STATE OF THE ART
Left Ventricular Hypertrophy and Clinical Outcomes
in Hypertensive Patients
Luis M. Ruilope1 and Roland E. Schmieder2
The prevalence of left ventricular hypertrophy (LVH) rises with
severity of Hypertension (HT), age, and obesity. Its prevalence
ranges from 20% in mildly hypertensive patients to almost 100%
in those with severe or complicated HT. However, the diagnosis of
LVH is not straightforward, and the definitions and criteria used in
clinical studies lack consistency. While many factors play a role in the
onset and progression of LVH, blood pressure (BP) is recognized as a
central factor. Twenty-four-hour BP measurements are more closely
related to LVH than conventional BP readings taken in the clinician’s
office. Increased renin–angiotensin system (RAS) activity also plays
an important role in the development of LVH, and various studies
show a correlation between plasma renin activity and left ventricular
mass (LVM). LVH is a recognized marker of HT-related target organ
damage, and a strong and independent risk factor for adverse
cardiovascular (CV) outcomes. CV risk increases with increasing LVM,
Left ventricular hypertrophy (LVH) is the heart’s adaptive
response to a chronically increased workload, with systemic
hypertension (HT) being a common cause. It is a recognized
intermediate marker of HT-related target organ damage, and a
strong predictor of congestive heart failure, coronary heart dis-
ease, and stroke.1–4 The risk of such cardiovascular (CV) events
increases with increasing left ventricular mass (LVM), and
there is no specific cutoff point for mass to indicate pathological
hypertrophy.5,6 LVH is, to a great extent, a reversible risk factor;
its regression in response to antihypertensive treatment signifi-
cantly improves the CV outcome and long-term prognosis.
This review concentrates on outcomes related to LVH in HT.
It briefly outlines the different ways of identifying LVH, and
focuses on reviewing the literature relating LVH to CV out-
comes and examining the role and economic implications of
current and future antihypertension strategies.
Measurement of lvh
The consistent identification of hypertensive patients with
LVH is important, both for clinical practice and for research.
Currently, LVH diagnosis is not straightforward, and the ­criteria
used for defining LVH in clinical studies lack ­consistency.
1Hospital 12 de Octubre, Avda. de Córdoba s/n, Madrid, Spain; 2Department of
Nephrology and Hypertension, University of Erlangen, Krankenhausstrasse 12,
Erlangen, Germany. Correspondence: Luis M. Ruilope (ruilope@ad-hocbox.com)
advance online publication 13 March 2008. doi:10.1038/ajh.2008.16
© 2008 American Journal of Hypertension, Ltd
500
nature publishing group
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and decreases with regression of LVH in response to antihypertensive
treatment. Therefore the detection, prevention, and reversal of LVH
are important goals in HT management. Most antihypertensive drugs
can attenuate BP and LVH. However, each drug class may induce LVH
regression to a different extent and these extents seldom correlate
with the degree of BP reduction achieved. Data from the few large
comparative studies in this area suggest that certain classes of
antihypertensive drugs and/or their combinations are more effective
than others. In particular, calcium channel blockers and drugs that
target the RAS, such as angiotensin-converting enzyme inhibitors
(ACEIs) and angiotensin receptor blockers (ARBs), appear to have
a specific effect on LVH, independent of BP reduction. Guidelines,
therefore, have recommended these drug classes for the treatment of
hypertensive patients with LVH.
Am J Hypertens 2008; 21:500-508 © 2008 American Journal of Hypertension, Ltd.
Table 1 outlines some of the advantages and ­disadvantages of
the available diagnostic methods.
In clinical practice, the electrocardiogram (ECG) is usu-
ally the first method used for assessing for the presence of
LVH. Many different validated criteria are available; examples
include the Sokolow–Lyon,7 Cornell voltage,8 Cornell voltage
QRS duration product criteria,9 the Gubner index,10 and the
Romhilt-Estes score.11,12 These ECG criteria generally have
high specificities and can therefore identify patients with the
greatest LVM and the highest risk. However, their low sensi-
tivities mean that a normal ECG does not exclude the presence
of LVH. M-mode echocardiography is currently the stan-
dard clinical diagnostic method; it detects all but the mildest
degrees of LVH. Cardiac magnetic resonance imaging and
three-dimensional echo are recommended for clinical trials
investigating LVM regression.13 Magnetic resonance imaging
is the method of choice when recruitment of large numbers of
patients is not possible, because it provides good accuracy and
reproducibility. Data from three-dimensional echo investiga-
tions are scarce and its reproducibility (which largely influ-
ences the required number of patients to be included in a trial)
has been insufficiently studied.
In clinical studies, LVH is frequently identified as LVM.
Different measures of body size, such as height, weight, body
