA, Left atrial;LV, Left ventricular; LVH, Left ventricular hypertrophy; NYHA, New York HeartAssociation

aCardiology Unit S. Giovanni-Addolorata Hospital, Rome, bEchocardiographyLaboratory, Villa Bianca Hospital, Trento and cDepartment of Clinical andExperimental Medicine, Naples, Italy

Correspondence to Gian Francesco Mureddu, MD, Cardiology Unit, Departmentof Cardiocirculatory Diseases, San Giovanni-Addolorata Hospital, Via AmbaAradam 8, 00184 Rome, ItalyTel: +39 06 77055399; fax: +39 06 8177587; e-mail: gfmureddu@tiscali.it

Received 27 November 2007 Revised 15 September 2008Accepted 17 September 2008

IntroductionLeft ventricular (LV) pressure overload is common to both

aortic stenosis and arterial hypertension (AH). However,

whereas aortic stenosis is the paradigm of pure pressure

overload, AH is typically a combined pressure–volume

overload state [1,2]. The two conditions are, therefore,

haemodynamically different. Both in aortic stenosis and in

AH, LV overload is thought to initially increase wall stress

and stimulate parallel myocyte growth leading to LV

hypertrophy (LVH), which is typically concentric [3,4].

According to this postulate, LVH would be finalized to

reduce wall stress and preserve LV pump function but over

time it becomes an inconvenient adaptation mechanism

[4], determining an alteration of myocardial structure that

leads to impairment of LV performance and progression

from compensated LVH to heart failure [5–12]. LV geo-

metric adaptations in conditions of pressure overload are

also closely related to changes in left atrial (LA) size and

function [2,13,14].

More recently, values of sex-specific LV mass exceeding

those expected for individual body size and stroke work,

called ‘inappropriate LV mass’, have been interpreted as

a ‘maladaptive response’ to increased LV load, emerging

as an independent predictor of adverse prognosis [15–

19]. The magnitude and characteristics of this pathophy-

siological state have been studied in patients with AH

[15–19], whereas they are unknown in patients with

aortic stenosis.

Accordingly, this study has been conceived to assess the

prevalence and the characteristics of inappropriate LV

mass in patients with aortic stenosis, compared with

patients with AH.

rized reproduction of this article is prohibited.

DOI:10.1097/HJH.0b013e32831cec98

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Ventricular mass growth in pressure overload Mureddu et al. 643

MethodsPatients aged more than 18 years with stable sinus

rhythm and any grade of aortic stenosis, defined as aortic

valve thickening on echocardiographic evaluation accom-

panied by a Doppler-measured peak flow velocity across

the valve of more than 2.5 m/s [20], were studied. They

were selected among patients consecutively referred to

the Echocardiography Laboratory of ‘Villa Bianca’ Hos-

pital in Trento by their general practitioners, for the

presence of cardiac murmur and suspected valve disease.

History of angina, syncope and/or worsening functional

status, as well as of AH, were not considered as

exclusion criteria.

A group of patients with AH was also included in the

study and compared with those with aortic stenosis,

matching the groups as explained below in the statistical

analysis section. These patients were consecutively

referred to the same echo-lab and during the same period

by their general practitioners, with AH as the indication

for the echocardiographic examination. AH was defined

as pharmacologically treated high blood pressure. The

same definition was used for those patients with aortic

stenosis who had these clinical characteristics, identifying

two subgroups of aortic stenosis patients (with and with-

out AH). In all AH and aortic stenosis patients, blood

pressure was well controlled for at least 6 months before

echocardiographic evaluation by pharmacological therapy

which was unchanged during that period.

For both groups the exclusion criteria were: previous

diagnosis of coronary heart disease (on the basis of history

of myocardial infarction, any procedure of coronary artery

revascularization and the results of exercise/echo-stress

test or coronary angiography), LV wall motion abnorm-

alities, any grade of mitral stenosis, moderate to severe

aortic and/or mitral regurgitation, and documented epi-

sodes of sustained atrial arrhythmias occurring within

3 months before the echocardiogram. Patients taking

medications to prevent recurrence of atrial arrhythmias

were also considered not eligible for this study.

