Hemodynamic Predictors of Mortality in Adults
with Sickle Cell Disease
Alem Mehari1,2*, Shoaib Alam1*, Xin Tian3, Michael J. Cuttica4, Christopher F. Barnett5,
George Miles6, Dihua Xu3, Catherine Seamon7, Patricia Adams-Graves8, Oswaldo L. Castro1,2,
Caterina P. Minniti7, Vandana Sachdev1, James G. Taylor VI7, Gregory J. Kato7y,
and Roberto F. Machado9y
1Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland;2Howard University College of Medicine,
Washington, DC;3Office of Biostatistics Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland;4Pulmonary and Critical Care
Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois;5Division of Cardiology, University of California San Francisco,
San Francisco, California;6Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland;7Hematology Branch, National Heart, Lung,
and Blood Institute, Bethesda, Maryland;8University of Tennessee Health Science Center, Memphis, Tennessee; and9Section of Pulmonary,
Critical Care Medicine, Sleep and Allergy, University of Illinois, Chicago, Illinois
Background: Pulmonary hypertension (PH) in adults with sickle cell
disease (SCD) is associated with early mortality, but no prior studies
have evaluated quantitative relationships of mortality to physiolog-
ical measures of pre- and postcapillary PH.
Objectives: To identify risk factors associated with mortality and to
estimate the expected survival in a cohort of patients with SCD with
PH documented by right heart catheterization.
Methods: Nine-year follow-up data (median, 4.7 yr) from the Na-
tional Institutes of Health SCD PH screening study are reported.
A total of 529 adults with SCD were screened by echocardiography
between 2001 and 2010 with no exclusion criteria. Hemodynamic
data were collected from 84 patients. PH was defined as mean pul-
monary artery pressure (PAP) > 25 mm Hg. Survival rates were
estimated by the Kaplan-Meier method, and mortality risk factors
were analyzed by the Cox proportional hazards regression.
Measurements and Main Results: Specific hemodynamic variables
were independently related to mortality: mean PAP (hazard ratio
[HR], 1.61; 95% confidence interval [CI], 1.05–2.45 per 10 mm Hg
increase; P ¼ 0.027), diastolic PAP (HR, 1.83; 95% CI, 1.09–3.08 per
10 mm Hg increase; P ¼ 0.022), diastolic PAP 2 pulmonary capillary
P ¼ 0.008), transpulmonary gradient (HR, 1.78; 95% CI, 1.14–
2.79 per 10 mm Hg increase; P ¼ 0.011), and pulmonary vascular
resistance (HR, 1.44; 95% CI, 1.09–1.89 per Wood unit increase;
P ¼ 0.009) as risk factors for mortality.
Conclusions: Mortality in adults with SCD and PH is proportional
to the physiological severity of precapillary PH, demonstrating its
prognostic and clinical relevance despite anemia-induced high
cardiac output and less severely elevated pulmonary vascular
Keywords: sickle cell; pulmonary hypertension; mortality; autopsy
Pulmonary hypertension (PH) is defined as a mean pulmonary
artery pressure (mPAP) > 25 mm Hg (1). Prospective (2–4)
and retrospective studies (5, 6), most using Doppler echocar-
diography to estimate systolic pulmonary artery pressure
(sPAP), report that 20 to 30% of adults with sickle cell dis-
ease (SCD) have higher than normal sPAP. Our group and
others recently reported a PH prevalence of 6 to 11% in
adults with, which is associated with increased hazard of
death (7, 8). The hemodynamic characteristics of PH in
adults with SCD are heterogeneous. PH may be precapillary
(pulmonary arterial hypertension) or postcapillary (pulmo-
nary venous hypertension) and may be passive or reactive
in nature (9–14), emphasizing the need for right heart cath-
eterization (RHC) to confirm the diagnosis of PH and for
accurate hemodynamic stratification to determine treatment
Pulmonary vascular lesions characteristic of precapillary PH,
including plexiform lesions, have been described in one third to
two thirds of patients with SCD in autopsy studies (15–18).
Precapillary PH is characterized by a progressive elevation in
pulmonary artery pressure and pulmonary vascular resistance,
leading to right ventricular failure and death (19). Despite only
modest elevation of estimated sPAP, patients with SCD and
(Received in original form July 16, 2012; accepted in final form January 18, 2013)
*These authors contributed equally to this work.
yThese senior authors contributed equally to this work.
This research was supported by the Division of Intramural Research of the Na-
tional Heart, Blood and Lung Institute of the National Institutes of Health (grants
1ZIAHL006011, 1ZIAHL006015, and 1ZIAHL006012) and by National Institutes
of Health grant K23HL098454 (R.F.M.).
