Right Ventricular Dysfunction in Systemic Sclerosis Associated

Transcription

Right Ventricular Dysfunction in Systemic Sclerosis Associated Pulmonary
Arterial Hypertension
Tedford et al: RV Dysfunction in SScPAH
Ryan J. Tedford, MD1; James O. Mudd, MD2; Reda E. Girgis, MD3;
Stephen C. Mathai, MD, MHS3 ; Ari L. Zaiman, MD3; Traci Housten-Harris, MS, RN3;
Danielle Boyce, MPH3; Benjamin W. Kelemen, BA1; Anita C. Bacher, MSN, MPH, MA1;
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
Ami A. Shah, MD, MHS4; Laura K. Hummers, MD4; Fredrick M. Wigley, MD4;
Stuart D. Russell, MD1; Rajeev Saggar, MD5; Rajan Saggar, MD6; W. Lowell Maughan, MD2;
Paul M. Hassoun, MD3; David A. Kass,, MD
MD1,7
1
Division of Cardiology,
logy, 3Divi
lo
Division
viisiionn ooff Pu
Pulm
Pulmonary
lmon
lm
onnarry an
and
nd Cr
C
Critical
itic
it
i all C
ic
Care,
are,, 4Di
ar
Division
ivi
vissioon
on ooff Rheumatology;
Department of Medicine,
ici
ici
cine
ne, Johns
ne
Joohn
h s Hopkins
Hoopk
pkin
inss Medical
in
M dica
Me
c l Institutions,
In
nstit
itut
it
utio
ut
i ns, Baltimore,
io
Baltim
Ba
imorre,
im
e, MD,
MD, USA
U
2
Division of Cardiology;
l
logy;
D
De
Department
partmentt ooff Medi
Medicine,
ici
cine
n , Or
O
Oregon
eg
gon
o Health & Science Un
University,
n
Portland, OR, USA
5
Heart Lung Institute,
e, St. Jo
Joseph
ose
seph
ph H
Hospital
osspittal aand
nd M
Medical
edic
ed
ical
ic
al C
al
Center,
ente
en
ter,
te
r, P
Phoenix,
hoen
ho
enix
en
ix,, AZ
ix
A
6
Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen
School of Medicine at UCLA, Los Angeles, CA
7
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD
Correspondence to:
Ryan J. Tedford, MD
Johns Hopkins Medical Institutions
568 Carnegie; 600 North Wolfe Street; Baltimore, MD 21287
Telephone: 410-955-5708
Fax: 410-955-3478
Email: [email protected]
DOI: 10.1161/CIRCHEARTFAILURE.112.000008
Journal Subject Codes: Heart Failure: 11 (Other heart failure), Hypertension 18 (Pulmonary
circulation and disease
Abstract
Background—Systemic sclerosis associated pulmonary artery hypertension (SScPAH) has a
worse prognosis compared to idiopathic pulmonary arterial hypertension (IPAH), with a median
survival of 3 years after diagnosis often due to right ventricular (RV) failure. We tested if
SScPAH or systemic sclerosis related pulmonary hypertension with interstitial lung disease
(SSc-ILD-PH) imposes a greater pulmonary vascular load than IPAH and/or leads to worse RV
contractile function.
Methods and Results—We analyzed pulmonary artery pressures and mean flow in 282 patients
with pulmonary hypertension (166 SScPAH, 49 SSc-ILD-PH, 67 IPAH). An inverse relation
between pulmonary resistance (RPA) and compliance (CPA) was similar for all three groups, with
a near constant resistance u compliance product. RV pressure-volume loops
p were measured in a
subset, IPAH (n=5) and SScPAH (n=7) as well as SSc without PH
H (SSc-no-PH,
(SSc
(S
Sc-n
Sc
-no-n
o-PH
oPH,, n=7) to derive
PH
contractile indexes (end
(end-systolic
d-ssys
y to
t li
licc elastance [Ees] andd preload recr
recruitable
rui
u table stroke work
wo [Msw]),
measures of right ventricular
ent
ent
ntrricular load
load
d (arterial
(ar
arte
teri
te
rial
ri
al eelastance
last
la
sttancee [E
stan
Ea])
]), and
and RV
RV-p
RV-pulmonary
-p
pul
ulmo
mona
mo
nary
na
ry aartery
r
coupling
(Ees/Ea). RV afterload
oad was
oa
was similar
wa
ssiimi
imi
mila
laar in
i SScPAH
SSc
ScPA
PAH
PA
H and
and IPAH
IPAH (R
(RPA=7
=7.0±4.5
=7.0
.00±4
±4.5
.5 vvs.
s. 77.9±4.3
s.
.9±
.9
±
Wood units;
Ea=0.9±0.4 vs. 1.2±0.5
0 mmHg/mL; CPAA=2
0.5
=2.4±1.5
=2.4
.4±1
.4
±1.5
±1
. vvs.
.5
s. 11.7±1.1
.7
7±1
1.1
. m
mL/mmHg;
L/mmHg; p>0.3 ffor each).
Though SScPAH did
stiffening
d not
not have
have ggreater
reat
re
ater
at
er vvascular
ascu
as
cu
ula
larr st
sti
tiff
ffen
enin
en
in
ng co
ccompared
mpar
mp
par
ared
ed to
to IPAH,
IPAH
IP
AH,
A
H, RV
V contractility
was more depressed (Ees=0.8±0.3 vs. 2.3±1.1, p<0.01; Msw=21±11 vs. 45±16, p=0.01), with
differential RV-PA uncoupling (Ees/Ea=1.0±0.5 vs. 2.1±1.0, p=.03). This ratio was higher in
SSc-no-PH (Ees/Ea = 2.3±1.2, p=0.02 vs. SScPAH).
Conclusions—RV dysfunction is worse in SScPAH compared to IPAH at similar afterload, and
may be due to intrinsic systolic function rather than enhanced pulmonary vascular resistive
and/or pulsatile loading.
Key Words: Right ventricular failure, right ventricle-pulmonary arterial coupling, pulmonary
hypertension, pressure-volume relationship, systemic sclerosis
1
Systemic sclerosis (SSc, scleroderma) is a heterogeneous disorder characterized by
microvasculopathy, immune abnormalities, and tissue fibrosis. Pulmonary arterial hypertension
(PAH) is among its most serious complications and a leading cause of mortality1.
Pathologically, small vessel fibro-proliferation ultimately leads to marked vascular narrowing or
complete obliteration2. The accompanying rise in pulmonary resistance stimulates right
ventricular (RV) hypertrophy that initially helps maintain cardiac output, but over time can
progress with RV dilation, dysfunction, and failure3, 4. Among causes of PAH, patients with
systemic sclerosis (SScPAH) have the worst prognosis, with a median survival of 3 years after
cidence of PA
PAH
AH in SSc is
diagnosis5, 6, and RV failure is a primary cause of death. The incidence
9
approximately 10%7, 8, and with ~240/million SSc patients in the United
Unnit
i ed States
Sta
tate
tess alone
te
a
, the
population with SScPAH
cPAH may
cP
ay
y indeed
ind
dee
eedd exceed
exce
ex
ceed
ce
ed
d that
th
hat
a with
withh idiopathic
idio
id
iopa
io
path
pa
th
hic dis
disease
sea
ease
se ((IPAH)
IPAH
IP
AH))10. Our
AH
nder
nd
errly
lyin
in
ng ca
cau
usess for
for
o worsened
wor
orssen
ened
ed ssurvival
urvi
ur
viva
vi
vall in S
va
SccPA
ScPA
PAH
H re
ema
main
in poor.
understanding of thee uunderlying
causes
SScPAH
remains
Given the importance
mpo
port
rtan
rt
ance
an
ce of
of RV dysfunction
dys
y fu
func
ncti
nc
tion
ti
on in
in late-stage
late
la
te-s
te
-sta
-s
tage
ta
g PAH,
ge
PAH
AH, studies
stud
st
udie
ud
iess have
ie
have begun focusing
on features specific to SSc. Considered broadly, one can posit two major contributors for worse
RV performance, greater pulmonary arterial load perhaps due to stiffening/sclerosis of the
vessels that is missed by standard measures11, or primary cardiac depression. A comparison of
RV and left ventricular (LV) function in IPAH and SScPAH found similar global RV and LV
function by echocardiography at slightly lower RV afterload in one study12, but similar right
heart hemodynamics in another13. Mathai et al. examined tricuspid annular plane systolic
excursion (TAPSE), a measure of RV systolic function, and found it predicted clinical mortality
in SScPAH patients14. However, TAPSE also predicts survival in IPAH15 making it less likely to
have identified a specific feature of SSc. TAPSE is also load dependent and influenced by
2
overall cardiac motion. One study has suggested RV depression is greater in SScPAH than
IPAH16, but did not directly measure RV contractility.
Accordingly, we tested whether the RV of SSc patients with pulmonary hypertension
(PH), both in the presence and absence of interstitial lung disease (ILD), is subjected to greater
total afterload as compared with IPAH, including pulsatile load that is not reflected in mean
resistance. Right heart catheterization (RHC) data from PH databases at two institutions were
analyzed to assess relations between pulmonary vascular compliance and resistance. Secondly,
we tested whether the RV in SScPAH displays reduced contractility as compared to IPAH, as
e volume (PV)
V) relation
r
well as SSc without PH (SSc-no-PH) using invasive RV pressure-volume
analysis.