EchocardiographyStandard transthoracic Doppler-echocardiographic stu-

dies were performed in a dimly light room with all

patients in partial left decubitus position using a Megas

Esaote Biomedica machine (Florence, Italy) equipped

with a 2.5–3.5 MHz annular-array transducer. LV

chamber dimensions, septum and posterior wall thick-

ness and mass were measured according to the American

Society of Echocardiography [21,22], using M-mode tra-

cings. LV dimension was normalized for body height and

LV mass for height to the 2.7 power [23]. LV hypertrophy

was defined as LV mass more than 51 g/m2.7 [23]. Relative

wall thickness was calculated as two times the posterior

wall thickness/LV diastolic diameter ratio in all patients

independently of the presence of LV hypertrophy and

opyright © Lippincott Williams & Wilkins. Unauth

used as index of LV geometry. Values of this index

greater than 0.44 were considered to be indicative of

concentric geometry, whereas eccentric geometry was

identified for values less than 0.44, as previously reported

[1]. Thus, four subgroups of patients were identified

according to LV geometric pattern: patients with normal

geometry (mass <51 g/m2.7 and relative wall thickness

<0.44), concentric remodeling (mass <51 g/m2.7 and

relative wall thickness >0.44), concentric hypertrophy

(mass >51 g/m2.7 and relative wall thickness >0.44) and

eccentric hypertrophy (mass >51 g/m2.7 and relative wall

thickness <0.44). Wall LV mechanics were assessed by

computation of midwall fractional shortening according

to previously reported methods [10,11]. Circumferential

end-systolic stress was calculated, on the basis of a

cylindrical model, as previously described [10,11].

Stress-corrected midwall shortening less than 88% in

men and less than 89% in women was considered depres-

sed [24] and used as cut-off for definition of LV systolic

dysfunction. The area–length method was used to gen-

erate maximal LA volume [25]. Both LA and LV volumes

were normalized for height to the third power, consistent

with expected allometric relations between variables

with volumetric dimensions. LA systolic force was used

as an index of LA function and calculated according to the

formula previously validated by Manning et al. [26].

Aortic valve area was measured by the continuity

equation method and normalized for body surface area.

LV stroke work loss was also measured to assess the

degree of aortic stenosis [27]. Valve disease severity

(mild, moderate and severe aortic stenosis) was identified

by maximizing between-cluster value of aortic valve area

using Euclidean distance metric. Patients were also stra-

tified according to the values of LV stroke work loss using

the frequency procedure of tertiles.

Appropriateness of LV mass was defined as the ratio

between observed and predicted value [28]. LV mass

was predicted from stroke work, sex and body size by the

following reference equation:

Predicted LV mass ¼ 55:37þ ð6:63� height 2:7Þ

þ ð0:64� stroke workÞ � 18:1

� sex

where stroke work was estimated as systolic blood pres-

sure times stroke volume (using the method of Teichholz

et al.) [29] and converted to g�m by multiplying by

0.0144; sex was assigned the value of 1 for men and 2

for women. In aortic stenosis patients, stroke work was

obtained by adding the CW Doppler transaortic peak

gradient to brachial systolic blood pressure. LV mass was

defined as inappropriate when higher than 28% of the

value predicted (95th percentile of normal distribution)

and adequate for values equal to or smaller than 28% [28].

orized reproduction of this article is prohibited.

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644 Journal of Hypertension 2009, Vol 27 No 3

Table 1 General characteristics of study population: comparison between patients with systemic arterial hypertension and aortic stenosis(divided in two subgroups with or without hypertension)

VariablesHypertensives(200 patients)

Aortic stenosis withhypertension (37 patients)

Aortic stenosis withouthypertension (63 patients) P

Age (years) 74�7 78�7§ 74�10 0.02Male sex (%) 41 35 43 n.s.Body weight (kg) 72�13 70�16 70�14 n.s.Body height (m) 1.65�0.08 1.64�0.09 1.64�0.08 n.s.Body mass index (kg/m2) 26.6�4.2 26.5�4.0 26.4�4.0 n.s.Systolic blood pressure (mmHg) 151�19§ 160�15§ 132�13§ <0.0001Diastolic blood pressure (mmHg) 87�14§ 86�11§ 79�9§ <0.001Heart rate (beats min�1) 66�17 68�11 68�10 n.s.Medicationsa

Diuretics 32 (%) 38 (%) n.s.ACE inhibitors/AT1-RB 59 (%) 60 (%) n.s.Calcium antagonists 32 (%) 30 (%) n.s.Beta-blockers 30 (%) 28 (%) n.s.

RB, receptor blockers. a Patients with aortic stenosis without hypertension (n¼63) were off drugs. Medications (%) are calculated considering only the 37 patients withaortic stenosis and hypertension. § P<0.05 vs. all other groups.

Data on intraobserver/interobserver variability and

test/re-test variability for the assessment of LV mass

appropriateness measured by this method have become

available [30].

Statistical analysisData are reported as mean values� 1SD. Patients with

AH were statistically matched with their counterparts

affected by aortic stenosis for potential confounders

such as age, sex, body weight and height and body mass

index according to the following procedure: a Gower’s

generalized distance from each of the patients with aortic

stenosis was computed and ranked in ascending order.

The distance was calculated using the following vari-

ables: age, sex, body height, body weight, body mass

index. The AH group was then defined by taking for each

patient with aortic stenosis the two closest cases.

