Download Influence of Left Ventricular Diastolic Function on Exercise

131
J. St. Marianna Univ.
Vol. 6, pp. 131–139, 2015
Original article
Influence of Left Ventricular Diastolic Function on Exercise-induced
Pulmonary Hypertension in Patients with Systemic Sclerosis
Manabu Takai1, Kengo Suzuki1, Masaki Izumo1, Kanako Teramoto1, Yukio Sato1,
Maya Tsukahara1, Keisuke Minami1, Shingo Kuwata1, Ryo Kamijima1, Kei Mizukoshi1,
Seisyou Kou1, Akio Hayashi1, Sachihiko Nobuoka2, and Yoshihiro J. Akashi1
(Received for Publication: June 25, 2015)
Abstract
Background: Exercise-induced pulmonary hypertension (EIPH) can be caused not only by pulmonary vas‐
culopathy, but also by a significant increase in left ventricular (LV) filling pressure. This study evaluated the
influence of LV diastolic function on EIPH in patients with systemic sclerosis (SSc).
Methods: The study included 222 SSc patients (age 58.9 ± 13.1 years, 85% female) and 30 controls with
similar age distribution. In all patients, systolic pulmonary artery pressure (SPAP) and the ratio of early diastolic
transmitral flow velocity to early diastolic mitral annular velocity (E/e’), as an index of LV filling pressure, were
measured before and after exercise Doppler echocardiography using a Master’s two-step.
Results: The patients with SSc were classified into either the non-EIPH (SPAP < 50 mmHg, n = 123, 56%)
or EIPH (SPAP ≥ 50 mmHg, n = 97, 44%) group. No significant change from E/e’ at rest to E/e’ post exercise
was found in the controls (8.8 and 9.6), whereas significant changes were found in the non-EIPH (8.7 and 9.5 p
< 0.0001) and EIPH groups (10.3 and 12.6, p < 0.0001). In addition, significant differences in E/e’ at rest and
post exercise were found between the non-EIPH and EIPH groups (p <0.0001). Multivariate logistic regression
analysis identified age (odds ratio, 1.036; 95% confidence interval, 1.015–1.058, p < 0.0001) and E/e’ (odds
ratio, 1.154; 95% confidence interval, 1.066–1.246, p < 0.0001) as independent predictors of EIPH.
Conclusions: Our results suggest that approximately one third of SSc patients have EIPH. LV diastolic
function might be associated with EIPH in patients with SSc.
Key words
diastolic function, exercise doppler echocardiography,
exercise-induced pulmonary hypertension, systemic sclerosis
ture deaths2). Because of their complex nature, cardi‐
ovascular manifestations in SSc-pericardial effusion,
left ventricular (LV) hypertrophy, valvular heart dis‐
ease of various degrees, systolic and/or diastolic right
ventricular dysfunction due to pulmonary fibrosis or
PAH3,4)-represent a diagnostic challenge.
Recent data suggest that exercise echocardiogra‐
phy could be a potentially useful test for detecting ex‐
ercise-induced pulmonary hypertension (EIPH),
which may represent an intermediate stage between
Introduction
The introduction of epoprostenol for the treat‐
ment of pulmonary arterial hypertension (PAH) has
led to impressive clinical improvement and a reduc‐
tion in mortality; however, the prognosis is worse for
PAH related to systemic sclerosis (SSc) than for idio‐
pathic PAH1). A recent epidemiologic study under‐
lines that heart involvement is common in patients
with SSc, being responsible for 20–30% of all prema‐
1 Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine
2 Department of Laboratory Medicine, St. Marianna University School of Medicine
29
Takai M Suzuki K et al
132
physiologic responses and manifest PAH5,6). The inci‐
dence of PAH ranges from 5% to 10% in patients
with SSc7). An apparently inappropriate exercise-in‐
duced increase in pulmonary artery pressure is com‐
mon in these patients (prevalence up to approxi‐
mately 50%) and is suspected to be related to many
factors that affect LV diastolic function, pulmonary
vascular resistance, and interstitial lung disease8). The
different mechanisms may coexist and overlap in an
individual and also play a variable role in different
stages of the disease. Earlier published reports sug‐
gested that the prevalence of post-capillary pulmo‐
nary hypertension (PH) due to LV diastolic function
in patients with SSc was 20%9). Therefore, a signifi‐
cant number of SSc patients develop LV diastolic
dysfunction, leading to an abnormal increase in pul‐
monary artery pressure. The present study investiga‐
ted the prevalence of EIPH using simple exercise
echocardiography and evaluated the influence of LV
diastolic function on EIPH in patients with SSc.
