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PulmonaryHypertensionin2017
CatherineFallick,MD,FACCDirector,PulmonaryHypertension
MetroHealthMedicalCenterAssistantProfessor,CWRU
NodisclosuresNooff-labelusesofmedicaCons
Introduc8on
• 1.DefiniConandpathophysiologyofpulmonaryarterialhypertension
• 2.PrevalenceandprognosisofPAH
• 3.Diagnosisofpulmonaryarterialhypertension
• 4.Nonpharmacologictreatmentofpulmonaryarterialhypertension
• 1.DefiniConandpathophysiologyofpulmonaryarterialhypertension
• 2.PrevalenceandprognosisofPAH
• .Diagnosisofpulmonaryarterialhypertension
• 3.Nonpharmacologictreatmentofpulmonaryarterialhypertension
Pulmonary arterial hypertension (PAH) is a syndrome
resulting from restricted flow through the pulmonary arterial
circulation resulting in increased pulmonary vascular
resistance and ultimately in right heart failure and death. Multiple
pathogenic pathways have been implicated in the development
of PAH. The imbalance in the vasoconstrictor/vasodilator
milieu has served as the basis for current medical therapies,
although increasingly it is recognized that PAH also involves
an imbalance of proliferation and apoptosis (favoring
the former).
Defini8onofPAH
Panvasculopathy (endothelium dysfunction, medial hypertrophy and adventitial proliferation)""Predominant effect on resistance arteries""Thrombosis in situ""Inflammation""Plexiform lesions""
JACC Vol. 53, No. 17, 2009 April 28, 2009:1573–619"Expert Consensus Document on Pulmonary Hypertension"
Evolu8onofPAH:Mul8plesuspects!
• Atsmoothmusclecelllevel:– RiseinintracellularcalciumduetomulCplemechanisms(such
asinac*va*onofKvchannelsand/orOverexpressionofCa++channels),resulCngin:
• ContracCon/vasoconstricCon• ProliferaCon
– DysfuncConofBoneMorphogenicProteinreceptor(suchasinBMPRmuta*ons)resulCngin:
• IncreasedproliferaCon• Reducedapoptosis
• AtEndothelialcelllevel:– ReducedNitricoxideandprostacyclinproducConresulCngin
• SustainedvasoconstricCon• IncreasedinflammaCon
– DysfuncConinBMPreceptor(suchasinBMPRmuta*ons)resulCngin
• IncreasedAngiopoieCnproducConandincreasedproliferaConandangiogenesis.
– Over-expressionofEndothelinreceptors(notinthefigure)resulCngin
• VasoconstricCon• IncreasedinflammaCon
Yuan JX et al. Circulation 2005"
Introduc8on
• 1.DefiniConandpathophysiologyofpulmonaryarterialhypertension
• 2.PrevalenceandprognosisofPAH
• .Diagnosisofpulmonaryarterialhypertension
• 3.Nonpharmacologictreatmentofpulmonaryarterialhypertension
EpidemiologyofPH:
• Prevalence:– iPAHandheritablePHarerare:5-15permillion– PAH-HIV:lessthan1%ofHIVpaCents)– PAH-ACHD:increasinglyseenaspopulaConwithACHDisrapidlyincreasing.– PAH-CTD:5-12%ofpaCentswithSystemicSclerosis(SSc)andCRESTsyndrome.RareinotherCTD(SLE,mixed
CTD,RA,dermatomyosiCs,andSjo¨gren’ssyndrome)– PoPAH:1-5%ofpaCentswithportalhypertension(withorwithoutcirrhosis)– PVOD:Extremelyrare.Obenassociatedwithpulmonaryhemangiomatosis– WHOgroup2PH:ItisesCmatedtoinvolve70-90%ofpaCentslebHF– WHOgroup3,4,and5:Prevalenceunknown.
• MostcommoninUS:PH-LHD• Mostcommonworldwide:schistosomiasis-associatedPHandhighalCtudePH
Nazzarino Galie et al. European Heart Journal 2015"Redfield MM et al. JACC 2009"
Familial PAH
– 6-10%ofIPAHpaCents– MutaConsinBMPR-2,ALK-1geneswhichbelongtotheTGFβsuperfamilyofgrowthfactors
– Two-thirdsofFPAHpaCentshaveBMPR-2mutaCon– ALK-1mutaConassociatedwithHHT(Osler-Weber-Rendudisease)
– PresenceofBMPR-2mutaConconfersa10-20%riskofdevelopingPAH
Prevalence of PAH Associated with SSc
0
5
10
15
20
25
30
Prevalence
New PHTotal PH
• “UNCOVER” study • Point prevalence of PAH in
50 • community clinics • Pts with SSc or MCTD
without • known PAH screened with • ECHO, PFT • 89/669 (13.3%) had RVSP
>40 • mm Hg. • Total prevalence was 89
(new) • + 122 (known) = 211/791 • (26.7%) “New” PAH found in 13% of patients with SSc, MCTD
SurvivalinSclerodermaPa8entsWithPAH,LungInvolvement,orNoMajorOrganInvolvement
Koh ET et al. Br J Rheumatol. 1996;35:989-993.
