Significance of BMPR2 mutations in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a debilitating disease that results from progressive remodeling and inflammation of pulmonary arteries. PAH develops gradually, is difficult to diagnose, and has a high mortality rate. Although mutation in the bone morphogenetic protein receptor 2 (BMPR2) gene has been identified as the main genetic cause of PAH, the underlying pathways involving the pathophysiology of PAH are complex and still not fully understood. Endothelial dysfunction has been observed in PAH development that results in a multitude of disturbances in the cellular processes in pulmonary vessels. Changes in the pulmonary vasculature caused by the disruption of BMPR2 signaling are observed in three main vascular components; endothelial cells, smooth muscle cells, and fibroblasts. BMPR2 also has a prominent role in maintenance of the immune system. The disruption of BMPR2 signaling pathway causes an increased degree of inflammation and decreases the ability of the immune system to resolve it. Inflammatory processes and changes in pulmonary vasculature interact with one another, resulting in the progression of chronic PAH. In this review, we highlight the various components of vascular remodeling and immune response that are caused by disruption of BMPR2 signaling, including the clinical evidence and the prospects of these components as a potential target for PAH therapy. Indeed, development of drugs to target the pathogenic pathways involved in PAH may complement existing treatment regimens and improve patient prognosis.     

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??Abstract??Pulmonary arterial hypertension (PAH) commonly arises in patients with congenital heart disease (CHD).Management of PAH-CHD can involve surgical correction of the cardiac defect and/or treatment of the PAH.Prostacyclin analogues??phosphodiesterase type-5 inhibitors and bosentan may have benefits in advanced pulmonary vascular disease.Transplantation surgery can be curative but is not without limitations.The timing of intervention in patients with PAH-CHD is important.     

先天性心脏病相关肺动脉高压患者的管理

先天性心脏病相关肺动脉高压的发病机制复杂,本病对患者的生活质量有相当大的影响。虽然目前对这类疾病尚无有效的治疗措施,但通过合理的治疗干预可以延长患者的生存时间,改善其临床症状和生活质量。因此,有必要通过多学科小组的交流对这类患者进行适当的管理,以改善患者的生活质量和预后。     

先天性心脏病并发肺动脉高压的研究进展

由于先天性心脏病（先心病）并发肺动脉高压（PAH）患者的死亡率和致残率均较高,人们重新审视了先心病并发PAH的流行病学特征及分类,并探索新的治疗手段,发掘新的能够反映PAH严重程度及预后的生物学标志物,为先心病并发PAH诊治水平的提高开辟了广阔的前景。     

BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives.

This study investigated whether patients developing pulmonary arterial hypertension (PAH) after exposure to the appetite suppressants fenfluramine and dexfenfluramine have mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene, as reported in primary pulmonary hypertension. BMPR2 was examined for mutations in 33 unrelated patients with sporadic PAH, and in two sisters with PAH, all of whom had taken fenfluramine derivatives, as well as in 130 normal controls. The PAH patients also underwent cardiac catheterisation and body mass determinations. Three BMPR2 mutations predicting changes in the primary structure of the BMPR-II protein were found in three of the 33 unrelated patients (9%), and a fourth mutation was found in the two sisters. No BMPR2 mutations were identified in the 130 normal controls. This difference in frequency was statistically significant. Moreover, the mutation-positive patients had a somewhat shorter duration of fenfluramine exposure before illness than the mutation-negative patients, a difference that was statistically significant when the two sisters were included in the analysis. In conclusion, the present authors have detected bone morphogenetic protein receptor 2 mutations that appear to be rare in the general population but may combine with exposure to fenfluramine derivatives to greatly increase the risk of developing severe pulmonary arterial hypertension.     

