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.     

A case of pulmonary vascular occlusive disease: comparison of post-mortem radiography and histology

A case of rapidly progressing fatal pulmonary hypertension in a nine-year-old boy showing histological narrowing and occlusion of pulmonary veins and arteries is described. Post-mortem radiography of the air-inflated, excised lung without use of additional contrast media nicely demonstrated the vascular lesions.     

Sarcoidosis with pulmonary hypertension exacerbated by Takayasu-like large vessel vasculitis

A 72-year-old male visited the hospital with a complaint of dyspnea. Under the diagnosis of pulmonary hypertension (PH) due to chronic thrombotic and/or embolic disease, this patient received anti-coagulant therapy. Unfortunately, the respiratory state deteriorated and died 34 days after admission. At autopsy, noncaseating granulomas, which were diagnostic of sarcoidosis, were found in bilateral enlarged hilar lymph nodes, lungs, heart, liver, spleen, testis and epididymis. In pulmonary vasculature, the following three kinds of lesions were observed; (i) sarcoid granulomatous vasculitis at the peripheral arteries and veins, (ii) intimal fibrous lesions ubiquitously found in proximal and peripheral arteries which were thought to be organized thromboemboli, (iii) Takayasu-like large vessel vasculitis with a huge fresh mural thrombus narrowing the lumen of most proximal portion of right pulmonary artery. Autopsy findings indicate that chronic sustained PH state in this patient was attributable to thrombotic and/or thromboembolic disease, and Takayasu-like vasculitis with thrombus played a role in the final deterioration of respiratory state through exacerbation of PH. In sarcoidosis patients, vasculitic lesions which can be formed in both small and large pulmonary arteries must be raised as the differential diagnosis for the initial cause of PH as well as the accelerating factor of PH.     

A practical approach to vascular pathology in pulmonary hypertension

Pulmonary hypertension (PH) is the common physiological denominator in an otherwise heterogeneous disease. While pulmonary hypertension itself is not a pathologists' diagnosis, various patterns of pulmonary vasculopathy may be recognized in pulmonary hypertension. These patterns of vasculopathy are at the basis of classification, as they point towards (groups of) risk factors and aetiology. However, as surgical lung biopsy is a high risk procedure in PH, the role for histopathological evaluation is now mainly in retrospective evaluation on explanted lung or tissue obtained at autopsy, taking clinical work-up, including haemodynamic parameters and HRCT imaging, into account. Such multidisciplinary evaluation and classification may help assess the prognosis, including risk of recurrence in a transplant, and possible risk of PH in family members. More generally, systematic evaluation may identify clues as to pathogenesis and may help to fill the knowledge gap between histopathology and non-invasive diagnostic procedures such as imaging. This will hopefully eventually lead to a patho-physiologic rationale for classification, and to improved treatment strategies. This review aims to offer some practical guidelines for pathologists, pointing out pitfalls along the way.     

The histopathology of 36 cases of plexogenic pulmonary arteriopathy

A detailed histopathological study was made of the lungs of 36 cases of plexogenic pulmonary arteriopathy coming to combined heart-lung transplantation. It revealed two dissimilar processes involved in the pathogenesis of this disease. One comprised histological appearances consistent with constriction of muscular pulmonary arteries, a condition that would be likely to be reversed by pulmonary vasodilators. The other was the proliferation of myofibroblasts in the intima and lumen of pulmonary arteries, a disorder of growth unlikely to be influenced by this type of therapy. In previous ultrastructural studies we have shown that the source of these cells of muscular pedigree is muscle cells from the inner half of the media which migrate into the intima through gaps in the inner elastic lamina. In the present study we found a similar proliferation of myofibroblasts in the intima, not only of pulmonary arteries, but also of pulmonary veins, in plexogenic pulmonary arteriopathy. Arterial thrombi found were considered to be a complication rather than a cause of plexogenic pulmonary arteriopathy. Siderophages, cholesterol granulomas and focal fibrosis in the lung were considered to be a consequence of intrapulmonary haemorrhage early in the course of the disease. It is concluded that, while plexogenic pulmonary arteriopathy has an important vasoconstrictive element, it is also based on a disorder of growth of cells of muscular pedigree. This view has clear implications for the therapy of primary plexogenic pulmonary arteriopathy.     

