Sustained endothelial progenitor cell dysfunction after chronic hypoxia-induced pulmonary hypertension

Circulating endothelial progenitor cells (EPCs) contribute to neovascularization of ischemic tissues and repair of injured endothelium. The role of bone marrow-derived progenitor cells in hypoxia-induced pulmonary vascular remodeling and their tissue-engineering potential in pulmonary hypertension (PH) remain largely unknown. We studied endogenous mobilization and homing of EPCs in green fluorescent protein bone marrow chimeric mice exposed to chronic hypoxia, a common hallmark of PH. Despite increased peripheral mobilization, as shown by flow cytometry and EPC culture, bone marrow-derived endothelial cell recruitment in remodeling lung vessels was limited. Moreover, transfer of vascular endothelial growth factor receptor-2+/Sca-1+/CXCR-4+-cultured early-outgrowth EPCs failed to reverse PH, suggesting hypoxia-induced functional impairment of transferred EPCs. Chronic hypoxia decreased migration to stromal cell-derived factor-1alpha, adhesion to fibronectin, incorporation into a vascular network, and nitric oxide production (-41%, -29%, -30%, and -32%, respectively, vs. normoxic EPCs; p < .05 for all). The dysfunctional phenotype of hypoxic EPCs significantly impaired their neovascularization capacity in chronic hind limb ischemia, contrary to normoxic EPCs cultured in identical conditions. Mechanisms contributing to EPC dysfunction include reduced integrin alphav and beta1 expression, decreased mitochondrial membrane potential, and enhanced senescence. Novel insights from chronic hypoxia-induced EPC dysfunction may provide important cues for improved future cell repair strategies.     

内皮祖细胞在肺动脉高压中的研究进展

肺动脉高压(pulmonary hypertension,PH)是指在海平面静息状态下平均肺动脉压(mean pulmonaryarterial pressure,mPAP)≥20 mmHg,肺血管阻力(pulmonaryvascular resistance,PVR)≥3 Wood units 的一种疾病或病理生理综...     

内皮祖细胞临床应用的研究进展

内皮祖细胞是内皮细胞的前体细胞,在某些生理、病理状态下,可随血液流至相应组织,分化为内皮细胞,并进一步形成血管。内皮祖细胞参与血管新生的作用,对于创伤修复、缺血性疾病的治疗以及肿瘤的靶向治疗具有重要意义,在临床上具有广阔的应用前景。     

肺动脉高压患者生活质量及其影响因素

目的：了解肺动脉高压患者的生活质量状况并探讨其影响因素。方法：采用整群抽样的方法选择2014年6月至2015年6月期间在中南大学湘雅医院住院治疗的68例肺动脉高压患者作为研究对象。采用一般资料问卷、中文版简明健康调查量表(Short Form 36 Health Survey Questionnaire,SF-36)对其进行调查,运用单因素分析及多元线性回归法分析其影响因素。结果：肺动脉高压患者SF-36量表各维度评分均低于常模,差异均有统计学意义(P<0.05)。影响生活质量生理健康的因素为性别、6分钟步行试验距离(6-minute walking distance,6MWD)、是否合并右心衰竭、是否坚持氧疗;影响生活质量心理健康的因素为性别、文化程度、有无医疗保险。结论：肺动脉高压患者生活质量不高。医护人员应对女性、文化程度低、无医疗保险、6MWD短、合并右心衰竭、未坚持氧疗的患者给予更多的关注。     

Autologous endothelial progenitor cells transplantation for the therapy of primary pulmonary hypertension

Primary pulmonary hypertension (PPH) is a fatal cardiovascular disease characterized by increased pulmonary vascular resistance and progressive right heart failure. It is associated with a very high morbidity and mortality rate. The therapeutic effects of current pharmacological management of PPH are limited. Recent studies have demonstrated that endothelial dysfunction and cell loss play a critical role in the pathogenesis of PPH. Emerging evidence also shows that circulating endothelial progenitor cells instigate new vessel formation via vasculogenesis and revascularization, and provide ongoing endothelial repair by homing to site of endothelial damage. We hypothesized that autologous endothelial progenitor cells transplantation may be a feasible adjunctive therapeutic option for PPH.     