Meeth
thod
ds
Methods
Patient Groups
ove
vedd byy IInstitution
nsti
ns
titu
ti
tuti
tu
tion
ti
on R
evie
ev
iew
ie
wB
oard
oa
rdss of eeach
rd
achh in
ac
inst
stit
st
itut
it
utio
ut
ionn [J
io
[JHM
HM-HM
This study was approved
Review
Boards
institution
[JHM-IRB-1:
NA_00027124, JHM-IRB-1: #NA_00014540, OPRS UCLA IRB #12-000738] and informed
consent was obtained for all patients. The diagnosis of SSc was based on 1 of 3 definitions: the
American College of Rheumatology criteria (formerly, the American Rheumatism Association)
17
; the presence of three of five features of the CREST syndrome; or definite Raynaud's
phenomenon, abnormal nailfold capillaries typical of scleroderma, and the presence of a specific
scleroderma-related autoantibody12. PAH was diagnosed by a mean pulmonary artery pressure
(mPAP) 25mmHg and pulmonary capillary wedge pressure (PCWP) 15mmHg, measured by
RHC. The diagnosis of SSc-related pulmonary hypertension with interstitial lung disease (SScPH-ILD) was based on criteria previously reported18. IPAH patients had all known causes of
PAH excluded.
3
Analysis of pulmonary resistance-compliance relations
To analyze pulmonary vascular load, cohorts of SScPAH, SSc-ILD-PH, and IPAH patients with
RHC and pulmonary function testing (PFT) data were identified from the Johns Hopkins (JH)
and UCLA PH databases, spanning the period from January 1, 1995 to May 31, 2012: SScPAH
(77% JH, 23% UCLA), SSc-ILD-PH (100% UCLA), IPAH (100% JH). For any patient with
more than one RHC study in the database, the first study recorded was used. Pulmonary vascular
resistance (RPA) was equal to (mPAP-PCWP)/cardiac output (expressed as mmHgxsecondsxmLDownloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
1
), and total pulmonary arterial compliance (CPA) was determined from stroke volume (SV)/pulse
Hyperbolic
yp
perboliic RPA-CPA
pressure (mLxmmHg-1), the latter validated by several studies19, 20. Hyp
relations19, 21, 22 were then derived for each group to assess whether
her co
comp
compliance
omp
mpli
lian
li
ance
an
ce w
was less for any
given resistance.
Loop
o Analysis
Ana
naly
lysi
ly
siss
si
Pressure-Volume Loop
To measure RV contractile function and pulmonary vascular interaction, we prospectively
studied patients referred for RHC at Johns Hopkins from November 2009 to February 2013 for
diagnosis or management of PAH (with or without SSc). After completing the RHC, a pressurevolume catheter (model SPC-570-2, Millar Instruments, Houston, TX) was advanced through the
internal jugular vein and positioned at the RV apex under fluoroscopic guidance. The catheter
was connected to a digital stimulator micropressor (Sigma V, Leycom, The Netherlands) that
supplied a high frequency low amperage excitation current to electrodes at the RV apex and right
atrium. Measured voltage differences between intervening electrode pairs were inversely
proportional to segmental volume, and RV intracavitary segments were then added to yield total
volume. This methodology is similar to that developed by our laboratory for the LV23, 24. The
4
RV conductance signal was calibrated to match independently determined RV ejection fraction
(proximate study using magnetic resonance imaging n=14, or echocardiography n=5), and
thermodilution cardiac output measured at time of catheterization (mean loop width was matched
to SV). To vary loading conditions and derive sets of pressure-volume relations, subjects
performed a Valsalva maneuver. Phase 2 of the maneuver (period of preload decline) was used
to generate pressure-volume relations. End-systolic pressure-volume points were determined by
an iterative technique23, and fit by perpendicular regression to derive the slope (end-systolic
elastance (Ees), and intercept V0). Preload recruitable stroke work (Msw) was calculated as
lculated as thee ratio
r
of end
previously described23, 24. Effective arterial elastance (Ea) was calculated
systolic pressure to SV. Ees was also normalized to end-diastolic volu
volume
lu
ume
m ((EDV)
EDV)
ED
V by the equation:
V)
(Ees(norm) = Ees *EDV/100).
V/100).255 Da
V/
V/1
D
Data
ta w
were
eree an
er
anal
analyzed
alyzzed
al
e w
with
ithh cu
cust
custom
s om
om ssoftware
o tw
of
war
aree (W
(Win
(WinPVAN
inPV
in
PV
3.5.10).
e at
elat
el
atio
ion
io
n analysis
anal
an
alys
al
y is during
ys
dur
urin
ingg Valsalva
in
Vals
Va
lsal
ls
alva
al
va
Validation of PV relation
We employed a Valsalva maneuver to assess PV relations rather than inferior vena caval
occlusion (IVCO) as this previously employed method would require femoral venous
catheterization in a procedure otherwise performed via a jugular vein. Valsalva involves rapid
elevation of intrathoracic pressure, which increases all intracardiac pressures, though so long as
this is fairly constant for several seconds, subsequent cycles measured during the ensuing decline
in preload are equally offset and the derived PV relations should be similar to that from IVCO.
We directly tested this in studies performed in the LV in which both maneuvers were recorded
(n=20, patients with hypertrophy or normal ventricles). Figure 1 shows PV tracings from a
patient with data measured by both methods. Valsalva induced an upward pressure-shift but this
was well maintained as shown by the co-linearity of the diastolic PV curves and the resulting
5
systolic and diastolic PV relations comparable (other than the offset). For the 20 patients Ees and
Msw were well correlated.
Statistics
Results are presented as the mean ± standard deviation. Curve fits (linear or non-linear) were
generated and statistical analysis was performed using commercial software (SigmaPlot
11.0/Systat 10.2). Comparisons between groups on continuous variables were performed by
Student t-test or Mann-Whitney Rank-Sum Test. A Chi-Square test or Fisher Exact test was
as used to com
mp resistanceused to compare categorical variables. Analysis of covariance was
compare
depe
peend
nden
en
nt variable;
varri
va
ria
compliance relations after log transformation (log (compliance): dependent
covariates –
omp
m arison
onn ooff RC tim
imes
im
es bbetween
ettwee
e n pa
atien
tien
ti
ent gr
ggroups
rou
ouups
p w
as pperformed
erfo
er
form
fo
rmee using multiple
rm
log (resistance)). Comparison
times
patient
was
C – de
ddependent;
epe
pend
pe
nden
nd
e tt;; co
en
ccovariates
v ri
va
riat
ia es – rresistance,
esis
es
isstaanc
ncee, aage,
ge, PC
ge
PCWP
WP, an
WP
nd mP
mPA
A
linear regression (RC
PCWP,
and
mPAP).
An F-test
pulm
pu
lmon
lm
onar
on
aryy and
ar
and systemic
syyst
stem
emic
em
ic RC time
tim
imee variances.
vari
va
rian
ri
ance
an
cess. A p value
ce
valu
va
luee of <0.05
lu
<
was used to comparee pulmonary
(twosided) was considered statistically significant. There was no adjustment for multiple
comparisons.
Results
Patient Characteristics
Table 1 summarizes the clinical characteristics and resting hemodynamics for IPAH (n=67),
SScPAH (n=166), and SSc-ILD-PH (n=49) groups. Compared with SScPAH, IPAH patients
were younger at the time of RHC (p=<0.001), and had significantly higher mPAP and RPA, and
lower CPA. Thus, overall resistive and reactive load was higher in the IPAH group. Both groups
had a similar cardiac index (2.4±0.8 vs. 2.6±0.8 L/min/m2; p=0.16), and there were no
6
differences in PCWP. The SScPAH group had a shorter 6-minute walk distance (1056±332 feet,
(n=61) vs. 1289±443 feet, (n=41); p=0.003).
Compared with SScPAH, SSc-ILD-PH patients were more likely to be male, had less of a
Caucasian predominance, and were younger (Table 1). Other than heart rate, which was faster in
the ILD cohort (88 vs. 82 beats per minute (bpm); p=0.01), there were no statistically significant
differences in hemodynamics. As expected, PFT parameters were all significantly worse in the
ILD cohort (Online Supplement 1; p<0.001).
Pulmonary Resistance-Compliance Relationship
nt inverse
in
nve
vers
rsee re
rs
rela
relationship
laati
tio
indicating
Unlike the systemic vasculature, RPA and CPA display a consistent
a co-dependence between
tween th
tw
them
hem
m19, 21, 22, 26. IImportantly,
m or
mp
o ta
t nt
ntly,, th
this
iiss iinverse
n ers
nv
rse re
rela
relationship
laati
tion
tion
onsh
ship
sh
ip is
i not
rmi
mine
mi
nneed (e.g.
( .gg. by a shared
(e
sha
h red SV in
in the
th
he numerator
nume
nu
mera
me
rato
ra
torr off CPA aand
to
ndd denominator
den
of
mathematically determined
RPA)22. If SScPAH disproportionately
disp
di
spro
sp
ropo
ro
p rt
po
rtio
iona
io
nate
na
tely
te
ly
y impacted
imp
pac
acte
tedd vessel
te
ves
esse
sell stiffness,
se
stif
st
iffn
if
fnes
fn
esss, and
es
and ttherefore,
here
he
refo
re
fore
fo
re, vvessel
re
compliance independent of resistance, then the relation should shift downward compared with
that for IPAH. Figure 2A displays relations for each group showing them to be well fit by
hyperbolic decays (SScPAH: CPA= 0.70/(0.082 + RPA), r2=0.80, and IPAH: 0.73/(0.086 + RPA),
r2=0.86) that were virtually superimposable. Log-transformation of both variables yielded linear
plots (Figure 2B), and analysis of co-variance found no difference between the SScPAH and
IPAH groups (p=0.71). The product of RPA x CPA (the RC time) provides a time constant for
pulmonary arterial diastolic pressure decay. The RC time was slightly lower in SScPAH patients
but this disparity was lost after adjusting for patient age, consistent with a recent study22. Plots
of RPA x CPA versus mean pulmonary or systemic pressure showed both groups to have
superimposable data, with the pulmonary value highly constrained (Figure 2C), and the systemic
7
value quite variable (Figure 2D; p<10-5 for F-test of variance difference between RC time in
Figure 2C and Figure 2D). As expected, there was a small but significant rise in pulmonary and
systemic RC times with greater respective mean pressures. RPA-CPA relations and the RC
product were also similar in SScPAH and SSc-ILD-PH patients (Figure 3A-D).
