Current Respiratory Medicine Reviews - Volume 20, Issue 2, 2024

Pulmonary hypertension is a rare, progressive disease characterized by increased pulmonary arterial pressure and right ventricular failure due to pulmonary vascular remodeling. The disease definition and management have evolved over time. The 6th WSPH now defines it as a mean pulmonary arterial pressure >20mmHg, while recent ESC/ERS guidelines recommend lowering the threshold for pulmonary vascular resistance to 2WU. Understanding of the disease has improved through registries, classifying it into five distinct groups with similar histology, pathophysiology, and therapeutic approaches. These groups include PAH, with heritable and idiopathic causes, as well as various clinical subsets involving connective tissue disease, HIV, portopulmonary hypertension, congenital heart disease, and schistosomiasis. Long-term responders to calcium channel blockers, PAH with venous/capillaries involvement, and persistent PH of newborns are categorized under Group 1, now re-classified as IPAH. A comprehensive workup for suspected patients includes various tests like electrocardiogram, pulmonary function testing, autoimmune workup, HIV testing, echocardiogram, right heart catheterization, and cardiopulmonary exercise testing. This review emphasizes the disease's definition and epidemiology, delving into each subset and providing updated workup guidelines. The subsequent article will focus on risk stratification and treatment strategies.

Risk assessment (or risk stratification) and both current and future therapies for pulmonary arterial hypertension (PAH) will be discussed in part B. Risk assessment is key in the initial evaluation and follow-up of persons with PAH. Risk assessment provides information on disease severity and mortality, which, over time, have been incorporated into the application of PAH therapies. After the initial risk assessment, a 4-strata approach is recommended at subsequent follow- up evaluations by the 2022 ERS/ESC pulmonary hypertension (PH) guidelines as described initially in COMPERA 2.0. This method appears to have increased sensitivity to changes in risk from baseline to follow-up and to changes in long-term mortality risk. Current PAH therapies target the prostacyclin, endothelin, and nitric oxide pathways. A sequential approach to therapy has been recommended since publication of the 2009 guidelines and, in the most recent iteration incorporates the 4-strata approach at follow-up. Additional therapy is recommended when intermediate- high or high-risk status is present. New therapies are under active investigation that include targeting novel pathways. Sotatercept, a fusion protein that binds to and sequesters select transforming growth factor β superfamily ligands, is the most promising novel therapy at this time. A recent phase 3, randomized, double-blind, placebo-controlled study in group 1 PAH patients showed a statistically significant improvement in 6-minute walk distance and additional studies of this drug in PH populations are ongoing. Progress in phenotyping this heterogeneous disease is being made, and as PAH therapies continue to evolve, the use of personalized treatment regimens may be possible in the care of this complex, and highly morbid and mortal disease.

Pulmonary Arterial Hypertension (PAH) is a progressive disease associated with occlusive pulmonary arterial remodeling of vessels < 500 μm 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 TGFβ/ 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.

Pulmonary Hypertension secondary to left heart disease (PH-LHD) is the most common form of pulmonary hypertension (PH) and is a frequent complication of heart failure. It is associated with increased morbidity and mortality. The definitions of both PH and PH-LHD have changed over time and now generally follow those established by the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018 and the most recent European Society of Cardiology (ESC) guidelines in 2022. A systematic approach including clinical history and noninvasive testing is required to properly diagnose PH-LHD, and accurate hemodynamics by right heart catheterization, sometimes involving provocative testing, are often needed to diagnose PH-LHD but are essential to further subclassify PH-LHD into either isolated post-capillary pulmonary hypertension (Ipc-PH) versus combined pre and post-capillary pulmonary hypertension (Cpc-PH). This distinction is important as it guides therapeutic decisions and carries prognostic implications. Cpc-PH, in particular, shares some histo-pathologic and hemodynamic characteristics with pulmonary arterial hypertension (PAH) and, hence, the rationale for the potential use of pulmonary vasodilator therapy. To date, however, there is no strong evidence to support PAH-specific medications for Cpc- PH, and the mainstay of treatment for PH-LHD remains to treat the underlying cause of LHD. Further research is warranted to refine therapeutic approaches, improve long-term outcomes, and explore novel treatment modalities to alleviate the burden of PH in this patient population.

Patients with Chronic Lung Disease (CLD) are frequently burdened by pulmonary hypertension (PH), which is associated with reduced functional capacity, poor quality of life, increased oxygen requirements, and increased morbidity and mortality. The development of PH associated with chronic lung disease (PH-CLD) is complex and multifactorial and varies between different types of CLD. In this review, we provide an update on PH-CLD, with a particular focus on Interstitial Lung Disease (ILD), chronic obstructive pulmonary disease (COPD), obstructive sleep apnea (OSA), and obesity hypoventilation syndrome (OHS). We discussed epidemiology, histopathology, pathophysiology, diagnostic evaluation, and treatment approaches. There are limited data on the use of pulmonary arterial hypertension-specific treatments in PH-CLD, so it has been proposed to phenotype patients based on their degree of pulmonary vascular disease to guide individualized care. The heterogeneity within PH-CLD highlights the importance of identifying novel molecular pathways unique to each subgroup to ultimately achieve precision medicine.