Author Contributions: Obtaining funding: G.J.K., R.F.M., and J.G.T. Study design:
G.J.K., R.F.M., J.G.T., and O.L.C. Patient enrollment: A.M., S.A., C.S., P.A.-G.,
O.L.C., C.P.M., J.G.T., G.J.K., and R.F.M. Data collection: A.M., S.A., M.J.C., C.F.B.,
G.M., C.S., C.P.M., V.S., J.G.T., G.J.K., and R.F.M. Data analysis: X.T. and D.X.
Manuscript drafting: A.M., S.A., G.J.K., and R.F.M. Critically revising the manu-
script for important intellectual content: X.T., M.J.C., C.F.B., G.M., D.X., C.S.,
P.A.-G., O.L.C., C.P.M., V.S., and J.G.T.
Correspondence and requests for reprints should be addressed to Gregory J. Kato,
M.D., Hematology Branch, NHLBI, National Institutes of Health, 9000 Rockville
Pike, Bethesda, MD. E-mail: firstname.lastname@example.org
This article has an online supplement, which is accessible from this issue’s table of
contents at www.atsjournals.org
Am J Respir Crit Care Med
Published 2013 by the American Thoracic Society
Originally Published in Press as DOI: 10.1164/rccm.201207-1222OC on January 24, 2013
Internet address: www.atsjournals.org
Vol 187, Iss. 8, pp 840–847, Apr 15, 2013
AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject
It is a matter of scientific controversy whether precapillary
pulmonary hypertension (PH) in adults with sickle cell dis-
ease (SCD) leads to mortality and whether its characteristics
are different from PH in other patients.
What This Study Adds to the Field
Our results indicate that mortality in catheterized adults with
SCD is proportional to several gold-standard hemodynamic
measurements of precapillary PH severity. This epidemi-
ological evidence implies that precapillary PH promotes
early mortality in this patient population.
estimated sPAP 2 SD above the normal mean have 10-fold
higher risk for early mortality compared with patients with
SCD without this echocardiographic abnormality (2–4, 20).
However, these noninvasive data have provoked controversy
(21–23), with some researchers expressing skepticism that PH
in SCD is clinically significant (24). Few SCD studies have pre-
sented confirmatory physiologic measurements with RHC, the
standard for PH diagnosis (4, 8–10, 25), and no prospective
studies have adequately examined hemodynamic predictors
of mortality other than the single threshold value of mPAP
to diagnose PH.
Data from idiopathic pulmonary arterial hypertension studies
identify baseline hemodynamic variables as an important predic-
tor of survival (26–28). Other studies of idiopathic pulmonary
arterial hypertension and precapillary PH associated with other
disorders have shown clinical variables, such as poor exercise
capacity as measured by the 6-minute walk distance (6MWD)
test and advanced World Health Organization functional class
(WHO FC), and certain biomarkers are predictors of a poor
prognosis (29, 30). However, Simonneau and Parent have criti-
cally questioned the clinical relevance of PH in SCD (24), in part
because of the atypically high cardiac output that is an adaptive
response to severe anemia and the very low oxygen-carrying
capacity in these patients and the pulmonary vascular resistance
that, due to adaptation to high flow, is not as highly elevated. We
recently reported the prevalence and prognostic significance of
PH in a large cohort of adults with SCD (7), but all published
analyses have only evaluated a threshold effect of mean pulmo-
nary artery pressure that satisfies consensus diagnostic criteria.
We hypothesize that that severity of PH, especially precapillary
PH, is proportional to mortality in SCD. Our new analysis in this
study demonstrates the quantitative relationship of well accepted
right heart catheterization–defined precapillary PH variables to
death in adults with SCD. Some of the results of these studies
have been previously reported in the form of an abstract (31).
This registrystudy was approved bythe Institutional ReviewBoardat the
NationalInstitutes ofHealth. Allsubjectsprovided writteninformed con-
sent to studies in which clinical, laboratory, echocardiographic, and/or
RHC data were obtained (ClinicalTrials.gov identifiers NCT00011648,
NCT00081523, NCT00023296, and NCT00352430). Subjects who under-
went RHC between March 13, 2002 and June 8, 2010 were included. The
diagnosis of SCD was confirmed by HPLC of hemoglobin. The selection
process is summarized in Figure 1. The cohort was assembled from
529 subjects with SCD enrolled and screened at the National Institutes of
Health or at Howard University Hospital, of whom approximately 2%
were referred with suspected or proven pulmonary hypertension. Out of
the 529 subjects with SCD, 84 underwent RHC based on elevated tricus-
pid regurgitant velocity (TRV) on echocardiography and clinical suspi-
cion of PH defined as TRV > 2.8 m/s accompanied by 6MWD , 500 m
or unexplained dyspnea or oxygen desaturation. RHC was performed in
33% of subjects with TRV > 2.5 m/s, 52% of subjects with TRV > 2.8 m/s,
and 66% of those with TRV > 3 m/s. The PH group was categorized
hemodynamically to have postcapillary PH if mPAP was >25 mm Hg
and pulmonary capillary wedge pressure (PCWP) was .15 mm Hg, and
precapillary PH if mPAP > 25 mm Hg, PCWP < 15 mm Hg (32). These
results were presented in part at the annual meeting of the American
Society of Hematology (31). Additional details are provided in the online
Baseline characteristics of subjects who underwent RHC (n ¼
84) and the noncatheterized subjects with SCD (n ¼ 445) are
shown in Table E1 in the online supplement. Most study
participants were of African descent (98%), and the predomi-
nant sickle cell phenotype was hemoglobin SS disease (73%).
