Ultrastructure of early plexogenic pulmonary arteriopathy

A lung biopsy specimen from a young woman with the clinical features of primary pulmonary hypertension showed grade 2 plexogenic pulmonary arteriopathy. Electron microscopy revealed 'dark', electron-dense smooth muscle cells in the inner part of the media of muscular pulmonary arteries. Many of these transformed myocytes had migrated into the lumens of pulmonary arteries and arterioles which they occluded. This migration of smooth muscle cells was associated with a substantial increase in the number of pulmonary endocrine cells in the bronchioles containing bombesin and calcitonin.     

The ultrastructure of plexogenic pulmonary arteriopathy

The lungs from 16 cases of plexogenic pulmonary arteriopathy obtained at heart-lung transplantation, half of which had primary pulmonary hypertension, were examined by electron microscopy. From these the probable pathogenesis of pulmonary arterial intimal fibrosis in plexogenic pulmonary arteriopathy was deduced. The earliest detectable change was migration of smooth muscle cells from the media, through the internal elastic lamina into the intima. These cells collected beneath the endothelium and lost many of their myofilaments to become myofibroblasts. They were associated with ground substance but scanty collagen fibrils. As the quantity of interstitial collagen increased, the myofibroblasts reverted to a muscular structure, became elongated, and assumed a regular, circumferential orientation. This later stage coincided with the development of plexiform lesions. At both early and later stages, the muscular pulmonary arteries were contracted but not markedly so, and muscular evaginations were not seen. On the other hand, the cellular intimal proliferations developed early and were occlusive. This suggests that occlusion of small pulmonary arterial vessels by myofibroblasts may be at least as important as vasoconstriction in the early elevation of the pulmonary vascular resistance in primary pulmonary hypertension.     

Immunohistochemical study of endothelin-1 and matrix metalloproteinases in plexogenic pulmonary arteriopathy

The matrix metalloproteinases (MMPs) and endothelin-1, a potent vasoconstrictor and mitogen for smooth muscle cells, have been shown to be involved in the pathogenesis of various vascular disorders. However, the expression of endothelin-1 and the activation of MMPs have not been fully evaluated in plexogenic pulmonary arteriopathy (PPA). Immunohistochemical and confocal microscopic studies were conducted to evaluate the reactivity of lung tissue from six patients with pulmonary hypertension for alpha-smooth muscle actin (alpha-SMA), desmin, vimentin, factor VIII, endothelin-1, various types of MMPs (MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9), membrane type-MMPs (MT-MMPs), tissue inhibitors of MMPs (TIMPs), and type IV collagen. Four major arterial morphological abnormalities were recognized in PPA: muscularization of pulmonary arterioles, onion-skin lesions, cellular and mature plexiform lesions, and atheromas in elastic pulmonary arteries. Reactivity for MMP-2 and MT-1-MMP was found in endothelial cells and, to a lesser extent, in myofibroblasts proliferating in various lesions of PPA. Increased expression of endothelin-1 was observed in the latter cells and in endothelial cells. Some myofibroblasts were positive for MMP-3 and MMP-7 in the vascular lesions except for mature plexiform lesions. MMP-1, MMP-9 and TIMP-2 tended to be positive only in the atheromatous lesions. Staining for type IV collagen showed focal thinning and discontinuities of the endothelial basement membrane in plexiform lesions. This study demonstrates colocalization of MMP-2 with MT-1-MMP and increased expression of endothelin-1 in various arterial lesions of PPA. These changes may play important roles in the remodeling of arterial structures, particularly of basement membranes, in this disorder.     

Grading of pulmonary vascular lesions-a reappraisal

Grading of pulmonary vascular alterations, introduced by Heath & Edwards (1958), has been widely used for assessment of the severity of hypertensive pulmonary vascular disease. Two factors call for a reappraisal of the grading principle: an increasing awareness of the complexity of the vascular lesions and an increasing use of lung biopsies for the pre-operative evaluation of the operability of an underlying cardiac defect. We suggest that the grading system, as well as the previously proposed variations of it, no longer fulfil the requirements of unambiguous assessment of the severity of vascular disease. The degree and extent of the various lesions, the different types of intimal fibrosis, and the eventual decrease in number and size of vessels should all be assessed, not only for arteries but also for other vessels. Careful consideration and weighing of all these features are necessary in order to form an opinion on diagnosis and prognosis. This cannot be achieved by using a single grade.     

