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A 45-year-old male with corrected transposition of great arteries and the ventricular septal defect (VSD) was considered to have no indication for the total repair because of severe pulmonary hypertension in his young age. He was suffered from heart failure with absence at the age of 44. Detail examinations revealed the severe tricuspid valve regurgitation with VSD. We reevaluated him for the operative indication by the aspect of pulmonary hypertension. His pulmonary vascular resistance decreased with the administration of 100% oxygen, and no pulmonary vascular obstructions were detected in the lung specimen. As a result, he underwent VSD patch closure and tricuspid valve replacement. His postoperative course was uneventful and he was discharged from our hospital at day 16 postoperatively. Our data suggested that reevaluation including lung biopsy should be important to determine operative indication for adult congenital heart disease.

PPARgamma is a member of a family of nuclear receptors/ligand-dependent transcription factors, which bind to hormone response elements on target gene promoters. An antiproliferative and proapoptotic action profile of PPARgamma has been described, but little is known about the role of PPARgamma in vascular remodeling. We reported a reduced PPARgamma gene and protein expression in the lungs from patients with severe pulmonary hypertension and loss of PPARgamma expression in their complex vascular lesion. We showed that fluid shear stress reduces PPARgamma expression in ECV304 endothelial cells and that ECV304 cells that stably express dominant-negative PPARgamma form lumen-obliterating lung vascular lesion in the artificial capillaries under fluid shear stress and in the intrapulmonary arteries after tail vein injection in nude mice. Recently, there are some evidences that PPARgamma may represent a novel therapeutic target in pulmonary hypertension.

Remodeling of the lung's vascular structure is the critical abnormality in the various types of pulmonary hypertension, including pulmonary arterial hypertension. Pulmonary hypertension consists of some structural changes and an adaptation to its presence (perhaps reversible component, including vasoconstriction). However, once pulmonary hypertension is a recognizable clinical problem, its basis is structural. The research for mediators of cell injury and tissue remodeling has been one of the most active fields of biomedical study. It offers an embarrassingly wide array of candidates for the cellular events. The normal structure of the lung's vascular bed holds the key to its remodeling. The cast of cells is similar at all levels of the pulmonary vascular bed, yet the various segments have special features and different patterns of response.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily, which regulates transcription of target genes in a ligand-dependent manner. Ligands for PPARgamma have been shown to attenuate proliferation of vascular smooth muscle cells, and to induce apoptosis in several cell lines in vitro. Since monocrotaline (MCT)-induced pulmonary hypertension in rats is characterized by proliferation of pulmonary vascular smooth muscle cells, we hypothesized that PPARgamma ligands may reduce MCT-induced pulmonary hypertension. To test this hypothesis, we treated MCT-injected rats with pioglitazone and troglitazone, synthetic ligands for PPARgamma, for three weeks and measured pulmonary artery pressure and pulmonary vessel wall thickness. TdT-mediated dUTP-biotin nick end labeling (TUNEL) and immunostaining for proliferating cell nuclear antigen (PCNA) were utilized to assess apoptosis and cell proliferation in the pulmonary arterial walls of pioglitazone-treated rats. MCT with pioglitazone or troglitazone treatment significantly reduced pulmonary hypertension and wall thickening of the pulmonary arteries. TUNEL-positive apoptotic cells were not seen in the pulmonary arterial walls of either MCT-injected or control rats with or without pioglitazone. PCNA-positive cells were only seen in the thickened pulmonary arterial walls of MCT rats, but not in the pulmonary arterial walls of controls and of pioglitazone-treated MCT rats. We conclude that PPARgamma ligands reduce MCT-induced pulmonary hypertension and pulmonary vascular wall thickening in rats. Inhibition of MCT-induced cell proliferation in the pulmonary arterial walls may account for this effect