Ambrisentan for pulmonary arterial hypertension due to congenital heart disease

Eisenmenger syndrome (ES) is a known complication of congenital heart disease associated with unrepaired systemic to pulmonary shunts. Evidence for use of targeted pulmonary arterial hypertension therapy in ES is limited. The early experience using ambrisentan was evaluated in a cohort of consecutive patients with ES who initiated ambrisentan at Columbia University's Pulmonary Hypertension Center from January 1, 2007, to August 1, 2008. Effects of ambrisentan on rest and exercise systemic arterial oxygen saturation (S(a)O(2)), exercise capacity, functional status, hemoglobin levels, and hemodynamics were evaluated and compared using paired Student's t tests. Seventeen patients were evaluated at short-term (mean 163 ± 57 days) and longer term (mean 2.5 ± 0.5 years) follow-up. At short-term follow-up, there was an improvement in exercise capacity (6-minute walking distance 389 ± 74 vs 417 ± 77 m, p=0.03, n=11) and maintenance of rest S(a)O(2) (89 ± 7% vs 89% ± 6%, p=0.75, n=15), exercise S(a)O(2) (75 ± 15% vs 77% ± 15%, p=0.33, n=11), functional class (improvement in 2 patients, no change in 13), and hemoglobin (16.5 ± 2.8 vs 15.8 ± 1.8 g/dl, p=0.11, n=14). At longer term follow-up compared to baseline and short-term follow-up, there was stability of exercise capacity, S(a)O(2), functional class, and hemoglobin. In conclusion, in this single-center cohort of patients with ES, ambrisentan was safe and was associated with increasing exercise capacity at short-term follow-up, with patients maintaining S(a)O(2), functional class, and hemoglobin, and with no significant evidence of clinical deterioration at longer term follow-up. Additional studies are required to further assess the efficacy of ambrisentan in patients with ES.     

Doppler echocardiographic prediction of pulmonary arterial hypertension in congenital heart disease

This study determines the accuracy of Doppler echocardiography (echo) for predicting the presence of pulmonary artery (PA) hypertension from Doppler PA velocity traces. The patient group included 17 patients with congenital cardiac disease who had undergone catheterization. The control group was composed of 15 normal subjects. Doppler traces were analyzed qualitatively and quantitatively. Qualitative assessment included evaluation for a negative presystolic velocity that was the equivalent of the pulmonary a wave detected by M-mode echo. Quantitative assessment included measurement of the following time intervals and ratio of intervals: preejection period (PEP), time to peak velocity (TPV), right ventricular ejection time (RVET), PEP/RVET and TPV/RVET ratios. In the patient group, systolic PA pressure ranged from 22 to 90 mm Hg (mean 50 +/- 23), and mean PA pressure ranged from 12 to 60 mm Hg (mean 32 +/- 17). Five patients had systolic PA pressures of less than or equal to 30 mm Hg and 12 had systolic PA pressures greater than 30 mm Hg. Of 15 control subjects, 14 had a negative presystolic a wave. Of 5 patients with PA pressure less than or equal to 30 mm Hg, 4 had a presystolic negative velocity, and all with higher pressures had no presystolic negative velocity. One patient with pressure less than 30 mm Hg and 2 with PA pressure greater than 30 mm Hg had indeterminate status of presystolic velocity pattern because of turbulence or baseline blanking. The best quantitative indexes for separating patients with normal PA pressure from those with elevated PA pressure were TPV and TPV/RVET, which respectively correlated negatively with systolic PA pressure (r = -0.82, standard error of the estimate [SEE] = 0.02; and r = -0.70, SEE = 0.05). These measurements also correlated negatively with mean PA pressure (r = -0.75, SEE = 0.02; and r = -0.76, SEE = 0.05). Other intervals and ratios had enough individual variability to make them less useful as predictors of PA hypertension.     

Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease

Background

The objective of this prospective study was to assess the efficacy of exercise training as add-on to medical therapy in patients with congenital heart disease associated pulmonary arterial hypertension (CHD–APAH).

Methods

Patients with invasively confirmed CHD–APAH received in-hospital exercise training for 3 weeks and continued at home. Efficacy parameters were evaluated at baseline, after 3 and 15 weeks. Medical treatment remained unchanged. Worsening events and survival rate were assessed in a follow-up period of 21 ± 14 months.

