Loss of alveolar membrane diffusing capacity and pulmonary capillary blood volume in pulmonary arterial hypertension.

0.27 MB·English

by  Farha, Samar

Farhaetal.RespiratoryResearch2013,14:6
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RESEARCH Open Access
Loss of alveolar membrane diffusing capacity and
pulmonary capillary blood volume in pulmonary
arterial hypertension
Samar Farha1*, Daniel Laskowski1,2, Deepa George2, Margaret M Park2,3, WH Wilson Tang3, Raed A Dweik1,2
and Serpil C Erzurum1,2
Abstract
Background: Reduced gas transfer inpatients with pulmonary arterial hypertension (PAH) is traditionally attributed
to remodeling and progressive loss ofpulmonaryarterial vasculature that resultsin decreased capillary blood
volume availablefor gas exchange.
Methods: We testedthis hypothesisby determinationof lung diffusing capacity (DL) and itscomponents,the
alveolar capillarymembranediffusingcapacity (D ) and lung capillary blood volume (V ) in28 individuals with PAH
m c
incomparison to 41 healthy individuals, and in19 PAH patients over time. Using single breath simultaneous
measure of diffusion ofcarbonmonoxide (DL ) and nitric oxide (DL ),DL and D were respectively determined,
CO NO m
and V calculated. D and V were evaluated over time inrelation to standard clinical indicators of disease severity,
c m c
including brain natriuretic peptide (BNP), 6-minute walk distance (6MWD) and right ventricular systolic pressure
(RVSP) by echocardiography.
Results: Both DL and DL were reduced in PAHas compared to controls and the lower DL in PAHwas due to
CO NO
loss of both D and V (all p<0.01). While DL ofPAH patients did not change overtime,DL decreased by
m c CO NO
24 ml/min/mmHg/year (p=0.01). Consequently, D decreased and V tended to increase over time, which led to
m c
deterioration of theD /V ratio, a measure of alveolar-capillary membranefunctional efficiency without changes in
m c
clinical markers.
Conclusions: The findingsindicate that lower than normal gas transfer in PAHis due to loss of both D and V ,
m c
butthatdeteriorationof D /V overtime is related to worseningmembranediffusion.
m c
Keywords: Membrane diffusion, Pulmonary arterial hypertension, Lung capillary blood volume
Background exchange capacity. Based on the Roughton and Forster
Lung diffusingcapacity for carbon monoxide (DL )isa model [2], DL is described as a series of resistances:
CO CO
valuable clinical tool in the assessment of pulmonary the diffusion of the gas across the alveolar-capillary
diseases. It measures the ability of the lungs to transfer membrane, the transfer into the plasma and across the
gas from the alveolar space to the red blood cells in the red blood cell membrane, and the chemical reaction of
pulmonary vessels. Measurement of DL is informative the gas with hemoglobin (Hgb). The following equation
for pathophysiologic diagnoses of lung diseases and ser- summarizesthese concepts:
ial measurements are used to follow the course of dis-
ease [1]. The components of DL can provide more 1=DL¼1=Dmþ1=θVc
detailed knowledge of the mechanisms of loss of gas
Where DL represents total lung diffusing capacity; D
m
alveolar-capillary membrane diffusing capacity; V pul-
c
*Correspondence:[email protected] monary capillary bed available for gas transfer; and θ is
1RespiratoryInstitute,ClevelandClinic,9500EuclidAvenue,Cleveland,OH
the rate of reaction of the gas with the red cell. Trad-
44195,USA
Fulllistofauthorinformationisavailableattheendofthearticle itionally, measure of the two components of DLCO relied
©2013Farhaetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.
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upon repeated performance of the test at different oxy- ExhaledNO,lungfunction,volumesanddiffusing
gen concentrations and solving the equation for D and capacityforcarbonmonoxideandnitricoxide
m
V. These technical challenges resulted in an arduous Single-breath on-line measurement of fractional NO
c
method and inaccuracies in measures that limited utility. concentration in expired breath (FE ) was mea-
NO
However, nitric oxide (NO) has a greater affinity to Hgb sured at the beginning of each visit using the NIOX
compared to CO or O , and thus NO diffusion is mainly (Aerocrine, NJ) [10].