surface area, are used for normalizing LVM, so as to enable com-
parison of individuals with different body statures. The choice of
the parameter used for indexing LVM determines the estimate
of outcome risk, depending upon the population studied.14
mAY 2008 | VOLUME 21 NUMBER 5 | 500-508 | AMERICAN JOURNAL OF HYPERTENSION
LVH and Clinical Outcomes in Hypertensive Patients
Table 1 | Advantages and disadvantages of the different methods of assessing LVH13
ECG M-mode
echocardiography
Sensitivity Low Moderate
Specificity High High
Cost Low Moderate
Availability High High
Complexity Low Low
Interpatient Moderate Moderate
reproducibility
Adapted from ref. 13. Reproduced with permission of Lippincott Williams & Wilkins.
Lvh in hypertensive patients
The prevalence of LVH is influenced by blood pressure (BP),
age, obesity, and gender. In the Framingham population, LVH
prevalence (detected by echocardiography) ranged from 6%
in persons under 30 years of age to 43% in those ≥70 years.15
LVH detected by ECG was more prevalent in women than in
men (2.9% vs. 1.5%), whereas echocardiographically detected
LVH was more common in men than in women (17.6% vs.
14.2%).16 The prevalence of LVH in patients with borderline
HT is estimated as 16.6%.17 Another study reported LVH
rates of 14% and 20% for men and women, respectively, in
a group of individuals with normal BP, and 25% and 26%,
respectively, in those with HT.18 When controlled for age, the
same study showed that only hypertensive subjects over 65
years of age had an increased prevalence of LVH. However,
the results quoted may be misleading because the samples
studied were small and the cutoff used for defining LVH was
high.18 A further study in men found an LVH prevalence of
2.7–3.2% in normotensive subjects, 4.2–5.4% in those with
borderline BP, and 11.8–14.5% in hypertensive subjects.19
Ethnicity also plays a role in the epidemiology of LVH. This
is probably attributable, in part, to the elevated risk of HT in
African-Americans and Africans, with one study showing an
almost fourfold increase in the incidence of LVH in blacks as
compared to whites (odds ratio 3.7; 95% confidence interval
3.2–4.4).20 Even after adjusting for age, systolic BP, and weight,
black patients with HT still had an odds ratio for LVH of 3.0
(1.6–6.1) compared with white patients.20
It is important to bear in mind, when interpreting the results
of individual epidemiologic studies, that the estimates of prev-
alence of LVH, based on distribution of normal values and
predefined sex-dependent differences, substantially depend
on how LVM is normalized for body size.14 For instance, if the
same cutoff point is used for men and women patients while
measuring parameters of LVM index that are strongly influ-
enced by sex, women will of course show a lower prevalence
of LVH. This difference might be offset if partition values for
AMERICAN JOURNAL OF HYPERTENSION | VOLUME 21 NUMBER 5 | mAY 2008
STATE OF THE ART
2D echocardiography 3D echocardiography Cardiac MRI
High High High
High High High
Moderate Moderate High
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High Low Low
Moderate High Moderate
Moderate Low High
women were set to a lower level. Similar arguments apply to
age and ethnicity.21 Therefore the chosen definition of LVH
predefines these differences.
LVH prevalence varies with severity of HT, ranging from
<20% in mild HT to almost 100% in severe or complicated
HT.3 There is evidence that HT-related LVH is more closely
associated with 24-h BP averages and BP variation, than
with clinic BP readings.22–28 In addition to raised BP, many
­nonhemodynamic factors are implicated in the pathogenesis
of hypertensive LVH, although there is no universal agreement
about the role of these factors.29 There is some evidence for
involvement of the renin–angiotensin system (RAS),29 with
impaired suppression of the RAS or increased sensitivity to
angiotensin II appearing to act as a stimulus for LVH in hyper-
tensive patients.29–32 Several studies confirm an association
between increasing plasma renin activity levels (a marker of
RAS activity) and increased LVH (Table 2).33–37
Experimental evidence indicates that angiotensin II induces
hypertrophy and hyperplasia in myocytes and vascular smooth
muscle cells, and may regulate collagen synthesis.5,31,38 Excess
levels may lead to perivascular and interstitial fibrosis, and
interfere with collagen degradation. Aldosterone also may
stimulate extracellular collagen deposition and myocardial
fibrosis.5
There is much evidence that dietary salt intake plays a role
in the development of LVH in hypertensive patients, although
the precise mechanisms involved are still unclear.29,39,40 While
the finding of suppression of RAS activity by dietary salt load-
ing seems at first to be at variance with the evidence described
earlier, this suppression appears to be inadequate in nearly
half of the hypertensive population.39 In addition, although
systemic RAS activity may be decreased by a high salt intake,
there is evidence that cardiac aldosterone production, the
expression of angiotensin type I receptors in myocardial cells
