BLOOD PRESSURE 1996; 5: 5-1 5

REVIEW

Hypertensive Left Ventricular Hypertrophy: Pathophysiology,

Assessment and Treatment

JAN ERIK OTTERSTAD,’ OTTO SMISETH’ and SVERRE ERIK KJELDSEN3

Otterstad JE, Smiseth 0, Kjeldsen SE. Hq’pertensive Lcft Ventricular Hypertrophy: Pnr/ioph.l’siio/n~~,,
A.sses.s-
tnmt and Treatment. Blood Pressure 1996; 5: 5- 15.
Left ventricular hypertrophy (LVH) is a strong predictor of cardiovascular morbidity and mortality. LVH is
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associated with coronary events, and there is an association between cerebrovascular disease and increased left
ventricular mass (LVM). Experimental studies have elucidated the importance of non-myocytic cells inducing
increased perivascular and interstitial fibrosis along with thickening of the media of intramyocardial coronary
arteries in hypertensive LVH. M-mode echocardiography is the most accepted standard for the diagnosis and
quantification of LVH, but some controversies exist regarding the ideal methodology for serial assessment of
LVM. It is still a matter of debate whether 2-dimensional echo measurements represent a more accurate
method. Hopefully, both the introduction of 3-dimensional echo and new Doppler techniques can provide
more accurate measurements of LVM and additional information on changes in myocardial fibrosis and
stiffness. Experimental studies have shown that normalization of hypertensive myocardial and coronary artery
remodelling take place with drugs like angiotensin converting enzyme (ACE)-inhibitors and calcium antago-
nists. Two meta-analyses suggest that ACE-inhibitors may be the most efficient drugs in reducing LVM, but a
clinical correlate to this assumption is at present not available. There are some indications that regression or
For personal use only.

progression of LVH assessed by ECG and echocardiography may in fact be related to the incidence of
cardiovascular events. But large-scale controlled studies of various treatment regimens are still needed to
establish whether drug induced regression can improve the prognosis of hypertensive LVH independent of the
antihypertensive effect. Key words: left ventricular hypertrophy, hypcwension.

INTRODUCTION are simply those with severer hypertension and, there-

Left ventricular hypertrophy (LVH) predicts cardio-
vascular morbidity and mortality in the general popu-
lation [I-41 and in patients with hypertension [5-61.
According to Kannel [4] no other risk factor
approaches LVH in potency. The majority of cardio-
vascular events associated with LVH are various man-
ifestations of coronary heart disease, although recent
data from the Framingham Study also verify that
increased left ventricular mass (LVM) is an indepen-
dent risk factor for stroke in elderly patients [7].
The mechanisms underlying LVH, that lead to
increased cardiac morbidity and mortality are not
fully understood and may be multifactorial. Hyperten-
sive patients with LVH have an increased oxygen
consumption and a decreased coronary blood flow
reserve [X- 1 I ] which predispose to myocardial infarc-
tion and sudden death. These patients may also have a
high incidence of associated arteriosclerotic coronary
and carotid artery disease, for which LVH may be a
marker. Furthermore, LVH may predispose to malig-
nant ventricular arrhythmias [ 12, 131 and atrial fibril-
lation [14]. Finally, patients with an increased LVM
fore, they are at greater risk.
In the present review emphasis is placed on the
pathophysiology of this potentially serious condition,
the problems related to the assessment of LVH, with
particular focus on the role of echocardiography, and
finally, on the current treatment of hypertensive
LVH .
PATHOPHYSIOLOGY
LVH has been observed both in normotensive and
hypertensive individuals. Age, blood pressure, obesity
and glucose intolerance were found to be independent
contributors to LVH in the Framingham Study [4].
LVH is not present in all patients with hypertension
and seems to occur predominantly among patients
with established hypertension as opposed to those
with “white-coat hypertension” [ 151.
LVH has been shown to be present in the offspring
of hypertensive patients even before they become
hypertensive, suggesting that cardiac involvement
may precede elevation of blood pressure [16, 171.

