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Derivation and characterisation of endothelial cells from patients with chronic thromboembolic pulmonary hypertension.

ABSTRACT: Pulmonary endarterectomy (PEA) resected material offers a unique opportunity to develop an in vitro endothelial cell model of chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to comprehensively analyze the endothelial function, molecular signature, and mitochondrial profile of CTEPH-derived endothelial cells to better understand the pathophysiological mechanisms of endothelial dysfunction behind CTEPH, and to identify potential novel targets for the prevention and treatment of the disease. Isolated cells from specimens obtained at PEA (CTEPH-EC), were characterized based on morphology, phenotype, and functional analyses (in vitro and in vivo tubule formation, proliferation, apoptosis, and migration). Mitochondrial content, morphology, and dynamics, as well as high-resolution respirometry and oxidative stress, were also studied. CTEPH-EC displayed a hyperproliferative phenotype with an increase expression of adhesion molecules and a decreased apoptosis, eNOS activity, migration capacity and reduced angiogenic capacity in vitro and in vivo compared to healthy endothelial cells. CTEPH-EC presented altered mitochondrial dynamics, increased mitochondrial respiration and an unbalanced production of reactive oxygen species and antioxidants. Our study is the foremost comprehensive investigation of CTEPH-EC. Modulation of redox, mitochondrial homeostasis and adhesion molecule overexpression arise as novel targets and biomarkers in CTEPH.

SUBMITTER: Tura-Ceide O

PROVIDER: S-EPMC8458486 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Due to its effects, like an exaggerated negative intrathoracic pressure, sympathetic activation, systemic inflammation, oxidative stress, and endothelial dysfunction, obstructive sleep apnea (OSA) has been involved as a cause in multiple cardiovascular diseases. These diseases include coronary artery disease, hypertension, heart failure, and pulmonary hypertension (PH). Furthermore, OSA often coexists with chronic thromboembolic pulmonary hypertension (CTEPH) in clinical practice. However, few studies focus on OSA and its relationship with CTEPH. This study aims to determine whether OSA has an influence on the clinic status of patients with CTEPH, and to identify what possible factors are associated with OSA in CTEPH. Patients who were newly diagnosed with CTEPH and received overnight polysomnography (PSG) monitoring from September 2015 to December 2017 were enrolled. OSA was defined as apnea-hypopnea index (AHI) of ?5/h and the obstructive events at ?50%. Baseline clinical characteristics and parameters were collected and compared between CTEPH patients with and without OSA. In addition, logistic regression analysis was performed to identify possible factors associated with OSA in CTEPH. Fifty-seven patients with CTEPH were eventually enrolled. Among them, 32 patients were diagnosed with OSA by PSG. CTEPH patients with OSA showed an older age, a higher body mass index (BMI), a higher hemoglobin level, a lower oxygen saturation and a worse World Health Organization functional class (WHO FC) (all P<0.05) when compared to CTEPH patients without OSA. In addition, sleep data including AHI, oxygen desaturation index and minimum oxygen saturation were also statistically different between two groups (all P<0.05). Adjusted for age, sex and BMI, hemoglobin [odd ratio (OR) =1.057, 95% confidence interval (CI): 1.001-1.117, P=0.046], oxygen saturation (OR =0.718, 95% CI: 0.554-0.929, P=0.012), N-terminal pro-brain natriuretic peptide (OR =1.001, 95% CI: 1.000-1.002, P=0.016), mean right atrium pressure (OR =1.284, 95% CI: 1.030-1.600, P=0.026), mean pulmonary arterial pressure (mPAP) (OR =1.087, 95% CI: 1.001-1.180, P=0.048), cardiac index (CI) (OR =0.058, 95% CI: 0.008-0.433, P=0.037), pulmonary vascular resistance (OR =1.004, 95% CI: 1.001-1.007, P=0.014) and WHO FC III-IV (OR =18.550, 95% CI: 2.363-144.128, P=0.005) were associated with OSA in CTEPH. Multivariate logistic regression analysis demonstrated CI (OR =0.051, 95% CI: 0.003-0.868, P=0.040) was independently associated with OSA in CTEPH in addition to age, sex and BMI. OSA may aggravate the clinical status of CTEPH patients to some degree. In turn, a worse hemodynamics, oxygenation state and cardiac function are associated with OSA in CTEPH after being adjusted for age, sex and BMI. Among them, CI is the most important parameter in indicating the coexistence of OSA and CTEPH.

Project description:Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the leading causes of severe pulmonary hypertension (PH). The disease is still underdiagnosed, and the true prevalence is unknown. CTEPH is characterized by intraluminal non-resolving thrombus organization and fibrous stenosis, or complete obliteration of pulmonary arteries, promoted by progressive remodeling of the pulmonary vasculature. One consequence of this is an increase in pulmonary vascular resistance and pressure, resulting in PH and progressive right heart failure, leading to death if left untreated. Endovascular disobliteration by pulmonary endarterectomy (PEA) is the preferred treatment for CTEPH patients. PEA surgery is the only technique that can potentially cure CTEPH disease, especially in patients with fresh or organized thrombi of the proximal branches of pulmonary arteries. However, not all patients are eligible for PEA surgery. Recent research has provided evidence suggesting balloon pulmonary angioplasty (BPA) and targeted medical therapy as additional promising available treatments options for inoperable CTEPH and recurrent/persistent PH after PEA surgery. Studies on BPA have shown it to improve pulmonary hemodynamics, symptoms, exercise capacity and RV function in inoperable CTEPH. Subsequently, BPA has developed into an essential component of the modern era of CTEPH treatment. Large randomized controlled trials have demonstrated varying significant improvements with targeted medical therapy in technically inoperable CTEPH patients. Thus, treatment of CTEPH requires a comprehensive multidisciplinary assessment, including an experienced PEA surgeon, PH specialist, BPA interventionist and CTEPH-trained radiologist at expert centers. In this comprehensive review, we address the latest developments in the fast-evolving field of CTEPH. These include advancements in imaging modalities and developments in operative and interventional techniques, which have widened the range of patients who may benefit from these procedures. The efficacy and safety of targeted medical therapies in CTEPH patients are also discussed. As the treatment options for CTEPH improve, hybrid management involving multiple treatments in the same patient may become a viable option in the near future.

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Derivation and characterisation of endothelial cells from patients with chronic thromboembolic pulmonary hypertension.

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