Subjects who underwent RHC were older, with mean age of
41 6 13 years compared with 35 6 12 years for those not cathe-
terized (P , 0.001). Several laboratory markers were statisti-
cally significantly different in SCD and PH compared with the
noncatheterized patients with SCD (Table 1). Subjects with
SCD and PH demonstrated significantly abnormal cardiopul-
monary markers of clinical severity compared with those not
catheterized, including higher TRV (3.2 6 0.5 vs. 2.3 6 0.5 m/s;
P , 0.001), higher serum N-terminal prohormone of brain natri-
uretic peptide (NT-proBNP) level (median, 153 vs. 58 pg/ml; P ,
0.001), and poor exercise capacity (6MWD 387 6 118 m vs. 486 6
88 m; P , 0.001).
Logistic regression analysis showed that TRV and 6MWD are
significantlyassociated with PHdiagnosisatRHC.TRV> 2.8 m/s
was highly predictive of PH (compared with subjects with SCD
and TRV , 2.8 m/s; relative risk, 13.05; 95% CI, 5.19–32.85; P ,
0.001). Compared with the model with TRV alone, the C statistic
(area under the ROC curve) was significantly improved from 0.84
to 0.88 with the addition of 6MWD , 500 m in the multivariate
model. The clinical relevance of this combined model to predict
PH needs to be validated.
Fifty-five subjects (10.4%) out of the 529 screened SCD popula-
tion, or 55 out of 84 (65.5%) of those who underwent RHC, were
diagnosed with PH (Figure 1). The PH group was characterized
by mPAP 36 6 9 mm Hg, PVR 227 6 149 dyn$s$cm25, PVRi
4176 264dyn$s$cm25$m22,centralvenouspressure10 6 5mmHg,
and high cardiac output (8.4 6 2.5 L/min) (Table 1). Similarly, the
mean mixed venous oxygen saturation (SVO2) (69 6 8%) and
PVC (4.5 6 3.1 ml/mm Hg) were mildly depressed in subjects
with SCD and PH. A higher percentage of subjects with SCD
Figure 1. Schematic diagram of study population. mPAP ¼ mean pul-
monary artery pressure; PCWP ¼ pulmonary capillary wedge pressure;
PH ¼ pulmonary hypertension; precapillary PH ¼ pulmonary arterial
hypertension; postcapillary PH ¼ pulmonary venous hypertension; RHC ¼
right heart catheterization; SCD ¼ sickle cell disease.
Mehari, Alam, Tian, et al.: Mortality in Sickle Cell Pulmonary Hypertension841
with PH had advanced World Health Organization functional
class (WHO FC III or IV 33 vs. 14%; P ¼ 0.07) at the time of
diagnosis compared with subjects with SCD without PH. The
exercise capacity was significantly limited in the SCD-PH group
(6MWD 358 6 115 vs. 437 6 108 m; P ¼ 0.004) compared with
those without PH.
Thirty-one (5.9% of the 529 screened subjects; 56.4% of the
subjects with PH) had precapillary PH, and 24 (4.5% of the
screened population; 43.6% of subjects with PH) werediagnosed
with postcapillary PH,with mean values mPAP of 37 6 9 mm Hg
and PCWP 20 6 4 mm Hg. Hemodynamic values in subjects
with precapillary PH included mPAP of 36 6 9 mm Hg, PCWP
12 6 3 mm Hg, transpulmonary gradient (TPG) 24 6 9 mm Hg,
PVR 272 6 156 dyn$s$cm25, and CO 8.0 6 2.7 L/min (Figure 1;
Table E2). Sixteen of the 31 subjects with precapillary PH had
a PVR of 240 dyn$s$cm25or higher.