Survival %
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 Years from diagnosis of PH
PAH
Lung involvement (without PAH)
None
Copyright Case/UHHS CME 2005 All Rights Reserved
PAH-CongenitalHeartDisease
• Left to Right Shunts • ASD • VSD • PDA • Surgical Shunts
Complex Lesions • DORV • Truncus Arteriosus
• TGV/VSD
Survival in Eisenmenger’s Syndrome
20
1 – –
0.8 – –
0.6 – –
0.4 – –
0.2 – –
0 –
Survival
Age (years)
Vongpatanasin et al. Ann Intern Med. 1998; 128: 745-755.
30 40 50 60 70
Patients (n) 78 40 13 4
n = 109
Mean age of death 45 yrs
20 % die during a medical procedure or ill advised activity
Classifica8onofPHbasedone8ology:
Nazzarino Galie et al. European Heart Journal 2015"
Familial PAH
– 6-10%ofIPAHpaCents– MutaConsinBMPR-2,ALK-1geneswhichbelongtotheTGFβsuperfamilyofgrowthfactors
– Two-thirdsofFPAHpaCentshaveBMPR-2mutaCon– ALK-1mutaConassociatedwithHHT(Osler-Weber-Rendudisease)
– PresenceofBMPR-2mutaConconfersa10-20%riskofdevelopingPAH
Introduc8on
• 1.DefiniConandpathophysiologyofpulmonaryarterialhypertension
• 2.PrevalenceandprognosisofPAH
• 3.Diagnosisofpulmonaryarterialhypertension
• 4.Nonpharmacologictreatmentofpulmonaryarterialhypertension
DiagnosCctestsforevaluaCngpaCentswithpulmonaryhypertension
• Toestablishdiagnosis:– Echocardiogram– RightheartcatheterizaCon
• Todetermineprognosisandresponsetotherapy– 6MWD– CardiopulmonaryexercisetesCng– LaboratorytesCng:BNP,NT-Pro-BNP,Troponin– CardiacMRI:AssessRVfuncCon
• TodetermineeCology– VenClaCon/perfusionscan/CTA/pulmonaryangiogram– PulmonaryfuncContesCng– HighresoluConCTscan– Bronchoscopy/Lungbiopsy– HepaCcultrasound– MRI:ACHD,ruleoutCTEPHinpregnancy,evaluateRV– LaboratorytesCng:HIVserology,Auto-immunetesCng,hepaCCsserology,thrombophiliaworkup– GeneCctesCng
Clinical Signs of PH:
• Presence of PH – Loud P2 – RV lift – Systolic murmur (TR) – Diastolic murmur (PR) – RV S4
• Presence of RV failure – JVD, V wave – RV S3 – Hepatomegaly – Edema – Ascites
PH: Diagnostic Approach
Symptoms / Physical Exam Screening Procedures PH Suspicion
Incidental Findings ECG
PH Detection Chest Radiograph
Echocardiogram
Pulmonary Function, oxygenation
PH Characterization
Exercise Capacity Hemodynamics
Adapted from: ESC Guidelines. Eur Heart J 2004; 25:2243
6 Min Walk Test, peak VO2 Right Heart Cath + Vasoreactivity
Ventilation Perfusion Scan CT angio and HRCT Pulmonary angiogram Serology, LFT, HIV,
RVH
RV Strain
RAD
RAE
EKG in PH:
In IPAH, RAD seen in 79%, and RVH in 87%. EKG as a screening tool for IPAH: sensitivity 55%, specificity 70%.
RV"
RA"RA"
LA"
LV"
Pulmonary Arterial Hypertension: Diagnosis
• Establish presence and severity
• Echo • Cath • ? MRI or CT angio
• EstablisheCology• Blood Work to r/o CTD, HIV, • SSD, CLD • PFT/CT/X-ray to r/o lung • disease • VQ/ CT/PA angiogram to r/o • CTEPH • Sleep study • TTE/TEE/Cath/MRI to r/o • heart disease
3"
Hemodynamicdefini8onandclassifica8onofPH
Nazzarino Galie et al. European Heart Journal 2015"
whyisitimportanttodeterminecauseofpulmonaryhypertension?
• PaCentswithpulmonaryarteryhypertensionneedtreatment,andneeditbeforetherightventriclebeginstofail.
• PaCentswithnonGroup1diseasecanbetreatedthroughCtraConofmedicaConsforGroup2andpossiblyevaluaConforadvancedtherapies,evaluaConofpulmonarydiseaseforGroup3paCents,treatmentofpulmonaryemboli(medicalvssurgical)forGroup4paCents,andappropriateunusualdiagnosescanbemadeforGroup5paCents.
