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Pulmonary hypertension, in association with congenital heart diseases, is seen in large systemic-to-pulmonary communications such as ventricular septal defect, patent ductus arteriosus, etc. Certain cyanotic congenital heart diseases with large pulmonary blood flow also have pulmonary hypertension. Pulmonary vascular disease, secondary to pulmonary hypertension, may develop if the defect is not repaired in infancy or early childhood. Progressive pulmonary vascular disease leads to irreversible changes in the vessel wall with reversal of shunt and this condition is termed Eisenmenger syndrome. Once Eisenmenger syndrome develops, repair of congenital heart disease is contraindicated. In those with borderline changes in pulmonary vasculature, a comprehensive assessment must be made to test for operability. This assessment should include cardiac catheterization for obtaining hemodynamic data in basal state and after challenge with vasodilators. Lung biopsy may be needed in select cases and should be performed if expertise is available for histological interpretation of the biopsy specimen. Patients with pulmonary hypertension and congenital heart disease should undergo repair of the defect in time, usually in the first year of life. Once Eisenmenger syndrome sets in, the treatment is generally supportive. Pulmonary vasodilators, such as sildenafil, bosentan, have been found to be beneficial in some cases of Eisenmenger syndrome. Lung or heart/lung transplantation should be reserved for severely symptomatic cases. The natural history of patients with Eisenmenger syndrome is considerably better than that of idiopathic pulmonary hypertension. Over half of the patients survive for more than 50 years. Pregnancy and noncardiac surgery may adversely affect the course of the disease.

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Pulmonary arterial hypertension (PAH) develops in 10-16% of patients with atrial septal defect (ASD). The determinants of occurrence of PAH in ASD are not clear. There does not appear to be a relationship between duration of exposure to increased pulmonary blood flow and the development of PAH. Once PAH develops, it is challenging to determine operability and predict outcomes after repair in borderline situations. Two illustrative cases of ASD and PAH; an infant and an adult who were evaluated for operability and factors that were considered in decision-making are discussed. Their subsequent follow-up is also presented to illustrate their modified history following closure of the ASD.

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Pulmonary hypertension (PH) is a life-threatening disease characterized by a marked and sustained elevation of pulmonary artery pressure. The disease results in right ventricular failure and death. The pathogenesis of PH is complex and multifactorial. Vasoconstriction, remodeling of the pulmonary vessel wall and thrombosis contribute to increased pulmonary arterial pressure in PH. The current therapeutic approaches (prostacyclin analogs, endothelin-receptor antagonists, and phosphodiesterase type 5 inhibitors) for the treatment of PH mainly provide symptomatic relief, as well as some improvement of prognosis. However, they do not appear to reverse or modify the disease. Recently, several growth factors and growth factor receptor tyrosine kinases (RTK) have been implicated in the abnormal proliferation and migration of pulmonary arterial smooth muscle cells, including platelet-derived growth factor (PDGF), epidermal growth factor (EGF), fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) and others. Hence, this review describes the potential role of RTKs in pulmonary vascular remodeling and emergence of RTK inhibitors as promising therapeutic targets.

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The authors provide histopthological images of pulmonary vascular lesions from patients with diseases of several etiologies and clinically presenting with pulmonary hypertension. The sources are lung for the purpose of presurgical evaluation in children with congenital heart disease, lung explants in cases of lung transplantation, and lung tissue from necropsies. Lesions are classified as nonspecific or specific, according to the histopathological features that may allow the recognition of etiology or a specific form of presentation.

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Pulmonary hypertension is a common complication of sickle cell disease and is a major independent predictor of mortality. The pathogenesis of pulmonary hypertension in sickle cell disease is likely multifactorial, including hemolysis, impaired nitric oxide bioavailability, chronic hypoxemia, thromboembolism, parenchymal and vascular injury due to sequestration of sickle erythrocytes, chronic liver disease and asplenia. There is currently limited data on the effects of any specific treatment modality for pulmonary hypertension in patients with sickle cell disease. It is likely that maximization of sickle cell disease therapy in all patients, and treatment with selective pulmonary vasodilators and antiproliferative agents, in patients with severe disease, would be beneficial. A large trial evaluating the effects of therapy for pulmonary hypertension in the sickle cell disease population is underway.