Pressure-Volume Loop Analysis
PV analysis was attempted on 30 patients referred for invasive right heart catheterization to
assess dyspnea and PAH (Online Supplement 2). Twenty-two patients had analyzable PV loops,
0% female, 10
00 Caucasian)
and 12 of 22 met hemodynamic criteria for PAH: IPAH (n=5; 100%
100%
riccan
a ). P
rreel
and SScPAH (n=7; 86% female, 71% Caucasian, 29% African Amer
American).
Preload
reduction in
the RV occurred almost
m st imm
mos
mo
immediately
media
ed
diaate
tely
ly uupon
ponn in
po
init
initiation
itia
it
iati
ia
t on
n off Va
Vals
Valsalva
sal
alva
vaa aand
nd
dm
maximal
a im
ax
imal
al rreduction
e
occurred
mean
an ppreload
reelo
oad ((end-diastolic
en
ndd ddiiassto
toli
licc vo
li
volu
volume)
lu
ume
me)) re
redu
duct
du
ctio
ct
iioon by V
allsaalv
va was 23±14mL.
within 10 beats. Thee me
reduction
Valsalva
p re
ppre
pp
reci
ciab
ci
ably
ab
ly
y cchange
hang
ha
ngee du
ng
duri
ring
ri
ngg Ph
Phas
asee Ias
I-II
II ((0.4±3.7
0.4±
4±33.77 bp
4±
pm or P
hase
ha
se IIII
I (-0.6±5.3
Heart rate did not appreciably
during
Phase
bpm
Phase
bpm), and thus overall (-0.2±5.3 bpm); (Online Supplement 3). Chronic medications for the three
patient groups are provided in Online Supplement 4.
Table 2 provides routine hemodynamic parameters including RPA in these cohorts, and
shows no significant difference between them. However, PV analysis revealed a significant
disparity in RV contractile function between groups. Figure 4 displays example PV loops and
relations from both groups. The steady state data (left panels) were similar in shape, with RV
pressure rising throughout ejection and peaking at end-systole, consistent with increased RV
afterload from pulmonary hypertension. Net afterload (Ea) was similar between cohorts (Table
2). Of note, while right atrial pressure and corresponding RV-diastolic pressures were somewhat
elevated, the diastolic pressure-volume relations were relatively flat, with little difference in
8
pressure from the onset to end of chamber filling. Loops generated from all patients in both
cohorts are shown in Figure 5.
Figure 4 (right panels) also shows corresponding pressure-volume data obtained during
Valsalva. The upward pressure shift reflects the rise in intra-thoracic pressure due to Valsalva
(phase 1), but this is held as constant as possible during the beat-to-beat decline in filling volume
(phase 2). The end-systolic pressure-volume relation is shown in each graph and its slope (Ees)
was reduced in SScPAH subjects compared to IPAH patients. As Ees is known to be chamber
volume dependent25, we also normalized the value to end-diastolic volume (Table 2); for the
(p<0.001)
1 V0 (the
group, Ees(norm) was approximately 70% lower in SScPAH versus IPAH (p<0.01).
volume-intercept) of the end-systolic pressure volume relation was
as llower
ower
ow
e iin
er
n th
thee S
SScPAH than
IPAH, consistent with
reduced
ith tthe
it
he re
edu
duce
cedd Eeess aatt similar
ce
simi
si
m laar ch
mi
cchamber
ambe
am
berr vo
be
volu
volumes
lume
lu
mes ch
me
char
characterizing
arac
ar
a te
teri
rizi
ri
zing
zi
ng the former
i ccontractile
ontrrac
on
ontr
acti
tile
l ffunction
u ct
un
ctio
ionn in
io
nS
ScPA
Sc
PA
PAH
AH co
omp
mpar
ared
ar
ed w
ithh IP
it
IPAH
AH w
as further
group. The decline in
SScPAH
compared
with
was
confirmed by a lower
e preload-recruitable
er
pre
relo
load
lo
ad--re
ad
recr
crui
cr
uita
ui
tabl
ta
blee stroke
bl
stro
st
roke
ro
ke work
wor
orkk (Msw, p=0.011),
p 0.01
p=
011)
01
1),, an iindex
1)
ndex
nd
ex tthat is chamber
size independent. The ratio of Ees to Ea, an index of ventricular-PA coupling, was lower in the
SScPAH group (1.0 ± 0.5 vs. 2.1 ± 1.0), suggesting differential coupling, with an inability of the
RV in SScPAH to compensate for the higher afterload. Diastolic function assessed by
isovolumetric relaxation rate, end-diastolic pressure, and peak filling rate was similar between
groups.
Lastly, we compared the SScPAH group to SSc-no-PH (n=7, 71% female, 86%
Caucasian, 14% African American). As expected, steady state loops were more rectangular in
patients without PH (Figure 6), with RV pressure fairly constant or slightly declining during
systole. Despite the lower afterload, contractile function was essentially the same as in SScPAH
subjects (Table 2), thus RV-PA coupling similar to IPAH. The maximal rate of pressure decline
9
was greater in SScPAH as compared to SSc-no-PH, likely reflecting the higher end-systolic
pressures with the former, but other measures of diastolic function were similar.
Discussion
The present study tested whether pulmonary arterial loading or intrinsic RV function differs
between patients with SScPAH and IPAH. The results support intrinsic RV systolic dysfunction
in SSc and an inability of the RV to compensate for higher afterload, rather than differences in
load. These findings may offer a potential explanation for poor survival observed in SScPAH.
st ppresented by
The pulmonary load analysis utilized a simple yet elegantt approach firs
first
nshiip. Th
They
ey sshowed
ho
ho
this to be
Vonk-Noordegraaf and colleagues involving the RPA-CPA relationship.
little altered in patients
ntss withh or without
wit
itho
hout
ho
ut PAH,
PAH
AH,, PH from
fro
rom
m chronic
chro
ch
roni
ro
nicc thromboembolic
ni
thro
th
r mb
mboe
oemb
oe
mbol
mb
olic
ol
i disease, and
221,
1,, 26
26
PAH before and after
e ppulmonary
er
ulmo
ul
mona
mo
naary
y vvasodilator
a od
as
dil
i at
atorr ttreatment
reat
re
atme
at
ment
me
ntt19, 21
. W
Wee re
rece
recently
cent
ce
ntly
l cconfirmed
onff
on
this
2
relationship in a large
ge group
grou
gr
oupp off patients
ou
pat
atie
ient
ie
ntss with
nt
with or
or without
with
wi
thou
th
outt PH22
ou
. N
No
o prior
p io
pr
iorr study
stud
st
udyy has
ud
ha specifically
investigated the potential impact of SSc on the RPA-CPA relationship. Prior estimates have put
the contribution of proximal to total CPA at ~19%26, though this value was derived from patients
without SScPAH. In SSc, deposition of collagen and other matrix components in the vascular
walls has been proposed to increase arterial stiffening27-30 and is correlated with worse prognosis.
However, if true, then the calculated CPA should decline for any corresponding RPA, shifting the
RPA-CPA curve down and to the left; yet this was not observed. As with other forms of PH, the
pulsatile load is dependent principally on factors that influence mean pulmonary vascular
resistance. The small but statistically significant rise in RC time with increasing mPAP is related
to the finding that even in the pathophysiological range of elevated pulmonary pressures, total
compliance does not fall to zero, requiring inclusion of a positive constant in the denominator of
10
the hyperbolic decay equation. Our prior analysis also showed no change in the RPA-CPA relation
in patients with severe ILD22, although most of those patients had pulmonary pressures in the
normal range. The new SSc-ILD-PH cohort presented here had pulmonary hypertension with an
average RPA of 7.4 Wood units, yet still no change was observed. Although pulmonary artery
impedance spectra analysis is recognized as the gold standard for assessing pulsatile vascular
loading, CPA and Ea are useful lumped parameters that combine components due to vascular
stiffening, characteristic impedance (mean impedance at high frequencies) and wave reflections
into a single term. In sum, these data do not support the speculation that the mechanical
ent in SSc.
properties of the pulmonary vasculature are fundamentally different
he pr
pres
esen
es
entt da
en
ddata
t represent the
While admittedly a small patient group, to our knowledgee th
the
present
as
chro
ch
roni
ro
niic RV function
nic
fun
unct
ctio
ionn in the
he presence
pre
rese
senncee of
se
of PAH
PAH byy invasive
inv
nvass pressurefirst effort to date to assess
chronic
fir
irst
st to
to show
shhow PV
PV relations
r laation
re
onss generated
on
gen
ner
erat
ated
at
ed using
usiing the
thhee V
alsa
al
salv
lvaa ma
m
a
volume analysis, andd first
Valsalva
maneuver.
The
igna
ig
nall ca
na
cali
libr
li
brat
br
atio
at
ionn re
io
reli
lied
li
ed iin
n pa
ppart
rt oon
n im
imag
ag
gee-ba
base
ba
sedd de
se
dete
term
te
rmin
rm
inat
in
atii of ejection
at
conductance catheterr ssignal
calibration
relied
image-based
determination
fraction measured at a separate though proximate time, and upon thermodilution cardiac output.
