u|monary nypertens|on

Llsa k Moores, Mu
AsslsLanL uean for Cllnlcal Sclences
rofessor of Medlclne
1he unlformed Servlces unlverslLy of Lhe PealLh
Sclences
Iacu|ty D|sc|osures
nCnL
Learn|ng Cb[ecnves
Aer Lhls sesslon, learners wlll be able Lo:
uescrlbe Lhe epldemlology and paLhophyslology of
pulmonary hyperLenslon (P)
8ecall Lhe sLeps ln Lhe dlagnosls of pulmonary arLerlal
hyperLenslon
LlsL Lhe recommended LreaLmenL reglmens for pulmonary
hyperLenslon
An
uenluon, classlcauon
aLhophyslology
ulagnosls
1reaLmenL opuons
Dehn|non
Syndrome resulung from resLrlcLed ow Lhrough Lhe
pulmonary arLerlal clrculauon resulung ln lncreased
pulmonary vascular reslsLance and ulumaLely rlghL
hearL fallure
Dehn|non
ulmonary arLerlal hyperLenslon (AP)
Pemodynamlc sLaLe dened by
SusLalned elevauon of pulmonary arLerlal pressure Lo > 23
mm Pg aL resL or 30 mm Pg wlLh exerclse
CW < 13 mm Pg
Many experLs would llke Lo see lncreased v8 a requlred
elemenL as well (v8 > 3 Wood unlLs)
Whlch ls shared by many condluons
C|ass|hcanon
lnlual auempLs dlvlded Lhe dlsease lnLo prlmary and
secondary
uld noL address dlagnosuc and LreaLmenL
heLerogenelLy of Lhe secondary group
C1u, Plv, llver dlsease can be assoclaLed wlLh
vascular dlsease LhaL mlmlcs P cllnlcally and
paLhologlcally
now classled as AP vs vP vs condluons LhaL alLer
resplraLory sLrucLure and fxn
Wor|d nea|th Crgan|zanon (WnC) Group I pu|monary arter|a| hypertens|on
c|ass|hcanon of kLVLAL panents at enro|ment.
8adesch D 8 et a|. Chest 2010,137:376-387
IAn
no rlsk facLor, famlly hlsLory or geneuc muLauon
Leadlng cause of AP (40 mosL serles)
More common ln women
Mean age 32
lamlllal AP and anorexlgen-lnduced share cllnlcal,
funcuonal, hemodynamlc and geneuc facLors wlLh
lAP
nL!M 2004,331:1660
Genenc Abnorma||nes
ApproxlmaLely 100 famllles worldwlde have been
ldenued as havlng lAP
1wo genes ln Lhe 1Cl-8 recepLor famlly have been
llnked Lo lAP.rsL ls 8M82, oLher ls ALk1
Llkely requlres muluple hlLs as noL all folks wlLh Lhe
geneuc markers develop AP..suscepuble person
requlres addluonal lnsulL



Genetic Predisposition PAH

Modifier Genes
Environmental Factors
Dietary supplements
HIV
Connective tissue disease
Viruses
Liver disease
Assoc|ated An
C1u: 13 ln reglsLrles, pauenLs wlLh sysLemlc
sclerosls have worsL prognosls
Plv: 6, lncldence decllnlng ln era of A81, lndlrecL
acuon of lnfecuon
ShlsLosomlasls, may be mosL prevalenL form of AP
worldwlde
Slckle cell dlsease, 20 wlll have mlld-moderaLe
lncreased A, lncreased rlsk of deaLh
athophys|o|ogy
Maln vascular changes
vasoconsLrlcuon
SmooLh muscle cell and endoLhellal cell prollferauon
1hrombosls

