The Basics of Pulmonary Hypertension Lana Melendres-Groves Assistant Professor of Medicine Director,...

The Basics of Pulmonary Hypertension

Lana Melendres-GrovesAssistant Professor of Medicine

Director, Adult Pulmonary Hypertension ProgramDivision Pulmonary & Critical Care Medicine

UNMHSC

Objectives

• Definition of PH/PAH and pathophysiology• WHO groups• Natural history of PAH• Clinical presentation/PE/studies• Timing and type of work-up• Who gets therapy• Monitoring of therapy

Case #1

• 27yo woman with PMHx significant for exercise induced asthma and anxiety presenting to the ED after “almost passing out”.

• She has a 10mnth old daughter and felt that maybe she just hadn’t gotten into shape after having the baby.

• SOB when she tries to jog or walk up her stairs.

Case #2

• 29yo man with HIV presenting to the ED with 2 month h/o of worsening SOB on exertion that has dramatically worsened over the past week to the point that he is now having SOB at rest and feeling dizzy when standing not on any medications.

• Recently moved from California and has no information in our system.

Case #3

• 42yo obese woman who doesn’t like doctors that presented after she had worsening fatigue and sob with minimal activity.

• She is a hairdresser and overall is upset that she is overweight so never steps on a scale.

• She doesn’t take any medications.• Has noticed swelling in her legs.• TTE shows severe RV enlargement and PASP of

95mmHg with rt to left shunt seen.

Case #4

• 65yo woman with little PMHx presenting with SOB and exhaustion. Has no medical problems that she knows of, just retired from teaching for the past 40years in California and relocated to Ruidoso, NM.

• Previously playing 18 holes of golf, now only able to walk 15ft before needing to stop and rest.

• Massive LEE and decreased mobility of her hands.

Case #5

• 83yo woman has been healthy her whole life now presenting with worsening fatigue with exertion.

• Previously able to swim for 30 minutes a day and walk for 30min, now sob with much less. Unable to keep up with her friend.

• Experiencing palpitations and chest pressure intermittently.

• TTE shows mild RA and RV enlargement with a PASP of 55mmHg

Case #6

• 52yo man with ESRD on HD, htn, DM, CAD, cirrhosis from hep C and prior ETOH abuse and mild COPD, no longer smoking, admitted after missing two HD appointments with profound fluid overload.

• Also notes that he has had worsening SOB over the past year and fluid retention.

Normal Cardiac Hemodynamics

Diagnostic Definition: Pulmonary Hypertension

Rest:- Mean PAP >25 mmHg

PAH = above + PCWP or LVEDP <15 mmHg– + PVR >3 WU

Associated with adverse changes- In the pulmonary vasculature (arteriopathy)- At the level of the right ventricle (hypertrophy)

No longer part of the definition:Exercise:

- Mean PAP > 30 mmHg

Gaine et al. The Lancet, 1998.

Aberrant Pathways in PAH

Loss of Biological “Balance” in PAH

VasodilationApoptosis

VasoconstrictionProliferation

VasodilationApoptosis

VasoconstrictionProliferation

SMC

Endotheliumelastic lamina injury

serum leak

SMC PROLIFERATION & MIGRATION

The Pathobiology Of Pulmonary Hypertension

5th World Symposium: Classification of Pulmonary Hypertension

(Nice, France 2013)

1. Pulmonary Arterial Hypertension 1.1 Idiopathic PAH1.2 Heritable

1.2.1. BMPR21.2.2. ALK1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown.

1.3 Drug- and toxin-induced1.4 Associated with

1.4.1. Connective tissue disease1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart diseases1.4.5 Schistosomiasis

1’ Pulmonary veno-occlusive disease (PVO) and/or pulmonary capillary hemangiomatosis (PCH)

1’’ Persistent pulm hypertension of the newborn (PPHN)

2. Pulmonary hypertension due to left heart disease

2.1 LV Systolic dysfunction2.2 LV Diastolic dysfunction2.3 Valvular disease2.3 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies

3. Pulmonary hypertension due to lung diseases and/or hypoxia3.1 Chronic obstructive pulmonary disease3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung disease

4. Chronic thromboembolic pulmonary hypertension (CTEPH)

5. PH with unclear multifactorial mechanisms5.1 Hematologic disorders: chronic hemolytic anemia myeloproliferative disorders splenectomy.5.2 Systemic disorders, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis.

