Pulmonary Hypertension in 2017 - Ohio-ACCPulmonary arterial hypertension (PAH) is a syndrome...

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"