Circulating plasmablasts are elevated and produce pathogenic anti‐endothelial cell autoantibodies in idiopathic pulmonary arterial hypertension

Idiopathic pulmonary arterial hypertension (IPAH) is a devastating pulmonary vascular disease in which autoimmune and inflammatory phenomena are implicated. B cells and autoantibodies have been associated with IPAH and identified as potential therapeutic targets. However, the specific populations of B cells involved and their roles in disease pathogenesis are not clearly defined. We aimed to assess the levels of activated B cells (plasmablasts) in IPAH, and to characterize recombinant antibodies derived from these plasmablasts. Blood plasmablasts are elevated in IPAH, remain elevated over time, and produce IgA autoantibodies. Single‐cell sequencing of plasmablasts in IPAH revealed repertoires of affinity‐matured antibodies with small clonal expansions, consistent with an ongoing autoimmune response. Recombinant antibodies representative of these clonal lineages bound known autoantigen targets and displayed an unexpectedly high degree of polyreactivity. Representative IPAH plasmablast recombinant antibodies stimulated human umbilical vein endothelial cells to produce cytokines and overexpress the adhesion molecule ICAM‐1. Together, our results demonstrate an ongoing adaptive autoimmune response involving IgA plasmablasts that produce anti‐endothelial cell autoantibodies in IPAH. These antibodies stimulate endothelial cell production of cytokines and adhesion molecules, which may contribute to disease pathogenesis. These findings suggest a role for mucosally‐driven autoimmunity and autoimmune injury in the pathogenesis of IPAH.     

Transplantation of endothelial progenitor cells into the lung to alleviate pulmonary hypertension in dogs

Primary pulmonary hypertension (PPH) is still a refractory disease, and patients deteriorate despite any treatment. We hypothesized that neovascularization in the lung could increase the volume of the vascular bed in the pulmonary circulation and thus reduce the development of pulmonary hypertension (PH). Endothelial progenitor cells (EPCs) might be a potential cell source for neovascularization. We examined the effects of EPC transplantation into the lungs of dogs with dehydromonocrotaline-induced PH. The lung parenchyma of PH model dogs was injected with ex vivo-expanded, autologous EPCs originated from peripheral blood (experiments, n=4) or culture medium (control, n=3), using a bronchoscope. EPC transplantation gave significant improvements in mean pulmonary artery pressure, cardiac output, and pulmonary vascular resistance. Histological evaluation revealed both improvement in the medial thickness of the small pulmonary artery and neovascularization of the lung tissue. These results indicate that EPC transplantation into the lung is effective at preventing the progression of dehydromonocrotaline-induced PH in dogs, and suggest a new therapeutic option for PPH.     

Vasoactive intestinal peptide gene alterations in patients with idiopathic pulmonary arterial hypertension

Pulmonary arterial hypertension is a progressive disease, characterised by increased proliferation of pulmonary artery smooth muscle cells, vasoconstriction and remodelling of the vascular wall leading to right heart failure and death. The idiopathic form is rare (idiopathic arterial primary hypertension (IPAH); formerly PPH, MIM# 178600). Our group correlated a deficiency in vasoactive intestinal peptide (VIP; MIM# 192320) levels in serum and lung tissue with the pathogenesis of IPAH. The aim of this study was to investigate the relevance of genetic alterations in VIP to the development of IPAH. We screened 10 patients (age 4-66 years) for alterations in the coding, the noncoding regions and the enhancer region of the VIP gene by direct sequencing. In eight of 10 patients, we found alterations compared to the wild-type sequence. We detected nine alterations. In the noncoding regions, eight alterations were in the introns 1, 2, 3 and 4 (g.448G>A g.501C>T g.764T>C g.2267A>T g.2390C>T g.3144T>C g.3912A>G g.4857A>G). In the coding regions, a single alteration in the 3' untranslated region in exon 7 (g.8129T>C) was observed in five patients. It appeared in 46% of the control group. The frequency of this alteration in the coding region of the VIP gene could therefore not be correlated with the appearance of IPAH. Apart from the importance of VIP signalling, genetic and/or environmental modifiers might therefore contribute to the development and perpetuation of the disease.     

