to Left-Ventricular Filling Pressures in Advanced Heart Failure

Relationship of Right- to Left-Ventricular Filling Pressures in Advanced Heart Failure:
Insights from the ESCAPE Trial
Drazner et al: Ratio of RAP to PCWP in Advanced Heart Failure
Mark H. Drazner*, MD, MSc; Mariella Velez-Martinez*, MD; Colby Ayers†, MS;
Sharon C. Reimold*, MD; Jennifer T. Thibodeau*, MD; Joseph D. Mishkin*, MD;
Pradeep P.A. Mammen*, MD; David W. Markham*, MD; Chetan B. Patel‡, MD
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 20, 2016
Division of Cardiology*, Department of Internal Medicine, and Department of Biostatistics†,
University of Texas Southwestern Medical Center, Dallas, TX
Division of Cardiology‡, Duke University Medical Center, Durham,
am, NC
Correspondence to::
Mark Drazner, MD, MSc
University of Texas So
Sout
Southwestern
uthw
ut
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este
tern
te
rn M
Medical
ed
dic
ical
al C
Center
ente
en
terr
te
lvdd D
lv
Dallas
alla
al
lass T
Texas
exas
ex
as 75
75390
7539
3900 90
9047
47
5323 Harry Hines Blvd,
Dallas,
Texas,
75390-9047
E-mail: [email protected]
Telephone: 214-645-7500
Fax: 214-645-7501
DOI: 10.1161/CIRCHEARTFAILURE.112.000204
Journal Subject Codes: Heart failure: [11] Other heart failure
1
Abstract
Background—Although right atrial pressure (RAP) and pulmonary capillary wedge pressure
(PCWP) are correlated in heart failure, in a sizeable minority of patients the RAP and PCWP are not
tightly coupled. The basis of this variability in the RAP to PCWP ratio, and whether it conveys
prognostic value, is not known.
Methods and Results—We analyzed the Evaluation Study of Congestive Heart Failure and
Pulmonary Artery Catheterization Effectiveness (ESCAPE) database. Baseline characteristics
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including echocardiographic assessment of right ventricular (RV) structure and function, and
invasively measured hemodynamic parameters, were compared among tertiles of the RAP/PCWP
ssoc
ss
occia
iati
tion
ti
on ooff RA
RAP
P
ratio. Multivariable Cox proportional hazard models assessed the association
RAP/PCWP
ratio
CAPE
CAP
APE
AP
E ou
outc
outcome
t om
ome [6-month death oorr hospitalizatio
hospitalization
ion (days)] adjust
io
adju
t
with the primary ESCAPE
adjusting
for systolic
N six
N,
six
i minut
te wa
alk distance,
distancce, and
n PCWP.
PCW
WP.
P The
Thee RAP/PCWP
RAP
P/P
PCW
WP ttertiles
erttilee were: 0.27-0.4
blood pressure, BUN,
minute
walk
.6
622-1.
1 21
1.
21(t
(tter
e tilee 33).
). IIncreasing
nccre
reas
a in
as
ingg RAP/PCWP wa
a associated with
(tertile 1); 0.41-0.6155 (tertile 2), and 0.6
0.62-1.21(tertile
was
resp
re
spec
ecti
t ve
ti
vely
l , p<
ly
pp<0.005),
<0.
00.005),
005)
00
5 , RV
5)
R aarea
reaa in diastole (21,
re
ghtt at
gh
atrial
atri
rial
all aarea
reaa (2
re
(23,
3, 226,
66,, 2299 cm2, respectively,
increasing median right
27, 27 cm2, respectively, p<0.005), and pulmonary vascular resistance (2.4, 2.9, 3.6 woods units,
respectively, p=0.003), and lower RV stroke work index (8.6, 8.4, 5.5 g-m/m2 per beat, respectively,
p<0.001). RAP/PCWP ratio was associated with death or hospitalization within 6 months [HR 1.16
(1, 1.4), p<0.05].
Conclusions—Increased RAP/PCWP ratio was associated with higher pulmonary vascular
resistance, reduced RV function (manifest as a larger right atrium and ventricle and lower RV stroke
work index), and an increased risk of adverse outcomes in patients with advanced heart failure.
Key Words: hemodynamics, heart failure, right ventricle, renal function, pulmonary hypertension
2
Elevated right-ventricular and left-ventricular filling pressures contribute to many of the
symptoms of patients with advanced heart failure. In both systolic1 and diastolic2 heart failure,
right-ventricular filling pressure (i.e., right atrial pressure, RAP) is significantly correlated to
left-ventricular filling pressure (i.e., pulmonary capillary wedge pressure, PCWP). This
relationship is robust enough such that estimation of the PCWP is often based upon assessment
of the jugular venous pressure (JVP) in patients with heart failure.3 Further, the relationship of
the RAP and PCWP has been shown to be stable over a 14 year time period (1993 to 2007) in the
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 20, 2016
Cardiac Transplant Research Database (CTRD), a registry of patients with advanced heart failure
ority of patien
patients
nts with heart
undergoing cardiac transplantation.4 However, in a sizeable minority
failure (25-30%), the RAP and PCWP are not tightly coupled.4, 5 The
hee bbasis
a is ooff th
as
the variability in
the relationship of rightigh
igh
ghtt- to le
lleft-sided
ft-s
ft
- id
ded ventricular
ven
entr
tric
tr
iccul
ular
a filling
ar
fillliingg pressures
pre
ress
ssur
ss
u es (wh
ur
(which
whic
wh
icch ca
ich
cann be
b expressed as the
ratio of the RAP to PCWP)
PCWP
PC
WP))4 iss no
nnott w
well
ell uunderstood.