I( ) 1996 Scandinavian University Press. ISSN 0803-7051 BLOOD PRESSURE 1996

 6 J . E. Otterstad et al.
Increased carotid wall thickness and lumen diameter
have been observed in patients with uncomplicated
hypertension that parallel findings in the left ventricle,
i.e. an increase in absolute and relative wall thickness
as well as LVM [18]. There is also evidence to suggest
that higher LVM as detected by echocardiography is
associated with the presence of carotid arteriosclerosis
[19]. Recent observations from the Framingham study
have further verified that echocardiographically deter-
mined LVM is associated with the risk for cerebrovas-
cular events [7]. The mechanism for this association is
not known. But the findings of both carotid artery wall
changes [18,19] and increased incidence of atrial fibril-
lation in patients with increased LVM [I41 may in part
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offer an explanation for this association.
In athletes, LVH develops as an adaptation to
regular exercise and is characterized by intact and
normal relaxation of the myocardium and preserva-
tion of myocardial structure [20-221.
“Volume overload” relates to an increased volume
of the ventricular cavity in proportion to LVM
(eccentric LVH) while with “pressure overload” there
is an increased left ventricular (LV) wall thickness
without a concomitant increase in the cavity volume
For personal use only.
(concentric LVH). In the study of Koren et al. [6]
hypertensive patients with LVH had a higher incidence
of cardiovascular events during 10 years follow-up
0’701
0.60
0.50~
I 1 I I 1 I I I
20 40 60 80 100 120 140
Duration of follow-up (months)
Fig. I. Age-adjusted, cardiovascular event-free survival in
253 patients with essential hypertension, including 69
patients with left ventricular hypertrophy (-) and 184
patients without hypertrophy (- - - -) (LV mass index < 125 g/
m2) ( p = 0.01). Data are adjusted for age using a Cox
analysis. Eighty-five percent of the patients were event-free
and followed for at least 84 months; 5 1O h were event-free and
were followed for at least 120 months (from ref. [6], with
permission).
BLOOD PRESSURE 1996
than those without LVH (Fig. I). Among the 69
patients with increased LVM in that study, 29 had
concentric and 40 eccentric LVH. The incidence of
cardiovascular deaths was 21 YOin the former and 10%
in the latter LVH subgroup ( p < 0.001). Thus, LV
geometry may play an important prognostic role for
such patients.
Recent studies in human and rat have suggested that
myocyte hypertrophy is related to haemodynamic
stress and sympathetic activity [22, 231. Cardiac non-
myocytes play an important role in the development of
hypertensive LVH. It has been shown that arterial
hypertension together with stimulation of the renin-
angiotensin-aldosterone (RAAS) system are asso-
ciated with interstitial and perivascular myocardial
fibrosis [20-221. Furthermore, growth of endothelial
and smooth muscle cells lead to intimal and medial
thickening of coronary arteries and arterioles
[2 1, 24, 251.
Schwartzkopff et ul. [26] observed structural remo-
delling of intramyocardial coronary arterioles in
hypertensive patients with normal coronary angio-
grams. These patients had thickened vascular walls
and pronounced perivascular fibrosis as compared to
normotensive controls (Fig. 2A and B). Both the
amount of vascular and perivascular fibrosis corre-
lated significantly with the impairment of coronary
blood flow reserve. On the other hand, no correlation
was found between LVM and indices of coronary flow.
Thus, inappropriate development of fibrosis seems to
be an essential factor underlying the reduced coronary
flow reserve which has been demonstated in these
patients [9- 1 1, 27, 281.
It is possible that these changes may, in part explain
the high incidence of ventricular arrhythmias and
sudden death observed in hypertensive LVH [4, 6,
291. In a recent study, Mandrawat el 01. [30] observed
reduced heart rate variability in hypertensive patients
with electrocardiographic LVH including the LV
strain pattern. A continuous inverse relationship
between heart rate variability and LVM index was
found, suggesting that impaired cardiac autonomic
function in LVH may contribute to the mechanisms
of sudden death.
Recent observations in the Framingham Study
have also linked LVH to the development of non-
rheumatic atrial fibrillation [ 141. Increased left atrial
size, LV wall thickness and reduced LV shortening
fraction were all independent echocardiographic pre-
dictors for atrial fibrillation. Possible mechanisms for
this development may be alterations in ventricular
filling patterns and impaired left atrial emptying
which may induce atrial changes that facilitate the
development of atrial fibrillation.

