1. Shilpa Johri, MD, MBBS, FCCP Pulmonary Associates of Richmond
Pulmonary Hypertension: An Overview of Updated Classification, Diagnostic Algorithm and Treatment Options
Shilpa Johri, MD, MBBS, FCCP
Pulmonary Associates of Richmond

2. Objectives: Conflict of Interest
Definition and updated classification of PH
Clinical presentation in patients with PH
Work up algorithm in suspected PH
Identify predictors of increased morbidity and mortality
Review management guidelines
Clinical case examples
Conflict of Interest
Consultant and Advisory Board: Gilead Sciences
Speaker’s Bureau: Gilead Sciences and Bayer Pharmaceuticals
Research funding: Bellephoron Therapeutics and United Therapeutics

3. Definition of Pulmonary Hypertension
General definition
Mean PAP ≥ 25 mm Hg at rest, measured by right heart catheterization
Hemodynamic characterization of PAH
Mean PAP ≥ 25 mm Hg, PAWP ≤ 15 mm Hg, elevated PVR (> 3 Wood Units)
PAP = pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; PVR = pulmonary vascular resistance
Several recommendations were published following the 5th world symposium on pulmonary hypertension. First, the general definition for pulmonary hypertension was agreed to be a mean PAP ≥ 25 mm Hg at rest as measured by right heart catheterization. Also, the hemodynamic characterization of PAH was determined to be a mean PAP ≥ 25 mm Hg, PAWP ≤ 15 mm Hg, and an elevated PVR (> 3 Wood Units).
Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50. 3

4. Hemodynamic measurements
Cardiac output: 5 L/min
Systemic BP: 120/80 mmHg
PAP: 25/10 mmHg
PAWP: mmHg
Mean PAP : mmHg
(SPAP + 2x DPAP)/3
PVR : 0.5 – 2 WU
Mean PAP- PAWP/ CO

5. Clinical Classification of Pulmonary Hypertension
The next several slides focus on the subcategories of group 1 PAH.
Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. 5

6. Clinical Classification of Pulmonary Hypertension- 5th World Symposium at Nice
1. Group I PAH
Idiopathic
BMPR2
ALK-1, ENG, SMAD9, CAV1, KCNK3
Unknown
Heritable
Drug- and toxin-induced
Connective tissue disease (7-12% of patients with scleroderma)
HIV infection (0.5% of patients with HIV)
Portal hypertension (2-6% of patients with portal hypertension)
Congenital heart disease (10% of the adults with CHD)
Schistosomiasis (5% of affected patients)
Associated with:
BMPR2 = bone morphogenetic protein receptor type 2; ALK-1 = activin A receptor type II-like kinase-1; ENG = endoglin; CAV1 = caveolin-1
The types of PAH are listed on the slide. Idiopathic PAH is designated as Heritable PAH is designated as 1.2 and includes patients with the following genetic mutations: BMPR2, ALK-1, ENG, SMAD9, CAV1, KCNK3, and unknown. Drug and toxin induced PAH is designated as Associated conditions are found under the last category of PAH (1.4) and include: connective tissue disease, HIV infection, portal hypertension, congenital heart disease, and Schistosomiasis.
1’ Pulmonary venoocclusive disease
1” Primary pulmonary hypertension of new born
Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. 6

7. Clinical Classification of Pulmonary Hypertension- 5th World Symposium at Nice
2. PH owing to left heart disease
2.1. Left ventricular systolic dysfunction
2.2. Left ventricular diastolic dysfunction
2.3. Valvular disease
2.4. Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies
4. CTEPH
5. PH with unclear multifactorial mechanisms
5.1. Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy
5.2. Systemic disorders: sarcoidosis, pulmonary Langerhans cellhistiocytosis: lymphangioleiomyomatosis, neurofibromatosis, vasculitis
5.3. Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
5.4. Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH
3. PH owing to lung diseases and/or hypoxia
3.1. Chronic obstructive pulmonary disease
3.2. Interstitial lung disease
3.3. Other pulmonary diseases with mixed restrictive
and obstructive pattern
3.4. Sleep-disordered breathing
3.5. Alveolar hypoventilation disorders
3.6. Chronic exposure to high altitude
3.7. Developmental lung diseases
Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D34-D41

