Rain, Silvia and Handoko, M Louis and Trip, Pia and Gan, C Tji-Joong and Westerhof, Nico and Stienen, Ger J and Paulus, Walter J and Ottenheijm, Coen A C and Marcus, J Tim and Dorfmüller, Peter and Guignabert, Christophe and Humbert, Marc and Macdonald, Peter S and Dos Remedios, Cris and Postmus, Piet E and Saripalli, Chandra and Hidalgo, Carlos G and Granzier, Henk L and Vonk-Noordegraaf, Anton and van der Velden, Jolanda and de Man, Frances S (2013) Right ventricular diastolic impairment in patients with pulmonary arterial hypertension. Circulation, 128 (18). pp. 2016-25, 1. ISSN 1524-4539
Full text not available from this repository.Abstract
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.
METHODS AND 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.
(No Australian funders listed)
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 07 Jan 2016 04:09 |
| Last Modified: | 04 Feb 2016 00:39 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/137 |
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