Unpaired Student’s test and x2 statistics were used for

descriptive statistics. Between-group comparisons of con-

tinuous and normally distributed variables were per-

formed by the analysis of variance (ANOVA). Least

squares linear regressions were used to investigate the

relation of observed/predicted LV mass and the indices of

LV and LA function. Stepwise multiple linear regression

was used to identify independent correlates of inap-

propriate LV mass both in aortic stenosis and AH

patients, entering variables significantly related to inap-

propriate LV mass in univariate analysis. SPSS 11.0

Release (SPSS Inc., Chicago, Illinois, USA) was used

for statistical analysis. A two-tailed value of P less than

0.05 was considered statistically significant.

ResultsStudy populationThe recruitment period lasted from March 2004 to March

2006. During this period, 100 patients with aortic stenosis

(63 without AH and 37 with AH) met the enrollment

criteria and entered the study. Among the 336 patients

with AH who were eligible during the same period, 200

opyright © Lippincott Williams & Wilkins. Unautho

were selected and matched with the aortic stenosis group

accordingly to the previously described procedure and

formed the final study group of AH patients. The main

characteristics of the study groups are listed in Table 1.

Among 100 aortic stenosis patients, only 4 declared

symptoms potentially due to aortic valve disease (1

had high threshold stable angina, 3 had reduced func-

tional NYHA class). The remaining 96 patients with

aortic stenosis and all 200 AH patients were free of

symptoms and physical signs of cardiac disease. Patients

with aortic stenosis exhibited greater LV mass and more

concentric LV geometry than those with AH. Prevalence

of LV hypertrophy, LA volume and systolic force were

significantly greater in the groups with aortic stenosis

(Table 2). Patients with aortic stenosis without AH had

reduced indices of LV systolic function in comparison

with the other two groups.

Prevalence of inappropriate left ventricular massEchocardiographic characteristics of the study groups are

shown in Table 2. Prevalence of inappropriate LV mass

was similar in patients with aortic stenosis and AH (24 and

27.5%, respectively, P¼NS), but some differences

emerged when examining LV geometric patterns

(Fig. 1). Prevalence of inappropriate LV mass was not

significantly different in aortic stenosis and AH when LV

geometry was normal – a condition more frequent in AH

than in aortic stenosis (51 and 31%, respectively;

P¼ 0.001). However, in the presence of LVH, inap-

propriate LV mass was more frequent in AH than in

aortic stenosis (P< 0.01), independent of LV geometric

pattern (P¼ 0.04 and 0.001 in concentric and eccentric

LVH, respectively). No difference was found in the

presence of concentric LV remodelling.

Inappropriate left ventricular mass in aortic stenosispatients with and without aortic hypertensionAmong 100 aortic stenosis patients, 37 (37%) also had AH.

These patients were older and had higher systolic and

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Ventricular mass growth in pressure overload Mureddu et al. 645

Table 2 Echocardiographic characteristics of study population: comparison between patients with systemic arterial hypertension and aorticstenosis (divided into two subgroups with or without hypertension)

VariablesHypertensives(200 patients)

Aortic stenosis withhypertension (37 patients)

Aortic stenosis withouthypertension (63 patients) P

LV end-diastolic diameter (cm/h) 2.94�0.28 2.9�0.30 3.0�0.33 N.S.Relative wall thickness 0.42�0.07§ 0.45�0.08 0.44�0.08 0.02LV mass (g) 182�53§ 194�52 208�60 0.001LV mass index (g/m2.7) 52�12M 57�16 59�13 0.001LV hypertrophy [n (%)] 56 (28%)§ 52 (43%) 52 (57%) 0.001Cess (kdyn/cm2) 139�44y 133�44 120�44 0.02Stress-corrected MFS (%) 88�16y 85�11 79�14 0.002LV systolic dysfunction (%) 100 (50%)y 69 (55%) 69 (73%) 0.002LA maximal volume (ml/h3) 8.5�2.6§ 11.8�4.2 10.4�3.3 0.000001LA systolic force (kdyn/cm2) 9.2�6§ 16.0�10 17.2�10 0.00001Predicted LV mass (g) 159�37§ 189�48 177�48 0.00001Observed/predicted LV mass (g) 116�31 107�26 117�28 N.S.

Cess, Circumferential end-systolic stress; LA, left atrial; LV, left ventricular. LV systolic dysfunction, stress-corrected midwall shortening<88% in men and<89% in women;MFS, midwall fractional shortening. § P<0.05 vs. all other groups. yP<0.05 vs. aortic stenosis without HT. MP<0.05 vs. aortic stenosis with HT.

diastolic blood pressure at the time of study evaluation

than their counterparts without AH. All patients with

aortic stenosis and hypertension were receiving antihy-

pertensive medications at the time of study evaluation,

whereas those without hypertension were off drugs

(Table 1). The two subgroups of patients did not differ

for any other clinical and echocardiographic parameter.