Toshiba Medical Systems, Japan) equipped with a
broad-band transducer. All images were acquired in
the second harmonic mode with the patients lying in
the left lateral decubitus position. Two-dimensional
echocardiography measured each chamber dimen‐
sion, volume, and wall thickness according to the rec‐
ommendations of the American Society of Echocar‐
diography11). Mitral inflow was analyzed for peak
early diastolic mitral inflow velocity (E), peak late di‐
astolic velocity (A), the E/A ratio, and the decelera‐
tion time of E; peak early diastolic mitral annular ve‐
locity (e’) was determined at the septal mitral annulus
in the apical 4-chamber view using tissue Doppler
imaging. The E/e’ ratio was calculated to estimate LV
filling pressure. SPAP was estimated using the sim‐
plified Bernoulli equation, SPAP = 4 × v2 + right at‐
rial pressure, where “v” was the peak velocity of the
tricuspid regurgitation jet (m/s), and right atrial pres‐
sure was estimated from the diameter and breath-in‐
duced variability of the inferior vena cava. Stroke
volume was measured from the LV outflow tract di‐
ameter and the time velocity integral, as previously
described. Cardiac output was determined as stroke
volume × heart rate. Tricuspid annular plane systolic
excursion was measured for right ventricular func‐
tion12). All patients underwent exercise echocardiog‐
raphy using a Master’s two-step placed at their bed‐
side; they ascended and descended the stairs
repeatedly for 3 minutes. Immediately after the exer‐
cise test, the patients lay down on the bed and another
echocardiographic examination was performed for
the measurement of post, post 3-minute, and post 5minute tricuspid regurgitation velocity, as previously
reported13,14). Blood pressure and heart rate were
measured at the same time. All data were analyzed
off-line by two observers who were blind to the pa‐
tients’ characteristics. Intraobserver and interobserver
variability were less than 4.0% for measurements at
rest and less than 6.0% for those at post exercise.
Materials and Methods
This study prospectively enrolled 256 consecu‐
tive patients with SSc, in World Health Organization
functional classification 1 and 2, identified by rheu‐
matologists between August 2010 and October 2013.
Patients with a history of PH or systolic pulmonary
artery pressure (SPAP) ≥50 mmHg at rest10) based on
previous echocardiograms; those receiving endothelin
receptor antagonists, phosphodiesterase-5 inhibitors
and/or prostanoids; those with coronary artery dis‐
ease (angina pectoris, previous myocardial infarction,
electrocardiographic and/or echocardiographic signs
of myocardial ischemia) and/or previous diagnosis of
heart failure, atrial fibrillation/flutter, interstitial lung
disease (chest high-resolution computed tomography
and/or forced vital capacity < 80% of the predicted
value), systolic LV dysfunction (LV ejection fraction
< 60%), or significant valvular disease and systemic
hypertension (resting systolic blood pressure > 150
mmHg or resting diastolic blood pressure > 90
mmHg on medications): those who could not perform
the exercise stress test; and those with poor-quality
echocardiographic images were excluded from this
study. Finally, 222 patients and 30 controls with simi‐
lar age and sex distribution underwent simple exer‐
cise echocardiography.
Statistical analysis
Statistical analysis was performed using com‐
mercially available software (SPSS 18.0 software,
SPSS Inc., Chicago, Illinois). All continuous data are
reported as mean ± SD and categorical data as per‐
centages. The level of p < 0.05 was considered statis‐
tically significant. Variables were compared between
the groups using one-way analysis of variance, Tur‐
key’s test and the chi-square test. Correlations be‐
tween parameters were assessed using the nonpara‐
metric Spearman correlation coefficient analysis or
Echocardiography at rest and post exercise
Echocardiography was performed using a com‐
mercially available ultrasound machine (Artida,
30
Diastolic function in systemic sclerosis
Pearson correlation, as appropriate. Multivariate lo‐
gistic regression analysis was used to determine any
relation between EIPH and age, sex, systolic blood
pressure, or E/e’, given the suspected association be‐
tween EIPH and these parameters7,15).
