On this week’s episode, we’re continuing our Guidelines Series exploring the 2022 ESC/ERS Guidelines for the diagnosis and treatment of Pulmonary Hypertension. If you missed our first episode in the series, give it a listen to hear about the most recent recommendations regarding Pulmonary Hypertension definitions, screening, and diagnostics. Today, we’re talking about the next steps after diagnosis. Specifically, we’ll be discussing risk stratification, establishing treatment goals, and metrics for re-evaluation. We’ll additionally introduce the mainstays of pharmacologic therapy for Pulmonary Hypertension.

Meet Our Co-Hosts

Rupali Sood grew up in Las Vegas, Nevada and made her way over to Baltimore for medical school at Johns Hopkins. She then completed her internal medicine residency training at Massachusetts General Hospital before returning back to Johns Hopkins, where she is currently a pulmonary and critical care medicine fellow. Rupali’s interests include interstitial lung disease, particularly as related to oncologic drugs, and bedside medical education.

Tom Di Vitantonio is originally from New Jersey and attended medical school at Rutgers, New Jersey Medical School in Newark. He then completed his internal medicine residency at Weill Cornell, where he also served as a chief resident. He currently is a pulmonary and critical care medicine fellow at Johns Hopkins, and he’s passionate about caring for critically ill patients, how we approach the management of pulmonary embolism, and also about medical education of trainees to help them be more confident and patient centered.

Key Learning Points

1) Episode Roadmap

How to set treatment goals, assess symptom burden, and risk-stratify patients with suspected/confirmed pulmonary arterial hypertension (PAH).
What tools to use to re-evaluate patients on treatment
Intro to major PAH medication classes and how they map to pathways.

2) Case-based diagnostic reasoning

Patient: 37-year-old woman with exertional dyspnea, mild edema, abnormal echo, telangiectasias + epistaxis → raises suspicion for HHT (hereditary hemorrhagic telangiectasia) and/or early connective tissue disease.

Key reasoning move: start broad (Groups 2–5) and narrow using history/exam/testing.
In a young patient without obvious left heart or lung disease, think more about Group 1 PAH (idiopathic/heritable/associated).

HHT teaching point: HHT can cause PH in more than one way:

More common: high-output PH from AVMs (often hepatic/pulmonary)
Rare (1–2% mentioned): true PAH phenotype (vascular remodeling; associated with ALK1 in some patients), behaving like Group 1 PAH.

3) Functional class assessment

WHO Functional Class:

Class I: no symptoms with ordinary activity, only with exertion
Class II: symptoms with ordinary activity
Class III: symptoms with less-than-ordinary activity (can’t do usual chores/shopping without dyspnea)
Class IV: symptoms at rest

Practical bedside tip they give:

Ask if the patient can walk at their own pace or keep up with a similar-age peer/partner. If not, think Class II (or worse).

4) Risk stratification at diagnosis: why, how, and which tools

Big principle: treatment choices are driven by risk, and the goal is to move patients to low-risk quickly.

ESC/ERS approach at diagnosis (as described):

Use a 3-strata model predicting 1-year mortality:
- Low: <5%
- Intermediate: 5–20%
- High: >20%

ESC/ERS risk assessment variables (10 domains discussed):

Clinical progression, signs of right heart failure, syncope
WHO FC
Biomarkers (NT-proBNP)
Exercise capacity (6MWD)
Hemodynamics
Imaging (echo; sometimes cardiac MRI)
CPET (peak VO₂; VE/VCO₂ slope)

They note: even if you don’t have everything, the calculator can still be useful with ≥3 variables.

REVEAL 2.0:

Builds on similar core variables but adds further patient context (demographics, renal function, BP, DLCO, etc.)

Case result: both tools put her in intermediate risk (ESC/ERS ~1.6; REVEAL 2.0 score 8), underscoring that mild symptoms can still equal meaningful mortality risk.

5) Treatment goals and follow-up philosophy

What they explicitly prioritize:

Help patients feel better, live longer, and stay out of the hospital
Use risk tools to communicate prognosis and to track improvement
Reassess frequently (they mention ~every 3 months early on) until low risk is achieved
“Time-to-low-risk” is an important treatment goal

Also emphasized:

The diagnosis is psychologically heavy; patients need clear counseling, reassurance about the plan, and connection to support groups.

