1) Pulmonary hypertension (PH) is defined as elevated pulmonary artery pressure, while pulmonary arterial hypertension (PAH) is a subtype caused by constriction and remodeling of small pulmonary arteries. 2) PAH is a progressive disease that involves proliferation of cells in the pulmonary arteries leading to increased pulmonary vascular resistance and right heart failure if left untreated. 3) The document reviews classification of PH, diagnostic testing and evaluation algorithms, goals of treatment, and approved therapies for PAH.

1. Pulmonary
Hypertension
Basics 2021
NOVEMBER 5, 2021
DUKE PULMONARY
VASCULAR DISEASE
CENTER
Terry Fortin MD
Associate Professor of Medicine
Division of Cardiology
Duke University Hospital

2. Agenda
• Definitions of Pulmonary Hypertension (PH) and Pulmonary
Arterial Hypertension (PAH)
• Basic Physiology
• Classification- Groups of PH
• Updates since 2018
• Guidance
• Proceedings of the 6th World Symposium of Pulmonary HTN
2018
Name MRN

3. Pulmonary Hypertension (PH) vs. Pulmonary
Arterial Hypertension (PAH)
• Pulmonary hypertension: Elevated pulmonary pressure on an
echo or Right Heart Cath with multiple potential etiologies.
Not specific as to whether this is a pre or post capillary or flow
mediated
Pulmonary arterial hypertension (PAH) results from restricted
flow through pulmonary arterial circulation
– Leads to  pulmonary vascular resistance (PVR), ultimate right heart
failure
– Predominant cause – loss of vascular luminal volume from vascular
remodeling, excessive cell proliferation, ↓ apoptosis
McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the
American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed
in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension
Association. J Am Coll Cardiol. 2009;53:1573-1619.

4. Pulmonary Arterial Hypertension PAH
• Pulmonary arterial hypertension
(PAH) is a progressive, incurable
disease of the small pulmonary
arteries characterized by vascular cell
proliferation, aberrant remodeling,
and thrombosis in situ.
• Degree of vascular constriction varies
1. Farber HW, et al. N Engl J Med. 2004;351:1655-1665.

5. Adapted from: Sitbon O et al. J Am Coll Cardiol. 2002;40:780-788. D’Alonzo GE et al. Ann Intern Med.
1991;115:343-349. McLaughlin VV et al. Chest. 2004;126:78S-91S.
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
0
20
40
60
80
100
Years of follow-up
Percentage
surviving
NIH registry
Sitbon historical control
ACCP estimate
• Incidence: 2-6 cases per
million in US
• Poor prognosis in an era
lacking therapy
• Therapeutic options and
research efforts now offer
more hope
• In these registries age 45

6. Rajan Saggar med Ed on the go. How are CTD and
PAH related
Pulmonary Hypertension (PH)

7. • Mean PAP > 20 mmHg
1
• Wedge < 15 mmHg
2
• PVR > 3 WU (240 dynes)
3
Definition of PAH: Clinical, Hemodynamic
6th World Symposium 2018
6th World Symposium on PH 2018

8. Precapillary arteriolar
discontinuity

9. Pathology of PAH
Gaine S. JAMA. 2000;284:3160.
WHO Group I: Characterized by progressive growth
and vasoconstriction of small pulmonary arteries

10. NORMAL REVERSIBLE DISEASE IRREVERSIBLE DISEASE
Gaine S. JAMA. 2000;284:3160-3168.

11. PROGRESSIVE AND LIFE-LIMITING DISORDER
CO
mPAP
PVR
Decreasing mean
PAP may
not reflect
improvement
Pathological changes in the pulmonary arteries
Hemodynamic impairment
Adapted from Gaine S. JAMA. 2000;284:3160-3168.

12. Time
PAP
PVR
CO
Pre-symptomatic/
Compensated
Symptomatic/
Decompensating
Symptom Threshold
Right Heart
Dysfunction
Declining/
Decompensated
PAH: A Progressive Disease
Rich et al. In: Harrison’s Principles of Internal Medicine. 15th ed. 2001:1506-1507.