133
fied into the either the non-EIPH (SPAP < 50 mmHg,
n = 123) or EIPH (SPAP ≥ 50 mmHg, n = 97)
group16) (Figure 1).
Results
Characteristics and echocardiographic parameters
There was a significant difference in age be‐
tween the non-EIPH and EIPH groups. No significant
differences in brain natriuretic peptide, carbon mon‐
oxide diffusion capacity by body surface, or resting
heart rate were found between the two groups,
whereas post-exercise heart rate was higher in the
EIPH group than the non-EIPH group (Table 1). Sig‐
nificant differences in left atrial size, LV wall thick‐
ness, and LV diastolic indices were found between
the two groups, whereas there were no significant dif‐
ferences in LV ejection fraction or tricuspid annular
plane systolic excursion (Table 2).
Of the 256 patients, 34 were excluded according
to the exclusion criteria (previous diagnosis of heart
failure, n = 3; atrial fibrillation, n = 2; interstitial lung
disease, n = 7; significant valvular disease, n = 5; sys‐
temic hypertension, n =6; inability to perform the ex‐
ercise stress test, n = 6; and poor imaging, n = 5). The
remaining 222 patients subsequently underwent sim‐
ple exercise echocardiography for screening PH; 220
patients (99%) completed the procedure. The patients
(age 58.9 ± 13.1 years, 85% female) were then classi‐
Changes in SPAP and E/e’ at rest and post exercise
Significant changes from SPAP at rest to SPAP
at post exercise were found in the controls (21.9 ± 4.7
mmHg and 31.6 ± 7.3 mmHg, p < 0.0001), and in the
non-EIPH (25.4 ± 4.1 mmHg and 36.9 ± 6.8 mmHg,
p < 0.0001) and EIPH groups (36.2 ± 9.8 mmHg and
60.6± 9.8 mmHg, p < 0.0001; Figure 2). No signifi‐
cant change from E/e’ at rest to E/e’ post exercise
was found in the controls (8.8 ± 2.1 and 9.6 ± 2.7),
Ethics
The present study was performed in accordance
with the ethical principles set forth in the Declaration
of Helsinki. The study protocol was approved by the
St. Marianna University School of Medicine Institu‐
tional Committee on Human Resources, Kawasaki,
Japan (No.1798). The participants were well in‐
formed prior to the test and gave their written consent
before enrollment.
Figure 1 Flowchart representing the algorithm and the assessments of the present
study.
SSc, systemic sclerosis; WHO FC, World Health Organization func‐
tional classification; TR, tricuspid regurgitation; EIPH, exercise-in‐
duced pulmonary hypertension; SPAP, systolic pulmonary artery pres‐
sure
31
Takai M Suzuki K et al
134
Table 1 Patients’ Characteristics
* p < 0.05, Controls vs. Non-EIPH; ** p < 0.05, Controls vs. EIPH; † p < 0.05, Non-EIPH vs. EIPH
EIPH, exercise-induced pulmonary hypertension; BNP, brain natriuretic peptide; %DLco, carbon
monoxide diffusion capacity by body surface; SBP, systolic blood pressure; DBP, diastolic blood
pressure.
whereas significant changes were found in the nonEIPH (8.7 ± 2.3 and 9.5 ± 2.2, p < 0.0001) and EIPH
groups (10.3 ± 3.4 and 12.6 ± 3.1, p < 0.0001; Figure
3). In addition, significant differences in E/e’ at rest
and post exercise were found between the non-EIPH
and EIPH groups (p < 0.0001).
tion was found between SPAP post exercise and E/e’.
In the multiple logistic regression analysis, age and
E/e’ were independently associated with EIPH.