nder
nd
erst
er
stoo
st
ood.
oo
d F
Further,
urth
ur
ther
th
er, wh
er
whet
whether
ethe
et
herr the
he
th
he ratio
rati
ra
t o of
ti
of the RAP to
PCWP is associated w
with
ithh ou
it
outc
outcome
tcom
tc
omee in tthe
om
he bbroader
road
ro
adeer ad
ad
adva
advanced
vanc
va
nced
nc
ed heart
hea
eart
rt failure
fai
ailu
lure
lu
re population,
p pu
po
pula
lati
la
tii as it is in
patients undergoing left ventricular assist device implantation6 or cardiac transplantation,4 has
not previously been assessed to our knowledge. The ESCAPE (Evaluation Study of Congestive
Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial, in which patients with
advanced heart failure underwent careful hemodynamic and echocardiographic assessment, as
well as longitudinal follow-up, afforded an excellent opportunity to further define the
physiologic basis and prognostic utility of the ratio of RAP to PCWP in this patient population.
3
Methods
ESCAPE Trial
The ESCAPE trial assessed the effectiveness of right heart catheterization in hospitalized
patients with New York Heart Association (NYHA) IV symptomatic heart failure. Patients had
to have left ventricular ejection fraction ” 30%, 3 months of symptoms despite ACE-inhibitor
and diuretic therapy, a systolic blood pressure ” 125 mm Hg, and at least one sign and one
symptom of congestion. Of the 433 patients randomly assigned, 215 were assigned to the
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 20, 2016
pulmonary artery catheter arm. The trial was conducted in the United States and Canada between
een published
d.7 The protocols
2000 and 2003 at 26 sites. The primary results of the trial have been
published.
were approved at each site and written informed consent was obtained
taineed from
from all
all patients
p
prior to
randomization. This analysis
ESCAPE
an
s was
was conducted
con
ondu
duct
du
cted
ct
ed with
wit
ithh a public
pub
bli
licc release
reele
leas
ase
as
se off tthe
he E
SCAP
SC
A E database.
Right heart catheterization
e iz
eriz
er
izat
atio
at
ion
io
n and
and hemodynamic
hemo
he
mody
mo
dyyna
nami
micc classification
mi
clas
cl
assi
as
sifi
si
fica
fi
cati
ca
tion
ti
on
The sites participating in ESCAPE were selected for known expertise in invasive monitoring and
clinical management of patients with HF. Paper printouts were used for hemodynamic
measurements. Cardiac output was measured by thermodilution in triplicate. In this analysis, we
assessed both the initial hemodynamics and the final hemodynamics at right heart catheter
removal. The average length of time the right heart catheter was in place was 1.9 days. We
excluded three patients due to measurements that were extreme outliers possibly due to
erroneous data entry: two with baseline RAPs of 71 and 85 mm Hg, respectively, and one with
PCWP of 0 mm Hg. Subjects were classified into tertiles of the ratio of RAP to PCWP: 0.27 to
0.40 (tertile 1); 0.41 to 0.61 (tertile 2); and 0.62 to 1.21 (tertile 3).
4
Echocardiography
Details of components of the echocardiographic examination in ESCAPE have been published.8
In brief, echocardiograms were performed within 24 hours of right heart catheterization.
Echocardiograms were analyzed at the core center at the University of Texas Southwestern
Medical Center. Measurements were performed offline by a single sonographer or physician in
accordance with the criteria of the American Society of Echocardiography, and were made in
triplicate and averaged. Measurements were obtained from the apical 4-chamber view (right
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atrial area, RV area at end-diastole and end-systole, left atrial area, mitral regurgitant color jet
area, and left ventricular end-diastolic and end-systolic volumes by Simpson
Simpson’ss m
method of discs),
pirat
attio
ion)
n).. De
n)
Deri
rive
ri
v measures
and subcostal view (inferior vena cava size in inspiration and expiration).
