Bosentan in pulmonary arterial hypertension: a comparison between congenital heart disease and chronic pulmonary embolism

Background. In patients with pulmonary hypertension, it is unknown whether the treatment effect of bosentan is dependent on the duration of pulmonary vessel changes. Therefore, we studied the response to bosentan in patients with life-long pulmonary vessel changes (pulmonary arterial hypertension (PAH) due to congenital heart disease (CHD)) and in patients with subacutely induced pulmonary vessel changes (chronic thromboembolic pulmonary hypertension (CTEPH)). Methods. In this open-label study, 18 patients with PAH due to CHD and 16 patients with CTEPH were treated with bosentan for at least one year. All patients were evaluated at baseline and during follow-up by means of the six-minute walk distance (6-MWD) and laboratory tests. Results. Improvement of 6-MWD was comparable in patients with PAH due to CHD (444±112 m to 471±100 m, p=0.02), and in CTEPH (376±152 m to 423±141 m, p=0.03) after three months of treatment. After this improvement, 6-MWD stabilised in both groups. Conclusion. Although duration of pulmonary vessel changes is strikingly different in patients with PAH due to CHD and CTEPH, the effect of one year of bosentan treatment was comparable. The main treatment effect appears to be disease stabilisation and decreasing the rate of deterioration. (Neth Heart J 2009;17:334–8.)     

Clinical worsening after pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension

Introduction

Pulmonary endarterectomy (PEA) is the most effective treatment for chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study is to evaluate long-term survival and freedom from clinical worsening after PEA.

Methods

All patients who underwent PEA in our hospital between May 2000 and August 2009 were included. Follow-up parameters were all-cause mortality and time to clinical worsening, defined as a combination of death, need for pulmonary hypertension-specific medication or 15% decrease in six-minute walk distance without improvement in functional class. The Cox proportional hazard regression was used to identify predictors.

Results

Seventy-four consecutive patients (mean age 55.9 ± 13.8 years, 51% female) underwent PEA. Prior to surgery, 55 patients were in NYHA functional class III or higher. The mean pulmonary artery pressure was 41.3 ± 11.9 mmHg with a mean pulmonary vascular resistance of 521 ± 264 dyn·s·cm⁻⁵ (range 279–1331 dyn·s·cm⁻⁵). Five patients (6.8%) died in-hospital. Out of hospital, 5 out of 69 patients (7.2%) died during a median follow-up of 3.7 ± 2.2 years [range 0.1–8.5 years]). The one- and five-year survival rates were 93% and 89%, respectively. During follow-up, clinical worsening occurred in 13 out of 69 patients (18.8%). The one- and five-year rates of freedom from clinical worsening were 94% and 72%, respectively. The baseline NT-pro BNP level tended to be a predictor for occurrence of clinical worsening.

Conclusion

Pulmonary endarterectomy is associated with good long-term survival in patients with CTEPH. However, clinical worsening occurred in a substantial number of patients at long-term follow-up.     

Differences of cardiac output measurements by open-circuit acetylene uptake in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: a cohort study

Background

As differences in gas exchange between pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) have been demonstrated, we asked if cardiac output measurements determined by acetylene (C₂H₂) uptake significantly differed in these diseases when compared to the thermodilution technique.

Method

Single-breath open-circuit C₂H₂ uptake, thermodilution, and cardiopulmonary exercise testing were performed in 72 PAH and 32 CTEPH patients.

Results

In PAH patients the results for cardiac output obtained by the two methods showed an acceptable agreement with a mean difference of -0.16 L/min (95% CI -2.64 to 2.32 L/min). In contrast, the agreement was poorer in the CTEPH group with the difference being -0.56 L/min (95% CI -4.96 to 3.84 L/min). Functional dead space ventilation (44.5 ± 1.6 vs. 32.2 ± 1.4%, p < 0.001) and the mean arterial to end-tidal CO₂ gradient (9.9 ± 0.8 vs. 4.1 ± 0.5 mmHg, p < 0.001) were significantly elevated among CTEPH patients.

Conclusion

Cardiac output evaluation by the C₂H₂ technique should be interpreted with caution in CTEPH, as ventilation to perfusion mismatching might be more relevant than in PAH.     