Importantly, the contractility measures were designed to minimize the impact of any error in
absolute volume estimation. For example, Msw has units of force, and is insensitive to absolute
volumes (one obtains a similar value in the normal heart of small rodents and other mammals as
in humans). Normalization of Ees to volume also reduced the impact of calibration error in this
regard. PV analysis also depended upon the Valsalva response, and while the magnitude of
loading induced by this maneuver varied between individuals, it was sufficient to derive the
relations. Work by Wang et al recently highlighted the effects of Valsalva on RV preload, and
compared with the LV, the more rapid preload decline is similar to what we observed 31. Just as
with IVCO, the extent of load change during Valsalva will vary among patients depending upon
11
RV contractility, vascular load, and Valsalva effort. However, this does not have to be the same
to determine PV relationships.
The PV analysis found similar total RV afterload between groups, confirming our RC
analysis, but did reveal systolic impairment in SScPAH without apparent differences in diastolic
function. Only one prior study has reported on RV contractility in SScPAH16, but this analysis
was heavily based on theoretical calculations (e.g. estimation of peak RV pressure at infinite
afterload, and maximal ejection at zero load – neither of which can be measured). Lower
contractile function relative to pulmonary afterload in SScPAH, reflected by a reduced Ees/Ea
y observed. Pr
rio
i studies support
ratio, suggests a blunting of the adaptive process that is normally
Prior
32, 33
enhanced contractile function at least initially in response to high
h ch
chronic
hro
r ni
nicc RV aafterload
f
ft
, and
similar findings are rreported
eportedd in
ep
n tthe
he LV exposed
exp
xpos
osed
d to
to chronic
chro
ch
oni
nicc hypertension
hype
hy
pert
pe
rten
rt
e si
sion
on34. T
The
he uunderlying cause
f nct
fun
ctio
i n in S
io
SccPA
ScPA
P H re
rema
maain
inss un
unkn
k ow
kn
ownn, tho
houg
ho
uggh it
ugh
itss co
coup
uppli
l ng tto
o relatively
for RV systolic dysfunction
SScPAH
remains
unknown,
though
coupling
unaltered relaxation m
may
ay hhint
intt at cchanges
in
hang
ha
ngges iin
nm
myofilament
y fi
yo
fila
lame
la
ment
me
nt ffunction.
unct
un
ctio
ct
ionn. In
io
Inab
Inability
abil
ilit
ityy of tthe
it
h RV to
hypertrophy to compensate for elevated afterload is another possibility. Further studies are
clearly needed to explore this finding.
We did not observe major differences in diastolic function between our patient groups.
Prior studies using echo-Doppler analysis have revealed diastolic abnormalities in patients with
SSc versus healthy controls. These may relate to RV load in one study35 but could not in
another36. The current data are the most reported to date based on direct intracavitary
measurements, and no prior studies have compared groups with PAH with or without SSc.
The clinical characteristics, including demographics, hemodynamics, and functional data
of the IPAH and SScPAH cohorts are very consistent with those of subgroups of similar patients
we have previously reported4, 12, 37. Despite less severe baseline hemodynamic impairment,
12
SScPAH have more functional impairment as assessed by the 6-minute walk distance and a 2-3
fold elevation in serum NT-proBNP. The latter finding37, 38 remains unexplained but is consistent
with the current results that SScPAH have intrinsic myocardial dysfunction.
Among the limitations of the PV analysis is that we do not have true control data for
comparison, i.e. patients with normal RVs and without SSc or PH. Thus, truly normal values for
human RV Ees or Msw remain unknown. However, animal studies support the utility of both
metrics to assess RV contractility independent of loading change39, 40. The conductance catheter
method works for the RV, though placement can be somewhat challenging due to heavy
rds the RV ap
peexx With
trabeculation and difficulties in advancing the distal pigtail towards
apex.
%. A simplified
sim
mpl
plif
ifie
if
ie approach
increasing experience, however, our success rate is exceeding 90%.
3 41, 42
ta tto
ta
o esti
ima
mate
te Ees hhas
as also
alsso be
bbeen
een
e ddescribed
esscr
crib
ibed
ib
ed33,
, bu
butt iss yyet
et too be validated in
using single-beat data
estimate
y, our
our study
stud
st
udyy adds
ud
addds further
ad
fur
u th
therr support
sup
uppo
port
po
rtt that
tha
hatt the
the volume
v lu
vo
lume
mee iintercept
nterrceept
nt
p oof RV Ees cannot
humans. Importantly,
42
be assumed to be zero
ro in ppatients
atie
at
ient
ie
ntss wi
nt
with
th P
PH
Hw
when
henn us
he
usin
using
ingg si
in
sing
single
ng
gle bbeat
eatt es
ea
esti
estimate
tima
ti
mate
ma
te ttechniques
echn
ec
hn
n
. While
statistically significant differences were observed in the PV analysis, we recognize the small
cohort means the results may be subject to a type II error. Lastly, some patients in both the
resistance-compliance analysis and PV loop analysis (Online Supplement 4) were on PAH
specific treatment at the time of hemodynamic measurements. It has previously been shown that
treatment of PAH does not alter the RPA-CPA relationship21, and while such therapies are not
known to principally alter RV contractility, some contribution cannot be ruled out. The SScPAH
and SSc-no-PH cohorts each had only one patient on chronic vasodilator therapy at the time of
PV loop measures and had identical measures of contractile function despite marked differences
in afterload. The failure of the SScPAH patients to augment contractility in response to higher
13
afterload which is the anticipated response32, 33 again points to an intrinsic myocardial deficit in
this cohort, rather than drug-induced enhancement of RV function in the IPAH group.
In conclusion, patients with SScPAH have relatively depressed RV function despite
similarly augmented pulmonary afterload compared with IPAH. The similarity between
pulmonary RPA-CPA relations among all patient groups, including SSc patients with PH and
interstitial fibrosis indicates that exacerbated pulsatile afterload is unlikely a cause for the
worsened cardiac function and outcome in SScPAH patients. The similar contractile function in
SSc patients with or without PAH further suggests a lack of adaptations to enhanced loading in
determined
d, but the finding
this syndrome. The factors that cause this impairment remain to be determined,
likely contributes to the worsened prognosis in this patient group..
Sou
So
urce
cess of Funding
Fun
undi
ding
di
ng
Sources
ackn
know
kn
owle
ow
ledg
le
dg
ge fu
fund
ndin
nd
ingg fr
in
from
om
m tthe
he N
atio
at
iona
io
nall He
na
Hear
art,
ar
t, L
ung,
un
g aand
g,
nd B
The authors wish to ac
acknowledge
funding
National
Heart,
Lung,
Blood Institute
[Grant: 5P50HL084946-05; 1R01HL114910-01] as well as the NIH [Grants: K23-HL086714,
KL2-RR024156, K23-AR061439], the Robert Wood Johnson Physician Faculty Scholars
Program, the Catherine Keilty Memorial Fund for Scleroderma Research, the Scleroderma
Research Foundation, and the Herbert and Florence Irving Scholar Award.
Disclosures
None.
14
References
1. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972–2002. Annals
of the Rheumatic Diseases. 2007; 66: 940-944.
2. Overbeek MJ, Vonk MC, Boonstra A, Voskuyl AE, Vonk-Noordegraaf A, Smit EF, Dijkmans
BAC, Postmus PE, Mooi WJ, Heijdra Y, Grünberg K. Pulmonary arterial hypertension in limited
cutaneous systemic sclerosis: a distinctive vasculopathy. European Respiratory Journal. 2009;
34: 371-379.
3. Haddad F, Doyle R, Murphy DJ, Hunt SA. Right Ventricular Function in Cardiovascular
Disease, Part II. Circulation. 2008; 117: 1717-1731.
4. Campo A, Mathai SC, Le Pavec J, Zaiman AL, Hummers LK, Boyce D, Housten T,
Champion HC, Lechtzin N, Wigley FM, Girgis RE, Hassoun PM. Hemodynamic Predictors of
Survival in Scleroderma-related Pulmonary Arterial Hypertension. Am J Respir Crit Care Med.
2010; 182: 252-260.
5. Hesselstrand R, Wildt M, Ekmehag B, Wuttge DM, Scheja A. Survival in patients with
pulmonary arterial hypertension associated with systemic sclerosis from a Swedish single centre:
1277 1
prognosis still poor and prediction difficult. Scand J Rheumatol. 2011; 40: 127-132.
man A
J, C
offe
of
feyy CS, Frost A,
fe
6. Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman
AJ,
Coffey
ictin
ng Su
Surv
rviv
rv
ival
iv
al iin Pulmonary
Barst RJ, Badesch DB, Elliott CG, Liou TG, McGoon MD. Predicting
Survival
Arterial Hypertension:
on: Insights
Ins
n ig
ight
h s From
F
th
the Registry
R i t to
t Evaluate
E l t E
Early
arly and Long-T
ar
Long-Term Pulmonary
Arterial Hypertension
on D
on
Disease
iseas
a e Ma
as
Mana
Management
nage
na
geme
ge
ment
me
nt ((REVEAL).
REVE
RE
VEAL
EAL
L)).. Circulation.
Circ
Ci
rcul
rc
ullat
ation.
n. 2010;
2010
20
100; 122:
122 164-172.
12
Meune C,, Be
erettaa L, Die
ieeud
de P
aram
ar
aam
mschhi P
Tiev K
Cappe
app
pp
pe S, Diot E,
7. Avouca J, Airò P,, Meune
Beretta
Dieude
P,, Car
Caramschi
P,, Ti
K,, C
Cappelli
Vacca A, Cracowskii J,
J, Sibilia
Sibiili
Si
Sibi
liaa J,
J, Kahan
Kah
a an
n A,
A, Matucci-Cerinic
Matu
Ma
tucc
tu
c ii--Ce
cc
Ceri
rini
ri
nicc M,
ni
M A
Allanore
llllan
nor
oree Y.