The role of MIF,cyclinD1 and ERK in the development of pulmonary hypertension in broilers

Pulmonary hypertension (PH) is a major disease in the broiler breeding industry. During PH, the pulmonary artery undergoes remodelling, which is caused by pulmonary vascular smooth muscle cell proliferation. CyclinD1 regulates cell proliferation. This study investigated the role of cyclinD1 in the development of PH in broilers, and which bioactivators and signalling pathway are involved in the pathological process. The PH group contained 3–4-week-old broilers with clinical PH, and the healthy group broilers from the same flock without PH. Histopathology indicated pulmonary arterial walls were thicker in the PH group compared with the healthy group. Target gene expressions of macrophage migration inhibitory factor (MIF), extracellular signal-regulated kinase (ERK), and cyclinD1 detected by quantitative real-time PCR were upregulated in the PH group compared with the healthy group. Immunohistochemistry showed MIF, phosphorylated ERK (p-ERK) and cyclinD1 were present on pulmonary vascular walls; MIF was present in the cytoplasm of arterial endothelial cells and smooth muscle cells; p-ERK and cyclinD1 were present in smooth muscle cell cytoplasm. Western blotting demonstrated that MIF, p-ERKand cyclinD1 levels were significantly higher (P?相似文献   

Pulmonary hypertension in patients with 9q34.3 microdeletion‐associated Kleefstra syndrome

Kleefstra Syndrome is a rare genetic disorder caused by mutations in EHMT1, Euchromatin Histone Methyl Transferase 1, or deletions encompassing EHMT1 on 9q34.3. Congenital heart defects are among the major findings in patients with 9q34.3 microdeletion/Kleefstra Syndrome along with recognizable facial appearance, developmental delay/intellectual disability including severely delayed or absent speech, hypotonia, seizures, behavioral and sleep abnormalities. Pulmonary hypertension (PH) is a rare condition associated with increased pulmonary artery and right heart pressures that can lead to right heart failure and death if untreated. PH can be idiopathic, heritable, or associated with co‐morbid conditions including congenital heart disease (CHD), lung diseases and other metabolic disorders. Genetic factors play important roles in heritable and idiopathic PH development and are particularly relevant but more diverse in etiology in children. PH is also reported in some chromosomal disorders such as Down syndrome in which congenital heart defects are common; however, PH has rarely been reported in patients with 9q34.3 microdeletion/Kleefstra Syndrome. Here, we present three patients with 9q34.3 microdeletions with CHD and PH along with review of five similar cases reported in the literature and discuss the potential association of PH with Kleefstra syndrome.     

Expression des Angiotensin converting enzyme (ACE) bei pulmonaler Hypertonie

We studied angiotensin I converting enzyme (ACE) expression in lung tissue from patients with different forms of pulmonary hypertension (PH) in comparison with that from morphologically normal lung specimens. ACE antigen expression was analysed by immunohistochemistry in morphologically normal lung tissue from 33 patients (19 males, 32-77 years; 14 females, 34-93 years) and compared to that in specimens from 94 patients (67 males, 30-97 years; 27 females: 27-90 years) with different clinically proven forms of PH (according to Venedig classification). Type specific vessel expression pattern as described for normal lung tissue was generally intensified in arteries, arterioles and capillaries of the lung specimens with PH. Specimens with PH due to left heart disease and chronic obstructive pulmonary disease (COPD) showed only very weak or no augmented arterial ACE expression, while PH due to collagenoses or interstitial lung disease showed significantly higher ACE expression. In human PH there is--comparable to animal models--a raised ACE expression in pulmonary lung vessels, with differences between the various forms of PH. These differences in ACE expression may be relevant for subtly differentiated therapeutic anti-ACE therapy regimes.     

