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Cell landscape atlas for patients with chronic thromboembolic pulmonary hypertension after pulmonary endarterectomy constructed using single-cell RNA sequencing.

ABSTRACT: This study aimed to construct an atlas of the cell landscape and comprehensively characterize the cellular repertoire of the pulmonary endarterectomized tissues of patients with chronic thromboembolic pulmonary hypertension (CTEPH). Five pulmonary endarterectomized tissues were collected. 10× Genomics single-cell RNA sequencing was performed, followed by the identification of cluster marker genes and cell types. Gene Ontology (GO) enrichment analysis was conducted. Seventeen cell clusters were characterized, corresponding to 10,518 marker genes, and then classified into eight cell types, including fibroblast/smooth muscle cell, endothelial cell, T cell/NK cell, macrophage, mast cell, cysteine rich secretory protein LCCL domain containing 2 (CRISPLD2)+ cell, cancer stem cell, and undefined. The specific marker genes of fibroblast/smooth muscle cell, endothelial cell, T cell/NK cell, macrophage, mast cell, and cancer stem cell were significantly enriched for multiple functions associated with muscle cell migration, endothelial cell migration, T cell activation, neutrophil activation, erythrocyte homeostasis, and tissue remodeling, respectively. No functions were significantly enriched for the marker gene of CRISPLD2+ cell. Our study, for the first time, provides an atlas of the cell landscape of the pulmonary endarterectomized tissues of CTEPH patients at single-cell resolution, which may serve as a valuable resource for further elucidation of disease pathophysiology.

SUBMITTER: Miao R

PROVIDER: S-EPMC8266372 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Pulmonary endarterectomy is the treatment of choice for patients with operable chronic thromboembolic pulmonary hypertension (CTEPH) as it is potentially curative. In expert centers that conduct > 50 pulmonary endarterectomy procedures per year, peri- and post-surgical mortality rates are very low and long-term outcomes are excellent, with three-year post-operative survival of > 80%. Therapeutic decisions in CTEPH are based largely on the location of the arterial obstruction, with pulmonary endarterectomy for obstructions in main, lobar, and segmental vessels, and balloon pulmonary angioplasty and medical therapy for small-vessel disease. Medical therapy is also an option for patients with persistent/recurrent pulmonary hypertension after pulmonary endarterectomy or balloon pulmonary angioplasty. With increasing surgical experience and improvements in instruments and procedures, an increasing number of patients are now considered operable who would previously have been inoperable, including some patients with subsegmental disease. At our University (University of California San Diego), around 200 pulmonary endarterectomy procedures are performed every year and several advances have been developed, including resection of more distal disease, availability of pulmonary endarterectomy to patients previously considered to be at too high risk for surgery, improved management of post-pulmonary endarterectomy complications, and minimally invasive pulmonary endarterectomy. Pulmonary endarterectomy can be combined with other treatment modalities, including balloon pulmonary angioplasty, medical therapy for persistent/recurrent pulmonary hypertension after pulmonary endarterectomy, and medical therapy or balloon pulmonary angioplasty as bridging therapy before surgery. Data on these combinations are, however, limited. Combination treatment should therefore be considered on an individual patient basis. In the future, however, multimodal therapy with pulmonary endarterectomy, balloon pulmonary angioplasty, and/or medical therapy is likely to be an important treatment option for many patients.

Project description:Pulmonary endarterectomy (PEA) is the only definitive and potentially curative therapy for chronic thromboembolic pulmonary hypertension (CTEPH), associated with impressive improvements in symptoms and haemodynamics. However, it is only offered at a few centres in South Africa. The characteristics and outcomes of patients undergoing PEA in Cape Town have not been reported previously. To assess the difference in World Health Organization functional class (WHO-FC) before and at least 6 weeks after surgery. We interrogated the adult cardiothoracic surgery database at the University of Cape Town between December 2005 and April 2021 for patients undergoing PEA at Groote Schuur Hospital and a private hospital. A total of 32 patients underwent PEA, of whom 8 were excluded from the final analysis owing to incomplete data or a histological diagnosis other than CTEPH. The work-up of these patients for surgery was variable: all had a computed tomography pulmonary angiogram, 7 (29%) had a ventilation/perfusion scan, 5 (21%) underwent right heart catheterisation, and none had a pulmonary angiogram. The perioperative mortality was 4/24 (17%): 1 patient (4%) had a cardiac arrest on induction of anaesthesia, 2 patients (8%) died of postoperative pulmonary haemorrhage, and 1 patient (4%) died of septic complications in the intensive care unit. Among the survivors, the median (interquartile range) improvement in WHO-FC was 2 (1 - 3) classes (p=0.0004); 10/16 patients (63%) returned to a normal baseline (WHO-FC I). Even in a low-volume centre, PEA is associated with significant improvements in WHO-FC and a return to a normal baseline in survivors. What the study adds. South African patients undergoing pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) have a marked improvement in functional status, with many returning to a normal functional baseline. However, the small number of patients included in this study indicates that PEA is probably underutilised. Pre- and postoperative assessment is inconsistent, despite availability of established guidelines.Implications of the findings. More patients should be referred to specialist centres for assessment for this potentially curative procedure. Use of guidelines to standardise investigations and monitoring of patients with CTEPH may improve patient selection for surgery.

Project description:Background Pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension improves resting hemodynamics and right ventricular (RV) function. Because exercise tolerance frequently remains impaired, RV function may not have completely normalized after PEA. Therefore, we performed a detailed invasive hemodynamic study to investigate the effect of PEA on RV function during exercise. Methods and Results In this prospective study, all consenting patients with chronic thromboembolic pulmonary hypertension eligible for surgery and able to perform cycle ergometry underwent cardiac magnetic resonance imaging, a maximal cardiopulmonary exercise test, and a submaximal invasive cardiopulmonary exercise test before and 6 months after PEA. Hemodynamic assessment and analysis of RV pressure curves using the single-beat method was used to determine load-independent RV contractility (end systolic elastance), RV afterload (arterial elastance), RV-arterial coupling (end systolic elastance-arterial elastance), and stroke volume both at rest and during exercise. RV rest-to-exercise responses were compared before and after PEA using 2-way repeated-measures analysis of variance with Bonferroni post hoc correction. A total of 19 patients with chronic thromboembolic pulmonary hypertension completed the entire study protocol. Resting hemodynamics improved significantly after PEA. The RV exertional stroke volume response improved 6 months after PEA (79±32 at rest versus 102±28 mL during exercise; P<0.01). Although RV afterload (arterial elastance) increased during exercise, RV contractility (end systolic elastance) did not change during exercise either before (0.43 [0.32-0.58] mm Hg/mL versus 0.45 [0.22-0.65] mm Hg/mL; P=0.6) or after PEA (0.32 [0.23-0.40] mm Hg/mL versus 0.28 [0.19-0.44] mm Hg/mL; P=0.7). In addition, mean pulmonary artery pressure-cardiac output and end systolic elastance-arterial elastance slopes remained unchanged after PEA. Conclusions The exertional RV stroke volume response improves significantly after PEA for chronic thromboembolic pulmonary hypertension despite a persistently abnormal afterload and absence of an RV contractile reserve. This may suggest that at mildly elevated pulmonary pressures, stroke volume is less dependent on RV contractility and afterload and is primarily determined by venous return and conduit function.

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Cell landscape atlas for patients with chronic thromboembolic pulmonary hypertension after pulmonary endarterectomy constructed using single-cell RNA sequencing.

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