Right Ventricular Diastolic Impairment in Patients With Pulmonary Arterial Hypertension

被引：299

作者：

Rain, Silvia ^{[1
,2
]}

Handoko, M. Louis ^{[2
,3
]}

Trip, Pia ^{[1
]}

Gan, C. Tji-Joong ^{[1
]}

Westerhof, Nico ^{[1
,2
]}

Stienen, Ger J. ^{[2
]}

Paulus, Walter J. ^{[2
]}

Ottenheijm, Coen A. C. ^{[2
]}

Marcus, J. Tim ^{[4
]}

Dorfmueller, Peter ^{[5
,6
]}

Guignabert, Christophe ^{[5
,6
]}

Humbert, Marc ^{[5
,6
,7
]}

MacDonald, Peter ^{[8
,9
]}

dos Remedios, Cris ^{[10
]}

Postmus, Piet E. ^{[1
]}

Saripalli, Chandra ^{[11
]}

Hidalgo, Carlos G. ^{[11
]}

Granzier, Henk L. ^{[11
]}

Vonk-Noordegraaf, Anton ^{[1
]}

van der Velden, Jolanda ^{[2
,12
]}

de Man, Frances S. ^{[1
,2
]}

机构：

[1] Vrije Univ Amsterdam Med Ctr, Inst Cardiovasc Res, Dept Pulmonol, NL-1081 HV Amsterdam, Netherlands

[2] Vrije Univ Amsterdam Med Ctr, Inst Cardiovasc Res, Dept Physiol, NL-1081 HV Amsterdam, Netherlands

[3] Vrije Univ Amsterdam Med Ctr, Inst Cardiovasc Res, Dept Cardiol, NL-1081 HV Amsterdam, Netherlands

[4] Vrije Univ Amsterdam Med Ctr, Inst Cardiovasc Res, Dept Med Phys, NL-1081 HV Amsterdam, Netherlands

[5] Univ Paris 11, Le Kremlin Bicetre, France

[6] Ctr Chirurg Marie Lannelongue, INSERM UMR 999, LabEx LERMIT, Le Plessis Robinson, France

[7] DHU Thorax Innovat, Serv Pneumol, Hop Bicetre, AP HP, Le Kremlin Bicetre, France

[8] St Vincents Hosp, Heart & Lung Transplant Unit, Sydney, NSW 2010, Australia

[9] Victor Chang Cardiac Res Inst, Sydney, NSW, Australia

[10] Univ Sydney, Inst Biomed Res, Muscle Res Unit, Sydney, NSW 2006, Australia

[11] Univ Arizona, Dept Physiol, Sarver Mol Cardiovasc Res Program, Tucson, AZ USA

[12] ICIN Netherlands Heart Inst, Utrecht, Netherlands

来源：

CIRCULATION | 2013年 / 128卷 / 18期

关键词：

diastole; heart failure; hypertension; pulmonary; sarcomeres; HEART-FAILURE; EJECTION FRACTION; RESTING TENSION; DYSFUNCTION; PRESSURE; TITIN; STIFFNESS; SURVIVAL; RATS;

D O I：

10.1161/CIRCULATIONAHA.113.001873

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 meanSEM. RV diastolic stiffness () 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 m(2) versus control, 218 +/- 21 m(2); 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%; P-interaction<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.

引用

页码：2016 / 2025

页数：10

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