D-二聚体、NT-proBNP对慢性阻塞性肺疾病并肺动脉高压的诊断价值

目的 分析血浆D-二聚体(DD)及N端脑钠肽前体(NT-proBNP)对慢性阻塞性肺疾病(COPD)并肺动脉高压(PH)的诊断价值.方法 选择自2013年1月至2016年1月我院呼吸内科住院并确诊为COPD的500名患者,根据有无合并PH分为PH组(n=236)和非PH组(n=264),并对COPD并PH的相关危险因素进行多因素Logistic回归分析,利用ROC曲线分析相关指标的诊断价值.结果 ①单因素分析示,PH组和非PH组两组间DD(t=9.912,P<0.05)、NT-proBNP(t=5.592,P<0.05)、LDH(t=7.592,P<0.05)、HCO3-(t=6.471,P<0.05)、PO2(t=5.461,P<0.05)、PCO2(t=6.618,P<0.05)、年龄>65岁(χ2=10.307,P<0.05)、慢性心功能不全(χ2=8.307,P<0.05)差异有统计学意义;②多因素Logistic回归分析示,DD、NT-proBNP、HCO3-、慢性心功能不全是COPD并PH的独立危险因素(P<0.05);③ROC曲线示,DD曲线下面积为0.830,最佳阈值为2.18mg/L,灵敏度为0.816,特异性为0.712;NT-proBNP曲线下面积为0.794,最佳阈值为3225ng/L,灵敏度为0.820,特异性为0.782.结论 联合DD及NT-proBNP水平对COPD并PH具有较高的诊断价值.     

Gax在肺动脉高压大鼠肺动脉中的表达变化

目的:使用低氧及野百合碱(monocrotaline,MCT)诱导的两种肺动脉高压(pulmonary arterialhypertension,PAH)大鼠模型,观察生长终止特异性同源盒(growth arrest-specific homeobox,Gax)在肺动脉的表达变化。方法:Sprague Dawley大鼠随机分为四组:低氧模型组(n=16)、低氧对照组(n=16)、MCT模型组(n=16)及MCT对照组(n=16)。采用插管法测定大鼠的右心室压力及肺动脉压力。右心室质量除以左心室和室间隔质量,计算右心肥厚指数。采用定量RT-PCR法测定肺动脉主干及肺组织Gax mRNA表达;采用Western免疫印迹法测定肺动脉主干Gax蛋白表达;免疫组织化学染色观测Gax在肺内的分布及表达变化。结果:低氧模型组及MCT模型组大鼠的右心压力、肺动脉压力及右心肥厚指数均显著高于相应对照组(P<0.01),两种模型大鼠的肺动脉血管均出现明显重构。与对照组比较,Gax mRNA在两种模型组大鼠的肺组织表达降低(P<0.05),而在肺动脉主干表达升高(P<0.05)。Gax蛋白在肺内主要表达在微小动脉。与对照组比较,两种模型组大鼠的肺动脉主干和肺微小动脉Gax蛋白表达均升高(P<0.05),而肺组织Gax蛋白表达下降(P<0.05)。结论:Gax主要表达在肺微小动脉,在PAH发生时表达上调。     

Influence of hypobaric hypoxia in infancy on the subsequent development of vasoconstrictive pulmonary vascular disease in the Wistar albino rat

A group of Wistar albino rats was injected subcutaneously with monocrotaline to induce vasoconstrictive hypertensive pulmonary vascular disease characterized by medial hypertrophy of small pulmonary arteries, the appearance of muscular pulmonary arterial vessels of arteriolar dimensions (less than 20 microns) in diameter), and exudative changes in the lung parenchyma. The vascular abnormalities were quantified by measuring the percentage medial thickness of small pulmonary arteries, the number of muscular pulmonary arterial vessels below 20 microns in diameter per cm2 of lung section and by determining the smallest arterial vessels in each case showing muscularity. A second group of rats was born in a decompression chamber and kept in hypobaric hypoxia for a month of the neonatal period, developing hypoxic hypertensive pulmonary vascular disease as a consequence. The animals in this group were allowed to recover in room air for a period of 3 months and were then injected with the same dose of monocrotaline as that given to the first group. The rats previously exposed to hypoxia exhibited an exaggerated response to the alkaloid, showing in particular many more small muscular pulmonary arterial vessels which were of a smaller diameter than those found in the eupoxic rats treated with the alkaloid. The experiment demonstrates the perinatal hypoxia exaggerates the effects of agents inducing vasoconstrictive pulmonary hypertension with a shift of the segment of the pulmonary arterial tree involved to the periphery as in hypoxia. Reports of a similar phenomenon are noted as occurring in babies born at high altitude, spending their infancy there and subsequently developing primary pulmonary hypertension later in life.     

