What is the mechanism of pulmonary hypertension (PH) in idiopathic cases?

Mechanism of Pulmonary Hypertension in Idiopathic PAH

Idiopathic pulmonary arterial hypertension results from a multifactorial pathobiology involving endothelial dysfunction, abnormal smooth muscle cell proliferation with impaired apoptosis, genetic mutations (particularly BMPR2), vasoconstriction, thrombosis, and inflammation that collectively cause progressive pulmonary vascular remodeling and increased pulmonary vascular resistance. 1

Core Pathogenic Mechanisms

Endothelial Dysfunction

• Impaired production of vasodilators (nitric oxide and prostacyclin) combined with overexpression of vasoconstrictors (endothelin-1 and thromboxane A2) creates a fundamental imbalance that drives both vasoconstriction and cellular proliferation 1
• Reduced plasma levels of vasoactive intestinal peptide, another vasodilator and antiproliferative substance, further contributes to disease progression 1
• This endothelial dysfunction is not merely functional but represents a persistent pathological state that promotes ongoing vascular remodeling 1

Abnormal Smooth Muscle Cell Biology

• Pulmonary artery smooth muscle cells (PASMCs) exhibit a critically decreased apoptosis/proliferation ratio, meaning cells proliferate excessively while failing to undergo normal programmed cell death 1
• Specific molecular abnormalities include:
  • Inappropriate activation of transcription factors HIF-1 alpha and NFAT 1
  • Decreased expression of voltage-gated potassium channels (Kv1.5 and Kv2.1), leading to membrane depolarization and calcium overload 1
  • De novo expression of survivin, an antiapoptotic protein that prevents normal cell death 1
  • Abnormal mitochondrial hyperpolarization contributing to impaired apoptosis 1
• Excessive proliferation in response to transforming growth factor beta further drives unwanted cell accumulation 1
• Increased expression of transient receptor potential channels promotes calcium overload and PASMC proliferation 1

Genetic Factors

• BMPR2 mutations are present in up to 25% of idiopathic PAH cases, despite the absence of family history 1
• These mutations cause loss of function in the SMAD signaling pathway, which normally regulates vascular cell growth 1
• The high frequency of "sporadic" IPAH cases and reduced penetrance (only 20% of BMPR2 mutation carriers develop disease) indicates that additional triggers beyond genetics are required 1
• Potential additional genetic factors include polymorphisms in serotonin transporter gene, nitric oxide synthase, and carbamyl-phosphate synthase gene 1

Vascular Remodeling

• All three layers of the vessel wall undergo pathological changes: intimal hyperplasia, medial hypertrophy, and adventitial proliferation 1
• The process involves multiple cell types including endothelial cells, smooth muscle cells, and fibroblasts 1
• Increased production of extracellular matrix components (collagen, elastin, fibronectin, tenascin) in the adventitia contributes to vessel wall thickening 1
• The adventitia becomes fragmented, permitting cell migration and creating mitogenic peptides like tenascin 1
• Plexiform arteriopathy represents the most severe form of vascular remodeling, characterized by actively proliferating endothelial cells without evidence of apoptosis 2

Thrombotic Mechanisms

• Prothrombotic abnormalities are consistently demonstrated, with thrombi present in both small distal pulmonary arteries and proximal elastic pulmonary arteries 1
• Elevated fibrinopeptide A levels (reflecting thrombin activity) and elevated thromboxane A2 levels indicate ongoing thrombotic activity 1
• Elevated plasminogen activator inhibitor-1 and reduced tissue plasminogen activator create a procoagulant state 1

Inflammatory Component

• Inflammatory cells are ubiquitous in PAH pathological changes 1
• Pro-inflammatory cytokines are elevated in plasma of PAH patients 1
• Platelets play a significant role through the serotonin pathway, with platelets depleted of serotonin and elevated plasma serotonin levels 1, 3

Integrated Pathophysiology

The mechanisms operate through interconnected pathways rather than in isolation, creating a self-perpetuating cycle 1:

• The imbalance between thrombogenic, mitogenic, and proinflammatory factors versus anticoagulant, antimitotic, and vasodilating mechanisms initiates and perpetuates vasoconstriction, proliferation, thrombosis, and inflammation 1
• These interacting processes produce the obstructive pathological changes characteristic of PAH 1
• The consequent increase in pulmonary vascular resistance leads to right ventricular overload and eventually right ventricular failure 1

Clinical Implications

• Medial hypertrophy is believed to be an earlier and more reversible lesion compared to intimal fibrosis or plexogenic arteriopathy 1
• The distribution of vascular lesions may be diffuse or focal, and individual patients may manifest all types of arterial abnormalities 1
• Right ventricular function is a major determinant of functional capacity and prognosis, though the adequacy of RV compensatory response varies considerably among patients 1
• Current therapies targeting prostanoids, endothelin receptor antagonism, and PDE-5 inhibition address the vasoconstrictor/vasodilator imbalance but increasingly it is recognized that therapies must also address the proliferation/apoptosis imbalance 1