ulmonary endoLhellal cell ln[ury leadlng Lo an lmbalance ln
vasodllaLors/consLrlcLors
CrowLh lnhlblLors/mlLogens
AnuLhrombouc/pro Lhrombouc facLors
uesnon 1
1he cellular mechanlsms lnvolved ln Lhe
developmenL of AP lnclude:
1. lncreased prosLacyclln synLhase
2. lncreased nlLrlc oxlde synLhase
3. lncreased endoLhelln levels
Mechan|sms
8educed prosLacyclln avallablllLy caused by
dlmlnlshed prosLacyclln synLhase
LlevaLed endoLhelln levels resulung from enhanced
producuon and reduced clearance
uecreased nlLrlc oxlde synLhase expresslon
AcuvlLy of auLoanubodles and prolnammaLory
cyLoklngs
lmbalance of prollferauon and apopLosls (favorlng
former)
roLhrombouc sLaLe
PumberL M eL al. n Lngl ! Med 2004,331:1423-1436
AP ls a anvasculopaLhy"
lncreased pulmonary arLerlal Lhlckness
ullaLed caplllarles
lexlform leslons whlch obsLrucL Lhe vessel lumen
AL rlsk for ln slLu Lhrombosls secondary Lo plaLeleL
aggregauon
AlLhough classlcally consldered a dlsease a vasoconsLrlcuon, should now be
consldered a dlsease of prollferauon and lnammauon.
An angloprollferauve/neoplasuc dlsorder
Lva|uanon of An
ls Lhe pauenL aL rlsk for AP?
ls AP llkely presenL?
LsLabllsh cause of dyspnea
Can Lhe underlylng euology be clarled?
Lxclude LreaLable causes of AP
Pow severe ls lL and whaL ls Lhe funcuonal
llmlLauon?
use Lhls lnformauon Lo gulde LreaLmenL
anents at k|sk
lamlly hlsLory of AP/ known 8M82 muLauon
use of anorexlgens, ampheLamlnes, llllclL drugs
AssoclaLed condluons
C1u (esp C8LS1 30)
Plv (.3)
CPl
Llver dlsease (1-6)
CCu, lLu (40 lf lLv1 < 1L)
CSA (9, noL relaLed Lo APl)
v1L
Suspect An
Consldered ln any pauenL wlLh perslsLenL,
unexplalned dyspnea, or dyspnea ouL of proporuon
Lo exlsung dlsease
More llkely ln Lhose aL rlsk
SympLoms
Lxerclse lnLolerance, faugue, C, palplLauons, n cough,
syncope
Slgns (oen subLle)
1achycardla, promlnenL 2, 18..8Pl, !vu, hepaLomegaly,
edema, asclLes
wave >2.S mm ta|| |n II, III, aVI

C|ass|c hnd|ngs of concentr|c kVn are prom|nent k wave |n V1, pers|stence of S waves |n
the |atera| precord|a| |eads, r|ght ax|s dev|anon (kAD).


An L|ke|y
CbLaln echocardlogram
8esL screenlng LesL wlLh adequaLe sensluvlLy
LsumaLe AS
8v slze, Lhlckness, funcuon
LvaluaLe for le hearL dlsease, valvular dlsease
8ubble sLudy Lo r/o CPu
SpeclclLy moderaLe, A overesumaLed ln pauenLs wlLh advanced
lung dlsease
MeLa-analysls reveals correlauon coemclenL of 0.70 beLween echo
and rlghL hearL caLh, overall sensluvlLy 83, speclclLy 72
Weaker ln pauenLs wlLh severe AP, dlmculL ln pauenLs wlLh
CCu, underesumaLes lf 18 [eL ls poor quallLy
Surlnder ! eL al. PearL 2011, 97:612-22
uesnon 2
All pauenLs wlLh evldence of AP by echocardlogram
should undergo
1. CvernlghL polysomnography
2. venulauon-perfuslon scannlng
3. AnA, 8l, and Plv Lesung
C|ar|fy Lno|ogy
PlsLory of LuS, snorlng or apneas?
nSC
ArLhralglas, arLhrlus, myalglas, skln leslons
Serologlc w/u for C1u
8lsk of/ exposure Lo Plv?
Screen for C1Ln
Many pauenLs wlll noL have hlsLory of v1L
v/C scan recommended
Conhrm D|agnos|s
8lghL hearL caLheLerlzauon
Conrm AP
Addluonal screen for LPu
Addluonal assessmenL for C1LP
AssessmenL of severlLy (prognosls)
Culde LreaLmenL
AcuLe vasodllaLor challenge
lnC (20-40 ppm for 3 mlnuLes), lv epoprosLenol, lv
adenoslne
lall ln mean A pressure >10 mmPg Lo mean <40
mmPg wlLh lncreased or unchanged CC
Card|ac Magnenc kesonance Imag|ng
(CMk)
Plgh accuracy and low lnLerobserver varlablllLy
Assess 8v mass, volumes and funcuon
8auo of sepLal curvaLure
8v e[ecuon fracuon
8v volume
Cardlac lndex
ACCl/APA LxperL Consensus uocumenL. Clrculauon 2009,119:2230-2294
Iuncnona| Assessment
WPC funcuonal classlcauon
CLx
vC2 max correlaLes wlLh morLallLy (<10.4 ml/kg)
Lxpenslve, noL unlversally avallable
6MW1
8ellable, valldaLed
CorrelaLes wlLh survlval
Common endpolnL ln Lherapeuuc Lrlals
WnC Iuncnona| C|ass
Class l: pauenLs wlLh AP wlLh no llmlLauon of usual
acuvlLy
Class ll: pauenLs wlLh AP who have mlld llmlLauon
of acuvlLy, no dlscomforL aL resL
Class lll: pauenLs wlLh AP who have marked
llmlLauon of acuvlLy buL no resL sympLoms
Class lv: pauenLs wlLh AP who have resL sympLoms
and/or slgns of 8v fallure
8|omarkers
n-Lermlnal ro-8n
PyponaLremla
neurohormonally released vasopresslon
SLrongly assoclaLed wlLh advanced 8Pl and poor survlval
CrowLh-dlerenuauon facLor (Cul)-13, a sLress-
responslve cyLoklne, shows promlse
uesnon 3
A 32 year-old female was dlagnosed wlLh AP 2
years ago, buL refused speclc Lherapy aL LhaL ume.
She now reLurns complalnlng of severe SC8 wlLh
acuvlues of dally llvlng. She has also noLed new
abdomlnal swelllng and bllaLeral perlpheral edema.
uesnon 3
ln addluon Lo general supporuve Lherapy (oxygen,
dlureucs), speclc Lherapy for Lhls pauenL should be:
1. Cral slldenal
2. Cral bosenLan
3. lv eposprosLenol