先天性心脏病合并重度肺动脉高压的外科治疗体会

目的总结先天性心脏病合并重度肺动脉高压的外科治疗及有关围手术期的处理经验。方法1998年12月~2006年12月手术治疗先心病合并重度肺动脉高压共121例,男56例,女65例,年龄2~54岁,平均(18.0±9.5)岁。术前肺动脉和体动脉收缩压比Pp/Ps均>0.75,平均(0.95±0.16),动脉血氧饱和度SaO275%~96%。结果手术死亡10例(8.26%)。主要并发症:低心排血量2例,肺高压危象8例。死亡原因:低心排血量,肺高压危象。术后SaO290%~97%,平均(94±2.1)%。患者心功能均较术前改善。结论低心排血量和肺高压危像是合并重度肺高压的先心病患者术后的主要并发症和死亡原因,围术期处理是提高生存率的关键。     

Histopathology of pulmonary hypertensive diseases

The spectrum of histopathological lesions of pulmonary hypertensive vascular disease is extraordinarily varied. A number of distinct patterns can be recognized, and these correlate with aetiological factors and clinical data. Recent research has yielded important new insights on the pathogenesis of pulmonary hypertension at the molecular and cellular level, and various key mechanisms are emerging. These include induction and maintenance of vasoconstriction, endothelial activation and proliferation, and thrombosis. In the light of these developments, a re-evaluation of lesions at the histopathological level is receiving a new level of significance, as histological data complement those from research based on non-morphological techniques. We review the main histopathological features of hypertensive pulmonary vascular disease in this perspective.     

Transesophageal echocardiography guided patent ductus arteriosus occlusion in adults with severe pulmonary hypertension through a parasternal approach

Between April 2010 and April 2014, 39 consective adult patients (> 18 years) with PDA associated severe pulmonary hypertension underwent transesophageal echocardiography guided patent ductus arteriosus occlusion through a parasternal minimally invasive approach. Among 39 patients, the procedure was successful in 32 cases (82.1%) and failed in 7 cases (17.9%). In the failed cases, 3 cases had a large residual shunt and 4 cases had persistent pulmonary hypertension. The mean minimum miameter of the successfully closed PDAs was 15.2 ± 2.1 mm (range 9 to 24), and the mean diameter of the mushroom-shaped occluder was 17.5 ± 2.5 mm (range 11 to 26). The pulmonary artery pressure decreased significantly after occlusion (P < 0.05), but there were no significant differences in the aortic pressure and blood oxygen saturation before and after occlusion (P > 0.05). Echocardiography performed on the first postoperative day showed decreased volume within the left atrium, left ventricle, and pulmonary artery in 23 cases, decreased volume within the left atrium and left ventricle in 4 cases, and no change in the volume of the atrium and ventricle in 3 cases. A minor residual shunt was observed in 6 cases. The posteroanterior chest X-ray showed improved pulmonary congestion in all cases and significantly reduced cardiothoracic ratio in 25 cases. Patients were followed-up at least for 1 year. No symptoms including palpitation, dyspnoea, or chest tightness were observed. The heart function ranged from NYHA class I to II. A minor residual shunt was observed only in one case. There were varying degrees of decrease in volume within the atrium and ventricle. In conclusion, transesophageal echocardiography guided patent ductus arteriosus occlusion through a parasternal minimally invasive approach is a feasible and effective method for the treatment of PDA in adults with severe pulmonary hypertension.     

Fatal pulmonary arterial occlusive vascular disease following chemotherapy in a 9-month-old infant

Fatal pulmonary hypertension developed in an infant during the 7-month period in which he received, via a central venous catheter, combination chemotherapy for stage IV neuroblastoma as well as intermittent parenteral feeding. In a lung biopsy and at autopsy, small pulmonary arteries showed diffuse medial hypertrophy and peripheral muscularization, very extensive concentric intimal fibrosis, and focal eccentric fibrosis evolving from organizing thrombi. Pulmonary veins were normal. Hypothetically, chemotherapeutic drug therapy (possibly potentiated either by the parenteral nutrition or simply by the vehicular fluids causing volume loading of the pulmonary circulation) could cause occlusive pulmonary arterial disease by several mechanisms, but the association has not been described previously, although use of such drugs has been reported with pulmonary veno-occlusive disease.     