13. PAH: RV Changes
Normal PH
RA
LA
RV
LV
TTE apical
4-chamber view

14. The Right Ventricle in PAH
• RV pressure/volume overload
• RV failure
Progressive structural changes in the RV
due to poor adaptation to increasing PVR
RA LA
RV LV
Cross section

15. Chronic RV Failure/Decompensated PAH
RV Failure causing
Underfilled LV
Low Output
Shock

16. Revised Clinical Classification of PH
WHO Groups
 1. Pulmonary Arterial Hypertension (PAH)
 2. PH owing to left heart disease
 3. PH owing to lung diseases and/or hypoxemia
 4. Chronic thromboembolic pulmonary
hypertension
 5. PH with unclear or multifactorial causes
(sarcoid, myleproliferative, ESRD, sarcoma
hemoglobinopathy)

17. 1.1 Idiopathic PAH
1.2 PAH with vasoreactivity (Table 1)
1.3 Heritable PAH (Table 2)
1.4 Drugs and toxins induced (Table 3)
1.5 Associated with:
1.5.1 Connective tissue disease
1.5.2 HIV infection
1.5.3 Portal hypertension
1.5.4 Congenital heart disease (Table 4)
1.5.5 Schistosomiasis
1.6 PAH with overt signs of venous/capillaries
(PVOD/PCH) involvement (Table 5)
1.7 Persistent PH of the Newborn syndrome (Table P1)
1. Pulmonary Arterial Hypertension
2.1 PH due to heart failure with preserved E.F
2.2 PH due to heart failure with reduced E.F
2.3 Valvular heart disease
2.4 Congenital post-capillary obstructive lesions (Table
P2)
2. PH due to left heart disease
3.1 Obstructive lung disease
3.2 Restrictive lung disease
3.3 Other lung disease with mixed restrictive/obstructive
pattern
3.4 Hypoxia without lung disease
3.5 Developmental lung disorders (Table P3)
3. PH due to lung diseases and/or hypoxia (Table 6)
4.1 Chronic thromboembolic PH
4.2 Other pulmonary artery obstructions (Table 7)
4. PH due to pulmonary artery obstruction
5.1 Haematologic disorders
5.2 Systemic disorders
5.3 Others
5.4 Complex congenital heart disease (Table P4)
5. PH with unclear mechanisms (Table 8)
WSPH 2018: New Clinical Classification of PH

18. Echocardiogram
PFTs
Polysomnography
VQ Scan
• Sleep Disorder
• Chronic PE
Functional Test
(6MWT, CPET)
Overnight Oximetry
History
Exam
CXR
ECG
HIV
ANA
LFTs
RH Cath
TEE
Exercise Echo
Pulmonary Angiography
Chest CT Angiogram
Coagulopathy Profile
Vasodilator Test
Exercise RH Cath
Volume Loading
ABGs
• Index of Suspicion of PH
• RVE, RAE, RVSP, RV Function
• Left Heart Disease
• VHD, CHD
• Ventilatory Function
• Gas Exchange
Other CTD Serologies
• HIV Infection
• Scleroderma, SLE, RA
• Portopulmonary Htn
• Establish Baseline
• Prognosis
• Confirmation of PH
• Hemodynamic Profile
• Vasodilator Response
Pivotal Tests Contingent Tests Contribute to Assessment
of:
Left Heart Cath
McLaughlin VV et al. J Am Coll Cardiol.
2009;53:1573-1619.
Current
ACCF/AHA
Diagnostic
Algorithm

19. Catheterization is required when pulmonary
hypertension is suspected.
Diagnostic Cardiac Catheterization—Right Heart
• Establish the presence of PH
• Make the diagnosis of PAH
– measure wedge pressure and/or LVEDP
• Determine severity and prognosis of disease
• Determine cardiac output
• Exclude Shunts/ assess congenital heart disease
• Perform acute vasodilator test
– Prognosis. Use of Calcium Blocker only if positive

20. Not All PH is the Same

21. CTEPH
First option Improved survival
Consider surgical therapy with
pulmonary
thromboendarterectomy
Consider
Balloon pulmonary angioplasty if
more distal disease or poor
surgical candidate
Pulmonary vasodilator medicines
Riociguat

22. McLaughlin VV and McGoon M. In press.
Lower Risk Determinants of Risk Higher Risk
No
Clinical evidence of
RV failure
Yes
Gradual Progression Rapid
II, III WHO class IV
Longer (>400 m) 6MW distance Shorter (<300 m)
Minimally elevated BNP Very elevated
Minimal RV
dysfunction
Echocardiographic
findings
Pericardial effusion,
significant RV
dysfunction
Normal/near normal
RAP and CI
Hemodynamics High RAP, low CI

