One Hundred Years of Research in the Pathogenesis of Pulmonary Hypertension

Pulmonary hypertension (PH) is defined hemodynamically as a systolic pulmonary artery pressure (PAP) greater than 30 mm Hg, or elevation of mean PAP in excess of 25 mm Hg.Behind this rather simple physiologic definition lie a large number of cellular and molecular alterations of the pulmonary arteries that ultimately account for the disease.The immense progress in the past 100 years of basic and clinical research of PH illustrates how biomedical science ultimately results in life-saving therapies, dramatically influencing patient morbidity and mortality (Figure 1).Since the autopsy observation of the first case of "pulmonary vascular sclerosis" by Romberg in 1891, our understanding of PH has evolved in parallel with the scientific achievements of the last century-each "small step" from the viewpoint of hindsight represents a significant achievement when framed in its historical context.Notwithstanding our tendency to consider only the most recent scientific advancements, we owe our current knowledge to those investigators dedicated to PH research over the past 100 years.PH is a syndrome that probably includes several diseases, all of which share increased pulmonary artery pressures.As such, any single clinical characterization or disease model used falls short of comprehensively addressing this complex syndrome, which varies with regards to its severity, the site of increased vascular resistance, and its association to underlying clinical conditions as outlined in a recently updated classification of pulmonary arterial hypertension (PAH [1]).Although this review emphasizes some of the most important human and animal experimental findings related to PH in general, a significant focus of the past 100 years of research has been the study of the rare, idiopathic form of PAH (IPAH, previously known as primary pulmonary hypertension or PPH).In this review, we will describe the early understanding of PH as a "novel disease" in the beginning of the century, based on the initial recognition of the clinical presentation in cohorts of patients with pulmonary hypertension, and the pathologic characterization of diseased pulmonary arteries.We will then emphasize the impact of the development of hemodynamic assessment of the pulmonary circulation, and highlight the modern age of cellular, molecular, and genetic milestones in the understanding of PH.