Prevalence of inappropriate LV mass in aortic stenosis

patients with and without AH was similar (16 and 29%,

respectively, P¼NS).

Inappropriate left ventricular mass and severity of valvediseaseAortic stenosis patients were categorized into three sub-

groups according to the valve area measured by the

continuity equation method (mild aortic stenosis¼ area

>0.75 cm2/m2, moderate aortic stenosis¼ area between

0.74 and 0.56 cm2/m2, severe aortic stenosis¼ area

<0.56 cm2/m2). Prevalence of LVH was similar between

the three subgroups (50, 44 and 64%, respectively).

opyright © Lippincott Williams & Wilkins. Unauth

Fig. 1

Prevalence (%) of the different left ventricular geometric patterns in thewhole hypertensive and aortic stenosis groups (white and blackcolumns, respectively) and prevalence (%) of inappropriate leftventricular mass in each study subgroup (spotted columns).

Prevalence of inappropriate LV mass was marginally

higher in the subgroups with moderate (9 of 34¼ 26%)

and severe (9 of 28¼ 32%) aortic stenosis than in that

with mild grade of valvular obstruction (6 of 38¼ 16%), a

difference that did not achieve, however, statistical sig-

nificance. Similarly, no significant difference in preva-

lence of inappropriate LV mass emerged among the

tertiles of LV stroke work loss (22, 31 and 25% in tertiles

with low, moderate and high LV stroke work loss,

respectively, P¼NS).

Characteristics of inappropriate left ventricular massTable 3 shows that, in the presence of inappropriate LV

mass, both patients with aortic stenosis and those with

AH were similarly characterized by high LV mass and

concentric LV geometry, reduced indexes of LV systolic

performance and higher LA volume as compared to those

with appropriate LV mass. Close negative linear relations

were found between excess of LV mass (expressed by the

observed/predicted ratio) and LV midwall shortening

both in aortic stenosis (r¼�0.76, P< 0.00001) and in

AH patients (r¼�0.77, P< 0.00001) (Fig. 2), whereas no

significant relation was found between excess of LV mass

and LA systolic force (r¼ 0.11 and 0.14 in aortic stenosis

and AH patients, respectively).

In multiple linear regression analyses run separately in

patients with aortic stenosis (with and without AH) and

AH (including age, systolic blood pressure, body weight,

body mass index, LV end-diastolic diameter and mass,

relative wall thickness, LV midwall shortening, stress-

corrected LV midwall shortening, LV endocardial frac-

tional shortening and LA maximal volume), reduced LV

systolic function (expressed as stress-corrected LV mid-

wall shortening) emerged as a variable mutually associ-

ated with LV mass excess in either study group (Table 4).

DiscussionEvaluation of the appropriateness of LV mass response to

cardiac load allows to investigate the nature of compen-

satory LV hypertrophy in AH. Values of sex-specific LV

orized reproduction of this article is prohibited.

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646 Journal of Hypertension 2009, Vol 27 No 3

Table 3 List of variables that were significantly different between patients with appropriate and inappropriate left ventricular mass

Variables Appropriate left ventricular mass Inappropriate left ventricular mass P

Aortic stenosis with hypertension [n (%)] 45 (71%) 18 (29%)Relative wall thickness 0.43�0.07 0.53�0.09 0.004LV ejection fraction (%) 60�68 68�7 0.02LV mass index (g/m2.7) 49�11 60�10 0.03LV midwall shortening (%) 16.2�2.8 11.8�2.1 0.001Stress corrected midwall shortening (%) 87�16 68�8 0.0001LA maximal volume (ml/height3) 11.0�3.8 15.6�5.3 0.01

Aortic stenosis without hypertension [n (%)] 31 (84%) 6 (16%)Age (years) 72�11 78�6 0.03Systolic blood pressure (mmHg) 139�13 126�11 0.02Relative wall thickness 0.43�0.08 0.47�0.08 0.03LV mass index (g/m2.7) 51�13 64�14 0.001LV midwall shortening (%) 16.0�2.6 12.2�2.1 0.0001Stress corrected midwall shortening (%) 85�12 65�10 0.00001Endocardial fractional shortening (%) 37�10 28�7 0.0001

Hypertensives [n (%)] 145 (72.5%) 55 (27.5%)Age (years) 73�6 76�7 0.02Systolic blood pressure (mmHg) 153�23 148�21 0.03Body mass index 25.8�3.9 27.6�4.1 0.004LV end-diastolic diameter (cm/h) 2.9�0.2 3.0�0.3 0.01LV mass (g) 159�37 256�53 0.0001LV mass index (g/m2.7) 42�10 58�12 0.0000001Relative wall thickness 0.40�0.06 0.47�0.07 0.0000001LV midwall shortening (%) 17.6�2.3 13.6�2.3 0.0000001Stress corrected midwall shortening (%) 95�11 74�11 0.0000001Endocardial fractional shortening (%) 39�7 32�8 0.00001Stroke work (ml/mmHg) 197�57 167�55 0.02LA maximal volume (ml//height3) 7.9�2.1 9.8�2.8 0.000001

