Pathophysiology of Pulmonary Hypertension

DEFINITION & HEMODYNAMIC THRESHOLD

WHO CLASSIFICATION (5 Groups) - Pathomechanical Basis

I. CORE PATHOPHYSIOLOGICAL MECHANISMS OF PAH (Group 1)

1. SUSTAINED VASOCONSTRICTION

• A rise in cytosolic free Ca²⁺ ([Ca²⁺]cyt) in pulmonary arterial smooth muscle cells (PASMCs) is the primary trigger for vasoconstriction and key stimulus for PASMC proliferation and migration.
• Resting [Ca²⁺]cyt is elevated in proliferating PASMCs vs. growth-arrested cells, linking Ca²⁺ homeostasis to both vasoconstriction and vascular remodeling.

• HPV is an intrinsic property of PASMCs (demonstrated in isolated, endothelium-free arteries and single PASMCs).
• It is adaptive acutely - redirecting blood away from poorly ventilated areas to optimize V/Q matching.
• In chronic hypoxia (COPD, high altitude), two factors elevate PAP: (a) sustained vasoconstriction and (b) structural vascular remodeling from PASMC proliferation, developing over weeks.
• The remodeling is characterized by medial thickening of small pulmonary arteries and arterioles.

2. IMBALANCE OF VASOACTIVE MEDIATORS

• eNOS uncoupling occurs when L-arginine becomes limited, switching NO production to ROS (reactive oxygen species) production instead.
• High arginase activity competes for L-arginine, promoting vascular remodeling and neointima formation.
• Nitration of protein kinase G (PKG) by reactive nitrogen species attenuates cGMP-mediated vasodilation and increases smooth muscle proliferation - an early event in PAH.

• NOX2 and NOX4 isoforms are upregulated in PASMCs; NOX-derived superoxide causes medial thickening, disordered proliferation/migration, impaired angiogenesis.
• Xanthine oxidase (XO) activity dominates over xanthine dehydrogenase in PAH, contributing to ROS excess. XO is elevated in IPAH patients; allopurinol reduces right ventricular hypertrophy in animal models.

3. VASCULAR REMODELING

• Aneurysmatic dilatations of small muscular arteries/arterioles, found in IPAH and in PAH associated with L-to-R shunts, HIV, cirrhosis, and scleroderma.
• Contain collections of proliferating endothelial cells, smooth muscle cells, myofibroblasts, and matrix proteins that partially or completely occlude the vessel lumen.
• In IPAH: arise from monoclonal endothelial proliferation (analogous to neoplasia).
• In other forms of PAH: arise from polyclonal cell populations, suggesting different mechanisms.
• Often coexist with concentric laminar intimal thickening and medial destruction.

• Somatic mutations, microsatellite instability, and aneuploidy in PAH lung vascular cells.
• Anti-apoptotic signaling: decreased apoptosis maintains the hypertrophied vascular wall; induction of apoptosis causes regression in animal models.
• miRNAs: BMP pathway regulates miRNA processing; attenuated in BMPR2/SMAD9 mutations; multiple other miRNAs implicated independently.

4. IN SITU THROMBOSIS

• Monoclonal endothelial proliferation, PASMC migration, and accumulation of inflammatory cells, platelets, and progenitor cells cause occlusion of small vessels.
• Represents a local imbalance of pro- vs. anticoagulant forces (not embolic in origin).
• Elevated shear stress from high pressure shifts endothelium from anti- to procoagulant activity.
• Platelets release vasoactive and mitogenic factors: thromboxane metabolites, serotonin, PDGF, TGF-β, and VEGF - all contributing to further vascular remodeling.

5. INCREASED ARTERIAL WALL STIFFNESS

• Accelerated turnover of extracellular matrix proteins; increased tenascin-C expression in experimental PH models and in PAH patients.
• Decreased vascular compliance: inability to recruit previously unperfused vessels.
• Modest increases in pulmonary blood flow elicit disproportionate PAP elevations (contrast: normal lung tolerates substantial parenchymal loss without developing PH).