Purpose: The purpose of this study was to demonstrate and compare the imaging findings of hepatopulmonary syndrome and portopulmonary hypertension., Materials and Methods: We retrospectively reviewed the imaging findings of five patients with hepatopulmonary syndrome and four patients with portopulmonary hypertension. We evaluated chest radiographs, chest and abdominal computed tomography (CT) scans, 99mTc-macroaggregated albumin (MAA) lung perfusion scans, and pulmonary angiograms., Results: In patients with hepatopulmonary syndrome, the presence of peripheral pulmonary vascular dilatation was detected by chest radiograph, chest CT scan, and pulmonary angiogram, especially the basilar segment. 99mTc-MAA lung perfusion scan showed extrapulmonary tracer distribution (brain, thyroid, and kidney), which revealed pulmonary R-L shunting. In patients with portopulmonary hypertension, chest radiographs and chest CT scans showed the classic findings of primary pulmonary hypertension. In patients with both disorders, extrahepatic features of portal hypertension including ascites, splenomegaly, and portosystemic collateral vessels were seen on abdominal CT., Conclusion: In conclusion, chest radiographs and CT in hepatopulmonary syndrome usually showed peripheral pulmonary vascular dilatation, whereas those in portopulmonary hypertension showed central pulmonary artery dilatation. The extrahepatic features of portal hypertension might be helpful for the diagnosis of both disorders.

A 14-year-old girl with severe pulmonary hypertension (PH) associated with ventricular septal defect was scheduled for intracardiac repair surgery. Preoperative pulmonary arterial pressure (PAP) was 85/47 mmHg, and the pulmonary vascular resistance was 8.2 unit.m-2. After the induction of general anesthesia, PAP (75/31 mmHg) remained unchanged and eventually exceeded arterial pressure (AP, 70/30 mmHg). Neither pulmonary vasodilatation therapy with the inspiration of high oxygen concentration nor intravenous administration of vasodilators (ATP or prostaglandin-I2) could decrease the PAP, but resulted in the exacerbation of systemic arterial hypotension. Accordingly, we cancelled the cardiac surgery considering the possibility of lethal postoperative pulmonary hypertension. Eleven days later, lung biopsy under one-lung ventilation anesthesia was performed. During the one-lung ventilation anesthesia, we applied PEEP with 100% of oxygen onto the independent lung in order to avoid pulmonary vasoconstriction. Although mild hypoxemia (SpO2 = 93%) and transient elevation in PAP to 130/80 mmHg (equal to AP) were observed, the biopsy was completed without any major problems. A histological examination revealed pulmonary plexogenic arteriopathy, the complete contraindication to cardiac surgery. In the anesthetic management of adolescent cases with PH, we should consider the existence of extremely severe pulmonary arterial obstructive changes not diagnosed by preoperative hemodynamic evaluations. Careful monitoring of pulmonary hemodynamics and the application of strategies to avoid lethal PH should be considered.

We report a case of subacute pulmonary hypertension caused by microscopic pulmonary tumor embolism due to the dissemination of gastric cancer cells. The patient, a 61-year-old man with no history of malignant diseases, was admitted to our hospital on October 14 in 1998 because of cough and dyspnea on effort, that had developed since the previous month. On admission, chest radiography including CT scans showed slight cardiomegaly and disseminated reticulonodular shadows predominating in the lower lung fields of both lungs, and arterial blood gas analysis disclosed severe hypoxemia. Lung perfusion scintigraphy revealed multiple irregular defects in both lungs. Echocardiography indicated right ventricular overload, and the pulmonary artery systolic pressure was estimated to be higher than 80 mmHg. Disseminated intravascular coagulation (DIC) developed on the 6th day of hospitalization. Multiple pulmonary embolism with DIC of unknown cause was diagnosed, and the patient was given anticoagulant therapy with heparin. However, he died of respiratory failure on the 7th day of hospitalization. At autopsy, an invasive cancer was found in the stomach, resembling type IIc early gastric cancer. The lumens of the pulmonary arterioles were significantly narrowed by fibrocellular proliferation and thrombi accompanying tumor cell clusters, and some of the microvessels were completely occluded. Disseminated microscopic pulmonary metastasis of malignant tumors should be included in the differential diagnosis of subacute pulmonary hypertension due to multiple pulmonary embolism of unknown cause.

