转化生长因子β/骨形成蛋白通路与肺动脉高压遗传学机制的研究进展

肺动脉高压由多种心、肺疾病所致,以动脉压力进行性升高、肺血管阻力逐渐增加为特征,最终导致右心衰竭和死亡,其发病机制至今尚未完全阐明.近期有研究发现,转化生长因子β/骨形成蛋白通路对肺动脉高压的发生发展可产生重要影响.针对转化生长因子β/骨形成蛋白通路的研究为肺动脉高压的防治提供了新的理论依据.该文就转化生长因子β/骨形成蛋白通路与肺动脉高压遗传学机制作一综述.     

Idiopathic pulmonary arterial hypertension in children

PURPOSE OF REVIEW: Until recently, the diagnosis of idiopathic pulmonary arterial hypertension was virtually a death sentence, particularly for children. Although there is no cure for idiopathic pulmonary arterial hypertension, recent medical advances have dramatically changed the course of this disease in children. A review of some of the latest medical advances will provide the reader with a better understanding of the most current treatment options for children with idiopathic pulmonary arterial hypertension. RECENT FINDINGS: The literature reviewed demonstrate sustained clinical and hemodynamic improvement in children with various types of pulmonary arterial hypertension as well as increased survival in patients with idiopathic pulmonary arterial hypertension using current treatment strategies. SUMMARY: This article will provide an overview of how the current diagnostic and treatment strategies of idiopathic pulmonary arterial hypertension in children have advanced over the last several years and how this impacts on clinical practice.     

Oral sildenafil for treatment of severe pulmonary hypertension in an infant

We report the use of oral sildenafil in a 5-month-old preterm infant with severe bronchopulmonary dysplasia and pulmonary arterial hypertension refractory to inhaled nitric oxide treatment, maximal ventilatory support and conventional vasodilator therapy. Sildenafil was prepared as a liquid suspension by the method of trituration and administered via an orogastric tube to the patient. Forty-eight hours after sildenafil treatment, echocardiography revealed that the tricuspid incompetence was substantially diminished and the contractility of both ventricles improved, indicating a marked reduction in pulmonary arterial pressure. Oral sildenafil treatment was continued for 6 months until complete resolution of pulmonary arterial hypertension, and oxygen supplement was weaned off. There was no adverse effect during the treatment period. Oral sildenafil may be useful in reducing pulmonary vascular resistance and can be considered for treatment of severe pulmonary arterial hypertension secondary to bronchopulmonary dysplasia.     

Hypertension artérielle sans atteinte rénale au cours d’un purpura rhumatoïde de l’enfant

Henoch-Sch?nlein purpura (HSP) is an IgA mediated vasculitis that affects small vessels. In this condition, arterial hypertension is most often linked with renal involvement, but it can also occur in the absence of urinary abnormalities. We report the case of a 12-year-old girl who presented with HSP and hypertension in the absence of renal involvement. Hypertension responded to oral therapy with nicardipine, and disappeared after healing of the disease. In the case of hypertension during HSP in the absence of renal involvement, other causes of childhood's arterial hypertension have to be ruled out.     

Severe pulmonary arterial hypertension in type 1 glycogen storage disease

Pulmonary arterial hypertension is characterised by the presence of pulmonary hypertension (mean pulmonary artery pressure > 25 mmHg at rest or >30 mmHg during exercise) and normal pulmonary wedge pressure (<12 mmHg). Several risk factors for pulmonary arterial hypertension have been described. In the absence of any factor or condition suspected to play a causal or facilitating role in the process, pulmonary hypertension is “unexplained” (primary pulmonary hypertension, PPH). PPH is a rare condition, with an estimated incidence of 2 per million people. Recent genetic studies have identified mutations in the bone morphogenetic protein receptor-II (BMPR-II) gene, a receptor member of the transforming growth factor-beta family, in a majority of familial cases of PPH. Interestingly, 25% of patients displaying sporadic PPH may also have mutations in theBMPR-II gene, emphasising the relevance of genetic susceptibility for this severe condition. Other molecular and biochemical processes behind the complex vascular changes associated with pulmonary arterial hypertension are currently investigated. Type 1a glycogen storage disease caused by a deficiency of glucose-6-phosphatase has an estimated incidence of 1 per 100,000 with a few reported cases of unexplained severe pulmonary hypertension. The occurrence of pulmonary arterial hypertension in type 1a glycogen storage disease could be due to vasoconstrictive amines such as serotonin, a pulmonary vasoconstrictor and growth factor for vascular smooth muscle cells stored in platelets. Published online: 31 July 2002     

