Genetic aspect of pulmonary arterial hypertension

This paper concentrates on the genetic aspects of pulmonary arterial hypertension (PAH), a diagnostically based subclass of pulmonary hypertension that includes primary pulmonary hypertension (PPH). During the past year, patients with familial and sporadic PPH were found to have germline heterozygous missense, nonsense and frameshift mutations in bone morphogenetic protein receptor II (BMPRZ). Mutations in BMPR2, a member of the transforming growth factor-β (TGF-β) receptor superfamily, are predicted to interrupt the bone morphogenetic protein (BMP) signalling pathway, resulting in proliferation, rather than apoptosis of cells within small arterioles. Mechanistically, haploinsufficiency was found by using in vitro gene expression experiments, but a dominant-negative mechanism has not been excluded. The failure to find BMPR2 mutations in all families with familial PPH and in all patients with sporadic PPH suggests that other genes remain to be identified. Mutations in ALK1, a TGF-β type 1 receptor, previously known to cause type 2 hereditary haemorrhagic telangiectasia (HHT), have also been reported in a few HHT families with clinical and histological features of PPH. The clinical development of PPH, as in neoplasia, appears to require ‘two hits’. The two hits can be provided either by genetic or environmental factors.     

CT诊断肺动脉高压Meta分析

目的 采用Meta分析评价CT在肺动脉高压中的诊断价值。方法 通过检索Pubmed、Elsevier和中国期刊网数据库(CNKI),获得相关中、英文文献,采用QUADAS-2工具对纳入的研究进行质量评价。采用Meta-disc 1.40软件对纳入的文献进行异质性检验,根据随机效应模型,汇总敏感度、特异度,并绘制综合受试者工作特征(SROC)曲线,计算曲线下面积。结果 共12篇文献符合要求,纳入其中8篇文献、均以肺动脉直径/升主动脉直径>1或≥1作为肺动脉高压的诊断标准,纳入对象共计1111例。Deeks漏斗图分析提示各文献间无明显发表偏倚(P=0.501)。汇总后的敏感度、特异度分别为74%(95%可信区间:70%~77%)、81%(95%可信区间:76%~85%),SROC曲线下面积为0.8535。结论 CT检查肺动脉直径/主动脉直径诊断肺动脉高压具有一定的临床应用价值。     

风湿性瓣膜病变合并肺动脉高压87例观察

目的:总结87例风湿性瓣膜病变合并肺动脉高压患者行手术治疗的围术期处理经验。方法:87例风湿性瓣膜病变合并肺动脉高压患者行二尖瓣置换75例,二尖瓣置换 主动脉瓣置换12例。结果:此组患者手术过程顺利,术后并发低心输出量综合征5例,严重心律失常9例,早期死亡2例,病死率2.3%,其中低心排1例,1例因多脏器功能衰竭死亡。结论:风湿性瓣膜病变合并肺动脉高压患者病情较重,注意围术期各环节处理,即重视术前心功能改善,术中加强心肌保护,合理纠正病变,术后严密监护,可提高手术成功率。     

雾化吸入伊洛前列素治疗肺动脉高压的护理管理及随访

目的 探讨雾化吸入伊洛前列素治疗肺动脉高压患者的护理安全管理及随访要点.方法 通过对25例肺高压患者在常见治疗基础上进行6个月伊洛前列素吸入及随访,对比吸入前后患者的6 min步行距离指标.结果 患者用药后疗效显著,且无严重不良反应.结论 雾化吸入伊洛前列素在治疗肺高压上效果较好,可明显改善患者身体状况与生活质量.在整个治疗过程中对患者实施全方位的护理安全管理,定期规律地进行随访,提高了患者治疗的信心和依从性,从而进一步增强治疗效果.     

Bosentan: a novel agent for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease that, without treatment, ultimately results in right heart failure and death. For the majority of patients with advanced PAH, therapy requires cumbersome drug delivery devices with serious side effects. Endothelin, a potent endogenous vasoconstrictor, is increased in individuals with PAH. The development of bosentan, a novel, well-tolerated, orally active endothelin antagonist, has significantly changed the therapeutic approach to PAH. Recent clinical trials have demonstrated that treatment with bosentan produces favourable effects on cardiopulmonary haemodynamics, exercise capacity, WHO functional class and time to clinical worsening in PAH.     

Diagnosis and treatment of pediatric pulmonary arterial hypertension

Introduction: Pediatric pulmonary arterial hypertension (PAH) remains a rare and severe disease with a poor prognosis. PAH may be idiopathic, heritable or associated with systemic conditions in particular associated with congenital heart disease.