and expression of growth-stimulating genes are all increased,
thereby provoking hypertrophic and fibrotic responses in the
myocardium.29
501
STATE OF THE ART
Table 2 | Studies showing an association between LVH and plasma renin activity levels
First author (year) Inclusion criteria
Malmqvist (2002)34 114 HT + LVH; 38 age- and
gender-matched controls with
HT; 38 with no HT
Koga (1998)36 Japanese with untreated HT,
mean age 52 years
Aronow (1997)33 HT, age 60–98 years
Vlahakos (1997)35 Chronic, stable hemodialysis patients
ECG, electrocardiogram; HT, hypertension; LVH, left ventricular hypertrophy; LVMI, left ventricular mass index; PRA, plasma renin activity.
LVH is an independent risk factor for CV disease in
patients with HT. The underlying factors for this association
may include a combination of electrophysiological altera-
tions, anatomical changes, and increased sympathetic and
RAS activity.40,41 Key studies demonstrating the relationship
between LVH and CV outcomes (surrogate and clinical) in
hypertensive populations are summarized later in this article.
The results of these studies indicate that there is a continuous
relationship between increasing LVM and CV morbidity and
mortality. The studies show also that the different geomet-
ric patterns that can develop in the left ventricle in response
to HT can signify different levels of risk, with concentric
LVH representing the greatest risk.40,42,43 Furthermore, the
studies also indicate that antihypertensive treatment can
induce LVH regression, and thereby improve long-term CV
prognosis.
LVH is accepted as HT-related target organ damage in sev-
eral clinical practice guidelines, and it represents an interme-
diate unfavorable prognostic marker.1–3 Table 3 provides an
overview of studies in hypertensive populations that demon-
strate the correlation between LVH and other surrogate CV
outcome measures, such as urinary albumin excretion and
intima-medial thickening of the carotid arteries.
Lvh and cv morbidity and mortality
The association between electrocardiographically determined
LVH and CV morbidity and mortality in the general popula-
tion was clearly demonstrated in the Framingham study.44
Various clinical studies in hypertensive populations have since
502
LVH and Clinical Outcomes in Hypertensive Patients
n Study design Key outcomes
190 Case-control PRA and serum aldosterone were higher in those
with HT + LVH vs. those with HT and no LVH
(0.95 ± 0.78 vs. 0.21 ± 0.19 ng/ml/h, P < 0.001;
and 330 ± 128 vs. 269 ± 146 pmol/l, P < 0.05). In
multiple regression analyses of all subjects, PRA was
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significantly related to LVMI (P < 0.001)
108 Cross-sectional PRA was higher, but not significantly, in those with
ECG LVH. In multiple regression analysis, PRA was
significantly associated with ECG LVH in males
(P < 0.01) and females (P < 0.05)
472 Cross-sectional 81% of those with high PRA, 60% of those with
normal PRA and 54% of those with low PRA had
echo LVH at baseline (P < 0.018 for high vs. low PRA)
33 Cross-sectional LVMI was 123.3 ± 11.8 g/m2 in the low PRA group
(≤1 ng/ml/h), 147.5 ± 14.3 in the medium PRA
group (1–4 ng/ml/h) and 197.9 ± 13.8 in the high
PRA group (>4 ng/ml/h), P < 0.001. In multiple
linear regression analysis, pre-dialysis PRA was
significantly associated with LVMI (P < 0.01)
confirmed that LVH (identified by ECG or echo) is an indepen-
dent risk factor for CV outcomes (Table 4).45
The study by Schillaci and colleagues6 in 1,925 Caucasian
hypertensive subjects demonstrated a continuous and strong
relationship between LVM index and risk of CV disease,
even after adjusting for other CV risk factors (Figure 1). The
increased CV risk was already detectable at LVM values of
>105 g/m2 in men and >91 g/m2 in women, which are consid-
erably lower than the traditional upper normal limits. The mul-
ticenter Massa Ventricolare Sinistra nell’Ipertensione (MAVI)
study, which evaluated 1,033 subjects with uncomplicated HT
for an average of 3 years, also showed a strong and indepen-
dent relationship between LVM and subsequent CV morbidity.
For every 39 g/m2 increase in LVM there was an independent
40% rise in the risk of major adverse CV events.4
Several studies have shown that regression of LVH sig-
nificantly improves CV outcome and long-term prognosis
(Table  5). In a meta-analysis of studies reporting echocar-
diographic LVM before and during antihypertension therapy,
LVH regression was associated with a 59% reduction in the risk
of CV events when compared with persistence or new develop-
ment of LVH.46 The large Losartan Intervention for Endpoint
Reduction (LIFE) study clearly demonstrated that regression
of ECG-determined LVH with antihypertension treatment
improved prognosis, independent of BP.47,48 A prospective
study of 436 hypertensive subjects by Muiesan et al. indicates
that the response of LV geometry to treatment may also have
prognostic significance.49 In this study, the ­persistence or
development of concentric geometry was associated with an
MAY 2008 | VOLUME 21 NUMBER 5 | AMERICAN JOURNAL OF HYPERTENSION
LVH and Clinical Outcomes in Hypertensive Patients STATE OF THE ART