2
limitedbythe transferofgasacrossthe alveolar capillary The forced expiratory volume at 1 second (FEV )
1
membrane [3]. Based on this, DL can be used as a and vital capacity (FVC) were measured by spirometry
NO
direct measure of D . Recent advances allow measure of (MasterLab; Viasys/Jaeger; Höchberg, Germany) follow-
m
DL and DL simultaneously and direct determin- ing established guidelines [11]. Total lung capacity
NO CO
ation of D and V from single breath maneuver at one (TLC) was measured using the single breath measure-
m c
oxygen tension [3,4]. Few studies have evaluated the ment method [12]. Helium was used as a tracer gas
components of DL in pulmonary hypertension (PH) in following the ATS/ERS guidelines.
an attempt to understand the pathophysiology of the Single breath measurements of DL and DL were
CO NO
decreased DL. Cross-sectional data from studies are in- performed using a modified Masterscreen PFT (Viasys/
consistent and there are no longitudinal data. In 1968, Jaeger; Höchberg, Germany) adapted to measure nitric
Nadel et al. showed that DL was reduced in PH as a oxide. The measurement was performed with the patient
CO
result of low V [5]. Borland et al. were the first to apply rested in a seated position using a nose clip. The
c
a single breath technique to measure DL and DL inspired gas contained 70 ppm nitric oxide (Ikara, NJ)
NO CO
and identified that both were reduced in PH [6]. How- and a blend of ultra high purity 21% oxygen, 0.28%
ever, recent studies have attributed the low DL to a loss carbon monoxide, 9.5% helium and balance nitrogen.
of D ratherthan V [7,8]. Oppenhiemeret al. measured The single breath DL method was performed in du-
m c CO
D and V in different groups of PH patients and found plicate to a maximum of 4 measurements to obtain 2
m c
that D was reduced out of proportion to V as shown measurements within 5%, ~4 minutes apart using a
m c
by a reduction in the ratio of D /V [9]. Measuring the washout volume of 750 ml and an alveolar volume of
m c
components of DL in PAH would give insight into the 750 ml per standard guidelines [1,13]. The breathhold
disease, especially that recent advances have unveiled time was ~6 seconds [13]. The instrument was cali-
the intricacy of the pathogenesis of PAH. We hypothe- brated daily. D was calculated as DL divided by
mCO NO
sizedthatbothD andV aredecreasedinPAHpatients 1.97 based on solubility factors for CO and NO re-
m c
and that there is progressive decline of DL and its com- spectively of 0.0183 and 0.0364 [14].
ponents over time in parallel to disease progression. To V wascalculated from thefollowing formula[2]:
c
test this, DL and DL were measured by single
NO CO
breath technique in PAH patients in comparison to 1=V ¼ð1=DL –1=D Þ(cid:2)θ ;where1=θ
c CO mCO CO CO
healthy controls and over time in order to evaluate ¼ð0:73þ0:0058(cid:2)P Þ(cid:2)14:6=Hb¼1:474
AO2
changes in D and V in relation to clinical parameters
m c
includingechocardiography,6MWDandBNPlevels. P ¼F (cid:2)ðPatm(cid:3)47ÞandHb¼14:6
AO2 AO2
Materials and methods
41 healthy controls and 28 subjects with PAH were en- Echocardiogram
rolled in the study. The Institutional Review Board at Two dimensional echocardiograms and doppler exams
the Cleveland Clinic approved the study and all subjects wereperformedonthesamedayastheDLtestorinsome
gave written informed consent (IRB 7853). Healthy con- cases(mainlyforthefirstvisit)withinupto8weeksofthe
trols were recruited from the community, had no med- DLtestforconvenienceoftheparticipant.
ical problems and were on no medications. PAH
subjects were recruited from the PH clinic. They had an Echocardiographicanalysis
established diagnosis of PAH based on right heart All echocardiographic analysis were performed following
catheterization. Their medical records were reviewed to the American Society of Echocardiography Guidelines
verify diagnosis. Clinical data including 6MWD, BNP, andStandards[15].
complete cell count and metabolic panel were collected From the parasternal long axis view the Interventricu-
from the medical records when available. Lung function lar septal (IVS) thickness in end-diastole, left ventricular
testing including spirometry, lung volumes, DL and end-diastolic dimension (LVEDD), left ventricular end-
CO
DL as well as exhaled NO and echocardiogram were systolic dimension (LVESD) and posterior wall thickness
NO
measured as part of the study. These tests were repeated in diastole were measured from the 2D parasternal long
longitudinally fora subgroupofPAHpatients. axis image following ASE guidelines. Left ventricular
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(LV)masswasdeterminedfrom 2Dmeasurementsusing test the null hypotheses of zero mean slopes for the
the cubed formula: PAH patients. The 2 groups were compared with respect
(cid:1) (cid:3) to baseline variables using Fisher's exact and chi-square
LVMass¼1:04 ðIVSþPWþLVEDDÞ3(cid:3)LVEDD3 tests for categorical variables, and Kruskal-Wallis and
–13:6gðDevereauxRegressionÞ Wilcoxon rank sum tests for quantitative variables.
