Insufficient development of vessels and alveoli in lungs of infants with trisomy 18-Features of pulmonary histopathological findings from lung biopsy.

The aim of this study was to evaluate the features of pulmonary histopathological changes in cases of trisomy 18 complicated with congenital heart disease and pulmonary arterial hypertension. Twenty-eight patients with trisomy 18 underwent open lung biopsy at the time of primary operation in our hospital between 2008 and 2019. We compared these histopathological findings with those from previously described groups without trisomy 18. Mean age at primary cardiac surgery was 37 days (range, 9-69 days). According to the Heath-Edwards (HE) classification, 1, 8, 12, and 5 patients were graded as 0, 1, 2, and 3, respectively, whereas 2 patients were not classifiable due to medial defects in the small pulmonary arteries (MD). Four (14.3%) and 13 (46.4%) patients presented with MD and hypoplasia of the small pulmonary arteries (HS). Fifteen (53.6%) and 21 (75.0%) patients presented with alveolar hypoplasia (AH) and alveolar wall thickening (AT). MD, HS, and AH in trisomy 18 were present frequently, differing significantly from previous reports. These findings might be associated with congenital inadequate development of vessels and alveoli in the lung, contributing to a high risk of PAH in trisomy 18.

In situ thrombosis of small pulmonary arteries in pulmonary hypertension developing after chemotherapy for malignancy.

A few reports have provided histopathological insight into pulmonary hypertension developing after antitumor chemotherapy. In general, plexogenic pulmonary arteriopathy is a commonly observed finding in patients with severe pulmonary hypertension. We herein report a novel pathological finding that may characterize the histopathological change occurring in patients with pulmonary hypertension after chemotherapy for malignancy. Lung biopsy or autopsy was performed in 7 patients with pulmonary hypertension that developed during or after chemotherapy between 2006 and 2013 to examine the pulmonary vascular changes or to determine the cause of death. Pathological findings included in situ thrombosis in the small pulmonary arteries in 4 of 7 patients. In 2 of 4 patients, pulmonary hypertension was controlled by anticoagulants and antithrombotic agents. One patient who had organized thrombi attained spontaneous remission with oxygen therapy. The other patient died of sudden cardiopulmonary arrest during chemotherapy. Autopsy showed complete occlusion of the peripheral small pulmonary arteries and veins by thrombi. These results demonstrate that in situ thrombosis in the small pulmonary arteries could cause pulmonary hypertension after chemotherapy.

Histopathological examination by lung biopsy for the evaluation of operability and postoperative prognosis in patients with chronic thromboembolic pulmonary hypertension.

BACKGROUND: To evaluate the prognosis after pulmonary thromboendarterectomy (PTE) in patients with chronic thromboembolic pulmonary hypertension (CTEPH), a lung biopsy was performed in 34 patients with central CTEPH and in 7 patients with peripheral CTEPH during PTE. METHODS AND RESULTS: Postoperative prognosis was classified from A to E based on the postoperative hemodynamic parameters and clinical condition, and was compared with the index of occlusion (IOCTEPH), which indicates the degree of occlusion in the small pulmonary arteries. Criteria of (A-E) were established only for central CTEPH. Category (A) corresponded to an IOCTEPH from 1.0 to 1.4, (B) from 1.5 to 1.7, (C) from 1.8 to 2.0, and (D) from 2.1 to 2.4. One patient with an index of 3.0 was rated as (E). This patient had collateral vessels around the obstructed small pulmonary arteries and died postoperatively. In all 12 patients who underwent PTE after the criteria were established, postoperative hemodynamic parameters and clinical conditions were consistent with the IOCTEPH. One patient with a high degree of medial atrophy in their small pulmonary arteries died after PTE. CONCLUSIONS: These results indicate that a lung biopsy during PTE is useful for prognostication in patients with CTEPH.

An infant with primary pulmonary vein stenosis, associated with fatal occlusion of intraparenchymal small pulmonary veins.

