Cases Of Primary Pulmonary Hypertension Research Articles

Efficacy of long-term medication of Beraprost and Olprinone on a case of primary pulmonary hypertension

Efficacy of long-term medication of Beraprost and Olprinone on a case of primary pulmonary hypertension

Pathobiology of pulmonary arterial hypertension.

Recent years have witnessed important advances in the understanding of the pathophysiology of primary pulmonary hypertension (PPH). Both genetic and mechanistic studies have succeeded in identifying new molecular pathways relevant to the process of pulmonary vascular remodelling, which underlies PPH. Mutations in the type II bone morphogenetic protein (BMP) receptor (BMPR)-II are now considered to be the genetic basis for familial PPH and approximately 30% of cases of sporadic PPH. The identification of the relevance of the BMP pathway to the aetiology of PPH now raises many questions about the link between the BMPR-II mutant genotype and the PPH phenotype. As PPH does not develop in all subjects with BMPR-II mutations, environmental or associated genetic factors may play a crucial role. Among these, the finding of an association between PPH and the L-allelic variant of the serotonin transporter (5-HTT) gene indicates that 5-HTT, which controls smooth muscle hyperplasia, probably contributes to susceptibility to PPH or is an important modifier of the PPH phenotype. Recognition of these molecular pathways should provide insight into the pathogenesis not only of primary pulmonary hypertension, but also of secondary forms of pulmonary hypertension. This should soon lead to the development of new and more selective therapeutic approaches to pulmonary hypertension.

SILDENAFIL FOR PRIMARY PULMONARY HYPERTENSION: SHORT AND LONG‐TERM SYMPTOMATIC BENEFIT

SUMMARYWe report two cases of primary pulmonary hypertension (PPH) who benefited from oral sildenafil therapy. Both demonstrated a substantial improvement in exercise ability, which has been sustained at 3 and 6 months. Sildenafil acting as a phosphodiesterase 5 inhibitor may have an important role to play in the management of PPH and we believe further study to be of importance.

Primary Pulmonary Hypertension Is Associated With Reduced Pulmonary Vascular Expression of Type II Bone Morphogenetic Protein Receptor

Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-beta (TGF-beta) superfamily, underlie many familial and sporadic cases of primary pulmonary hypertension (PPH). Because the sites of expression of BMPR-II in the normal and hypertensive lung are unknown, we studied the cellular localization of BMPR-II and the related type I and II receptors for TGF-beta by immunohistochemistry in lung sections from patients undergoing heart-lung transplantation for PPH (n=11, including 3 familial cases) or secondary pulmonary hypertension (n=6) and from unused donor lungs (n=4). In situ hybridization was performed for BMPR-II mRNA. Patients were screened for the presence of mutations in BMPR2. In normal lungs, BMPR-II expression was prominent on vascular endothelium, with minimal expression in airway and arterial smooth muscle. In pulmonary hypertension cases, the intensity of BMPR-II immunostaining varied between lesions but involved endothelial and myofibroblast components. Image analysis confirmed that expression of BMPR-II was markedly reduced in the peripheral lung of PPH patients, especially in those harboring heterozygous BMPR2 mutations. A less marked reduction was also observed in patients with secondary pulmonary hypertension. In contrast, there was no difference in level of staining for TGF-betaRII or the endothelial marker CD31. The cellular localization of BMPR-II is consistent with a role in the formation of pulmonary vascular lesions in PPH, and reduced BMPR-II expression may contribute to the process of vascular obliteration in severe pulmonary hypertension.

Hypertension artérielle pulmonaire primitive au cours de l’infection par le virus de l’immunodéficience humaine. Étude de neuf observations et revue de la littérature

Purpose. – In medical literature, primary pulmonary hypertension occurs in 0.5% of human immunodeficiency virus (HIV)-infected patients, irrespective of the stage of the HIV disease, and is more frequent in drug users. Plexogenic arteriopathy is the most frequent histological lesion. Methods. – We retrospectively report on nine cases of primary pulmonary hypertension during HIV infection. Results. – The subjects were four women and five men, mean age 38 years old. Four of them had been sexually contaminated and five had contracted the disease through intravenous drug use. At the time primary pulmonary hypertension was diagnosed, mean CD4 cell count was 234 ± 217/mm 3 and the viral load was low or undetectable. Primary pulmonary hypertension has been diagnosed an average of 7 months after the first cardiovascular clinical signs had started. Despite anti-coagulant (7/9 cases), vasodilatator (4/9 cases) and/or diuretic (7/9 cases) therapy, the progression of the disease quickly turned out to be negative (seven deaths). Conclusion. – Diagnosis of primary pulmonary hypertension should be considered when unexplained dyspnea occurs in an HIV-positive patient. At initial evaluation, alterations of hemodynamic parameters are usually less severe than during idiopathic primary pulmonary hypertension, but their progression is quicker and more severe, independent of the patient’s immune status. Current data do not allow the determination of whether antiretroviral therapy is active in primary pulmonary hypertension evolution. Therapeutic evaluation with prostacyclin is currently being carried out. While the life expectancy of HIV-infected patients extends, primary pulmonary hypertension occurrence could increase and call for early diagnosis, thus allowing for specific care.