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Fig 2. (A) Intramyocardial arteriole (normotensive) with little amount of periarteriolar collagen. (B) Intramyocardial arteriole
in hypertension. The vascular wall is thickened by medial hypertrophy with increased nuclear size and width of vascular smooth
muscle cells. The reddish-stained periarteriolar fibrosis is clearly seen (Elastica van Gieson) (from ref. [27], with permission).
ASSESSMENT O F LVH
ECG
While ECG assessments gave valuable prognostic infor-
mation in the Framingham Study [l], they have limited
sensitivity for the diagnosis of LVH [31-341. Thus, the
For personal use only.
highest sensitivity for ECG criteria for LVH may be
approximately 50%, although specificity is usually
greater than 95% [33]. Effectively, ECGs may be useful
in screening for LVH but the pickup rate may not be very
good. New techniques, such as signal-averaging ECG
and LVH defined by orthogonal Frank leads may
improve ECG detection of LVH [33, 351.
Echocardiogrcyphy
1. M-mode: This method has proven its value as a
simple and accurate tool in LVM determination pro-
vided the patients are “echogenic” and without a
distorted LV. Ample data on normal findings are
available [36-381, and all the epidemiology on LVM
as a cardiovascular risk factor is based on M-mode
recordings [3-61. The formula introduced by Devereux
and Reichek [39] using the Penn convention has
proven valid when tested against postmortem LVM
measurements [39, 401:
LVM = 1.04((IVS + LVPW + LVEDD)3
- (LVED)3]- 13.6g
where IVS = intraventricular septum, LVPW = LV
posterior wall, LVEDD = LV end-diastolic diameter
and 1.04 the specific gravity of LV myocardium. The
principles for echo measurements of LV end-diastolic
dimensions with the Penn convention vs. the American
Society of Echocardiography recommendations [41]
Hypertensive lefi ventricular hypertropy 7
are shown in Fig. 3. Measurement of LV relative
wall thickness (LVRWT) as described by Reichek &
Devereux [42] is helpful in identifying patients with
concentric LVH:
2 x LVPW
LVRWT
=
LVEDD,
with a cut-off point of 2 0 . 4 5 for the diagnosis of
concentric LVH [42].
The limitations of M-mode are improper angulation
of the ultrasonic beam to LV walls, non-echogenic
patients and a suboptimal reproducibility. Thus,
changes of 40 to 50g in M-mode echocardiographi-
cally determined LVM are needed to exceed 95%
confidence limits for temporal variability of separate,
ASE criteria Penn criteria
LVIDD 4 LVIDD 4 Chord-
/ tendleae
,Endocardium
LV posterlor
~ freewall ~ freewall
Fig. 3. Principles for M-mode echocardiographic measure-
ments of LV end-diastolic dimensions. To the left: As recom-
mended by the American Society of echocardiography (ASE,
ref. 41). To the right: Penn criteria, as applied for determina-
tion of LV mass (see text). A line denotes measurements at
the Q wave in ASE and at the R wave in Penn.
BLOOD PRESSURE 1996
 8 J . E. Otterstad r t id.
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For personal use only.