Primary pulmonary vein stenosis (PVS) is rare within the pediatric population and its pathophysiology remains unclear, especially as to how the histopathology relates to its refractoriness to treatment. We report the case of a 4-month-old girl with primary PVS. The lesion in this patient was characterized by fatal obstruction of intraparenchymal small pulmonary veins, associated with localized stenosis at the four pulmonary veno-atrial junctions. All four localized stenoses underwent transcatheter stent implantation. Although the procedure was technically successful, her clinical status failed to improve, and she died 2 months after stenting. Histopathological examination of lung specimens showed severe luminal obstruction by marked intimal proliferation with fibrosis in the intraparenchymal small pulmonary veins, and these findings were present in every lobe. To the best of our knowledge, the histopathological findings and clinical course in this case, including the response to treatments, are extremely rare. We suggest that the histological findings of the small pulmonary veins are important in deciding the indication and appropriate timing of intervention. .

Medial defects of the small pulmonary arteries in fatal pulmonary hypertension in infants with trisomy 13 and trisomy 18.

Congestive heart failure is a major cause of early death in patients with trisomy 13 or 18 and congenital heart disease (CHD). Pulmonary artery banding for these patients early in life is preferred to protect the lungs from high pulmonary flow rates and improve survival. We performed open lung biopsies in 11 patients with trisomy 13 or 18 accompanied by CHD and severe pulmonary artery hypertension (PAH) between 2009 and 2011. Two (18.2%) of these 11 patients had medial defects of the small pulmonary arteries. One patient with trisomy 13 and an atrial septal defect developed lung hemorrhage and lung edema at the age of 9 months and died at the age of 13 months. The lumens of the small pulmonary arteries of the other patient with trisomy 18 and a ventricular septal defect became occluded due to the intimal proliferation of fibrous tissues at the age of 2 months. This patient died at the age of 27 months. The deaths of both patients were associated with heart-related factors. Patients with medial defects are vulnerable to intimal proliferation in the small pulmonary arteries. More patients with trisomy 13 or 18 and CHD might have similar pulmonary vascular changes. The small pulmonary arteries of patients with trisomy 13 and 18 should be further analyzed.

Pulmonary vascular disease associated with pulmonary hypertension in 445 patients: diagnosis from lung biopsy and autopsy.

PURPOSE: Diagnosis from lung biopsy or autopsy was performed in 445 patients with congenital (385) or acquired (60) heart disease from all over Japan. The purpose of this study is the presentation of these prospective data collections. METHODS: Of the patients with congenital heart disease, 354 were biopsied to determine whether surgery was indicated. Decisions regarding surgery were based on the index of pulmonary vascular disease in simple cardiac anomalies or atrioventricular septal defects (AVSD). In total anomalous pulmonary venous connection (TAPVC), operative indication was determined by the degree of hypoplasia of small pulmonary arteries. Operability of Fontan procedure was based on the degree of residual medial hypertrophy after pulmonary artery banding. RESULTS: In patients with simple cardiac anomalies, radical surgery was indicated in 166. Radical surgery was indicated in 50 patients with AVSD. In 26 patients with TAPVC, radical surgery was not indicated in 10. In 68 Fontan candidates, surgery was not indicated in 49. Among 7 patients with tetralogy of Fallot, 1 was not a surgical candidate. Of the 60 acquired heart disease patients, 16 had idiopathic pulmonary arterial hypertension and 36 had chronic thromboembolic pulmonary hypertension. In 6 patients, lung biopsy revealed pulmonary veno-occlusive disease; 2 patients had combined valvular disease. CONCLUSION: The cardiac surgeon, pediatric cardiologist, and cardiologist who requested diagnosis from lung biopsy or autopsy were gratified with the results.

Pulmonary hypertension in patients with congenital portosystemic venous shunt: a previously unrecognized association.