Spearman correlation coefficients measured at specified
LV function: LV ejection fraction was determined by
time points, were used to describe relationships among
visual assessment, and/or apical biplane volumes. LV
pairs of quantitative variables in a manner free of the
end-diastolic and end-systolic volumes were calculated
normality assumption. All analyses were performd using
from the apical 4 and 2 chamber views using the modi-
R version 2.4.1. (R Development Core Team (2011). R
fied Simpson method. LV fractional shortening was
Foundation for Statistical Computing, Vienna, Austria.
determined from parasternal 2D analysis as [(LVEDD-
ISBN3-900051-07-0,URLhttp://www.R-project.org/).
LVESD)/LVEDD]×100.
Right ventricular (RV) function: RV end-diastolic area
Results
(RVAD) and end-systolic area (RVAS) were measured in
Patients were classified according to Dana Point classifi-
the apical 4-chamber view by tracing the endocardial
cation of pulmonary hypertension: Class 1.1 (n=21)
border of the RV and the tricuspid annular plane. RV
75%, Class 1.2 (n=3) 10.7%, Class 1.3 (n=1) 3.6% and
fractionalareachangewascalculated asfollows:
Class 1.4 (n=3) 10.7%. Three patients were Class 1.4
RVfractionalarea¼½ðRVAD(cid:3)RVASÞ=RVAD(cid:4) and respectively had systemic sclerosis, lupus and
(cid:2)100 chronic hemolytic anemia. None of the PAH patients
had interstitial lung disease or obstructive lung disease
Right atrial volume was measured in the apical 4 cham- basedonclinicalhistory,exam,computerizedchesttom-
berviewbyusingthesingleplanearealengthmethod. ography imaging, as part of the evaluation and assign-
The right ventricular systolic pressure (RVSP) was ment of PAH class. One patient had mild pulmonary
estimated from the systolic pressure gradient between edema on chest X-ray. Height, weight and gender distri-
the RV and the right atrium by the peak continuous- bution was similar among PAH patients and controls;
wave Doppler velocity of the TR jet using the modified however, PAH patients were older (p<0.01). Table 1
Bernoulli equation plus estimated right atrial pressure shows the baseline characteristics of the two groups
(RAP). RAP was estimated from the subcostal window and Table 2 lists the clinical data of the PAH patients.
approach measuring changes in inferior vena caval size The study spanned 15 months with a mean time of
and collapsibility as determined by the respiratory sniff 5 months between visit 1 and visit 2 and of 4 months
test following ASE guidelines. between visit 2 and visit 3. Twenty-eight PAH patients
Echo-Doppler estimation of pulmonary vascular resist- were evaluated at baseline, of those 19 elected to con-
ance (PVR): The highest Doppler continuous wave tri- tinue with the longitudinal study and were followed
cuspid valve peak velocity jet obtained from multiple over time. Fourteen patients completed all 3 visits.
views (parasternal long axis, parasternal short axis, ap- There was no difference in baseline characteristics be-
ical 4 chamber, subcostal or apical off-axis imaging) was tween the patients who were followed longitudinally
determined as the maximum tricuspid regurgitant vel- and those who were not. The patients followed longitu-
ocity (TRV). Pulsed wave Doppler sample was placed in dinally had mainly idiopathic PAH [Class 1.1 (N=15)
the right ventricular outflow tract (RVOT) at the level of 79%, Class 1.2 (N=2) 11%, Class 1.3 (N=1) 5% and
the aortic valve in the parasternal short axis view just Class 1.4 (N=1) 5%]. During the time span of the
below the pulmonic valveso that pulmonic valve closure study, none of the PAH patients developed new find-
is identified. The Doppler spectrum was traced to deter- ings on chest imaging performed as part of their clin-
mine the time velocity integral of the RVOT (RVOT- ical follow up.
