Contractile Dysfunction of Left Ventricular Cardiomyocytes in Patients With Pulmonary Arterial Hypertension |
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| Authors: | Emmy Manders,Harm-Jan Bogaard,M. Louis Handoko,Marielle C. van de Veerdonk,Anne Keogh,Nico Westerhof,Ger J.M. Stienen,Cristobal G. dos Remedios,Marc Humbert,Peter Dorfmü ller,Elie Fadel,Christophe Guignabert,Jolanda van der Velden,Anton Vonk-Noordegraaf,Frances S. de Man,Coen A.C. Ottenheijm |
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| Affiliation: | ∗ Department of Pulmonology, Vrije Universiteit (VU) University Medical Center, Amsterdam, the Netherlands;† Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands;‡ Cardiology Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands;§ Heart Transplant Unit, St. Vincent''s Hospital, Sydney, Australia;‖ Department of Physics and Astronomy, VU University, Amsterdam, the Netherlands;¶ Muscle Research Unit, Bosch Institute, The University of Sydney, Sydney, Australia;# 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;‡‡ Service d''Anatomie Pathologique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France;§§ Service de Chirurgie Thoracique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France;‖‖ ICIN Netherlands Heart Institute, Utrecht, the Netherlands |
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| Abstract: | BackgroundAfter 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.ObjectivesThe 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.MethodsLV 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.ResultsMagnetic 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.ConclusionsThe 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. |
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| Keywords: | contractile protein phosphorylation left ventricular dysfunction myocyte physiology pulmonary arterial hypertension |
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