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Right ventricular hypertrophy (RVH) is a serious clinical problem that complicates many disease processes, including pulmonary arterial hypertension (PAH). PAH is a lethal syndrome of pulmonary hypertension due to the obstruction, obliteration, and constriction of small pulmonary arteries. One of the most important prognostic factors in PAH is RV function. Nowadays, surprisingly little work has been done on the change in RV function by PAH. Recent evidence suggests that there is a change in metabolism in PAH, reminiscent of the Warburg effect (i.e. increased glycolysis and decreased glucose oxidation occurs despite abundant PO ₂ ). In PAH, the increased expression of pyruvate dehydrogenase kinase (PDK) may inhibit pyruvate dehydrogenase (PDH), limiting oxidative metabolism. PDK-4, a key regulator of glucose metabolism, is activated in monocrotaline (MCT)-induced RVH. This phosphorylates and inhibits PDH, thereby decreasing oxidative metabolism. There appears to be a compensatory increase glycolysis in RVH. This is associated with an increase in the expression of the glucose transported, GLUT4. RVH-related changes in metabolism may alter cardiac repolarization, which could predispose PAH patients to arrhythmia and decreased contractile function. We have noted altered shape and duration of cardiac action potential (AP) repolarization in RVH (largely dependent on dynamic changes in K ⁺ channel expression). Our preliminary data show that there is AP prolongation in RVH. We propose the concept that altered metabolism may alter ion channel expression in RVH and that this in turn causes AP prolongation. Based on our preliminary data and the literature, we hypothesize that a Warburg effect occurs in RVH and suggest that this may constitute a new therapeutic target.

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Children with Down's syndrome (DS) are at an increased risk of developing pulmonary arterial hypertension (PAH) due to multiple factors: congenital heart disease (CHD) with persistent left-to-right shunts, chronic upper airway obstruction, abnormal pulmonary vasculature growth, alveolar hypoventilation, and recurrent pulmonary infections. Congenital cardiac defects are reported in 19-43% of cases. With the common lesion is an endocardial cushion defect in 43%. DS and CHD seem to develop PAH at a faster rate and have persistent disease after cardiac surgery compared to non-DS patients with similar defects. The upper airway obstruction is common in DS due to midfacial hypoplasia, macroglossia, narrowing of the nasopharynx, tonsillar and adenoidal enlargement, laryngomalacia, tracheomalacia, and congenital malformations of the larynx and trachea. The incidence of OSA was reported to be in a range of 30-50%. Exacerbating factors including obesity and gastroesophageal reflux may contribute to the occurrence of sleep apnea. In this report, I review the causes of pulmonary hypertension in this population, and its management.

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Right ventricular (RV) function is an important determinant of prognosis in a large number of cardiopulmonary disease conditions and its assessment is a challenge in day-to-day clinical practice, mostly because of the complex geometry of the chamber. The search for, and validation of reliable indexes of RV function are ongoing. In particular, a large body of evidence has accumulated regarding the use of the tricuspid annular plane systolic excursion (TAPSE) as an index of RV systolic function in a variety of pathologic conditions. We will review the different areas of application of TAPSE to date.

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Although the prognosis for patients with Pulmonary Hypertension (PH) has improved over recent decades, it is still difficult to predict clinical outcome in individual patients. In all forms of the disease, right ventricular (RV) function remains the most important determinant of survival and the difficulties encountered in predicting prognosis in individuals reflects the heterogeneous response of the RV. Our understanding of the mechanisms that underpin RV failure or adaptation in response to PH has greatly improved over recent years, as has our ability to accurately identify prognostically significant RV dysfunction in patients with PH. These advances have been driven by significant improvements in established RV imaging tools, such as 2-D echocardiography, and by the development of entirely new techniques, such as 3-D echocardiography, tissue Doppler imaging and cardiovascular magnetic resonance imaging. The purpose of this article is to review these techniques and to summarize these recent advances.

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The authors provide histopathological images of pulmonary vascular lesions from patients with diseases of several etiologies and clinically presenting with pulmonary hypertension. The first part of this article was published in the PVRI REVIEW Vol 1, Issue 1, January 2009). In this second part, the discussion and images are about specific vascular lesions, which include the following:

1. Obstruction to pulmonary venous drainage
2. Pulmonary occlusive venopathy
3. Pulmonary microvasculopathy (formerly, capillary hemangiomatosis)
4. Chronic thromboembolic pulmonary vascular lesions
5. Pulmonary arterial obstruction by parasites or their eggs
6. Pulmonary tumor thrombotic microangiopathy

The sources were lung biopsies obtained for pre-surgical evaluation in children with congenital heart disease, lung explants in cases of lung transplantation and lung tissue from necropsies.

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Monge's disease or Chronic Mountain Sickness is characterized by an excessive polycythemia (hemoglobin >21 g/dl in men and >19 g/dl in women) in high-altitude dwellers, with a prevalence of 5-18% above 3200 m. Clinical signs include headache, fatigue, sleep disturbances, dyspnea, dizziness, tinnitus, paresthesia and digestive complains. Pulmonary hypertension is frequently associated, which might lead to congestive heart failure. Hypoxemia due to alveolar hypoventilation may play a central role in the over-stimulation of erythropoiesis leading to increased red cell mass and blood viscosity, systemic and pulmonary hypertension. Acetazolamide is the first efficient pharmacological treatment of Monge's disease without adverse effects, by reducing nocturnal hypoventilation and blunting erythropoiesis. Its low cost might allow a wide development with a considerable positive impact on public health in high-altitude regions. Further studies are necessary to evaluate the prevalence and importance of pulmonary hypertension and its consequences on cardiac function.