Areas covered: A thorough and extensive diagnostic approach is required for a correct diagnosis. The outcome has improved over the last decade with a better diagnostic approach and with the initiation of new targeted therapies. However, there is still significant progress to achieve as there is still no cure for this devastating disease.

Expert opinion: Adapted clinical studies to define the best therapeutic approach are needed. Even if the treatment approach is still mainly derived from adult data and expert consensus, several studies and registries are currently underway and should deliver important information in the next future.

This review aims to give an overview of the current diagnosis and treatment strategies of PAH.     

慢性阻塞性肺疾病相关性肺动脉高压与炎症反应关系的研究

目的 探讨慢性阻塞性肺疾病(COPD)相关性肺动脉高压(PAH)的发生率及其与诱导痰炎症细胞、血清超敏C-反应蛋白(hs-CRP)、IL-8及TNF-α之间的关系.方法 对COPD稳定期患者68例和健康体检者30例常规行肺动脉、动脉血气分析、X线胸片等检查.对诱导痰进行炎症细胞分类计数,免疫比浊法测定血清hs-CRP,ELISA法测定血清IL-8与TNF-α.COPD组行超声心动图检查推算肺动脉收缩压(PASP),并测量心脏有关腔室大小.根据PASP>30 mm Hg,将COPD患者分为PAH组和单纯COPD组.结果 COPD组患者PAH发生率53%(36/68),分层研究发现轻、中、重度COPD患者PAH发生率分别为27%(3/11)、38%(5/13)和64%(28/44),差异具有统计学意义(χ26.020,P<0.05).PAH组PASP与右心室游离壁厚度(RVWT)显著高于单纯COPD组,差异具有统计学意义[PASP:PAH组(52±15)mm Hg,单纯COPD组(23±12)mm Hg,t=3.32,P<0.01;PVWT:PAH组(5.03±1.04)mm,单纯COPD组(3.78±0.57)mm,t=2.36,P<0.05)].PAH组诱导痰炎症细胞总数、中性粒细胞计数、血清hs-CRP、IL-8及TNF-α水平明显高于单纯COPD组和健康对照组,差异具有统计学意义[痰炎症细胞总数:PAH组(2.84±0.56)×109/L,单纯COPD组(1.73±0.42)×109/L.健康对照组(0.68±0.23)×109/L;中性粒细胞计数:PAH组(2.78±0.52)×109/L,单纯COPD组(2.57±0.26)×109/L,健康对照组(0.63±0.21)×109/L;血清hs-CRP:PAH组(32±12)mg/L,单纯COPD组(23±11)mg/L,健康对照组(11±4)mg/L;IL-8:PAH组(113±34)ng/L,单纯COPD组(69±24)ng/L,健康对照组(38±11)ng/L;TNF-α:PAH组(206±63)ng/L;单纯COPD组(153±54)ng/L,健康对照组(75±26)ng/L](P均<0.05).PAH组PASP与第1秒用力呼气量占预计值%(FEV<,1>%)呈负相关(r=-0.48,P<0.01),与血清IL-8、TNF-α及诱导痰中性粒细胞计数呈正相关(r分别为0.43、0.56、0.47,P均<0.01).方法 COPD相关性PAH发生率不低,炎症反应是PAH形成的重要因素.     

特发性肺纤维化合并肺动脉高压的诊治进展

特发性肺纤维化(idiopathic pulmonary fibrosis, IPF)是病因不明,组织病理学主要为普通间质性肺炎,局限于肺部的慢性纤维化型间质性肺炎。该病致死率高,对人群健康危害性高。近年来,随着人口老龄化、空气污染的加剧导致其发病率逐年上升,我们对于IPF的认识也在不断提高,研究发现IPF患者常合并其他疾病,包括肺气肿、肺癌、心血管疾病等。存在合并症的IPF患者临床症状更多,患者的生存质量差。其中合并肺动脉高压会降低IPF患者的生存率,本文就IPF合并肺动脉高压进行综述,以期为IPF合并肺动脉高压的诊疗方案与进一步研究提供新思路,以期提高 IPF患者的生活质量及改善预后。     

Cancer antigen-125 is a predictor of mortality in patients with pulmonary arterial hypertension

