title: Contractile dysfunction of left ventricular cardiomyocytes in patients with pulmonary arterial hypertension.
abstract: BACKGROUND
  After lung transplantation, increased left ventricular (LV) filling can lead to LV failure, increasing the risk of post-operative complications and mortality. LV dysfunction in pulmonary arterial hypertension (PAH) is characterized by a reduced LV ejection fraction and impaired diastolic function.
  
  
  OBJECTIVE
  The pathophysiology of LV dysfunction in PAH is incompletely understood. This study sought to assess the contribution of atrophy and contractility of cardiomyocytes to LV dysfunction in PAH patients.
  
  
  METHODS
  LV function was assessed by cardiac magnetic resonance imaging. In addition, LV biopsies were obtained in 9 PAH patients and 10 donors. The cross-sectional area (CSA) and force-generating capacity of isolated single cardiomyocytes was investigated.
  
  
  RESULTS
  Magnetic resonance imaging analysis revealed a significant reduction in LV ejection fraction in PAH patients, indicating a reduction in LV contractility. The CSA of LV cardiomyocytes of PAH patients was significantly reduced (~30%), indicating LV cardiomyocyte atrophy. The maximal force-generating capacity, normalized to cardiomyocyte CSA, was significantly reduced (~25%). Also, a reduction in the number of available myosin-based cross-bridges was found to cause the contractile weakness of cardiomyocytes. This finding was supported by protein analyses, which showed an ~30% reduction in the myosin/actin ratio in cardiomyocytes from PAH patients. Finally, the phosphorylation level of sarcomeric proteins was reduced in PAH patients, which was accompanied by increased calcium sensitivity of force generation.
  
  
  CONCLUSIONS
  The contractile function and the CSA of LV cardiomyocytes is substantially reduced in PAH patients. We propose that these changes contribute to the reduced in vivo contractility of the LV in PAH patients.
authors.affiliation: Department of Pulmonology, Vrije Universiteit (VU) University Medical Center, Amsterdam, the Netherlands; Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Emmy
authors.initials: E
authors.lastname: Manders
authors.affiliation: Department of Pulmonology, Vrije Universiteit (VU) University Medical Center, Amsterdam, the Netherlands.
authors.forename: Harm-Jan
authors.initials: HJ
authors.lastname: Bogaard
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands; Cardiology Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: M Louis
authors.initials: ML
authors.lastname: Handoko
authors.affiliation: Department of Pulmonology, Vrije Universiteit (VU) University Medical Center, Amsterdam, the Netherlands.
authors.forename: Marielle C
authors.initials: MC
authors.lastname: van de Veerdonk
authors.affiliation: Heart Transplant Unit, St. Vincent's Hospital, Sydney, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Keogh
authors.affiliation: Department of Pulmonology, Vrije Universiteit (VU) University Medical Center, Amsterdam, the Netherlands; Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: Westerhof
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands; Department of Physics and Astronomy, VU University, Amsterdam, the Netherlands.
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Stienen
authors.affiliation: Muscle Research Unit, Bosch Institute, The University of Sydney, Sydney, Australia.
authors.forename: Cristobal G
authors.initials: CG
authors.lastname: Dos Remedios
authors.affiliation: University of Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France; Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, Département Hospitalo-Universitaire, Thorax Innovation (DHU TORINO), Hôpital Bicêtre, Le Kremlin-Bicêtre, France; Inserm U999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique (LabEx LERMIT), Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.affiliation: University of Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France; Inserm U999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique (LabEx LERMIT), Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France; Service d'Anatomie Pathologique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Dorfmüller
authors.affiliation: University of Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France; Inserm U999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique (LabEx LERMIT), Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France; Service de Chirurgie Thoracique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors.forename: Elie
authors.initials: E
authors.lastname: Fadel
authors.affiliation: University of Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France; Inserm U999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique (LabEx LERMIT), Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Guignabert
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands; ICIN Netherlands Heart Institute, Utrecht, the Netherlands.
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
authors.affiliation: Department of Pulmonology, Vrije Universiteit (VU) University Medical Center, Amsterdam, the Netherlands.
authors.forename: Anton
authors.initials: A
authors.lastname: Vonk-Noordegraaf
authors.affiliation: Department of Pulmonology, Vrije Universiteit (VU) University Medical Center, Amsterdam, the Netherlands. Electronic address: fs.deman@vumc.nl.
authors.forename: Frances S
authors.initials: FS
authors.lastname: de Man
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands. Electronic address: c.ottenheijm@vumc.nl.
authors.forename: Coen A C
authors.initials: CA
authors.lastname: Ottenheijm
mesh_terms: D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000473:pathology / Q000503:physiopathology*; D055815:Young Adult
keywords: contractile protein phosphorylation; left ventricular dysfunction; myocyte physiology; pulmonary arterial hypertension