Derived
ulaar ejection
ejecctiion fraction,
fra
ract
ctt on, right
ctio
rig
ght ventricular
ven
ntrriccular
ular fractional
ul
frac
fr
a ti
ac
tion
o al shortening
sho
hort
rtten
rten
enin
ingg [(RV area
in
included left ventricular
ystole)/RV
yst
tol
ole)
e)/R
)/R
RV area
area diastole],
diaast
stol
ole], an
ol
andd th
the
he ratio
rati
ra
tioo of tthe
ti
he m
mitral
ittra
rall regurgita
rregurgitant
egu
gurg
rg
gitta color jet area
diastole- RV area systole)/RV
to the left atrial area.. Variable definitions
Creatinine clearance was estimated by the Modification of Diet in Renal Disease equation.9
Transpulmonary gradient was calculated as mean pulmonary artery-PCWP. Pulmonary vascular
resistance was calculated as transpulmonary gradient/cardiac output. Right ventricular stroke
work index was calculated as (cardiac index/heart rate) x (mean pulmonary artery pressure-mean
RAP) x 13.6. Pulmonary compliance was calculated as stroke volume/(PA systolic pressure-PA
diastolic pressure).10
5
Statistics
Data are presented as median (interquartile range) or number (percentage). To compare
characteristics across ordinal, increasing tertiles of baseline RAP/PCWP, we used the CochranArmitage trend test for categorical variables and the Jonckheere-Terpstra trend test for
continuous data. The chi-squared statistic was used to assess any overall racial significance.
Spearman correlation coefficients were calculated between baseline RAP/PCWP and other
invasively measured hemodynamics. Outcome analysis was with the primary outcome of
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 20, 2016
ESCAPE, number of days alive outside the hospital at 180 days post randomization. In a
ents who underwent
undder
ew
secondary analysis, we used overall morality as an outcome. Patients
nsorred in
in another
anot
an
othhe
ot
he analysis. For
LVAD/transplant were treated as dead in 1 analysis and were censored
sis, we excluded
si
ex
xcllud
uded
ed patients
pat
atie
ient
ie
ntss who
nt
whho were
weree lost
we
los
ostt to follow-up
fol
ollo
l ww-up
up (N=5).
(N=
N=5)
N=
5). After
5)
A
the outcomes analysis,
observing
f r the
the Schoenfeld
S ho
Sc
hoen
en
nfe
feld
d residuals,
ressiiddua
uals
ls, Cox
ls
Coox proportional
prop
pr
opor
op
orti
or
tion
ti
onal
on
al hazards
haz
azar
ards
ar
dss models
mod
odee were used to
no trends with time for
or a 1 sstandard
tand
ta
ndar
nd
ardd de
ar
devi
viat
vi
atiion iincrease
at
ncre
nc
reas
re
asee in tthe
as
he R
AP/P
AP
/PCW
/P
CWP
CW
P ra
rati
tioo in
ti
i both
assess hazard ratios ffor
deviation
RAP/PCWP
ratio
unadjusted and adjusted analyses. For the adjusted analyses, model 1 adjusted for six minute
walk, BUN, Systolic blood pressure. Model 2 adjusted for the covariates in model 1 with the
addition of PCWP. Two-sided probability values (p-value) were used in all statistical analysis
with a p-value <0.05 considered statistically significant. All statistical analyses were performed
using SAS (v. 9.2; SAS Institute, Inc., Cary, North Carolina).
Results
The distribution of the ratio of the RAP/PCWP is shown (Figure 1). The median (interquartile
range) was 0.50 (0.37, 0.68). The RAP was significantly correlated with the PCWP (r=0.59,
p<0.001). The ratio RAP/PCWP measured on the initial hemodynamics was significantly
6
correlated to that measured on the hemodynamics measured at the time of right heart catheter
removal (r=0.49, p<0.001). Of subjects with baseline RAP/PCWP tertile 1, 12% had shifted to
RAP/PCWP tertile 3 when hemodynamics were reassessed prior to right heart catheterization
removal. Similarly, 11% of subjects with baseline RAP/PCWP tertile 3 shifted to final
RAP/PCWP tertile 1 (Table 1).
Relationship of baseline characteristics and renal function to RAP/PCWP ratio
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Baseline characteristics are shown by tertile of RAP/PCWP (Table 2). Increasing RAP/PCWP
gher baselinee ccreatinine
r
was associated with impaired renal function as evidenced by a higher
and
als
lsoo associated
asso
as
soci
so
ciat
ci
at with the
BUN and a lower creatinine clearance. Increasing RAP/PCWP was also
al B
al
UN (2
((28,
28,
8 333,
8,
3, 440
0 mg
mg/d
/d
dl)
l , di
ddischarge
sccharg
rgee BU
rg
BUN
N (2
(25, 334,
4, 335
5 mg
mg/d
/ l and discharge
maximum in-hospital
BUN
mg/dl),
mg/dl),
m
mg
g/d
/dl)
l),
l)
) re
resp
spec
sp
e ti
tive
veely
l ((p”0.005
p”0.00
0055 for
for all).
all)). Increasing
al
Inc
ncre
reeas
asin
ing RAP/PCWP
in
RAP/
RA
P/P
P/
P
creatinine (1.2, 1.5, 1.66 mg/d
mg/dl),
respectively
was also
rig
ight
ht sided
sid
ided
ed heart
hea
eart
rt failure
fail
ilur
uree including
ur
incl
in
clud
cl
udin
ud
ingg elevated
in
elev
el
evat
ev
ated
at
ed jugular
jugu
ju
g la
gu
larr venous
veno
ve
nouu pressure,
no
associated with signss of right
ascites and peripheral edema. In contrast, there was no association of elevated RAP/PCWP with
orthopnea and other clinical predictors associated with worse outcomes such as NYHA class and
systolic blood pressure.
