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October 26, 2018

Pulmonary Hypertension

Jason Stienecker, DOPulmonary/Critical Care

No Financial Conflicts of Interest

Speaker for Bayer and Actileon

Served on Advisory board for Understanding Clinical Decision Making for the Early Use of Treprostinil

Sponsored by United Therapeutics

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Pulmonary Hypertension

Definition: Increased pressure through the pulmonary artery with a mean pulmonary artery pressure of >= 25mmHg.

Five World Health Organization (WHO) classes of pulmonary hypertension

Pulmonary arterial hypertension (PAH) is only WHO I and IV

Pulmonary hypertension (PH) is WHO II, III, V

Sometimes referred to as pulmonary VENOUS hypertension

PH vs. PAH

Definition of PHMean PAP ≥25 mmHg

PAWP ≤15 mmHg

Mean PAP ≥25 mmHg

PVR >3 Wood units

Definition of PAH

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PH vs. PAH

Swan‐Ganz

VC RA RV PA PC PV

LA LV Ao

WHO IWHO IV

WHO IIWHO IIIWHO V

Pre‐Capillary (PAH)Post‐Capillary (PVH)

Treatable with PAH Medications1 Pulmonary arterial hypertension

1.1 Idiopathic PAH1.2 Heritable PAH

1.2.1 BMPR21.2.2 ALK‐1, 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 disease1.4.5 Schistosomiasis

1′ PVOD and/or pulmonary capillary hemangiomatosis1″ PPHN

2 Pulmonary hypertension due to left heart disease2.1 Left ventricular systolic dysfunction2.2 Left ventricular diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart inflow/outflow tract 

obstruction and congenital cardiomyopathies

3 Pulmonary hypertension due to lung diseases and/or hypoxia3.1 COPD3.2 ILD3.3 Other pulmonary diseases with mixed reactive 

and obstructive pattern3.4 Sleep‐disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases

4 CTEPH

5 Pulmonary hypertension with unclear multifactorial mechanisms5.1 Hematologic disorders: chronic hemolytic 

anemia, myeloproliferative disorders, splenectomy5.2 Systemic disorders: sarcoidosis, pulmonary 

histiocytosis, lymphangioleiomyomatosis5.3 Metabolic disorders: glycogen storage disease, 

Gaucher disease, thyroid disorders5.4 Others: tumoral obstruction, fibrosing 

mediastinitis, chronic renal failure, segmental PH

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Symptoms

Dyspnea - 95% (cardinal symptom of PH)

Breathlessness - 60% (first with exertion then at rest)

Starts occasionally with carrying things like groceries

Sensations of fatigue and weakness

Substernal chest pain usually with exertion which radiates to the left shoulder/axilla

Dizziness, or Syncope

Hemoptysis

Hoarseness

Physical Exam Findings

Patients in their early stages will manifest no symptoms of the disease

Hands/feet of the patient will be cold, with diminished peripheral pulses

Prominent jugular venous a wave, exaggerated by hepatojugular reflux

prominent c-v waves - indicating tricuspid regurgitation

Left chest palpation: right ventricular lift sustained throughout the pressure-overloaded cardiac contraction

Accentuated P2 with a closely split S2, increasing on inspiration

Peripheral edema, abdominal distension due to ascites

Cyanosis with exertion, then at rest in late stage

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Diagnosis of PH/PAH

Must have a clinical suspicion, most commonly missed/under diagnosed cause of dyspnea.

Echocardiogram is the first screening test for this disease

Definitive diagnosis must be performed by a right heart catheterization (Swan-Ganz)

Optimization of every PH (WHO II,III,V) disease, and lab/radiologic testing for every PAH (WHO I,IV) disease

ACCF/AHA Guidelines for Diagnosing PAH

Echocardiogram

PFTs

Polysomnography

V/Q Scan

• Sleep Disorder

• Chronic PE

Functional Test(6MWT, CPET)

Overnight Oximetry

HistoryExam

Chest X‐rayECG

HIVANALFTs

RHC

TEEExercise Echocardiogram

Pulmonary AngiographyChest CT AngiogramCoagulopathy Profile

Vasodilator TestExercise RHC

Volume LoadingLHC

ABGs

• Index of Suspicion of PH

••RVE, RAE, RVSP, RV Function• Left Heart Disease•VHD, CHD

••Ventilatory Function•Gas Exchange

Other CTD Serologies

• Establish Baseline• Prognosis

• Confirmation of PH•Hemodynamic Profile•Vasodilator Response

PIVOTAL TESTS CONTINGENT TESTS CONTRIBUTE TO ASSESSMENT OF:

••HIV Infection• Scleroderma, SLE, RA• Portopulmonary hypertension

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Diagnostic Modalities of PH/PAH• Assessing RV size and

function provides disease process information

• RVSP < 40 (age dependent)

• TAPSE > 2cm

• RV S’ > 10cm/s

• RVOT AT (AcT) > 120ms

• RV FAC > 35%

• Functional capacity– Prognosis– Disease severity and

progression

• Diagnosis confirmation requires assessment of RV-related hemodynamics

Swan‐Ganz catheter

Tools for Assessing the RV

Echocardiography

Right Heart Catheterization

Diagnostic Criteria for PAH

mPAP ≥25

mm Hg PAWP ≤15 mm Hg

PVR>3 WU

• mPAP ≥25 mm Hg • PAWP ≤15 mm Hg• PVR >3 Wood units

PVR = TPG

CO= Wood units

x 80 = dyne•sec•cm-5

TPG = mPAP – PAWP

DPG = dPAP – PAWP

If PCWP > 15, but TPG > 12 and DPG >= 7 - suggests “out of proportion” PAH on PH

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RHC: Pulmonary Artery Hypertension