Fig. 4 . (A) Area-length method for lcft ventricular mass (LVM) determination: 2-dimensional echocardiographic short-axis
end-diastolic LV image at mid papillary muscle level in a patient with hypertension. The endocardium is traced with inclusion
of the papillary muscles as recommended in the original work by Reichek r t d.[44]. Note that in the guidelines for LVM
calculations by this method provided by the American Society for echocardiography, papillary muscles are not to be included
[39]. The epicardial tracing is also shown. By measuring endocardial (A end) and epicardial areas (A epi), the average LV wall
thickness (WT) can be calculated. (B). Two-dimensional echocardiographic LV 4-chamber image in end-diastole from the same
patient. LV endocardial cavity length (L end) has been drawn from apex to mid-mitral annulus plane. LV epicardial length (L
epi) is then calculated arbitrarily as L end + 1 cm (44). In modern echo equipment Lepi is calculated a s L end + WT. Then
LVM = 1.055 X 5/6 (A epi x L epi - A end x L end) (ref. [44]. see text).

independently interpreted echocardiograms [43]. In
groups of 10 patients the amount of LVM changes is
reduced to 16g and in 50 patients to 7.2g [43]. In
patients without distorted LV shape there is no evi-
dence that the accuracy or reproducibility achieved by
M-mode is inferior when compared with 2-dimen-
sional recordings. The standard error of estimate for
2-dimensional measurements versus necropsy LV
weight was 41 g and for M-mode measurements 43 g
(R. Devereux, personal communication). Thus, at least
in most hypertensive patients M-mode measurements
are easier to make and will be more directly compar-
able with almost all of the epidemiologic and hyperten-
sion literature, with little loss of accuracy (R.
Devereux. personal communication).
2. 2-dirncwsional echo: Several factors indicate that
2-dimensional recordings of LVM may be superior to
M-mode. First of all it can be applied in patients with
distorted LV shape. M-mode echo only reflects a small
portion of the LV, and small error in measurements
may in unexperienced hands give large variations in
LVM and in relative wall thickness. Hence, 2-dimen-
sional echocardiographic methods for LVM calcula-
tions have been developed. Two such methods, an area
length model [44] and a truncated elipsoid model [45,
461, have been reliable in both animal models and adult
humans. At present, the most widely applied method is
the former, using the following forinula as introduced
by Reichek el ul. [44]:
LVM = 1.05 x 5/6(Aepi x Lepi - Aend x Lend)
where Aepi = LV parasternal short axis epicardial
area measured as depicted in Fig. 4A and Lepi = LV
epicardial long axis measured in the apical 4-chamber
view as shown in Fig. 4B. Aend is the endocardial area