Results

Twenty consecutive CHD–APAH patients (16 female, 4 male, mean pulmonary arterial pressure 60 ± 23 mm Hg) were included. Patients significantly improved the mean distance walked in 6 min compared to baseline by 63 ± 47 m after 3 weeks (p < 0.001) and by 67 ± 59 m after 15 weeks (p = 0.001). Quality of life-score (p = 0.05), peak oxygen consumption (p = 0.002) and maximal workload (p = 0.003) improved significantly by exercise training after 15 weeks. The 1- and 2‐year survival rates were 100%, the transplantation-free survival rate was 100% after 1 year and 93% after 2 years.

Conclusion

Exercise training as add-on to medical therapy may be effective in patients with CHD–APAH and improved work capacity, quality of life and further prognostic relevant parameters. It was associated with an excellent long-term survival. Further randomized controlled studies are needed to confirm these results.     

Hemodynamic changes with enalapril in pulmonary arterial hypertension secondary to congenital heart disease

Enalapril was used to treat five patients with pulmonary arterial hypertension secondary to congenital cardiopathy, three with ventricular septal defect, one with arterial septal defect, and one with patent ductus arteriosus. The dose of enalapril was 20 mg/day. All patients underwent pretreatment and posttreatment cardiac catheterization. It was concluded that enalapril may be a useful drug in the treatment of pulmonary arterial hypertension secondary to congenital cardiopathy.     

Pulmonary arterial hypertension in congenital heart disease

Pulmonary arterial hypertension (PAH) is a recognized complication of congenital systemic to pulmonary arterial cardiac shunts. The prognosis of PAH in this situation is better than primary or other secondary forms of PAH. Our knowledge of the pathophysiology of PAH complicating congenital heart disease has evolved over the past decade. Despite differences in etiology and pathobiology, therapies that have proven successful for primary PAH may benefit this group of patients.     

Pulmonary arterial hypertension in adults with congenital heart disease

Pulmonary arterial hypertension is a chronic, persistent elevation in pulmonary artery pressure without evidence of left heart failure. Pulmonary hypertension is common in patients with adult congenital heart disease and is usually the result of an increase of pulmonary blood flow through a large left to right shunt. This condition is progressive and patients are symptomatic and usually die between the third and fifth decades of life. To date, there is no standardized treatment for this condition and a general policy of non-intervention to avoid destabilization of the balanced physiology is recommended. Intravenous prostanoids have been shown to have an effect but they are invasive and associated with major side effects. Lung and combined heart and lung transplantation might be a therapeutic option for selected patients. However, donor shortage is a major issue. Oral advanced therapies have been recently shown to improve haemodynamics and survival in idiopathic pulmonary hypertension or in pulmonary hypertension related to scleroderma and may have a role in patients with pulmonary hypertension secondary to congenital heart disease.     

儿童先天性心脏病合并重度肺动脉高压根治术随访分析

目的:通过对儿童非限制性左向右分流型先天性心脏病合并重度肺动脉高压根治术后的随访,分析超手术指征患儿术后的生存现状并探讨手术指征。方法:收集2005年1月至2016年6月,在我院进行手术治疗的左向右分流型先天性心脏病合并重度肺动脉高压的儿童患者临床资料,所有患儿均有经心导管检查获得的血流动力学资料,随访其术后症状、体征、超声心动图。按术前肺血管阻力指数(PVRI)6WU/m~2和PVRI≥6WU/m~2分为两组,根据患儿生活质量情况进行生存分析并做Logrank检验,再根据术后是否存在肺动脉高压绘制ROC曲线。结果:59例患儿(男性27例,女性32例),平均8.4岁,主要诊断为室间隔缺损、动脉导管未闭、房间隔缺损、完全型心内膜垫缺损、主肺动脉窗、高压型右室双出口等左向右分流型先天性心脏病,随访时间4~127个月平均69.3个月。PVRI6WU/m~2组12例(男性6例,女性6例),失访3例,所有患儿随访均无术后PAH;PVRI≥6WU/m~2组患儿47例(男性21例,女性26例),失访15例,除4例患儿随访超声心动图显示无肺动脉高压外,均有不同程度术后肺动脉高压。比较两组患儿无阳性事件的生存曲线,PVRI6WU/m~2组明显优于PVRI≥6WU/m~2组(Log-rank检验P=0.0496),ROC曲线显示PVRI是预判手术后是否存在肺动脉高压的敏感指标(曲线下面积0.90),且PVRI以8.15WU/m~2为界点时,敏感度为84.2%,特异度为80%。结论:PVRI是评价手术远期预后的关键指标;PVRI6WU/m~2的患儿手术预后明显好于PVRI≥6WU/m~2的患儿。     