Even though subjects with SCD and PH have a less severe
hemodynamic profile compared with other forms of precapillary
PH, functional capacity measures such as mean 6MWD and per-
centage of subjects in WHO functional class III and IV were se-
verely abnormal, suggesting that even mild PH in adults with
SCD is associated with significant functional impairment (Table
E2). Both PH hemodynamic groups had worse functional capacity
measured by 6MWD (postcapillary PH: 329 6 119 m [P , 0.001];
precapillary PH: 379 6 108 m; [P , 0.001]) when compared with
uncatheterized patients with SCD (485 6 88 m) (Tables E1and
E2). Both of the PH subgroups showed significantly higher
LDH levels (postcapillary PH: 473 6 247 IU/L [P ¼ 0.011];
precapillary PH: 476 6 229 IU/L [P , 0.001]) compared with
uncatheterized control subjects with SCD (340 6 151 IU/L)
(Table E1). Subjects with postcapillary PH exhibited an ele-
vated transpulmonary gradient (normal TPG , 12 mm Hg),
suggesting a subgroup of these subjects have reactive postca-
Survival and Risk Factors for Mortality
Median follow-up time was 4.7 years, with a maximum follow-
up of 11 years for all subjects alive, with 15% of enrolled sub-
jects not yet due for biannual follow-up. A total of 77 deaths
were observed. All-cause mortality was higher in patients with
PH compared with patients without PH by RHC or the unca-
theterized patients (log-rank test, P , 0.001). The 5-year mor-
tality rates were 31.7, 15.9, and 14.4%, respectively. Death
certificates were available for 15 out of 23 (65%) subjects with
PH, and 80% of these subjects were reported to have had
right heart failure or sudden cardiac death stated as a cause
To identify hemodynamic risk factors associated with mortal-
ity, survival estimates since catheterization for 84 subjects under-
going RHC were used. Survival estimates for the subjects with
SCD and PH versus those subjects without PH by RHC were
89 versus 100% at 1 years, 76 versus 93% at 3 years, and 63 versus
83% at 5 years from diagnosis by RHC, respectively. The esti-
mated median survival time was 6.8 years after RHC for subjects
with SCD and PH. The survival was not different among the pre-
capillaryand postcapillaryPHsubgroups(log-ranktest,P ¼ 0.23).
Several hemodynamic and laboratory variables were associ-
ated with mortality in the subjects undergoing RHC, particularly
univariate Cox regression analysis of all potential predictors,
sPAP, dPAP, mPAP, dPAP 2 PCWP, TPG, PVR, PVRI, phe-
notype, WHO FC, 6MWD, direct bilirubin, alkaline phosphatase,
and serum ferritin level were significantly associated with mor-
tality (Table 2). Kaplan-Meier survival estimates dichotomized
by mPAP > 25 mm Hg, TPG > 12 mm Hg, 6MWD, and WHO
FC were statistically significant (Figure 2). The estimated unad-
justed HRs for mortality were 3.02 (95% CI, 1.04–8.76; P ¼ 0.042)
for mPAP > 25 mm Hg, 3.55 (95% CI, 1.43–8.80; P ¼ 0.003)
for TPG > 12 mm Hg, 2.68 (95% CI, 1.06–6.77; P ¼ 0.031) for
6MWD , 400 m, and 3.64 (95% CI, 1.65–8.05; P , 0.001) for
WHO FC III–IV, compared with the corresponding counter-
part of subjects undergoing RHC.
To adjust for potential confounding factors, age, gender, phe-
notype (SS vs. SC or S-b thalassemia), hematocrit, hemoglobin
F, hemoglobin S, creatinine, direct bilirubin, and NT-proBNP
were included in the multivariate Cox regression analyses of
mortality and each of the hemodynamic variables. The mPAP
(adjusted HR, 1.61 per 10 mm Hg; 95% CI, 1.05–2.45; P ¼
0.027), dPAP (adjusted HR, 1.83 per 10 mm Hg; 95% CI,
1.09–3.08; P ¼ 0.022), TPG (adjusted HR, 1.78 per 10 mm Hg;
95% CI, 1.14–2.79; P ¼ 0.011), PVR (HR, 1.44 per Wood unit;
95% CI, 1.09–1.89; P ¼ 0.009), and dPAP 2 PCWP (adjusted
HR, 2.19 per 10 mm Hg; 95% CI, 1.23–3.89; P ¼ 0.008) were
predictive in a multivariate model, and sPAP was borderline
significant (Table 3). The five multivariate models had compa-
rable AIC values, suggesting that they had similar goodness of
fit and the five hemodynamic variables had nearly equal HR
for mortality controlling for multiple risk factors. Moreover,
mPAP, TPG, and PVR were dichotomized around their median
values (mPAP > 28 mm Hg, TPG > 12 mm Hg, and PVR >
115 dyn$s$cm25), respectively, and each of these dichotomized
variables was statistically significant in the multivariate model
(Table 3). Sickle cell variant phenotype was also a significant
