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However, there is growing evidence that patients with PAH also exhibit systemic vascular dysfunction, as evidenced by impaired brachial artery flow\u2013mediated dilation, abnormal cerebral blood flow, skeletal myopathy, and intrinsic kidney disease. Although some of these anomalies are partially due to right ventricular insufficiency, recent data support a mechanistic link to the genetic and molecular events behind PAH pathogenesis. This review serves as an introduction to the major systemic findings in PAH and the evidence that supports a common mechanistic link with PAH pathophysiology. In addition, it discusses recent studies describing morphological changes in systemic vessels and the possible role of bronchopulmonary anastomoses in the development of plexogenic arteriopathy. On the basis of available evidence, we propose a paradigm in which metabolic abnormalities, genetic injury, and systemic vascular dysfunction contribute to systemic manifestations in PAH. This concept not only opens exciting research possibilities but also encourages clinicians to consider extrapulmonary manifestations in their management of patients with PAH.<\/jats:p>","DOI":"10.1164\/rccm.201903-0656ci","type":"journal-article","created":{"date-parts":[[2019,9,12]],"date-time":"2019-09-12T18:04:35Z","timestamp":1568311475000},"page":"148-157","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":86,"title":["Beyond the Lungs: Systemic Manifestations of Pulmonary Arterial Hypertension"],"prefix":"10.1093","volume":"201","author":[{"given":"Nils P.","family":"Nickel","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Yuan","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Dorfmuller","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Giessen, Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steeve","family":"Provencher","sequence":"additional","affiliation":[{"name":"Centre de Recherche de l\u2019Institut Universitaire de Cardiologie et de Pneumologie de Quebec, Quebec, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Chun","family":"Lai","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Indiana University, Bloomington, Indiana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastien","family":"Bonnet","sequence":"additional","affiliation":[{"name":"Centre de Recherche de l\u2019Institut Universitaire de Cardiologie et de Pneumologie de Quebec, Quebec, Quebec, 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Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7730-2427","authenticated-orcid":false,"given":"Fr\u00e9d\u00e9ric","family":"Perros","sequence":"additional","affiliation":[{"name":"Centre de Recherche de l\u2019Institut Universitaire de Cardiologie et de Pneumologie de Quebec, Quebec, Quebec, Canada"},{"name":"Inserm Universit\u00e9 Paris Sud\u2013Centre chirurgical Marie Lannelongue 999, Universit\u00e9 Paris Sud\u2013Paris Saclay, H\u00f4pital Marie Lannelongue, Le Plessis Robinson, France; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9358-6922","authenticated-orcid":false,"given":"David","family":"Montani","sequence":"additional","affiliation":[{"name":"Inserm Universit\u00e9 Paris Sud\u2013Centre chirurgical Marie Lannelongue 999, Universit\u00e9 Paris Sud\u2013Paris Saclay, H\u00f4pital Marie Lannelongue, Le Plessis Robinson, France; and"},{"name":"Service de 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