Buermans, H.P.J.

Paulus, W.J.S.

English

DSpace at VU

Editorial
Iconoclasts topple adaptive myocardial hypertrophy
in aortic stenosis
Henk P.J. Buermans and Walter J. Paulus*
Laboratory of Physiology, Institute for Cardiovascular Research, VU Medical Centre, Van der Boechorststraat 7,
1081 BT Amsterdam, The Netherlands
Online publish-ahead-of-print 23 May 2005
This editorial refers to ‘Left ventricular hypertrophy
in aortic valve stenosis: preventive or promotive of
systolic dysfunction and heart failure?’† by M. Kupari
et al., on page 1790
For more than 30 years, the development of concentric left
ventricular (LV) hypertrophy in pressure overload was con-
sidered adaptive because the parallel deposition of new sar-
comeres and the corresponding LV wall thickening
succeeded in normalizing LV systolic wall stress despite the
high intracavitary systolic pressure.1 In aortic stenosis, the
validity of this paradigm was demonstrated by haemo-
dynamic studies, which established an inverse relationship
between LV systolic wall stress and LV ejection fraction
(EF) and by clinical outcome studies, which demonstrated
worse post-operative prognosis if LV performance fell
below this inverse LV wall stress–LVEF relationship.2,3 This
clinical paradigm of adaptive myocardial hypertrophy devel-
oping during progression of aortic stenosis clearly withstood
the test of time despite the mounting epidemiological evi-
dence of LV hypertrophy being associated with excess
cardiac mortality and despite the ominous signiﬁcance of
LV hypertrophy in congenital aortic stenosis.
Kupari et al.4 were the ﬁrst to challenge the time-
honoured concept of adaptive LV hypertrophy in aortic ste-
nosis. In a carefully designed prospective study of patients
with isolated aortic stenosis, they observed an inverse
relationship between LV mass index and LVEF and a higher
prevalence of LV hypertrophy in patients suffering of heart
failure. They therefore concluded that the development of
LV hypertrophy was actually promoting heart failure
instead of preventing it.
Basic inspiration
When Kupari et al.4 started their prospective study 5 years
ago, they were well ahead of the crowd in appreciating emer-
ging basic evidence on pressure overload-induced myocardial
hypertrophy and in translating it to clinical cardiology.5
During LV pressure overload, the raised biomechanical stress
on the cardiomyocytes stimulates various signal transduction
pathways to the nucleus6 and induces autocrine production
and secretion of angiotensin II and endothelin, whose recep-
tors are coupled to Gq proteins. It was in a mouse model with
cardiorestricted deﬁciency in Gq signalling that the paradigm
of adaptive LV hypertrophy during pressure overload received
a ﬁrst serious blow.7 After 1 week of aortic constriction,
control mice showed complete normalization of LV systolic
wall stress in contrast to the cardiac gene-targeted mice,
which had a blunted hypertrophic response and were unable
to reduce LV systolic wall stress. After 8 weeks of aortic con-
striction, despite initial normalization of wall stress, control
mice developed an increase in chamber dimensions and
progressive deterioration of LV function with echocardio-
graphic fractional shortening falling from 59 to 35%. In con-
trast, cardiac gene-targeted mice with blunted LV
hypertrophy and persistent elevation of LV systolic wall
stress showed, after 8 weeks, only limited LV dilatation and
preserved LV function with an echocardiographic fractional
shortening of 52%. From these experiments, it was concluded
that in pressure overload, the left ventricle is better off being
‘stressed out’ than being hypertrophied.
In other models of experimental pressure overload, inves-
tigators, however, clearly succeeded in creating adaptive or
physiological hypertrophy. One of these models was a rat
model of right ventricular (RV) hypertrophy caused by mono-
crotaline (MCT)-induced pulmonary hypertension.8 When
rats were given 30 mg/kg of MCT subcutaneously, they
developed slow-onset pulmonary hypertension and adaptive
RV hypertrophy, but when rats were given 80 mg/kg of MCT,
there was rapid development of pulmonary hypertension,
which was accompanied by RV failure and premature
death. Fourteen days after MCT injection, RV hypertrophy
was still identical in rats having received 30 or 80 mg/kg
of MCT. However, when RV myocardium was subjected to a
microarray analysis 14 days after MCT injection, 63 genes
out of the 3010 cardiac genes screened were already differ-
entially expressed between rats that had received 30 mg/kg
of MCT and were going to develop adaptive RV hypertrophy
and rats that had received 80 mg/kg of MCT and were
going to develop RV failure. This study implies that adaptive
hypertrophy does not precede maladaptive hypertrophy in
pressure overload and that the magnitude of the initial
& The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org
The opinions expressed in this article are not necessarily those of the
Editors of the European Heart Journal or of the European Society of
Cardiology.
* Corresponding author. Tel: þ31 204448110; fax: þ31 204448255.
E-mail address: wj.paulus@vumc.nl
{ doi:10.1093/eurheartj/ehi290
European Heart Journal (2005) 26, 1697–1699
doi:10.1093/eurheartj/ehi344
 at Vrije Universiteit - Library on April 4, 2011
e
u
rheartj.oxfordjournals.org
D
ow
nloaded from
 