predictor of all-cause mortality in each of the multivariate mod-
els. Similar results were obtained when the analysis was limited to
the 55 patients with PH (Table E3). Other factors were not sta-
tistically significant in the multivariate models, and the addition
TABLE 1. HEMODYNAMIC AND CLINICAL CHARACTERISTICS
OF CATHETERIZED PATIENTS ACCORDING TO PULMONARY
Characteristic (N ¼ 84)
sPAP, mm Hg
dPAP, mm Hg
PP, mm Hg
mPAP, mm Hg
CVP, mm Hg (n ¼ 83)
PCWP, mm Hg
TPG, mm Hg
dPAP-PCWP, mm Hg
Cardiac output, L/min
Cardiac index, L$min21$m22
PVC, ml/mm Hg
SVR, dyn$s$cm25(n ¼ 82)
SVO2, % (n ¼ 78)
6MWD, m (n ¼ 80)
O2saturation, per unit %
WHO FC III or IV, n (%)
PH (n ¼ 55)
58 6 15
26 6 7
32 6 12
36 6 9
10 6 5
16 6 5
21 6 10
10 6 8
8.4 6 2.5
117 6 35
64 6 21
4.5 6 3.1
227 6 149
417 6 264
835 6 333
69 6 8
3.3 6 0.5
358 6 115
95 6 4
No PH (n ¼ 29)
31 6 6
13 6 4
17 6 5
19 6 4
6 6 3
11 6 3
8 6 3
2 6 3
9.3 6 2.3
5.3 6 1.3
133 6 43
74 6 24
8.4 6 4.4
72 6 37
131 6 70
740 6 254
73 6 9
2.9 6 0.4
437 6 108
97 6 3
Definition of abbreviations: CVP ¼ central venous pressure; dPAP ¼ diastolic
pulmonary artery pressure; mPAP ¼ mean pulmonary artery pressure; PCWP ¼
pulmonary capillary wedge pressure; PP ¼ pulmonary artery pulse pressure;
PVC ¼ pulmonary artery capacitance; PVRI ¼ pulmonary vascular resistance index;
sPAP ¼ systolic pulmonary artery pressure; SV ¼ stroke volume; SVI stroke volume
index; SVO2¼ mixed venous oxygen saturation; SVR ¼ systemic vascular resis-
tance; TPG ¼ transpulmonary gradient; TRV ¼ tricuspid regurgitant jet velocity;
WHO FC ¼ World Health Organization functional class; 6MWD ¼ 6-min-walk
*Data were summarized by the mean 6 SD and by frequency (percentage).
842 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINEVOL 187 2013
of other hemodynamic variables such as CI, CO, PCWP, SV,
SVI, PVC, and SVR to the model produced virtually no change
in the results.
Six of the patients with PH who died underwent postmortem ex-
amination. The mean time from RHC to death in these subjects
was 3.23 years (range, 0.07–7.91 yr). Mean mPAP was 41 mm Hg
(range, 28–51 mm Hg), mean TPG was 26 mm Hg (range, 12–
36), mean PVR was 273 dyn$s$cm25(range, 93–661), mean SVO2
was 68% (range, 63–74), and mean 6MWD was 261 m (range,
126–399). Four out of the six subjects had precapillary PH, and
two had postcapillary PH, one of which had a TPG of 24 mm Hg
and PVR of 300 dyn$s$cm25. Histopathologic examination
showed dilated pulmonary arteries, widespread and extensive
vascular changes with moderate to severe medial proliferation,
and intimal thickening associated with grade III–IV plexiform
lesions (31) in their pulmonary arteries (Figure 3).
There has been controversy regarding the prevalence of PH in
SCD and its contribution to mortality (21, 22, 24). Our recent
publication on this same cohort has documented the linkage of
catheterization-proven pulmonary hypertension to mortality in
adults with SCD. What this study adds to the literature is sig-
nificant epidemiological evidence that mortality is proportional
to several specific gold standard hemodynamic markers of se-
verity of precapillary PH pathophysiology, such as PVR and
TPG. Our new results also deemphasize the mortality signifi-
cance of PCWP, a marker of postcapillary PH and left ventric-
ular disease. Although a prospective registry study cannot prove
the etiology of death in this cohort, this finding supports preca-
pillary PH as a risk factor for early mortality in adults with
SCD. Furthermore, by providing a detailed analysis of our
previously published data from this cohort, we show that the
mortality rate is proportional to the severity of PH as indi-
cated by all measures of pulmonary artery disease, highlighted
by the robust association of mortality to multiple physiologic
Figure 2. Kaplan-Meier survival curves after right heart
catheterization for important clinical variables in adults
with sickle cell disease. Curves indicate survival in years
after catheterization for 84 adults with sickle cell disease.
Significant differences in survival are observed subjects with
mean pulmonary artery pressure (mPAP) > 25 mm Hg
(upper left) and transpulmonary gradient (TPG) >12 mm Hg
(upper right), advanced World Health Organization Func-
tional Class (WHO FC III or IV, lower left), or 6-minute walk
distance (6MWD) ,400 m (lower right).