In patients with SSc, dyspnea may be related to
pulmonary fibrosis, pulmonary arterial vasculopathy,
LV involvement, systemic arterial hypertension, or
deconditioning because of skin, muscle, and joint in‐
volvement17). The occurrence of PH is one of the
main clinical problems in SSc and is now the most
common cause of SSc-related death18). Many SSc pa‐
tients develop PH as a result of pulmonary arteriopa‐
thy, whereas some patients develop it as a result of
pulmonary fibrosis19). Furthermore, LV involvement
in SSc has been associated with perivascular and my‐
ocardial fibrosis on endomyocardial biopsies20) and
with myocardial fibrosis on magnetic resonance
imaging21). Thus, a significant number of SSc patients
develop LV diastolic dysfunction, leading to an ab‐
normal increase in pulmonary artery pressure due to
upstream transmission of the associated increase in
LV diastolic pressure (pulmonary venous hyperten‐
sion)22). Accordingly, the parameters affecting LV di‐
astolic function, such as age23) and systemic arterial
hypertension, may potentially influence exercise-in‐
duced increases in pulmonary artery pressure. D’Alto
et al.8) stressed that we should exercise caution in in‐
terpreting the results of exercise echocardiography in
Relationship between SPAP post exercise and E/e’
A weak correlation was found between SPAP
post exercise and E/e’ (r = 0.34, p < 0.0001; Figure
5A). Furthermore, a significant positive correlation
was found between SPAP post exercise and E/e’
(r=0.42, p < 0.001; Figure 4). The univariate analysis
demonstrated that EIPH was associated with age, fe‐
male sex, systolic blood pressure, and E/e’. In the
multiple logistic regression analysis, age and E/e’
were independently associated with EIPH (Table 3).
Discussion
The present study prospectively investigated pa‐
tients with SSc in World Health Organization func‐
tional classification 1 and 2, employed a Master’s
two-step for exercise echocardiography, and assessed
the prevalence of EIPH. In this study, 44% of the pa‐
tients were identified as having EIPH. Significant dif‐
ferences in LV diastolic indices were found between
the non-EIPH and EIPH groups. A positive correla‐
32
Diastolic function in systemic sclerosis
135
Table 2 Echocardiographic Parameters
* p < 0.05, Controls vs. Non-EIPH; ** p < 0.05, Controls vs. EIPH; † p < 0.05, Non-EIPH vs. EIPH
PAH, pulmonary arterial hypertension; LAD, left atrial diameter; LAVI, left atrial volume index;
PW, posterior wall; LVDd, left ventricular end-diastolic diameter; LVDs, left ventricular end-sys‐
tolic diameter; LVEF, left ventricular ejection fraction; E/A, the ratio of early diastolic (E) and late
diastolic (A) transmitral inflow velocities; Dct, deceleration time of E wave velocity; E/e’, the ratio
of early diastolic transmitral flow velocity to early diastolic mitral annular velocity; TAPSE, tricus‐
pid annular plane systolic excursion; SPAP, systolic pulmonary artery pressure
patients with SSc because abnormal pulmonary vas‐
cular reserve might be related to the presence of mild
to moderate interstitial lung disease and subtle signs
of LV diastolic dysfunction. In the present study, in‐
terstitial lung disease was excluded. Accurate diagno‐
sis of the cause of dyspnea is important for directing
therapy.
Several studies have documented a limited exer‐
cise capacity in patients with normal resting but ele‐
vated post-stress echocardiographic pulmonary pres‐
sures24,25). However, whether such patients have an
early manifestation of PAH-referred to as EIPH5)-or
pulmonary venous hypertension secondary to LV dia‐
stolic dysfunction is not apparent from the earlier
study. While exercise hemodynamics provide a way
to distinguish the early stages of PH from heart fail‐
ure with preserved ejection fraction26), there is no
consensus regarding the role of exercise in evaluating
PH27).
The present study attempted to characterize the
hemodynamic profiles of SSc patients who had clini‐
cal dyspnea and/or echocardiographic evidence of
normal resting pulmonary systolic pressures that in‐
creased post exercise. From the statistical analysis,
E/e’ was associated with EIPH rather than with fe‐
male sex and systolic blood pressure. The results
should be interpreted with caution because of the E/e’
elevation inconsistency in the EIPH group.
Some limitations of the present study should be
highlighted. Exercise echocardiography is usually
performed on a supine bicycle ergometer in the left
tilt position28). However the present study employed
the Master’s two-step for screening PAH. Earlier
study results suggest that up to 40–60% of SSc pa‐
33
136
Takai M Suzuki K et al
Figure 3 Changes in E/e’ from rest to post exercise.