LA, left atrial; LV, left ventricular. Separate analyses (univariate model) in patients with aortic stenosis and systemic arterial hypertension.

mass exceeding those expected for body size and stroke

work, namely ‘inappropriate LV mass’, have been con-

sidered as a redundant and harmful biological response to

increased LV load. Several studies conducted in patients

with AH demonstrated that inappropriate LV mass is

likely to be related to adverse metabolic profile and high-

risk cardiovascular phenotype, including greater preva-

lence of concentric LV geometry and impairment of LV

opyright © Lippincott Williams & Wilkins. Unautho

Fig. 2

Lef

t ven

tric

ula

r m

idw

all s

ho

rten

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(%

)

2001801601401201008060406

8

10

12

14

16

18

20

22

24

Excess of LV mass (observed/predicted LVM ratio)

Aortic stenosis(100 patients)

r = -- 0.76

Relationship between left ventricular midwall shortening and left ventricularobserved/predicted left ventricular mass ratio (%) in patients with aortic stelinear correlation and 95% confidence limits are shown.

systolic and diastolic function, that justifies the evidence

of adverse prognosis [14–18,31,32].

To our knowledge, this is the first study providing infor-

mation on prevalence and functional characteristics

associated with inappropriate LV mass in individuals

with aortic stenosis. The main result of our study is that

approximately one-fourth of patients with aortic stenosis

rized reproduction of this article is prohibited.

22020018016014012010080606

8

10

12

14

16

18

20

22

24

Excess of LV mass (observed/predicted LVM ratio)

Lef

t ven

tric

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r m

idw

all s

ho

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(%

)

Arterial hypertension(200 patients)

r = -- 0.77

mass excess (inappropriate left ventricular mass) expressed as thenosis (left panel) and arterial hypertension (right panel). Scatter plot of

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Ventricular mass growth in pressure overload Mureddu et al. 647

Table 4 Multiple regression analyses applied in patients withhypertension, aortic stenosis with and without hypertension:variables independently associated with inappropriate leftventricular mass expressed as ratio observed/predicted leftventricular mass (%)

Arterial hypertension Exp (beta) P

Stress-corrected midwall shortening (%) �0.56 0.0000001Left ventricular end-diastolic diameter (cm) 0.49 0.000001

Relative wall thickness 0.46 0.000001Multiple r¼0.89; r2¼0.79; intercept¼�3.6; SEE¼12.6; F¼236;P¼0.0000001

Aortic stenosis with arterial hypertension Exp (beta)

Stress-corrected midwall shortening (%) �0.69 0.0000001Relative wall thickness 0.37 0.000001

Multiple r¼0.90 r2¼0.82 intercept¼132.2 SEE¼9.2 F¼58.1P¼0.0000001

Aortic stenosis without arterial hypertension Exp (beta)

Stress-corrected midwall shortening (%) �0.68 0.0000001Left ventricular mass (g/h2.7) 0.39 0.000001

Multiple r¼0.84, r2¼0.71, intercept¼175.0, SEE¼13.5, F¼51.4,P¼0.0000001.

exhibit inappropriately high LV mass, a prevalence which

is not statistically different from that found in our hyper-

tensive patients. A similar magnitude of inappropriate LV

mass was reported in other studies conducted on AH

patients [14–18,31]. This phenomenon does not seem to

be influenced by the coexistence of AH in aortic stenosis

patients, because the prevalence of inappropriate LV

mass was similar between the two study aortic stenosis

subgroups, with and without AH.

In the AH and aortic stenosis groups, inappropriate LV

mass was recognized in a small proportion of patients with

normal LV geometry. In these patients, evidently, the

simple measurement of LV mass could underestimate

the risk for cardiovascular events. Conversely, the preva-

lence of inappropriate LV mass was particularly high in

the subgroups of patients with LV hypertrophy, and this

behaviour was detected more frequently in patients with

AH than aortic stenosis. It is possible that the role of

nonhaemodynamic factors as determinants of LV mass

inappropriateness such as proto-oncogenes and other

growth factors, cytokines, plasma noradrenaline and other

neurohormones has more influence in AH than aortic

stenosis patients [33–35]. Recent studies documented a

significant increase in a member of the interleukin-6

superfamily, ‘cardiotrophin-1’, in patients with inap-

propriate LV mass. This finding was detected both in

patients with AH [36], in whom cardiotrophin-1 increased

or decreased according to the regression or persistence of

mass excess during the time, respectively, and in those

with aortic stenosis [37], whose plasma levels of cardio-

trophin-1 were proportional to the valvular severity.

