Right Ventricular Diastolic Impairment in Patients With Pulmonary Arterial Hypertension

• Published in: Circulation (New York, N.Y.) Vol. 128; no. 18; pp. 2016 - 2025
• Main Authors: Rain, Silvia, Handoko, M. Louis, Trip, Pia, Gan, C. Tji-Joong, Westerhof, Nico, Stienen, Ger J., Paulus, Walter J., Ottenheijm, Coen A.C., Marcus, J. Tim, Dorfmüller, Peter, Guignabert, Christophe, Humbert, Marc, MacDonald, Peter, dos Remedios, Cris, Postmus, Piet E., Saripalli, Chandra, Hidalgo, Carlos G., Granzier, Henk L., Vonk-Noordegraaf, Anton, van der Velden, Jolanda, de Man, Frances S.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD by the American College of Cardiology Foundation and the American Heart Association, Inc 29.10.2013; Lippincott Williams & Wilkins
• Subjects: Adult; Aged; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiac Catheterization; Cardiac Volume - physiology; Cardiology. Vascular system; Collagen - metabolism; Connectin - metabolism; Diastole - physiology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Familial Primary Pulmonary Hypertension; Female; Heart; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Humans; Hypertension, Pulmonary - physiopathology; Hypertrophy, Right Ventricular - metabolism; Hypertrophy, Right Ventricular - pathology; Hypertrophy, Right Ventricular - physiopathology; Magnetic Resonance Imaging; Male; Medical sciences; Middle Aged; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Pneumology; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Sarcomeres - metabolism; Sarcomeres - pathology; Ventricular Dysfunction, Right - metabolism; Ventricular Dysfunction, Right - pathology; Ventricular Dysfunction, Right - physiopathology; Ventricular Pressure - physiology; Human; Hypertension; Heart failure; Diastole; Respiratory disease; Lung; Right ventricle; hypertension, pulmonary; Patient; Cardiovascular disease; sarcomeres; Respiratory system; Artery; Pulmonary hypertension; Heart disease; Blood vessel; Circulatory system; Cardiology; Sarcomere; heart failure; diastole
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.113.001873

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 ratioPAH, 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.