No significant changes in E/e’ from rest to post
exercise were found in the controls (8.8 ± 2.1 and
9.6 ± 2.7), whereas significant changes were
found in the non-EIPH (8.7 ± 2.3 and 9.5 ± 2.2, p
< 0.0001) and EIPH groups (10.3 ± 3.4 and 12.6
± 3.1, p < 0.0001).
EIPH, exercise-induced pulmonary hypertension;
E/e’, the ratio of early diastolic transmittal flow
velocity to early diastolic mitral annular velocity;
Figure 2 Changes in systolic pulmonary artery pressure
(SPAP) from rest to post exercise.
Significant changes in SPAP from rest to post ex‐
ercise were found in the controls (21.9 ± 4.7
mmHg and 31.6 ± 7.3 mmHg, p < 0.0001), and in
the non-EIPH (25.4 ± 4.1 mmHg and 36.9 ± 6.8
mmHg, p < 0.0001) and EIPH groups (36.2 ± 7.2
mmHg and 60.6 ± 9.8 mmHg, p < 0.0001).
EIPH, exercise-induced pulmonary hypertension;
SPAP, systolic pulmonary artery pressure
Figure 4 Relationship between SPAP at post exercise and E/e’.
A significant positive correlation was found between SPAP post
exercise and E/e’ (r=0.42, p < 0.001).
SPAP, systolic pulmonary artery pressure; E/e’, ratio of early dia‐
stolic transmittal flow velocity to early diastolic mitral annular ve‐
locity;
34
Diastolic function in systemic sclerosis
137
Table 3 Multivariable Logistic Regression Analysis for Predicting EIPH
SBP, systolic blood pressure; E/e’, the ratio of early diastolic transmitral flow ve‐
locity to early diastolic mitral annular velocity
tients develop EIPH29), whereas 44% patients were
identified as having EIPH in the present study. The
lower prevalence of EIPH in our study could have
been due to the non-conventional exercise test using a
Master’s two-step instead of the more commonly em‐
ployed bicycle ergometer, which may account for the
low maximum cardiac output and heart rate. It re‐
mains unclear whether the Master’s two-step method
is useful in a multi-center trial, because this approach
has not yet been validated by clinical investigation.
4)
5)
Conclusions
6)
The present study demonstrated that EIPH was
common in patients with SSc, even when resting
SPAP was normal. LV diastolic function might be as‐
sociated with EIPH in patients with SSc.
Acknowledgements
7)
We would like to thank Mrs. Keiko Kohno and
the technicians at the Center of Ultrasonics, St. Ma‐
rianna University School of Medicine Hospital, for
their assistance.
References
1) Rubenfire M, Huffman MD, Krishnan S, Seibold
JR, Schiopu E, McLaughlin VV. Survival in sys‐
temic sclerosis with pulmonary arterial hyper‐
tension has not improved in the modern era.
Chest 2013; 144: 1282–1290.
2) Komócsi A, Vorobcsuk A, Faludi R, Pintér T,
Lenkey Z, Költo G, Czirják L. The impact of
cardiopulmonary manifestations on the mortality
of SSc: a systematic review and meta-analysis of
observational studies. Rheumatology (Oxford)
2012; 51: 1027–1036.
3) Faludi R, Komócsi A, Bozó J, Kumánovics G,
Czirják L, Papp L, Simor T. Isolated diastolic
dysfunction of right ventricle: stress-induced
8)
9)
35
pulmonary hypertension. Eur Respir J 2008; 31:
475–476.
Komócsi A, Pintér T, Faludi R, Magyari B,
Bozó J, Kumánovics G, Minier T, Radics J,
Czirják L. Overlap of coronary disease and pul‐
monary arterial hypertension in systemic sclero‐
sis. Ann Rheum Dis 2010; 69: 202–205.
Tolle JJ, Waxman AB, Van Horn TL, Pappagia‐
nopoulos PP, Systrom DM. Exercise-induced
pulmonary arterial hypertension. Circulation
2008; 118: 2183–2189.
Lewis GD, Bossone E, Naeije R, Grünig E, Sag‐
gar R, Lancellotti P, Ghio S, Varga J, Rajagopa‐
lan S, Oudiz R, Rubenfire M. Pulmonary vascu‐
lar hemodynamic response to exercise in
cardiopulmonary diseases. Circulation 2013;
128: 1470–1479.