A low resting heart rate at diagnosis predicts favourable long-term outcome in pulmonary arterial and chronic thromboembolic pulmonary hypertension. A prospective observational study

Background

A low resting heart rate (HR) is prognostically favourable in healthy individuals and in patients with left heart disease. In this study we investigated the impact of HR at diagnosis on long-term outcome in patients with differently classified precapillary pulmonary hypertension (pPH).

Methods

pPH patients diagnosed as pulmonary arterial (PAH) or inoperable chronic thromboembolic pulmonary hypertension (CTEPH) were registered and regularly followed at our centre Baseline characteristics and events defined as either death or lung transplantation were noted. The prognostic value of HR was analysed using Kaplan Meier estimates, live tables and Cox regression.

Results

206 patients with PAH (148) and inoperable CTEPH (58) were included. The median HR was 82 bpm. pPH with a HR below 82 bpm had a significantly longer overall event-free survival (2409 vs.1332 days, p = .000). This advantage was similarly found if PAH and CTEPH were analysed separately. Although a lower HR was associated with a better hemodynamic and functional class, HR was a strong and independent prognostic marker for transplant free survival even if corrected for age, sex, hemodynamics and functional status.

Conclusion

We show that resting HR at diagnosis is a strong and independent long-term prognostic marker in PAH and CTEPH. Whether reducing HR by pharmacological agents would improve outcome in pPH has to be assessed by future trials with high attention to safety.     

Anxiety and depression disorders in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

Background

The objective of this prospective study was to assess the prevalence of anxiety and depression disorders and their association with quality of life (QoL), clinical parameters and survival in patients with pulmonary hypertension (PH).

Methods

We prospectively assessed 158 patients invasively diagnosed with pulmonary arterial hypertension (n = 138) and inoperable chronic thromboembolic PH (n = 20) by clinical measures including quality of life (QoL, SF-36 questionnaire), cardiopulmonary exercise testing and six minute walking distance and by questionnaires for depression (PHQ-9) and anxiety (GAD-7). According to the results of the clinical examination and the questionnaires for mental disorders (MD) patients were classified into two groups, 1) with moderate to severe MD (n = 36, 22,8%), and 2) with mild or no MD (n = 122). Patients were followed for a median of 2.7 years. Investigators of QoL, SF-36 were blinded to the clinical data.

Results

At baseline the 2 groups did not differ in their severity of PH or exercise capacity. Patients with moderate to severe MD (group 1) had a significantly lower QoL shown in all subscales of SF-36 (p < 0.002). QoL impairment significantly correlated with the severity of depression (p < 0.001) and anxiety (p < 0.05). During follow-up period 32 patients died and 3 were lost to follow-up. There was no significant difference between groups regarding survival. Only 8% of the patients with MD received psychopharmacological treatment.

Conclusion

Anxiety and depression were frequently diagnosed in our patients and significantly correlated with quality of life, but not with long term survival. Further prospective studies are needed to confirm the results.     

Chronic thromboembolic pulmonary hypertension

Chronic pulmonary thromboembolic disease is an important cause of severe pulmonary hypertension, and as such is associated with significant morbidity and mortality. The prognosis of this condition reflects the degree of associated right ventricular dysfunction, with predictable mortality related to the severity of the underlying pulmonary hypertension. Left untreated, the prognosis is poor. Pulmonary endarterectomy is the treatment of choice to relieve pulmonary artery obstruction in patients with chronic thromboembolic pulmonary hypertension and has been remarkably successful. Advances in surgical techniques along with the introduction of pulmonary hypertension-specific medication provide therapeutic options for the majority of patients afflicted with the disease. However, a substantial number of patients are not candidates for pulmonary endarterectomy due to either distal pulmonary vascular obstruction or significant comorbidities. Therefore, careful selection of surgical candidates in expert centres is paramount. The current review focuses on the diagnostic approach to chronic thromboembolic pulmonary hypertension and the available surgical and medical therapeutic options.

Electronic supplementary material

The online version of this article (doi:10.1007/s12471-014-0592-2) contains supplementary material, which is available to authorized users.     

Safety and efficacy of balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension in the Netherlands

Background

Balloon pulmonary angioplasty (BPA) is an emerging treatment in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic disease (CTED). We describe the first safety and efficacy results of BPA in the Netherlands.

Methods

We selected all consecutive patients with inoperable CTEPH and CTED accepted for BPA treatment who had a six-month follow-up in the St. Antonius Hospital in Nieuwegein and the Amsterdam University Medical Center (UMC) in Amsterdam. Functional class (FC), N?terminal pro-brain natriuretic peptide (NT-proBNP), 6?minute walking test distance (6MWD) and right-sided heart catheterisation were performed at baseline and six months after last BPA. Complications for each BPA procedure were noted.