8. 55 year old Caucasian female with history of HTN was referred for exertional dyspnea for 4 years
Actively working with frequent travel- started finding it difficult to walk through airports with hand baggage
Previous work up had included a negative stress test (3 years ago), negative left heart cath (2 years ago) and relatively unremarkable echo with PASP estimated at 35 one year ago, CTA negative for pulmonary emboli 2 years and 6 months ago.
Was on treatment with beta blockers and benzodiazepines were added for dyspnea attributed to anxiety
She worsened to a point where she had to stop several times before she could reach her seat in the 13th row during basketball games at UNC
Accentuated P2 on exam, both previous CTA s showed dilated central PA

9. CT scan 2 years apart
RHC: PAP 91/39, mean 60, PAWP 5, SvO2 79%, TDCO 6.97, PVR 7.89 Wood Units
Sequential therapy, currently on 3 agents

10. PAH distribution
Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D34-D41

11. Epidemiology of PAH Prevalence in the U.S.- 15-50 cases/million
Only 1/3 to 1/2 of those are diagnosed and treated
Historically: Due to rapid progression of morbidity and mortality, once patients were diagnosed with pulmonary hypertension they were described as entering “the kingdom of the near-dead”
Modern day: Patient survival has dramatically improved as treatment options for PAH have increased
Robin ED. The kingdom of the near-dead: the shortened unnatural life history of primary pulmonary hypertension. Chest. 1987;92:330-4.
The prevalence of PAH is estimated at nearly 50,000 to 100,000, with only 15,000 to 25,000 patients diagnosed and treated. The disease course and prognosis for patients with PAH has dramatically improved over the last several decades.
McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9. 11

12. Mechanisms of Pathology for PAH
Endothelin pathway
Prostacyclin pathway
Nitric oxide pathway
Endothelial cells
L-arginine
Preproendothelin
Proendothelin
Arachidonic acid
Prostaglandin I2
NOS
Nitric oxide
Endothelin-1
Prostaglandin I2
sGC stimulator
Endothelin-receptor A
GTP
Endothelin-receptor B
The graphic shows three pathways that are believed to play a key role in the pathology of PAH: the endothelin pathway, nitric oxide pathway, and the prostacyclin pathway. The illustration also shows the sites and targets for common treatment options. Endothelin receptor antagonists act on the endothelin receptors in that pathway. The target for the phosphodiesterase-5 inhibitors, as well as the newly-approved agent riociguat, is the nitric oxide pathway. Meanwhile, the prostacyclin analogs target the prostacyclin pathway.
Exogenous nitric oxide
Prostacyclin analogues
Endothelin-receptor antagonists
cGMP
cAMP
Phosphodiesterase type 5
Vasodilatation and antiproliferation
Vasodilatation and antiproliferation
Vasoconstriction and proliferation
Phosphodiesterase type 5 inhibitor
Adapted from: Humbert, et al. N Engl J Med. 2004;351: 12

13. Mechanisms in PAH Increased pulmonary vascular resistance
Sustained vasoconstriction
Excessive pulmonary vascular remodeling
In situ thrombosis
Increased pulmonary vascular resistance is the hallmark of pulmonary hypertension. This increase is due to: sustained vasoconstriction, excessive pulmonary vascular remodeling, and in situ thrombosis.
Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12. 13

14. Pathology of PAH

16. Symptoms Suspect PH? Clinical symptoms Unexplained dyspnea on exertion
Presyncope
Syncope
Signs of right ventricular dysfunction
Other non-specific symptoms in patients with PAH
Fatigue, weakness, angina, abdominal distension, edema
In general, the clinical symptoms associated with PAH are rather non-specific, and may go unreported by patients or unrecognized by clinicians. Patients can present with one or more of the following symptoms: breathlessness, fatigue, weakness, angina, syncope, abdominal distension, and edema. Patients who present with unexplained dyspnea on exertion, presyncope, syncope, or signs of right ventricular dysfunction are candidates for additional diagnostic screening.
Suspect PH?
Galie, et al. Eur Heart J. 2009;30:
Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50. 16