Gargani L, Pignone A, Agoston G, Moreo A,
Capati E, Badano LP, Doveri M, Bazzichi L,
Costantino MF, Pavellini A, Pieri F, Musca F,
Muraru D, Epis O, Bruschi E, De Chiara B, Per‐
fetto F, Mori F, Parodi O, Sicari R, Bombardieri
S, Varga A, Cerinic MM, Bossone E, Picano E.
Clinical and echocardiographic correlations of
exercise-induced pulmonary hypertension in
systemic sclerosis: a multicenter study. Am
Heart J 2013; 165: 200–207.
D’Alto M, Ghio S, D’Andrea A, Pazzano AS,
Argiento P, Camporotondo R, Allocca F, Scelsi
L, Cuomo G, Caporali R, Cavagna L, Valentini
G, Calabrò R. Inappropriate exercise-induced in‐
crease in pulmonary artery pressure in patients
with systemic sclerosis. Heart 2011; 97: 112–
117.
Avouac J, Airò P, Meune C, Beretta L, Dieude
P, Caramaschi P, Tiev K, Cappelli S, Diot E,
Vacca A, Cracowski JL, Sibilia J, Kahan A, Ma‐
tucci-Cerinic M, Allanore Y. Prevalence of pul‐
138
10)
11)
12)
13)
14)
Takai M Suzuki K et al
monary hypertension in systemic sclerosis in
European Caucasians and metaanalysis of 5
studies. J Rheumatol 2010; 37: 2290–2298.
Galiè N, Hoeper MM, Humbert M, Torbicki A,
Vachiery JL, Barbera JA, Beghetti M, Corris P,
Gaine S, Gibbs JS, Gomez-Sanchez MA, Jon‐
deau G, Klepetko W, Opitz C, Peacock A, Ru‐
bin L, Zellweger M, Simonneau G; ESC Com‐
mittee for Practice Guidelines (CPG).
Guidelines for the diagnosis and treatment of
pulmonary hypertension: the Task Force for the
Diagnosis and Treatment of Pulmonary Hyper‐
tension of the European Society of Cardiology
(ESC) and the European Respiratory Society
(ERS), endorsed by the International Society of
Heart and Lung Transplantation (ISHLT). Eur
Heart J 2009; 30: 2493–2537.
Lang RM, Bierig M, Devereux RB, Flach‐
skampf FA, Foster E, Pellikka PA, Picard MH,
Roman MJ, Seward J, Shanewise JS, Solomon
SD, Spencer KT, Sutton MS, Stewart WJ;
Chamber Quantification Writing Group; Ameri‐
can Society of Echocardiography’s Guidelines
and Standards Committee; European Associa‐
tion of Echocardiography. Recommendations for
chamber quantification: a report from the Amer‐
ican Society of Echocardiography’s Guidelines
and Standards Committee and the Chamber
Quantification Writing Group, developed in con‐
junction with the European Association of Echo‐
cardiography, a branch of the European Society
of Cardiology. J Am Soc Echocardiogr 2005;
18: 1440–1463.
Rudski LG, Lai WW, Afilalo J, Hua L, Hand‐
schumacher MD, Chandrasekaran K, Solomon
SD, Louie EK, Schiller NB. Guidelines for the
echocardiographic assessment of the right heart
in adults: a report from the American Society of
Echocardiography endorsed by the European
Association of Echocardiography, a registered
branch of the European Society of Cardiology,
and the Canadian Society of Echocardiography.
J Am Soc Echocardiogr 2010; 23: 685–713.
Suzuki K, Akashi YJ, Manabe M, Mizukoshi K,
Kamijima R, Kou S, Takai M, Izumo M, Kida
K, Yoneyama K, Omiya K, Yamasaki Y, Ya‐
mada H, Nobuoka S, Miyake F. Simple exercise
echocardiography using a Master’s two-step test
for early detection of pulmonary arterial hyper‐
tension. J Cardiol 2013; 62: 176–182.
Suzuki K, Izumo M, Kamijima R, Mizukoshi K,
15)
16)
17)
18)
19)
20)
21)
22)
23)
24)
36
Takai M, Kida K, Yoneyama K, Nobuoka S, Ya‐
mada H, Akashi YJ. Influence of pulmonary
vascular reserve on exercise-induced pulmonary
hypertension in patients with systemic sclerosis.