Results

A hundred and seventy-two BPA procedures were performed in 38 patients (61% female, mean age 65?±?15 years). Significant improvements six months after BPA treatment were observed for functional class (63% FC I/II to 90% FC I/II, p?=?0.014), mean pulmonary artery pressure (?8.9?mm?Hg, p?=?0.0001), pulmonary vascular resistance (?2.8 Woods Units (WU), p?=?0.0001), right atrial pressure (?2.0?mm?Hg, p?=?0.006), stroke volume index (+5.7?ml/m², p?=?0.009) and 6MWD (+48m, p?=?0.007). Non-severe complications occurred in 20 (12%) procedures.

Conclusions

BPA performed in a CTEPH expert centre is an effective and safe treatment in patients with inoperable CTEPH.

     

Exercise training improves exercise capacity and quality of life in patients with inoperable or residual chronic thromboembolic pulmonary hypertension

Background

Aim of this prospective study was to evaluate the effects of exercise training in patients with inoperable or residual chronic thromboembolic pulmonary hypertension (CTEPH).

Methods

Thirty-five consecutive patients with invasively confirmed inoperable or residual CTEPH (16 women;19 men; mean age 61±15 years, mean pulmonary artery pressure, 63±20 mmHg; primary inoperable n = 33, persisting pulmonary hypertension after pulmonary endarterectomy n = 2) on stable disease-targeted medication received exercise training in-hospital for 3 weeks and continued at home for 15 weeks. Medication remained unchanged during the study period. Efficacy parameters have been evaluated at baseline, after 3 and 15 weeks by blinded-observers. Survival rate has been evaluated in a follow-up period of median 36.4 months (interquartile range 26.6–46.6 months).

Results

All patients tolerated exercise training without severe adverse events. Patients significantly improved the mean distance walked in 6 minutes compared to baseline by 61±54 meters after 3 weeks (p<0.001) and by 71±70 meters after 15 weeks (p = 0.001), as well as scores of quality-of-life questionnaire, peak oxygen consumption and maximal workload. NT-proBNP improved significantly after 3 weeks of exercise training (p = 0.046). The 1-year survival rate was 97%, 2-year survival rate was 94% and the 3-year-survival 86% respectively.

Conclusion

Training as add-on to medical therapy may be effective in patients with CTEPH to improve work capacity, quality of life and further prognostic relevant parameters and possibly improves the 1-, 2- and 3-year survival rate. Further multicentric randomized controlled studies are needed to confirm these promising results.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01398345","term_id":"NCT01398345"}}NCT01398345     

Ischaemia-modified albumin in pulmonary hypertension

Background: Pulmonary hypertension (PH) may be associated with subendocardial ischaemia. We investigated whether ischaemia-modified albumin (IMA), an established marker of ischaemia, is elevated in stable patients with PH.

Methods: We studied 32 patients with PH and an equal number of age-matched normal volunteers. We assessed serum IMA levels with the albumin cobalt-binding test.

Results: Patients’ mean ± SD (range) pulmonary arterial pressure was 56?±?12 (33–73) mmHg and their exercise capacity was 394?±?145 (121–688) m in the 6-min walk test. IMA was 92?±?14 (69–115) U ml^?1 in the patient group and 93?±?9.4 (76–122) U ml^?1 in the control group with no significant difference between the two (p?=?0.85), although almost one-third of the patients had detectable troponin-I.

Conclusions: We conclude that IMA, a marker of ischaemia, does not differ in patients with advanced clinically stable PH compared with normal subjects.     