Relationship of invasively-measured hemodynamics to RAP/PCWP ratio
Invasively measured hemodynamics (Table 3) are shown by tertile RAP/PCWP. Increasing
RAP/PCWP was associated with a higher right atrial pressure but was not associated with
pulmonary capillary wedge pressure. Subjects with a higher RAP/PCWP also had a higher mean
PA pressure, transpulmonary gradient, and pulmonary vascular resistance than those with a
lower RAP/PCWP. Cardiac index and RV stroke work index were lower in those with higher
7
RAP/PCWP. In correlation analysis, RAP/PCWP ratio correlated significantly with RAP
(r=0.78, p<0.001), transpulmonary gradient (r=0.24, p=0.001), pulmonary vascular resistance
(r=0.23, p=0.002), cardiac index (r=-0.15, p<0.05), and RV stroke work index (r=-0.43,
p<0.001), but not PCWP (r=0.01, p=0.9). In a subgroup analysis restricted to subjects with a
PCWP •22 mm Hg, similar associations of RAP/PCWP ratio with invasively measured
hemodynamics were found including increasing PVR among those with increasing RAP/PCWP:
2.4 (tertile 1); 3 (tertile 2); 4.3 Wood units (tertile 3), P<0.001 (other data not shown). There was
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 20, 2016
no difference in administration of milrinone (p=0.75), nitroprusside (p=0.15) or dobutamine
(p=0.6) among tertiles RAP/PCWP.
hocardio
ho
ogr
grap
aphi
ap
hicc parameters
hi
para
pa
rame
ra
m teers
me
r too RA
RAP/
P/PC
P/
PCWP
PC
WP ratio
rat
atio
io
Relationship of echocardiographic
RAP/PCWP
pparameters
rame
ra
mete
me
mete
ters
rss aare
ree sshown
hown
ho
wn amo
mong
mo
ng te
erttille RA
RAP/
P PC
P/
PCWP
WP aatt ba
bbaseline
seli
se
line
li
ne ((Figure 2).
Echocardiographic para
among
tertile
RAP/PCWP
her R
AP/P
AP
/PCW
/P
CWP
CW
P ra
rati
tioo ha
ti
hadd ec
echo
hoca
ho
card
ca
rdio
rd
iogr
io
g ap
gr
phi
hicc ma
mark
rker
rk
erss of rright
er
ight
ig
htt ventricular
Subjects with a higher
RAP/PCWP
ratio
echocardiographic
markers
dysfunction including a larger right atrial area, right ventricular area in both systole and diastole,
and a larger inferior vena cava both in inspiration and expiration. There was no significant
association of RAP/PCWP ratio with right ventricular fractional shortening (0.25 [0.2, 0.3] tertile
1; 0.2 [0.13, 0.29] tertile 2; 0.21 [0.15, 0.28] tertile 3, p=0.2). There was also no significant
association of the RAP/PCWP ratio with left atrial area, tricuspid regurgitation velocity, LV enddiastolic or end-systolic volume, LV ejection fraction, or ratio of mitral regurgitation to left atrial
area (p•0.2 for all; data not shown).
8
Relationship of RAP/PCWP ratio and outcome
The association of the baseline and final RAP/PCWP with six-month outcome (Table 4) is
shown. In the whole cohort, increasing baseline RAP/PCWP was associated with death or
hospitalization (days) in a model adjusted for six minute walk, systolic blood pressure, BUN, and
pulmonary capillary wedge pressure. The correlation between RAP/PCWP and PCWP was
statistically insignificant, and thus multicollinearity was not an issue. In the subgroup of subjects
who had elevated PCWP (•22 mm Hg), increasing baseline RAP/PCWP was associated with
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 20, 2016
death or hospitalization (days) both in univariate and multivariable analysis. In analyses in which
PCWP, qualita
taati
the final RAP/PCWP ratio was substituted for the baseline RAP/PCWP,
qualitatively
similar
in
ng si
ssix-month
x mo
xmonnt
nth mortality as
associations with outcome were noted. In our secondary analysis usin
using
ven
ven
entt rate in
in increasing
i cr
in
crea
easi
ea
sing
si
ng baseline
baasseliine
n RAP/PCWP
RAP
P/P
/PCW
CWP
CW
P wa
w
16%
% (t
(ter
erti
er
tile
ti
l 1), 21% (tertile
the outcome, the event
wass 16
(tertile
p=00.09.
p=0
.009.
2), 29% (tertile 3), p=0.09.
Discussion
Although right-ventricular and left-ventricular filling pressures are significantly correlated in
patients with advanced heart failure, there is a large distribution of the RAP/PCWP ratio. The
basis for the variability of this trait (RAP/PCWP ratio) is not well understood, nor is its
prognostic utility. In the ESCAPE trial which enrolled patients with advanced heart failure
selected for signs and symptoms of congestion, most of whom had elevated PCWPs, increasing
RAP/PCWP ratio resulted from increasing RAP. Subjects with a low RAP/PCWP ratio had
better right ventricular function as assessed by several echocardiographic measures (including
smaller right atrial and right ventricular area) and by the right ventricular stroke work index,
while those with a higher RAP/PCWP ratio had a higher pulmonary vascular resistance.