BLOOD PRESSURE 1996


in the parasternal short axis view (Fig. 4A) and Lend
the endocardial LV long axis in the apical 4-chamber
view (Fig. 4B). In the original work of Reichek et al.
[44], Icm was arbitrarily added to account for myo-
cardial thickness in estimating epicardial LV length. At
present, most echo-machines contain analysis modules
which calculate the average LV wall thickness from the
mean difference between LV epicardial and endocar-
dial areas in the LV short axis view (Fig. 4A).
In 1989, the American Society of Echocardiography
[47] recommended that inclusion of the papillary
muscles (as applied in the original study of Reichek el
al. [44]) are to be excluded when measuring the short axis
area at the level of the papillary muscle tip. Fig. 4A
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illustrates how papillary muscles may be included or not.
Although both 2-dimensional and M-mode echo-
cardiographic LVM calculations have been tested
versus necropsy weights, the normal range for 2-
dimensional recordings seems to be lower than for
M-mode [36-38, 46, 481. The reproducibility of 2-
dimensional assessment of LVM is approximately
10% [49]. Problems involved in the reproducibility of
this technique include: i erroneous recordings of the
true LV long axis; ii lack of standardized short axis
For personal use only.
level; iii improper gain setting for estimation of inter-
face thickness; and iv problems with endocardial edge
detection and resolution, especially in the apical region.
'RESTRICTIVE'
PHYSIOLOGY
INCREASE0 PE
OlMlNlSHEO PA
INCREASE0 P W A
OlMlNlSHED IVAT
SHORTENEO OT
M-hl-
ACMO MC
CONSTRICTIVE PERCARDITIS
RESTRICTWE CARMOMYOPATHY
(AMYLcnoOslS)
Fig. 5 . Principle changes in mitral inflow pattern as recorded with pulsed Doppler in patients with LV diastolic dysfunction.
C A D =coronary artery disease; HOCM = hypertrophic obstructive cardiomyopathy; LVH = left ventricular hypertrophy;
PHT = pulmonary hypertension; PE = peak early velocity; PA = peak atrial velocity; IVRT = isovolumic relaxation time;
DT = deceleration time; AC = aortic closure; M O = mitral opening; MC = mitral closure (from ref. [53],with permission).
Hypertensive I l f i ventricular hypertropy 9
Since there are still unresolved problems both with
M-mode and 2-dimensional recordings, studies on
LVH regression should probably comprise the use of
both methods in order to obtain reliable results (M. St.
John Sutton, P. Douglas, T. Plappert, personal com-
munication). In the future, however, 3-dimensional
echocardiography may be the method of choice.
King et a/. [50]recently demonstrated that computer-
aided 3-dimensional reconstruction of LV volume and
mass achieved more than a threefold improvement of
interobserver variability compared with 2-dimensional
echocardiography .
3 . Doppler: Since abnormalities in LV diastolic filling
are common in hypertensive patients [51], and
impaired LV filling might contribute significantly to
the development of congestive heart failure [52], a
suitable technique for assessing LV diastolic function
is desirable in these patients. The understanding of
diastolic dysfunction, however, is at present limited by
the lack of appropriate clinical investigative tools. The
available non-invasive techniques measure filling pat-
terns, but provide no direct measure of the fundamen-
tal characteristics of diastolic function, i.e. rate of LV
relaxation and the LV diastolic pressure-volume rela-
tionship. With pulsed Doppler echocardiography,
however, it is possible to measure the impact of altered
"RELAXATION'
ABNORMALITY
PA
OlMlNlSHEO PE
INCREASED PA
MMINISHEO P W A
PROLONGED IVRT
PROLONGED DT
ACMO MC
NORMAL AGING
CAO
HOCM
LVH
PHT
BLOOD PRESSURE 1996
 10 J . E. Otterstad et al.
LV diastolic filling on the transmitral blood flow
velocity pattern [53, 541. When LV relaxation is pro-
longed, alterations in ventricular filling rates are
found. This is reflected in a “relaxation abnormality”
mitral flow signal as shown in Fig. 5. On the other
hand, development of reduced LV compliance, by
creating an increased afterload for atrial contraction
and an increased left atrial pressure, results in aug-
mented early diastolic flow and diminshed flow during
atrial systole. This development, which is often paral-
lelled by impaired systolic function, results in so-called
“pseudo-normalization” and is followed by a “restric-
tive filling pattern” as demonstrated in Fig. 5.