BackgroundCarbohydrate antigen 125 (CA 125), known as a tumor marker for ovarian cancer, has been reported to increase and be associated with severity in heart failure and chronic obstructive pulmonary disease. Patients with pulmonary arterial hypertension may also die due to developing right heart failure. The aim of this study is to evaluate the prognostic role of CA-125 in PAH patients.MethodsA total of 40 consecutive patients with PAH were evaluated prospectively. The mean age of patients was 52 ± 11 years (12% males, 88% females) with a median follow-up period of 16 months.ResultsAfter follow-up period, 12 out of 40 patients (30%) died. CA-125 levels were higher among those who died compared to those who survived [78.5 (11.0–292) vs. 27.5 (2.10–138) U/ml, p = 0.001]. The optimal cut-off value of CA-125 to predict mortality was found as 35.29 U/ml, with 85.7% specificity and 75% sensitivity. In multivariable Cox proportional-hazards model with forward stepwise method; CA-125 > 35.32 U/ml on admission (HR = 7.645, 95% CI: 1.356–43.121, p = 0.021), age (HR = 1.132, 95% CI: 1.040–1.233, p = 0.004), TAPSE (HR = 0.740, 95% CI: 0.549–0.998, p = 0.048) and uric acid (HR = 1.444, 95% CI: 1.022–2.042, p = 0.037) remained associated with an increased risk of death.ConclusionIn this study, we showed for the first time that serum CA-125 values were an independent predictor for the long-term mortality in PAH patients.     

Sitaxsentan: an endothelin-A receptor antagonist for the treatment of pulmonary arterial hypertension

Endothelin (ET-1) is a potent vasoconstrictor and smooth muscle mitogen that mediates its effects through activation of ET-A and ET-B receptors. Pulmonary arterial hypertension (PAH) encompasses a heterogeneous group of disorders characterised by inappropriate overactivation of the ET system. There is clear evidence that strategies that block both ET receptors are associated with clinical improvement in PAH. However, there are theoretical physiological advantages to treatments that specifically inhibit only the ET-A receptor. Sitaxsentan is an orally active selective ET-A receptor antagonist that in recent clinical trials has demonstrated improvements in exercise capacity, functional class and haemodynamics in PAH patients with modified New York Heart Association class II, III and IV symptoms.     

钾通道开放剂烟酰胺对肺动脉高压血浆内皮素1影响的临床观察

目的 探讨钾通道开放剂烟酰胺对肺动脉高压患者血浆内皮素的影响.方法 入选66例缺氧性肺动脉高压患者,随机分为烟酰胺治疗组(治疗组)和常规治疗组(对照组),每组33例,测定2组肺动脉高压患者治疗前后血浆内皮素1变化.结果 治疗组治疗后较治疗前血浆内皮素1明显降低(P＜0.01).对照组治疗前后自身比较,血浆内皮素1无明显变化(P＞0.05);治疗组与对照组治疗前后的差值比较有统计学意义(P＜0.01).结论 烟酰胺可保护内皮细胞,减少内皮素1的分泌和释放,对缺氧性肺动脉高压有治疗作用.     

Pulmonary arterial hypertension

PAH is a chronic disease requiring lifelong therapy, regardless of chosen treatment options. Nurses and other providers must allow for open, honest discussion on the risks and benefits of each therapy. Determining the best treatment option for patients requires consideration of the patient's overall function and social support. These patients benefit from comprehensive and collaborative support from facilities or centers trained in the management of the disease.     

Drug-associated pulmonary arterial hypertension

Introduction: While pulmonary arterial hypertension remains an uncommon diagnosis, various therapeutic agents are recognized as important associations. These agents are typically categorized into “definite”, “likely”, “possible”, or “unlikely” to cause pulmonary arterial hypertension, based on the strength of evidence.

Objective: This review will focus on those therapeutic agents where there is sufficient literature to adequately comment on the role of the agent in the pathogenesis of pulmonary arterial hypertension.

Methods: A systematic search was conducted using PubMed covering the period September 1970– 2017. The search term utilized was “drug induced pulmonary hypertension”. This resulted in the identification of 853 peer-reviewed articles including case reports. Each paper was then reviewed by the authors for its relevance. The majority of these papers (599) were excluded as they related to systemic hypertension, chronic obstructive pulmonary disease, human immunodeficiency virus, pulmonary fibrosis, alternate differential diagnosis, treatment, basic science, adverse effects of treatment, and pulmonary hypertension secondary to pulmonary embolism.

Agents affecting serotonin metabolism (and related anorexigens): Anorexigens, such as aminorex, fenfluramine, benfluorex, phenylpropanolamine, and dexfenfluramine were the first class of medications recognized to cause pulmonary arterial hypertension. Although most of these medications have now been withdrawn worldwide, they remain important not only from a historical perspective, but because their impact on serotonin metabolism remains relevant. Selective serotonin reuptake inhibitors, tryptophan, and lithium, which affect serotonin metabolism, have also been implicated in the development of pulmonary arterial hypertension.