9
Additionally, an elevated RAP/PCWP ratio was associated with a lower cardiac index and
impaired renal function at baseline and with a worse outcome at 6 months.
Whether the RAP/PCWP ratio is a stable and reproducible parameter in patients with
heart failure is not well known. In the CTRD, there was a significant correlation (r=0.33) of the
RAP/PCWP ratio when measured at least 1 day apart (median time 188 days).4 In the present
study, we confirmed this finding in patients with decompensated, advanced heart failure. In the
ESCAPE trial, the correlation between ratios of RAP/PCWP measured ~1.9 days apart was 0.49
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 20, 2016
(p<0.001). Additionally, there was relatively little shifting (11-12% of subjects) between tertiles
er, these data su
sug
1 and 3 from baseline to final hemodynamic assessment. Together,
suggest that the
it in
n ppatients
atie
at
ieent
ntss wi
w
t advanced
RAP/PCWP ratio does, in part, reflect an underlying intrinsic trait
with
heart failure.
AP/P
AP
/PCW
CWP
CW
P ca
cann be
be iinfluenced
nflu
nf
lu
uen
nce
cedd by cchanges
han
ange
gess in eeither
ge
ithe
it
herr th
he
thee RA
RAP
P oorr the PCWP. In
The ratio RAP/PCWP
high
gh R
AP/P
AP
/PCW
/P
CWP
CW
P oc
occu
curr
cu
rred
rr
ed oon
n th
thee ba
basi
siss of aan
si
n el
elev
evat
ev
ated
at
ed R
AP rather than a
the ESCAPE trial, a hi
RAP/PCWP
occurred
basis
elevated
RAP
reduced PCWP (Table 3). In addition to a higher measured RAP, subjects in the highest tertile of
RAP/PCWP ratio also had clinical findings that provided confirmation of an elevated RAP
including more severe peripheral edema and ascites, and an elevated jugular venous pressure. In
contrast, in the CTRD, subjects in the highest quartile of RAP/PCWP ratio not only had the
highest RAP but they also had the lowest PCWP.4 This difference is likely due to the selection of
patients for the ESCAPE trial on the basis of signs and symptoms of congestion.
To our knowledge, only two prior studies have attempted to determine characteristics
associated with the relationship of the RAP to PCWP in patients with heart failure.4, 5 In a cohort
of patients with advanced heart failure undergoing cardiac transplant evaluation, female gender
was the only characteristic found to be associated with the RAP to PCWP relationship as
10
assessed by 4 categories based on whether the RAP was •10 mm Hg and PCWP • 22 mm Hg.5
In the present study, female gender was not associated with RAP/PCWP ratio. Also in contrast to
the present study, renal dysfunction, PVR, cardiac index, and echocardiographic assessment of
RV dysfunction were not significantly different among the four hemodynamic profiles in the
prior study.5 We postulate that this difference is in part based on the analytic approach used; i.e.,
a hemodynamic classification based on dichotomous values of RAP and PCWP or via the
RAP/PCWP ratio. Nevertheless, both studies demonstrated significant variability in the
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 20, 2016
relationship of right and left ventricular filling pressures in patients with advanced heart failure.
ssociated with
h younger
yo
In the CTRD, increasing quartile of RAP/PCWP was associated
age,
sch
chem
em
mic
ic,, in
inc
female gender, etiology of cardiomyopathy other than idiopathic or is
ischemic,
increased number
s hhigher
s,
igherr PV
PVR,
R llower
R,
owe
werr CI
CI, an
nd lo
oweer cr
crea
eati
ea
tini
ti
niine cle
lear
le
aran
ar
ance
an
ce..4 In
ce
In the present
of prior sternotomies,
and
lower
creatinine
clearance.
a oc
assoc
ocia
i te
ia
tedd with
with
h the
the R
AP/P
AP
/PCW
/P
CWP
CW
P ra
rratio.
ati
t o. T
ti
hiss di
hi
diff
ffeere
ff
renc
ncee ma
nc
mayy bbee due to inclusion
study, age was not associated
RAP/PCWP
This
difference
of a broader range off patients
pati
pa
tien
ti
ents
en
ts in the
the CTRD
CTR
TRD
D (e.g.,
( .g
(e
g.,, complex
com
ompl
plex
pl
ex congenital
con
onge
g ni
ge
nita
tall heart
ta
hear
he
artt disease)
ar
dise
di
seaa than in the
se
ESCAPE trial. In the ESCAPE database, the number of prior sternotomies was not captured. The
present study confirmed the association of increasing RAP/PCWP with declining renal function,
reduced cardiac index, and higher PVR first reported in the CTRD,4 indicating that these
associations warrant further discussion.
