Introduction to Review Series on Pulmonary Vascular Disease and Right Ventricular Heart Failure

The history of pulmonary hypertension is a short one to date—not even 75 years since a living human was found to have this condition by Dresdale et al¹ in 1951. This seminal diagnosis was the culmination of hundreds of years of physiological research in the pulmonary circulation. Drawing on the work of early pioneers such as Ibn Al-Nafis and others, Sir William Harvey in “Du Moto Cordis et Sanguinis” in 1628 explained the elegant simplicity of blood circulation with a separate circulation in the lungs and its own pump, the right ventricle (RV). Animal studies in the late 1800s demonstrated the feasibility of left and right heart catheterization,² but it was not until Dr Werner Forssmann³ performed a right heart catheterization on himself using a urologic catheter in 1922 that it would be even possible to measure the pressure in the pulmonary circulation. The use of this groundbreaking procedure allowed others such as Drs Andre Cournand and Dickson Richards, with whom Forssmann later shared the Nobel Prize, to make seminal discoveries on the function of the cardiopulmonary unit.⁴ Nearly 30 years later, Dresdale et al described a patient with pulmonary hypertension (PH).

The clinical report by Dresdale et al was the beginning of a field of study that is the subject of this review series in Circulation Research: Pulmonary Hypertension. An early understanding of the drivers of pulmonary hypertension was penned by Dr Paul Wood,⁵ who considered the major physiological disorders of the pulmonary circulation to be (1) passive pulmonary hypertension, (2) obliterative pulmonary hypertension, (3) hyperkinetic pulmonary hypertension, and (4) vasoconstrictive pulmonary hypertension. Dr Wood’s framework for disorders of the pulmonary vasculature offered a construct for study and for different treatments. In this period, there was a rapid expansion in recognition of disorders of the pulmonary circulation and RV that culminated in the first World Symposium on Pulmonary Hypertension in 1973.⁶ In particular, this first World Symposium introduced the term primary pulmonary hypertension (now termed pulmonary arterial hypertension) and provided a classification system for these conditions. Moreover, this classification allowed the development of targeted therapies such as calcium channel blockers⁷ and prostacyclins.⁸ There have been 5 subsequent World Symposia that have refined classification of pulmonary hypertension, identified timely key unmet needs, made up-to-date therapeutic recommendations, and advanced the field of both clinical care and research.

This special review series is a testament to the advances in the field of pulmonary vascular disease since it’s recognition in 1951 and the first World Symposium on Pulmonary Hypertension in 1973. We now use a classification of pulmonary hypertension that is based, in part, on shared pathology and treatment responses.⁹ The major classes of pulmonary hypertension include group 1 pulmonary arterial hypertension, group 2 due to left heart disease, group 3 due to parenchymal lung disease or hypoxia, group 4 due to chronic thromboembolic disease, and group 5 that includes miscellaneous conditions. While the greatest advances in understanding and therapy have occurred in group 1 PAH, mortality remains unacceptably high in all forms of pulmonary hypertension, and there is limited understanding of etiology, epidemiology, and therapy of non–group 1 pulmonary hypertension.

This review series focuses on the pulmonary circulation, including pulmonary hypertension and right heart failure. These manuscripts collectively demonstrate the state of the art in understanding key aspects of pulmonary vascular disease and RV dysfunction. They further provide a road map of the tools and techniques that will bring this field through the next several decades.

Perhaps the greatest advances in understanding the molecular etiology of pulmonary hypertension have occurred through the relentless pursuit of gene mutations that underlie disease. The first of these was the recognition that mutations in BMPR2 (bone morphogenetic protein receptor type 2), a transforming growth factor beta receptor family member, underlie ≈70% of heritable forms of the disease and up to 20% of idiopathic forms.^10–12 Using advance genomic analyses and large cohorts with genetic data, there have been several newly identified gene mutations and variants both in pulmonary arterial hypertension and also in pulmonary veno-occlusive disease. There are emerging data on the function of these mutations, and their impact is discussed by Aldred et al.¹³ The article provides a timely and relevant discussion of the use of these novel findings for the clinician at the bedside. Finally, with 2 decades of research on BMPR2 mutations and their function, there are emerging therapeutics that are targeting this pathway. Their mechanisms of action and potential therapeutic role are discussed as well.