Interferon and related medications: Interferon alfa and sofosbuvir have been linked to the development of pulmonary arterial hypertension in patients with other risk factors, such as human immunodeficiency virus co-infection.

Antiviral therapies: Sofosbuvir has been associated with two cases of pulmonary artery hypertension in patients with multiple risk factors for its development. Its role in pathogenesis remains unclear.

Small molecule tyrosine kinase inhibitors: Small molecule tyrosine kinase inhibitors represent a relatively new class of medications. Of these dasatinib has the strongest evidence in drug-induced pulmonary arterial hypertension, considered a recognized cause. Nilotinib, ponatinib, carfilzomib, and ruxolitinib are newer agents, which paradoxically have been linked to both cause and treatment for pulmonary arterial hypertension.

Monoclonal antibodies and immune regulating medications: Several case reports have linked some monoclonal antibodies and immune modulating therapies to pulmonary arterial hypertension. There are no large series documenting an increased prevalence of pulmonary arterial hypertension complicating these agents; nonetheless, trastuzumab emtansine, rituximab, bevacizumab, cyclosporine, and leflunomide have all been implicated in case reports.

Opioids and substances of abuse: Buprenorphine and cocaine have been identified as potential causes of pulmonary arterial hypertension. The mechanism by which this occurs is unclear. Tramadol has been demonstrated to cause severe, transient, and reversible pulmonary hypertension.

Chemotherapeutic agents: Alkylating and alkylating-like agents, such as bleomycin, cyclophosphamide, and mitomycin have increased the risk of pulmonary veno-occlusive disease, which may be clinically indistinct from pulmonary arterial hypertension. Thalidomide and paclitaxel have also been implicated as potential causes.

Miscellaneous medications: Protamine appears to be able to cause acute, reversible pulmonary hypertension when bound to heparin. Amiodarone is also capable of causing pulmonary hypertension by way of recognized side effects.

Conclusions: Pulmonary arterial hypertension remains a rare diagnosis, with drug-induced causes even more uncommon, accounting for only 10.5% of cases in large registry series. Despite several agents being implicated in the development of PAH, the supportive evidence is typically limited, based on case series and observational data. Furthermore, even in the drugs with relatively strong associations, factors that predispose an individual to PAH have yet to be elucidated.     

Sitaxsentan: a novel endothelin-A receptor antagonist for pulmonary arterial hypertension

Sitaxsentan is an orally active, selective endothelin-A receptor antagonist that may benefit patients with pulmonary arterial hypertension by blocking the vasoconstrictive effects of endothelin-A receptors, while maintaining the vasodilator and endothelin-1 clearance functions of the endothelin-B receptors. In its first randomized, placebo-controlled study, sitaxsentan improved exercise capacity assessed by the 6-min walk test, New York Heart Association functional class, cardiac index and pulmonary vascular resistance in New York Heart Association Class II, III and IV patients with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension related to connective tissue disease or congenital heart disease. Although doses of 100 and 300 mg once daily demonstrated equivalent efficacy, the lower dose had a better safety profile. Additional studies are ongoing to assess the relative safety and efficacy of 50 and 100 mg once-daily dosing. The most common side effects include rhinitis, headache, peripheral edema, chest pain, nausea, constipation, increased prothrombin time/international normalized ratio (in patients on warfarin), flushing and insomnia. As with other endothelin receptor antagonists, increases in hepatic transaminases have been observed with sitaxsentan. Initial studies using the selective oral endothelin-A receptor antagonist sitaxsentan in pulmonary arterial hypertension patients have revealed a favorable risk–benefit therapeutic profile with the 100 mg once-daily dose.     

Comparison of inhaled nitric oxide with aerosolized prostacyclin or analogues for the postoperative management of pulmonary hypertension: a systematic review and meta-analysis

Abstract

Background: This study aims to compare the effectiveness of inhaled prostacyclin or its analoguesversus nitric oxide (NO) in treating pulmonary hypertension (PH) after cardiac or pulmonary surgery remains unclear.

Methods: PubMed, Cochrane, and Embase databases were searched for literature published prior to December 2019 using the following keywords: inhaled, nitric oxide, prostacyclin, iloprost, treprostinil, epoprostenol, Tyvaso, flolan, and pulmonary hypertension. Randomized controlled trials and multiple-armed prospective studies that evaluated inhaled NO versus prostacyclin (or analogues) in patients for perioperative and/or postoperative PH after either cardiac or pulmonary surgery were included. Retrospective studies, reviews, letters, comments, editorials, and case reports were excluded.