Increasingly, it is recognized that systemic venous congestion is an important contributor
to the cardiorenal syndrome.11, 12 In the ESCAPE trial, an elevated RAP previously was shown to
be weakly correlated with baseline renal function13 consistent with the findings of the present
study. Here we show that impaired renal function was prominent when right- and left-sided
ventricular filling pressures began to approximate one another. In such subjects, pericardial
constraint may lead to exaggerated diastolic ventricular interaction.14, 15 This pathophysiology
11
may mediate the reduction in cardiac index associated with increasing RAP/PCWP ratio. A
disproportionately elevated RAP in relationship to the PCWP may therefore represent one
“hemodynamic signature” of patients with advanced systolic heart failure and cardiorenal
syndrome, and suggests that consideration of the right-left relationship may be important when
considering therapeutic strategies for treating congestion in heart.
The RAP/PCWP ratio also appears to have important relationships to the pulmonary
vasculature and the performance of the right ventricle. Increasing RAP/PCWP ratio was found to
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 20, 2016
be a marker for RV failure manifested by an enlarged right atrial area, enlarged right ventricular
ndex. The RAP/PCWP
RAP/
P//P
P
area (both in systole and diastole) and a lower RV stroke work index.
ratio was
veeri
rity
ty of m
itr regurgitation,
it
not associated with left ventricular volumes, ejection fraction, or seve
severity
mitral
tha
at thiss ra
rati
t o re
refl
flec
ecte
tedd ri
te
rright
ghht ve
entri
ricu
ri
cula
cu
l r pe
pperformance.
rfor
rf
o ma
manc
nce.
nc
e. T
e.
he hhemodynamic
further emphasizing th
that
ratio
reflected
ventricular
The
a tthe
at
he R
AP/P
AP
/P
PCW
CWP ra
rratio
tio wa
ti
wass re
rrelated
late
la
t d to cchanges
te
hang
ha
nges
ng
ess iin
n th
thee pu
pulm
lm
mon
on
data also suggest that
RAP/PCWP
pulmonary
vasculature
AP/P
AP
/PCW
/P
CWP
CW
P ra
rati
tioo wa
ti
wass as
asso
soci
so
ciat
ci
ated
at
ed w
ithh a hi
it
high
g er P
gh
VR despite
des
espi
pite
pi
te a similar PCWP
because increasing R
RAP/PCWP
ratio
associated
with
higher
PVR
in each tertile. It is well known that there is variability in the increase of the pulmonary artery
pressure and PVR in response to an elevated PCWP in patients with heart failure. The basis of
this variability is not yet well understood16 but pulmonary hypertension is now being tested as a
therapeutic target in patients with heart failure.17 We hypothesize that an exaggerated response in
the pulmonary vasculature in response to an elevated PCWP (i.e., an increased PVR) is a
proximal pathophysiological event, leading to RV dysfunction and subsequently an increased
RAP/PCWP ratio. Studies with serial imaging and hemodynamic assessments are needed to test
this hypothesis.
Whether the ratio of RAP/PCWP is associated with outcome in patients with heart failure
has not previously been investigated to our knowledge. A high RAP/PCWP ratio was associated
12
with worse outcomes in patients with advanced heart failure who undergo LVAD implantation6
or transplantation.4 An elevated jugular venous pressure, consistent with a high RAP, has been
shown to be an independent risk factor for outcome in patients with NYHA class II-III heart
failure.18 In the ESCAPE trial (Table 4), a high baseline RAP to PCWP ratio was associated
with adverse events at 6 months as assessed by the primary outcome of the ESCAPE trial
(number of days alive outside the hospital) but not with crude mortality. A lack of association
with mortality may represent limited power given that a higher RAP/PCWP ratio was associated
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 20, 2016
with markers of RV dysfunction and with impaired renal function, both well known risk factors
a
as
with
for adverse outcomes in heart failure.19-22 The final RAP/PCWP was similarlyy associated
the primary ESCAPE outcome. The association of increasing RAP/PCWP
AP/PC
PC
CWP ratio
rat
atio
io w
with outcome
was more consistentt in thosee with
of assessing
wit
i h a PCWP•
PCWP
PC
WP•
WP
• 22
22 mm
m Hg,
Hg, highlighting
highl
ig
ghl
h ig
ght
h in
ng the
the importance
impo
im
port
po
ra
this ratio in patients who
whom
hom
ho
m ha
hhave
ave
ve el
elev
elevated
evatted lleft-sided
ev
eftef
t-si
tside
si
dedd ventricular
de
v nt
ve
ntri
ricu
ri
cula
cu
larr filling
la
fil
illi
lliingg pressures.
pre
r ss
s ur
u es
es. Overall, these
findings reinforce the
h importance
he
imp
mpor
orta
or
tanc
ta
ncee off RV
nc
RV function
func
fu
ncti
nc
tion
ti
on in
in patients
p ti
pa
tien
ents
en
ts with
wit
ithh advanced
adv
dvan
ance
an
cedd heart
ce
hear
he
artt failure.
ar
Limitations
This was a retrospective analysis. The associations of RAP/PCWP with death and hospitalization
did not reach conventional levels of statistical significance in all models, perhaps because the
overall size of the cohort in ESCAPE who underwent right heart catheterization was relatively
small. As such, the prognostic utility of the RAP/PCWP ratio needs to be validated in other,
larger datasets.