These studies could support the hypothesis that a chronic

opyright © Lippincott Williams & Wilkins. Unauth

excess of cardiotrophin-1 may predispose hearts to pro-

gress to heart failure and/or other cardiovascular compli-

cations through the development of an excess of LV

mass, but data on the link between this biochemical

marker and clinical events are not yet available.

In this study, the prevalence of inappropriate LV mass

was similar in the three groups of patients with different

degrees of aortic stenosis, suggesting a possible appli-

cation of this bioassay for decision making. Whether the

presence of inappropriate LV mass might help identify

the time for aortic valve replacement and/or stratify the

risk of cardiovascular morbidity and mortality remains to

be clarified.

Also, interestingly, this study demonstrates that, despite

differences in LV overload between the two pathophy-

siological models, the cardiac characteristics associated

with inappropriate LV mass are identical in aortic stenosis

and AH patients. In both overload patterns, inappropriate

LV mass is associated with concentric LV geometry and

reduced systolic function, visible at both endocardial and

midwall levels, paralleling lower brachial systolic pres-

sure, as a possible indirect marker of LV pump failure.

However, differences between the two models of LV

overload exist that should be highlighted.

In aortic stenosis, LV systolic function appears to be more

severely reduced than in AH, and, on the basis of our

findings, to be relatively independent of myocardial after-

load, being most probably related to more impaired

myocardial contractility, as also suggested by the con-

comitant preserved LV chamber dimension (a raw index

of preload). This adverse cardiac phenotype in aortic

stenosis is amplified in the presence of inappropriate

LV mass. Aortic stenosis patients with inappropriate

LV mass exhibit the lowest level of LV systolic function

and the greatest LA volume (nearly twice the LA volume

found in the AH patients with appropriate LV mass),

strongly suggesting also a severe, albeit asymptomatic,

global LV dysfunction, also including LV diastolic dys-

function [38]. Merging this functional impairment with

the highly prevalent concentric LV geometric pattern and

LA dilatation (as a raw marker of LV diastolic dysfunc-

tion) [38] found in the aortic stenosis group, a cluster of

adverse characteristics emerges that was recently hypoth-

esized to potentially lead to cardiac decompensation,

even in the absence of coronary heart disease [16,39].

Abnormalities in LV size, geometric pattern and

performance, however, cannot completely explain the

magnitude of LV mass excess in aortic stenosis. Micro-

structural abnormalities including increased micro-

tubules, nuclear DNA mutations, ACE and TGF-ß1

up-regulation and apoptosis parallel LV hypertrophy

and dysfunction in aortic stenosis experimental models

[6,40]. Whether these alterations simply represent a

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648 Journal of Hypertension 2009, Vol 27 No 3

negative ‘side effect ‘ of LV mass growth or, instead, an

important determinant has to be yet understood.

ConclusionAlthough LV and LA geometric adaptation in aortic

stenosis is quite different from AH, reflecting a near-pure

pressure overload, aortic stenosis patients have a similar

prevalence of inappropriately high LV mass to those with

AH and the variables associated with this condition are

analogous in the two groups. Particularly, as already

demonstrated in AH, the strong negative relationship

between LV mass excess and LV systolic function could

be of clinical relevance also in aortic stenosis patients.

Future studies should investigate whether inappropriate

LV mass may provide prognostic information also in

aortic stenosis patients, whose timing for surgery could

be better arranged.

References1 Ganau A, Devereux RB, Roman MJ, de Simone G, Pickering TG, Saba PS,

et al. Patterns of left ventricular hypertrophy and geometric remodeling inessential hypertension [see comments]. J Am Coll Cardiol 1992;19:1550–1558.

2 Chinali M, de Simone G, Liu JE, Bella JN, Oberman A, Hopkins PN, et al.Left atrial systolic force and cardiac markers of preclinical disease inhypertensive patients: the Hypertension Genetic Epidemiology Network(HyperGEN) Study. Am J Hypertens 2005; 18:899–905.

3 Grossman W, Jones D, McLaurin LP. Wall stress and patterns ofhypertrophy in human left ventricle. J Clin Invest 1975; 56:56–64.

4 Meerson FZ. The myocardium in hyperfunction, hypertrophy and heartfailure. Circ Res 1969; 25 (Suppl 163).

5 Devereux RB, de Simone G, Ganau A, Koren MJ, Mensah GA, Roman MJ.Left ventricular hypertrophy and hypertension. Clin Exp Hypertens 1993;15:1025–1032.