Use of inhaled nitric oxide for emergency Cesarean section in a woman with unexpected primary pulmonary hypertension

Use of inhaled nitric oxide (iNO) could be of importance in emergency cases of primary pulmonary hypertension (PPH) in pregnant patients during labour and delivery. iNO acts as a selective pulmonary bed vasodilator avoiding systemic hemodynamic effects due to its ease of administration. Pulmonary bed vasodilation improves right ventricular function directly and left ventricular function indirectly. We report the case of a pregnant patient with unexpected PPH in whom an emergency Cesarean section (CS) had to be performed. PPH was diagnosed on admission as she arrived in active labour at 34 weeks gestational age. An emergency CS was performed under epidural anesthesia for breech presentation . All along labour, delivery and the first 24 hr, iNO was administered via a noninvasive ventilation device. CS was uneventful. A severe pulmonary hypertensive crisis was observed 12 hr after delivery and resolved with an increase of iNO concentration and administration of isoprenalin. The patient and baby returned home on day ten. The ease of administration of iNO allowed the optimal control of pulmonary arterial hypertension. No interaction with epidural anesthesia was observed. Use of iNO can improve the management of urgent CS in women with unexpected PPH.

Genetic and molecular mechanisms of pulmonary hypertension

Pulmonary arterial hypertension frequently occurs secondary to common cardiopulmonary diseases, and more rarely as a primary condition. Observations in animals and man have suggested genetic influences underlying the susceptibility to pulmonary hypertension. A gene underlying many cases of familial and apparently sporadic cases of primary pulmonary hypertension has now been identified, and a genetic approach to hypoxia-induced pulmonary hypertension promises to reveal new insights into the unique nature of the pulmonary circulation. The exploration of potential candidate genes influencing susceptibility and the identification of new genes promise new therapeutic approaches to the treatment of pulmonary hypertension.

BMPR2 Haploinsufficiency as the Inherited Molecular Mechanism for Primary Pulmonary Hypertension

Primary pulmonary hypertension (PPH) is a potentially lethal disorder, because the elevation of the pulmonary arterial pressure may result in right-heart failure. Histologically, the disorder is characterized by proliferation of pulmonary-artery smooth muscle and endothelial cells, by intimal hyperplasia, and by in situ thrombus formation. Heterozygous mutations within the bone morphogenetic protein type II receptor (BMPR-II) gene (BMPR2), of the transforming growth factor beta (TGF-beta) cell-signaling superfamily, have been identified in familial and sporadic cases of PPH. We report the molecular spectrum of BMPR2 mutations in 47 additional families with PPH and in three patients with sporadic PPH. Among the cohort of patients, we have identified 22 novel mutations, including 4 partial deletions, distributed throughout the BMPR2 gene. The majority (58%) of mutations are predicted to lead to a premature termination codon. We have also investigated the functional impact and genotype-phenotype relationships, to elucidate the mechanisms contributing to pathogenesis of this important vascular disease. In vitro expression analysis demonstrated loss of BMPR-II function for a number of the identified mutations. These data support the suggestion that haploinsufficiency represents the common molecular mechanism in PPH. Marked variability of the age at onset of disease was observed both within and between families. Taken together, these studies illustrate the considerable heterogeneity of BMPR2 mutations that cause PPH, and they strongly suggest that additional factors, genetic and/or environmental, may be required for the development of the clinical phenotype.

Distribution of obstructive intimal lesions and their cellular phenotypes in chronic pulmonary hypertension. A morphometric and immunohistochemical study.