Élastopathie calcifiante artérielle diffuse. À propos d’un cas

Diffuse arterial calcified elastopathy is a very rare and little known hereditary disease, characterized by diffuse calcifications of the arterial wall. It seems common in North Africa and in the Caucasian region. Its incidence appears to be underestimated in Morocco. Clinical pattern is dominated by renovascular hypertension often associated with symptoms of heart failure. Risk of sudden death from myocardial infarction is particularly important. Thus, the diagnosis of diffuse arterial calcified elastopathy must always be suspected in front of an apparently unexplained heart failure or renovascular hypertension occurring in an infant. We report a case of diffuse arterial calcified elastopathy discovered in a neonatal intensive care unit, during management of a cardiogenic shock in a 3-months old infant. This observation demonstrates the importance of systematic measurement of the arterial tension, family screening and the impact of the ultrasound in the detection of vascular calcifications. Treatment remains essentially symptomatic.     

Platelets in Pulmonary Hypertension: a Causative Role or a Simple Association?

Pathophysiology of pulmonary arterial hypertension is based on three basic mechanisms: thrombotic pulmonary vascular lesions, vasoconstriction and vascular remodeling. Platelets are related to all of these mechanisms by their aggregation, production, storage and release of several mediators. The role of platelets is more prominent in some types of pulmonary arterial hypertension, including those which are secondary to inflammatory and infectious diseases, hemoglobinopathies, essential thrombocythemia, drugs, thromboembolism, and cardiac surgery. Most pulmonary antihypertensive drugs have a negative effect on platelets. In this review, the mechanisms of platelets association with pulmonary arterial hypertension, those types of pulmonary arterial hypertension with greatest platelet contribution to their pathophysiology, and the effects of pulmonary antihypertensive drugs on platelets are summarized.     

Hypertension due to Angiodysplasia

Renovascular hypertension is non essential hypertension, wherein anatomically evident arterial occlusive disease and increased blood pressures are related as cause and effect. The hypertension is due to renal ischemia. Angiodysplasia is an uncommon angiopathy associated with heterogeneous histological changes that may affect the carotid circulation and the visceral and peripheral arteries.     

Pulmonary arterial hypertension from a pediatric perspective.

This review of pediatric pulmonary arterial hypertension provides a framework within which to view pulmonary hypertension in children. Classification schemes, including the latest recommendations from the World Health Organization, are discussed, and the histopathology of severe pulmonary hypertension is reviewed. New information is provided regarding idiopathic and familial forms of the disease. Specific childhood etiologies, including persistent pulmonary hypertension of the newborn and congenital heart disease, are reviewed. Additionally, we examine the role of collagen vascular diseases, portal hypertension, and viruses in the pathogenesis of severe pulmonary arterial hypertension.     

Evidence for hydroxyl radical involvement in group B streptococcus-induced pulmonary hypertension and arterial hypoxemia in young piglets

Early onset neonatal GBS infection is associated with pulmonary hypertension, pulmonary edema, and arterial hypoxemia. Although the mechanisms underlying these cardiopulmonary disturbances are not completely understood, multiple lines of evidence suggest that inflammatory mediators may be involved. This study examined the actions of dimethylthiourea (DMTU), a relatively selective scavenger of hydroxyl radical, on GBS-induced pulmonary hypertension, arterial hypoxemia, and pulmonary edema formation in young piglets. Relative to control animals, intravenous infusion of GBS (10(8) organisms/kg/min for 60 min) provoked sustained increases in pulmonary arterial pressure (Ppa: +88%) and total pulmonary resistance (TPR: 128%). GBS infusion also was associated with profound decreases in arterial PO2 (-58%). Pulmonary edema was present in GBS-treated animals as evidenced by an 8.4% increase in the lung wet-to-dry weight ratio. After pretreatment with DMTU (0.75 g/kg administered intravenously over 30 min), GBS increased Ppa by 33% and TPR by only 16%. Similarly, after DMTU pretreatment GBS decreased arterial oxygen tension by only 12%. DMTU also limited the GBS-induced increase in lung wet-to-dry weight ratio to 2.6%. These findings demonstrate that DMTU attenuates GBS-induced pulmonary hypertension, pulmonary edema, and arterial hypoxemia and suggest that hydroxyl radicals play an important role in these cardiopulmonary disturbances.     

