Right ventricular diastolic impairment in patients with pulmonary arterial hypertension

Silvia Rain, M. Louis Handoko, Pia Trip, C. Tji Joong Gan, Nico Westerhof, Ger J. Stienen, Walter J. Paulus, Coen A C Ottenheijm, J. Tim Marcus, Peter Dorfmüller, Christophe Guignabert, Marc Humbert, Peter Macdonald, Cris Dos Remedios, Piet E. Postmus, Chandra Saripalli, Carlos G. Hidalgo, Hendrikus "Henk" Granzier, Anton Vonk-Noordegraaf, Jolanda Van Der VeldenFrances S. De Man

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158 Scopus citations

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 μm versus control, 218±21 μm; 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.

Original languageEnglish (US)
Pages (from-to)2016-2025
Number of pages10
JournalCirculation
Volume128
Issue number18
DOIs
Publication statusPublished - Oct 29 2013

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ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Rain, S., Handoko, M. L., Trip, P., Gan, C. T. J., Westerhof, N., Stienen, G. J., ... De Man, F. S. (2013). Right ventricular diastolic impairment in patients with pulmonary arterial hypertension. Circulation, 128(18), 2016-2025. https://doi.org/10.1161/CIRCULATIONAHA.113.001873