伴肺动脉高压的先天性心脏病患儿肺组织病理学观察

目的　探讨左向右分流型先天性心脏病患儿肺组织的病理形态学改变、超微结构改变与肺动脉高压 (pulmonaryhy pertension ,PH)形成的关系。方法　应用光镜、电镜、组织化学染色 ,对 4 1例先心病患儿肺组织及肺各级小动脉进行研究、分析。结果　伴有PH的肺组织各级小动脉 (包括部分肌型及肌型动脉 )数量增加、管壁增厚、管腔狭窄 ,尤以中重度PH患者显著 ,主要表现血管中膜平滑肌 (SMC)和内皮细胞 (EC)增生 ,内弹力膜增厚 ,外膜胶原纤维增多。先天性心脏病患儿肺组织内无肌型小动脉肌化、部分肌型及肌型小动脉数量增加 ,随着PH的增高 ,差异有显著性 (P <0 0 1)。超微结构改变包括 :①肺泡隔纤维化逐渐明显 ,胶原纤维增生 ;②小动脉中膜SMC层数明显增加 ,SMC细胞面积增大 ,核染色质增粗 ,细胞间间隙明显增宽 ,血管外膜胶原纤维高度密集 ;③小动脉血管内皮细胞增生呈高柱状 ,细胞线粒体肿胀、空泡化 ,吞饮小泡多见 ;④毛细血管充血、瘀血 ,基膜明显增厚。结论　先心病引起缺氧导致肺血管重建 ,使肺血管阻力增加 ,是PH形成的关键因素 ,肺毛细血管的超微结构病变所致微循环障碍更加促进了PH的发生、发展。     

Pulmonary vascular disease in 57 necropsy cases of total anomalous pulmonary venous connection

In a semi-quantitative necropsy study, total anomalous pulmonary venous connection (TAPVC) was an isolated anomaly in 35 cases and was associated with asplenia and either pulmonary stenosis or pulmonary atresia in 22 cases. A comparison of the two groups showed pulmonary venous obstruction (26% vs. 4%), a small interatrial communication (51% vs. 4%), a patent ductus arteriosus or operative shunt (40% vs. 64%), medial hypertrophy of muscular pulmonary arteries (80 vs. 23%), muscularization of arterioles (80% vs. 23%), capillary engorgement (60% vs. 27%) alveolar wall thickening (29% vs. 0%), interlobular septal oedema (34% vs. 14%), dilated lymphatics (80% vs. 45%), arterialization of pulmonary veins (86% vs. 68%), medial hypertrophy of veins (26% vs. 0%), and venous dilatation (74% vs. 50%). Only one patient, a 5-year-old girl with isolated TAPVC, had severe plexogenic pulmonary arteriopathy. In the remainder, the pulmonary lesions were those generally associated with reversible pulmonary venous hypertension; they were most striking in patients with pulmonary venous obstruction, and were least prominent in patients with pulmonary stenosis or puimonary atresia.     

P-selectin gene polymorphism associates with pulmonary hypertension in congenital heart disease

Objective: To investigate the relationship between P-selectin gene polymorphism and congenital heart disease (CHD) with pulmonary hypertension (PAH). Methods: 58 CHD patients with PAH (PAH-CHD), 43 CHD patients without PAH and 205 healthy subjects were included in this study. The concentration of plasma P-selectin was determined by ELISA kits; the direct sequencing of PCR products was used to analyze the P-selectin genotypes. Results: The concentration of plasma P-selectin was markedly higher in PAH-CHD patients than that in CHD subjects and controls, while no difference was observed between CHD group and control. A significant difference of P-selectin genotype -825T/C polymorphism was observed between patients with PAH-CHD and healthy subjects (P<0.05). Logistic analysis showed that the subjects with haplotypes A-G and G-G had lower risk of PAH-CHD compared with the ones with haplotype A-A (OR=0.47, 95% CI=0.24-0.92). In the subjects of PAH-CHD and control, plasma P-selectin concentration was higher in subjects with -825TT genotype than the ones with haplotypes T-C and C-C (P<0.05). Conclusion: P-selectin probably involves in the development of PAH-CHD. The polymorphism of -825T/C is associated with the risk of PAH-CHD, and may be one of its risk factors.     