52

10 12

RA RV PA PA PCW

0

20

40

60

80

100

Pressure, m

m Hg

80/1580/40

CO = 5 L/minTPG = 40 mm HgPVR = 8 WU

RHC: Pulmonary Venous Hypertension

RA RV PA PA PCW

0

20

40

60

80

100CO = 4 L/minTPG = 7 mm HgPVR = 1.75 WU

Pressure, m

m Hg

32

5

25

45/5 45/25

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RHC: Vasodilator Testing• Positive response defined by a ≥10 mm Hg DECREASE in mPAP

and mPAP ≤40 mm Hg and without decreased CO• ~13% of patients with IPAH have a positive response

• Adenosine (IV), NO(inhaled) or epoprostenol (IV/inhaled)

iNO, 40 ppm

Pulmonary Artery Hypertension

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Normal Pulmonary Physiology

Remodeling

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Pathways of PAH

Endothelin PathwayProstacyclin Pathway Nitric Oxide Pathway

Endothelial cells

pro‐ET

Endothelial cells

Arachidonic acid L‐arginine

Endothelial cells

SMCs SMCs SMCs

Prostacyclin Nitric OxideEndothelin‐1

Vasoconstriction Proliferation

sGC

VasodilationAntiproliferation

cAMP

PDE‐5

GMP

cGMP

VasodilationAntiproliferation

ETA ETBIP

Time

PAP

PVRRAP

CO

Presymptomatic/ compensated

Symptomatic/ decompensating

Symptom threshold

Right heart dysfunction

Declining/ decompensated

Right Heart FailureRight Heart Dysfunction

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Treatment of PAH

Determine the patient’s functional class

New York Heart Classification (NYHC)

1: no symptoms or limitations

2: mild shortness of breath, slight limitation during ordinary activity

3: marked limitation of activity even during less than normal ordinary activity (short distance walks)

4: severe limitations, symptoms at rest, syncope

Vaso-reactivity during RHC

Treatment of PAH

Prostacyclin pathway: treprostinil (IV,SQ,Inh,PO), epoprostenol(IV), selexipag (PO), iloprost(Inh)

Endothelial pathway: ERA: macitentan(PO), ambristentan(PO), bosentan(PO)

Nitric oxide pathway: SGc: riociguat(PO), PD5i: tadalafil(PO), sildenafil(PO)

If responded to vasodilator testing: calcium-channel blocker

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Treatment of PAH

WHO I

NYHC 1: PD5i vs. ERA alone vs. SGc

NYHC 2: PD5i vs. PD5i+ERA vs. SGc

NYHC 3: PD5i+ERA vs. PD5i+ERA+Prostacyclin vs. SGc + ERA vs. SGc+ERA+Prostacylcin

NYHC 4: PD5i+ERA+Prostacyclin vs. SGc+ERA+Prostacyclin

WHO IV

If cannot have surgery or bridge to surgery:

NYHC 1-3: SGc

NYHC 4: SGc + Prostacyclin

Risk Assessment in PAH

Determinants of Prognosis Low Risk < 5% Intermediate Risk 5-10% High Risk > 10%

Clinical signs of right heart failure

Absent Absent Present

Progression of symptoms No Slow Rapid

Syncope No Occassional Repeated

WHO functional class I,II III IV

6MWD > 440m 165-440m <165m

CPETPeak VO2 > 65% VE/VCO2

slope < 36VO2 35-65%, VE/VCO2 36-

44.9VO2 < 35% VE/VCO2 >=45

NT-proBNP BNP < 50 Pro < 300 BNP 50-300, Pro 300-1400 BNP > 300, Pro > 1400

Imaging RA < 18cm2, No effusionRA 18-26cm2 minimal or no

effusionRA > 26cm2 effusion

HemodynamicsRA < 8, CI >=2.5, SvO2

>65%RAP 8-14, CI 2-2.4, SvO2

60-65%RAP > 14, CI < 2.0, SvO2 <

60%

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Goals of Treatment for PAH

Stop or delay remodeling and worsening of the disease process

Increase 6MWD and exercise capacity

Decrease BNP

Decrease right heart failure/strain

Decrease NYHC functional class

Vasodilate the pulmonary arteries, allowing the right heart to compensate

Pitfalls of Treatment

Treating PVH (WHO II,III,V) with PAH (WHO I, IV) medications:

Vasodilates the pulmonary arteries, allowing the right heart to pump more blood volume into the pulmonary veins/left heart

PVH diseases have an elevated venous pressure/inability to accept further blood volume

This forces all of the extra blood volume into the pulmonary parenchyma causing severe pulmonary edema

Causes central sleep apnea, higher oxygen needs, worsening dyspnea, etc…

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Complications

Once medications for PAH are started, they cannot be stopped without weaning them

Pulmonary artery will rapidly increase the pressure against the right ventricle, without time to adapt causing failure (like an acute massive pulmonary embolism)

PAH medications can cause inhibition to platelet aggregation

Most oral PAH medications cannot be given IV, for example if a patient is NPO

Hemodynamic Complications

PAH and Right heart failure (cor pulmonale) are very physiologically complicated diseases

The majority of PAH/RHF patients are hypervolemic

The more fluid the patient is given, the larger the right heart will get -further compressing the left ventricle

This will cause a pseudo-diastolic dysfunction, and underfilling of the left ventricle

This progresses to a drop in cardiac output

This causes acute kidney injury, hypotension, altered mentation

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Summary

PAH/PH is a physiologically and diagnostically complicated rare disease process

Treatment of these diseases requires a multidimensional approach

There are 5 hospitals in Ohio where you can start inpatient IV PAH medications: OSU, UC, UHCW, CCF and Lima Memorial

Questions?