1reatment
revenuon
Screenlng of hlgh-rlsk pauenLs
Cpumlze Lherapy for relaLed dlseases
Supporuve (almed aL consequences of AP)
vascular LargeLed Lherapy (reduce or reverse
vasoconsLrlcuon, prollferauon)
Surglcal (aLrlal sepLosLomy, LransplanLauon)
Suppornve treatment
Vascu|ar targeted therapy
1reatment: Spec|hc
Ca|c|um Channe| 8|ockers
nLvL8 glven emplrlcally
8eserved for responders"
auenLs wlLh a phenoLype of lncreased vascular Lone as
opposed Lo remodellng
near normallzauon (A <40) and normal CC
Plgh dose nlfedlplne or dlluazem
Cnly half of acuLe responders wlll geL long Lerm beneL
8esponse monlLored and LreaLmenL escalaLed lf
deLerlorauon
rostacyc||ns
roduced by endoLhellum, vasodllaLory, anuplaLeleL,
anuprollferauve eecLs
rosLacycllne synLhase reduced ln pauenLs wlLh AP
lv epoprosLenol, SC and lv and lnhaled LeprosLenol,
lnhaled lloprosL
lmprove exerclse/funcuonal capaclLy,
hemodynamlcs, survlval (epoprosLenol)
Lpoprosteno|
Cochrane revlew of 7 8C1's of lv 8x conrm
lmprovemenL ln exerclse capaclLy, funcuonal class,
hemodynamlcs, and survlval
SafeLy
ShorL half-llfe requlres conunuous lnfuslon, Lhus
lndwelllng caLheLer
ALs of [aw paln, dlarrhea, ushlng, headaches nausea,
vomlung, anorexla common
Cardlol Cllnlcs 2004, 22:441-32.
Lndothe||n keceptor Antagon|sts
L1-1 produced by endoLhellal cells (poLenL
vasoconsrlcLor and mlLogen)
8osenLan oral non-selecuve
AmbrlsenLan selecuve L8 A" anLagonlsL
lmprove exerclse/funcuonal sLaLus, ume Lo cllnlcal
worsenlng
8osenLen also shown Lo lmprove hemodynamlcs,
lmproved survlval compared wlLh hlsLorlcal conLrols
Women and whlLes respond beuer
LkA's
Cochrane revlew: lmproved exerclse capaclLy, 8org
dyspnea scores, hemodynamlcs (lssue 2, 2003)
luLure quesuons
8ole ln early AP
8ole ln comblnauon Lx
value of selecuve vs non-selecuve
8ole ln Lreaung C1LP and oLher brouc lung dlsease
hosphod|esterase Inh|b|tors
Plgh concenLrauons of cycllc nucleoude
phosphodlesLerase -3 (uL-3) ln Lhe lung
uL-3 degrades cycllc CM
Slldenal lnhlblLs uL-3
lmproved exerclse capaclLy, funcuonal sLaLus, and
hemodynamlcs
1adalal also approved, advanLage of once-dally
doslng
Comb|nanon 1herapy
Maxlmlze emcacy whlle mlnlmlzlng LoxlclLy
8 Lrlals (lnvolvlng over 1600 pauenLs) now publlshed
varlous comblnauons
Cenerally 12-16 weeks
6MWu prlmary endpolnL ln mosL
Conlcung resulLs, only modesL lmprovemenLs ln
exerclse capaclLy ln posluve Lrlals
MeLa-analysls of 8C1s shows lmprovemenL ln 6MWu buL
noL funcuonal class, cllnlcal worsenlng, or deaLh
Comb|nanon 1herapy
now recommended for:
Class lll and lv pauenLs who fall Lo lmprove
Class ll pauenLs wlLh cllnlcal deLerlorauon
1wo drug comblnauons lnlually, Lhree can be
consldered
unknown whlch comblnauon mosL emcaclous
unknown lf upfronL comblnauon or sequenual
Lherapy ls more beneclal
C'Callaghan uS eL al. 8esp Med 2010 (epub ahead of prlnL)