Table 3 | Studies in hypertensive populations demonstrating the association between LVH and other surrogate
markers of CV outcomes
First author (year) Inclusion criteria n Study design Key outcomes
Dell’omo (2003)63 Untreated HT, male, 330 Cross-sectional Microalbuminuria prevalence was double in LVH group vs. no LVH
no DM group (P < 0.001). After adjustment for BP, HR for microalbuminuria
was 2.8 (CI 1.1–6.1, P = 0.03) for concentric LVH vs. normal
geometry

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Leoncini (2002)64 Untreated HT, no DM 346 Cross-sectional Microalbuminuria was significantly correlated with LVMI
(univariate analysis, P < 0.0001)
Tsioufis (2002)65 Untreated essential HT, 249 Cross-sectional LVMI was significantly and independently associated with log
30–70 years, no DM 24-h UAE. The concentric LVH group had higher log 24-h UAE
levels than those with eccentric LVH, concentric LV remodeling or
normal LV geometry (P < 0.001)
Wachtell (2002)66 Untreated HT, LVH, 8,029 Cohort (derived LVH on two consecutive ECGs (persistent LVH) was associated with
55–80 years from LIFE) a 1.6-fold increased prevalence of microalbuminuria and a 2.6-fold
increased prevalence of macroalbuminuria compared with those
without persistent ECG LVH
Vaudo (2000)67 Untreated HT, 18–54 96 Cross-sectional Those with echo LVH (n = 33) had a greater C-IMT (0.84 ± 0.2 vs.
years 0.71 ± 0.2 mm, P < 0.0001) and F-IMT (0.77 ± 0.1 vs. 0.64 ± 0.1 mm,
P < 0.0001) compared with those with no LVH
Saitoh (1998)68 Untreated HT 174 Cross-sectional In those with echo LVH, 20% had proteinuria and 13% had grade III
retinal vascular changes, compared to 8% (P < 0.05) and 0%
(P < 0.01) of those with no LVH
Agrawal (1996)69 HT, mean age 57 years, 11,343, 17% Cross-sectional 44.2% of those with LVH had microproteinuria, compared with
no DM had LVH survey 28.7% of those without LVH (P < 0.001)
Roman (1996)70 Untreated HT, 25–88 271 Cross-sectional C-IMT was greater in those with concentric hypertrophy
years (0.96 ± 0.2 mm, P < 0.005 vs. normal geometry) compared with
those with normal geometry (0.8 ± 0.18), concentric remodeling
(0.85 ± 0.22) or eccentric hypertrophy (0.89 ± 0.21)
BP, blood pressure; CI, 95% confidence interval; C-IMT, carotid intima-media thickness; CV, cardiovascular; DM, diabetes mellitus; ECG, electrocardiogram; F-IMT, femoral intima-media
thickness; HR, hazard ratio; HT, hypertension; LIFE, Losartan Intervention for Endpoint Reduction study; LV, left ventricular; LVH, left ventricular hypertrophy; LVMI, left ventricular mass
index; UAE, urinary albumin excretion.