6 Hein S, Arnon E, Kostin S, Schonburg M, Elsasser A, Polyakova V, et al.Progression form compensated hypertrophy to failure in the pressure-overloaded human heart. Structural deterioration and compensatorymechanisms. Circulation 2003; 107:984–991.

7 Verdecchia P, Schillaci G, Borgioni C, Ciucci A, Battistelli M, Barroccini C,et al. Adverse prognostic significance of concentric remodeling of the leftventricle in hypertensive patients with normal left ventricular mass. J AmColl Cardiol 1995; 15:871–878.

8 Krumholz HM, Larson M, Levy D. Prognosis of left ventricular geometricpatterns in the Framingham Heart Study. J Am Coll Cardiol 1995;879–884.

9 Shimizu G, Hirota Y, Kita Y, Kawamura K, Saito T, Gaasch WH. Leftventricular midwall mechanics in systemic arterial hypertension. Myocardialfunction is depressed in pressure-overload hypertrophy. Circulation 1991;83:1676–1684.

10 de Simone G, Devereux RB, Roman MJ, Ganau A, Saba PS, Alderman MH,Laragh JH. Assessment of left ventricular function by the midwall fractionalshortening/end-systolic stress relation in human hypertension. J Am CollCardiol 1994; 23:1444–1451.

11 de Simone G, Devereux RB, Koren MJ, Mensah GA, Casale PN, Laragh JH.Midwall left ventricular mechanics. An independent predictor ofcardiovascular risk in arterial hypertension. Circulation 1996; 93:259–265.

12 Aurigemma GP, Silver KH, McLaughlin M, Mauser J, Gaasch WH. Impact ofchamber geometry and gender on left ventricular systolic function inpatients >60 years of age with aortic stenosis. Am J Cardiol 1994;74:794–798.

13 Cioffi G, Mureddu GF, Stefenelli C, de Simone G. Relationship between leftventricular geometry and left atrial size and function in patients withsystemic hypertension. J Hypertens 2004; 22:1–8.

14 Cioffi G, Stefenelli C. Comparison of left ventricular geometry and left atrialsize and function in patients with aortic stenosis vs. those with pure aorticregurgitation. Am J Cardiol 2002; 90:601–606.

15 de Simone G, Verdecchia P, Pede S, Gorini M, Maggioni AP. Prognosis ofinappropriate left ventricular mass in hypertension: the MAVI Study.Hypertension 2002; 40:470–476.

opyright © Lippincott Williams & Wilkins. Unautho

16 Chinali M, De Marco M, D’Addeo G, Benincasa M, Romano C, Galderisi M,de Simone G. Excessive increase in left ventricular mass identifieshypertensive subjects with clustered geometric and functionalabnormalities. J Hypertens 2007; 25:1073–1078.

17 de Simone G, Palmieri V, Koren MJ, Mensah GA, Roman MJ, Devereux RB.Prognostic implications of the compensatory nature of left ventricular massin arterial hypertension. J Hypertens 2001; 19:119–125.

18 Palmieri V, Wachtell K, Gerdts E, Bella JN, Papademetriou V, Tuxen C, et al.Left ventricular function and hemodynamic features of inappropriate leftventricular hypertrophy in patients with systemic hypertension: the LIFEstudy. Am Heart J 2001; 141:784–791.

19 Mureddu GF, Pasanisi F, Palmieri V, Celentano A, Contaldo F, de SimoneG. Appropriate or inappropriate left ventricular mass in the presence orabsence of prognostically adverse left ventricular hypertrophy. J Hypertens2001; 19:1113–1119.

20 American College of Cardiology/American Heart Association Task Forceon Practice Guidelines; Society of Cardiovascular Anesthesiologists;Society for Cardiovascular Angiography and Interventions; Society ofThoracic Surgeons. Bonow RO, Carabello BA, Kanu C, de Leon AC Jr,Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT,O’Rourke RA, Otto CM, Shah PM, Shanewise JS, Smith SC Jr, Jacobs AK,Adams CD, Anderson JL, Antman EM, Faxon DP, Fuster V, Halperin JL,Hiratzka LF, Hunt SA, Lytle BW, Nishimura R, Page RL, Riegel B. ACC/AHA 2006 guidelines for the management of patients with valvular heartdisease: a report of the American College of Cardiology/American HeartAssociation Task Force on Practice Guidelines (writing committee to revisethe 1998 Guidelines for the Management of Patients With Valvular HeartDisease): developed in collaboration with the Society of CardiovascularAnesthesiologists: endorsed by the Society for CardiovascularAngiography and Interventions and the Society of ThoracicSurgeons. Circulation 2006; 114:84–231. J Am Coll Cardiol 2006;48:1–148.

21 Sahn DJ, Demaria A, Kisslo J, Weyman A. The committee on M-Modestandardization on the American Society of Echocardiography:recommendations regarding quantitation in M-Mode echocardiography.Results of a survey study of echocardiographic measurements. Circulation1978; 58:1072–1083.