TABLE 2. UNIVARIATE ANALYSIS FOR MORTALITY RISK FACTORS
Characteristic (N ¼ 84)
Age, per 10 yr
Phenotype (SS vs. SC or S-b thalassemia)
sPAP, per 10 mm Hg
dPAP, per 10 mm Hg
mPAP, per 10 mm Hg
TPG, per 10 mm Hg
PVR, per 1 Wood Unit
PVRI, per 1 Wood Unit/m2
PP, per 10 mm Hg
dPAP-PCWP, per 10 mm Hg
CVP, per 10 mm Hg (n ¼ 83)
PCWP, per 10 mm Hg
Cardiac output, L/min
Cardiac index, L$min21$m22
SVO2, % (n ¼ 78)
6MWD, per 100 m (n ¼ 80)
Oxygen saturation, per unit %
WHO FC (III–IV vs. I–II)
Alkaline phosphatase, U/L per 100
Bilirubin, direct, mg/dl
Ferritin, mg/L per 1,000 (n ¼ 83)
Ferritin, .1,000 mg/L (n ¼ 83)
Unadjusted HR (95% CI)P Value
Definition of abbreviations: CVP ¼ central venous pressure; dPAP ¼ diastolic pul-
monary artery pressure; dPAP 2 PCWP ¼ diastolic pulmonary artery pressure minus
pulmonary capillary wedge pressure; mPAP ¼ mean pulmonary artery pressure;
PCWP ¼ pulmonary capillary wedge pressure; PP ¼ pulmonary artery pulse pressure;
PVR ¼ pulmonary vascular resistance; PVRI ¼ pulmonary vascular resistance index;
6MWD ¼ 6-min-walk distance; sPAP ¼ systolic pulmonary artery pressure; TPG ¼
transpulmonary gradient; WHO FC ¼ World Health Organization functional class.
Mehari, Alam, Tian, et al.: Mortality in Sickle Cell Pulmonary Hypertension 843
indicators of precapillary PH severity, including the PVR,
TPG, and the gradient between pulmonary arterial diastolic
and PCWP. In fact, we find that sPAP, PP, TPG, and PVR
were nearly equally and independently associated with mor-
tality when combined with the previously established SCD
mortality serum biomarkers creatinine, alkaline phosphatase,
and ferritin. These results emphasize that mortality rate in
adults with SCD is proportional to the severity of precapillary
PH. Consistent with this observation, patients with SCD with
PH can have histopathological changes more severe than might
be expected from relatively modest hemodynamic abnormalities
Left ventricular dysfunction, characterized by markers of di-
astolic heart failure, is frequently encountered in adults with
SCD and has been associated with risk of mortality additive
to echocardiographic markers of PH (33). In our cohort, these
subjects are represented by the postcapillary subgroup. Al-
though the postcapillary PH subgroup shares a high mortality
rate, the PCWP is not significant as a predictor of mortality,
suggesting that precapillary PH physiology dominates mortality
risk in SCD. Consistent with this interpretation, the mean TPG
is above 12 mm Hg in the postcapillary PH group, suggesting
that even the postcapillary PH group shares some physiological
characteristics of the precapillary remodeling. Likely our cathe-
terized cohort lacks sufficient statistical power to characterize
potentials interaction between precapillary PH and postcapil-
lary PH upon prognosis, as previously suggested (33). However,
RHC physiologic markers of left ventricular dysfunction in
adults with SCD and PH appear to have less prognostic signif-
icance than those of precapillary PH.
Our findings are in agreement with previous studies describ-
ing the hemodynamic etiology of PH in SCD as heterogeneous
(8, 9). Our findings are similar to a French study that classified
its adult subjects as 46% precapillary (11/24) and 54% postca-
pillary among subjects with SCD and PH (8). Unlike the French
study, which reported PH in only 25% of subjects who under-
went RHC (n ¼ 96) and in 6% in the whole screened cohort
(n ¼ 385), we found prevalence of PH of all types of 65.5% (55/
84) in those who underwent RHC or 10.4% (55/531) in our
screened cohort. These differences may be related in part to
the French protocol including all subjects with TRV > 2.5 m/s
regardless of 6MW but also their exclusion of subjects with liver
dysfunction, chronic renal insufficiency, or low total lung ca-
pacity. Exclusion of these subjects likely underestimated the
true prevalence of PH because markers of renal insufficiency,
TABLE 3. MULTIVARIATE ANALYSIS FOR MORTALITY
(95% CI)P ValueAIC†
mPAP, per 10 mm Hg
dPAP, per 10 mm Hg
dPAP 2 PCWP, per 10 mm Hg
TPG, per 10 mm Hg
PVR, per Wood unit
sPAP, per 10 mm Hg
Dichotomized Variable by Median
mPAP > 28 mm Hg
TPG > 12 mm Hg
PVR > 115 dyn$s$cm25
Definition of abbreviations: CI ¼ confidence interval; dPAP ¼ diastolic pul-
monary artery pressure; dPAP 2 PCWP ¼ diastolic pulmonary artery pressure
minus pulmonary capillary wedge pressure; HR ¼ hazard ratio; mPAP ¼ mean
pulmonary artery pressure; PCWP ¼ pulmonary capillary wedge pressure;
PP ¼ pulmonary artery pulse pressure; PVR ¼ pulmonary vascular resistance;
6MWD ¼ 6-min-walk distance; sPAP ¼ systolic pulmonary artery pressure;
TPG ¼ transpulmonary gradient.