TVI).PVRcalculation wasdeterminedby:
Airflowanddiffusioncapacity
PVRðWoodunitsÞ¼10(cid:2)TRVðm=secÞ=RVOT OxygensaturationatrestwaslowerinPAHpatientscom-
(cid:3)TVIðcmÞþ:16 paredtocontrols[Table1].PAHpatientshadreducedair-
flow as compared to controls [Table 1]. As previously
Statistics reported in PAH patients treated with prostacyclins
For PAH patients, individual patient slopes representing [16,17], exhaled NO of patients was similar to controls
changes over actual time were calculated using linear re- [Table 1]. DL measured by CO or NO was lower in PAH
gression for each continuous study variable. For individ- as in previous reports [Table 1]. The alveolar volume was
ual variables, Wilcoxon signed rank tests were used to not different in PAH compared to controls [Table 1]. DL
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Table1Baselinecharacteristicsofthetwostudygroups Table2ClinicaldataofPAHgroup
Variable Healthy PAH p-value EtiologyofPAHn(%)
N=41 N=28 Idiopathic 21(75%)
Age(years) 34±2 45±2 <0.01 Heritable 3(10.7%)
Gender(M/F) 17/24 6/22 0.09 Drugandtoxin-induced 1(3.6%)
Smokinghistory(never/current/ 40/0/1 24/1/3 0.1 Associatedwith 3(10.7%)
exsmoker)
NYHAclassn(%)
Height(cm) 169±1 167±3 0.3
I 4(14%)
Weight(kg) 79±3 89±7 0.2
II 14(50%)
O Saturation(%ofHgb) 98±0.2 96±0.4 <0.01
2 III 10(36%)
FE (ppb) 19±2 18±2 0.7
NO IV 0(0%)
FVC(%) 98±2 91±3 0.2
Medicationsn(%)
FEV (%) 93±2 80±4 <0.01
1 Prostacyclin 6(21.4%)
FEV/FVC 81±1 75±1 <0.01
1 PDE5i 4(14.3%)
TLC(%) 85±2 82±2 0.4
ERA 4(14.3%)
V (L) 4.9±0.2 4.3±0.2 0.1
A Prostacyclin+PDE5i 4(14.3%)
DL (ml/min/mmHg) 24±1 17±1 <0.01
CO Prsoatcyclin+ERA 2(7.15%)
DL (ml/min/mmHg) 94±4 66±5 <0.01
NO ERA+PDE5i 2(7.15%)
D (ml/min/mmHg) 48±2 33±2 <0.01
m Prostacyclin+PDE5i+ERA 6(21.4%)
V (ml) 78±4 63±5 <0.01
c 6-MWD(m) 487±24
D /V (1/min/mmHg) 0.6±0.02 0.6±0.04 0.8
m c Rightventricularsystolicpressure(mmHg) 78±5
Hgb(g/dl) 13.3±0.3 13.5±0.4 0.9
Meanpulmonaryarterialpressure(mmHg) 52±3
F/M:female/male.
FE :fractionalexhalednitricoxide. Meanpulmonarycapillarywedgepressure(mmHg) 13±1
NO
FVC:forcedvitalcapacity.
Cardiacoutput(L/min) 6±0.4
FEV:forcedexpiratoryvolumeinonesecond.
1
TLC:totallungcapacity. Cardiacindex(L/min/m2) 3±0.2
V :alveolarvolume.
DAL:lungdiffusionforcarbonmonoxide(DL )andfornitricoxide(DL ). Pulmonaryvascularresistance(woodunits) 7.8±0.9
CO NO
Dm:alveolar-capillarymembranediffusingcapacity. PAH:pulmonaryarterialhypertension.
Vc:lungcapillarybloodvolume. NYHA:newyorkheartassociation.
Hgb:hemoglobin. PDE5i:phosphodiesterasetype5inhibitor.
PAH:pulmonaryarterialhypertension. ERA:endothelinreceptorantagonist.
6-MWD:6minutewalkdistance.
corrected for V was reduced in PAH compared to con-
A p=0.7], there was a significant decline in DL and
trols [DLCO/VA (1/min/mmHg): PAH 3.9±0.1, controls hence D [median DL =−23.8 ml/min/mmHNOg/year
5±0.1; p<0.01, DLNO/VA (1/min/mmHg): PAH 14.9± (IQR −36m.8, -9.9), WilcoxNoOn SR p=0.01] [median D =
0.7, controls 19.3±0.4; p<0.01]. Similarly, DL corrected −11.9ml/min/mmHg/year(IQR−18.5,-4.3),WilcoxonmSR
for Hgb was lower in PAH [DL corrected for Hgb
CO p=0.01](Figure1)[Table3].Ontheotherhand,V tended
(ml/min/mmHg): PAH 17.3±1.0, controls 23.6±1.3; p< c
to increase over time, accounting for stability of DL
0.01, DL corrected for Hgb (ml/min/mmHg): PAH CO
NO [median V =10.9 ml/year (IQR 4.2, 46.9), Wilcoxon SR
65.5±4.5, controls 90.4±5.0; p<0.01]. Both D and V c
m c p=0.07] (Figure 1). The ratio of D /V decreased over
were reduced in PAH [Table 1]. To delineate whether m c
time, which indicated a disproportionate loss of mem-
proportionate loss was accountable for the lower DL in
brane diffusion compared to capillary bed [median D /
PAH, the ratio of Dm/Vc was calculated. The ratio was V =−0.4 1/min/mmHg/year (IQR −0.5, -0.05), Wilcoxomn
similarbetweenthetwogroups,suggestingaproportionate c
SR p=0.04] [Table 3]. Hgb did not vary over time
loss of D and V in PAH [Table 1]. Mean variabilities of
m c [Table 3]. Likewise, DL corrected for Hgb did not
DL and DL for healthy controls were 3% and 5% re- CO
CO NO vary significantly (Wilcoxon SR p=0.3) whereas DL
spectivelyandforPAH4%and7%. NO
corrected for Hgb decreased (Wilcoxon SR p<0.01).