The pulsatile components of the pulmonary vein
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flow signal are closely related to the cyclic pressure
changes in the left atrium [55, 561. During atrial systole
there is marked deceleration of flow and often regur-
gitation into the pulmonary veins. The degree of
reversal increases when atrial pressure is elevated
[56]. Possibly, the combined use of flow patterns in
the pulmonary veins and at the tip of the mitral valve
may provide important information regarding LV
diastolic function [57]. Rossvold & Hatle [58] recently
suggested that the relationship between duration of
For personal use only.
antegrade transmitral flow and pulmonary vein flow
reflects LV end-diastolic pressure.
The Doppler-derived indices of transmitral flow
(Fig. 5) are valuable when comparing groups of
patients, but there is considerable overlap with
normal individuals. This is mainly due to a strong
influence from changes in heart rate and loading
conditions [59, 601.
Digitized M-mode echocardiography has been used
to identify patients with impaired diastolic function.
Using this method, Topol et al. [61] could identify
elderly hypertensives with a syndrome that included
severe concentric hypertrophy, a small LV cavity, and
supernormal indices of systolic function without con-
current medical illness or ischaemic disease. Compared
with controls they had abnormal diastolic function as
manifested by a prolonged early diastolic filling period
and a reduced peak diastolic dimension increase. In
spite of their normal systolic function, nearly half of
these patients presented with heart failure which
responded well on either beta-blockers or calcium
antagonists.
Nuclear magnetic resonance ( N M R ) imuging
NMR gives a high-quality image of LV wall thickness
and internal dimensions and seems an appropriate
technique for evaluating regression of LVH. The pos-
sible error in LV wall thickness measurements is about
1 mm [62] and the applicability of this technique has
BLOOD PRESSURE 1996
been proven in follow-up studies of hypertensive
patients showing reduction of LV wall thickness
during angiotensin converting enzyme (ACE)-
inhibitor treatment [62, 631. However, at present
NMR is still not available for routine assessment of
antihypertensive treatment. Although similar values to
those obtained by echocardiography have been
reported [63], there are no epidemiological data on
the prognostic importance of LVH as measured
with NMR. The development of smaller and more
inexpensive N M R machines, hopefully combined with
Doppler, may result in a wider application of this
technique.
Coronary hlood,flow measurrmtws
LVH has been proven to be associated with increased
wall thickness of coronary arterioles due to medial
hypertrophy and additional perivascular fibrosis (Fig.
2B). During antihypertensive treatment, an ideal
approach would be to follow the changes in coronary
blood flow in parallel with changes in LV anatomy
toward the normal. In one such study in 31 patients
with LVH, hypertensive microvascular angina pectoris
and a normal coronary angiogram, coronary flow
reserve was measured repeatedly after 9- 12 months
treatment with either a beta-blocker, calcium antago-
nist or ACE-inhibitor ([64, 651 W. Motz, personal
communication). LVM was reduced by approximately
lo%, and the increase in coronary flow reserve in these
studies was 56% with the ACE-inhibitor (enalapril),
48% with the calcium antagonist (diltiazem) and 22Y0
with the beta-blocker (bisoprolol). Possible mechan-
isms for these findings may be a decrease in medial wall
thickness, an increase in capillary density and a
decrease in perivascular fibrosis. On the myocardial
level a decrease in myocytic hypertrophy and the
amount of interstitial collagen may be considered.
Interestingly, Krayenbuhl et al. [66] could not verify
reduction of myocardial fibrosis in patients with aortic
valve disease studied with endomyocardial biopsies
before and 2 years following aortic valve replacement.
Although LVM was reduced and LV ejection fraction
improved, these findings may support the notion that
in addition to relief of the haemodynamic burden,
“anti-fibrotic” drug treatment may be necessary to
reduce the excess of myocardial fibrosis connected
with the development of LVH.
TREATMENT O F LVH
Goals of treatment
The main goal of treating LVH is to reduce the
incidence of “hard events” by a reduction of LVH