13
Conclusions
In patients with advanced heart failure selected for signs and symptoms of congestion, there was
a wide distribution in the ratio of RAP to PCWP. A high RAP/PCWP ratio was associated with a
high RAP, underlying RV dysfunction in the setting of an elevated pulmonary vascular
resistance, and was an adverse prognostic finding associated with impaired renal function and a
worse 6-month outcome.
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 20, 2016
Sources of Funding
iology at UT Southwestern
So
Dr. Drazner is supported by the James M. Wooten Chair in Cardiology
Medical Center.
Disc
Di
sclo
sc
losu
lo
su
ure
r s
Disclosures
None.
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Increased central venous
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nd mortality in a
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16
Table 1. Relationship of the baseline to final RAP/PCWP tertile
Final RAP/PCWP tertile
T1
T2
T3
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 20, 2016
Baseline
T1
27 (54%)
17 (34%)
6 (12%)
RAP/PCWP
T2
16 (34%)
15 (32%)
16 (34%)
tertile
T3
5 (11%)
16 (35%)
25 (54%)
Data are presented as number (% of subjects within baseline RAP/PCWP tertile who were within
denoted final RAP/PCWP tertile).
17
Table 2. Baseline characteristics by baseline ratio of RAP to PCWP
Tertile RAP/PCWP
P
1
2
3
N=63
N=62
N=63
57 [47, 63]
58 [50, 66]
59 [48, 70]
0.14
Ethnicity: White
35 (56%)
39 (63%)
36 (57%)
0.7
Male
42 (67%)
48 (77%)
49 (78%)
0.16
Ischemic etiology
35 (56%)
31 (50%)
33 (52%)
0.7
Idiopathic etiology
21(33%)
22(36%)
23(37%)
23
( 7%
(3
7%))
0.7
Hypertension
32 (51%)
28 (45%)
32 (51%)
(51
51%)
%
1.000
Diabetes
14 (24%)
(24
24%)
%
255 (40%)
(40%
(4
0%))
0%
22 (36%)
(36
36%)
%)
0.2
NYHA class IV
60 ((95%)
95%)
554
4 (8
(87%
(87%)
7%))
7%
555 ((87%)
87%
87
%)
0.1
JVP • 8 cm
47 ((77%)
7 %)
77
559
9 (9
(98%
(98%)
8%))
8%
59 (97%)
(97 )
0.0002
Ascites • moderate
1 (2%)
11 (18%)
16 (25%)
0.0002
Peripheral edema • 2+
9 (14%)
28 (45%)
39 (62%)
<.0001
Orthopnea • 2 pillows
54 (86%)
50 (81%)
51 (82%)
0.6
109 [98, 120]
0.7
Age, y
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Systolic blood pressure, mm Hg
111 [97, 120] 108 [98, 116]
Heart rate, bpm
81 [71, 91]
79 [67, 91]
81 [69, 91]
0.8
Body mass index, kg/m2
25 [22, 30]
27 [24, 32]
29 [24, 35]
0.03
1.3 [0.9, 1.6]
1.5 [1.1, 1.8]
1.5 [1.2, 2]
0.004
CrCl, ml/min
62 [41, 91]
52 [44, 67]
52 [37, 68]
0.010
BUN, mg/dL
26 [16, 33]
33 [22, 51]
30 [22, 49]
0.003
Creatinine, mg/dL
18
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Table 3. Association of baseline RAP to PCWP ratio with invasively measured hemodynamics
Tertile RAP/PCWP
P
1
2
3
6 [4, 8]
13.5 [11, 17]
20 [13, 23]
<.0001
Pulmonary capillary wedge pressure, mm Hg
23 [18, 30]
225
5 [2
[22,
2, 32]
24 [19, 30]
0.7
Pulmonary artery systolic, mm Hg
50 [[40,
4 , 60
40
60]
0]
58 [[50,
50,, 70]
50
52 [42, 67]
0.08
Pulmonary artery diastolic, mm Hg
24 [[18,
1 , 29
18
29]]
29 [25,, 36]
25 [20, 35]
0.02
Mean pulmonary artery pressure, mm Hg
42
42 [33,
[333 49]
[3
49]
49
49 [42,
[422 56]
[4
45 [35, 57]
0.049
9 [7, 12]
12 [8, 15]
13 [9, 17]
0.001
2.4 [1.8, 3.4]
2.9 [2, 4.1]
3.6 [2, 4.7]
0.003
3.9 [3, 4.5]
3.9 [3.2, 4.6]
3.3 [2.8, 4.9]
0.2
Cardiac index, liters/min/m2
2.1 [1.7, 2.3]
1.9 [1.7, 2.3]
1.8 [1.5, 2.2]
0.049
Mixed venous saturation, %
60 [44, 67]
54 [41, 62]
55 [44, 68]
0.45
Stroke volume, ml
47 [39, 56]
51 [41, 63]
44 [33, 60]
0.6
Right atrial pressure, mm Hg
Transpulmonary gradient, mm Hg
Pulmonary vascular resistance, WU
Cardiac output, liters/min
19
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Systemic vascular resistance, dyne-sec-cm-5
Right ventricular stroke work index, g-m/m2 per beat
Pulmonary arterial compliance, ml/mm Hg
1387 [1042, 1664]
1310 [1089, 1596.5]
1322 [848, 1987]
0.9
8.6 [6.9, 12]
8.4 [6.1, 11]
5.5 [4, 7.6]
<.0001
1.83 [1.33, 2.58]
1.61 [1.3, 2.47]
1.65 [1.14, 2.27]
0.25
20
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Table 4. Association of the RAP to PCWP ratio with death or hospitalization (days) at 6 months
Whole cohort*
Subgroup PCWP•22 mm Hg*
Transplant/LVAD
Transplant/LVAD
Transplant/LVAD
Transplant/LVAD
count as dead
count as alive
count as dead
count as alive
HR (95% CI)
P Value
HR (95% CI)
P value
HR (95% CI)
P Value
HR (95% CI)
P value
Baseline RAP/PCWP
P
Unadjusted
1.1 (0.97, 1.3)
0.14
4
11.12
1.