Monocrotaline (MCT) is a pyrrolizidine alkaloid extracted from seeds of Crotalaria spectabilis that has been used to induce structural changes in the pulmonary arteries associated with progressive pulmonary hypertension in rodents. Recent studies have demonstrated that several mediators such as elastase, vasoconstrictors (Endotheline-1), vasodilators (Nitric oxide, PGI2) and cytokines (IL-1, MCP-1) play important roles in MCT-induced pulmonary hypertension, and that the changes in pulmonary hemodynamics are required for neointimal formation in pulmonary arteries. We have recently provided the evidence that macrophage migration inhibitory factor (MIF) is also involved in this model. The MCT-induced pulmonary hypertension in animals is useful as an experimental model for understanding the pathophysiology of primary pulmonary hypertension.

A 71-year-old man who had been suffering from slowly progressive dyspnea on exertion for 16 years was admitted because of hemoptysis and severe dyspnea in 1997. His medical history included respiratory failure in 1986. At that time, chest X-ray films showed cardiomegaly and striking enlargement of hilar pulmonary arteries, while a lung perfusion scan revealed segmental defects. A diagnosis of chronic thromboembolic pulmonary hypertension (CTPH) was made on the basis of multiple filling defects detected by pulmonary angiography and marked pulmonary hypertension (104/29 mmHg) measured by right heart catheterization. The patient died unexpectedly 1 month later. Autopsy revealed a large new thrombotic lesion straddling the organizing thrombotic lesion in the right pulmonary artery. It is important to keep CTPH in mind when examining and treating patients with unexplained dyspnea. In this respect, our case was considered of value to an understanding of the natural course of CTPH.

A 38 year old woman with paroxysmal nocturnal hemoglobinuria was admitted to our hospital because of hemoptysis. Pulmonary infarction was diagnosed by the perfusion lung scan. In spite of the administration of prednisolone, dextran, low molecular weight heparin, and warfarin, she died of pulmonary infarction and secondary pulmonary hypertension. Autopsy revealed thromboembolism of both pulmonary arteries and hepatic central vein thrombosis. Recent understanding of the pathogenesis and incidence of thromboembolism in paroxysmal nocturnal hemoglobinuria was discussed.

In congenital heart defects, it is sometimes difficult to decide the operative indication in patients, who has severe pulmonary hypertension (PH) and right to left shunting, from clinical symptoms and cardiac catheterization. We here report a case of incomplete atrioventricular septal defect. The patient is 9 months old with the Down's syndrome. The cardiac catheterization showed severe PH and right to left shunting. Preoperative mean pulmonary artery pressure was 75 mmHg, pulmonary systemic pressure to systemic pressure ratio (PP/PS) was 1.17, pulmonary systemic flow to systemic flow ratio (QP/QS) was 0.79, pulmonary systemic resistance to systemic resistance ratio (RP/RS) was 1.54 and pulmonary vascular resistance (PVR) was 9.6 woodunits.m2. These data suggested that the irreversible pulmonary vascular disease was present. However the PVR decreased from 9.6 to 3.6 woodunits.m2 after inspiration of 100% oxygen. We therefore performed open lung biopsy for further evaluation of the pulmonary vascular bed. The pathological findings obtained at lung biopsy indicated that there was no irreversible pulmonary vascular disease. This case was diagnosed suitable for a corrective surgery. Total repair was performed and the subsequent clinical course was satisfactory. We thus suggest that the open lung biopsy is useful to decide the surgical indication when it is difficult to determine an operative indication from hemodynamic measurement alone.

