title: Pulmonary arterial hypertension in congenital heart disease: translational opportunities to study the reversibility of pulmonary vascular disease.
abstract: Pulmonary arterial hypertension (PAH) is a progressive and lethal pulmonary vascular disease (PVD). Although in recent years outcome has improved by new treatments that delay disease progression, a cure has not yet been achieved. In PAH associated with congenital heart disease (CHD), remodeling of the pulmonary vasculature reaches an irreversible phenotype similar to all forms of end-stage PAH. In PAH-CHD, however, also an early stage is recognised, which can be completely reversible. This reversible phase has never been recognised in other forms of PAH, most likely because these patients are only diagnosed once advanced disease has developed. We propose that the clinical model of PAH-CHD, with an early reversible and advanced irreversible stage, offers unique opportunities to study pathophysiological and molecular mechanisms that orchestrate the transition from reversible medial hypertrophy into irreversible plexiform lesions. Comprehension of these mechanisms is not only pivotal in clinical assessment of disease progression and operability of patients with PAH-CHD; specific targeting of these mechanisms may also lead to pharmacological interventions that transform 'irreversible' plexiform lesions into a reversible PVD: one that is amenable for a cure. In recent years, significant steps have been made in the strive to 'reverse the irreversible'. This review provides an overview of current clinical and experimental knowledge on the reversibility of PAH, focussing on flow-associated mechanisms, and the near-future potential to advance this field.
authors.affiliation: Centre for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Centre Groningen, University of Groningen, The Netherlands.
authors.forename: Diederik E
authors.initials: DE
authors.lastname: van der Feen
authors.affiliation: Centre for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Centre Groningen, University of Groningen, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Bartelds
authors.affiliation: Experimental Cardiology, Department of Cardiology, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands.
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
authors.affiliation: Centre for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Centre Groningen, University of Groningen, The Netherlands.
authors.forename: Rolf M F
authors.initials: RMF
authors.lastname: Berger
mesh_terms: D000328:Adult; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002648:Child; D004195:Disease Models, Animal; D018450:Disease Progression; D006330:Heart Defects, Congenital / Q000150:complications* / Q000503:physiopathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000503:physiopathology / Q000628:therapy*; D011652:Pulmonary Circulation / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D066253:Vascular Remodeling / Q000502:physiology; D014657:Vasculitis / Q000503:physiopathology
chemical_list: D000959:Antihypertensive Agents; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta
keywords: Congenital heart disease ; Neointimal/plexiform lesions; Pulmonary blood flow ; Reversible/irreversible•Operability ; Vascular remodelling 