Pulmonary arterial hypertension: the clinical syndrome

Abstract

Pulmonary arterial hypertension is a progressive disorder in which endothelial dysfunction and vascular remodeling obstruct small pulmonary arteries, resulting in increased pulmonary vascular resistance and pulmonary pressures. This leads to reduced cardiac output, right heart failure, and ultimately death. In this review, we attempt to answer some important questions commonly asked by patients diagnosed with pulmonary arterial hypertension pertaining to the disease, and aim to provide an explanation in terms of classification, diagnosis, pathophysiology, genetic causes, demographics, and prognostic factors. Furthermore, important molecular pathways that are central to the pathogenesis of pulmonary arterial hypertension are reviewed, including nitric oxide, prostacyclin, endothelin-1, reactive oxygen species, and endothelial and smooth muscle proliferation.

Keywords: hemodynamics; hypertension, pulmonary; nitric oxide.

Figure 1. Clinical classification of PH from Dana Point

Figure 2. Algorithm for diagnosis and severity rating of PH

Figure 3. Natural history of PAH and right heart failure

The normal pulmonary vasculature is a low-resistance, high-flow system. In the case of PAH, the small pulmonary arteries are progressively narrowed, leading to an increase in PVR and the pulmonary artery pressures. Right heart catheterization is the gold standard for diagnose of PAH. When the mPAP is elevated above 25 mm Hg and the PAOP is less than 15 mm Hg, PAH is diagnosed. The progressive increase in PVR and pulmonary pressures subsequently lead to reduced CO and right heart failure.

Figure 4. BMP-BMPRII signaling

Following BMPs binding, BMPRII forms heterotetrameric complexes with BMPRI to generate and transduce a phosphorylation to receptor-mediated Smads (R-Smads) 1, 5, and 8, which in turn forms transcriptional complex with the co-Smad, Smad4. This complex then translocates to the nucleus to regulate target gene transcription (e.g., antiproliferative effects). Among the many BMPRII mutations have been identified in PAH patients, about 70% introduce a premature termination codon (PTC) and follow the process of nonsense-mediated decay, resulting in haplo-insufficiency. Cysteine residues substitutions in the ligand-binding or the kinase domain of BMPRII causes impaired trafficking of BMPRII to the cell membrane, as well as alters subcellular localization of BMPRI. Noncysteine mutations in the kinase domain reach the cell membrane but fail to activate BMP signaling. In contrast, BMPRII mutants in the cytoplasmic tail retain the ability to transduce BMP signals.

Figure 5. Pie charts showing a comparison of PAH subgroups in the French Registry and REVEAL Registry

Figure 6. Comparison of survival rate for a PAH patient according to different Registries' survival equations

Figure 7. Classic vasodilator and vasoconstrictor systems and their translational therapies for PAH

NO activates vasodilation and antiproliferation of smooth muscle cells via a cGMP-dependent mechanism. Inhalation of NO, administration of nitrite and/or nitrate, sGC stimulator (riociguat), PDE5 inhibitors (sidenafil and tadalafil) and BH4 analogue (6R-BH4) have been shown effective in the treatment of PAH. Prostacyclin activates vasodilation and inhibits proliferation of smooth muscle cells via a cAMP-dependent mechanism. Prostacyclin and its derivatives (epoprostenol, treprosinil, iloprost, and beraprost) and IP receptor agonist (selexipag) provide therapeutic benefit in PAH. Endothelin-1 stimulates vasoconstriction and proliferation via activation of both ET_A and ET_B receptors on smooth muscle cells. ET_A blocker (ambrisentan) and dual endothelin-1 blockers (bosentan and macitentan) prove useful in the treatment of PAH.

Figure 8. Cellular changes in PAH

Healthy endothelium regulates the balance between vasodilation and vasoconstriction and inhibits smooth muscle cell proliferation to maintain a low-resistance pulmonary vasculature. In PAH, dysfunctional endothelium alters vasodilator/vasoconstrictor balance to increase contractility of pulmonary arteries. In addition, abnormal proliferation of smooth muscle cells, the earliest pathobiological features of vascular remodeling, leads to muscularization of peripheral pulmonary arteries and medial hypertrophy in pulmonary muscular arteries. Increased proliferation and progressive migration of smooth muscle cells further results in intimal fibrosis. In the late stage of disease progression, formation of plexiform lesions and in situ thrombus occlude the vessel lumen. These dysregulated events lead to progressive reducing of the blood flow, thus causing PAH.