The alveolar volume did not change over time (Wilcoxon
D andV insubjectswithPAHovertime SRp=0.4)[Table3].
m c
Although DL was stable over time [median DL = The rest of the lung functions measured and exhaled
CO CO
−1.2 ml/min/mmHg/year (IQR −2.8, 1.5), Wilcoxon SR NOdidnotvary (allWilcoxonSRp>0.05).
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Table3ChangesovertimeinthePAHgroup
Variable Estimatedunit/year WilcoxonSR
change p-value
FEV (ml) −144 0.1
1
FEV (%) −3 0.12
1
FVC(ml) −190 0.2
FVC(%) −5 0.2
FEV/FVC 0.8 0.4
1
V (ml) 20 0.4
A
FE (ppb) 0.5 0.4
NO
TLC(%) 0.7 0.5
DL (ml/min/mmHg) −1.2 0.7
CO
DL (ml/min/mmHg) −24 0.01
NO
D (ml/min/mmHg) −12 0.01
m
V (ml) 11 0.07
c
D /V (1/min/mmHg) −0.4 0.04
m c
Hgb(g/dl) 0.05 0.6
FE :fractionalexhalednitricoxide.
NO
FVC:forcedvitalcapacity.
FEV1:forcedexpiratoryvolumeinonesecond.
TLC:totallungcapacity.
Va:alveolarvolume.
DL:lungdiffusionforcarbonmonoxide(DLCO)andfornitricoxide(DLNO).
Dm:alveolar-capillarymembranediffusingcapacity.
Vc:lungcapillarybloodvolume.
Hgb:hemoglobin.
p=0.09). DL and its components did not correlate
with left ventricular systolic and diastolic function (all
Figure1Lungdiffusioncapacityanditscomponentsovertime p>0.1). DL correlated with the 6MWD (Spearman
CO
inpulmonaryarterialhypertension.Lungdiffusingcapacityfor R=0.5,p=0.05)[Table4].
NO(DLNO)andthealveolar-capillarymembranediffusingcapacity
(D )decreasesovertime(bothp=0.01).Lungcapillaryblood
m Discussion
volume(V)tendstoincreaseovertime(p=0.07).Conversely,DLCO
c
didnotchangesignificantly(p=0.7). This is the first longitudinal study to describe the
changes in gas transfer in PAH over time. Lung diffus-
ing capacity for NO, but not CO, dropped due to the
Changesinclinicalparametersovertime disproportionate loss of membrane diffusion, Dm, as
Baseline clinical data for the PAH patients are sum- compared to changes in the vascular bed available for
marized in Table 2. Right heart catheterization data gas exchange, Vc. These findings suggest that the effi-
were retrieved from the medical records and the most ciency of the alveolar-capillary unit in PAH worsens
recent one was used. Some (N=15) were performed over time independent of traditional clinical and echo-
within the same year, however others were performed cardiographic measures. The results also put forward
in past years. Clinical parameters including echocardio- the potential utility of DL in tracking progression of
NO
gram, 6MWD and BNP, did not decline significantly disease in PAH.
over time of the study. At baseline, DL and D did As in prior work, DL was reduced in PAH patients.