6) Medication classes for the treatment of PAH

Nitric oxide–cGMP pathway

PDE5 inhibitors: sildenafil, tadalafil
Soluble guanylate cyclase stimulator: riociguat
Important safety point: don’t combine PDE5 inhibitors with riociguat (risk of significant hypotension/hemodynamic effects)

Endothelin receptor antagonists (ERAs)

“-sentan” drugs: bosentan (less used due to side effects/interactions), ambrisentan, macitentan
Teratogenicity emphasized
Hepatotoxicity that requires LFT monitoring
Can cause fluid retention and peripheral edema

Prostacyclin pathway

Prostacyclin analogs/agonists:
- Epoprostenol (potent; short half-life; IV administration)
- Treprostinil (IV/SubQ/oral/inhaled options)
- Selexipag (oral prostacyclin receptor agonist)

7) Sotatercept (post-guidelines)

They note sotatercept wasn’t in 2022 ESC/ERS but is now “a game changer” in practice:

Mechanism: ligand trap affecting TGF-β signaling / remodeling biology
Positioned as potentially more disease-modifying than pure vasodilators
Still evolving: where to place it earlier vs later in regimens is an active question in the field

8) How risk category maps to initial treatment intensity

General approach they outline:

High risk at diagnosis: parenteral prostacyclin (IV/SubQ) strongly favored, often aggressive early
Intermediate risk: at least dual oral therapy (typically PDE5i + ERA); escalate if not achieving low risk
Low risk: at least one oral agent; many still use dual oral depending on etiology/trajectory

For the case: intermediate-risk → start dual oral therapy (they mention tadalafil + ambrisentan as a typical choice), reassess in ~3 months; add a third agent (e.g., selexipag/prostacyclin pathway) if not low risk.

References and Further Reading

Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P, Ferrari P, Ferreira DS, Ghofrani HA, Giannakoulas G, Kiely DG, Mayer E, Meszaros G, Nagavci B, Olsson KM, Pepke-Zaba J, Quint JK, Rådegran G, Simonneau G, Sitbon O, Tonia T, Toshner M, Vachiery JL, Vonk Noordegraaf A, Delcroix M, Rosenkranz S; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022 Oct 11;43(38):3618-3731. doi: 10.1093/eurheartj/ehac237. Erratum in: Eur Heart J. 2023 Apr 17;44(15):1312. doi: 10.1093/eurheartj/ehad005. PMID: 36017548.

Condon DF, Nickel NP, Anderson R, Mirza S, de Jesus Perez VA. The 6th World Symposium on Pulmonary Hypertension: what’s old is new. F1000Res. 2019 Jun 19;8:F1000 Faculty Rev-888. doi: 10.12688/f1000research.18811.1. PMID: 31249672; PMCID: PMC6584967.

Maron BA. Revised Definition of Pulmonary Hypertension and Approach to Management: A Clinical Primer. J Am Heart Assoc. 2023 Apr 18;12(8):e029024. doi: 10.1161/JAHA.122.029024. Epub 2023 Apr 7. PMID: 37026538; PMCID: PMC10227272.

Hoeper MM, Badesch DB, Ghofrani HA, Gibbs JSR, Gomberg-Maitland M, McLaughlin VV, Preston IR, Souza R, Waxman AB, Grünig E, Kopeć G, Meyer G, Olsson KM, Rosenkranz S, Xu Y, Miller B, Fowler M, Butler J, Koglin J, de Oliveira Pena J, Humbert M; STELLAR Trial Investigators. Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2023 Apr 20;388(16):1478-1490. doi: 10.1056/NEJMoa2213558. Epub 2023 Mar 6. PMID: 36877098.

Ruopp NF, Cockrill BA. Diagnosis and Treatment of Pulmonary Arterial Hypertension: A Review. JAMA. 2022 Apr 12;327(14):1379-1391. doi: 10.1001/jama.2022.4402. Erratum in: JAMA. 2022 Sep 6;328(9):892. doi: 10.1001/jama.2022.13696. PMID: 35412560.

116. Guidelines Series: Pulmonary Hypertension – Risk Stratification and Treatment Goals

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