Tensions in Taxonomies: Current Understanding and Future Directions in the Pathobiologic Basis and Treatment of Group 1 and Group 3 Pulmonary Hypertension

Abstract

In the over 100 years since the recognition of pulmonary hypertension (PH), immense progress and significant achievements have been made with regard to understanding the pathophysiology of the disease and its treatment. These advances have been mostly in idiopathic pulmonary arterial hypertension (IPAH), which was classified as Group 1 Pulmonary Hypertension (PH) at the Second World Symposia on PH in 1998. However, the pathobiology of PH due to chronic lung disease, classified as Group 3 PH, remains poorly understood and its treatments thus remain limited. We review the history of the classification of the five groups of PH and aim to provide a state-of-the-art review of the understanding of the pathogenesis of Group 1 PH and Group 3 PH including insights gained from novel high-throughput omics technologies that have revealed heterogeneities within these categories as well as similarities between them. Leveraging the substantial gains made in understanding the genomics, epigenomics, proteomics, and metabolomics of PAH to understand the full spectrum of the complex, heterogeneous disease of PH is needed. Multimodal omics data as well as supervised and unbiased machine learning approaches after careful consideration of the powerful advantages as well as of the limitations and pitfalls of these technologies could lead to earlier diagnosis, more precise risk stratification, better predictions of disease response, new sub-phenotype groupings within types of PH, and identification of shared pathways between PAH and other types of PH that could lead to new treatment targets.

Pulmonary hypertension in chronic obstructive pulmonary disease: current understanding, knowledge gaps and future directions

“…The mechanisms for development of pulmonary vasculopathy in WHO group 3 PH (due to lung diseases) has recently been reviewed in depth [1,2 ▪▪ ,3]. Hypoxic vasoconstriction appears to play a role but the molecular mechanisms driving vascular remodeling inherent to PAH are also commonly seen in PH-COPD including endothelial cell dysfunction, fibroblast proliferation and dysregulated angiogenesis.…”

Alveolar hypoxia induces organ‐specific inflammasome‐related inflammation in male mouse lungs

“…In experimental models of hypoxia‐induced pulmonary hypertension, inflammation precedes vascular remodeling, suggesting that inflammation is a cause rather than a consequence of pulmonary hypertension (Cero et al., 2015 ; Larsen et al., 2008 ; Pugliese et al., 2015 ; Rabinovitch et al., 2014 ; Udjus et al., 2019 ). Increased levels of proinflammatory cytokines, such as interleukin (IL)‐18, have been shown in patients suffering from chronic lung diseases (Chung, 2001 ; Imaoka et al., 2008 ), who are prone to develop both alveolar hypoxia and pulmonary hypertension (Gu et al., 2023 ). Elevated circulating levels of inflammatory mediators, like IL‐18, have also been observed in pulmonary arterial hypertension (PAH), which seem to correlate with worse clinical outcome (Cracowski et al., 2014 ; Ross et al., 2012 ; Soon et al., 2010 ).…”