Large animal model of chronic pulmonary hypertension

A large animal model is needed to study artificial lung attachment in a setting simulating chronic lung disease with significant pulmonary hypertension (PH). This study sought to create a sheep model that develops significant PH within 60 days with a low rate of mortality. Sephadex beads were injected in the pulmonary circulation of sheep every other day for 60 days at doses of 0.5, 0.75, and 1 g (n = 10, 10, 7). Mean pulmonary artery pressure, pulmonary capillary wedge pressure, and cardiac output were obtained every 2 weeks. In the 0.5, 0.75, and 1-g groups, 90, 70, and 14.3% of sheep completed the study, respectively, with the remainder experiencing heart failure. By the 60th day, pulmonary vascular resistance had increased (p < 0.01) from 0.89 +/- 0.3 to 3.2 +/- 0.9 mm Hg/(L/min) and from 0.9 +/- 0.3 to 4.3 +/- 3.2 mm Hg/(L/min) in the 0.5 and 0.75-g groups, respectively. Significant right ventricular hypertrophy was observed in the 0.75-g group but not in the 0.5-g group. Data from the 1-g group were insufficient for analysis due to high mortality. Thus, the 0.5 and 0.75-g groups generate significant PH, but the 0.75-g group is a better model of chronic PH in lung disease due to the development of right ventricular hypertrophy.     

Screening for precapillary pulmonary hypertension in chronic myeloproliferative disorders: the role of N-terminal pro-B-type natriuretic peptide and vascular endothelial growth factor – a pilot study

IntroductionPrecapillary pulmonary hypertension (PH) implies a worse prognosis in myeloproliferative neoplasms (MPN). N-terminal pro-B-type natriuretic peptide (NT-proBNP) is elevated in cardiopulmonary involvement. In MPN patients with precapillary PH, elevated vascular endothelial growth factor (VEGF) values, but in left heart (LH) disease patients, decreased values were reported. Our aim was to determine whether a combination of NT-proBNP and VEGF is suitable for the detection of the precapillary forms of PH in MPN patients.Material and methodsEighty-one MPN patients were investigated. Pulmonary hypertension was defined as Doppler-derived systolic pulmonary artery pressure (sPAP) ≥ 40 mm Hg. Patient groups with cardiopulmonary involvement (precapillary PH, PH due to LH disease, left ventricular ejection fraction < 50%, atrial fibrillation) or LH disease (PH due to LH disease, left ventricular ejection fraction < 50%, atrial fibrillation) were identified.ResultsIn 9 patients PH was associated with LH disease. In 2 patients precapillary PH was found with extremely high NT-proBNP values. NT-proBNP significantly correlated with sPAP (r = 0.550; p < 0.001). NT-proBNP ≥ 466 pg/ml was the best predictor of cardiopulmonary involvement (AUC: 0.962, sensitivity: 86.7%, specificity: 93.9%). No correlation was found between VEGF levels and sPAP values. VEGF ≤ 431 pg/ml was the best predictor of LH disease (AUC: 0.609, sensitivity: 76.9%, specificity: 62.7%).ConclusionsNT-proBNP levels reflect cardiopulmonary involvement with high accuracy, but the combination of NT-proBNP and VEGF is not suitable for the detection of precapillary PH as the diagnostic power of VEGF is limited. Highly elevated NT-proBNP levels may suggest precapillary PH but further investigation is necessary for the exclusion of LH disease or atrial fibrillation.     

Early increase in pulmonary vascular reactivity with overexpression of endothelin-1 and vascular endothelial growth factor in canine experimental heart failure

Heart failure is a cause of pulmonary vasoconstriction and remodelling, leading to pulmonary hypertension (PH) and decreased survival. The pathobiology of PH in heart failure remains incompletely understood. We investigated pulmonary vascular function and signalling molecules in early stage PH secondary to experimental heart failure. Eight beagle dogs with overpacing-induced heart failure underwent haemodynamic assessment and postmortem pulmonary arterial reactivity, morphometry and quantification of genes encoding for factors involved in vascular reactivity and remodelling: endothelin-1 (ET-1), ETA and ETB receptors, vascular endothelial growth factor (VEGF), VEGF receptors 1 and 2 (VEGFR1 and VEGFR2), endothelial nitric oxide synthase, angiopoietin-1, bone morphogenetic protein receptors (BMPR1A and BMPR2), serotonin transporter (5-HTT) and the 5-HT(2B) receptor. Overpacing was associated with a decrease in cardiac output and an increase in pulmonary vascular pressures. However, there were no changes in pulmonary vascular resistance or in arteriolar medial thickness. There were increased expressions of genes encoding for ET-1, ETB, VEGF and VEGFR2, while expression of the other genes analysed remained unchanged. In vitro, pulmonary arteries showed decreased relaxation and increased reactivity, while systemic mammary arteries were unaffected. Early PH in heart failure is characterized by altered vasoreactivity and increased ET-1/ETB and VEGF/VEGFR2 signalling.     