Pathophysiology and potential treatments of pulmonary hypertension due to systolic left heart failure

Pulmonary hypertension (PH) due to left heart failure is becoming increasingly prevalent and is associated with poor outcome. The precise pathophysiological mechanisms behind PH due to left heart failure are, however, still unclear. In its early course, PH is caused by increased left ventricular filling pressures, without pulmonary vessel abnormalities. Conventional treatment for heart failure may partly reverse such passive PH by optimizing left ventricular function. However, if increased pulmonary pressures persist, endothelial damage, excessive vasoconstriction and structural changes in the pulmonary vasculature may occur. There is, at present, no recommended medical treatment for this active component of PH due to left heart failure. However, as the vascular changes in PH due to left heart failure may be similar to those in pulmonary arterial hypertension (PAH), a selected group of these patients may benefit from PAH treatment targeting the endothelin, nitric oxide or prostacyclin pathways. Such potent pulmonary vasodilators could, however, be detrimental in patients with left heart failure without pulmonary vascular pathology, as selective pulmonary vasodilatation may lead to further congestion in the pulmonary circuit, resulting in pulmonary oedema. The use of PAH therapies is therefore currently not recommended and would require the selection of suitable patients based on the underlying causes of the disease and careful monitoring of their progress. The present review focuses on the following: (i) the pathophysiology behind PH resulting from systolic left heart failure, and (ii) the current evidence for medical treatment of this condition, especially the role of PAH‐targeted therapies in systolic left heart failure.     

Impaired structural remodelling of pulmonary arteries in newborns with congenital diaphragmatic hernia: a histological study of 29 cases

Congenital diaphragmatic hernia (CDH) is associated in many cases with lung hypoplasia and pulmonary hypertension (PH). The pathogenetic mechanisms underlying the pulmonary hypertension in CDH are not completely understood. In order to alleviate the pulmonary hypertension, new therapeutic modalities have been introduced including extracorporeal membrane oxygenation (ECMO). This paper reports a study of the histology of the lungs of 29 CDH autopsy cases, with special attention to the pulmonary arteries, and relating the findings to gestational age and ECMO treatment. Formalin-fixed and paraffin-embedded specimens were stained with haematoxylin and eosin (H&E) and elastic van Gieson (EvG) stains, followed by morphometric measurements of the arterial media and adventitia. As expected, there was a significant decrease in adventitial percentage and total wall thicknesses of small pulmonary arteries with an external diameter less than or equal to 150 µm in term control newborns compared with pre-term controls ( p=0·0004 and 0·05). In CDH newborns, all the measured values of the arterial wall remained significantly higher. The increase of adventitial thickness also affected the supernumerary arteries in CDH neonates. CDH newborns subjected to ECMO treatment showed a significantly thinner arterial adventitia than CDH cases who did not receive ECMO ( p=0·0001), the former approaching normal values. These results indicate that in CDH, there is failure of the normal arterial remodelling processes occurring in the perinatal period. The adventitial thickening, which has been reported previously in term CDH patients only, was related in the present study to differences in gestational ages. This appears to be partially reversed by ECMO treatment, thus constituting one of the mechanisms by which ECMO treatment aids in alleviating the associated PH in CDH newborns. Copyright © 1999 John Wiley & Sons, Ltd.     

Surgical pathology of pulmonary thromboendarterectomy: a study of 54 cases from 1990 to 2001