Echocardiography 2015; 32: 428–435.
Argiento P, Vanderpool RR, Mulè M, Russo
MG, D’Alto M, Bossone E, Chesler NC, Naeije
R. Exercise stress echocardiography of the pul‐
monary circulation: limits of normal and sex dif‐
ferences. Chest 2012; 142: 1158–1165.
Baptista R, Serra S, Martins R, Salvador MJ,
Castro G, Gomes M, Santos L, Monteiro P, da
Silva JA, Pêgo M. Exercise-induced pulmonary
hypertension in scleroderma patients: a common
finding but with elusive pathophysiology. Echo‐
cardiography 2013; 30: 378–384.
Gabrielli A, Avvedimento EV, Krieg T. Sclero‐
derma. N Engl J Med 2009; 360: 1989–2003.
Steen VD, Medsger TA. Changes in causes of
death in systemic sclerosis, 1972–2002. Ann
Rheum Dis 2007; 66: 940–944.
Vachiéry JL, Coghlan G. Screening for pulmo‐
nary arterial hypertension in systemic sclerosis.
Eur Respir Rev 2009; 18: 162–169.
Fernandes F, Ramires FJ, Arteaga E, et al. Car‐
diac remodeling in patients with systemic scle‐
rosis with no signs or symptoms of heart failure:
an endomyocardial biopsy study. J Card Fail
2003; 9: 311–317.
Tzelepis GE, Kelekis NL, Plastiras SC, Ianni
BM, Bonfá ES, Mady C. Pattern and distribution
of myocardial fibrosis in systemic sclerosis: a
delayed enhanced magnetic resonance imaging
study. Arthritis Rheum 2007; 56: 3827–3836.
Huez S, Roufosse F, Vachiéry JL, Pavelescu A,
Derumeaux G, Wautrecht JC, Cogan E, Naeije
R. Isolated right ventricular dysfunction in sys‐
temic sclerosis: latent pulmonary hypertension?
Eur Respir J 2007; 30: 928–936.
Lam CS, Borlaug BA, Kane GC, Enders FT,
Rodeheffer RJ, Redfield MM. Age-associated
increases in pulmonary artery systolic pressure
in the general population. Circulation 2009; 119:
2663–2670.
Kovacs G, Maier R, Aberer E, Brodmann M,
Scheidl S, Tröster N, Hesse C, Salmhofer W,
Graninger W, Gruenig E, Rubin LJ, Olschewski
H. Borderline pulmonary arterial pressure is as‐
sociated with decreased exercise capacity in
scleroderma. Am J Respir Crit Care Med 2009;
180: 881–886.
Diastolic function in systemic sclerosis
25) Alkotob ML, Soltani P, Sheatt MA, Katsetos
MC, Rothfield N, Hager WD, Foley RJ, Silver‐
man DI. Reduced exercise capacity and stressinduced pulmonary hypertension in patients
with scleroderma. Chest 2006; 130: 176–181.
26) Borlaug BA, Nishimura RA, Sorajja P, Lam CS,
Redfield MM. Exercise hemodynamics enhance
diagnosis of early heart failure with preserved
ejection fraction. Circ Heart Fail 2010; 3: 588–
595.
27) Badesch DB, Champion HC, Sanchez MA,
Hoeper MM, Loyd JE, Manes A, McGoon M,
Naeije R, Olschewski H, Oudiz RJ, Torbicki A.
139
Diagnosis and assessment of pulmonary arterial
hypertension. J Am Coll Cardiol 2009; 54: S55–
S66.
28) Bossone E, D’Andrea A, D’Alto M, Citro R, Ar‐
giento P, Ferrara F, Cittadini A, Rubenfire M,
Naeije R. Echocardiography in pulmonary arte‐
rial hypertension: from diagnosis to prognosis. J
Am Soc Echocardiogr 2013; 26: 1–14.
29) Lau EM, Manes A, Celermajer DS, Galiè N.
Early detection of pulmonary vascular disease in
pulmonary arterial hypertension: time to move
forward. Eur Heart J 2011; 32: 2489–2498.
37