The principal pathways involved in the in vivo modulation of hypoxic pulmonary vasoconstriction,pulmonary arterial remodelling and pulmonary hypertension

Hypoxic pulmonary vasoconstriction (HPV) serves to optimize ventilation–perfusion matching in focal hypoxia and thereby enhances pulmonary gas exchange. During global hypoxia, however, HPV induces general pulmonary vasoconstriction, which may lead to pulmonary hypertension (PH), impaired exercise capacity, right‐heart failure and pulmonary oedema at high altitude. In chronic hypoxia, generalized HPV together with hypoxic pulmonary arterial remodelling, contribute to the development of PH. The present article reviews the principal pathways in the in vivo modulation of HPV, hypoxic pulmonary arterial remodelling and PH with primary focus on the endothelin‐1, nitric oxide, cyclooxygenase and adenine nucleotide pathways. In summary, endothelin‐1 and thromboxane A₂ may enhance, whereas nitric oxide and prostacyclin may moderate, HPV as well as hypoxic pulmonary arterial remodelling and PH. The production of prostacyclin seems to be coupled primarily to cyclooxygenase‐1 in acute hypoxia, but to cyclooxygenase‐2 in chronic hypoxia. The potential role of adenine nucleotides in modulating HPV is unclear, but warrants further study. Additional modulators of the pulmonary vascular responses to hypoxia may include angiotensin II, histamine, serotonin/5‐hydroxytryptamine, leukotrienes and epoxyeicosatrienoic acids. Drugs targeting these pathways may reduce acute and/or chronic hypoxic PH. Endothelin receptor antagonists and phosphodiesterase‐5 inhibitors may additionally improve exercise capacity in hypoxia. Importantly, the modulation of the pulmonary vascular responses to hypoxia varies between species and individuals, with hypoxic duration and age. The review also define how drugs targeting the endothelin‐1, nitric oxide, cyclooxygenase and adenine nucleotide pathways may improve pulmonary haemodynamics, but also impair pulmonary gas exchange by interference with HPV in chronic lung diseases.     

4种肺动脉高压动物模型肺血管重构模式的差异研究

目的：探讨4种肺动脉高压（PH）动物模型肺血管重构模式的差异。方法:雄性SD大鼠（350-400g），分别通过腹主动脉-腔静脉分流（A-VF, n=10）、左肺切除（PE, n=10）、野百合碱注射（MCT, n=10）、左肺切除+MCT（PE+MCT,n=12）4种方法建立PH模型。检测平均肺动脉压力(mPAP）、RV/(LV+S)重量比值、肺小动脉中膜厚度百分比（WT%）、无肌性动脉肌化程度和新生内膜(neointima)形成、新生内膜增殖度和血管阻塞计分（VOS）。结果:在PE+MCT组（肺切除术后5周，MCT注射后4周）右肺腺泡内血管出现了新生内膜病变，其它组均没有新生内膜病变形成。PE+MCT组的动物出现了严重的右心室肥大，动脉中膜明显增厚，平均肺动脉压（mPAP）和无肌性血管肌化程度显著增加；A-VF、PE和MCT组仅形成轻-中度的右心室肥大、mPAP升高和小动脉肌化。结论:左肺切除联合应用MCT能成功诱导大鼠PH新生内膜模型，该模型能更好地模拟人类严重PH的病理改变，是研究梗阻性PH更为适用的动物模型。     

Bosentan improved persistent pulmonary hypertension in a case after implantation of a left ventricular assist device

No medical treatment has been established to ameliorate pulmonary hypertension (PH) due to left heart disease. Heart transplantation (HTx) is thus far the definitive therapy for stage D heart failure, but concomitant PH is one of the major risk factors for death after HTx. Recently, implantation of a left ventricular assist device (LVAD) has been reported to improve PH and has become a major bridge tool for HTx. We experienced a rare case with persistent PH even after the implantation of a continuous-flow LVAD. The administration of an endothelin receptor antagonist, bosentan, significantly decreased pulmonary vascular resistance. Combination therapy with LVAD implantation and anti-PH medication may be useful for patients with stage D heart failure complicated with severe PH.     