pressure overload stimulus pre-destines the myocardium to
development of an adaptive or maladaptive phenotype. In
accordance with these results, development of heart
failure in the mice-aortic constriction model and in the clini-
cal aortic stenosis is related, respectively, to the tightness
of the aortic band and to the progression of valvular steno-
sis. Clinical trials, which try to slow the progression of valv-
ular stenosis with statins or angiotensin converting enzyme
inhibitors, could test the validity of this assumption by
demonstrating slower progression of valvular stenosis to be
accompanied by reduced incidence of heart failure.
Clinical translation
Before converting to the iconoclastic view that
aortic stenosis in LV hypertrophy is maladaptive, a critical
appraisal of the evidence provided by Kupari et al. seems
justiﬁed. The following issues are of concern: (i) failure to
identify and to characterize aortic stenosis patients with
LV hypertrophy and no heart failure, i.e. with adaptive LV
hypertrophy; (ii) no demonstration of a persistent elevation
of LV wall stress in the aortic stenosis patients without LV
hypertrophy, and (iii) presence of discordant LVEF–LV hyper-
trophy relationships when LV hypertrophy is assessed either
by LV mass index or by relative wall thickness.
Sixty-three aortic stenosis patients were free of heart
failure and had evidence of LV hypertrophy deﬁned by an
LV mass index .110 g/m2 in women and .134 g/m2 in
men. This group was larger than the group of aortic stenosis
patients presenting with heart failure and similar evidence
of LV hypertrophy (n ¼ 39). Aortic stenosis patients with
adaptive LV hypertrophy, therefore, outnumbered aortic
stenosis patients with maladaptive LV hypertrophy in this
prospective study population. The investigators failed to
look for clinical features discriminating patients with adap-
tive LV hypertrophy from patients with maladaptive LV
hypertrophy. Such discriminating clinical features could
have identiﬁed a hormonal or an environmental background,
which predisposes pressure overload hypertrophy to evolve
into a maladaptive phenotype. In this respect, body mass
index and arterial blood pressure were signiﬁcantly higher
in patients who developed heart failure. Obesity and hyper-
tension are established risk factors for LV diastolic dysfunc-
tion9 and as aortic stenosis progresses, these comorbidities
can direct LV hypertrophy towards a maladaptive phenotype
with diastolic heart failure. Obesity and hypertension are
both associated with insulin resistance, which lowers myo-
cardial nitric oxide (NO) content by reducing protein
kinase B-mediated endothelial NO synthase (NOS3) phos-
phorylation. Myocardial NO content is a potent modulator
of the hypertrophy process as recently demonstrated in
transgenic mice with cardiomyocyte-restricted NOS3 over-
expression.10 Hence, development of maladaptive LV hyper-
trophy should not necessarily be ascribed to the hypertrophy
gene programme but could also result from deleterious
modiﬁcation of its expression by hormonal and environ-
mental factors.
Normalization of LV wall stress is a key feature of the adap-
tive hypertrophy paradigm in pressure overload. In the orig-
inal studies that applied this paradigm to aortic stenosis,
failure to normalize LV wall stress was considered to be
responsible both for contractile dysfunction2 and for poor
post-operative outcome.3 The study by Kupari et al.4 comes
to the opposite conclusion as they observe better contractile
function in the absence of LV hypertrophy. Absence of LV
hypertrophy in their study does not, however, imply persist-
ent elevation of LV wall stress, which they unfortunately
failed to measure. As mentioned earlier, LV hypertrophy was
diagnosed when LV mass index exceeded pre-set values.
Because LV mass index also depends on LV end-diastolic
volume index, its use to categorize patients for LV hypertro-
phy can cause patients with small LV volumes and moderate
increase in LV wall thickness to end up in the group ‘without
LV hypertrophy’. This indeed happened as evident from
Table 3, which shows patients ‘without LV hypertrophy’ to
have elevated septal (13+ 0.3 mm) and posterior
(12+ 0.4 mm) wall thickness and an LV end-diastolic diam-
eter smaller than the patients ‘with LV hypertrophy’.
Patients labelled as having no LV hypertrophy could well
have developed sufﬁcient LV hypertrophy to normalize LV
wall stress for a small LV cavity and their superior contractile
performance was therefore no surprise. To clarify this issue,
the study needs to be implemented with an invasive assess-
ment of LV wall stress.
Finally, because LV mass index depends on LV end-
diastolic volume index and because LV end-diastolic
volume index was signiﬁcantly larger in the heart failure
group, the inverse relation between LV mass index and
LVEF can also be explained by an inadequacy of LV hypertro-
phy to normalize LV wall stress for a large LV cavity. In fact,
when LV mass index was replaced by relative wall thickness
(i.e. septal and posterior wall thickness divided by end-
diastolic diameter), this inadequacy of LV hypertrophy was
accounted for and the relation between LVEF and LV hyper-
trophy actually reversed, with a higher LVEF now being
observed at a higher relative wall thickness.
Conclusions
Avoidance or modiﬁcation of maladaptive LV hypertrophy
remains a major clinical challenge. The study by Kupari
et al.4 deserves credit for being the ﬁrst to translate recent
basic evidence on maladaptive myocardial hypertrophy to
the clinical setting of valvular heart disease. At present,
their iconoclastic idea on LV hypertrophy in aortic stenosis
awaits further conﬁrmation by invasive studies. As with all
iconoclastic acts, history will tell whether it cleared perspec-
tives or spoiled the view.
References
1. Grossman W, Jones D, Mc Laurin LP. Wall stress and patterns of
hypertrophy in the human left ventricle. J Clin Invest 1975;56:56–64.
2. Gunther S, Grossman W. Determinants of ventricular function in pressure-
overload hypertrophy in man. Circulation 1979;59:679–688.
3. Carabello BA, Green LH, Grossman W, Cohn LH, Koster JK, Collins JJ Jr.
Hemodynamic determinants of prognosis of aortic valve replacement in
critical aortic stenosis and advanced congestive heart failure.
Circulation 1980;62:42–48.
4. Kupari M, Turto H, Lommi J. Left ventricular hypertrophy in aortic valve
stenosis – preventive or promotive of systolic dysfunction and heart
failure? Eur Heart J 2005;26:1790–1796. First published on April 28,
2005, doi:10.1093/eurheartj/ehi290.
5. Marban E. Translation, translation, translation. Circulation research in
cardiology’s new golden age. Circ Res 2005;96:4–5.
6. Frey N, Katus HA, Olson EN, Hill JA. Hypertrophy of the Heart. Circulation
2004;109:1580–1589.
7. Esposito G, Rapacciuolo A, Prasad SVN, Takaoka H, Thomas SA, Koch WJ,
Rockman HA. Genetic alterations that inhibit in vivo pressure-overload
1698 Editorial
 at Vrije Universiteit - Library on April 4, 2011
e
u
rheartj.oxfordjournals.org
D
ow
nloaded from
 