Table I. Goals of treatment of hypertensive left ventri-
cular hypertrophy ( L V H )
Reduction of cardiovascular events related to reduction/
elimination of LVH and not just to reduction/normalization
of blood pressure
BJ)normulization qf
Left ventricular mass
Left ventricular relative wall thickness
Excessive myocardial fibrosis
Media hypertrophy of coronary arteries/arterioles
In addition
Normalize coronary flow reserve
Eliminate the influence of eventual coronary atheromato-
sis (induce regress, eventually have PTCA or bypass
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surgery performed if clinically indicated)
Normalize parallel structural changes in extracardiac
arteries (e.g. carotides)
per se, and not solely by the indirect means of lowering
blood pressure. As shown in Table I, treatment should
aim to achieve a normalization of LV remodelling and
of structural changes in intra- and extracardiac arteries
and arterioles. In order to achieve these ambitious
goals, at least in part, a combination of non-pharma-
For personal use only.
cological, pharmacological and in some cases even
surgical interventions should be considered.
What is the optimal antihypertensive treatment?
There is little doubt that regression of hypertensive
LVH as judged from serial echocardiographic and
NM R recordings is possible during antihypertensive
treatment. Also, non-pharmacological intervention
can induce regression of LVH. MacMahon et al. [67]
could demonstrate a significant reduction of LVM
with weight reduction in a well controlled study. In
the Treatment of Mild Hypertension Study (TOMHS)
[68] LVM was reduced by an average of 25 g in patients
randomized to a combined exercise and weight reduc-
tion regimen with reduced alcohol and dietary sodium
intake.
Recent experimental studies have focused on the
importance not only of influencing myocyte hyper-
trophy, but also of repairing the structural remodelling
related to stimulation of the circulating RAAS system
[20, 21, 69-71]. This remodelling may lead to LV
diastolic dysfunction and subsequently to deteriora-
tion of systolic function and heart failure [69].
In experimental studies it has been demonstrated
that pharmacologic agents that interfere with the
adrenergic nervous system may induce regression in
myocardial mass due to reduction in myocyte size, but
with unchanged or even increased myocardial collagen
concentration [72]. Treatment of spontaneously
Hyprrtcwsive left ventricular hypertropy 11
regresslon progreailon
-
3 I 1
-25 -20 -15 -10 -5 5 10 15
Fig. 6. Unadjusted change in LV mass in percentage of LV
mass at baseline expressed as mean (vertical bars) and 95%
confidence intervals for placebo, ACE-inhibitors, beta-
blockers, calcium antagonists and diuretics (ref. [76], with
permission).
hypertensive rats with the ACE-inhibitor lisinopril
resulted in a complete normalization of this remodel-
ling including coronary flow reserve [73]. Similar
findings have been observed with captopril [74] and
the calcium antagonist nifedipine [75].
Thus, based upon experimental experience adrener-
gic blocking drugs seem to induce regression of LVH
mainly by reducing myocyte hypertrophy, whereas
calcium antagonists and ACE-inhibitors may have
favourable effects on structural myocardial and cor-
onary artery remodelling as well.
More than 100 studies have dealt with the regression
of LVH during antihypertensive drug treatment in
humans in the past 15 years. In the meta-analysis by
Dahlof et al. [76] comprising over 2000 patients, the
average reduction of LVM was 12% of the pretreat-
ment value. Mean arterial blood pressure was reduced
by 15% and the correlation between these two treat-
ment effects was highly significant (r = 0.51,
p < 0.001). However, only 17% of these studies were
performed in a controlled manner with a randomised,
double blind design. Follow-up has only occasionally
exceeded one year (average 10 months), the number of
patients per study was on average 2 I , characterisation
of study populations has often been poor and most
studies had a lack of blinding of the echocardiographic
measurements [77]. With these reservations in mind, a
subanalysis of those on monotherapy [76] indicates
that the greatest LVM reduction was found with ACE-
inhibitors followed by diuretics, calcium antagonists
and beta-blockers (Fig. 6). All these drug classes except
BLOOD PRESSURE 1996
 12 J . E. Otterstad et a/.
Table 11. Drug-class efects of left ventricular ( L V ) mass and geometry in hypertensive L V H
Abbreviations: WT = wall thickness; ID = internal diameter; RWT = relative wall thickness.
Drug class LV mass LV WT
ACE-inhibitors 11 11
Beta-blockers 1 1
Ca-antagonists 1 1
Diuretics 1 (1)
diuretics, in addition induced a significant reduction of
LV relative wall thickness.
Table I1 summarises the effets on LVM and LV
geometry of the different drug classes, based upon the
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principal results from the meta-analyses by Dahlof et
al. [76], Cruickshank et al. [78] and the findings from a