It is paradoxical (and frustrating for providers) that the most common cause of pulmonary hypertension—left heart disease—lacks effective therapies. Challenges underlying this therapeutic gap include evolution of hemodynamic classification of group 2 pulmonary hypertension and a poor understanding of the pathophysiology. Huston and Shah¹⁴ present the current diagnostic framework for group 2 PH and offer insights into the broad potential mechanisms for the development of pulmonary vascular dysfunction in patients with left heart disease. This article closes with a succinct view of the major knowledge gaps and pressing questions regarding the pathophysiology of group 2 PH, thus offering the scientific community a road map for clinical and preclinical investigations to understand and reduce morbidity in this sizeable PH population.

A growing and particularly challenging to understand etiology is pulmonary hypertension due to chronic lung diseases. These patients have among the worst prognosis of any cause of PH¹⁵ and, like group 2 PH, share the challenges of poorly understood pathology and preclinical models that incompletely recapitulate human disease. Recent advances give cause for optimism, including the new recognition that group 3 patients may have a disproportionate RV dysfunction phenotype and a positive, seminal trial of inhaled prostacyclin in patients with PH due to interstitial lung disease.¹⁶ Here, Singh et al¹⁷ synthesize putative molecular mechanisms, review available animal models, and highlight clinical trial data to inform the current and future therapeutic options for group 3 PH.

The most salient conclusion from the last decade of molecular work in the pulmonary hypertension field is that the more we seek, the more complexity we find. Single molecular events pointing to disease etiology or treatment targets are rare, which necessitates the need to look for and make sense of complex molecular interactions across multiple biologic pathways. The abundance of big data from omics platforms, genomics, health records, and imaging (among other sources) is difficult to distill and interpret in a manner that can benefit patients, providers, and scientists. Rhodes et al¹⁸ take on this challenging task in the context of pulmonary hypertension, drawing from recent investigations linking clinical pulmonary hypertension cohorts with proteomics, metabolomics, transcriptomics, and other high-dimensional data. The article also provides an accessible and timely introduction to cutting-edge analytic approaches for synthesizing big data, including machine learning, network medicine, and personalized drug selection.

Functional imaging of the RV–pulmonary vascular unit has evolved and advanced significantly over recent years. RV function and the interaction between pulmonary vascular dysfunction and RV compensation are key prognostic determinants in patients with PH. Echo-cardiography and cardiac magnetic resonance imaging remain the primary clinical tools for these assessments, but even these conventional modalities boast important technical advancements that now inform clinical decision-making, including speckle tracking, 3-dimensional imaging, and tissue characterization. Perhaps the most exciting advances in PH-related imaging relate to the emerging ability to observe and quantify pulmonary vascular structure and function. New approaches under investigation include positron emission tomography tracers targeting pulmonary vascular markers, hyperpolarized xenon magnetic resonance studies of pulmonary gas exchange, and machine learning analysis of pulmonary vascular morphology. Alenezi et al¹⁹ share their expertise and insight with a summary of recent literature of these imaging techniques that hold promise to improve diagnosis, prognosis, and inform therapeutic response for patients with PH.

Access to human pulmonary vascular tissue is almost exclusively limited to end stage disease, and there are similar challenges with access to RV samples from humans. This limitation makes understanding of early disease and the effect of therapy on relevant tissues highly challenging. Ultimately, therefore, uncovering the molecular etiology of the diverse forms of pulmonary hypertension and right heart failure and studies of novel therapeutics require relevant animal models. Boucherat et al²⁰ provide a timely and balanced review of the state of the field of animal models of the pulmonary circulation. While animal models are most established in group 1 pulmonary arterial hypertension, this review complements other reviews in this series by also discussing animal models of group 2 and 3 pulmonary hypertension and RV dysfunction that may be used to move these under-studied fields forward.

We hope this forward-looking review series will be a source of insight and inspiration to those in the pulmonary hypertension field and the next generation of investigators and providers.