hypertrophy prevent cardiac dysfunction despite increased wall stress.
Circulation 2002;105:85–92.
8. Buermans HPJ, Redout EM, Schiel AE, Musters RJP, Zuidwijk M, Eijk PP,
van Hardeveld C, Kasanmoentalib S, Visser FC, Yistra B, Simonides WS.
Micro-array analysis reveals pivotal divergent mRNA expression proﬁles
early in the development of either compensated ventricular hypertrophy
or heart failure. Physiol Genomics 2005; (epub ahead of print).
9. Fischer M, Baessler A, Hense HW, Hengstenberg C, Muscholl M, Holmer S,
Doring A, Broeckel U, Riegger G, Schunkert H. Prevalence of left
ventricular diastolic dysfunction in the community. Results from a
Doppler echocardiographic-based survey of a population sample. Eur
Heart J 2003;24:320–328.
10. Janssens S, Pokreisz P, Schoonjans L, Pellens M, Vermeersch P, Tjwa M,
Jans P, Scherrer-Crosbie M, Picard MH, Szelid Z, Gillijns H, Van de Werf
F, Collen D, Bloch KD. Cardiomyocyte-speciﬁc overexpression of nitric
oxide synthase 3 improves left ventricular performance and reduces com-
pensatory hypertrophy after myocardial infarction. Circ Res
2004;94:1256–1262.
Editorial 1699
 at Vrije Universiteit - Library on April 4, 2011
e
u
rheartj.oxfordjournals.org
D
ow
nloaded from
 


Determinants of ventricular function in pressureoverload hypertrophy in man. Circulation

Hemodynamic determinants of prognosis of aortic valve replacement in critical aortic stenosis and advanced congestive heart failure. Circulation

Hypertrophy of the Heart. Circulation 2004;109:1580–1589.

Left ventricular hypertrophy in aortic valve stenosis – preventive or promotive of systolic dysfunction and heart failure? Eur Heart J

Micro-array analysis reveals pivotal divergent mRNA expression proﬁles early in the development of either compensated ventricular hypertrophy or heart failure. Physiol Genomics 2005; (epub ahead of print).

Prevalence of left ventricular diastolic dysfunction in the community. Results from a Doppler echocardiographic-based survey of a population sample.

Translation, translation, translation. Circulation research in cardiology’s new golden age. Circ Res

Wall stress and patterns of hypertrophy in the human left ventricle.

Iconoclasts topple adaptive myocardial hypertrophy in aortic stenosis

Henk P.J. Buermans

Walter J. Paulus

Crossref

Iconoclasts topple adaptive myocardial hypertrophy in aortic stenosisThe opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

Iconoclasts topple adaptive myocardial hypertrophy in aortic stenosis

Abstract

Similar works

Full text

Available Versions

DSpace at VU

Crossref