Back to the Cases

• What do all the patients presented have in common? – Each patient was found to have pulmonary arterial

hypertension after full w/u and diagnosis by right heart catheterization.

Pulmonary Arterial Hypertension

• Case #1: IPAH

• Case #2: PAH associated with HIV

PAH

• Case #3: PAH assoc with drugs/toxins

- The list gets longer andlonger

• Case #4: PAH assoc with CTD

- Sometimes the PH presentsbefore other complications of the disease

Drugs and Toxins Associated PAH

Definite• Aminorex• Fenfluramine• Dexfenfluramine• Toxic rapeseed oil• Benfluorex• SSRIsLikely• Amphetamines• L-tryptophan• Methamphetamines• Dasatinib

Possible• Cocaine• Phenylpropanolamine• St John’s Wort• Chemotherapeutic agents• Interferon alpha/beta• Amphetamine-like drugsUnlikely• Oral contraceptives• Estrogen• Cigarette smoking

PAH

• Case #5: PAH assoc with CHD

• Case #6: PAH assoc with portal htn

MixedPH

Pre-capillary PHHigh-flow PH(O2 sat run)

Hemodynamic Classification of PH(mean PAP >25 mm Hg)

VC RA RV PA PVPC

LA LV Ao

Post-capillary PH

Diagram courtesy of Teresa De Marco, MD, UCSF

Hemodynamic Classification of PH(mean PAP >25 mm Hg)

VC RA RV PA PV

PVPPC

LA

LAP

LV Ao

LVEDP

Post-capillary PH PCWP>15 mm Hg; PVR normal

Diagram courtesy of Teresa De Marco, MD

Hemodynamic Classification of PH(mean PAP >25 mm Hg)

VC RA RV PA PV

PVPPC

LA

LAP

LV Ao

LVEDP

Post-capillary PH PCWP>15 mm Hg; PVR normal

Diagram courtesy of Teresa De Marco, MD

Systemic HTNAoV diseaseMyocardial Disease

Dilated CMP-ischemic/non-ischemicHypertrophic CMPRestrictive/infiltrative CMPObesity related CMPPericardial disease

MR

Hemodynamic Classification of PH(mean PAP >25 mm Hg)

VC RA RV PA PV

PVPPC

LA LV Ao

Post-capillary PH PCWP>15 mm Hg; PVR normal

Diagram courtesy of Teresa De Marco, MD

PV Compression

Hemodynamic Classification of PH(mean PAP >25 mm Hg)

VC RA RV PA PVPC

LA LV Ao

Pre-capillary PHPCWP <15 mm Hg;PVR >3 woods units

{

{

PAHLung diseases +/- hypoxemia

CTEPH

Diagram courtesy of Teresa De Marco, MD

5th World Symposium: Classification of Pulmonary Hypertension

(Nice, France 2013)

1. Pulmonary Arterial Hypertension 1.1 Idiopathic PAH1.2 Heritable

1.2.1. BMPR21.2.2. ALK1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown.

1.3 Drug- and toxin-induced1.4 Associated with

1.4.1. Connective tissue disease1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart diseases1.4.5 Schistosomiasis

1’ Pulmonary veno-occlusive disease (PVO) and/or pulmonary capillary hemangiomatosis (PCH)

1’’ Persistent pulm hypertension of the newborn (PPHN)

2. Pulmonary hypertension due to left heart disease

2.1 LV Systolic dysfunction2.2 LV Diastolic dysfunction2.3 Valvular disease2.3 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies

3. Pulmonary hypertension due to lung diseases and/or hypoxia3.1 Chronic obstructive pulmonary disease3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung disease

4. Chronic thromboembolic pulmonary hypertension (CTEPH)

5. PH with unclear multifactorial mechanisms5.1 Hematologic disorders: chronic hemolytic anemia myeloproliferative disorders splenectomy.5.2 Systemic disorders, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis.

Natural History of PAH: NIH Registry1,2

NIH = National Institutes of Health.Predicted survival according to the NIH equation. Predicted survival rates were 69%, 56%, 46%, and 38% at 1, 2, 3, and 4 years, respectively. The numbers of patients at risk were 231, 149, 82, and 10 at 1, 2, 3, and 4 years, respectively. *Patients with primary pulmonary hypertension, now referred to as idiopathic pulmonary hypertension.