We investigated the distribution of pulmonary arteriopathy in chronic pulmonary hypertension (PH) in a quantitative histopathologic study, using computer-assisted image analysis. We also examined the histologic manifestations and cellular phenotypes of various obstructive intimal lesions in PH with an immunohistochemical method. A total of 53 lungs removed at autopsy or explantation were obtained for the study from 51 documented cases of moderate to severe PH (15 cases of primary pulmonary hypertension [PPH], eight cases of Eisenmenger's syndrome [EISEN], 22 cases of chronic major-vessel thromboembolic disease [CTED], and three cases of PH associated with other known causes), and two unused donor lungs served as normal controls. Intimal thickening in PPH was most prominent in small pulmonary arteries and arterioles less than 200 micrometer in diameter. Plexiform lesions in PPH were associated with significantly smaller arteries than in EISEN. Arteries larger than 400 micrometer showed a significant intimal thickening only in CTED. Obstructive intimal lesions in PH comprised a morphologic spectrum with frequent intermediate forms between plexiform and thrombotic lesions. Most cells within various intimal lesions showed an immunoprofile of myofibroblasts that were positive for vimentin and alpha-smooth muscle actin, but negative for desmin and endothelial markers including Factor VIII, clonal designator (CD)31, and CD34. Endothelial markers were positive only in the single layer of cells lining slitlike lumens, when the latter were present. In conclusion, major types of PH had characteristic distribution patterns of obstructive intimal lesions, showing mainly a myofibroblastic phenotype and variable endothelial/vascular differentiation.

A Case of Primary Pulmonary Hypertension with the Congenital Absence of Inferior Vena Cava

A Case of Primary Pulmonary Hypertension with the Congenital Absence of Inferior Vena Cava

Increased plasma levels of adrenomedullin in patients with pulmonary hypertension

Adrenomedullin, a potent hypotensive peptide, reduces blood pressure and pulmonary vascular resistance, and increases pulmonary blood flow. The mRNA for adrenomedullin and its receptor is highly expressed in the lung, suggesting a regulatory role for adrenomedullin in the pulmonary circulation. To investigate the clinical significance of adrenomedullin in patients with pulmonary hypertension, we studied the relationship between plasma levels of adrenomedullin and pulmonary haemodynamics. Venous, arterial and pulmonary arterial blood samples were obtained during cardiac catheterization and plasma levels of adrenomedullin were measured by specific radioimmunoassay in 33 consecutive patients with severe pulmonary hypertension (12 cases of primary pulmonary hypertension, 21 with chronic thromboembolic pulmonary hypertension; age 49+/-16 years, mean pulmonary arterial pressure 50+/-15mmHg). In addition, plasma levels of adrenomedullin were measured before and after acute nitric oxide inhalation. The changes in plasma adrenomedullin during the follow-up period of 10.3+/-4.3 months were also evaluated (n=5). Sixty-two healthy subjects served as the control group. Adrenomedullin was measured in an antecubital vein in the controls. Plasma levels of adrenomedullin were significantly higher in the patients with pulmonary hypertension than in the control subjects (10.1+/-8.7 versus 4.9+/-1.1pmol/l, P<0.01). Plasma levels of adrenomedullin, expressed as their natural logarithm, were significantly correlated with mean right atrial pressure (r=0.71, P<0.01), stroke volume (r=-0.63, P<0.01), total pulmonary resistance (r=0.60, P<0.01), mean pulmonary arterial pressure (r=0.37, P<0.05), and the natural logarithm of plasma atrial natriuretic peptide (r=0. 63, P<0.01). Plasma levels of adrenomedullin did not change significantly after nitric oxide inhalation, but significantly increased in association with the elevation of the total pulmonary resistance during the long-term follow-up period. These results suggest that plasma levels of adrenomedullin increase in proportion to the extent of pulmonary hypertension.

An Autopsied Case of Primary Pulmonary Hypertension

An Autopsied Case of Primary Pulmonary Hypertension

Primary Pulmonary Hypertension in a Patient With CD8/T-cell Large Granulocyte Leukemia*: Amelioration by Cladribine Therapy

We report a case of primary pulmonary hypertension in an adult man with CD8/T-cell large granulocyte leukemia. Successful treatment of his leukemia with cladribine resulted in dramatic and sustained improvement of his pulmonary hypertension.

A Case of Primary Pulmonary Hypertension Associated with Pregnancy

Primary pulmonary hypertension is a rare, incurable, and progressive clinical entity. When associated with pregnancy, the prognosis of primary pulmonary hypertension is worsened with maternal mortality rates of at least 50%. The patient was a 29-year-old mother in her 2nd pregnancy, with previous uncomplicated gestation, 5 years ago. She had been well until the 28th week of present gestation when she was admitted because of increasing dyspnea on exertion. She was a housewife with no remarkable family and past histories. We have experienced a patient with primary pulmonary hypertension in pregnancy. She was treated with an oral calcium-channel blocker and low-molecular-weight heparin and was delivered vaginally with good maternal and fetal outcome. So we report a case of primary pulmonary hypertension associated with pregnancy and review literature.

THE DEXFENFLURAMINE CONTROVERSY: NO EASY ANSWERS.