23. MECHANISMS OF ACTION OF APPROVED THERAPIES FOR PAH
Adapted from Humbert M et al. N Engl J Med. 2004;351:1425-1436.
cGMP
cAMP
Vasoconstriction and
proliferation
Endothelinrece
ptor A
Endothelin-
receptor
antagonists
Endothelinrece
ptor B
Phosphodiesterase type 5
inhibitor
Vasodilation
and antiproliferation
Phosphodiesterase type 5
Vasodilation
and antiproliferation
Prostacyclin
derivatives
Nitric Oxide
Endothelin-1
Pre-proendothelin
L-arginine
Prostaglandin I2
L-citrulline
Nitric Oxide
Pathway
Endothelin
Pathway
Prostacyclin
Pathway
Endothelial cells
Proendothelin
Endothelial cells
Arachidonic acid
Smooth muscle cells
Prostacyclin (prostaglandin I2)
Smooth muscle cells
Exogenous
nitric oxide
sGC stimulator

24. PAH-Specific, FDA-Approved Therapies for Use in the US
Endothelin Receptor
Antagonists
NO-cGMP Pathway
Prostanoids –
Prostacyclin Analogs
Prostacyclin Agonists
Bosentan (PO)
(Tracleer®)
FDA Approved: 2001
Sildenafil (PO)
(Revatio®)
FDA Approved: June 2005
Epoprostenol (IV)
(Flolan® or Veletri®)
Flolan FDA Approved: September 1995
Veletri FDA Approved: June 2008
Selexipag (PO)
(Uptravi®)
FDA Approved: December 2015
Ambrisentan (PO)
(Letairis®)
FDA Approved: June 2007
Tadalafil (PO)
(Adcirca®)
FDA Approved: May 2009
Treprostinil (IV, SC, PO, and
inhaled)
(Remodulin®, Tyvaso®, Orenitram®)
First (SC formulation) FDA Approved:
July 2002
Macitentan (PO)
(Opsumit®)
FDA Approved: October 2013
Riociguat (PO)
(Adempas®)
FDA Approved: October 2013
Iloprost (inhaled)
(Ventavis®)
FDA Approved: December 2004
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed April 1, 2016.

25. Goals of Treatment in 2018: Improvement Not Preservation
• However, improvement and normalization of ALL clinical parameters to make patients LOW RISK is the goal in PAH
treatment.
• Preservation or prevention of worsening is no longer the goal.
Determinants of prognosis*
(estimated 1-year mortality)
Low Risk (<5%)
AT GOAL!!!
Intermediate Risk (5-10%)
NOT AT GOAL
High Risk (>10%)
NOT AT GOAL
Clinical Signs of Right Heart Failure Absent Absent Present
Progression of Symptoms No Slow Rapid
Syncope No Occasional Syncope Repeated Syncope
WHO Functional Class I, II III IV
6MWD > 440 m 165 – 440 m < 165 m
Cardiopulmonary Exercise Testing
Peak VO2 > 15 ml/min/kg
(>65% predicted)
VE/VCO2 slope < 36
Peak VO2 11 – 15 ml/min/kg
(35 – 65% predicted)
VE/VCO2 slope 36 – 44.9
Peak VO2 < 11 ml/min/kg
(< 35% predicted)
VE/VCO2 slope > 45
NT-proBNP levels
BNP < 50 ng/L
NT-pro BNP <300 ng/L
BNP 50 – 300 ng/L
NT-pro BNP 300 – 1400 ng/L
BNP > 300 ng/L
NT-pro BNP > 1400 ng/L
Imaging (ECHO or CMR)
RA area < 18 cm2
No pericardial effusion
RA area 18 – 26 cm2
No/minimal pericardial effusion
RA area > 26 cm2
Pericardial effusion
Hemodynamics
RAP < 8 mmHg
CI > 2.5L/min/m2
SvO2 > 65%
RAP 8 – 14 mmHg
CI 2.0 – 2.4 L/min/m2
SvO2 60 – 65%
RAP > 14 mmHg
CI < 2.0 L/min/m2
SvO2 < 60%
Adapted from Galie N, Humbert M, Vachiery J-L, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension.
European Heart Journal (2016) 37, 67–119

26. PAH Treatment Algorithm (WSPH 2018)
Galié N, Channick RN, Frantz RP, et al. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J 2018; in press [https://doi.org/10.1183/13993003.01889-
2018].
PAH Confirmed
by Expert
Center
Non-Vasoreactive
High Risk
(WHO FC IV)
Vasoreactive
After 3-6 Months of Treatment
Consider
Referral For
Lung
Transplantatio
n
Maximal Medical
Therapy and Listing
for Lung
Transplantation
Potential Role For Initial
Monotherapy
Treatment-
Naïve Patient
Patient Already
On Treatment
CCB Therapy
Acute Vasoreactivity Test
(IPAH/hPAH/DPAH Only)
Initial Oral
Combination
Initial Combination
Including IV PCA
Add On Therapy
(Double/Triple)
General Measures
Supportive Therapy
Intermediate Risk High Risk
Intermediate Risk High Risk
Intermediate Risk
Low Risk
Low Risk
Structured Follow-
Up
After 3-6 Months of Treatment