Y P
Prevalence
revv
re
of
Pulmonary Hypertension
in Systemicc Sclerosis
of 5
n
nsion
Scl
cler
eros
er
oossis
i in
in European
Eur
urop
opea
op
eaan Caucasians
Cauc
Ca
u asians and Metaanalysis
Mett
Studies. The Journall of Rheumatology.
2010;
Rhe
heum
umat
um
atol
at
olog
ol
oggy.
y 20
2010
10;; 37:
10
37: 2290-2298.
2290
22
90-2
90
-229
-2
2988.
29
8. Hachulla E, Gressin
V, Gu
L, C
P, Di
E, Si
ssin
in V
Guillevin
G
ille
il
l viin L
le
Carpentier
arpe
ar
pent
nttie
ierr P
Diot
D
ott E
Sibilia
Sibi
bili
bi
liaa JJ, K
li
Kahan
ah
han A,
A Cabane J,
Francès C, Launay D, Mouthon L, Allanore Y, Tiev KP, Clerson P, Groote Pd, Humbert M.
Early detection of pulmonary arterial hypertension in systemic sclerosis: A French nationwide
prospective multicenter study. Arthritis & Rheumatism. 2005; 52: 3792-3800.
9. Mayes MD, Lacey JV, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, Schottenfeld D.
Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US
population. Arthritis & Rheumatism. 2003; 48: 2246-2255.
10. Taichman D, Mandel J. Epidemiology of Pulmonary Arterial Hypertension. Clinics in chest
medicine. 2007; 28: 1-22.
11. Sanz J, Kariisa M, Dellegrottaglie S, Prat-Gonzalez S, Garcia MJ, Fuster V, Rajagopalan S.
Evaluation of Pulmonary Artery Stiffness in Pulmonary Hypertension With Cardiac Magnetic
Resonance. J Am Coll Cardiol Img. 2009; 2: 286-295.
12. Fisher MR, Mathai SC, Champion HC, Girgis RE, Housten-Harris T, Hummers L, Krishnan
JA, Wigley F, Hassoun PM. Clinical differences between idiopathic and scleroderma-related
pulmonary hypertension. Arthritis Care Res. 2006; 54: 3043-3050.
13. Kawut SM, Taichman DB, Archer-Chicko C, Palevsky HI, Kimmel SE. Hemodynamics and
Survival in Patients With Pulmonary Arterial Hypertension Related to Systemic Sclerosis*.
Chest. 2003; 123: 344-350.
14. Mathai SC, Sibley CT, Forfia PR, Mudd JO, Fisher MR, Tedford RJ, Lechtzin N, Boyce D,
Hummers LK, Housten T, Zaiman AL, Girgis RE, Hassoun PM. Tricuspid Annular Plane
15
Systolic Excursion Is a Robust Outcome Measure in Systemic Sclerosis-associated Pulmonary
Arterial Hypertension. The Journal of Rheumatology. 2011; 38: 2410-2418.
15. Forfia PR, Fisher MR, Mathai SC, Housten-Harris T, Hemnes AR, Borlaug BA, Chamera E,
Corretti MC, Champion HC, Abraham TP, Girgis RE, Hassoun PM. Tricuspid Annular
Displacement Predicts Survival in Pulmonary Hypertension. American Journal of Respiratory
and Critical Care Medicine. 2006; 174: 1034-1041.
16. Overbeek MJ, Lankhaar J, Westerhof N, Voskuyl AE, Boonstra A, Bronzwaer JGF, Marques
KMJ, Smit EF, Dijkmans BAC, Vonk-Noordegraaf A. Right ventricular contractility in systemic
sclerosis-associated and idiopathic pulmonary arterial hypertension. European Respiratory
Journal. 2008; 31: 1160-1166.
17. Masi AT, Subcommittee For Scleroderma Criteria of the American Rheumatism Association
Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of
systemic sclerosis (scleroderma). Arthritis & Rheumatism. 1980; 23: 581-590.
18. Le Pavec J, Girgis RE, Lechtzin N, Mathai SC, Launay D, Hummers LK, Zaiman A, Sitbon
O, Simonneau G, Humbert M, Hassoun PM. Systemic sclerosis?related pulmonary hypertension
associated with interstitial lung disease: Impact of pulmonary arterial hypertension therapies.
Arthritis & Rheumatism. 2011; 63: 2456-2464.
JT Postmus
Post
Po
stmu
st
muss PE,
mu
PE Vonk19. Lankhaar J, Westerhof N, Faes TJC, Marques KMJ, Marcus JT,
atient
n s wi
nt
with
th aand
n without
nd
Noordegraaf A. Quantification of right ventricular afterload in patients
pulmonary hypertension.
nsion.
nsion
on.. American
on
Amerric
Am
i an Journal of Physiology
Phys
ysio
ys
i logy - Heart
Hea
art
r and Circulato
Circulatory Physiology.
2006; 291: H1731-H1737.
H17
H17
1737.
20. Stergiopulos N, Se
Sege
Segers
g rs P, We
W
Westerhof
sterho
st
hof N. U
ho
Use
see ooff ppulse
ullse ppressure
reessurre me
method
ethod
od ffor
or eestimating
stt
total
arterial compliance in
i vvivo.
ivo.
iv
o American
o.
Amer
Am
eric
er
ican
ic
a Journal
Jou
urnal
al of
of Physiology
Phys
Ph
ysio
ys
io
iolo
olo
logy
gy - Heart
Hear
He
a t and
ar
and Circulatory
Circ
Ci
rccul
ua
Physiology.
1999; 276: H424-H428.
4
428.
21. Lankhaar J, Westerhof
s er
ster
st
erho
hoff N, Faes
ho
Fae
aess TJC,
TJC, Tji-Joong
Tji
j -J
-Joo
oong
oo
ng
g Gan
Gan C,
C, Marques
Marq
Ma
rq
que
uess KM,
KM Boonstra
Boon
Bo
onst
on
stt A, van den
Berg FG, Postmus P
PE,
A. P
PE
E V
Vonk-Noordegraaf
onkon
kN
kNooor
orde
d gr
de
graa
aaff A
Pulmonary
ullmon
onar
aryy va
vascular
vasc
scul
ullar rresistance
esis
es
i ttaanc
is
ncee an
andd compliance stay
inversely related during treatment of pulmonary hypertension. European Heart Journal. 2008;
29: 1688-1695.
22. Tedford RJ, Hassoun PM, Mathai SC, Girgis RE, Russell SD, Thiemann DR, Cingolani OH,
Mudd JO, Borlaug BA, Redfield MM, Lederer DJ, Kass DA. Pulmonary capillary wedge
pressure augments right ventricular pulsatile loading.. Circulation. 2012; 125: 289-297.
23. Kass DA, Midei M, Graves W, Brinker,Jeffrey A., Maughan,W. Lowell. Use of a
conductance (volume) catheter and transient inferior vena caval occlusion for rapid
determination of pressure-volume relationships in man. Cathet Cardiovasc Diagn. 1988; 15:
192-202.
24. Kass D, Midei M, Brinker J, Maughan W. Influence of coronary occlusion during PTCA on
end-systolic and end- diastolic pressure-volume relations in humans. Circulation. 1990; 81: 447460.
25. Sagawa K, Maughan L, Suga H, Sunagawa K. Effects of growth and aging of organisms on
ESPVR: normalization of Ees for heart size. In: Cardiac Contraction and the Pressure-Volume
Relationship. New York: Oxford; 1988: 352-353.
26. Saouti N, Westerhof N, Helderman F, Marcus JT, Stergiopulos N, Westerhof BE, Boonstra
A, Postmus PE, Vonk-Noordegraaf A. RC time constant of single lung equals that of both lungs
together: a study in chronic thromboembolic pulmonary hypertension. American Journal of
Physiology - Heart and Circulatory Physiology. 2009; 297: H2154-H2160.
16
27. Constans J, Germain C, Gosse P, Taillard J, Tiev K, Delevaux I, Mouthon L, Schmidt C,
Granel F, Soria P, Lifermann F, Etienne G, Bonnet F, Zoulim K, Farge-Bancel D, Marie I,
Allanore Y, Cabane J, Amonchot A, Macquin-Mavier I, Saves M, Zannad F, Conri C, the Ei.
Arterial stiffness predicts severe progression in systemic sclerosis: the ERAMS study. J
Hypertens. 2007; 25: 1900-1906.
28. Moyssakis I, Gialafos E, Vassiliou V, Taktikou E, Katsiari C, Papadopoulos DP, Sfikakis PP.
Aortic stiffness in systemic sclerosis is increased independently of the extent of skin
involvement. Rheumatology. 2005; 44: 251-254.
29. Peled N, Shitrit D, Fox BD, Shlomi D, Amital A, Bendayan D, Kramer MR. Peripheral
Arterial Stiffness and Endothelial Dysfunction in Idiopathic and Scleroderma Associated
Pulmonary Arterial Hypertension. The Journal of Rheumatology. 2009; 36: 970-975.
30. Timár O, Soltész P, Szamosi S, Dér H, Szántó S, Szekanecz Z, Szücs G. Increased Arterial
Stiffness as the Marker of Vascular Involvement in Systemic Sclerosis. The Journal of
Rheumatology. 2008; 35: 1329-1333.