1. Rich et al. Ann Intern Med. 1987;107:216-223. 2. D’Alonzo et al. Ann Intern Med. 1991;115:343-349.

Predicted survival*

69%

56%

46%

38%

Predicted survivalPerc

ent s

urvi

val

Years

Survival by PAH Etiology

CHD = congenital heart disease; CVD = collagen vascular disease; HIV = human immunodeficiency virus; PAH = pulmonary arterial hypertension; PPH = primary pulmonary hypertension; PoPH = portopulmonary hypertension.

Years

Perc

ent s

urvi

val

Prognosis in Mixed Treated/Untreated Cohorts

McLaughlin et al. Chest. 2004;126:78S-92S

Symptoms

• Breathlessness• Chest pain• Dizziness• Syncope• Loss of energy• Edema• Dry cough• Raynaud’s phenomenon

Physical Exam Findings in PAH

• Increased jugular venous pressure• Accentuated split S2• Presence S3• TR murmur- heard best LL sternal border• Edema and/or ascites• Hepatojugular reflux• Skin- telangiectasias, Raynaud’s, Sclerodactyly

CXR

CT Chest

McGoon et al. Chest 2004;126:14S-34S

No furtherevaluation

for PAH

Is PAH likely?Echo

Is there a reason to suspect PAHClinical history (symptoms, risk factors, family Hs.),

Exam, CXR, ECG

Is PAH due to LH disease?Echo

Is PAH due to CHD?Echo with contrast

Is PAH due to CTD, HIV?Serologies

Dx Scleroderma, SLE, other CTD, HIV: Medicaltreatment of PAH and further evaluation for

other contributing causes, including RHC

Dx abnormal morphology; shunt:Surgery. Medical treatment of PAH or evaluation for

further definition or other contributing causes, including R&LHC if necessary

Dx LV systolic, diastolic dysfunction; valvular disease:Appropriate treatment and further evaluation

if necessary, including R&LHC

TRV to measure RVSP; RVE; RAE; RV Dysfunction:

yes

yes

yes

Rationale

no

no

no

yes

yesno

no

Pulmonary Arterial Hypertension: Detection and Diagnosis

Is chronic PE suspected?VQ scan

McGoon et al. Chest 2004;126:14S-34S

Dx parenchymal lung disease, hypoxemia, or sleep disorder: Medical treatment, oxygen, positive pressure breathing

as appropriate, and further evaluation for other contributing causes, including RHC if necessary

yes

Document exercise capacity regardless of cause of PH: Establish baseline, prognosis and document progression/

response to treatment with serial reassessments

Document PA and RA pressures, PCWP (LV or LA pressureif PCWP unobtainable or uncertain), transpulmonary gradient

CO, PVR, SvO2, response to vasodilators: Confirm PAH, or IPAH if no other cause identified

Discuss genetic testing and counseling of IPAH

What limitations are caused bythe PAH?

Functional class; 6-minute walktest

What are the precise pulmonaryhemodynamics?

RHC

Is chronic PE suspected?VQ scan

Is PAH due to lung diseaseor hypoxemia?

PFTs, arterial saturation

Is chronic PE confirmed and operable?Pulmonary angiogram

Anatomic definition (CT, MRI may provide additional useful but not definitive information):

Thromboendarterectomy if appropriate or medical treatment; clotting evaluation; a/c

yesyes

no

no

no VQ normal

Pulmonary Arterial Hypertension: Detection and Diagnosis

NYHA Classification

Right Heart Catheterization is the Diagnostic Gold Standard

• Saturations– Rule Out Shunts

• Intra-cardiac• Intra-Pulmonary

• Hemodynamics– RAP– mPAP– PCWP

• Rule out left sided heart disease– CO/CI– PVR

• Angiography– Vessel properties– CTEPH

• Vasodilator Response

Rich et al. WHO Symposium on PPH. Evian, France,1998.

RHC can also Prognosticate!

Swan Ganz Physiology.mp4

Therapeutic Pathways

Therapies

• The only groups that have been approved for the specialized medications for pulmonary hypertension are Group 1 (pulmonary arterial hypertension/PAH) and Group 4 (CTEPH)

• The other groups require treatment of the underlying condition causing the elevated pressures.