NO m
not correlate with clinical markers [Table 4]. BNP was Although PAH patients and controls were not well
associated with V and D / V (V: Spearman R=0.5, matched by age and gender, the decrease in DL is not
c m c c
p=0.02; D / V: Spearman R=−0.5, p=0.03) (Figure 2) likely explained by age and gender alone. Earlier stud-
m c
at visit 1 but not at visit 2 or 3 (p>0.1). In addition, ies measured DL at two different oxygen concentra-
CO
V was inversely related to RV function (RVAD: tions and calculated D and V except for the study
c m c
Spearman R=0.4, p=0.05, RVAS: Spearman R=0.4, by Borland et al. where the single breath test measur-
p=0.04) suggesting that V increases with worsening ing both CO and NO uptake was used. All discovered
c
PAH/RV function. V and RV fractional area change a decrease in DL, but earlier studies showed predom-
c
did not correlate significantly (Spearman R=−0.4, inant loss of V while more recent ones showed that
c
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Table4Correlationsamongclinicalmarkersandlungdiffusioncapacityanditscomponentsatbaseline
Variables DL (ml/min/mmHg) DL (ml/min/mmHg) D (ml/min/mmHg) V (ml)
CO NO m c
BNP(pg/ml) R=0.3 R=−0.01 R=−0.01 R=0.5
P=0.2 P=0.9 P=0.9 p=0.02
6-MWD(m) R=0.5 R=0.4 R=0.4 R=0.3
p=0.05 p=0.1 p=0.1 P=0.2
Leftventricularfractionalshortening(%) R=−0.3 R=−0.3 R=−0.3 R=−0.3
p=0.1 p=0.2 p=0.2 p=0.3
Leftventricularejectionfraction(%) R=−0.1 R=−0.1 R=−0.1 R=−0.2
p=0.6 p=0.6 p=0.6 p=0.4
Rightventricularsystolicpressure(mmHg) R=0.09 R=−0.1 R=−0.1 R=0.3
p=0.7 p=0.6 p=0.6 p=0.2
Rightventricularenddiastolicarea(cm2) R=0.2 R=0.07 R=0.07 R=0.4
p=0.3 p=0.7 p=0.7 p=0.04
Rightventricularendsystolicarea(cm2) R=0.2 R=0.07 R=0.07 R=0.4
p=0.4 p=0.8 p=0.8 p=0.04
Rightventricularfractionalareachange(%) R=−0.2 R=−0.2 R=−0.2 R=−0.3
p=0.3 p=0.4 p=0.4 p=0.09
RVfractionalshortening(%) R=−0.2 R=−0.2 R=−0.2 R=−0.3
p=0.4 p=0.4 p=0.4 p=0.1
Rightventricularoutflowtractvelocitytimeinterval(cm) R=−0.3 R=−0.2 R=−0.2 R=−0.1
p=0.2 p=0.4 p=0.4 p=0.6
Meanpulmonaryarterialpressure(mmHg) R=0.2 R=0.06 R=0.06 R=0.4
p=0.3 p=0.8 p=0.8 p=0.05
Meanpulmonarycapillarywedgepressure(mmHg) R=0.2 R=−0.05 R=−0.05 R=0.2
p=0.5 p=0.8 p=0.8 p=0.4
Cardiacoutput(L/min) R=−0.3 R=−0.4 R=−0.4 R=−0.2
p=0.3 p=0.1 p=0.1 p=0.5
Pulmonaryvascularresistance(woodunits) R=0.2 R=0.2 R=0.2 R=0.3
p=0.4 p=0.4 p=0.4 p=0.1
6-MWD:6minutewalkdistance.
BNP:brainnatriureticpeptide.
DL:lungdiffusionforcarbonmonoxide(DL )andfornitricoxide(DL ).
CO NO
D :alveolar-capillarymembranediffusingcapacity.
m
V:lungcapillarybloodvolume.
c
D is reduced out of proportion to V. The difference cardiac output and local thrombosis of the vascular bed.
m c
between earlier studies and more recent ones could be Mechanisms underlying the reduced D may include an
m
attributed to differences in techniques or use of pul- increase in the alveolar-capillary membrane thickness
monary vasodilators leading to higher measured V. In caused by fibrotic or proliferative process, and/or inter-
c
this study, the single breath technique measuring stitial edema. Of note, none of the patients recruited for
DL and DL was used to assess D and V. D the study had interstitial lung disease. The decreased DL
NO CO m c m
was reduced proportionally to V in patients with PAH, in association with decreased D and V has been
c m c
and thus D /V was not different from controls. This described in chronic heart failure patients in stable clin-
m c
confirms the interdependence of D and V in pulmon- icalcondition[18].Thereisgrowingevidencethatasdis-
m c
ary vascular diseases and any change in the vascular bed easeprogresses;theleftventricularfunctionmaybecome
that reducesV would lead to a reduction in D through independently compromised in PAH [19,20]. This may
c m
areductioninthesurfaceareaavailabletogasexchange. contributetothereducedDL,D andV.
m c
In PAH, the reduction in V is likely multifactorial: Over time, the increase in V in association with a de-
c c
increased pulmonary vascular resistance, decreased crease in D could be explained by the effect of
m
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Figure2Associationofbrainnatriureticpeptide(BNP)tolungcapillarybloodvolume(V)andtotheratioofmembranediffusing
c
capacity(D )andV.D /V isinverselyrelatedtodiseaseseveritymeasuredbyBNPwhereasV correlatesdirectlytoBNP.Thepointsrepresent
m c m c c
measurementsobtainedattimeoffirstvisit.
