Right ventricular diastolic impairment in patients with pulmonary arterial hypertension.
BACKGROUND
The role of right ventricular (RV) diastolic stiffness in pulmonary arterial hypertension (PAH) is not well established. Therefore, we investigated the presence and possible underlying mechanisms of RV diastolic stiffness in PAH patients.


RESULTS
Single-beat RV pressure-volume analyses were performed in 21 PAH patients and 7 control subjects to study RV diastolic stiffness. Data are presented as mean ± SEM. RV diastolic stiffness (β) was significantly increased in PAH patients (PAH, 0.050 ± 0.005 versus control, 0.029 ± 0.003; P<0.05) and was closely associated with disease severity. Subsequently, we searched for possible underlying mechanisms using RV tissue of PAH patients undergoing heart/lung transplantation and nonfailing donors. Histological analyses revealed increased cardiomyocyte cross-sectional areas (PAH, 453 ± 31 μm² versus control, 218 ± 21 μm²; P<0.001), indicating RV hypertrophy. In addition, the amount of RV fibrosis was enhanced in PAH tissue (PAH, 9.6 ± 0.7% versus control, 7.2 ± 0.6%; P<0.01). To investigate the contribution of stiffening of the sarcomere (the contractile apparatus of RV cardiomyocytes) to RV diastolic stiffness, we isolated and membrane-permeabilized single RV cardiomyocytes. Passive tension at different sarcomere lengths was significantly higher in PAH patients compared with control subjects (>200%; Pinteraction <0.001), indicating stiffening of RV sarcomeres. An important regulator of sarcomeric stiffening is the sarcomeric protein titin. Therefore, we investigated titin isoform composition and phosphorylation. No alterations were observed in titin isoform composition (N2BA/N2B ratio: PAH, 0.78 ± 0.07 versus control, 0.91 ± 0.08), but titin phosphorylation in RV tissue of PAH patients was significantly reduced (PAH, 0.16 ± 0.01 arbitrary units versus control, 0.20 ± 0.01 arbitrary units; P<0.05).


CONCLUSIONS
RV diastolic stiffness is significantly increased in PAH patients, with important contributions from increased collagen and intrinsic stiffening of the RV cardiomyocyte sarcomeres.
Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Université Paris-Sud, Le Kremlin-Bicêtre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.); AP-HP, Hôpital de Bicêtre, Service de Pneumologie, DHU Thorax Innovation, Le Kremlin-Bicêtre, France (M.H.); Heart & Lung Transplant Unit, St. Vincent's Hospital and Victor Chang Cardiac Research Institute, Sydney, Australia (P.M.); Muscle Research Unit, Institute for Biomedical Research, University of Sydney, Sydney, Australia (C.d.R.); Sarver Molecular Cardiovascular Research Program, Department of Physiology, University of Arizona, Tucson (C.S., C.G.H., H.L.G.); and ICIN-The Netherlands Heart Institute, Utrecht, the Netherlands (J.v.d.V.).
Silvia
S
Rain
M Louis
ML
Handoko
Pia
P
Trip
C Tji-Joong
CT
Gan
Nico
N
Westerhof
Ger J
GJ
Stienen
Walter J
WJ
Paulus
Coen A C
CA
Ottenheijm
J Tim
JT
Marcus
Peter
P
Dorfmüller
Christophe
C
Guignabert
Marc
M
Humbert
Peter
P
Macdonald
Cris
C
Dos Remedios
Piet E
PE
Postmus
Chandra
C
Saripalli
Carlos G
CG
Hidalgo
Henk L
HL
Granzier
Anton
A
Vonk-Noordegraaf
Jolanda
J
van der Velden
Frances S
FS
de Man
D000328:Adult; D000368:Aged; D006328:Cardiac Catheterization; D002306:Cardiac Volume / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D064211:Connectin / Q000378:metabolism; D003971:Diastole / Q000502:physiology*; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D012518:Sarcomeres / Q000378:metabolism / Q000473:pathology; D018497:Ventricular Dysfunction, Right / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D017725:Ventricular Pressure / Q000502:physiology
D064211:Connectin; C577285:TTN protein, human; D003094:Collagen
diastole; heart failure; hypertension, pulmonary; sarcomeres