原文和中文译文均转自丁香园网站

【JACC】the Expert Consensus Document on pulmonary arterial hypertension associated with the congenital heart disease

Overall, the incidence of CHD is approximately 8 per 1,000 live births .Many different forms of CHD are associated with an increased risk for the development of pulmonary vascular disease (PVD). In patients with systemic-to-pulmonary shunts, the type and size of the defect, as well as the magnitude of the shunt, are risk factors for the development of PAH. Shear stress due to increased pulmonary blood flow and/or increased pulmonary artery pressure appears to play a major role in the development of PVD related to CHD.Based on natural history studies, approximately 30% of all children born with CHD who do not undergo surgical repair will develop PVD .However, to date we have limited ability to determine which patients develop early irreversible PVD. There appears to be a difference between the pre- and post-tricuspid shunt lesions. The laminar shear stress induced by the increase in pulmonary blood flow alone may not be the same as the laminar and circumferential pressure shear stress induced by post-tricuspid shunt lesions, for example, a ventricular septal defect. Patients with small- to moderatesized ventricular septal defects develop PVD in only approximately 3% of cases; in contrast, almost all patients with an unrepaired truncus arteriosus develop PVD, while approximately 50% with a large ventricular septal defect and 10% with an atrial septal defect develop PVD. In addition, there is significant biologic variability in the clinical presentation and prognosis. While some children with the same underlying CHD develop irreversible PVD in the first year of life, others with the same CHD may maintain acceptable levels of pulmonary vascular resistance for many years. A recent study demonstrated BMPR2 mutations in patients with PAH in CHD. Mutations in BMPR2 occur in patients with FPAH and IPAH. These data raise the possibility that the presence of a genetic predisposition in some patients with CHD may contribute to the observed biologic variability. Further investigation into the role of genetic mutations may offer insight into which children with CHD should undergo surgical repair during early infancy. However,whether early therapeutic interventions halt or reverse the progression of the PVD remains unclear.Over the past several decades, advances in pediatric cardiology/cardiac surgery have increased the number of patients with CHD surviving into adulthood. However, despite surgical correction of large systemic-to-pulmonary shunts in infancy, surgical repair does not guarantee that patients will not develop PVD postoperatively, and thus although early diagnosis and improved cardiac surgery have significantly decreased the number of patients overall with Eisenmenger syndrome, some of these patients, for reasons that remain unclear, develop progressive PVD following surgical repair. In addition to the symptoms and complications associated with PAH without Eisenmenger syndrome, patients with Eisenmenger syndrome have additional comorbid conditions due to right-to-left shunting and hypoxemia resulting in hematologic, hemostatic, cerebrovascular, renal, rheumatologic, and cardiac complications. With respect to therapeutic interventions, whether medical or surgical, risk:benefit considerations need to be carefully uated based on the natural history of the condition as well as on an individual basis. The survival and long term outcome for patients with classic Eisenmenger syndrome is quite different than for patients with other forms of PAH, such as IPAH/FPAH or PAH related to connective tissue disease . Untreated, survival rates are 80% at 5 years and approximately 40% at 25 years. Despite the differences in etiology and prognosis, PAH associated with CHD shares similarities with IPAH, for example, pulmonary vascular histopathology. Based on these similarities, therapeutic modalities demonstrated to be efficacious in patients with IPAH are beginning to be uated in patients with PAH associated with CHD based on presumed similar pathobiology.As opposed to patients with IPAH, in whom the likelihood of acute pulmonary vasoreactivity with effective long-term calcium channel blockade therapy is less than 10%, this is virtually nonexistent in patients with PAH related to CHD. To date, the only disease-specific targeted PAH therapy that has been demonstrated to be efficacious in patients with PAH related to CHD is the ETA/ETB receptor antagonist bosentan. Although this trial was only 16 weeks in duration, a relatively short period of time for patients with Eisenmenger syndrome in whom the natural history is significantly more protracted than for IPAH,bosentan improved exercise capacity and decreased pulmonary vascular resistance without worsening systemic arterial oxygen saturation; the safety and tolerability profile was comparable to that observed with previous PAH bosentan trials . In addition, although not randomized controlled trials, several open label uncontrolled studies have reported improved exercise capacity and hemodynamics (including improvement in systemic arterial oxygen saturation) with chronic intravenous epoprostenol . The risk of complications with chronic intravenous epoprostenol, such as paradoxical emboli, needs to be carefully weighed in patients with unrepaired or residual congenital heart defects. Whether nonparenterally administered prostanoids such as inhaled or oral prostanoids will prove to be efficacious remains to be determined. In addition, whether PDE-5 inhibitors such as sildenafil will be efficacious in patients with PAH/CHD will require further study.