randomized double blind trial of our own, comparing
a beta-blocker with a diuretic [79]. It would appear
that ACE-inhibitors have the most favourable proper-
ties. However, there is at present no firm clinical
evidence that the percent reduction of LVM or relative
LV wall thickness obtained by drug treatment is
associated with a similar reduction of cardiovascular
events [77]. Furthermore, some studies suggest that
For personal use only.
ACE-inhibitors, for unknown reasons, are less effec-
tive in black patients with hypertension [80, 8 11.
There may, however, be some clinical evidence that
progression or regression of LVH may be linked to the
clinical course. Thus, Yerenev et al. [82] could show
that a progression of LVM during 4 years' follow-up of
antihypertensive treatment was related to a higher
incidence of cardiovascular events. Similar results
were reported in an abstract by Koren et al. [83], but
in none of these studies could the clinical outcome be
associated with the treatment with a specific drug.
Furthermore, a recent report from the Framingham
Study [84] in patients with ECC determined LVH
verified an association between changes in LVH
status and age-adjusted cardiovascular disease inci-
dence during a 2-year follow-up period.
In TOMHS, nutritional-hygienic treatment in the
absence of drug therapy reduced average blood pres-
sure from a level of 140/90mmHg to about 130/80
mmHg and essentially normalized LVM [68]. How-
ever, patients treated with chlorthalidone showed a
significant LVM reduction when compared with the
other regimens [85], but this group had the highest
baseline LVM, giving it the best a priori opportunity
for LVH regression.
In view of the experimental studies presented it is, in
addition, very important to evaluate the diastolic
stiffness during antihypertensive treatment. A normal-
ization of the structural remodelling and fibrosis would
BLOOD PRESSURE 1996
Clinical events related to
LV ID LV RWT LVH regression
-
11 ?
1 11 ?
1 ')
11 - ?
inevitably be followed by improved diastolic LV func-
tion [20-22, 691. Hitherto, LVM reduction in humans
has not been found to correlate well with indices of
improved LV filling using Doppler recordings of the
mitral flow signal as reference [86, 871. On the other
hand, Kjeldsen et al. [88] could demonstrate improved
LV diastolic filling in patients with mild hypertension
and a normal LVM treated with an ACE-inhibitor.
There is some clinical evidence to support the view
that regression of LVH is associated with an improved
clinical outcome, and especially that progression is
associated with a poor prognosis [82-841.
According to Devereux & Dahlof [77] the following
three types of studies are needed in the future to
establish the usefulness of treating LVH per se, and
not just to lower the blood pressure:
1. Relatively small studies with 40-60 patients to
investigate pathophysiology in detail or explore effects
of new agents.
2. Medium-sized studies with 300-400 patients fol-
lowed up for at least 6 months to determine definitely
whether inter-agent differences in reduction of LV
mass exists, and
3. Large, long-term trials with at least 1200 patients
followed up for a minimum of 4 years to determine
whether LVH reversal improves prognosis over and
above blood pressure reduction and the type of treat-
ment used.
CONCLUSIONS AND FUTURE ASPECTS
Although hypertensive LVH is a well established and
an important risk factor for cardiovascular events, the
optimal treatment of this condition remains contro-
versial. There are unresolved methodological problems
in the proper assessment of treatment effects. Until
now, M-mode echocardiography has been the stan-
dard for the evaluation of LVM and LV geometry.
Probably 2-dimensional echo, and even NMR and 3-
dimensional echo in the future, should be used as
complementary tools to improve these measurements.
The introduction of an improved methodology to

evaluate L V diastolic function, such as new Doppler
techniques, is important, since such measurements
may reflect changes in myocardial fibrosis. Further-
more, incorporation of non-invasive c o r o n a r y flow
measurements is desirable.
Currently, based on animal and human studies,
ACE-inhibitors seem t o be t h e m o s t efficient class o f
drugs in reducing a n d preventing LVH. B u t this has
n o t been verified in controlled, comparative trials of
sufficient size and d u r a t i o n to establish which drug
regimen is the m o s t efficient in reducing t h e incidence
of cardiovascular events in hypertensive LVH. Until
such information is available, firm conclusions on
which drug class is superior c a n n o t be drawn.
Blood Press Downloaded from informahealthcare.com by Chulalongkorn University on 01/06/15
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Submitted April 7 , 1995; accepted June 22, 1995
Address f o r correspondence:
Jan Erik Otterstad, M D , FESC
Dept. of Internal Medicine
Division of Cardiology
Vestfold Central Hospital
N-3100 Tmsberg
Norway
Tel: +47 333 42 000
Fax: +47 333 13689
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