红花注射液对慢性低O2高CO2肺动脉高压的影响

目的：探讨红花注射液对大鼠在慢性低O2高CO2下肺动脉高压的抑制作用。方法：将SD大鼠分为对照组,慢性低O2高CO2组,慢性低O2高CO2＋红花注射液组。用电镜、放免等方法,观察各组大鼠肺动脉平均压、颈动脉平均压、肺细小动脉显微结构、血浆和肺匀浆TXB2及6-keto-PGF1a含量的变化。结果：①慢性低O2高CO2组mPAP比对照组显著增高,红花注射液组的mPAP比慢性低O2高CO2组显著降低,3组间mCAP比较差异无显著性。②慢性低O2高CO2组与对照组相比血浆和肺匀浆TXB2浓度、TXB2／6-keto-PGF1a比值显著增高,6-keto-PGF1a浓度显著下降;红花注射液组与慢性低P2高CO2相比血浆和肺匀浆TXB2浓度、TXB2／6-keto-PGF1a显著下降,6-keto-PGF1a显著升高。③光镜下慢性低O2高CO2组与对照组相比,肺细小动脉管壁面积／管总面积（WA／TA）和肺细小动脉中膜厚度（PAMT）均显著增高。红花注射液组WA／TA和PAMT显著降低。④电镜下慢性低O2高CO2组大鼠肺细小动脉内皮细胞吞饮小泡增多,血管壁增厚,中膜平滑肌细胞增生,纤维细胞增多,肺泡Ⅱ型上皮细胞微绒毛脱落;红花注射液组肺细小动脉中膜平滑肌细胞增生减轻,纤维细胞少,胶原纤维减少,肺泡Ⅱ型上皮细胞微绒毛丰富、结构清。结论：红花注射液有减轻慢性低O2高CO2性肺动脉高压和肺血管结构重建的作用,可能与抑制TXA2的合成,保护血管内皮细胞,使TXA2/PGI2比值降低有关.     

塞来昔布对慢性低O_2高CO_2大鼠肺动脉高压的影响及其机制研究

目的：探讨塞来昔布对慢性低O2高CO2大鼠肺动脉高压的作用。方法：将SD大鼠分为正常对照组,慢性低O2高CO2组,慢性低O2高CO2＋塞来昔布组。用电镜、放免等方法,观察各组大鼠肺动脉平均压、颈动脉平均压、肺细小动脉显微结构、血浆和肺匀浆血栓素B2（TXB2）及6-酮-前列腺素F1α（6-keto-PGF1α）含量的变化。结果：①慢性低O2高CO2组平均肺动脉压（mPAP）比正常组显著升高,塞来昔布组的mPAP比慢性低O2高CO2组显著升高,3组间平均颈动脉压（mCAP）比较差异无显著性。②慢性低O2高CO2组与正常对照组相比血浆和肺匀浆TXB2浓度、TXB2/6-keto-PGF1α比值显著增高,6-keto-PGF1α浓度显著下降;塞来昔布组与慢性低O2高CO2组相比血浆和肺匀浆TXB2浓度无明显变化、TXB2/6-keto-PGF1α显著升高,6-keto-PGF1α显著下降。③光镜下慢性低O2高CO2组与正常组相比,肺细小动脉管壁面积/管总面积（WA/TA）和肺细小动脉中膜厚度（PAMT）均显著增高。塞来昔布组与慢性低O2高CO2组相比WA/TA和PAMT显著增高。④电镜下慢性低O2高CO2组大鼠肺细小动脉内皮细胞吞饮小泡增多,血管壁增厚,中膜平滑肌细胞增生,纤维细胞增多,肺泡II型上皮细胞微绒毛脱落;塞来昔布组中膜平滑肌细胞增大、增多,胞浆肌丝丰富,平滑肌细胞间隙增宽,肺泡隔胶原纤维增生明显。结论：塞来昔布可能有加重慢性低O2高CO2性肺动脉高压和肺血管结构重建倾向,过度抑制COX-2,使TXA2/PGI2比值升高可能是其作用机制之一。     

外源性apelin对大鼠慢性低氧性肺动脉高压的防治作用

目的:探讨外源性给予小分子活性肽apelin对大鼠慢性低氧性肺动脉高压和肺血管重构的作用及其机制。方法:采用常压低氧法建立SD大鼠低氧性肺动脉高压模型。实验分4组(n=10)对照组(NC)、低氧组(HH)、低氧+apelin低剂量组(5nmol/(kg.d)(LA)和低氧+apelin高剂量组(10nmol/(kg.d)(HA),HA组和LA组通过皮下埋植微量渗透泵持续给药。低氧4周后,测定平均肺动脉压(mPAP)、右心室与左心室加室间隔的重量比[RV/(LV+S)]、肺细小动脉管壁面积/管总面积(WA/TA)、管腔面积/管总面积(CA/TA)、中膜厚度(PAMT)以及肺组织超氧化物歧化酶(SOD)活性与丙二醛(MDA)含量。结果:①mPAP和RV/(LV+S):HH组较NC组高,HA组较HH组低;LA组mPAP较HH低,而RV/(LV+S)两组间无显著性差异。②WA/TA和PAMT:HH组较NC组高,HA组、LA组均较HH低。③CA/TA:HH组较NC组低,HA组、LA组均较HH高。④肺组织SOD含量:HH组较NC低,HA组、LA组均较HH高。⑤MDA含量:HH组较NC高,HA组、LA组均较HH低。结论:Apelin对低氧性肺动脉高压和肺血管重构的形成具有防治作用,这种作用可能与直接舒张肺血管作用及改善氧化应激有关。     

