Circulation. 2013 Sep 20. [Epub ahead of print]

Right Ventricular Diastolic Impairment in Patients with Pulmonary Arterial Hypertension.

Rain S, Handoko ML, Trip P, Gan TJ, Westerhof N, Stienen G, Paulus WJ, Ottenheijm C, Marcus JT, Dorfmüller P, Guignabert C, Humbert M, Macdonald P, Dos Remedios C, Postmus PE, Saripalli C, Hidalgo CG, Granzier HL, Vonk-Noordegraaf A, van der Velden J, de Man FS.

VU University Medical Center / Institute for Cardiovascular Research, Amsterdam, The Netherlands.

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 controls to study RV diastolic stiffness. Data presented as mean±SEM. RV diastolic stiffness (β) was significantly increased in PAH-patients (PAH: 0.050±0.005 vs. control: 0.029±0.003; p<0.05) and closely associated to disease severity. Subsequently, we searched for possible underlying mechanisms, using RV tissue of PAH-patients undergoing heart-lung transplantation and non-failing donors. Histological analyses revealed increased cardiomyocyte cross-sectional areas (PAH: 453±31 vs. 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 vs. 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 compared to controls (+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 vs. control 0.91±0.08), but titin phosphorylation in RV-tissue of PAH-patients was significantly reduced (PAH: 0.16±0.01 vs. control 0.20±0.01 a.u.;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.

PMID:24056688