22 Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I,Reichek N. Echocardiographic assessment of left ventricular hypertrophy:comparison to necropsy findings. Am J Cardiol 1986; 57:450–458.

23 de Simone G, Devereux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH.Effect of growth on variability of left ventricular mass: assessment ofallometric signals in adults and children and their capacity to predictcardiovascular risk. J Am Coll Cardiol 1995; 25:1056–1062.

24 Bella JN, Palmieri V, Liu JE, Kitzman DW, Oberman A, Hunt SC, et al., TheHypertension Genetic Epidemiology Network (HyperGEN) Study.Relationship between left ventricular diastolic relaxation and systolicfunction in hypertension. Hypertension 2001; 38:424–428.

25 Lester SJ, Ryan EW, Schiller NB, Foster E. Best method in clinical practiceand in research studies to determine left atrial size. Am J Cardiol 1999;84:829–832.

26 Manning WJ, Silverman DI, Katz SE, Douglas PS. Atrial ejection force: anoninvasive assessment of atrial systolic function. J Am Coll Cardiol 1993;22:221–225.

27 Tobin JR Jr, Rahimtoola SH, Blundell PE, Swan HJ. Percentage of leftventricular stroke work loss. A simple hemodynamic concept forestimation of severity in valvular aortic stenosis. Circulation 1967; 35:868–879.

28 de Simone G, Devereux RB, Kimball TR, Mureddu GF, Roman MJ, ContaldoF, Daniels SR. Interaction between body size and cardiac workload.Influence of left ventricular mass during body growth and adulthood.Hypertension 1998; 31:1077–1082.

29 Teichholz LE, Kreulen T, Herman MV, Gorlin R. Problems inechocardiographic volume determinations: echocardiographic–angiographic correlations in the presence or absence of asynergy. Am JCardiol 1976; 37:7–11.

30 Muiesan ML, de Simone G, Ganau A, Longhini C, Verdecchia P, Mancia G,Agabiti-Rosei E, Working Group on Heart and Hypertension of ItalianSociety of Hypertension. Inappropriate left ventricular mass: reliability andlimitations of echocardiographic measurement for risk stratification andfollow-up in single patients. J Hypertens 2006; 24:2293–2298.

31 de Simone G, Kitzman DW, Palmieri V, Liu JE, Oberman A, Hopkins PN,et al. Association of inappropriate left ventricular mass with systolic anddiastolic dysfunction: the HyperGEN study. Am J Hypertens 2004;17:828–833.

32 Celentano A, Palmieri V, Esposito ND, Pietropaolo I, Crivaro M, MuredduGF, et al. Inappropriate left ventricular mass in normotensive andhypertensive patients. Am J Cardiol 2001; 87:361–363.

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33 Strand AH, Gudmundsdottir H, Os I, Smith G, Westheim AS, BjornerheimR, Kjeldsen SE. Arterial plasma noradrenaline predicts left ventricular massindependently of blood pressure and body build in men who develophypertension over 20 years. J Hypertens 2006; 24:905–913.

34 Olsen MH, Wachtell K, de Simone G, Palmieri V, Dige-Petersen H,Devereux RB, et al. Is inappropriate left ventricular mass related toneurohormonal factors and/or arterial changes in hypertension? A LIFEsubstudy. J Hum Hypertens 2004; 18:437–443.

35 de Simone G, Pasanisi F, Contaldo F. Link of nonhemodynamic factors tohemodynamic determinants of left ventricular hypertrophy. Hypertension2001; 38:13–18; Review.

36 Lopez B, Castellano JM, Gonzalez A, Barba J, Diez J. Association betweenplasma cardiotrophin-1 and inappropriate Lift ventricular mass in essentialhypertension. Hypertension 2007; 50:977–983.

37 Talwar S, Downie PF, Squire IB, Davies JE, Barnett DB, Nq LL. PlasmaN-terminal pro-BNP and cardiothophin-1 are elevated in aortic stenosis.Eur J Heart Failure 2001; 3:15–19.

38 Abhayaratna WP, Seward JB, Appleton CP, Douglas PS, Oh JK, Tajik AJ,Tsang TS. Left atrial size: physiologic determinants and clinicalapplications. J Am Coll Cardiol 2006; 47:2357–2363.

39 de Simone G, Gottdiener J, Chinali M, Maurer M. Left ventricular masspredicts heart failure not related to previous myocardial infarction: theCardiovascular Heart Study. Eur Heart J 2008; 29:741–747.

40 Zile MR, Green GR, Schuyler GT, Aurigemma GP, Miller DC, Cooper G4th. Cardiocyte cytoskeleton in patients with left ventricular pressureoverload hypertrophy. J Am Coll Cardiol 2001; 37:1080–1084.

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