31. Wang Z, Yuan L, Cao T, Yang Y, Duan Y, Xing C. Simultaneous Beat-by-Beat Investigation
of the Effects of the Valsalva Maneuver on Left and Right Ventricular Filling and the Possible
Mechanism. PLoS ONE. 2013; 8: e53917.
aann J.
aa
J B
ive
vent
ntrric
nt
ric
32. Leeuwenburgh BPJ, Helbing WA, Steendijk P, Schoof PH, B
Baan
Biventricular
systolic
cularr pressure
pres
pr
essu
es
sure
su
re ooverload.
v
function in young lambs subject to chronic systemic right ventricular
American Journal off Ph
Phys
Physiology
y io
ys
iolo
l gy - Heart
H t andd Circulatory
Circul
Ci ul
ulat
latory Physiology.
Phys
Phy io
iolo
logy.
l
2001; 281: H2697-H2704.
33. Kuehne T, Yilmaz
a S, Steendijk
az
Stee
eeend
n ijjk P, Moore
Moo
oore
re P,
P, Groenink
Gro
oen
nin
inkk M,
M Saaed
Saa
aaed
d M,
M, Weber
Webe
We
berr O,
be
O Higgins CB,
Ewert P, Fleck E, Nagel
age
gel E, Sch
Schulze-Neick
hulze
ze-N
Neick I,, La
L
Lange
anngee P
P.. M
Magnetic
a neetic Re
ag
Resonance
esonaanc
n e Im
Imaging
mag
Analysis of
Right Ventricular Pressure-Volume
r ssu
res
sure
r -V
re
-Vol
olum
umee Loops:
Lo
oop
opss: In
In Vivo
Vivo Validation
Val
alid
idat
id
atio
at
on an
andd Cl
Clin
Clinical
inic
in
i al
ic
a A
Application
pp
in
Patients With Pulmonary
Hypertension.
Circulation.
o
onary
Hypertensi
ion
on.. Ci
Circ
rcul
rc
u at
ul
a io
on. 2004;
2004
20
044; 110:
1110: 2010-2016.
34. Kawaguchi M, H
Hay
Fetics
B,, Ka
DA.
Combined
Ventricular
Systolic
ay II,, Fe
Feti
tics
ti
cs B
Kass
ss D
A. C
omb
mbin
ined
in
ed V
entr
en
tric
tr
icul
ic
ular
ul
ar S
y to
ys
toli
licc an
li
andd Arterial
Stiffening in Patientss With
Implications
for
Wit
ithh Heart
Hear
eartt Failure
Faillur
uree and
and Preserved
P es
Pr
eser
erve
vedd Ejection
Ejec
Ej
ecti
tiion Fraction:
Fra
ract
cttion
on:: Im
Implic
Impl
plic
pl
ic
Systolic and Diastolic Reserve Limitations. Circulation. 2003; 107: 714-720.
35. Giunta A, Tirri E, Maione S, Cangianiello S, Mele A, De Luca A, Valentini G. Right
ventricular diastolic abnormalities in systemic sclerosis. Relation to left ventricular involvement
and pulmonary hypertension. Annals of the Rheumatic Diseases. 2000; 59: 94-98.
36. Lindqvist P, Caidahl K, Neuman-Andersen G, Ozolins C, Rantapää-Dahlqvist S,
Waldenström A, Kazzam E. Disturbed Right Ventricular Diastolic Function in Patients With
Systemic Sclerosis. Chest. 2005; 128: 755.
37. Mathai SC, Bueso M, Hummers LK, Boyce D, Lechtzin N, Le Pavec J, Campo A, Champion
HC, Housten T, Forfia PR, Zaiman AL, Wigley FM, Girgis RE, Hassoun PM. Disproportionate
elevation of N-terminal pro-brain natriuretic peptide in scleroderma-related pulmonary
hypertension. European Respiratory Journal. 2010; 35: 95-104.
38. Chung L, Liu J, Parsons L, Hassoun PM, McGoon M, Badesch DB, Miller DP, Nicolls MR,
Zamanian RT. Characterization of Connective Tissue Disease-Associated Pulmonary Arterial
Hypertension From REVEAL. Chest. 2010; 138: 1383-1394.
39. Dickstein ML, Yano O, Spotnitz HM, Burkhoff D. Assessment of right ventricular
contractile state with the conductance catheter technique in the pig. Cardiovascular Research.
1995; 29: 820-826.
40. Karunanithi M, Michniewicz J, Copeland S, Feneley M. Right ventricular preload recruitable
stroke work, end-systolic pressure-volume, and dP/dtmax-end-diastolic volume relations
17
compared as indexes of right ventricular contractile performance in conscious dogs. Circulation
Research. 1992; 70: 1169-1179.
41. Brimioulle S, Wauthy P, Ewalenko P, Rondelet B, Vermeulen F, Kerbaul F, Naeije R.
Single-beat estimation of right ventricular end-systolic pressure-volume relationship. American
Journal of Physiology - Heart and Circulatory Physiology. 2003; 284: H1625-H1630.
42. Trip P, Kind T, van de Veerdonk MC, Marcus JT, de Man FS, Westerhof N, VonkNoordegraaf A. Accurate assessment of load-independent right ventricular systolic function in
patients with pulmonary hypertension. The Journal of Heart and Lung Transplantation. 2013;
32: 50-55.
18
Table 1. Clinical Characteristics and Hemodynamics
Cohort
Gender
Female (%)
Race
Caucasian (%)
African American (%)
Asian/Pacific Islander (%)
Hispanic/Latino (%)
Other/Unknown (%)
Age at catheterization (in years)
Body Surface Area (m2)
Body Mass Index (kg/m2)
Serum Creatinine (mg/dL)
Mean PAP (mmHg)
Systolic PAP (mmHg)
Diastolic PAP (mmHg)
Pulmonary Pulse Pressure
(mmHg)
Cardiac Output (L/min)
Cardiac Index (L/min/m2)
Pulmonary Artery O2
Saturation(%)
Stroke Volume (mL)
Heart Rate (beats per min)
Right Atrial Pressure (mmHg)
PCWP (mmHg)
RPA (mmHg*S*mL-1)
RPA (Wood units)
CPA (mL mmHg-1)
Pulmonary RC time (seconds)
Systemic MAP (mmHg)
Systemic RC time (seconds)
IPAH
(n=67)
SScPAH
(n=166)
P-value
(IPAH vs.
SScPAH)
SSc-ILD-PH
(n=49)
P-value
(SScPAH
vs. SScILD-PH)
53 (79)
145(87)
0.16†
33(67)
0.002†
50 (75)
12 (18)
1 (1)
3 (4)
1 (1)
133(80)
19(11)
1 (1)
10(6)
3(2)
0.07‡
-
17(35)
7(14)
8(16)
15(31)
2(4)
<0.001‡
-
48 ± 14
1.81 ± 0.35
31.3 ± 10.4
0.89 ± 0.25
(n=60)
60 ± 11
1.75 ± 0.21
27.8 ± 6.7
1.11 ± 0.56
(n=148)
<0.001
0.028
0.002
0.002
0.26
0.001
0.001
0 00
0.
001
1
54 ± 11
1.70 ± 0.22
24.4 ± 5.6
0.96 ± 0.54
(n=46)
51 ± 14
83 ± 23
32
2 ± 111
41 ± 13
67 ± 2222
25 ± 100
<0.001
<0
001
<0.001
<0
0.0
. 0
01
1
<0.001
40 ± 11
63 ± 17
26 ± 8
0.70
0.32
0.40
51
1 ± 16
4.4
4 ± 1.5
1.5
2.44 ±0.8(n=61)
2
2.
±0.8(
±0.8
±0
8(n
(n=6
=61)
=6
1))
42
4
2 ± 15
4.5
4.5 ± 1.5
1.5
2.6±0.8(
2.6
6±0.8
±0
0 8(n
(n=1
=162)
=162
=1
62))
62
2.6±0.8(n=162)
<0.001
0.76
0 16
0.
1
0.16
38 ± 12
4.7 ± 1.5
2.8 ± 0.9
0.07
0.37
0.06
65 ± 8(n=66)
56 ± 21
82 ± 13
9 ± 5 (n=66)
10 ± 3
0.63 ± 0.33
10.4 ± 5.5
1.3 ± 0.8
0.59 ± 0.14
65 ± 9(n=125)
56 ± 20
82 ± 13
8±5
10 ± 3
0.50 ± 0.36
8.4 ± 5.9
1.6. ±1.1
0.54 ± 0.13
54 ± 17
88 ± 13
7±4
10 ± 3
0.45 ± 0.26
7.4 ± 4.3
1.7 ± 1.0
0.56 ± 0.18
89 ± 11(n=65)
1.30 ± 0.41
89 ± 15
1.18 ± 0.44
0.76
0.88
0.61
0.71
0.76
0.001
0.001
0.028
0.009;
0.81¥
0.46
0.01;
0.76¥
0.63
0.01
0.07
0.95
0.64
0.64
0.41
0.93;
0.31¥
0.52
0.97;
0.13¥
87 ± 4(n=45)
1.14 ± 0.34
0.004
* Continuous variables shown as mean ± SD
Student t-test or Mann-Whitney Rank Sum Test as appropriate unless otherwise indicated
† = Chi-Square Test; ‡ = Fisher Exact Test
¥ = Multiple Linear Regression Model (adjusted for age and mean pressure)
PAP = Pulmonary Artery Pressure, 02 = Oxygen; PCWP = Pulmonary capillary wedge pressure; MAP = Mean
Arterial Pressure; RPA = Pulmonary Vascular Resistance; CPA = Pulmonary Arterial Compliance
Creatinine data within 60 days of right heart catheterization
Table 2. Pressure-Volume Loop Data and Hemodynamics
Cohort
WHO Functional Class
Age at catheterization (years)
Body Surface Area (m2)
IPAH
(n=5)
SScPAH
(n=7)
P -Value
(IPAH
vs.