*Age, gender, phenotype (SS vs. SC/b-thalassemia), hematocrit, hemoglobin
F, hemoglobin S, N-terminal prohormone of brain natriuretic peptide (NT-
proBNP), creatinine, and direct bilirubin were included in each of the multivariate
Cox regression models. Two patients with missing NT-proBNP were excluded.
yThe Akaike information criterion (AIC) was used to compare different regres-
sion models. The models with smaller AIC have better fit to the data.
Figure 3. Pulmonary vascular pathology in patients with
sickle cell disease (SCD). Microscopic examination of lung
tissue reveals widespread proliferative arteriopathy, vascu-
lar changes, and thrombosis consistent with pulmonary
arterial hypertension. Representative photomicrographs
from six patients with SCD who died and underwent au-
topsy in this study show dilated vasculature, medial hyper-
trophy, intimal proliferation of pulmonary arteries, and
numerous complex plexiform lesions scattered throughout
the lung parenchyma. (A) A 54-year-old man with mean
pulmonary artery pressure (mPAP) of 31 mm Hg and pulmo-
nary vascular resistance (PVR) of 105 dyn$s$cm25who died
with pneumonia. (B) A 30-year-old man with mPAP of
28 mm Hg and PVR of 226 dyn$s$cm25who died with
acute cor pulmonale during acute chest syndrome. (C)
A 44-year-old woman with mPAP of 51 mm Hg and PVR
of 830 dyn$s$cm25; sudden death at home. (D) A 35-year-old
man with mPAP of 44 mm Hg and PVR of 366 dyn$s$cm25;
sudden death at home. (E) A 54-year-old man with mPAP
of 51 mm Hg and PVR of 285 dyn$s$cm25who died of
hepatic cirrhosis complicating progressive right heart fail-
ure. (F) A 48-year-old woman with mPAP of 41 mm Hg
PVR of 300 dyn$s$cm25who died of right heart failure
decompensated by sepsis-related bone marrow embolism.
The micrographs illustrate the severity of histopathologic
findings of pulmonary arterial hypertension in SCD that is
often much greater than might be expected for the degree
of hemodynamic abnormality.
844AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 1872013
hepatic dysfunction, and iron overload are independent risk fac-
tors for high estimated pulmonary artery pressure in patients with
SCD (3, 4). The French study appeared to apply RHC to a larger
proportion of subjects with normal pulmonary pressure because
in our cohort subjects with RHC-proven PH had mPAP of 37 6
9 mm Hg, compared with their mPAP of 30 6 0.46 mm Hg. Given
that our study had no exclusion criteria, the prevalence rate of
10.4% is likely to be more accurate. Our prevalence rates are
consistent with a recent screening study from Brazil (34).
The 10.4% prevalence of PH and the prevalence of precapil-
lary PH of 6% in adults with SCD from the largest cohort of pro-
spectively identified subjects with SCD and PH ranks highly
among populations predisposed to PH. This prevalence would
place SCD as second only to scleroderma (12%) among associ-
ated conditions under WHO group I precapillary PH (35, 36)
and comparable to portopulmonary hypertension (1–6%) (37)
and HIV infection (0.5%) (38).
PH associated with SCD is characterized by relatively modest
elevations of mPAP and PVR and a high cardiac output, as seen
in this study and others (9, 10). Despite these seemingly favor-
able hemodynamic findings, subjects with SCD and PH have
a marked reduction in their functional capacity and high mor-
tality, suggesting that any level of PH in these severely anemic
patients portends a poor prognosis. Several echocardiographic
studies have reported that subjects with SCD and a high esti-
mated sPAP have a poor prognosis, with HRs for death ranging
from 4.4 to 10 (2–4, 6, 20). We currently find greater median
survival in SCD-PH of 6.8 years compared with Castro’s report
in symptomatic subjects of 2.1 years (10). This improved sur-
vival might arise from several possible reasons. Presymptomatic
screening in our study may be leading to case ascertainment at
an earlier age and stage of disease. A much larger number of
therapies approved for PH in the general population have be-
come available over the intervening years, potentially permitting
better PH control. Last, supportive care of SCD with hydroxy-
urea or chronic transfusion has been more aggressively promoted
in the last decade, and anecdotal evidence indicates that in some
cases this may lead to better control of pulmonary arterial pres-
sures (39, 40).