Hemodynamic Progression of PAH
Pre-symptomatic/ Compensated
Symptomatic/ Decompensating
Declining/ Decompensated
Symptom Threshold
Right Heart Failure
CO
RAP
TPG= PAP-PAW PVR=TPG/ CO
Predictorsofpoorprognosis
• 6minutewalk<300meters• Presenceofapericardialeffusion• RApressure>20mmhg• WHOclassIVsymptomsorsyncope• ElevatedBNP
RiskassessmentinPAH
Nazzarino Galie et al. European Heart Journal 2015"
PHCC,MetrohealthMedicalCenter
• Cardiologyrunwithpulmonarylead• DirectreferralfromPCPorthroughPulmonary,generalcardiology,orheartfailurecardiology
• Referralfromecholab• ReferralfrominpaCentconsults.
RightHeartCatheterizaConandVaso-reacCvitystudy
• RHCisrecommendedwhen:– Group1PAHissuspected– Group2,withLVfailureisbeingconsideredforHT– WhenPAHtherapyisbeingconsidered– ForfollowuptodetermineresponsetoPAHtherapy
• Vaso-reacCvitystudyisrecommendedwhen:– PAHissuspected(PCWP<15)
• LHCforLVEDPwhen:– PCWPcouldnotbeobtainedorconfirmed– PCWPreadingisnotconsistentwiththeclinicalpicture
• Shuntrunisrecommendedwhen:– SuspecCngL-Rshuntbyotherimagingorbyhistory– PAO2sat>75%
Nazzarino Galie et al. European Heart Journal 2015"
Months 0
0
20
Surv
ival
(%)
40
60
80
100
12 36 24 48 60
Response / Warfarin
No Response / Warfarin
Response / No Warfarin
No Response / No Warfarin
Survival in IPAH with CCB and Anticoagulation Therapy
Rich et al. NEJM 1992;327:76–81 Copyright Case/UHHS CME 2006 All Rights Reserved
64 pts"
Avg dilt dose 720 mg "Avg nifedipine dose 175 mgmg"
SurvivalCurveaSer12weeksEpoprostenol Therapy
Barst, NEJM 1996 Feb 1;334(5):296-302. "
Long-TermOutcomeinIPAHWithEpoprostenol
Sitbon O et al. J Am Coll Cardiol. 2002;40:780-788.
No. at risk 178 129 85 57 36 21 7 3 1 IV epo 135 59 34 20 11 4 2 2 1 Hist. control
1 C
umul
ativ
e su
rviv
al
Months
0.8
0.6
0.4
0.2
0
IV epoprostenol (n=178)
Historical control (n=135)
0 12 24 36 48 60 72 84 96 108 120
Months
McLaughlin VV et al. Circulation. 2002;106:1477-1482.
Expected
Observed (n=162)
*
*
*
20
40
60
80
100
% S
urvi
val
0 6 12 18 24 30 36
*p<0.001
p<0.0001
Copyright Case/UHHS CME 2006 All Rights Reserved
• 1.DefiniConandpathophysiologyofpulmonaryarterialhypertension
• 2.PrevalenceandprognosisofPAH
• 3.Diagnosisofpulmonaryarterialhypertension
• 4.Nonpharmacologictreatmentofpulmonaryarterialhypertension
Balloonatrialseptostomy
• RecommendedaspalliaCvetherapyorbridgetolungtransplantin:– FuncConalclassIVpaCentsfailingmedicaltherapy– RVfailuredespitemaximummedicaltherapy– Recurrentsyncopeduetoseverelylowcardiacoutput.
• Contraindicatedif:– RAP>20mmHg– ArterialO2saturaCon<85%
Nazzarino Galie et al. European Heart Journal 2015"
Otheradvancedop8onsinsevereRVfailure:
• Inotropicsupport(temporaryorhomeinfusion)• ECMOasabridgetolungtransplant• RVADisNOTanopConduetohighaberload• Lungtransplant
Treatmentofpulmonaryhypertension
• OpCmalmanagementoflebsidedheartfailure• OpCmalmanagementofsleepdisorderedbreathing(OSA)• EndarterectomyinselectedpaCentswithchronicpulmonaryemboli• Oxygentherapy
Thankyou!