A 51-year-old man having ventricular septal defect with severe pulmonary hypertension is reported. Operative indication that is denied was finally decided by open lung biopsy. He had pulmonary arterial pressure of 120/42 (70) mmHg. The ratio of pulmonary to systemic systolic pressure was 0.91, the ratio Of pulmonary to systemic flow was 1.26, the ratio of pulmonary to systemic vascular resistance was 0.34, and pulmonary vascular resistance was 14.2 unit x m2. For the reason of difficulty, in determination of operative indication through hemodynamic study, he received open lung biopsy. Histological assessment from biopsy specimen revealed severe occlusive pulmonary vascular disease exhibiting grade IV on the Heath Edwards classification. Open lung biopsy occasionally be selected in case with difficult determination of operative indication in severe pulmonary hypertension is a useful tool.

Gut-liver-lung axis hypothesis in the pulmonary hypertension complicated with the cirrhosis, that some humonal factors escaping the hepatic inactivation caused by the liver cirrhosis were responsible for the changes in the lung vessels and caused the pulmonary hypertension, was set up. To determine the relation between the pulmonary hypertension and the liver cirrhosis, the author studied experimentally the hemodynamics and the pathological changes in the lung in the cirrhotic rats induced with carbon tetrachloride and in the rats with the portacaval anastomosis. Pathologically the intimal and medial thickness of the small lung arteries were created in both grous. The right ventricular systolic pressure in the cirrhotic rats (25.6 +/- 1.4 torr) was higher than that of the rats with the portacaval anastomosis (21.3 +/- 2.0 torr), but the rate of the extrahepatic portasystemic shunt in the cirrhotic rats (3.3 +/- 1.2%), which was measured with using gamma-labelled microsphere, was conversely lower than that in the rats with the portacaval shunt (17.8 +/- 3.9%). The same pathological changes were also created in another cirrhotic rats induced with dimethylnitrosamine. The right ventricular systolic pressure increased as the liver function became severe. It was suggested that not only the extrahepatic portasystemic shunt but also the dysfunction of the reticuloendothelial system in the liver, was responsible for the mechanism of the pulmonary hypertension in the cirrhosis.

To study how and to what degree the vascular bed of the lung is narrowed in patients with advanced pulmonary hypertension, the number and density of advanced pulmonary vascular lesions in lung tissue were determined by 3-dimensional morphometry. The material included 17 autopsy lung specimens taken from different lobes of 5 patients ranging from 2 to 17 years and dying of congenital cardiac anomalies. In each specimen, computer-aided 3-D reconstruction was performed from serial sections, and the number of grade 3 and 4 lesions was counted in the computer display, also with their densities calculated. The number and density of obstructive vascular lesions were found varying to an unexpected degree, with a marked difference among the individuals and among the site of the lung. The total number of plexiform lesion tends to be greater in the lower lobes. The degree of vascular bed narrowing, defined as the numerical ratio of the obstructed to the total of what we call "acinar arteries", was also various, suggesting that there can be patients who, having a bed not strongly narrowed, are operable even in the presence of plexiform lesion. On the other hand, the result of morphometry provided a basis on which the reliability of open lung biopsy is to be re-assessed: it disclosed the need of semi-serial sectioning of specimen in order not to be missed plexiform lesions particularly when their density in the lung is very low.