先天性心脏病继发性肺动脉高压患者血浆中miRNA的研究

目的 应用微小RNA （microRNA,miRNA）芯片技术研究先天性心脏病合并重度肺动脉高压（pulmonary arterial hypertension,PAH）患者和不合并PAH患者血浆中miRNA表达谱的差异,并初步预测差异表达的miRNA调控的靶基因.方法 收集室间隔缺损（ventricular septal defect,VSD）合并重度PAH（PAH组）和不合并PAH患者（对照组）的血浆.分别提取总RNA,然后采用miRNA芯片进行miRNA表达谱差异分析,并对结果进行实时定量聚合酶链反应（polymerase chain reaction,PCR）验证.运用Targetscan、Pictar、Miranda软件预测可能调控的靶基因.结果 miRNA芯片结果提示：与对照组相比,左向右分流先天性心脏病继发重度PAH患者血浆中表达上调的miRNA有50个,表达下调的miRNA有36个.实时定量PCR验证miR-98与芯片结果一致,表达上调.靶基因预测软件显示内皮素（ET-1）为hsa-miR-98的重要靶基因.结论 miRNA在先天性心脏病继发重度PAH患者血浆中存在差异性表达,miRNA可能与PAH的发生、发展密切相关,血浆miR-98有可能成为先天性心脏病合并重度PAH的新的分子生物学标志物.     

先天性心脏病并肺动脉高压研究新进展

先天性心脏病并肺动脉高压主要与持续血容量增加所导致的肺血管收缩和血管壁重构、肺血管内皮细胞损伤和功能失调、肺动脉微血栓形成等因素有关,临床上常采用超声心动图,右心导管检测,药物试验评价肺高压的危害,指导并制定治疗策略;其临床研究进展迅速,现将相关内容进行综述,为先天性心脏病并肺动脉高压最佳治疗方案的制定提供理论依据。     

Pulmonary thromboembolism in congenital heart defects with severe pulmonary arterial hypertension

IntroductionCongenital heart defect (CHD) with shunt can lead to severe, even irreversible pulmonary arterial hypertension (PAH); in extreme form to Eisenmenger syndrome (ES). Despite relatively good long-term survival, these patients often suffer from cyanosis and multisystemic dysfunction, where pulmonary artery thrombosis can be a potentially fatal complication. Together with bleeding these are the most frequent causes of non-cardiac death in patients with severe PAH due to CHD.Patients and methodsProspective study of 40 patients with severe PAH due to CHD (28 female/12 male, median age 41.5 years) was performed, with the aim to analyze the presence of pulmonary artery thrombosis and correlating anatomical and laboratory risk factors.ResultsPrevious thrombosis and/or thromboembolic event was found in 7 patients (17.5%). Significant differences in cyanotic vs non-cyanotic patients were in red blood count parameters: median hemoglobin level 195 vs 141 (p<0.0001), median erythrocytes count 6.62 vs 4.88×10¹²/l (p<0.0001), median hematocrit 0.58 vs 0.44 (p<0.0001). Laboratory findings causing increased risk for thrombosis were increased thrombocytes aggregation in 15 patients (37.5%), hypercoagulation in 5 patients (12.5%) and endothelial dysfunction in 8 patients (20%). Anatomical risk factor—severe pulmonary artery dilatation (>40 mm in female and >45 mm in male) was found in 19 patients (51.4%).ConclusionsPatients with severe PAH due to CHD represent a high-risk group for pulmonary artery thrombosis with morphological and flow pathology combined with secondary erythrocytosis and coagulation abnormalities. A relatively high incidence of platelet hyperaggregability shown in our study would propose that aspirin therapy might be considered in some highly selected patients with severe PAH due to CHD. Further studies though are needed to support this data.