II. GENETIC/MOLECULAR BASIS

• Found in 70-80% of familial (heritable) PAH and 10-20% of IPAH patients.
• Autosomal dominant with incomplete penetrance: only ~27% of carriers develop disease (42% of women, 14% of men).
• Predominantly nonsense, frameshift, or splice-site mutations causing premature protein truncation.
• BMPR2 signaling normally promotes anti-proliferative, pro-apoptotic signaling in PASMCs via SMAD1/5/8 pathways - loss of this "brake" allows uncontrolled vascular cell proliferation.
• BMPR2 mutation carriers develop PAH earlier with more severe disease and higher risk of death/transplantation.

• ALK1 (ACVRL1) and Endoglin (ENG) - associated with hereditary hemorrhagic telangiectasia (HHT) + PAH.
• SMAD9 - encodes Smad8, a downstream BMPR2 mediator.
• GDF2 - encodes BMP9 (ligand for ALK1-BMPRII complex).
• TBX4 - enriched in pediatric PAH; critical for lung development.
• KCNK3 - potassium channel gene; loss of function promotes PASMC depolarization and vasoconstriction.
• CAV1, EIF2AK4, ATP13A3 - less common mutations.
• Epigenetic modifications and DNA damage/repair abnormalities are also well-documented.

III. RIGHT VENTRICULAR CONSEQUENCES (Cor Pulmonale)

1. Compensated phase: RV hypertrophy (concentric) - increased wall thickness maintains stroke volume. Coronary blood supply may become inadequate relative to the hypertrophied myocardial mass, causing RV ischemia and angina.
2. Decompensated phase: RV dilation (eccentric), tricuspid regurgitation, elevated right atrial pressure, systemic venous hypertension.
3. RV failure: Reduced RV stroke volume, decreased left ventricular filling (ventricular interdependence - D-shaped interventricular septum shifts leftward), low cardiac output, syncope, peripheral edema.
4. The dilated pulmonary artery trunk can compress the left main coronary artery, contributing to ischemia.

IV. PATHOPHYSIOLOGY BY WHO GROUP (Summary)

V. SUMMARY DIAGRAM OF PATHOGENESIS

↓ BMPR2 / genetic susceptibility
       ↓
Endothelial injury / dysfunction
       ↓
↓ NO  ↓ PGI₂  ↑ ET-1  ↑ TXA₂  ↑ 5-HT  ↑ ROS
       ↓
Vasoconstriction + PASMC proliferation ← ↑ [Ca²⁺]cyt
       ↓
Vascular remodeling (intima, media, adventitia)
Plexiform lesions + in situ thrombosis + arterial stiffness
       ↓
↑ PVR → ↑ mPAP
       ↓
RV hypertrophy → RV failure → low CO → death

KEY HIGH-YIELD POINTS FOR MD EXAM

1. Normal mPAP ~15 mmHg; PH defined as mPAP >20 mmHg at rest (right heart catheterization).
2. Normal pulmonary vascular impedance is 1/10th systemic - making it uniquely vulnerable to obliterative processes.
3. Hypoxia causes vasoconstriction in pulmonary vessels (opposite of systemic circulation) - an adaptive mechanism that becomes pathological when chronic.
4. Three cardinal mediator changes in PAH: ↓NO, ↓PGI₂, ↑ET-1 - these three pathways are the targets of all modern PAH drug therapy (PDE-5 inhibitors/sGC stimulators, prostanoids, ERAs).
5. BMPR2 mutations - 70-80% familial PAH; autosomal dominant, incomplete penetrance; loss of anti-proliferative brake on PASMCs.
6. Plexiform lesions = pathological hallmark of severe PAH; monoclonal endothelial proliferation in IPAH (cancer-like biology).
7. In situ thrombosis is distinct from pulmonary embolism - local coagulation imbalance, no remote embolic source.
8. 5-HT/serotonin hypothesis - basis of epidemic PAH from aminorex and fenfluramine anorexigens.
9. RV ischemia occurs in PAH because coronary supply cannot meet demands of hypertrophied RV working against high afterload.
10. PCWP (pulmonary capillary wedge pressure) distinguishes pre-capillary (PAH, Group 1) from post-capillary (Group 2) PH: normal PCWP (≤15 mmHg) in Group 1.

• Fishman's Pulmonary Diseases and Disorders, 5e - Chapters 28, 72 (pp. 512, 1104-1106, 1244-1248, 1314-1338)
• Murray & Nadel's Textbook of Respiratory Medicine, 7e - Chapters 9, 84 (pp. 889, 1920-1925)