BACKGROUND: Pulmonary arterial hypertension has been reported to be observed in association with acquired portal hypertension. However, the contribution of congenital anomalies occurring in the portal system to the development of pulmonary arterial hypertension remains to be elucidated. METHODS: Nine patients with congenital portosystemic venous shunt were studied from January 1990 through September 2005. RESULTS: Patent ductus venosus was detected in 5 patients, including 3 patients with an absence of the portal vein. The presence of either a gastrorenal or splenorenal shunt was evident in another 4 patients. Six patients had a history of hypergalactosemia with normal enzyme activities, as seen during neonatal screening. Six (66.7%) of the 9 patients were identified to have clinically significant pulmonary arterial hypertension (mean pulmonary artery pressure: 34-79 mm Hg; pulmonary vascular resistances: 5.12-38.07 U). The median age at the onset of pulmonary arterial hypertension was 12 years and 3 months. Histologic studies of lung specimens, which were available in 4 of the 9 patients with congenital portosystemic venous shunt, showed small arterial microthrombotic lesions in 3 patients. This characteristic finding was recognized even in the congenital portosystemic venous shunt patients without PAH. CONCLUSIONS: This study demonstrated thromboembolic pulmonary arterial hypertension to be a crucial complication in congenital portosystemic venous shunt, and this pathologic state may be latently present in patients with pulmonary arterial hypertension of unknown etiology.

Two-stage procedure for pulmonary vascular obstructive disease in Down syndrome with congenital heart disease.

BACKGROUND: Down syndrome patients are characterized by early progression of pulmonary vascular obstructive disease because of insufficient thickness of the pulmonary arterial media. For those with congenital heart disease (CHD) associated with pulmonary hypertension (PH), a 2-stage procedure of pulmonary artery banding (PAB) and then intracardiac repair (ICR) in early infancy is performed to prevent such pulmonary vascular diseases in early infancy. METHODS AND RESULTS: The subjects were 16 patients with Down syndrome who underwent lung biopsy during PAB and ICR. PAB was planned to be performed in early infancy and ICR approximately 1 year later. Efficacy of the 2-stage procedure was retrospectively examined with reference to pulmonary vascular disease and pulmonary diseases. The index of pulmonary vascular disease at PAB fulfilled the indication for ICR, and it was significantly lower at ICR than at PAB (p=0.0469); furthermore, PAB prevented progression of pulmonary diseases. CONCLUSIONS: The results of the lung biopsies support the safety of the 2-stage procedure and show that it is effective for Down syndrome patients with CHD and PH.

Lung biopsy diagnosis of operative indication in secundum atrial septal defect with severe pulmonary vascular disease.

OBJECTIVE: Surgical indication was determined by lung biopsy in 91 patients with secundum atrial septal defect (ASD) and severe pulmonary hypertension > 70 mm Hg of pulmonary arterial peak pressure and/or pulmonary vascular resistance of > 8 U/m(2). METHODS AND RESULTS: Pulmonary vascular disease (PVD) in ASD was classified into four types: (1) Musculoelastosis consisting of longitudinal muscle bundles and elastic fibers; surgery is indicated no matter how severely the peripheral small pulmonary arteries are occluded. Surgery was performed in all of the 20 patients, and the postoperative course was uneventful. (2) Plexogenic pulmonary arteriopathy: surgery is indicated for a PVD index < or = 2.3. Surgery was performed in 25 of the 32 patients. The remaining seven patients for whom surgery was not indicated are under follow-up observation. No deaths have occurred among the 32 patients. (3) Thromboembolism of small pulmonary arteries: Surgery is indicated for all such cases. Surgery was indicated in all of the five patients. (4) Mixed type of plexogenic pulmonary arteriopathy and musculoelastosis: Surgery is indicated if the collateral is not observed. Surgery was performed in 15 of the 25 patients. The remaining 10 patients for whom surgery was not indicated are under follow-up observation. Nine of these 91 patients associated with primary pulmonary hypertension were eliminated from this study. CONCLUSION: No deaths due to PVD occurred among the 82 patients who underwent lung biopsy diagnosis. Lung biopsy diagnosis is concluded to be very effective.

Reevaluation of histomorphometric analysis of lung tissue in decision making for better patient selection for fontan-type operations.

