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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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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