Recommenda8onsforgeneralmeasures
Nazzarino Galie et al. European Heart Journal 2015"
Recommenda8onsforsuppor8vetherapy
Nazzarino Galie et al. European Heart Journal 2015"
PAH-specificdrugs:Mono-therapy
Nazzarino Galie et al. European Heart Journal 2015"
Combina8ontherapy
Nazzarino Galie et al. European Heart Journal 2015"
PAH-specificdrugs:SequenCaltherapy
Nazzarino Galie et al. European Heart Journal 2015"
ManagementofPAH-ACHD
• ExcludePHsecondarytoLVdysfuncConorassociatedlungdisease.• StartPAHmedicaConsearly• ClosureofL-Rshuntifindicated• Othermanagementaspects:
– Oxygen,hydraCon– AnCcoagulaConinabsenceofhemoptysis– AvoidCa++blockers– IVfilterstopreventparadoxicalemboli
Nazzarino Galie et al. European Heart Journal 2015"
PAHassociatedwithconnecCveCssuedisease(PAH-CTD)
• ScreeningasymptomaCcpaCentsisrecommendedinSScwithannualechocardiogram,DLCOandbiomarkers.
• Evaluateforgroup2(duetodiastolicdysfuncCon)andgroup3(duetoILD)
• StartPAHmedicaConsearly
Nazzarino Galie et al. European Heart Journal 2015"
PAHassociatedwithportalhypertension(PoPH)
• PaCentstendtohavehigherCIandlowerPVR• ScreeningforPoPAHisrecommendedpriortolisCngforlivertransplant.• Associatedwithhighmortalitypostlivertransplant:
– 100%formPAP>50– 50%formPAP35-50mmHg
• SupporCvemeasures:– AvoidanCcoagulaCon– Avoidbetablockers(obenusedforEvarices)– AvoidERAs,especiallyBosentan
Nazzarino Galie et al. European Heart Journal 2015"
PAHassociatedwithHIVinfecCon:
• ScreeningasymptomaCcpaCentsisnotrecommendedduetolowincidence.
• Ruleout– PoPAH– drug-inducedPAH– group2(duetoLHD)– group3(ILD)– group4(CTEPH)
• BeawareofinteracConbetweenERAandHIVmedicaCons
Nazzarino Galie et al. European Heart Journal 2015"
PVOD/PCH
• Veryrare• Suspectwhen:
– Chronicpulmonaryedemawithhypoxia,clubbing,DOE– HemodynamicsconsistentwithPAH,butwithhighPCWP– SeverereducConinDLCO– CharacterisCcfindingsonHRCT:
• Sub-pleuralthickenedseptallines• ground-glassopaciCes• mediasCnallymphadenopathy• occultalveolarhemorrhageonBronchoscopy• ExaggeratedriseinPCWPduringreversibilitystudy
• Goldstandardislungbiopsybutobennotnecessary• Therapy:
– DiureCcs,Oxygen– SlowintroducConofPAHmedicaCons(obennottolerated)– ExperimentaluseofangiogenesisinhibitorssuchasINFalpha2– Lungtransplant
Nazzarino Galie et al. European Heart Journal 2015"
PH-LHD(group2PH)
• TreatunderlyingLVdysfuncConorvalvulardisease• PDE-5inhibitorshavebeenusedinpaCentsawaiCngHTandresultedinreducConofPVR
• OngoingtrialsfortheuseofPDE-5andERAinthesepaCents.– Sildenafil:SilHF(NCT01616381)– Macitentan:Melody-1(NCT02070991)
PHduetolungdiseaseand/orhypoxia(Group3PH)
• MostcommonlyseeninCOPD,ILD,IPF.• RarelyseeninOSAwithoutlebheartdisease• Usuallymildtomoderate.Ifsevere,lookforothercauses• NocorrelaConbetweenseverityoflungdiseaseandseverityofPH• Mechanismisthoughttobehypoxia-inducedchronicvasoconstricCon• O2therapycanslowdownprogressionofdisease• PAHmedicaConsarenotrecommendedunlessmixedeCology(groups1,3)is
suspected(asinscleroderma• VasodilatorsandPAHmeds,ifused,mayworsenhypoxia
Nazzarino Galie et al. European Heart Journal 2015"
ChronicthromboembolicPH(CTPH)Group4PH
• MajorityarediagnosedinpaCentwithnopriorclinicalhistoryofPE• LifelonganCcoagulaCon• Alwaysassesscandidacyforpulmonaryendarterectomy• StartPAHmedicaConsearlyonevenabersurgeryifPHdoesnotresolve
Nazzarino Galie et al. European Heart Journal 2015"
PHduetounclearand/ormulCfactorialmechanismsGroup5PH
• Heterogeneousgroupwithpoorlyunderstoodmechanismsincluding:– pulmonaryvasoconstricCon– proliferaCvevasculopathy– extrinsiccompression(Histoplasmosis/fibrosingmediasCniCs,hydatedcysts)– intrinsicocclusion(PVstenosisaberPVI)– high-outputcardiacfailure(chronicanemiaespeciallyhemolyCcanemia,AV-shunts)
• TreatmentistargeCngtheunderlyingcauseNazzarino Galie et al. European Heart Journal 2015"