BACKGROUND: The various types of cavopulmonary connection are occasionally unsuccessful even when the indications have been strictly fulfilled based on preoperative hemodynamic studies. We performed a detailed study of lung specimens from 60 patients who were judged to be candidates for the modified Fontan procedures based on a catheterizaton study in order to reevaluate the role of histologic studies of the pulmonary vasculature and to determine histologic criteria for the Fontan-type operation. METHODS: We performed a histomorphometric analysis of specimens from 53 biopsy and 7 autopsy cases (0.5 to 23 years of age), with single ventricle physiology. Twenty-eight cases were treated with a bidirectional Glenn shunt (BDGS) and 32 cases were treated by means of total cavopulmonary connections (TCPC) with or without fenestration, on the basis of the clinical and hemodynamic findings. To evaluate the medial thickness of small pulmonary arteries (SPAs), we used a measurement, D(R = 100 microm), that is unaffected by various degrees of vasoconstriction of the media or the age of the patients and that is representative of all SPAs in a section. Other variables, such as intimal lesions, SPA density, and the percentage of vessels containing a thrombus, were also measured. RESULTS: There was a significant difference in D(R = 100 microm) values between the BDGS cases with good and bad outcomes at p = 0.0007 (8.9 +/- 2.4 versus 13.4 +/- 1.9 microm), and the cutoff point for the success of BDGS was 13.7 microm. The same was true of the TCPC cases at p less than 0.0001 (8.4 +/- 1.7 versus 14.7 +/- 1.5 microm), and the cutoff point was 11.6 microm. There were no significant differences in other histomorphometric variables. Investigation of the relationship to hemodynamic data revealed a correlation between D(R = 100 microm) and mean pulmonary artery pressure at p = 0.028. There were no statistically significant correlations between other variables. CONCLUSIONS: The study revealed marked differences in D(R = 100 microm) values between patients with good and bad outcomes and provided D(R = 100 microm) cutoff points for BDGS and TCPC. In some cases, there were discrepancies between the results of the preoperative hemodynamic data and of the histomorphometric analysis; and because some patients were wrongly assessed based on clinical and hemodynamic criteria, histomorphometric study might be a useful method of supplementing the variety of clinical data used to determine the indications for this operation.

Hypoplasia of the small pulmonary arteries in hypoplastic left heart syndrome with restrictive atrial septal defect.

BACKGROUND: Restrictive atrial septal defect (ASD) (including intact atrial septum [IAS]) has been reported to be a risk factor that negatively impacts survival in hypoplastic left heart syndrome (HLHS). Although lymphangiectasia and "arterialization" of the veins of the lung in HLHS with restrictive ASD have been reported, they cannot fully explain the high mortality. We have introduced a new method of evaluating the development of the pulmonary vasculature in histological sections and used it to assess patients' lungs. We tested the hypothesis that the small pulmonary arteries (SPA), which are pulmonary arteries in a histological section whose radii are approximately 25 microm to 250 microm, in HLHS with restrictive ASD are hypoplastic, but that the alveoli are not, to elucidate the mechanism underlying the poor outcome of these patients. METHODS AND RESULTS: Fourteen HLHS patients between 1 day and 40 days of age were studied. In 8 cases, the ASD was restrictive [R(+) group], and in the other 6 cases it was not [R(-) group]. Specimens from 12 autopsies of cases with no congenital heart or pulmonary disease were examined as a control group (C group). As a novel histological parameter, we assessed the size of SPA in relation to the size of accompanying bronchioles to identify SPA underdevelopment. To evaluate the development of alveoli and interstitial tissue, radial alveolar counts (RAC), which reflect alveolar maturity and complexity, were also performed. Statistical comparisons between groups were made by analysis of covariance with age as a covariant factor. When the radius of the accompanying bronchiole was 100 microm, the radius of the SPA was 34.0+/-10.8 microm in the R(+) group, and significantly lower than the 46.6+/-8.5 microm in R(-) group (P=0.0022) and 70.5+/-8.4 microm in the C group (P<0.0001). The RAC was in 3.5+/-0.9 in the R(+) group, 3.4+/-0.6 in the R(-) group, and 3.7+/-0.9 in the C group (no significant differences between groups). CONCLUSIONS: The SPA in HLHS with restrictive ASD were underdeveloped compared with the SPA in HLHS with nonrestrictive ASD and the controls, but their alveoli were not hypoplastic. Based on these results, it is speculated that SPA hypoplasia may be responsible for the poor outcome of HLHS with restrictive ASD.

Atrial septal defect with borderline pulmonary vascular disease: surgery and long-term oral prostacyclin therapy for recalcitrant pulmonary hypertension.