vasodilator therapy on the diseased pulmonary vascula- asthma and PAH in experimental models [30,31].
ture. D would not be expected to increase proportion- Thus, although PAH is defined as a pure vascular dis-
m
ally to V with vasodilation alone as the thickened ease, impaired airflow occurs in patients on PAH ther-
c
alveolar-capillarymembraneisnot affected and the fibro- apies, suggesting a potential role for airway-directed
proliferative process is not responsive topulmonaryvaso- therapies in the care of these patients.
dilators.Anotherexplanationcouldbeworseningleftside There are several limitations to the study. Patients were
function with increase pulmonary capillary pressure and recruited from our PH clinic and the research testing was
congestionassociatedwithinterstitialedema.Infact,simi- doneonthedayoftheirscheduledclinicalvisits.Theirpri-
lar findings are noted in heart failure, in which acute de- mary physician scheduled follow up visits and adjusted
compensation and increased wedge pressurecausea drop PAH therapy. We had no control on the time interval
inD paralleledbyanincrease inV [21].WorseningRV between visits or on treatment. As such though most
m c
functioninPAHcanleadtoLVdysfunctionthroughven- patients were stable on their PAH therapies, the effect of
tricular interdependence. Our findings showed that V medications on the findings can not be excluded. Another
c
increased with worsening RV function but there was no limitation is the difference in age between the PAH and
relation between V and LV function. In view of the lim- control groups.However,thenovelfindinghereisthelon-
c
itations of echocardiography and the absence of re- gitudinal changes in the PAH group. The drop in D over
m
peat right heart catheterization, the contribution of time hasnotbeendescribed previously. Another limitation
LV dysfunction to the increase of V noted over time is the lack of concurrent hemodynamic data at the time of
c
remains undetermined. Overall, the lack of perceptible theDLmeasurements.FuturestudiesevaluatingD andV
m c
changes in standard clinical markers highlights the in relation to hemodynamic data are essential to better
limitations of available tests, and suggests the possi- understandthesignificanceofthechangesnotedhere.
bility that lung diffusing capacity as measured by NO,
i.e. the lung D , may be a potential marker for dis- Conclusion
m
ease progression in PAH. A limitation of the study is Insummary,areductioninbothD andV wasnotedin
m c
the small number of patients followed longitudinally PAHpatientsinassociationwithhighlyefficientalveolar-
and studies with a large cohort of PAH patients over capillary units. However, over time, there was a drop in
time in correlation with clinical parameters and out- D /V. Although the present study does not fully unveil
m c
comes are needed to confirm our findings. the clinical importance of the decline in D /V, it opens
m c
Evidence of airway obstruction in PAH is suggested thefieldtofurtherinvestigatethesinglebreath measure-
in this study based on the decreased %FEV and mentofDL /DL anditscomponentsinPAH.
1 NO CO
FEV /FVC. This is in keeping with published data that
1
Abbreviations
identifies peripheral airway obstruction in PAH by lung
BNP:Brainnatriureticpeptide;CO:Carbonmonoxide;DL:Lungdiffusionfor
functions and pathologic findings [22-26]. Inflamma- carbonmonoxide;DL :Lungdiffusionforcarbonmonoxide;DL :Lung
CO NO
tion typically surrounds plexiform lesions in PAH [27] diffusionfornitricoxide;Dm:Alveolar-capillarymembranediffusingcapacity;
F/M:Female/male;FE :Fractionalexhalednitricoxide;FEV:Forced
and abundant mast cells have been noted in PAH NO 1
expiratoryvolumeinonesecond;FVC:Forcedvitalcapacity;
lungs [28]. Lung biopsies show small airways narrow- Hgb:Hemoglobin;IVS:InterventricularSeptalthickness;LVEDD:Left
ing with thickened walls infiltrated by lymphocytes, Ventricularenddiastolicdiameter;LVESD:LeftVentricularendsystolic
diameter;NO:Nitricoxide;O:Oxygen;PAH:Pulmonaryarterialhypertension;
plasma cells and polymorphonuclear leukocytes [29]. 2
PH:Pulmonaryhypertension;PVR:Pulmonaryvascularresistance;
Moreover, studies reveal shared mechanistic features of PW:Posteriorwallthickness;RV:Rightventricle;RVAD:Rightventricularend-
Farhaetal.RespiratoryResearch2013,14:6 Page8of8
http://respiratory-research.com/content/14/1/6
diastolicarea;RVAS:Rightventricularend-systolicarea;RVOT-TVI:Right 11. MillerMR,HankinsonJ,BrusascoV,BurgosF,CasaburiR,CoatesA,CrapoR,
ventricularoutflowtract-timevelocityintegral;RVSP:Rightventricularsystolic EnrightP,vanderGrintenCP,GustafssonP,etal:Standardisationof
pressure;TLC:Totallungcapacity;TRV:Tricuspidregurgitantvelocity; spirometry.EurRespirJ2005,26(2):319–338.
