TY - JOUR
T1 - Contractile dysfunction of left ventricular cardiomyocytes in patients with pulmonary arterial hypertension
AU - Manders, Emmy
AU - Bogaard, Harm-Jan
AU - Handoko, M Louis
AU - van de Veerdonk, Marielle C
AU - Keogh, Anne
AU - Westerhof, Nico
AU - Stienen, Ger J M
AU - Dos Remedios, Cristobal G
AU - Humbert, Marc
AU - Dorfmüller, Peter
AU - Fadel, Elie
AU - Guignabert, Christophe
AU - van der Velden, Jolanda
AU - Vonk-Noordegraaf, Anton
AU - de Man, Frances S
AU - Ottenheijm, Coen A C
N1 - Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
PY - 2014/7/8
Y1 - 2014/7/8
N2 - 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.OBJECTIVES: 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.
AB - 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.OBJECTIVES: 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.
KW - Adolescent
KW - Adult
KW - Cells, Cultured
KW - Familial Primary Pulmonary Hypertension
KW - Female
KW - Humans
KW - Hypertension, Pulmonary/pathology
KW - Male
KW - Middle Aged
KW - Myocardial Contraction/physiology
KW - Myocytes, Cardiac/pathology
KW - Ventricular Dysfunction, Left/pathology
KW - Young Adult
U2 - 10.1016/j.jacc.2014.04.031
DO - 10.1016/j.jacc.2014.04.031
M3 - Article
C2 - 24998125
SN - 0735-1097
VL - 64
SP - 28
EP - 37
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 1
ER -