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Mechanistic Deep Dive
BMPR2 Pathway
- Most common heritable PAH (70% heritable)
- TGF-β superfamily receptor
- Loss-of-function â unopposed proliferation
- Reduced apoptosis of smooth muscle
- Sotatercept restores BMPR-II / activin balance
Vascular Remodeling
- Endothelial dysfunction
- Smooth muscle hypertrophy + proliferation
- Adventitial fibrosis
- In situ thrombosis
- Inflammation (macrophages, T cells)
- Plexiform lesions
Genetics
- BMPR2 (most common)
- ALK1, ENG (HHT-associated)
- SMAD9
- CAV1
- KCNK3 (potassium channel)
- TBX4 (Pulmonary disease + skeletal defect)
- Genetic counseling for familial cases
Recent Trials & Updates
STELLAR (2023) â Sotatercept
- N = 323 PAH on background therapy
- Sotatercept (activin ligand trap) vs placebo
- â 6MWT 40 m, â clinical worsening events
- FDA approved 2024 for PAH (Group 1)
- Novel mechanism â game changer
HYPERION (2024)
- Sotatercept in earlier-stage PAH
- Ongoing
INCREASE (2021)
- Inhaled treprostinil for ILD-PH (Group 3 with severe PH)
- â 6MWT 31 m
- Class IIa for ILD-PH (severe)
MERIT (2017)
- Macitentan for CTEPH
- Improved PVR, 6MWT
- Class IIa for inoperable / persistent CTEPH
RAPID + RACE (CTEPH BPA)
- BPA improves PVR, 6MWT, hemodynamics
- 10+ year experience from Japan, Europe
Anticoagulation Debate
- COMPERA registry: warfarin associated with worse survival in IPAH (paradoxical)
- 2022 ESC: no routine anticoagulation in IPAH/HPAH
- CTEPH still lifelong AC
CCB in Vasoreactive Responders
- Long-term survival ~ 70% at 5 years
- Use high-dose (amlodipine 20-30 mg, diltiazem 540-960 mg, nifedipine 240 mg)
- Only ~ 10% of IPAH
High-Yield Specialist Points
Risk Stratification (REVEAL 2.0)
- Composite score including age, etiology, gender, hemodynamics, functional class, 6MWT, BNP, RAP, CI, RV function
- Stratifies to low (†7), intermediate (8-12), high (⥠13)
- Predicts 1-year mortality
ESC/ERS 4-Strata Risk
- Low: WHO I-II, 6MWT > 440, BNP < 50, mRAP < 8, CI > 2.5
- Intermediate-low / intermediate-high / high based on combinations
- Treatment goal: achieve low-risk status
Pulmonary Rehab in PH
- 2022 ESC Class I
- Improves exercise capacity, QOL
- Multidisciplinary, supervised
Lung Transplant Listing
- Refractory PAH despite optimal therapy
- Bilateral lung > single-lung (PVR â better)
- Heart-lung for Eisenmenger or shunt
- LAS scoring
Atrial Septostomy
- Palliative for severe PAH with RV failure
- Creates RâL shunt to decompress RV
- Bridging procedure
CTEPH Workup + Referral
- V/Q scan most sensitive (90%+)
- Pulmonary angiography for surgical planning
- Refer to specialized PEA center
- Multidisciplinary CTEPH team
Scleroderma PAH
- Common cause (10-15% of scleroderma)
- DETECT screening algorithm
- Annual screening of asymptomatic scleroderma
- Worse prognosis than IPAH
- Multidisciplinary CTD + PAH team
CHD-PAH
- Pre-tricuspid (ASD, partial AVSD) vs post-tricuspid (VSD, PDA)
- Eisenmenger syndrome: reversed shunt
- Bosentan landmark BREATHE-5
- Specific risk-benefit balance
Drug Interactions
- Sildenafil + nitrates: severe hypotension (CONTRAINDICATED)
- Riociguat + PDE5i: severe hypotension (CONTRAINDICATED)
- Bosentan: CYP3A4 induces â â contraceptive efficacy
- Ambrisentan/macitentan: less LFT issues
- Selexipag: CYP2C8
Sotatercept Side Effects
- Telangiectasia, epistaxis
- Hgb / hct â (monitor)
- Subcutaneous q3-4 weeks
- High cost
Pearls
- mPAP > 20 (revised 2018 from > 25)
- 5 WHO groups; treatment varies dramatically by group
- V/Q scan ALWAYS in PH workup â donât miss CTEPH (curable!)
- PAH triple pathway: ERA + PDE5i/riociguat + prostanoid
- Initial combo > sequential (AMBITION)
- Sotatercept 2024 FDA â novel mechanism (activin)
- CTEPH cure = PEA at experienced center
- Vasoreactivity testing in IPAH only â 10% positive â CCB
- Pregnancy contraindicated in PAH (25-30% maternal mortality)