Earlier this year, primary care physicians in the United States found themselves besieged by inquiries from patients about dexfenfluramine, the first FDA-approved drug for the long-term management of obesity. But this first year of the drug's availability in the U.S. was not without controversy. In a recent case-control study that included 95 cases of primary pulmonary hypertension (PPH) from four European countries, the risk for PPH was significantly increased among users of appetite suppressants -- mostly dexfenfluramine and fenfluramine -- during the previous year (odds ratio, 10.1). The odds ratio climbed to 23.1 when these drugs were used for more than three months (N Engl J Med 1996; 335:609). Interestingly, an association between PPH and appetite suppressant drugs was first suspected several decades ago. Moreover, although the recent data were formally published after dexfenfluramine hit the U.S. market, they were well known to the manufacturer and the FDA prior to the drug's approval in …

A case of primary pulmonary hypertension with patent foramen ovale

A case of primary pulmonary hypertension with patent foramen ovale

Coancestry in Apparently Sporadic Primary Pulmonary Hypertension

To examine sporadic cases of primary pulmonary hypertension of coancestry. An epidemiologic study of families of patients with primary pulmonary hypertension. A university-affiliated referral population. Family members of 13 patients with primary pulmonary hypertension. Family pedigrees involving grandparents, parents, siblings, and children were supplemented by genealogic records. Coefficients of kinship (Ck) were calculated for the patients with primary pulmonary hypertension who demonstrated coancestry and compared with 500 sets of controls drawn at random from genealogic records. Two patients with sporadic primary pulmonary hypertension demonstrated coancestry. The great-great grandfather and great-great grandmother of one patient were the great-grandfather and great-grandmother of the other patient. No other cases of primary pulmonary hypertension were identified in these two families. The CK of the affected individuals (CK = 10.02 x 10(-5)) suggests strongly that the observed relationship did not occur by chance alone. Among 500 random sets of matched controls, only two sets yielded CK of 10.02 x 10(-5) or greater (p = 0.004). Coancestry could not be identified for the other five families of patients with sporadic primary pulmonary hypertension for whom genealogic records were available. The finding of coancestry in patients with sporadic primary pulmonary hypertension suggests that a genetic basis exists for some patients with apparently sporadic primary pulmonary hypertension. Familial primary pulmonary hypertension may be more common than previously recognized.

Transthoracic Visualization of Pulmonary Thrombus that Mimicked Left Atrial Thrombus

A forty-five-year-old woman with an unusual case of primary pulmonary hypertension is presented. She showed a progressive dilatation of the pulmonary arteries and pulmonary thrombus over twenty-one years. Transthoracic echocardiography showed the presence of pulmonary arterial thrombus that mimicked left atrial thrombus. However, when the transducer was rotated clockwise to obtain the short-axis view, a thrombus was observed in the right pulmonary artery with spontaneous echo contrast. Although the visualization of pulmonary arterial thrombus by echocardiography has been quite limited, it would be worthwhile since patients with primary pulmonary hypertension may have enlarged pulmonary arteries, as observed in the present case.

Nitric oxide and prostacyclin treatment of an infant with primary pulmonary hypertension

Primary pulmonary hypertension is a progressive disease with high mortality. The etiology of primary pulmonary hypertension in pediatric patients is unknown; some cases are thought to be familial, 1 but most are sporadic. Mortality is high if the disease is present in infants < 2 years of age 2,3 Younger children with primary pulmonary hypertension have a larger decrease in pulmonary vascular resistance (PVR) with vasodilators than older patients, suggesting vasoconstriction is more important than structural changes in the development of pediatric primary pulmonary hypertension. 4 Therefore, vasodilator therapy may be more successful in younger patients because of increased pulmonary vasoreactivity. Prostacyclin is often effective as an acute vasodilator in pediatric primary pulmonary hypertension. 4 Therapy with prostacyclin and other vasodilators is frequently limited because of systemic hypotension. Brief inhalation of nitric oxide selectively dilates the pulmonary vascular bed of adults with primary pulmonary hypertension 5 and children with primary pulmonary hypertension 6 and congenital heart disease, 7,8 but has not been used as prolonged therapy without assisted ventilation. We describe a case of primary pulmonary hypertension in which inhalation of nitric oxide successfully aided the transition to chronic prostacyclin infusion (therapy with oxygen and calcium antagonists was not effective and prostacyclin was not immediately available).

Maternal primary pulmonary hypertension associated with pregnancy

Primary pulmonary hypertension (PPH) is a very uncommon clinical entity, with a high mortality when associated with pregnancy. Three cases of PPH associated with gestation and different outcomes are reported, and a literature review concerning its management and outcome is made. We emphasize the importance of a strict control of such patients, with the supportive cardiovascular measures and surveillance of fetal well-being. The peculiar handling of the course of delivery and the type of aneasthesia is discussed.