5 1.5

Role of antihypertensive medications

4
Reduction of BP can reverse LVH. Major determinants are
(per 100 patient-years)

(per 100 patient-years)

Cardiovascular events

All-cause death

1
3 treatment duration and the degree of BP reduction, par-
2
0.5
1
0 0
1 2 3 4 5 1
Left ventricular mass index (quintiles)
Figure 1 | Relationship between increasing echocardiographic left ventricular
mass index and cardiovascular events or all-cause mortality.6 Partition values
between quintiles for left ventricular mass index were 92.3, 105.4, 119.8, and
138.2 g/m2 in men and 79.5, 91.2, 101.8, and 116.4 g/m2 in women. (Adapted
from ref. 6; Reproduced with permission of Lippincott Williams & Wilkins.)
increased CV risk after adjusting for other covariates, even
in those with follow-up LVM index values that were consid-
ered to be in the normal range. The benefits linked to LVH
regression are discussed further in a comprehensive review by
Schillaci and colleagues.50
ticularly the 24-h average BP.5,51 Minimal daily fluctuation
in BP control, as expressed by the smoothness index, also
seems to be important.52 However, while most antihyperten-
sive drugs can attenuate BP and LVH, each drug class may
2 3 4 5
induce LVH regression to different extents, and these regres-
sions do not always correlate with the degree of BP reduc-
tion achieved. This is illustrated by the results of the Pressioni
Arteriose Monitorate E Loro Associazioni (PAMELA) study in
a ­cross-section of 2,051 adults aged 25–74 years.53 Although
subjects with uncontrolled HT had the highest incidence of
LVH, even in hypertensive subjects with good 24-h BP control,
the incidence of LVH was almost five times greater than that
seen in normotensive subjects.
Many studies have endeavored to compare the effects of
­different antihypertensive treatments on LVH, but flawed
study designs and methodological problems have limited

AMERICAN JOURNAL OF HYPERTENSION | VOLUME 21 NUMBER 5 | mAY 2008 503

STATE OF THE ART LVH and Clinical Outcomes in Hypertensive Patients

Table 4 | Studies in hypertensive populations demonstrating the association between LVH and CV morbidity
and mortality outcomes
First author (year) Inclusion criteria n Study design Key outcomes
De Simone (2005)14 HT, No CVD, 47–80 1,026 Cohort (derived from the After a mean follow-up of 86 months, HRs for fatal and
years Strong Heart Survey) non-fatal CV events were 1.68 for LVM (CI 1.02–2.76, P < 0.05),
2.09 for LVH/BSA (CI 1.25–3.52, P < 0.005) and 1.33 for LVH/
height (CI 0.82–2.18, P > 0.2)

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Verdecchia (2001)4
Verdecchia (2001)71
Schillaci (2000)6
Verdecchia (1995)42
Koren (1991)43
BSA, body surface area; CI, 95% confidence interval; CV, cardiovascular; HR, hazard ratio; HT, hypertension; LV, left ventricular; LVH, left ventricular hypertrophy; LVM, left ventricular mass;
LVMI, left ventricular mass index; MAVI, Massa Ventricolare Sinistra nell’Ipertensione; MI, myocardial infarction; PIUMA, Progetto Ipertensione Umbria Monitoraggion Ambulatoriale;
SBP, systolic blood pressure.
HT, age ≥50 years 1,033 Multicenter, prospective For each 1 s.d. increase in LVM (39 g/m2) mass there was an
(MAVI) independent 40% rise in the risk of major CV events
(CI 14–72, P = 0.0013)
HT, mean age 2,363 Cohort (PIUMA) For each 1 s.d. increase in LVM (29 g/m2) mass there was an
51 ± 12 years independent 31% increase in the risk for a cerebrovascular
events (CI 9–58)
HT 1,925 Prospective cohort Compared with the 1st quintile (lowest) for LVMI, adjusted HR
for CV events was 1.6 (CI 0.8–3.1) for 2nd quintile, 1.9
(CI 1.01–4.0) for 3rd, 3.0 (CI 1.5–5.8) for 4th, and 3.5 (CI 1.8–6.8)
for the 5th quintile. HR for all-cause death in the 5th quintile of
LVMI compared with the 1st quintile was 4.3 (CI 1.2–13.4)
HT, normal echo 694 Cohort After mean follow-up of 2.71 years, CV morbidity
LVM (<125 g/m2) (expressed as number of fatal and non-fatal events per 100
patient-years) was 1.12 in those with normal LV geometry,
compared to 2.39 in those with concentric remodeling.
Adjusted HRs for CV events was 2.56 for concentric
remodeling group (CI 1.2–5.45, P < 0.01)
HT 280 Cohort CV events occurred in 26% of those with echo LVH vs. 12%
of those without (P = 0.006); CV deaths occurred in 14% of
those with echo LVH vs. 0.5% of those without (P = 0.001).
Those with concentric hypertrophy had the most adverse
outcomes

