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42
Circulation. 2012 Aug 14;126(7):851-9.
Determinants andprognostic signifcanceof exercise
pulmonary hypertension in asymptomatic severe
aortic stenosis.
Lancellotti P, Magne J, Donal E, O’Connor K, Dulgheru R, Rosca M, Pierard LA.
Abstract
BACKGROUND:
Recent studies emphasized the usefulness of exercise stress echocardiography in asympto-
matic patients with aortic stenosis. Nevertheless, the additive value of exercise pulmonary
hypertension (Ex-PHT) in such patients remains unexplored. We therefore aimed to identify
the determinants and to test the impact on outcome of Ex-PHT in asymptomatic patients
with severe aortic stenosis.
METHOD AND RESULTS:
Asymptomatic patients with severe aortic stenosis (n=105; aortic valve area <0.6 cm(2)/m(2);
age, 71±9 years; male, 59%) and preserved left ventricular systolic function (ejection fraction
≥55%) were prospectively submitted to exercise stress echocardiography. Resting PHT and
Ex-PHT were defned as a systolic pulmonary arterial pressure >50 and >60 mm Hg, respec-
tively. Ex-PHT was more frequent than resting PHT (55% versus 6%; P<0.0001). On multiva-
riable logistic regression, the independent predictors of Ex-PHT were male sex (odds ratio,
4.3; P=0.002), resting systolic pulmonary arterial pressure (odds ratio, 1.16; P=0.002), exercise
indexed left ventricular end-diastolic volume (odds ratio, 1.04; P=0.026), exercise e’-wave
velocity (odds ratio, 1.35; P=0.047), and exercise-induced changes in indexed left atrial area
(odds ratio, 1.36; P=0.006). Ex-PHT was associated with reduced cardiac event-free survi-
val (at 3 years, 22±7% versus 55±9%; P=0.014). In a multivariable Cox proportional hazards
model, Ex-PHT was identifed as an independent predictor of cardiac events (hazard ratio,
1.8; 95% confdence interval, 1.0-3.3; P=0.047). When exercise-induced changes in mean aortic
pressure gradient were added to the multivariable model, Ex-PHT remained independently
associated with reduced cardiac event-free survival (hazard ratio, 2.0; 95% confdence inter-
val, 1.1-3.6; P=0.025).
CONCLUSIONS:
In asymptomatic patients with severe aortic stenosis, the main determinants of Ex-PHT are
male sex, resting systolic pulmonary arterial pressure, and exercise parameters of diastolic
burden. Moreover, Ex-PHT is associated with a 2-fold increased risk of cardiac events. These
results strongly support the use of exercise stress echocardiography in asymptomatic aortic
stenosis.
Cardiovasc Res. 2012 Mar 1;93(3):480-9.
Metallothionein-dependent up-regulation of
TGF-β2 participates in the remodelling of the
myxomatous mitral valve.
Hulin A, Deroanne CF, Lambert CA, Dumont B, Castronovo V, Defraigne JO, Nusgens BV,
Radermecker MA, Colige AC.
Abstract
AIMS:
Although an excessive extracellular matrix remodelling has been well described in myxoma-
tous mitral valve (MMV), the underlying pathogenic mechanisms remain largely unknown. Our
goal was to identify dysregulated genes in human MMV and then to evaluate their functional
role in the progression of the disease.
METHODS AND RESULTS:
Dysregulated genes were investigated by transcriptomic, immunohistochemistry, andwestern
blot analyses of the P2 segment collected from human idiopathic MMV during valvuloplasty
(n = 23) and from healthy control valves (n = 17). The most striking results showed a decreased
expression of two families of genes: the metallothioneins-1 and -2 (MT1/2) and members
of the ADAMTS. The mechanistic consequences of the reduced level of MT1/2 were eva-
luated by silencing their expression in normal valvular interstitial cells (VICs) cultures. The
knock-down of MT1/2 resulted in the up-regulation of transforming growth factor-beta 2
(TGF-β2). Most importantly, TGF-β2 was also found signifcantly increased in MMV tissues.
The activation of VICs
in vitro
by TGF-β2 induced a down-regulation of ADAMTS-1 and an
accumulation of versican as observed in human MMV.
CONCLUSION:
Our studies demonstrate for the frst time that MMV are characterized by reduced levels
of MT1/2 accompanied by an up-regulation of TGF-β2. In turn, increased TGF-β2 signalling
induces down-regulation of aggrecanases and up-regulation of versican, two co-operating
processes that potentially participate in the development of the pathology.