Thromboendarterectomy is performed to treat chronic thromboembolic pulmonary hypertension with obstruction of main, lobar, or segmental pulmonary arteries. The present study evaluated surgical specimens removed between 1990 and 2001. Medical histories and microscopic slides were reviewed in each case. Study slides were stained with hematoxylin and eosin and Verhoeff-van Gieson and evaluated for thrombus, collagen, elastin, atherosclerosis, hemosiderin, calcification, and inflammation. The study group comprised 54 patients (30 women and 24 men), ranging in age from 33 to 77 years (mean, 58 years). Clinically, 28 (52%) had a history of deep leg vein thrombosis and 42 (78%) had a history of pulmonary embolism; 24 (44%) had both events. Coagulation abnormalities were documented in 15 (28%); autoimmune or hematologic disorders, in 8 (15%). Pulmonary thromboendarterectomy was bilateral in 52 patients (96%) and right-sided in 2. Six patients also had obstructions resected from the main pulmonary arteries. Obstruction limited to segmental arteries occurred only in women. Grossly, right-sided specimens were larger than left-sided ones (P = 0.003). Microscopically, ages of thrombi were uniform in 72% and variable in 28%. Intima was thickened in all patients and consisted of collagen (100%), elastin (67%), hemosiderin (56%), inflammation (53%), atherosclerosis (32%), and calcification (15%). We determined that pulmonary thromboendarterectomy was performed most often in middle-aged and elderly patients with a history of deep venous thrombosis or pulmonary embolism. Less than 50% of the patients had an identifiable coagulation, autoimmune, or hematologic abnormality. Most patients had bilateral disease and resections. Right-sided specimens were significantly larger than left-sided specimens, and lower lobe involvement was more common than involvement elsewhere. Resected tissues most commonly exhibited old organized thrombus.     

Enhanced expression of vascular endothelial growth factor in pulmonary plexogenic arteriopathy due to congenital heart disease

Congenital heart disease (CHD) leading to increased pulmonary blood pressure and flow is an important cause of pulmonary plexogenic arteriopathy (PPA). This type of arteriopathy tends to progress to an irreversible stage, hallmarked histologically by the emergence of a number of characteristic lesions, which include concentric laminar intimal proliferation and fibrosis, and plexiform lesions. The pathogenesis of these lesions, which connote a very poor prognosis, is not well understood. Since endothelial cell proliferation has been demonstrated in these lesions, it was hypothesized that vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, might play a role in their pathogenesis. Thirty-nine patients with various types of CHD, who underwent cardiac catheterization and subsequent cardiac surgery, were studied prospectively. On the basis of a detailed assessment of the type of cardiac defect, the haemodynamic abnormalities, and the histopathological features evident from open lung biopsies, taken in all instances, patients were histologically grouped into cases with moderate PPA (n=18), advanced PPA (n=7), pulmonary congestive vasculopathy (PCV, n=5), and controls lacking pulmonary hypertension or increased pulmonary blood flow (n=4). Five patients were excluded from analysis because of inadequate sample size or quality. The presence of VEGF was assessed immunohistochemically using standard procedures and was correlated with haemodynamic and histological data. Immunoreactive VEGF was detected in pulmonary arterial smooth muscle cells and endothelial cells in 13 out of 34 cases and was more frequent and more pronounced in patients with the histological lesions of advanced PPA than in those with moderate PPA (p<0.01). VEGF positivity was particularly prominent in the lesions characteristic of advanced PPA. No difference in VEGF expression was observed between controls, PVC, and moderate PPA cases. Measured haemodynamic parameters did not differ significantly between VEGF-positive and VEGF-negative cases. We conclude that VEGF may play a role in the angioproliferative changes of advanced PPA.     

The genetics of isolated congenital heart disease

The genetic mechanisms underlying congenital heart disease (CHD) are complex and remain incompletely understood. The majority of patients with CHD have an isolated heart defect without other organ system involvement, but the genetic basis of isolated CHD has been even more difficult to elucidate compared to syndromic CHD. Our understanding of the genetics of isolated CHD is advancing in large part due to advances in next generation sequencing, and the list of genes associated with CHD is rapidly expanding. Variants in hundreds of genes have been identified that may cause or contribute to CHD, but a genetic cause can still only be identified in about 20–30% of patients. Identifying a genetic cause for CHD can have an impact on clinical outcomes and prognosis and thus it is important for clinicians to understand when and what to test in patients with isolated CHD. This chapter reviews some of the known genetic mechanisms that contribute to isolated inherited and sporadic CHD as well as recommendations for evaluation and genetic testing in patients with isolated CHD.     

Familial total anomalous pulmonary venous return: A large Utah-Idaho family

Total anomalous pulmonary venous return (TAPVR) is a rare form of cyanotic congenital heart disease which, without surgical correction, has a high mortality rate in the first year of life. It usually occurs without a family history, and is generally thought to have a low recurrence risk. However, 15 instances of familial TAPVR have been reported previously, suggesting a genetic cause in some cases. We report on a large family in which TAPVR appears to be determined multifactorially or as an autosomal dominant trait with variable expressivity and reduced penetrance. © 1994 Wiley-Liss, Inc.