27. PAH Since 2018
• Triple therapy Retrospective vs Randomized Trials
– Triton
• Screening guidelines for CTD, genetic screening to advance
earlier therapy (DELPHI 2)
• Pulmonary Vasodilators in Group 3
– INCREASE (Inhaled Treprostinil in ILD)
• New Pathways
• BMPR2
– PULSAR Trial (Phase 2) Sotatercept showed improvement in PVR in
patients on background therapy
– Ongoing Phase 3 Stellar Trial
Name MRN

28. Pathways in PAH : Identified Processes Implicated in
PAH
+
Growth
cytokines
↓ apoptosis
Nuclear Transcription Factors
Gene activation
or repression
Apoptosis
Other products
Proliferative
phenotype
Cell Surface Receptors
Circulating Cells and Mediators
BMPs or
TGFb
EGF
TNFa
ANG II 5HT (serotonin)
Platelets
Anorexigens
5HT Transporter
NO restores
hypoxia blocks
Virus infection?
HIV, HHV-6
Estrogen
Angiopoletin
ALK/End or
BMPR 1-2
Endothelin
VEGF
O–
2
PO–
4
SMADs
ERK
JNH
MAP
Kinases
Intracellular
Signalling
NO Blocks
G protein
Apoptosis
SMC tone
ES Receptor
AML-1
Elastase
tenascin-c
K+ channels
KDR
B
A
TIE
+
–
+
–
+ –
PDGF
Adapted from Cover image. Newman JH. Advances in PH. Autumn 2004;3(3).

29. Goal of Treatment for Group 1 PAH Is to Reach FC I* and Up-front
Combination Therapy Is the Means
Patient Comes to
Clinical Attention
Treatment
Goals
Achieved
100 %
0 %
FC III
Time (Months)
FC II
FC I
FC IV
6 12
3 9
Initial
Monotherapy
Therapy Added
or Switched
Upon “Failure”
Therapy
Added or
Switched
Upon “Failure”
*FC I may be difficult to achieve in CTD due to concomitant cardiopulmonary and musculoskeletal
involvement
Graph is representative of a patient who is FC IIIb
Sequential “add-on” or
switch strategies may buy
time but do not push
patients to “GOAL”
Up-front
Combo
Therapy
Add
Therapy
Up-front
Triple Combo
Therapy?
Up-front combination
therapy strategy pushes
patient towards “GOAL”
Regular monitoring allows treatment escalation “at need”

30. Summary
• Determine if PAH vs PH
• Determine Group Classification 1-5
• Multiple tests including Right Heart Cath
• Consider therapy based on results of above and individual
characteristics of patient. Risk and Severity of disease.
• Consider up front combination therapy rather than sequential
therapy.
• Goal is to reduce patients to low risk category
Name MRN

33. N=483 of 4579 patients with echo PASP >40 mm Hg.
Gabbay E. Am J Respir Crit Care Med. 2007;175:A713.
Epidemiology of PH by Echo
• Single echo lab / Australian community of 160,000
• Etiology of PH noted on echocardiogram
Congenital heart
disease, 1.9%
Lung disease
Sleep-related
hypoventilation,
9.7%
CTEPH, 0.6%
PAH, 2.3% Unknown,
6.8%
Left heart
disease, 78.7%

34. Patients Have Multiple Reasons for Their PH/PAH
Group 1
PAH
Group 3
Interstitial
Lung Disease
Group 2
Pulmonary
Hypertension Due To
Left Heart Disease
RHF
Elevated
Right
Atrial
Pressure
Hypoxia
Lung
Scarring
Decreased
V/Q

35. Initial Management Of PAH In The Current Era
Gaine S, McLaughlin VV. Pulmonary arterial hypertension: tailoring treatment to risk in the current era. Eur Respir Rev 2017; 26: 170095
Majority of patients in the low- and intermediate-risk categories
should be started on dual therapy with an ERA plus a PDE-5i or sGC
stimulator
Newer data might
suggest up front Triple
therapy

36. Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72.
Sequential Combination
Therapy (I-A)
Referral for Lung
Transplantation (I-C)
Consider Eligibility for
Lung Transplantation
Inadequate Clinical
Response
on Maximal Therapy
INITIAL THERAPY WITH PAH-APPROVED DRUGS
PDE-5 I or
SGCs
ERAs
Prostanoids
+
+
+
Balloon Atrial
Septostomy (IIa-C)
Inadequate Clinical
Response

37. What Is the Optimal Treatment Strategy?
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Anticoagulate ± Diuretics ± Oxygen ±
Digoxin
Negative
No LOWER RISK DETERMINANTS OF RISK HIGHER RISK
No Clinical evidence of RV failure Yes
Gradual Progression of symptoms Rapid
II, III WHO class IV
Longer (>400 m) 6MWD Shorter (<300 m)
Peak VO2 >10.4 mL/kg/min CPET Peak VO2 <10.4 mL/kg/min
Minimal RV dysfunction Echocardiography
Pericardial effusion; significant RV
enlargement/dysfunction;
RA enlargement
RAP <10 mm Hg;
CI >2.5 L/min/m2 Hemodynamics
RAP >20 mm Hg;
CI <2.0 L/min/m2
Minimally elevated BNP Significantly elevated
Acute Vasoreactivity Testing
Sustained
Response
Continue CCB
Yes
Positive
Oral CCB

38. When the initial treatment approach results in a low risk status within 3-6 months the therapy should
be continued, and structured follow-up established according with ESC/ERS PH guidelines -Table 14.
after 3-6 months of treatment
Intermediate or High
Riskd
Add on Therapy
(double/triple)l
after 3-6 months of
treatment
Intermediate or High
Riskd
Low Riskd
Structured Follow-
upi
Maximal medical therapym
and listing for lung Txn
Consider
referral
for lung Tx
evaluation
PH Treatment Algorithm - Final Section
Galié N, Humbert M, Vachiery J-L, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. European
Heart Journal, 2016; 37:67–119

39. Updated classification of drugs and toxins associated with PAH
• Definite
• Aminorex
• Fenfluramine
• Dexfenfluramine
• Methamphetamines
• Dasatinib
• Toxic Rapeseed oil
• Possible
• Cocaine
• Phenylpropanolamine
• L-tryptophan
• St Johns wort
• Amphetamines
• Interferon alpha and beta
• Alkylating agents
• Bosutinib
• Direct acting viral agetns to Hep C
• Leflonamide
• Indirubin (qing-Dai)
Name MRN

40. • Passive or Post Capillary pressures cause congestion of venous
bed and passive PH
– Increased PA pressure with high wedge normal PVR
– TPG < 12 and /or DPG <7
• Reactive or precapillary PH physiologic/anatomic remodeling
of arterioles to compensate or protect upstream pulmonary
venous changes
– PVR>3, TPG >12, or DPG >7
• Early may be reversible and more Chronic irreversible
• Timing and treatment around time of measurement matters
Group 2 Pulmonary HTN

41. Increasing:
-mPAP,
-PVR
Decreasing:
RV function
Time
-FVC%
-DLco%
-6MWD
A
ILD primary determinant of outcomes PH primary determinant of outcomes
Decreasing:
Inflection point
Vascular ablation & vasculopathy
ILD Pathology Initiates Decline in Interstitial
Processes Until PH Pathology Takes Over
King CS, Nathan SD. Treatment of Pulmonary Hypertension in Interstitial Lung Disease. R.P. Baughman et al.
(eds.), Pulmonary Hypertension and Interstitial Lung Disease, DOI 10.1007/978-3-319-49918-5_4

42. Vascular Pressure in Systemic and
Pulmonary Circulations (mm Hg)
Pulmonary
Circulation
Systemic
Circulation
Systemic
Arteries
Pulmonary
Arteries
Systemic
Veins
Pulmonary
Veins
120/80, mean 93 25/8, mean 14
LA
Mean
5
RA
Mean 2-
5
RV
25 / 2-5
LV
120 / 5-10
Mean 12
Mean 30
Lung
Body
Kovacs G et al. ERJ. 2009;34:888-894.

43. Post-capillary PH
Pre-capillary PH
RA RV PA PV
PC
LA LV Ao
PCWP >15 mm Hg
PVR <3 Wood units
PCWP <15 mm Hg
PVR ≥3 Wood units
Other:
High CO
PCWP <15 mm Hg
PVR <3 Wood units
PH: Define the Lesion
Mixed PH
PCWP >15 mm Hg
PVR ≥3 Wood units
PCWP>15 and PVR< 3 Wood units
PH mean PAP >20