title: Reduced force of diaphragm muscle fibers in patients with chronic thromboembolic pulmonary hypertension.
abstract: Patients with pulmonary hypertension (PH) suffer from inspiratory muscle weakness. However, the pathophysiology of inspiratory muscle dysfunction in PH is unknown. We hypothesized that weakness of the diaphragm, the main inspiratory muscle, is an important contributor to inspiratory muscle dysfunction in PH patients. Our objective was to combine ex vivo diaphragm muscle fiber contractility measurements with measures of in vivo inspiratory muscle function in chronic thromboembolic pulmonary hypertension (CTEPH) patients. To assess diaphragm muscle contractility, function was studied in vivo by maximum inspiratory pressure (MIP) and ex vivo in diaphragm biopsies of the same CTEPH patients (N = 13) obtained during pulmonary endarterectomy. Patients undergoing elective lung surgery served as controls (N = 15). Muscle fiber cross-sectional area (CSA) was determined in cryosections and contractility in permeabilized muscle fibers. Diaphragm muscle fiber CSA was not significantly different between control and CTEPH patients in both slow-twitch and fast-twitch fibers. Maximal force-generating capacity was significantly lower in slow-twitch muscle fibers of CTEPH patients, whereas no difference was observed in fast-twitch muscle fibers. The maximal force of diaphragm muscle fibers correlated significantly with MIP. The calcium sensitivity of force generation was significantly reduced in fast-twitch muscle fibers of CTEPH patients, resulting in a ∼40% reduction of submaximal force generation. The fast skeletal troponin activator CK-2066260 (5 μM) restored submaximal force generation to levels exceeding those observed in control subjects. In conclusion, diaphragm muscle fiber contractility is hampered in CTEPH patients and contributes to the reduced function of the inspiratory muscles in CTEPH patients.
authors.affiliation: Department of Pulmonology, VU University Medical Center/Institute for Cardiovascular Research, Amsterdam, The Netherlands; Department of Physiology, VU University Medical Center/Institute for Cardiovascular Research, The Netherlands;
authors.forename: Emmy
authors.initials: E
authors.lastname: Manders
authors.affiliation: Department of Respiratory Medicine, Amsterdam Medical Center, University of Amsterdam, The Netherlands;
authors.forename: Peter I
authors.initials: PI
authors.lastname: Bonta
authors.affiliation: Department of Cardiothoracic Surgery, VU University Medical Center, Amsterdam, The Netherlands;
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Kloek
authors.affiliation: Department of Cardiothoracic Surgery, VU University Medical Center, Amsterdam, The Netherlands;
authors.forename: Petr
authors.initials: P
authors.lastname: Symersky
authors.affiliation: Department of Pulmonology, VU University Medical Center/Institute for Cardiovascular Research, Amsterdam, The Netherlands;
authors.forename: Harm-Jan
authors.initials: HJ
authors.lastname: Bogaard
authors.affiliation: Department of Physiology, VU University Medical Center/Institute for Cardiovascular Research, The Netherlands;
authors.forename: Pleuni E
authors.initials: PE
authors.lastname: Hooijman
authors.affiliation: Research & Early Development, Cytokinetics Inc., South San Francisco, California;
authors.forename: Jeff R
authors.initials: JR
authors.lastname: Jasper
authors.affiliation: Research & Early Development, Cytokinetics Inc., South San Francisco, California;
authors.forename: Fady I
authors.initials: FI
authors.lastname: Malik
authors.affiliation: Department of Physiology, VU University Medical Center/Institute for Cardiovascular Research, The Netherlands; Faculty of Science, Department of Physics and Astronomy, VU University, Amsterdam, The Netherlands; and.
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Stienen
authors.affiliation: Department of Pulmonology, VU University Medical Center/Institute for Cardiovascular Research, Amsterdam, The Netherlands;
authors.forename: Anton
authors.initials: A
authors.lastname: Vonk-Noordegraaf
authors.affiliation: Department of Pulmonology, VU University Medical Center/Institute for Cardiovascular Research, Amsterdam, The Netherlands;
authors.forename: Frances S
authors.initials: FS
authors.lastname: de Man
authors.affiliation: Department of Physiology, VU University Medical Center/Institute for Cardiovascular Research, The Netherlands; Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona c.ottenheijm@vumc.nl.
authors.forename: Coen A C
authors.initials: CA
authors.lastname: Ottenheijm
mesh_terms: D000368:Aged; D020013:Calcium Signaling; D003964:Diaphragm / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction; D018656:Muscle Fibers, Fast-Twitch / Q000502:physiology; D018657:Muscle Fibers, Slow-Twitch / Q000502:physiology; D018908:Muscle Weakness; D011655:Pulmonary Embolism / Q000503:physiopathology
keywords: contractile proteins; dyspnea; myocyte physiology; respiratory capacity