12 ((0.97,
0.97,
0.97
0.
97, 1.
97
1.3)
3
3)
00.14
.1
14
1.18
1.
18 ((1,
1, 11.
1.4)
.
<0.05
1.2 (1.01, 1.4)
0.04
Adjusted
1.13 (0.97, 1.3)
0.12
2
1.14 (0.99
(0.99,
9 , 1.
99
1.3)
3)
00.08
.088
.0
1.18 (0.98, 1.4)
0.08
1.2 (1, 1.5)
<0.05
1.16 (1, 1.4)
<0.05
1.19 (1.02, 1.4)
0.03
1.2 (1.02, 1.5)
0.03
1.3 (1.04, 1.5)
0.02
Model 1
Adjusted
Model 2
Final RAP/PCWP
Unadjusted
Adjusted
1.2 (1.1, 1.5)
0.001
1.3 (1.1, 1.5)
0.009
1.8 (1.2, 2.8)
0.009
1.8 (1.1, 2.7)
0.01
1.17 (0.99, 1.3)
0.07
1.17 (0.99, 1.4)
0.07
1.8 (1.1, 3.1)
0.03
1.8 (1.05, 3.1)
0.03
21
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Model 1
Adjusted
1.19 (.99, 1.4)
0.06
1.19 (0.99, 1.4)
0.06
1.7 (1.01, 3)
0.04
1.7 (0.99, 3)
0.05
Model 2
*Whole cohort: N=183 for baseline RAP/PCWP; N=137 for final RAP/PCWP; Subgroup PCWP • 22 mm Hg: N=137 for baseline
RAP/PCWP; N=35 for final RAP/PCWP.
Model 1 adjusted for six minute walk, BUN, Systolic blood pressure.
Model 2 adjusted for six minute walk, BUN, systolic blood pressure, PCWP.
Hazard ratios in whole cohort shown are for unit
standard
baseline
uni ratio
un
rattio
o cchange
hang
ha
ngee (1 sta
ng
t nd
ta
dard
rd ddeviation)
evia
ev
iaati
t onn) ba
base
seli
se
line
li
ne RAP/PCWP=0.235; for final
RAP/PCWP=0.306. Hazard ratios for subgroup
u P
up
PCWP•22
C P•22
CW
222 mm
mm Hg are
are for
for
o unit
uni
nit
i ratio change
ch
hange (1 standard deviation) baseline
RAP/PCWP 0.235; for final RAP/PCWP 0.20.
0
22
Figure Legends
Figure 1. The distribution of the RAP/PCWP ratio in the study cohort. RAP = right atrial
pressure; PCWP = pulmonary capillary wedge pressure
Figure 2. Association of echocardiographic measures of right ventricular dysfunction with
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 20, 2016
RAP/PCWP ratio (tertiles).
A. Right atrial area
B. Right ventricular area (diastole)
are
reaa (systole)
re
(ssys
y to
ole
l )
C. Right ventricular area
ize (expi
pirrattioon))
D. Inferior vena cavaa ssize
(expiration)
n).
n)
E. Inferior vena cavaa size (inspiration)
(inspiration).
as box-and-whisker
boxx-an
boxbo
andand
d wh
dwhisker
his
i ke
k r plots.
plot
pl
plots
otts
Data are presented as
RAP/PCWP ratios were Tertile 1 (T1): 0.27-0.4; Tertile 2 (T2): 0.41-0.61; Tertile 3 (T3): 0.62 –
1.21.
*P<0.005 † P<0.01
23
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Relationship of Right- to Left-Ventricular Filling Pressures in Advanced Heart Failure: Insights
from the ESCAPE Trial
Mark H. Drazner, Mariella Velez-Martinez, Colby Ayers, Sharon C. Reimold, Jennifer T. Thibodeau,
Joseph D. Mishkin, Pradeep P.A. Mammen, David W. Markham and Chetan B. Patel
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Circ Heart Fail. published online February 7, 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/2013/02/07/CIRCHEARTFAILURE.112.000204
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http://circheartfailure.ahajournals.org//subscriptions/