Therapeutic Options for PAH

Traditional therapies

• Supplemental O2

• Diuretics• Oral vasodilators– (CCB)

• Anticoagulants– warfarin

• Inotropic agents– Digitalis

FDA approved for PAH• Prostanoids

– Epoprostenol (flolan/veletri)

– Treprostinil (IV/SQ/Inhaled)

– Inhaled Iloprost– Oral treprostinil (Orenitram)

• ERA’s– Bosentan– Ambrisentan– Macitentan

• PDE-5 Inhibitors– Sildenafil– Tadalafil

• Guanylate Cyclase Stimulator– Riociguat

PAH Treatments ― a Historical Overview

CCB, anticoagulation, digitalis, diuretics

epoprostenolbosentan Iloprost

ambrisentan

sildenafil

SC treprostinil

IV treprostinil

<1995 1995 1996 1997 1998 1999 2000 2001 2002 20032004 2005 2006 2007

tadalafilInhaled treprostinil

20082009 2010 2011 2012 2013

RiociguatMacitentanOrenitram

veletri

Prostanoids

• Prostacyclin (PGI2)- member of the eicosanoids family, inhibits platelet activation and effective vasodilator.

• Prostacyclin released by healthy endothelial cells.

• Deficiency in PAH patients• Several routes of administration:– IV/parenteral, SQ, Inhaled, oral

IV Prostanoids

• Epoprostenol- Flolan and Veletri– Half-life approximately 2-5min

• Treprostinil- Remodulin – Half-life several hours– Both administered in ng/kg/min– Dosing never changes even if weight does, start

weight remains the same throughout duration of therapy.

Single Lumen Hickman Catheter

• Never stop infusion

• Never draw labs from line

• Never flush

CADD Legacy Pump

SQ Prostanoids

• Treprostinil (Remodulin) SQ– Small catheter placed

in SQ tissue of the abdomen

– Site changed every 3-5 weeks

Inhaled Prostanoids

• Iloprost (Ventavis)– 6-9 treatments per day– Fewer systemic effects than IV

• Treprostinil (Tyvaso)– QID and dosed as breaths

• e.g. 3 breaths each inhalation that is increased by increments of 3 up to 9.

• Single person nebulizer – Pt must bring in machine from home if hospitalized

Inhaled Prostanoids

Tyvaso Ventavis

Oral Prostacyclin

• Treprostinil (Orinetram)– Antiplatelet and vasodilatory actions, including

pulmonary vasodilation– FREEDOM-M trial (only study of 3 that met

endpoint)– Available as 0.125mg, 0.25mg, 1mg, 2.5mg ER BID• Starting dose 0.25mg bid and titrated Q3d as tolerated• Only showed improved 6MWD as monotherapy

Endothelin Receptor Antagonist

• Endothelian-1 (ET-1) levels are increased in PAH and found in the precapillary pulmonary microvasculature which is the site of the increased vascular resistance in PAH.– Two G protein-coupled receptors for ET-1 have been described:

“ETA” and “ETB”

• Bosentan- dual antagonist– 62.5 to 125mg BID

• Ambrisentan- Selective ETA receptor– 5-10mg daily

• Macitentan- Dual but with increased selectivity for ETA

– 10mg daily

Phosphodiestrase-5 Inhibitors

• PDE5 Inhibitor- blocks the degradative action of phosphodiesterdase type 5 on cyclic GMP in smooth muscle cells resulting in vasodilation of the vessels.

• Sildenafil- 20-80mg TID• Tadalafil- 20-40mg daily

Guanylate Cyclase Stimulator

• Riociguat has a dual mode of action– Synergist with endogenous nitric oxide – Directly stimulating guanylate cyclase independent

of NO availability• Phase 3 trial in the NEJM: 12 wk double-blind

randomized placebo-controlled trial at 124 centers in 30 countries for PAH patients showed improved walk distance and improvement in secondary end-points.

Cost per Year

• Ambrisentan (Letairis)- $76,047.60• Bosentan (Tracleer)- $76,543.20• Tadalafil (Adcirca)- $18,316.80• Epoprostenol (Flolan)- $34,170• Oral Treprostinil (Orinetram)- $500,000

Triple therapy can be over $130, 000/yr just for specialty medications.

Ongoing Management

• Standard of care is for PAH patients to be established with a PH center for ongoing care.– Multidisciplinary approach to care

• Patients on advance therapies to be seen every 3 months if not more frequently

• Ongoing escalation of care, more evidence coming out showing the importance of combination therapies.

Questions?