SScPAH
)
SSc-noPAH
(n=7)
P-Value
(SScPA
H vs.
SSc-noPAH)
2.0 ± 0.7
48 ± 13
1.90 ± 0.30
2.6 ± 0.5
56 ± 11
1.82 ± 0.24
0.14
0.26
0.62
n/a
57 ± 13
1.85 ± 0.25
n/a
0.89
0.83
49 ± 21
2.4 ± 0.6
67 ± 7
7±3
37 ± 12
2.4 ± 0.8
62 ± 3
8±4
0.23
0.88
0.12
0.58
18 ± 3
2.9 ± 0.3
72 ± 3
6±2
0.002
0.46
<0.001
0.17
11 ± 3
86 ± 15
10 ± 4
86 ± 8
1.0
0.76
8±3
94 ± 9
0.33
0.13
161 ± 47
130 ± 45
45
0.28
0.288
128 ± 32
0.94
1 7 ± 1.1
1.
1.1
1.7
7.9
7..9 ± 4.3
4.3
3
2 4 ± 1.5
2.
1..5
2.4
7.0
7.0 ± 4.5
4..5
0.42
0.
0.42
0.74
0.74
4
4.0 ± 1.6
1.8 ± 0.8
0.053
0.011
00.47
0.
.47 ± 0.26
0.226
11.2
1.
.2
2 ± 0.5
0.5
0 42 ± 0.27
0.
0.42
0.9
0..9 ± 0.4
0.4
0.74
0.30
0.30
30
0.11 ± 0.05
0.4 ± 0.1
0.011
0.001
43 ± 13
18.8 ± 9.7
2.3 ± 1.1
46 ± 37
47 ± 12
12.5 ± 5.9
0.8 ± 0.3
-31 ± 49
0.43
0.19
0.007
0.016
57 ± 1
5.5 ± 1.9
0.9 ± 0.6
21 ± 28
0.09
0.011
0.73
0.033
3.1 ± 1.4
45 ± 16
0.9 ± 0.3
21 ± 11
0.002
0.011
1.1 ± 0.7
20 ± 12
0.43
0.83
2.7 ± 0.9
105 ± 47
36 ± 9
-687 ± 274
2.9 ± 0.9
106 ± 18
39 ± 6
-420 ± 120
0.79
0.94
0.50
0.07
3.4 ± 1.1
131 ± 86
39 ± 12
-262 ± 63
0.33
1.0
0.94
0.009
1.0 ± 0.5
0.03
2.3 ± 1.2
0.016
Hemodynamics and Volumes
Mean Pulmonary Artery Pressure (mmHg)
Cardiac Index (L/min/m2)
Pulmonary Artery Oxygen Saturation (%)
Right Atrial Pressure (mmHg)
Pulmonary Capillary Wedge Pressure
(mmHg)
Mean Systemic Artery Pressure (mmHg)
Right Ventricular End Diastolic Volume
(mL)
RV afterload
Pulmonary Arterial Compliance
mpli
mp
lia
ance (mL
ance
mL mmHg1
)
Pulmonary Vascular Resistance
sist
si
stan
a ce ((Wood
Wood
Wo
d units)
un
nits
t)
Pulmonary Vascular Resistance
s an
sistan
nc e
(mmHg*S*ml-1)
Effective Arterial Elastance
a
ance
RV Systolic Function (Contractility)
RV Ejection Fraction (%)
RVSWI (mmHg*m-2*L-1)
End Systolic Elastance (Ees)
V0 (x-intercept of end systolic elastance)
End Systolic Elastance (normalized)
(Eesnorm)
Preload Recruitable Stroke Work (Mw)
RV Diastolic Function
Peak Fill Rate/End Diastolic Volume
(ms/mL)
Tau (Glantz) (ms)
Tau (Suga) (ms)
dp/dt/Min (mmHg/ms)
RV-Pulmonary Artery Coupling
2.1 ± 1.0
Ees/Ea
Student t-test or Mann-Whitney Rank Sum Test as appropriate
RVSWI = Right Ventricular Stroke Work Index
Figure Legends
Figure 1. Example of left ventricular pressure volume loops obtained via preload reduction with
inferior vena cava balloon occlusion (IVCBO; top left) and Valsalva maneuver (top right).
Relationship of end-systolic elastance (bottom left) and preload recrutiable stroke work (bottom
right) by each preload reduction method (n=20 for each).
Figure 2. Pulmonary Vascular Resistance-Compliance Relationship. A)RPA vs. CPA in SScPAH
(n=166) or IPAH (n=67). Data are fit by non-linear regression, and best fit cu
curves
urv
rve given by
CPA=0.70/ (0.082+RPA) and CPA=0.73/ (0.086+RPA), respectively.
y. B)) Log(R
Log(
Lo
g(R
g(
RPA)))-Log(C
-L
PA) plot
shows overlapping da
ddata
ata betwe
between
weeen ggroups
roup
ro
upss (p
up
(p=0
(p=0.71
=0.7
=0
71 fo
for
or gr
group
rou
oupp ef
effe
effect
f ct byy an
fe
anal
analysis
alys
alys
al
ysis
iss ooff ccovariance). C)
Product of RPAxCPA for
or ppulmonary
ullmo
ulmo
mona
naary oorr D) systemic
sysste
temi
micc vascular
mi
vasc
va
scul
sc
ular
ul
ar system,
sys
yste
teem, each
eac
achh plot
ppllot
o versus
ver
er
respective
mean pressure for patients
ati
tien
ents
en
ts iin
n bo
both
th S
SScPAH
ScPA
Sc
PAH
PA
H aand
nd IIPAH.
PAH
PA
H. Th
Thee RC pproduct
rodu
ro
duct
du
ct w
was
as hhighly
ig
g
constrained
in the pulmonary system, with no significant difference between groups when controlling for age
and pressure. The systemic RC product was far more variable (p<0.00001; F-test).
Figure 3. Pulmonary Vascular Resistance-Compliance Relationship. A) RPA vs. CPA in SScPAH
(n=166) or SSc-ILD-PH (n=49).
Data are fit by non-linear regression, and best fit curves given
by CPA=0.70/ (0.082+RPA) and CPA=0.70/ (0.082+RPA), respectively. B) Log(RPA)-Log(CPA) plot
shows overlapping data between groups (p=0.57 for group effect by analysis of covariance). C)
Product of RPAxCPA for pulmonary or D) systemic vascular system, each plot versus respective
mean pressure for patients in both SScPAH and SSc-ILD-PH.
Figure 4. Right Ventricular (RV) Pressure-Volume Loops in six patients, three with A) IPAH
and three with B) SScPAH. Steady-state loops (left) in both cohorts show RV pressure rising
throughout ejection and peaking at end-systole, consistent with increased RV afterload from
PAH. The black dot identifies the end-systolic pressure-volume point, and the dashed line mean
loop width (stroke volume). Ea was determined by the ratio of end systolic pressure to SV. In
the loops generated during Valsalva maneuver (right), the data are all shifted upward due to the
rise in intra-thoracic pressure, but while this is held, phase-2 of the Valsalva maneuver results in
a beat-to-beat decline in filling volume, various PV relations including the end-systolic pressure
ance (Ees).
volume relationship (black line). The slope is end-systolic elastance
Figure 5. Steady-State
atee signal-averaged
sig
igna
nal-av
na
averaged right ventricular
av
ventrric
icular (RV)) pressure-volume
pre
ressure-volume lloops for IPAH
re
(top) and SScPAH (bottom).
b t om). Pressure
bott
bo
Press
ssurre risess throughout
thro
roug
ghout
ut ejection
ejeectiionn consistent
co
onsiste
tennt with
te
wit
ithh increased
afterload.
Figure 6. Steady-State signal-averaged right ventricular (RV) pressure-volume loops for
patients without PH, SSc (top, n=7) and without SSc (bottom, n=1). The loops are more
rectangular in shape than those in Figure 5, as pressure stays constant or decreases during
ejection.