姜黄素对慢性低氧高二氧化碳大鼠肺动脉高压及肺动脉管壁胶原的影响

目的：研究姜黄素对慢性低氧高二氧化碳大鼠肺动脉压力及肺动脉管壁Ⅰ型胶原的影响。方法：36只SD大鼠随机分为正常对照组（NC组）,低O2高CO2 4周组（HH组）,低O2高CO2 4周＋姜黄素组（HC组）,采用免疫组化、图像分析等方法观察姜黄素对慢性低O2高CO2大鼠肺动脉压力、肺细小动脉显微和超微结构及肺动脉管壁Ⅰ型胶原的影响。结果：①血流动力学检测显示HH组mPAP明显高于NC组（P〈0．01）,HC组mPAP明显低于HH组（P〈0．01）,三组间mCAP无明显差异（P〉0．05）;②光镜下,肺细小动脉管壁面积／管总面积比值（WA／TA）、肺细小动脉中膜平滑肌细胞核密度（SMC）、肺细小动脉中膜厚度（PAMT）HH组较NC组明显增高（均P〈0．01）,HC组WA／TA、SMC和PAMT较HH组明显降低（均P〈0．01）;③电镜下,HH组肺细小动脉中膜平滑肌细胞增生,面积增大,染色质增多,外膜胶原纤维密集,HC组大鼠肺细小动脉内皮细胞结构基本正常,胶原少见,中膜平滑肌细胞和外膜胶原纤维增生较HH组明显为轻;④免疫组化法发现肺细小动脉Ⅰ型胶原平均吸光度值HH组明显高于Nc组（P〈0．01）,HC组明显低于HH组（P〈0．01）。结论：姜黄素具有降低慢性低O2高CO2性肺动脉高压、改善肺血管重建及抑制肺动脉管壁Ⅰ型胶原沉积的作用。     

Characterization of proximal pulmonary arterial cells from chronic thromboembolic pulmonary hypertension patients

Background

Chronic thromboembolic pulmonary hypertension (CTEPH) is associated with proximal pulmonary artery obstruction and vascular remodeling. We hypothesized that pulmonary arterial smooth muscle (PASMC) and endothelial cells (PAEC) may actively contribute to remodeling of the proximal pulmonary vascular wall in CTEPH. Our present objective was to characterize PASMC and PAEC from large arteries of CTEPH patients and investigate their potential involvement in vascular remodeling.

Methods

Primary cultures of proximal PAEC and PASMC from patients with CTEPH, with non-thromboembolic pulmonary hypertension (PH) and lung donors have been established. PAEC and PASMC have been characterized by immunofluorescence using specific markers. Expression of smooth muscle specific markers within the pulmonary vascular wall has been studied by immunofluorescence and Western blotting. Mitogenic activity and migratory capacity of PASMC and PAEC have been investigated in vitro.

Results

PAEC express CD31 on their surface, von Willebrand factor in Weibel-Palade bodies and take up acetylated LDL. PASMC express various differentiation markers including α-smooth muscle actin (α-SMA), desmin and smooth muscle myosin heavy chain (SMMHC). In vascular tissue from CTEPH and non-thromboembolic PH patients, expression of α-SMA and desmin is down-regulated compared to lung donors; desmin expression is also down-regulated in vascular tissue from CTEPH compared to non-thromboembolic PH patients. A low proportion of α-SMA positive cells express desmin and SMMHC in the neointima of proximal pulmonary arteries from CTEPH patients. Serum-induced mitogenic activity of PAEC and PASMC, as well as migratory capacity of PASMC, were increased in CTEPH only.

Conclusions

Modified proliferative and/or migratory responses of PASMC and PAEC in vitro, associated to a proliferative phenotype of PASMC suggest that PASMC and PAEC could contribute to proximal vascular remodeling in CTEPH.     