V :Alveolarvolume;V:Lungcapillarybloodvolume;6MWD:6-minutewalk 12. WangerJ,ClausenJL,CoatesA,PedersenOF,BrusascoV,BurgosF,Casaburi
A c
distance. R,CrapoR,EnrightP,vanderGrintenCP,etal:Standardisationofthe
measurementoflungvolumes.EurRespirJ2005,26(3):511–522.
13. CotesJ:LungFunction.Oxford:BlackwellScientificPublications;1993.
Competinginterests
14. MeyerM,SchusterKD,SchulzH,MohrM,PiiperJ:Pulmonarydiffusing
Theauthorsdeclarethattheyhavenocompetinginterests.
capacitiesfornitricoxideandcarbonmonoxidedeterminedby
rebreathingindogs.JApplPhysiol1990,68(6):2344–2357.
Authors’contributions
15. RudskiLG,LaiWW,AfilaloJ,HuaL,HandschumacherMD,ChandrasekaranK,
SFconductedthestudy,performedresearch,analyzedandinterpreteddata
SolomonSD,LouieEK,SchillerNB:Guidelinesfortheechocardiographic
andwrotethemanuscript,DLperformedresearch,DGconductedthestudy
assessmentoftherightheartinadults:areportfromtheAmerican
andrecruitedsubjects,MMPconductedresearchandrecruitedsubjects,
SocietyofEchocardiographyendorsedbytheEuropeanAssociationof
WHWTanalyzeddataandreviewedmanuscript,RADreviewedmanuscript,
Echocardiography,aregisteredbranchoftheEuropeanSocietyof
SCEdesignedresearch,analyzeddataandwrotethemanuscript.Allauthors
Cardiology,andtheCanadianSocietyofEchocardiography.JAmSoc
participatedinthestudyandhaveseenandapprovedthefinalversion. Echocardiogr2010,23(7):685–713.quiz786–688.
16. OzkanM,DweikRA,LaskowskiD,ArroligaAC,ErzurumSC:Highlevelsof
Acknowledgements nitricoxideinindividualswithpulmonaryhypertensionreceiving
DeepgratitudeandappreciationtoWernerSteinhaeusserforallhissupport. epoprostenoltherapy.Lung2001,179(4):233–243.
WethankIkariaforprovisionofgasesforDLNOmeasures.Wealsothank 17. MachadoRF,LondheNerkarMV,DweikRA,HammelJ,JanochaA,PyleJ,
JacquelineSharpforstudycoordination. LaskowskiD,JenningsC,ArroligaAC,ErzurumSC:Nitricoxideand
pulmonaryarterialpressuresinpulmonaryhypertension.FreeRadicBiol
Med2004,37(7):1010–1017.
Grants
ThisworkwassupportedbygrantHL60917andtheClevelandClinic 18. AgostoniP,BussottiM,CattadoriG,MarguttiE,ContiniM,MuratoriM,
MarenziG,FiorentiniC:Gasdiffusionandalveolar-capillaryunitinchronic
ResearchProgramsCouncil.
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19. TonelliAR,PlanaJC,HeresiGA,DweikRA:Prevalenceandprognostic
Authordetails
1RespiratoryInstitute,ClevelandClinic,9500EuclidAvenue,Cleveland,OH valueofleftventriculardiastolicdysfunctioninidiopathicandheritable
44195,USA.2DepartmentofPathobiology,LernerResearchInstitute, pulmonaryarterialhypertension.Chest2012,141(6):1457–1465.
ClevelandClinic,9500EuclidAvenue,Cleveland,OH44195,USA.3Heartand 20. PuwanantS,ParkM,PopovicZB,TangWH,FarhaS,GeorgeD,SharpJ,
PuntawangkoonJ,LoydJE,ErzurumSC,etal:Ventriculargeometry,strain,
VascularInstitute,ClevelandClinic,9500EuclidAvenue,Cleveland,OH44195,
USA. androtationalmechanicsinpulmonaryhypertension.Circulation2010,
121(2):259–266.
21. AgostoniP,CattadoriG,BianchiM,WassermanK:Exercise-induced
Received:23October2012Accepted:17January2013
pulmonaryedemainheartfailure.Circulation2003,108(21):2666–2671.
Published:22January2013
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