The hemodynamic determination of operability in atrial septal defect (ASD) with severe pulmonary hypertension is problematic. Therefore, we perform an open lung biopsy prior to the corrective surgery in cases with pulmonary vascular resistance greater than 8 units x m2 and/or pulmonary arterial peak pressure greater than 70 mmHg. We present 4 cases showing occlusion of more than 70% of the small pulmonary arteries and arterioles by musculoelastosis, thromboembolism and mixed-type (musculoelastosis and plexogenic arteriopathy) which was considered borderline in terms of operability. After complete closure of the ASD and postoperative long-term oral prostacyclin (PGI2) therapy, pulmonary artery peak pressure decreased from 110-72 (mean 84) to 105-45 (mean 74) mmHg immediately after operation and 65-40 (mean 57) mmHg after PGI2 therapy. The New York Heart Association functional status of the patients improved from class II-III to class I with oral PGI2 only. Our cases demonstrate that despite more than 70% occlusion of the small pulmonary arteries and arterioles, surgery and long-term PGI2 therapy can reduce pulmonary artery pressure and improve the quality of life.

Hypoplasia of the small pulmonary arteries in total anomalous pulmonary venous connection with obstructed pulmonary venous drainage.

OBJECTIVE: Preoperative pulmonary venous obstruction has been reported to be a risk factor negatively impacting survival in total anomalous pulmonary venous connection. We examined lung tissue from total anomalous pulmonary venous connection patients with pulmonary venous obstruction and demonstrated hypoplasia of small pulmonary arteries to elucidate the mechanism underlying the poor outcome. METHODS: Ten total anomalous pulmonary venous connection patients with preoperative pulmonary venous obstruction between the ages of 2 days and 10 months were studied. As histological parameters, we assessed the size of small pulmonary arteries in relation to the size of accompanying bronchioles to identify small pulmonary artery underdevelopment. Other parameters, such as the radial alveolar count, which reflects alveolar maturity, intimal lesions, lymphangiectasia, and the medial thickness of small pulmonary arteries and small pulmonary veins, were also examined. As a control group, we examined 24 autopsy cases with no congenital heart or pulmonary disease. RESULTS: When the radius of the accompanying bronchiole was 100 microm, the radius of small pulmonary artery in the control group was found to enlarge for the first 2 months and then remain stable at approximately 80 microm from 2 to 10 months. In total anomalous pulmonary venous connection with preoperative pulmonary venous obstruction, the radius was significantly lower than in the control (47.0 +/- 21.8 microm versus 75.9 +/- 9.8 microm, P <.001), and the difference between dead and surviving patients was significant at P <.001 (33.0 +/- 14.6 microm versus 68.2 +/- 9.2 microm). Examination of the alveoli yielded an radial alveolar count of 4.6 +/- 1.5 in the control group and 4.4 +/- 0.8 in the total anomalous pulmonary venous connection patients, and the difference was not significant (P =.71). CONCLUSIONS: The small pulmonary arteries of total anomalous pulmonary venous connection patients with preoperative pulmonary venous obstruction were underdeveloped compared with controls but their alveolae were not hypoplastic. These results suggested that the small pulmonary artery hypoplasia may be responsible for the poor outcome of these patients.

Pathological lesions causing pulmonary hypertension after closure of a ventricular septal defect.

A 15-year-old boy with a ventricular septal defect, pulmonary hypertension, Down's syndrome, and extremely thickened media (ETM) of the small pulmonary arteries died of heart failure and pulmonary hypertension 13 years after intracardiac repair. Microscopic examination of lung specimens collected prior to the intracardiac repair and at the time of autopsy revealed that the ETM had remained unchanged and that the arteries connected to the vessels with ETM had become severely thickened. The present case shows that even a small percentage of arteries with ETM can cause pulmonary hypertension, and illustrates one of the mechanisms of how pulmonary hypertension can fail to be resolved after intracardiac repair.

Severe unilateral pulmonary vascular changes in child with polysplenia.

A 12-year-old boy with polysplenia and single ventricle experienced recurrent episodes of pneumonia, hemoptysis, and pulmonary hypertension. Unilateral pulmonary vein obstruction was diagnosed, and a left pneumonectomy was performed. Microscopy of the resected specimen revealed pulmonary veno-occlusive disease in the small pulmonary venules, and old arteritis in the small pulmonary arteries.