阿斯匹林对大鼠在低O2高CO2下肺动脉高压的作用

目的：研究阿斯匹林(ASA)对慢性低O2高CO2性肺动脉高压的抑制作用。方法：将SD大鼠分为正常对照组,慢性低O2高CO2组,慢性低O2高CO2 阿斯匹林组。用光镜、放射免疫等方法,观察各组大鼠肺动脉平均压(mPAP)、颈动脉平均压(mCAP)、肺细小动脉显微结构、血浆和肺匀浆TXB2及6-keto-PGF1α含量的变化。结果：①低O2高CO2组mPAP比正常组显著增高,ASA组的mPAP比低O2高CO2组显著降低,3组间mCAP比较差异无显著性。②光镜下低O2高CO2组与正常组相比,肺细小动脉管壁面积／管总面积(WA／TA)和肺细小动脉中膜厚度(PAMT)均显著增高。ASA组WA／TA和PAMT显著降低。③低O2高CO2组血浆和肺匀浆TXB2、6-keto-PGF1α浓度以及TXB2／6-keto-PGF1α比正常组显著增高,而ASA组与低O2高CO2组相比显著降低。结论：ASA有抑制慢性低O2高CO2性肺动脉高压和肺血管重构的作用。     

内源性硫化氢在脂多糖引起的肺动脉高压中的作用

为观察硫化氢(hydrogen sulfide,H2s)在脂多糖(1ipopolysaccharide,LPS)引起的肺动脉高压中的作用,应用离体血管环张力测定方法测定肺动脉反应性,采用生物化学方法测定肺动脉组织中H2S产出率和胱硫醚-γ-裂解酶(cystathionine γ-lyase,CSE)活性,定量PCR方法测定肺动脉组织中CSE表达水平.结果如下:(1)与对照组相比,LPS可显著升高肺动脉平均压(mean pulmonary arterial pressure,mPAP)[(1.82±0.29)kPa vs(1.43±0.26)kPa,P<0.01],降低肺动脉组织中H2S产出率[(26.33±7.84)vs(42.92±8.73)pmoFg wet tissue per minute,P<0.01]和ACh诱导的肺动脉内皮依赖性舒张反应[(75.72±7.22)%vs(86.40±4.40)%,P<0.01];(2)NariS可部分逆转上述变化,而PPG加剧上述变化;(3)CSE活性和CSE mRNA表达的变化与H2S产出率的变化相同.结果提示,LPS对内皮依赖性舒张反应的抑制导致肺动脉高压的发生,此作用可能与H2S有关.     

Autophagy in pulmonary hypertension: Emerging roles and therapeutic implications

Autophagy is an important mechanism for cellular self-digestion and basal homeostasis. This gene- and modulator-regulated pathway is conserved in cells. Recently, several studies have shown that autophagic dysfunction is associated with pulmonary hypertension (PH). However, the relationship between autophagy and PH remains controversial. In this review, we mainly introduce the effects of autophagy-related genes and some regulatory molecules on PH and the relationship between autophagy and PH under the conditions of hypoxia, monocrotaline injection, thromboembolic stress, oxidative stress, and other drugs and toxins. The effects of other autophagy-related drugs, such as chloroquine, 3-methyladenine, rapamycin, and other potential therapeutic drugs and targets, in PH are also described.     