17. Diagnostic Algorithm for PAH
RHC is MANDATORY to confirm the diagnosis of PAH
V/Q = ventilation / perfusion lung scan; CTEPH = chronic thromboembolic pulmonary hypertension; RHC = right heart catheterization; PAP = pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; PVR = pulmonary vascular resistance; WU = wood units
A step-wise approach can be taken when evaluating patients for possible diagnosis of PAH. A diagnosis of PAH requires the exclusion of other causes of pulmonary hypertension. As such, heart and lung disease need to be ruled out. Also, chronic thromboembolic pulmonary hypertension (CTEPH) is ruled out by performing a V/Q scan and obtaining negative results. Right heart catheterization is mandatory for diagnostic confirmation.
Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50. 17

18. Diagnostic Approach to PAH
McLaughlin, V. V. et al. J Am Coll Cardiol 2009;53:

19. Chest X-Ray and ECG in PAH
McLaughlin, V. V. et al. J Am Coll Cardiol 2009;53:

20. Echocardiography for PAH
Evaluate left heart
Evaluate valves
Evaluate for structural lesions
Evaluate right heart size
Estimate right sided pressures
Measure indices of RV function
TAPSE
Tei index
Evaluate for pericardial effusion

21. 6 Minute Walk Test Easy to perform
Functional assessment during office visits
Assess response to therapy
Primary end point of clinical trials
Performed according to stated ATS guidelines to ensure reproducibility

22. 6 Minute Walk Test Correlation between RV function and cardiac output
Correlation with prognosis
3 year survival in patients with 6MWD of < 332 m: 20%
3 year survival in patients with 6MWD of > 332 m: 92%
Current goal directed therapy: aim for 380 m
Miyamoto, S, Nagaya, N, Satoh, T . Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension: Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2000;161(2 Pt 1):487–492.

23. RHC is more than just measuring
pressures!
Cardiac output: 5 L/min
Cardiac index: L/min/m2
PVR (mean PAP-PAWP/ CO): 0.6 to 2.5 WU
Pulmonary artery saturation (PA sat): 70%
Acute vasoreactivity test for PAH: Positive if decrease of >/= 10 in mPAP to < 40 without drop in cardiac output
Agents: iNO, adenosine, epoprostenol
Consider exercise, volume loading, LHC as indicated

24. Vasoreactive PAH Excellent prognosis !
9/2011: 52 YO man at NYHA FC III (long distance runner, 10K 62 mins), was unable to run a soccer field lap with his son >> DOE with 1 flight of stairs >> DOE level ground. Stress echo: Resting RVSP which rose to mmHg post exercise.
RHC – 10/2011
NYHA FC III
PAP: 83/21
mPAP: 42
mPAWP: 11
TDCO: 6.27
PVR: 344
Post iNO Data
PAP: 47/10
mPAP: 22
TDCO: 6.46
PVR: 86
RHC 5/2013
NYHA FC I
10K time of 56 mins!!
Echo: enlarged RV
PAP: 64/22 (36)
TDCO: 6.83
mPAWP: 15
PVR: 245
Post iNO Data
PAP 43/14 (23)
PVR: 126
TDCO: 6.3
SBP:102/65, HR 62
Tadalafil
40 mg added
10 K off limits!
Diltiazem
360 mg
8/ /2018
RVSP ~
Normal RV
NYHA FC I
10K still off limits
Vasoreactive PAH
Excellent prognosis !

25. Survival In PAH- Depends On The Right Ventricle
Patient 1
PASP 90
Normal RV size and function
Patient 2
PASP 50
Dilated RV with reduced function