Hemodynamic effects of sodium nitroprusside in patients with ventricular septal defect

During routine cardiac catheterization of ten patients with ventricular septal defect, the hemodynamic parameters were measured in the resting state and during sodium nitroprusside infusion at an average rate of 8 g/kg/min. Two distinct hemodynamic groups could be identified. Group I characterised by elevated left ventricular filling pressure showed a consistently favourable response to sodium nitroprusside infusion with a decrease in the left ventricular filling pressure, the pulmonary arterial pressures and the left to right shunt. The favourable effect was most pronounced in patients who had pulmonary arterial hypertension in addition to elevated left ventricular filling pressures. Group II patients characterised by normal left ventricular filling pressures showed a variable response to sodium nitroprusside administration. The left ventricular end-diastolic pressure fell or was unaltered. The pulmonary arterial pressures and pulmonary vascular resistance fell in those with pulmonary arterial hypertension. Patients without pulmonary arterial hypertension showed an increase in the magnitude of left to right shunt. On the basis of our data, we feel that vasodilator drugs have a specific role in the management of congestive heart failure secondary to large left to right shunts. The present study strongly indicates the need for further investigations utilizing orally effective vasodilators in patients with congestive heart failure due to left to right shunts.     

Sudden death caused by unsuspected pulmonary arterial hypertension, 10 years after surgery for extrahepatic biliary atresia

A case of extrahepatic biliary atresia presenting with an acute respiratory episode and rapid deterioration, 10 years after a successful portoenterostomy and a very active life, was the setting of unsuspected severe pulmonary arterial hypertension leading to sudden death. The pulmonary arteries showed widespread plexiform lesions, thickening of the muscular media, and subendothelial proliferation. Occasionally, eccentric arterial obstructive lesions and fibrinous thrombi were observed. There was marked reduction of preacinar arterioles with a consequent increase in the alveolar/arterial ratio. The pulmonary veins showed arterialization of their walls. There was marked hypertrophy of myocardial fibres in the right ventricle together with foci of myocardial degeneration and fibrosis. Areas of endocardial thickening were observed in both ventricles. The absence of clinical indicators of pulmonary arterial hypertension at any but the terminal stages of the disease precluded any form of conservative management. Lung-heart and presumably liver transplantation might have been the only option. Prospective assessment of pulmonary function and haemodynamic studies should be considered in cirrhotic patients with portal hypertension.     

Contribution of pulmonary surfactant with inhaled nitric oxide for treatment of pulmonary hypertension

BACKGROUND: Combined therapy of inhaled nitric oxide (iNO) with pulmonary surfactant replacement was reported to improve oxygenation in patients or animal models of persistent pulmonary hypertension of the newborn with pulmonary surfactant deficiency lung. To evaluate the potential of iNO for the treatment of persistent pulmonary hypertension of the newborn, pulmonary arterial pressure (PAP) was measured during iNO before and after pulmonary surfactant replacement in an animal model of pulmonary hypertension with surfactant deficiency. METHODS: Seven newborn piglets were injected with L-nitro-arginine-methylester to produce an animal model of pulmonary hypertension. After PAP increased, iNO (30 p.p.m.) was introduced. Then iNO was stopped, and animals were subjected to lung lavage with saline. After recording the effect of iNO, all animals then received exogenous pulmonary surfactant installation. After surfactant treatment, iNO was again introduced. RESULTS: Pulmonary arterial pressure and systemic arterial pressure were increased significantly by >30% after infusion of L-nitro-arginine-methylester. During iNO only PAP was reduced significantly. Respiratory system compliance decreased significantly after lung lavage, and increased significantly after pulmonary surfactant replacement with concomitant increase of PaO2. In contrast, significant reduction of PAP with iNO before and after pulmonary surfactant replacement were also observed. The reduction ratios of PAP under each condition were 75.2 +/- 7.4%, 81.3 +/- 3.1%, and 79.1 +/- 5.3%, respectively (not significant among conditions). CONCLUSION: These results suggest that iNO is still a potent pulmonary arterial vasodilator even under pulmonary surfactant deficiency in an animal model of pulmonary hypertension.     

Clinical practice: pulmonary hypertension in children

Introduction  

Pulmonary arterial hypertension is a rare disorder in childhood, the two most common types being idiopathic pulmonary arterial hypertension and pulmonary hypertension associated with congenital left-to-right shunt lesions, together accounting for almost 90% of cases.     

Fetal hypertension and the development of increased pulmonary vascular smooth muscle: a possible mechanism for persistent pulmonary hypertension of the newborn infant.

Chronic pulmonary arterial hypertension was produced in six fetal lambs. In four (126 to 139 days' gestation) unilateral fetal renal artery constriction caused systemic arterial mean blood pressure elevations. In another fetus, constriction of the umbilical artery caused a systemic mean blood pressure elevation; in the sixth, partial occlusion of the ductus arteriosus caused isolated pulmonary arterial hypertension. The right lung of each fetus was perfused with fixative at the in vivo mean arterial pressure and the amount of smooth muscle in the fifth generation (resistance) vessels analyzed using the medial width/external diameter ratio. There was a significant increase in the medial width/external diameter ratio in the six experimental animals as compared to that in six normal fetuses. In separate fetuses the increased ratios were due to a decreased external diameter, increased smooth muscle, or both these factors. The total number of resistance vessels was counted in the right lung of each fetus and no significant difference from normal was observed. We postulate that either fetal systemic hypertension or constriction of the ductus arteriosus causes fetal pulmonary hypertension in utero and that this produces increased smooth muscle development in pulmonary arterial resistance vessels; this may be a pathogenic mechanism for the syndrome of persistent pulmonary hypertension of the newborn infant.     