内质网应激在大鼠低氧高二氧化碳性肺动脉高压中的作用

目的：观察低氧高二氧化碳性肺动脉高压大鼠的肺血管重塑并探讨内质网应激（ERS）在肺动脉高压中的作用。方法：将40只SD大鼠随机分为四组：常氧对照组（N）、低氧高二氧化碳组（HH）、ERS通路抑制剂4-苯基丁酸（4-phenylbutyric acid）组（4-PBA）、ERS通路激动剂衣霉素（tunicamycin）组（TM）,n=10。测量各组大鼠的肺动脉平均压（mPAP）、颈动脉平均压以及右心室肥大指数,免疫荧光α-SMA标记法鉴定各组肺中小动脉平滑肌细胞,电镜观察肺组织及肺中小动脉形态学变化,原位末端标记法（TUNEL）检测各组肺动脉平滑肌细胞的凋亡指数,采用RT-PCR和Western blot分别检测各组大鼠葡萄糖调节蛋白78（GRP78）、C/EBP同源蛋白（CHOP）、c-Jun氨基末端激酶（JNK）、天冬氨酸特异性半胱氨酸蛋白酶-12（caspase-12）mRNA及蛋白质表达。结果：①与N组相比,HH组、4-PBA组、TM组mPAP、右心室游离壁重量/左心室加心室间隔重量[RV/（LV+S）]、肺动脉管壁面积/管总面积（WA/TA）比值增加（P<0.0 1）,肺动脉管腔面积/管总面积（LA/TA）比值减小（P<0.01）,细胞凋亡指数降低（P <0.05或P<0.01）。ERS相关蛋白质及mRNA的表达量升高,各差异均有统计学意义。②与HH组相比,4-PB A组mPAP和[RV/（LV+S）]、WA/TA值减小（P<0.01）,LA/TA值和细胞凋亡指数上升（P<0.05或P<0.01）,ERS相关蛋白质和mRNA的表达量均下调（P<0.05或P<0.01）;③与HH组相比,TM组mPAP、[RV/（LV+S）]、WA/TA值升高（P<0.05或P<0.01）;肺动脉中膜层增厚,LA/TA值和细胞凋亡指数降低（P<0.01）。ERS相关蛋白质及mRNA的表达量均升高,除GRP78蛋白质表达量无明显变化外,其余各差异均有统计学意义。结论：低氧高二氧化碳诱导的肺动脉高压大鼠肺血管重塑可能与肺动脉平滑肌细胞增殖过度及凋亡过少有关;ERS相关因子（JNK、caspase-12和CHOP）参与低氧高二氧化碳性肺动脉高压的调控。     

内源性硫化氢在大鼠早期高肺血流性肺动脉高压中的动态变化

目的:探讨大鼠早期高肺血流性肺动脉高压形成中内源性硫化氢体系的动态变化规律。方法:雄性SD大鼠80只,体重140~160 g,随机分为分流组(40只)和对照组(40只)。分流组大鼠经下腔静脉-腹主动脉穿刺术建立高肺血流动物模型。分别在术后1 d、3 d、1周、4周及8周各实验时间点测量肺动脉收缩压(SPAP)、肺组织匀浆中硫化氢(H2S)含量及CSE mRNA相对含量。结果:SPAP于分流后1周开始升高,8周明显升高;肺组织H2S及CSE mRNA含量于分流后3 d及4周显著升高;SPAP与肺组织H2S、CSEm RNA含量于分流后1周、4周及8周呈明显负相关。结论:大鼠高肺血流性动物模型可导致肺动脉高压,早期伴随内源性肺组织H2S及CSEmRNA含量的变化,提示内源性H2S体系可能与高肺血流性肺动脉高压形成有关,并在其中发挥保护性的调节作用。     

Endothelial-like cells in chronic thromboembolic pulmonary hypertension: crosstalk with myofibroblast-like cells

Background

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by intravascular thrombus formation in the pulmonary arteries.Recently, it has been shown that a myofibroblast cell phenotype was predominant within endarterectomized tissues from CTEPH patients. Indeed, our recent study demonstrated the existence of not only myofibroblast-like cells (MFLCs), but also endothelial-like cells (ELCs). Under in vitro conditions, a few transitional cells (co-expressing both endothelial- and SM-cell markers) were observed in the ELC population. We hypothesized that MFLCs in the microenvironment created by the unresolved clot may promote the endothelial-mesenchymal transition and/or induce endothelial cell (EC) dysfunction.

Methods

We isolated cells from these tissues and identified them as MFLCs and ELCs. In order to test whether the MFLCs provide the microenvironment which causes EC alterations, ECs were incubated in serum-free medium conditioned by MFLCs, or were grown in co-culture with the MFLCs.

Results

Our experiments demonstrated that MFLCs promoted the commercially available ECs to transit to other mesenchymal phenotypes and/or induced EC dysfunction through inactivation of autophagy, disruption of the mitochondrial reticulum, alteration of the SOD-2 localization, and decreased ROS production. Indeed, ELCs included a few transitional cells, lost the ability to form autophagosomes, and had defective mitochondrial structure/function. Moreover, rapamycin reversed the phenotypic alterations and the gene expression changes in ECs co-cultured with MFLCs, thus suggesting that this agent had beneficial therapeutic effects on ECs in CTEPH tissues.

Conclusions

It is possible that the microenvironment created by the stabilized clot stimulates MFLCs to induce EC alterations.