160
160
120
120
80
40
0
0
30
60
90
VOLUME
M ((mL)
ME
mL))
mL
120
120
40
200
200
Msw (IVCBO) mmHg
4
2
0
30
60
90
VOLUME (mL)
120
150
Y=
Y 0.73x + 19.4
R = 0.87, p<0.00001
150
100
50
0
0
0
Figure 1
80
0
150
15
50
YY=
=0
0.73x
73x
7
3x + 0
0.67
67
6
7
R = 0.83, p<0.00001
6
Ees (IVCBO) mmHg/mL
Valsalva
PRESSURE (mm Hg)
PRESSURE (mm Hg)
IVCBO
2
4
Ees (Valsalva) mmHg/mL
6
0
50
100
150
200
Msw(Valsalva) mmHg
250
IPAH (n=67)
SScPAH (n=166)
6
IPAH [y=0.73/(0.086+x); R2=0.86]
SScPAH [y=0.70/(0.082+x); R2=0.80]
5
4
3
2
1
0
0.0
0.5
1.0
1.5
2.0
2.5
2.5
1.0
IPAH (n=67)
SScPAH (n=166)
0.8
0.6
p=0.71
0.4
0.2
0.0
-0.2
-0.4
-0.6
-0.8
8
--1.2
1.2
.2
1)
Pulmonary Vascular Resistance (mmHg*S*mL
m
mHg*S*mL
L-1
D
3.0
IPAH (n=67)
SScPAH (n=166)
2.5
-0.8
-0.6
-0.4
1.5
1.0
0.5
-0.2
0.0
0.2
0.4
3.5
IPAH (n=67)
SScPAH (n=166)
3.0
p = 0.81 (group)
p = 0.009 (age)
p = <0.001 (pressure)
2.0
-1.0
-1.0
Log
g (Pulmonary Vascular Resistance)
RC Time (seconds)
C
B
7
L
o (Pulmonary Arterial Compliance)
Log
Pulmonary Arterial Compliance (mL/mmHg)
A
RC Time (seconds)
Figure 2
p = 0.76 (group)
p = <0.001 (age)
p = 0.032 (pressure)
2.5
2.0
1.5
1.0
0.5
0.0
0
20
40
60
80
100
0.0
40
60
80
100
120
140
Mean Systemic Arterial Pressure (mmHg)
160
B
7
6
SSc-ILD-PH (n=49)
SScPAH (n=166)
y=0.70/(0.082+x); r2=0.74
5
y=0.70/(0.082+x);r2=0.84
4
3
2
1
0
0.0
0.5
1.0
1.5
2.0
0
L
Log
(Pulmonary Arterial Compliance)
Pulmonary Arterial Compliance (mL/mmHg)
Figure 3
2.5
25
1.0
0.6
0.2
0.0
-0.2
-0.4
4
6
-0.6
-1.2
.2
2
-1
1.0
0
-1.0
-0.8
-0.6
-0.4
RC Time (seconds)
p = 0.31 (group)
p = 0.24 (age)
p = <0.001 (pressure)
1.5
1.0
0.5
-0.2
0.0
0.2
0.4
3.5
SSc-ILD-PH (n=49)
SScPAH (n=166)
3.0
2.5
2.0
p=0.57
0.4
L
o (Pulmonary Vascular Resistance)
Log
D
SSc-ILD-PH (n=49)
SScPAH (n=166)
SSc-ILD-PH (n=49)
SScPAH (n=166)
0.8
Pulmonary Vascular Resistance (mmHg*S*mL
m g*
mHg*
mH
g*S*
S*mL
S*
mL-1)
C 3.0
RC Time (Seconds)
A
p = 0.13 (group)
p = <0.001 (age)
p = 0.11 (pressure)
2.5
2.0
1.5
1.0
0.5
0.0
0
20
40
60
80
100
0.0
40
60
80
100
120
140
160
Mean Systemic Arterial Pressure (mmHg)
80
80
60
60
40
40
40
40
20
20
20
20
0 20
50
80 110 140 170 200
80 110 140 170 200
160
160
120
120
0 20
40
60
80
0
100
20
60
60
40
4
0
40
20
20
40
60
80
100
90
90
60
60
30
30
0
0
100 150
200
250 300
80
100
150
0
200 250 300
0
60
80
100
120
60
100
100
80
80
60
60
40
40
20
20
80
100
120
80
40
0
50
120
120
60
60
0 20
RV Pressure (mm Hg)
RV Pressure (mm Hg)
80
80
Figure 4
B. SScPAH
RV Pressure (mm Hg)
A. IPAH
40
30
60
90
120
150
RV Volume (mL)
180
0 30
60
90
120
150
RV Volume (mL)
180
0 20
40
60
80
100
120
RV Volume (mL)
0
20
40
60
80
100
RV Volume (mL)
120
120
120
120
120
120
100
100
100
100
100
80
80
80
80
80
60
60
60
60
60
40
40
40
40
40
20
20
20
20
20
0
120
150
180
210
240 270
0
120
140
160
0
200 40
180
60
RV Volume (mL)
RV Volume (mL)
80
100 120
0
50
80
RV Volume (mL)
110
140
170 200
0 30
60
RV Volume (mL)
90
120
150
RV Volume (mL)
SScPAH
RV Pressure (mm Hg)
RV Pressure (mm Hg)
IPAH
120
120
120
0
120
100
100
100
1
10
00
0
100
80
80
80
0
80
60
60
60
60
40
40
40
40
20
20
20
20
0
0
120
150
180
210
240 270
0
20
RV Pressure (mm Hg)
RV Volume (mL)
60
80
100 120
40
60
RV Volume (mL)
80
100
100
100
80
80
60
60
60
40
40
40
20
20
20
80
100
RV Volume (mL)
120
0
0
50
70
90
100
80
60
80
100
120
RV Volume (mL)
140
40
60
110
130
RV Volume (mL)
120
120
60
120 140
RV Volume (mL)
120
0 40
Figure 5
40
80
100 120 140
RV Volume (mL)
150
180
50
50
50
50
40
40
40
40
30
30
30
30
20
20
20
20
10
10
10
10
0
60
90
120
150
180
0 30
RV Volume (mL)
RV Pressure (mm Hg)
RV Pressure (mm Hg)
SSc without PAH
60
90
120
0 20
150
RV Volume (mL)
40
60
80
RV Volume (mL)
50
50
50
40
40
40
30
30
30
20
20
0
20
10
10
10
0 20
40
60
80
100
0 60
RV Volume (mL)
90
120
150
180
0 20
RV Volume (mL)
Figure 6
RV Pressure (mm Hg)
40
30
20
10
0 60
90
120
150
RV Volume (mL)
180
80
100
120
RV Volume (mL)
40
60
80
RV Volume (mL)
50
Dyspnea only
0 60
100
100
140
Right Ventricular Dysfunction in Systemic Sclerosis Associated Pulmonary Arterial
Hypertension
Ryan J. Tedford, James O. Mudd, Reda E. Girgis, Stephen C. Mathai, Ari L. Zaiman, Traci
Housten-Harris, Danielle Boyce, Benjamin W. Kelemen, Anita C. Bacher, Ami A. Shah, Laura K.
Hummers, Fredrick M. Wigley, Stuart D. Russell, Rajeev Saggar, Rajan Saggar, W. Lowell Maughan,
Paul M. Hassoun and David A. Kass
Circ Heart Fail. published online June 24, 2013;
Circulation: Heart Failure is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2013 American Heart Association, Inc. All rights reserved.
Print ISSN: 1941-3289. Online ISSN: 1941-3297
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circheartfailure.ahajournals.org/content/early/2013/06/24/CIRCHEARTFAILURE.112.000008
Data Supplement (unedited) at:
http://circheartfailure.ahajournals.org/content/suppl/2013/06/24/CIRCHEARTFAILURE.112.000008.DC1.html
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in
Circulation: Heart Failure can be obtained via RightsLink, a service of the Copyright Clearance Center, not the
Editorial Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about this
process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation: Heart Failure is online at:
http://circheartfailure.ahajournals.org//subscriptions/
SUPPLEMENTAL MATERIAL
Online Supplement 1.
Pulmonary Function Parameters
Cohort
FEV1
FEV1 ( % predicted)
FVC
FVC (% predicted)
FEV1/FVC
DLCO
DLCO (% predicted)
SScPAH
SSc-ILD-PH
(n=166)
(n=49)
1.91 ± 0.60 (n=144)
78 ± 18 (n=129)
2.52 ± 0.82 (n=145)
80 ± 18 (n=131)
76.4 ± 7.8 (n=144)
10.5 ± 4.0 (n=122)
52 ± 18 (n=108)
1.47 ± 0.44 (n=45)
53 ± 13 (n=46)
1.75 ± 0.58 (n=45)
50 ± 11
84.9 ± 8.3 (n=46)
8.2 ± 4.2 (n=40)
34 ± 14 (n=43)
P value
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
Comparisons by student t-test or Mann-Whitney Rank Sum Test as appropriate
Online Supplement 2. Chronic Medications
IPAH
(n=5)
SScPAH
(n=7)
P-Value
(IPAH vs.
SScPAH)
SSc-no-PH
(n=7)
P-Value
(SScPAH vs.
SSc-no-PAH)
PDE5A
inhibitor
2 (40)
1 (14)
0.52
1 (14)
1.0
Endothelin
Antagonist
2 (40)
0 (0)
0.15
0 (0)
1.0
Intravenous
Prostacyclin
1 (20)
0 (0)
0.42
0 (0)
1.0
Inhaled or SQ
Prostacyclin
2 (40)
0 (0)
0.15
0 (0)
1.0
Calcium Channel
Blocker
1(20)
2 (29)
1.0
3 (43)
1.0
Loop
Diuretic
3 (60)
1 (14)
0.22
2 (29)
1.0
Aldosterone
Antagonist
3 (60)
1 (14)
0.22
2 (29)
1.0
Medication
PAH = Pulmonary Arterial Hypertension; PDE5A = Phosphodiesterase 5A; SQ = Subcutanous
Comparisons by Fisher Exact Test
Online supplement 3
30 patients
enrolled
Right IJ
obstruction
(n=1)
Unable to place
catheter into RV
(n=2)
27 with successful
placement of
conductance catheter
into RV
Inadequate
PV loop
signals
No imaging
for volume
calibration
Patients with
analyzable PV
loop data
(n=4)
(n=1)
(n=22)
PAH
No PAH
(n=12)
(n=10)
IPAH
SScPAH
SSc
No SSc
n=5)
(n=7)
(n=7)
(n=1)
Probable
SSc-HFpEF
(n=2)
Online Supplement 4
100
Heart Rate (BPM)
90
80
70
60
50
Baseline
Phase 1-2
Phase 3
Online Supplement 3. Flow chart depicting patient enrollment in pressure-volume loop
analysis. HFpEF = Heart failure with preserved ejection fraction.
Online Supplement 4. Change in Heart Rate with Valsalva maneuver. 2-4 beats are averaged
just prior to initiation of Valsalva (baseline), during onset of initiation (phase 1-2), and after
release maneuver (phase 3).

Right Ventricular Dysfunction in Systemic Sclerosis Associated

Transcription

Similar documents

to - Pulmonary and Critical Care Associates

file

Edition 12

Hemodynamic Monitoring INTRODUCTION

Pulmonary oedema.

14th Annual Update in Pulmonary Hypertension

Basic concepts to Understand Basic concepts to Understand