their applicability. Recent well-designed trials that poten-
tially have sufficient power to compare the performances
of antihypertensive drugs in reversing HT-related LVH are
summarized in Table 6. It is important to note that in most
of the studies, a diuretic was added to the angiotensin-con-
verting enzyme inhibitor (ACEI) or the ARB in a significant
­proportion of patients.
The results of these studies are generally confirmed by a
meta-analysis of 80 double-blind antihypertension trials.54
This showed a significant difference (P = 0.004) among drug
classes after adjusting for treatment duration and BP change.
LVM index decreased by 13% with ARBs, by 11% with calcium
channel blockers, by 10% with ACEIs, by 8% with diuretics,
and by 6% with β-blockers. In pair-wise comparisons, ARBs,
calcium channel blockers, and ACEIs were all significantly
more effective at reducing LVM than β-blockers were.
The pathological role of angiotensin II in LVH development
suggests that agents targeting the RAS may offer beneficial
effects beyond BP reduction, possibly by inhibiting intracar-
diac RAS and, specifically, the tropic effects of angiotensin II
on the myocardium. The results of the LIFE trial confirm the
efficacy of ARBs in reducing HT-related LVH. However, during
this trial, the rate at which the primary endpoint was reached
in the losartan group still left room for further improvement
(23.8 per 1,000 patient years).55 Also, the results of the recent
Valsartan In Diastolic Dysfunction (VALIDD) trial showed
that ARBs bestowed no added benefits beyond BP reduction
in hypertensive patients with diastolic dysfunction, which is
a possible early measure of myocardial target organ damage
preceding LVH.56,57 The limitations of existing RAS drugs
may be because of downstream activation of RAS and eleva-
tion of plasma renin activity.58 More complete blockade of the
RAS, using a combination of RAS antihypertensive strategies
including direct renin inhibition, may offer more extensive
target organ protection.
Recent data from the Conduit Artery Function Evaluation
(CAFE) substudy of the Anglo-Scandinavian Cardiac
Outcomes Trial (ASCOT), and other evidence from O’Rourke’s
group, demonstrate that brachial artery BP (which is used for
quantifying BP in the clinical trials that are included in this