Pathology of pulmonary hypertension: A human and experimental study

To clarify the histopathological characteristics of pulmonary hypertension (PH) in Japan, and to clarify the role of serotonin and endclthelin in monocrotaline induced PH, human histopathologiical studies and experimental studies were carried out. An epidemiological study based on the Annual of the Pathological Autopsy Cases in Japan, and a morphological study on autopsy cases of congenital heart disease and idiopathic PH were performed. Plasma levels of serotonin and endothelin, vascular responsiveness to serotonin, and the effects of a selective serotonin antagonist, DV-7028, were investigated after monocrotaline injection. Plexogenic pulmonary arteriopathy was prevalent, and recurrent pulmonary thromboembolism and pulmonary veno-occlusive disease extremely rare among primary pulmonary hypertension in Japan. In secondary PH, systemic lupus erythematosus and mixed connective tissue disease were frequent and showedl particularly severe intimal and medial thickening. After an injection of monocrotaline, plasma serotonin and endotheliii levels were raised, and pulmonary arteries showed hyperreactivity to serotonin. DV-7028 (5-HT₂ receptor antagonist) attenuated the rise in pulmonary artery pressure and the various effects of monocrotaline. There may be some genetic difference between PH in Japan and other countries. Roles far serotonin and endothelin in the initiation and progression of monocrotaline induced PH are suggested.     

Pulmonary hypertension in a patient with primary Sjogren's syndrome, Hashimoto's disease, and primary biliary cirrhosis]

A 53-year-old woman was admitted to our hospital in May 1999, because of progressive dyspnea and liver dysfunction. She had been receiving the replacement therapy of thyroid hormone for thirteen years and suffering from Raynaud's phenomenon for 9 years. She experienced exertional dyspnea and sicca symptom for 3 years, and had an episode of syncope 4 months before admission. An echocardiogram showed dilation of the right ventricle, tricuspid regurgitation and the estimated mean pressure of the pulmonary artery was higher than 120 mmHg. She was diagnosed as having severe pulmonary hypertension (PH) complicated with primary Sjogren's syndrome and primary biliary cirrhosis without portal hypertension She was treated with anticoagulant (warfarin) and oral prostagrandin I2 (prostacyclin). However, right heart failure and jaundice gradually progressed and she suddenly died in December 1999. At autopsy, the heart was enlarged with right ventricular hypertrophy. Small arteries and arterioles in the lung showed concentric intimal proliferation and severe plexogenic vascular disease. Deposition of immunoglobulin was not observed in the pulmonary arteries. Since the prognosis of PH is poor, it is important to analyze the etiology of the disease for the development of the treatment.     

Decreased numbers of T-lymphocytes and predominance of recently recruited macrophages in the walls of peripheral pulmonary arteries from 26 patients with pulmonary hypertension secondary to congenital cardiac shunts.

INTRODUCTION: In the primary form of pulmonary hypertension (PH), the involvement of inflammation in the physiopathology of the vascular lesions is well established. Its role in secondary PH is yet to be investigated. We quantified the inflammatory cells on the walls of peripheral pulmonary arteries from patients with congenital heart shunts. METHODS: Twenty-six lung biopsies from patients with increased pulmonary flow and 10 lung fragments from control participants were examined. B-lymphocytes (CD20), T-lymphocytes (CD3), recently recruited macrophages (MAC387) and granulocytes (CD15) were quantified by area of the adventitia in arteries >50 microm. An index of inflammatory cells infiltrating the medial and intimal layers was also determined. RESULTS: There was no difference in the sum of densities of adventitial inflammatory cells between the groups. A prevalence of MAC387-labeled cells was detected in the PH group and of CD3-labeled cells in the controls. There was a lower density of T-lymphocytes in the PH group (P<.004). Patients with intimal proliferative lesions showed prevalence of MAC387-labeled cells (P=.004). PH participants showed a higher index of MAC387-labeled cells infiltrating the arterial medial and intimal layers (P<.001). CONCLUSION: The predominance of recently recruited macrophages in the PH group is compatible with ongoing inflammatory reaction in the arterial walls. This could be related to the pathogenesis of the vascular lesions, as a consequence of cytokines produced by the inflammatory cells. The smaller number of adventitial T-lymphocytes in patients with congenital shunts can reflect an impairment of their immune response.