Pathobiology of Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension (PAH) is a progressive disease associated with occlusive pulmonary arterial remodeling of vessels < 500 mu m for which there is no cure. Even in the era of PAH-specific combination therapies, aberrant lung pathology and progressive right ventricular (RV) dysfunction occur, culminating in a median survival of 6.2 years, according to the latest data in the treatment era. While better than a median survival from symptom onset of 2.8 years prior to PAH-specific therapies, it is still poor. Thus, there is an urgent need to move the opportunities forward for meaningful treatment strategies. Clearly, a better understanding of the highly complex pathobiology of PAH is needed if we are to achieve new and novel treatment strategies. This is especially so if we are to pursue a more personalized treatment approach to PAH in light of the multitude of pathobiological abnormalities described in PAH, which likely culminate in a final common pathway for PAH development. In this State-of-the-Art review, we provide comprehensive insights into the complex pathobiology of PAH to provide understanding and insights for the practicing clinician. We review the pathology of PAH and the cells involved and their impact in driving pathological abnormalities (pulmonary artery endothelial cells, smooth muscle cells, fibroblasts and pericytes) as well as the role of the extracellular matrix. Inflammation and immune dysfunction are considered important drivers of PAH and are comprehensively discussed. Another pathway relates to TGF beta/ bone morphogenic protein (BMP) imbalance, which is highlighted, as well as a new novel agent, sotatercept that impacts this imbalance. Genetic factors underlying heritable PAH (HPAH) are addressed, as well as epigenetic influences. Other important pathways highlighted include growth factor signaling, ion channels/channelopathy, hypoxia signaling pathways, and altered metabolism and mitochondrial dysfunction. We also address the "estrogen paradox", whereby PAH is more common in women but more severe in men. The basis for drug-induced PAH is discussed, including the new methamphetamine epidemic. We briefly provide insights into DNA damage and senescence factors in pathobiology and highlight commonalities between PAH and cancer pathobiology. Furthermore, we provide concluding insights for the treating physician. In conclusion, we need to pose the right questions to motivate novel and effective treatment strategies for the management of PAH based on pathobiological principles and understanding.