504 MAY 2008 | VOLUME 21 NUMBER 5 | AMERICAN JOURNAL OF HYPERTENSION

LVH and Clinical Outcomes in Hypertensive Patients
Table 5 | Studies showing that regression of LVH improves CV outcome
First author (year) Inclusion criteria n Study design
Verdecchia (2006)28 HT, mean age 880
48 years
Okin (2004)48 HT, ECG LVH, 9,193
55–80 years
Devereux (2004)47 HT, ECG LVH, 941
55–80 years
Verdecchia (2003)46 HT, mean age 1,064
45–51 years
BP, blood pressure; CI, 95% confidence interval; CV, cardiovascular; ECG, electrocardiogram; HR, hazard ratio; HT, hypertension; LIFE, Losartan Intervention for Endpoint Reduction
study; LVH, left ventricular hypertrophy; LVM, left ventricular mass; LVMI, left ventricular mass index; MI, myocardial infarction; PIUMA, Progetto Ipertensione Umbria Monitoraggion
Ambulatoriale; SBP, systolic blood pressure.
review), overestimates central aortic BP.59 This is important
because antihypertensive drugs of different classes do not
lower central aortic and brachial artery BP equally—ACEIs
lower central BP to a greater extent than β-blockers, but both
drug classes lower brachial artery pressure equally. It is there-
fore not clear whether benefits beyond BP control are indepen-
dent of afterload.
Economic perspectives
Antihypertensive patients with proven ability to control BP
and achieve regression of LVH can be expected to contribute
substantially to cost saving because of the positive impact on
CV outcomes. Anis and colleagues incorporated data from the
LIFE study into an economic model to perform a cost analysis
comparing losartan and atenolol in the treatment of HT and
LVH from the Canadian societal perspective.60 They used a
Markov state transition model to extrapolate the trial data
throughout the patients’ lifetimes. The results of this analysis
suggest that losartan is cost effective compared with atenolol
for the first-line treatment of hypertensive patients with LVH,
despite the higher acquisition costs associated with losartan.
AMERICAN JOURNAL OF HYPERTENSION | VOLUME 21 NUMBER 5 | mAY 2008
STATE OF THE ART
Key outcomes
Cohort (PIUMA) The risk of cerebrovascular events was 2.8-times higher
(CI 1.18–1.69) in those with a lack of regression or new
development of LVH, compared with those with LVH
regression or persistently normal LVM. This effect was
independent of age (P = 0.001) and 24-h SBP (P = 0.003)
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Cohort (LIFE) After at least 4 years of follow-up, adjusted HRs for a 1 s.d.
(1,050 mm × ms) decrease in the Cornell product were
0.86 (CI 0.82–0.8, P < 0.001) for composite endpoint, 0.78
(CI 0.73–0.83, P < 0.001) for CV deaths, 0.90 (CI 0.82–0.98,
P < 0.01) for MI, and 0.90 (CI 0.84–0.96, P < 0.002).
Corresponding values for a 1 s.d. (10.5 mm) decrease in
the Sokolow–Lyon voltage were 0.83 (CI 0.73–0.87,
P < 0.001), 0.90 (CI 0.81–1.00, P < 0.04), 0.81
(CI 0.75–0.89, P < 0.001)
Cohort After the first year of treatment (and independent of
(LIFE echocardiography baseline LVMI, study treatment and BP lowering), HRs per
substudy) 1 s.d. decrease in in-treatment LVMI (25.3 g/m2) were 0.74
(CI 0.65–0.91, P = 0.003) for composite endpoint
(CV death, MI or stroke), 0.57 (CI 0.45–0.76, P < 0.001) for
CV mortality, 0.88 (CI 0.64–1.2, P = 0.41) for MI, 0.78
(CI 0.59–0.95, P = 0.02) for stroke, and 0.7 (CI 0.58–0.86,
P < 0.001) for all-cause mortality
Meta-analysis of studies LVH regression was associated with a 59% reduction in
reporting echo LVM the risk of CV events compared with persistence or new
before and during development of LVH (P = 0.0068). Those with normal LVM
antihypertensive therapy before and during treatment showed a 36% reduced risk
of CV events compared with those with regression of LVH
(P = 0.21)
However, it is important to remember that the LIFE study was
based on ECG-defined LVH, which represents the most severe
degree of LVH. Therefore, the conclusions from the study
should not be extrapolated to patients with echographically
determined LVH—a wider population with a broader range of
CV risk. Furthermore, this study did not consider other impor-
tant indicators of cost/benefit, such as population-attributable
risk and indirect costs of disease.
In general, there appear to be more pharmacoeconomic
studies in HT with proteinuria, stroke or nephropathy as out-
come variables, than with LVH.61 For reimbursement and
reference pricing decisions, there is a need for data from head-
to-head comparisons of ACEIs, ARBs, and ACEI/ARB com-
binations to model all possible costs and effects of ACEIs and
ARBs. Similar considerations would apply to the novel renin
inhibitors. This will result in more robust pharmacoeconomic
analyses, in which all types of drugs can be appropriately com-
pared before making healthcare decisions.61 It is also pos-
sible that modeling techniques for 24-h BP may allow a better
understanding of the impact of poor 24-h BP control on LVH,
and consequently the economic burden.62 The fact that LVH
505
STATE OF THE ART LVH and Clinical Outcomes in Hypertensive Patients