2009年先天性心脏病相关肺动脉高压指南解读

    先天性心脏病(congenital heart disease, CHD)在存活婴儿中的发生率大概是0.8%。各种类型的CHD增加了肺血管疾病发生发展的的风险。体-肺分流引起的肺动脉高压(pulmonary arterial hypertension，PAH)发生发展的危险因素包括：缺损的大小、类型及分流量。一般来说，缺损越大、分流量越多，出现PAH的可能性越大，在室间隔缺损(ventricular septal defect, VSD)、房间隔缺损(atrial septal defect, ASD)及动脉导管未闭(patent ductus arteriosus, PDA)中，VSD更容易形成PAH。肺血流量增多形成的剪切力和(或)肺动脉压力的升高在CHD相关PAH的发生发展中可能扮演了重要的角色。根据自然病史研究，所有未行手术矫治的CHD儿童，约30%的患儿会出现肺血管疾病。
    但到目前为止，仍没有办法判断哪些CHD患者早期即形成不可逆的肺血管疾病。三尖瓣前与三尖瓣后的分流对肺血管的损伤是不一样的。单纯由肺血流增加所致的层状切应力可能和三尖瓣后分流病变（如室间隔缺损）所致的层、环状切应力不同。小或中度的VSD的患者形成肺血管疾病的概率是3%，而几乎所有的未行矫治的动脉干畸形都会形成肺血管疾病、未行矫治的大的VSD、ASD发展成肺血管疾病的概率分别为50%、10%。此外，同一种CHD不同人其临床表现及预后可有明显差异。比如同样的CHD，某些患儿在出生后的第一年即进展为不可逆的肺血管病变，而另一些患儿尽管也有肺血管病变，但肺阻力多年维持在可接受的水平。最近一项研究发现，部分CHD相关PAH的患者存在骨形成蛋白受体-2的变异，而特发性肺动脉高压(IPAH)及家族性肺动脉高压(FPAH)也存在骨形成蛋白受体-2的变异。对基因变异在CHD相关PAH所起作用的进一步研究可能有助于判断哪些CHD患者在婴儿期即应接受手术治疗。但早期干预治疗能否终止或逆转肺血管病变的进展仍不明确。
    在过去的几十年里，儿科心脏病学及心脏外科手术的进展使得先心病患者存活到成人的人数增加。虽然大的体-肺分流CHD在婴儿期即进行了外科手术矫治，但矫治术后并不能保证患者不会形成肺血管疾病。早期诊断及改良的心脏外科手术使得CHD患者形成艾森曼格综合征的人数显著减少，但仍有部分患者术后形成进展性的肺血管疾病，原因并不清楚。除了有PAH的相关症状及并发症外，艾森曼格综合征尚有因右向左分流和低氧血症导致的血流动力学、凝血功能、脑血管、肾脏、风湿及心脏等并存疾病。
    在权衡非手术治疗和手术治疗的风险获益比时，要根据该病自然病史及个体的情况进行全面的评估。艾森曼格综合征的生存率及远期预后与其它类型的PAH(如 IPAH、FPAH、结缔组织病相关PAH)是明显不同的。艾森曼格综合征即使不干预治疗，其5年的生存率是80%、25年的生存率大概是40%。虽然 CHD相关PAH的病因、预后与IPAH不同，但两者的组织病理学改变是相似的，如内膜增厚，丛样病变。鉴于CHD相关PAH与IPAH两者在组织病理学方面的相似性，用于治疗IPAH证明有效的药物，正用于治疗CHD相关PAH并对其有效性及安全性进行评估。IPAH的患者当中，急性肺血管扩张试验阳性且长期使用钙离子拮抗剂有效的比例不到10%，这一点与CHD相关PAH不同，急性肺血管扩张试验阳性且长期使用钙离子拮抗剂有效的情况在CHD相关 PAH几乎是不存在的。到目前为止，唯一证明治疗CHD相关PAH有效的靶向治疗药物是非选择性的内皮素受体拮抗剂波生坦。波生坦治疗CHD相关PAH的该项临床试验仅持续了16周，对于艾森曼格综合征的自然病程来说还相对较短，结果表明波生坦能够改善艾森曼格综合征的活动耐力、降低肺阻力，而动脉血氧饱和度不降低。其安全性、耐受性与先前的波生坦治疗其它类型的PAH的研究结果相似。另外，长期静脉泵入依前列醇治疗CHD相关PAH的几项开放性非随机对照试验结果显示，依前列醇能够改善CHD相关PAH患者的活动耐力、血流动力学及动脉血的氧饱和度。对于未行手术矫治或术后有残余分流的CHD 患者，需要密切观察长期静脉应用依前列醇的并发症如反常栓塞。非静脉给药的前列环素类似物如吸入伊洛前列环素或口服贝前列环素治疗CHD相关PAH的疗效尚未明确。5-型磷酸二酯酶抑制剂如西地那非治疗CHD相关PAH是否有效需进一步研究。