In order to study pathogenesis, reversibility, and treatment of pulmonary hypertension in congenital heart disease, a new experimental model to induce pulmonary vascular diseases has been designed. Previous models by other investigators were anastomosis between a systemic artery and pulmonary artery of one lung lobe, and these could not provide constant induction of pulmonary vascular diseases. Furthermore the postoperative mortalities in their experiences were quite high and acute iatrogenic pathological changes such as bleeding, edema and emphysema developed in the pulmonary vasculature and parenchyma of the anastomosed lobe. Use of our adjustable pulmonary artery band has eliminated such unwanted complications. The surgical procedure includes an end-to-side anastomosis of the left main pulmonary artery to the descending thoracic aorta, and banding of the anastomosed pulmonary artery using the adjustable band. The band was gradually loosened by extrathoracic manipulation during three to four weeks observation after operation. This technique provided dogs to survive sufficiently long enough and with a high success rate, and to produce extremely advanced pulmonary vascular diseases. Of the twenty dogs operated such, eighteen survived the first postsurgical week and thirteen dogs developed hypertensive pulmonary vascular diseases. Development of the medial hypertrophy was evident at one week and gradually advanced. In eight weeks, intimal cellular proliferation (Grade 2 of the Heath & Edwards' classification) became apparent. In twelve weeks, the intimal proliferation became fibrous and acellular (Grade 3) and caused complete obstruction of the lumen of some muscular arteries. In twenty weeks specimen, typical plexiform lesions (Grade 4) and dilatation lesions (Grade 5) involved the small muscular arteries in the whole left lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Most patients with primary pulmonary hypertension (PPH) die within two to four years of the onsets of their symptoms. However, several reports have described patients with PPH who have lived more than 10 years including a case with regression. We studied prognoses and the various determinants in 21 patients (7 men and 14 women; 18 deceased and three living) with PPH to elucidate its pathophysiology. Age at the onset of the disease varied from 12 to 73 years, with a mean of 29 years. All causes of death were of right heart failure, except for two cases of non-cardiac deaths. The prognoses were as follows: less than one year, two cases; 1-2 years, seven (one living); 2-3 years, five; 3-4 years, two; 4-5 years, one; more than six years, four (two living), with a mean of three years and five months. Pulmonary artery pressure decreased 10 years later (mean pressure, from 54 to 41 mmHg) in one patient, who lived for 13 years, followed by a non-cardiac death. Various clinical and pathological factors, including age at the onset of disease, sex, relationship to pregnancy, immunological abnormalities (4, positive; 17, negative), patent foramen ovale (five, patent; 16, not patent), PaO2, hemodynamic parameters, treatments, pathological subtypes (10, plexogenic pulmonary arteriopathy; two, pulmonary micro-thromboembolism; one, pulmonary veno-occlusive disease) numbers of plexiform lesion/cm2 were examined for prognostic correlations. None of the above factors were found to correlate significantly with prognoses. The only significant correlation was between the cardiac index (r = 0.981, p less than 0.001, n = 6), and total pulmonary resistance (r = -0.894, p less than 0.02, n = 6) in patients with pregnancy-related PPH. There was variability in the state of progression, namely, from rapid progression to regression. Clinically as well as pathologically, PPH may consist of several subgroups. However, whether it is due to differences in etiology or reactions of the disease is not clear. The pregnancy-related cases may comprise a homogenous subgroup within PPH.

Right ventricular anterior wall thickness measured by M-mode echocardiography and right ventricular systolic pressure obtained by right heart catheterization were correlated in 62 patients with chronic right ventricular overload including congenital heart disease and primary pulmonary hypertension. The patients were divided into two groups; one, with right ventricular systolic pressures of 39 mmHg or less; the other, 40 mmHg or more. The following results were obtained. 1. The correlation coefficient for right ventricular anterior wall thickness and right ventricular systolic pressure was r = 0.90 (p less than 0.001), and the regression equation was y = 13.2x-1.3. 2. Right ventricular end-diastolic dimension increased significantly in both groups, but no statistically significant differences were detected between the two. Right ventricular anterior wall thickness increased significantly in the group with higher right ventricular pressures (7.1 +/- 0.5 mm vs 3.1 +/- 0.5 mm). 3. When right ventricular anterior wall thickness was more than 4.0 mm, pulmonary hypertension was detected, with a sensitivity of 97.5% and a specificity of 90.9%. In conclusion, measurements of right ventricular anterior wall thickness by M-mode echocardiography via the anterior chest wall proved to be potentially useful in predicting right ventricular systolic pressures in patients with chronic right ventricular overloads.

