Manders Emmy, Bonta Peter I, Kloek Jaap J, Symersky Petr, Bogaard Harm-Jan, Hooijman Pleuni E, Jasper Jeff R, Malik Fady I, Stienen Ger J M, Vonk-Noordegraaf Anton, de Man Frances S, Ottenheijm Coen A C
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;
Department of Respiratory Medicine, Amsterdam Medical Center, University of Amsterdam, The Netherlands;
Am J Physiol Lung Cell Mol Physiol. 2016 Jul 1;311(1):L20-8. doi: 10.1152/ajplung.00113.2016. Epub 2016 May 17.
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.
肺动脉高压（PH）患者存在吸气肌无力。然而，PH患者吸气肌功能障碍的病理生理学尚不清楚。我们推测，作为主要吸气肌的膈肌无力是PH患者吸气肌功能障碍的重要原因。我们的目标是将体外膈肌肌纤维收缩性测量与慢性血栓栓塞性肺动脉高压（CTEPH）患者的体内吸气肌功能测量相结合。为了评估膈肌收缩性，在肺内膜剥脱术期间，对同一组CTEPH患者（N = 13）通过最大吸气压力（MIP）进行体内功能研究，并对膈肌活检组织进行体外研究。接受择期肺手术的患者作为对照（N = 15）。在冷冻切片中测定肌纤维横截面积（CSA），并在通透化肌纤维中测定收缩性。在慢肌纤维和快肌纤维中，对照组和CTEPH患者的膈肌肌纤维CSA均无显著差异。CTEPH患者慢肌纤维的最大力量产生能力显著降低，而快肌纤维中未观察到差异。膈肌肌纤维的最大力量与MIP显著相关。CTEPH患者快肌纤维中力量产生的钙敏感性显著降低，导致次最大力量产生降低约40%。快速骨骼肌肌钙蛋白激活剂CK-2066260（5 μM）可将次最大力量产生恢复到超过对照组观察到的水平。总之，CTEPH患者的膈肌肌纤维收缩性受到损害，这导致了CTEPH患者吸气肌功能的降低。