内皮祖细胞与高血压病的应用研究进展

BACKGROUND: Structural and functional changes of endothelial cells are the common pathological basis of cardiovascular disease. Severe structural and functional damage of endothelial cells are found in patients with hypertension or coronary heart diseases.     

慢性肺动脉高压大鼠肺小动脉内HIF-1α的表达增强并与NO有关

慢性低氧引起肺血管收缩、肺血管重建而致肺血管阻力持续升高,最终可导致肺动脉高压和右心室肥大,其发病机制至今尚不十分清楚。低氧诱导因子-1α(H IF-1α)作为一种转录因子,是一种重要的肺动脉对低氧反应的中介物。本实验采用慢性低氧伴高二氧化碳性肺动脉高压大鼠模型,观察H     

Prognostic value of late gadolinium enhancement mass index in patients with pulmonary arterial hypertension

PurposeDysfunction of the right ventricle (RV) is an important determinant of survival in patients with pulmonary arterial hypertension (PAH). The presence of late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR) at RV insertion points (RVIPs) has been found in majority of PAH patients and was associated with parameters of RV dysfunction. We hypothesize, that more detailed quantification of LGE may provide additional prognostic information.Material and methodsTwenty-eight stable PAH patients (mean age 49.9 ​± ​15.9 years) and 12 healthy subjects (control group, 44.8 ​± ​13.5 years) were enrolled into the study. Septal LGE mass was quantified at the RVIPs and subsequently indexed by subject’s body surface area. Mean follow-up time of this study was 16.6 ​± ​7.5 months and the clinical end-point (CEP) was defined as death or clinical deterioration.ResultsMedian LGE mass index (LGEMI) at the RVIPs was 2.75 ​g/m2 [1.41–4.85]. We observed statistically significant correlations between LGEMI and hemodynamic parameters obtained from right heart catheterization – mPAP (r ​= ​0.61, p ​= ​0.001); PVR (r ​= ​0.52, p ​= ​0.007) and from CMR – RVEF (r ​= ​−0.54, p ​= ​0.005); RV global longitudinal strain (r ​= ​0.42, p ​= ​0.03). Patients who had CEP (n ​= ​16) had a significantly higher LGEMI (4.49 [2.75–6.17] vs 1.67 [0.74–2.7], p ​= ​0.01); univariate Cox analysis confirmed prognostic value of LGEMI. Furthermore, PAH patients with LGEMI higher than median had worse prognosis in Kaplan-Meier analysis (log-rank test, p ​= ​0.0006).ConclusionsThe body surface indexed mass of LGE at RV septal insertion points are suggestive of RV hemodynamic dysfunction and could be a useful non-invasive marker of PAH prognosis.     

肺腺泡内动脉构形重建与肺动脉高压等的关系

以野百合碱一次性皮下注射复制大鼠肺动脉高压和肺心病模型。应用光镜、电镜、免疫组织化学和形态定量等方法，观察了肺腺泡内动脉不同病变在肺动脉高压中的作用。结果表明了肺循环功能与结构之间的关系，反映出肺腺泡内动脉构形重建是肺动脉高压形成的病理学基础。结果提示肺腺泡内动脉壁周细胞的增生和肌样分化，对无肌型肺动脉的肌化意义重大。     

MRI assessment of aortic flow in patients with pulmonary arterial hypertension in response to exercise

Background

While primarily a right heart disease, pulmonary arterial hypertension (PAH) can impact left heart function and aortic flow through a shifted interventricular septum from right ventricular pressure overload and reduced left ventricular preload, among other mechanisms. In this study, we used phase contrast (PC) MRI and a modest exercise challenge to examine the effects of PAH on systemic circulation. While exercise challenges are typically performed with ultrasound in the clinic, MRI exercise studies allow for more reproducible image alignment, more accurate flow quantification, and improved tissue contrast.