Results: Seven studies with a total of 195 patients were included. No difference in the improvement of mean pulmonary arterial pressure (pooled difference in mean change= ?0.10, 95% CI: ?3.98 to 3.78, p?=?.959) or pulmonary vascular resistance (pooled standardized difference in mean change= ?0.27, 95% CI: ?0.60 to 0.05, p?=?.099) were found between the two treatments. Similarly, no difference was found in other outcomes between the two treatments or subgroup analysis.

Conclusions: Inhaled prostacyclin (or analogues) was comparable to inhaled NO in treating PH after cardiac or pulmonary surgery.

• Key messages

• This study compared the efficacy of inhaled prostacyclin or its analogues versus inhaled NO to treat PH after surgery. The two types of agent exhibited similar efficacy in managing MPAP, PVR, heart rate, and cardiac output was observed.

• Inhaled prostacyclin may serve as an alternative treatment option for PH after cardiac or pulmonary surgery.

     

Eisenmenger syndrome and other types of pulmonary arterial hypertension related to adult congenital heart disease

Introduction: Eisenmenger syndrome (ES) is the most advanced form of pulmonary arterial hypertension (PAH) in patients with congenital heart disease (CHD). It is characterised by a severe rise in pulmonary vascular resistance resulting in shunt reversal and cyanosis.

Areas covered: In this paper, an overview of ES and other types of PAH related to CHD (PAH-CHD) in adults is provided. The modern management of PAH-CHD in tertiary centers is described, with an emphasis on co-morbidities and complications.

Expert opinion: PAH-CHD describes a wide spectrum of conditions, of which ES is the archetype. The size and location of the shunt, the degree of adaptation of the right ventricle to the increased afterload and other compensatory mechanisms, such as secondary erythrocytosis, define the clinical presentation and natural history of these patients. PAH therapies have improved the quality of life and outcome of many patients with PAH-CHD, but expert multidisciplinary management remains essential in optimising the care of this rare and complex group of patients.     

缬沙坦对野百合碱诱导肺动脉高压模型大鼠肺动脉重构的影响

目的:观察缬沙坦(valsartan)对野百合碱(monocrotaline)所致肺动脉高压大鼠肺血管重构的影响.方法:将健康雄性Wistar 大鼠随机分为3 组:M 组(肺动脉高压模型组)一次性项背部注射野百合碱(60 mg / kg)后自由摄食、饮水;V 组(缬沙坦干预组),同M 组注射野百合碱并同等条件饲养,4 周后开始用缬沙坦20 mg / (kg·d)灌胃,持续4 周达实验终点;C 组(正常对照组)一次性项背部注射等量生理盐水后与实验组同等条件饲养.然后经微导管介入测定大鼠肺动脉平均压(mPAP);计算右室肥大指数[RV/ (LV + S)];分别采用HE 染色、弹力纤维染色及VG 染色观察肺动脉结构的改变,计算肺动脉管壁厚度和管腔面积,评价缬沙坦对肺动脉重构的影响.结果:缬沙坦可有效降低野百合碱所致肺动脉高压大鼠模型肺动脉管壁的厚度,增大管腔面积(P ＜ 0.01).结论:缬沙坦可有效抑制肺动脉高压大鼠肺动脉重构,作用机制可能与其抑制AngⅡ介导的增殖效应有关.     

Effects of age and pulmonary arterial hypertension on the different phases of right atrial function

To evaluate the effects of age and pulmonary hypertension on phasic right atrial function we measured right atrial volumes at 3 different points in the cardiac cycle in 57 healthy subjects and 33 patients with pulmonary arterial hypertension. Right atrial reservoir function was assessed by systolic filling volume and passive and active emptying by passive and active emptying volume and fraction of total emptying. We compared these phases of right atrial function in 30 healthy subjects <60 and 27 >/= 60 years old, and in a separate analysis, in 33 patients with pulmonary arterial hypertension and 33 matched controls. Healthy subjects >/=60 years had lower passive emptying fraction (46.0 +/- 23.3% vs 59.9 +/- 15.4%, P = 0.011) and larger active emptying volume (7.0 +/- 3.5 vs 4.9 +/- 2.5 ml/m(2), P = 0.013 ) and fraction (54.0 +/- 23.3% vs 40.1 +/- 15.4%, P = 0.011) compared to those <60. Patients with pulmonary arterial hypertension had larger right atrial volumes, systolic filling volume (18.3 +/- 6.9 vs 12.3 +/- 4.9 ml/m(2), P 相似文献