Severe hypertension due to renal polar artery stenosis in an adolescent treated with coil embolization

A 12-year-old boy presented with severe arterial hypertension due to a severe subsegmental renal artery stenosis. Treatment consisted of selective embolization of the stenosed polar artery, which resulted in near normalization of the arterial pressures. Renal artery stenosis should always be considered, even in young adolescents, as a cause for arterial hypertension. Only selective angiography was able to demonstrate the subsegmental artery stenosis in this patient.     

Low dose inhaled nitric oxide causing selective pulmonary vasodilation in child with idiopathic pulmonary hypertension

Low dose (3 ppm) inhaled nitric oxide caused selective pulmonary vasodilation with improved systemic arterial pressure, cardiac index and arterial oxygenation in an infant with primary pulmonary hypertension. Methaemoglobin levels did not exceed 0.6 %, and nitrogen dioxide concentrations remained within 0.05 ppm.     

磷酸二酯酶5抑制剂治疗先天性心脏病合并肺动脉高压

肺动脉高压在先天性心脏病中很常见,有效地降低患儿肺血管阻力,能够改善其远期生存率.对肺动脉高压病理生理的研究发现,使用磷酸二酯酶5抑制剂可使肺血管舒张,降低肺血管阻力.目前磷酸二酯酶5抑制剂西地那非在国外已用于治疗肺动脉高压.多个临床试验已经证明磷酸二酯酶5抑制剂能够显著降低肺血管阻力,改善患者远期生存率和生活质量,且能较好地被患者耐受.     

Effects of prostaglandin D2 on pulmonary arterial pressure and oxygenation in newborn infants with persistent pulmonary hypertension

We studied the effects of prostaglandin D2 (PGD2) in six newborn infants, 1 to 2 days of age, who had persistent pulmonary hypertension syndrome and a PaO2 less than 75 torr during mechanical hyperventilation with an inspired oxygen concentration of 100%. Tolazoline and dopamine were used to treat some of the patients. No patients had congenital heart disease or sepsis. Catheters were placed to measure pulmonary and systemic arterial blood pressures. PGD2 was infused intravenously at doses of 1 to 25 micrograms/kg/min. Pulmonary and systemic arterial blood pressures, heart rate, and descending aortic blood gas values were measured before each dose change. Only two of six patients had a transient increase in PaO2. All had an increase in heart rate. Two of six patients had an increase in pulmonary arterial blood pressure. No deleterious effects occurred during the infusion. Four of six patients subsequently died. Although PGD2 is a specific pulmonary vasodilator in fetal and newborn animals, it did not lower pulmonary arterial blood pressure nor improve oxygenation in newborn infants with persistent pulmonary hypertension syndrome.     

Tezosentan decreases pulmonary artery pressure and improves survival rate in an animal model of meconium aspiration

Acute pulmonary arterial hypertension in acute lung injury aggravates the clinical course and complicates treatment. Increased release and turnover of endogenous endothelin-1 is known to be a major determinant in the pathophysiology of pulmonary arterial hypertension of various etiologies. We tested whether intravenous tezosentan, a dual endothelin receptor antagonist, reduced pulmonary artery pressure in a pig model of acute lung injury induced by meconium aspiration. Acute pulmonary arterial hypertension was induced in 12 anesthetized and instrumented pigs by instillation of human pooled meconium in a 20% solution. Hemodynamic and gas exchange parameters were recorded every 30 min. Six animals received tezosentan 5 mg/kg after 0 and 90 min; six animals served as controls. Tezosentan led to a decrease of mean pulmonary artery pressure (PAP) from 33.4 +/- 4.0 mm Hg to 24.7 +/- 2.1 mm Hg and pulmonary vascular resistance (PVR) from 7.8 +/- 1.4 mm Hg.L(-1).min.m2 to 5.2 +/- 0.7 mm Hg.L(-1).min.m2. All animals treated with tezosentan survived, whereas in the control group four out of six animals died. Tezosentan improved survival and decreased pulmonary artery pressure in a porcine model of acute pulmonary arterial hypertension after meconium aspiration. Tezosentan has the potential for effective pharmacological treatment of pulmonary arterial hypertension following acute lung injury.