Methods

Six PAH patients and fifteen healthy controls (8 older age-matched, 7 younger) exercised in the magnet bore with an MRI-compatible exercise device that allowed for scanning immediately following cessation of exercise. PC scans were performed in the ascending aorta during a breath hold immediately after modest exercise to non-invasively measure stroke volume (SV), cardiac output (CO), aortic peak systolic flow (PSF), and aortic wall stiffness via relative area change (RAC).

Results

Images following exercise showed mild blurring, but were high enough quality to allow for segmentation of the aorta. While SV was approximately 30% lower in PAH patients (SV_PAH,rest?=?67?±?16?mL; SV_PAH,stress?=?90?±?42?mL) than age-matched controls (SV_,older,rest?=?93?±?16?mL; SV_older,stress?=?133?±?40?mL) at both rest and following exercise, CO was similar for both groups following exercise (CO_PAH,stress?=?10.8?±?5.7?L/min; CO_older,stress?=?11.8?±?5.0?L/min). This was achieved through a compensatory increase in heart rate in the PAH subjects (74% increase as compared to 29% in age-matched controls). The PAH subjects also demonstrated reduced aortic peak systolic flow relative to the healthy controls (PSF_PAH,_rest?=?309?±?52?mL/s; PSF_older,_rest?=?416?±?114?mL/s; PSF_PAH,_stress?=?388?±?113?mL/s; PSF_older,_stress?=?462?±?176?mL/s). PAH patients and older controls demonstrated stiffer aortic walls when compared to younger controls (RAC_PAH,rest?=?0.15?±?0.05; RAC_older,rest?=?0.17?±?0.05; RAC_young,rest?=?0.28?±?0.08).

Conclusions

PC MRI following a modest exercise challenge was capable of detecting differences in left heart dynamics likely induced from PAH. These results demonstrated that PAH can have a significant influence on systemic flow, even when the patient has no prior left heart disease. Image quantification following exercise could likely be improved in future studies through the implementation of free-breathing or real-time MRI acquisitions.

Trial registration

Retrospectively registered on 02/26/2018 (TRN:NCT03523910).

     

POEMS综合征合并肺动脉高压临床分析

目的 分析POEMS综合征合并肺动脉高压患者的临床特点.方法 回顾性分析北京协和医院确诊POEMS综合征患者的临床资料,并将超声心动图证实合并肺动脉高压的患者与肺动脉压正常的患者以及未行超声心动检查的患者的临床表现进行比较,描述合并肺动脉高压的POEMS综合征患者的临床特点.结果 POEMS综合征117例,合并肺动脉高压49例,肺动脉压正常33例,未行超声心动检查35例;肺动脉高压患病率41.9%.肺动脉高压组临床表现主要为胸闷、憋气,发生率42.9%(21/49),显著高于另外两组(P≤0.05),但一半以上患者无明显胸闷、憋气;肺动脉高压组并发胸水、腹水、心包积液发生率较另外两组高(P≤0.01),其他临床表现无显著差异.结论 POEMS综合征超声心动图检测肺动脉高压患病率高达40%以上,但半数以上患者无胸闷、憋气,提示在POEMS综合征诊治过程中应重视肺动脉高压的筛查和早期发现.     

Increased mortality in African Americans with idiopathic pulmonary arterial hypertension

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disorder that usually culminates in right ventricular failure and death without treatment. OBJECTIVE: To assess mortality trends by race and gender for idiopathic pulmonary arterial hypertension in the United States from 1994-1998. METHODS: The U.S. National Center for Health Statistics data for the years 1994-1998 was reviewed for deaths in which the underlying cause was primary pulmonary hypertension (ICD-9 code 416.0), now known as IPAH. The age, gender, race and state of residence of the deceased were abstracted from the Centers for Disease Control Wonder System (http://wonder.cdc.gov). Average annual age-adjusted region-, race- and gender-specific rates were then calculated. RESULTS: African-American women demonstrated the highest mortality rates for IPAH across all age groups compared to other racial and gender groups. No geographical differences in mortality rates were noted. An increase in mortality rates with advancing age was observed in all racial and gender groups, with the highest mortality rates for IPAH noted in the elderly. DISCUSSION: African Americans with IPAH exhibit a substantially increased mortality compared with Caucasians, particularly African-American women.