Table 6 | Major comparative antihypertensive trials in hypertensives with LVH

Trial, first author (year)
PICXEL, Dahlöf, (2005)72
Trial name
Perindopril/indapamide
in a double blind controlled
study vs. enalapril in LVH
Study population Comparators Key outcomes
556 hypertensives Perindopril 2 mg/indapamide After one year, LVMI decreased
with echo LVH, 0.625 mg combination; Enalapril significantly more in the
≥18 years 10 mg; Doses doubled if BP perindopril/indapamide
inadequately controlled group than the enalapril group
(between-group difference

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9.3 g/m2, P < 0.0001)
LIFE, Okin (2003)73 Losartan intervention for 9,193 Losartan 50 mg; Atenolol 50 mg; After 6 months (adjusting for
endpoint reduction hypertensives with If necessary, HCTZ 12.5 mg added, baseline LVH, baseline and
ECG LVH, 55–80 then losartan/atenolol doses doubled, in-treatment BP, and
years then CCB added for diuretic therapy)
losartan-based therapy
was associated with greater
regression of both Cornell
product (adjusted means, –200
vs. –69 mm × ms, P < 0.001) and
Sokolow–Lyon voltage (–2.5 vs.
–0.7 mm, P < 0.001) than was
atenolol-based therapy. Greater
regression of LVH persisted
at each subsequent annual
evaluation in the losartan-treated
group (P < 0.001)
4E, Pitt, (2003)74 The 4E left ventricular 153 hypertensives Eplerenone 200 mg; Enalapril 40 mg; After 9 months, change in LVM
hypertrophy study with echo or ECG Eplerenone 200 mg + enalapril 40 mg (assessed by MRI) was –14.5 ±
LVH 3.36 g for eplerenone group,
–19.7 ± 3.2 g for enalapril and
–27.2 ± 3.39 g for eplerenone +
enalapril group (P = 0.007 vs.
eplerenone group)
PRESERVE, Devereux Prospective randomized 303 hypertensives Enalapril 10 mg; Nifedipine 30 mg; After 48 weeks, enalapril-based
(2001)75 enalapril study evaluating with echo LVH, if necessary, doses increased to therapy and nifedipine-based
regression of ventricular ≥50 years 20 mg/60 mg respectively, then therapy resulted in similar
enlargement HCTZ 25 mg added, then atenolo reductions in BP and LVMI
l 25 mg added (–15 vs. –17 g/m2, P > 0.2)
LIVE, Gosse, (2000)76 LVH regression: 505 hypertensives Indapamide SR 1.5 mg; Enalapril After 48 weeks, indapamide SR
indapamide vs. with echo LVH, 20 mg; if necessary, prazosin 5 mg significantly reduced LVMI
enalapril ≥20 years or doxazocin 2 mg added (–8.4 ± 30.5 g/m2 from baseline,
P < 0.001) but enalapril did not
(–1.9 ± 28.3 g/m2)
More than 150 patients per treatment group for ECG/echo studies, fewer for MRI studies.
BP, blood pressure; CCB, calcium channel blocker; ECG, electrocardiogram; HCTZ, hydrochlorothiazide; LIFE, Losartan Intervention for Endpoint Reduction; LIVE, Regression of Left
ventricular hypertrophy in hypertensive patients treated with Indapamide SR 1.5 mg Versus Enalapril 20 mg (the LIVE study); LVH, left ventricular hypertrophy; LVMI, left ventricular
mass index; MRI, magnetic resonance imaging; PICXEL, Perindopril Indapamide combination in Controlled study Versus Enalapril; PRESERVE, Prospective Randomized Enalapril Study
Evaluating Regression of Ventricular Enlargement; SR, sustained release.

levels have prognostic implications, with higher levels being
associated with faster progression of CVD, may also be use-
fully modeled to study health economic outcomes.
Conclusion
While most classes of antihypertensive drugs demonstrate
an ability to induce regression of LVH, most data are from
small trials or meta-analyses of these trials. Results from the
few high-quality studies that have been conducted suggest
that certain drug classes and/or their combinations are more
e­ ffective than others. Data from the large LIFE study indicate
that ARBs appear to have a specific effect on LVH, indepen-
dent of BP reduction, and this is associated with more favor-
able CV outcomes. More complete blockade of the RAS, using
a ­combination of RAS antihypertensive agents, may offer addi-
tional target organ protection.
Disclosure: The authors declared no conflict of interest.
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