At their usual baseline, due to their high cardiac output, sub-
jects with SCD with normal mPAP have PVR between 22 and
62 dyn$s$cm25(11). Although PVR is useful, the current pre-
capillary PH classification does not require it as a diagnostic
criterion (1, 41). PVR values may not adequately characterize
pulmonary vascular disease in the severely anemic population
because the associated high cardiac output induces a compensa-
tory decrease in PVR, and the low blood viscosity of anemia
reduces developed pressure at any given rate of flow.
Our study reports hemodynamic markers of PH severity as
risk factors for poor survival in SCD. Caution is required in com-
parisons with pulmonary arterial hypertension in other popula-
tions in which cardiac output or stroke volume is associated with
risk of mortality. In subjects with idiopathic pulmonary arterial
hypertension, the NIH registry suggested that three hemody-
namic variables (increased PAP, increased CVP, and decreased
cardiac index) predicted increased risk of death (26). Although
we observed trends in our analyses, some of these traditional
hemodynamic parameters were not independently associated
with mortality in our cohort, suggesting that there may be a dif-
ferent mode of demise in SCD-PH. Another potential explana-
tion for these findings would be the high variability observed in
the data related to right ventricular function given the confound-
ing effects of anemia on cardiac output and filling pressures.
Additionally, the acute increase in pulmonary artery pressure
in the sickle cell vasoocclusive pain crisis (42) and the acute
chest syndrome associated with mortality (43) might be more
likely to be lethal in these patients with SCD and PH with di-
minished functional reserve. Finally, TPG and PVR are indepen-
dent risk factors for death, suggesting that these measures may be
more relevant indices of pulmonary vascular dysfunction in
patients with SCD and PH. Not surprisingly, rising mPAP was
proportional to survival. Subjects with mPAP > 28 mm Hg (me-
dian value in our RHC cohort) had 4.8-fold higher hazard of
dying compared with those with a mPAP ,28 mm Hg. The
hazard increased by 1.6 for every 10 mm Hg increase in mPAP.
Similarly, Castro and colleagues reported that each 10 mm Hg
increase in mPAP was associated with a 1.7-fold increase in
death rate (10). The prognostic value of PVR and TPG is shared
with scleroderma-associated precapillary PH (44), PH after
heart transplantation (45), and portopulmonary hypertension
after liver transplantation (46).
Our results confirm several associations previously de-
scribed in adults with SCD with echocardiographic-estimated
high pulmonary artery pressure. Lower hemoglobin and hemat-
ocrit and higher serum levels of AST and LDH than the general
sickle cell control group in this study are associated with PH
proven by RHC, as seen previously with echocardiography
(2–4, 47–50). These markers have also been linked to acceler-
ated hemolysis and alterations in nitric oxide bioavailability
(48, 51). Alkaline phosphatase and ferritin were elevated in
subjects with SCD with PH and were risk factors for death in
the univariate and multivariate analyses, confirming previous
findings from echocardiography (4). Another previously iden-
tified risk factor, direct bilirubin, reflects an association ob-
served in precapillary PH without SCD (52). Increasing age
is reported with an increased risk of PH in previous studies
(2, 4), but mortality was not explained by old age among
patients with PH in our study. Our results indicate that sub-
jects with SCD and PH had 3-fold increased risk for death than
subjects with SCD of similar age who were documented by RHC
not to have PH.
A number of limitations must be noted. First, our registry
study was performed in a single center, with a retrospective anal-
ysis of prevalent and incident cases. As a consequence, survival
rates might have been overestimated and the prevalence of PH
could have been overestimated due to referral bias. Additional
limitations are the observational nature of our findings and our
inability to draw conclusions regarding cause and effect.Because
RHC was not performed in every subject initially screened for
PH, we cannot calculate the precise sensitivity and specificity
of TRV as a predictor of PH by RHC.
PH documented by RHC is strongly associated with worse func-
tional capacity and increased risk of death in adults with SCD.
Several measures of precapillary disease severity are indepen-
our data provide definitive physiological evidence that, despite
the atypical hemodynamic features imparted by the compensa-
tory response to severe anemia in SCD, the dominant features
of precapillary PH, including mPAP, PVR, and TPG, are pro-
portional to the poor prognosis in catheterized patients with
SCD and PH. Additional clinical research with intervention
targeted at precapillary PH is warranted in this complex and
Author disclosures are available with the text of this article at www.atsjournals.org.
Acknowledgment: The authors acknowledge Dr. Mark T. Gladwin for many helpful
discussions.TheauthorsthankMaryK.Hallforexpert protocol management,thepro-
tocol coordinators who contributed to this study (James Nichols, Wynona Coles, and
Lori Hunter), and the patients with sickle cell disease who participated in this study.
Mehari, Alam, Tian, et al.: Mortality in Sickle Cell Pulmonary Hypertension845
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