A new method for inserting ultrasonic crystals into the interventricular septum (IVS) of dogs was performed to measure the right and left ventricular septum-to-free wall dimensions (RVD, LVD) in a line. The advantage of this technique is minimal damage of the pericardium and no damage of the ventricular wall. The segmental lengths in the right and left ventricles (RVSL, LVSL) were also measured. Stepped elevation of pulmonary arterial pressure induced by ligation of pulmonary arterial branches caused an increase in RVD and a decrease in LVD. IVS shifted to the left and transseptal pressure gradient was reduced. RVD and RVSL increased and percent shortening in RVD and RVSL during ejection decreased with pulmonary hypertension. Although the change in RVD and RVSL basically related each other, those changes in RVD was more evident than in RVSL. Thus, the measurement of RVD and RVSL is indispensable for investigating the right ventricular function. There was a high correlation between the stroke volume and the shortening in RVD (expressed as percent of the control value, respectively) during ejection in pulmonary hypertension (F = 13.88 greater than F 1(20)(0.005) = 9.94), therefore we speculate that right ventricular bellows action is essential in blood ejection from the right ventricle. Furthermore the stroke volume decreased as the shortening in RVSL during ejection decreased (F = 3.17 greater than F 1(20)(0.1) = 2.97), therefore shortening in RVSL is thought to be an important factor causing bellows action, however further investigation is necessary.

The prevalence of pulmonary hypertension among patients with portal hypertension, especially following a shunt operation, is significantly higher than that of primary pulmonary hypertension, suggesting the hypothesis that large portasystemic shunt plays a major role in development of pulmonary hypertension. To support this hypothesis, I studied experimentally the hemodynamic changes and the pathological findings in lung in 97 rats killed between one and 24 months after portasystemic shunt operations. The right ventricular systolic pressure (RVSP) and the right ventricular wall thickness were significantly high in the 82 rats raised over 3 months after the operations. In these rats the pathological findings in the lung revealed a thickness of pulmonary arterioles with medial hypertrophy, concentric intimal proliferation, and plexiform lesions. The values of endotoxin in central venous blood were significantly high and related with RVSP and shunt ratio. In pulmonary venous blood, thromboxane B2 increased and 6-keto PGF1a decreased. In conclusion, some of the rats developed pulmonary hypertension fter receiving a portasystemic shunt operation. It is suspected that endotoxin passing through the shunt plays a role in the development of pulmonary hypertension.

A 14-year-old girl was admitted with chief complaints of edema and chest pain. She had hepatomegaly, but did not have heart murmur and accentuation of the pulmonary component of the second heart sound. The electrocardiogram showed right axis deviation, negative T wave in V3,4 and ST depression in III, aVF. But right ventricular hypertrophy was not dominant. Chest radiography showed a cardiothoracic ratio of 54% and a slight prominence of proximal pulmonary arteries. The edema was soon diminished only by the diuretics, but it appeared again without the diuretics. At the cardiac catheterization 3 months after the onset of symptoms, the pulmonary arterial pressure was 150/85 mmHg and the pulmonary resistance was 3,232 dyn/sec/cm5. The right atrial pressure was 9.5 mmHg and oxygen saturation at the pulmonary artery was 31.0%. Prostaglandin E1 reduced the pulmonary artery pressure only a little, but raised the systemic pressure. The patient was treated with several vasodilators, but her condition deteriorated rapidly and she developed severe right ventricular failure. She died only 8 months after the onset of symptoms and 5 months after the catheterization. At autopsy, histological examination demonstrated intimal fibrotic thickening of the small-sized pulmonary arteries and organizing thrombus. But there was not plexiform lesion. Heart failure was easily improved when she was first admitted. But after 3 months the cardiac catheterization revealed that her condition was already severe. Several vasodilators was not effective to such a rapidly progressive primary pulmonary hypertension.