Current 1herapeunc Approaches
8LvLAL 8eglsLry (2438 pauenLs)
ApproxlmaLely 30 of pauenLs recelvlng L8A or
uL-3 lnhlblLor
Comblnauon Lherapy common across all funcuonal
classes, up Lo 13 on more Lhan Lwo drugs
rosLacyclln use ln 30 Class l/ll, 43 Class lll, 38
Class lv
8adesch u 8 eL al. ChesL 2010,137:376-387
Cutcome w|th 1argeted 1herapy
MeLa-analysls of 21 8C1s (<3000 pauenLs)
lmproved 6MW1 dlsLance by 43
uecreased morLallLy ln pauenLs on vascular-LargeLed
Lherapy
Calle n. Lur PearL ! 2009, 30:394-403
CopyrlghL resLrlcuons may apply.
Ga||e, N. et a|. Lur neart I 2009 30:394-403
Cverall 88 0.37 (0.33-0.93)
Iuture Agents
Long-acung oral prosLacyclln analogs (oral Lreposunll
undergolng Lrlals)
rosLacyclln recepLor agonlsLs (selexlpag)
vasoacuve lnLesunal epude (vl)
oLenL vasodllaLor, lnhlblLs plaLeleL acuvauon and prollferauon
of vascular smooLh-muscle cells
SS8l's
SeroLonln appears Lo play a role ln paLhogenesls of AP, noL yeL
LesLed
SlmvasLaun
uCl paLhway: lmaunlb
Surg|ca| Cpnons
ALrlal sepLosLomy
8educed 8vLu, lncreased Cl, lncreased exerclse capaclLy,
aL expense of decreased aC2
Cpuon ln pauenLs unresponslve Lo max 8x
8rldge Lo LransplanLauon
Lung LransplanLauon
1yplcally 8L1, PearL-lung for pauenLs wlLh AP relaLed Lo
CPu
ulmonary LhromboendarLerecLomy for pauenLs
wlLh C1LP
8adesch, D. 8. et a|. Chest 2007,131:1917-1928
ACC and ACCl/APA
1reatment Sequence
WPC Class l and ll
no speclc Lherapy
Who Class lll
Cral Lherapy
WPC Class lv and Lhose who progress on oral Lx
lv rosLacyclln
8ole of comblnauon Lx uncerLaln
ACCl/APA LxperL Consensus uocumenL. Clrculauon 2009, 119:2230-2294
rognos|s
oor: 13 1-year morLallLy on modern Lherapy PumberL M eL al.
Clrculauon 2010, 122:136-163
Markers of poor prognosls
Advanced funcuonal class
oor performance on 6MW1
Plgh 8A pressure
SlgnlcanL 8v dysfuncuon
8v fallure
Low Cl (pauenLs wlLh normallzauon of Cl wlLh Lherapy have
beuer prognosls. Mlura ? eL al. Clrculauon 2010, 74:1963-71
LlevaLed 8n
orLal P1n or C1u assoclaLed AP
rognos|s
8LvLAL 8eglsLry
~3000 pauenLs wlLh WPC Croup l AP ln 34 cenLers
uaLa collecLed prospecuvely analyzed for prognosuc
facLors
Conrmed prlor facLors, ldenued new facLors
lamlly hlsLory of AP, men >60
ldenued proLecuve facLors
nP?A Class l, 6MWu >440 m, 8n <30 pg/mL, predlcLed
uLCC >80
8enza 8L eL al. Clrculauon 2010, 122:164-172
kLVLAL kISk CALCULA1Ck
Chest. 2012;142(2):448-456

Summary of key o|nts
AP complex dlsease characLerlzed by vascular
remodellng, prollferauon, & lnammauon
vasoconsLrlcuon may play less of a role Lhan
prevlously LhoughL
ulagnosuc evaluauon warranLed ln unexplalned
dyspnea and condluons known Lo be assoclaLed
vascular LargeLed Lheraples now avallable and
appear Lo be lmprovlng quallLy of llfe and morLallLy
luLure research may allow more lndlvlduallzauon of
Lherapy