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The identification of heterozygous germline mutations in the bone morphogenetic protein type II receptor (BMPR-II), a receptor for the transforming growth factor-β (TGF-β) superfamily, in families with pulmonary arterial hypertension (PAH) was a major leap forward in our understanding of this hitherto enigmatic disease. Altered BMP/TGF-β signalling is now recognised as a major factor in the pathobiology of this condition. Further research is now elucidating the cell and tissue specific affects of dysfunctional BMP signalling necessary for the development of PAH and identifying new targets for therapeutic intervention. In addition, the interaction of this pathway with other important mediators of pulmonary hypertension is being determined. This review summarises the present state of knowledge of dysfunctional BMP/TGF-β signalling in PAH and identifies further areas for research.

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The management of paediatric patients with pulmonary hypertension are mostly based on reports on adult patients. There is a long felt need to establish guidelines which are relevant to the pediatric population. In this report we attempt to summarize the diagnostic and the management guidelines that have been reported in the literature in the pediatric age group.

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A hipertensão Pulmonar, em associação com a doença cardíaca congênita, é observada nas comunicações sistêmico-pulmonares de grande tamanho, como comunicação interventricular (CIV), persistência do canal arterial (PCA), etc. As cardiopatias congênitas cianogênicas com aumento do fluxo pulmonar também provocam hipertensão pulmonar. A doença vascular pulmonar, secundária à hipertensão pulmonar, pode se desenvolver se o defeito não for reparado no lactente e no infante. A doença vascular pulmonar progressiva produz mudanças irreversíveis na parede vascular, com inversão do "shunt", que passa a ser da direita para a esquerda, condição essa chamada de Síndrome de Eisenmenger. Uma vez estabelecida essa condição, o reparo do defeito cardíaco congênito está contra-indicado. Aqueles com repercussões "borderline" na vasculatura pulmonar necessitam de avaliações detalhadas, para definir a operabilidade do caso. Essas avaliações incluem: Cateterização cardíaca com medidas hemodinâmicas em condições basais e com testes de reatividade; biópsia pulmonar pode ser necessária em casos selecionados e deve ser realizada quando se dispõe de patologista experiente na interpretação dos achados histológicos. Pacientes com hipertensão pulmonar consequente a cardiopatia congênita devem ser submetidos ao reparo do defeito precocemente, de preferência no primeiro ano de vida. Se a síndrome de Eisenmenger se instalou, o tratamento é apenas de suporte. Vasodilatadores pulmonares como sildenafila e bosentena tem se mostrado benéfico em alguns desses pacientes. Transplante cardíaco ou cardiopulmonar deve ser reservado para os casos severamente afetados. A história natural dos pacientes com síndrome de Eisenmenger é consideravelmente melhor do que a daqueles com hipertensão pulmonar idiopática. Mais da metade dos pacientes sobrevive além dos 50 anos. Gravidez e intervenções cirúrgicas não cardíacas afetam o curso dessa doença.

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The field of pulmonary hypertension pathogenesis has struggled with the pseudo-dichotomy of the causal role of pulmonary vascular endothelium vis-ΰ-vis smooth muscle cells as the central element of the disease. Medial hypertrophy and intima thickening due to migration or proliferation of vascular smooth muscle cells is seen in all forms of pulmonary hypertension, while endothelial cell lesions, particularly plexiform and concentric lesions, predominate in cases of severe pulmonary hypertension. Growing insight that the pathogenesis of pulmonary hypertension involves metabolic alterations of pulmonary vascular cells, including vascular smooth muscle and endothelial cells, opens new venues for therapies and diagnoses.

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Recent evidence has challenged old notions that the development of blood vessels in the lung passively follows that of the airways. Rather, lung blood vessels actively promote alveolar growth during development and contribute to the maintenance of alveolar structures throughout postnatal life. These observations may be relevant for lung diseases characterized by arrested alveolar growth/loss of alveoli and pulmonary hypertension. This short review summarizes the recently recognized role of angiogenic growth factors during normal alveolar development, injury, and repair.

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Despite the early surgical repair of congenital cardiac defects in most institutions of developed countries, advanced pulmonary vasculopathy associated with unrepaired shunts remains a major problem, particularly in underserved areas of developing nations. The so called Eisenmenger syndrome (reversed right-to-left shunting caused by heightened pulmonary vascular resistance, sometimes above the systemic level) is a multisystemic disorder associated with progressive right cardiac failure and hypoxemia. Management of this disorder is far beyond the simple administration of vasodilators. Rather, in the era of the "new drugs" for treatment of pulmonary hypertension, general therapeutic measures remain central in patient care. These include monitoring of blood viscosity and prevention of hyperviscosity states, prophylaxis against pulmonary and systemic infections and thrombotic events, monitoring of renal function and systemic blood pressure, contraception in females, and management of specific cardiac complications such as myocardial ischemia and arrhythmias.

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