Primary pulmonary hypertension is a rare, often fatal disease that tends to occur with particular frequency in women during their third or fourth decade. 1 , 2 The factors leading to its development remain enigmatic. The occurrence of familial primary pulmonary hypertension suggests a genetic susceptibility. 3 Reports have also suggested that portal hypertension 4 , 5 and recent pregnancy 6 may have causative roles. Exogenous factors have been suspected as well, including cocaine use, 7 infection with the human immunodeficiency virus (HIV), 8 oral-contraceptive use, 9 , 10 and the use of anorexic agents. 11 – 13 In the 1960s, there was an epidemic of primary pulmonary hypertension in Switzerland, Germany, . . .
Objective: To compare the effects of aerosolization of prostacyclin and its stable analog iloprost with those of nasal oxygen, inhaled nitric oxide, and intravenous prostacyclin on hemodynamics and gas exchange in patients with severe pulmonary hypertension. Design: Open uncontrolled trial. Setting: Justus-Liebig-University, Giessen, Germany. Patients: 4 patients with primary pulmonary hypertension and 2 patients with severe pulmonary hypertension associated with calcinosis, the Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia (the CREST syndrome). All were classified as New York Heart Association class III or class IV. Intervention: Short-term applications of O-2, inhaled nitric oxide, intravenous prostacyclin, aerosolized prostacyclin, and aerosolized iloprost during repeated catheter investigation of the right side of the heart within a 1-month period. One patient had long-term therapy with inhaled iloprost. Results: Aerosolized prostacyclin decreased pulmonary artery pressure in 6 patients from (mean +/- SE) 62.3 +/- 4.1 mm Hg to 50.8 +/- 5.5 mm Hg and reduced pulmonary vascular resistance from 1721 +/- 253 dyne/s . cm(-5) to 1019 +/- 203 dyne/s . cm(-5), and it increased cardiac output from 2.75 +/- 0.21 L/min to 4.11 +/- 0.54 L/min, mixed venous oxygen saturation from 51.1% +/- 3.4% to 66.3% +/- 4.1%, and arterial oxygen saturation from 90.6% +/- 2.7% to 93.8% +/- 23% (P < 0.05 for all changes). Mean systemic arterial pressure was only slightly affected. The responses lasted for 10 to 30 minutes after inhalation was terminated. Aerosolized iloprost had an identical efficacy profile but was associated with a longer duration of the pulmonary vasodilatory effect (60 min to 120 min). In comparison, intravenous prostacyclin reduced pulmonary vascular resistance with corresponding efficacy but produced a more pronounced decline in systemic artery pressure and no clinically significant decrease in pulmonary artery pressure. Nitric oxide and O-2 were less potent pulmonary vasodilators in these patients. In one patient, 1 year of therapy with aerosolized iloprost (100 mu g/d in six aerosol doses) resulted in sustained efficacy of the inhaled vasodilator regimen and clinical improvement. Conclusion: Aerosolization of prostacyclin or its stable analog iloprost causes selective pulmonary vasodilatation, increases cardiac output, and improves venous and arterial oxygenation in patients with severe pulmonary hypertension. Thus, it may offer a new strategy for treatment of this disease.
Primary pulmonary hypertension is a disease characterized by the progressive elevation of pulmonary-artery pressure and vascular resistance, ultimately producing right ventricular failure and death. 1 – 3 A variety of treatments have been used, including vasodilators, 4 – 7 anticoagulant agents, 6 , 8 and lung or heart–lung transplantation, 9 – 13 but none have resulted in improved survival in a prospective, randomized trial. Epoprostenol (formerly called prostacyclin or prostaglandin I 2 ) is a potent, short-acting vasodilator and inhibitor of platelet aggregation that is produced by vascular endothelium. Short-term infusions of epoprostenol decrease pulmonary vascular resistance in a dose-dependent manner in patients with primary pulmonary hypertension, and . . .
Reactive oxygen species play an important role in a variety of (patho)physiological vascular processes. Recent publications have produced evidence of a role for putative non-phagocyte NADP oxidase(s) in the vascular production of reactive oxygen species. In the present review, we discuss the detection of the different components of NADP oxidase(s) in the vascular system, together with the putative role of reactive oxygen species produced by vascular NADPH oxidase(s), in both in vitro and in vivo studies.,BackgroundThe list of Mendelian disorders of the epigenetic machinery has expanded rapidly during the last 5 years. A few missense variants in the chromatin remodeler CHD1 have been found in several large-scale sequencing efforts focused on uncovering the genetic aetiology of autism.ObjectivesTo explore whether variants in CHD1 are associated with a human phenotype.MethodsWe used GeneMatcher to identify other physicians caring for patients with variants in CHD1. We also explored the epigenetic consequences of one of these variants in cultured fibroblasts.ResultsHere we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features. Importantly, three of these variants occurred de novo. We also report on a subject with a de novo deletion covering a large fraction of the CHD1 gene without any obvious neurological phenotype. Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in CHD1.ConclusionsOur results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease.
To characterize the prevalence of undiagnosed pulmonary hypertension in patients with limited and diffuse scleroderma. Prospective cross-sectional study. University-based outpatient clinic. Thirty-four consecutive patients with limited (n=29) or diffuse (n=5) scleroderma but without the clinical diagnosis of pulmonary hypertension. All patients had 12-lead ECGs and two-dimensional and Doppler echocardiograms. The pulmonary artery systolic pressure (PA ) was calculated as the sum of the Doppler transtricuspid pressure gradient and the right atrial pressure as estimated by the caval respiratory index. Thirty-three patients (97%) had adequate spectral signals of tricuspid regurgitation. The velocity of tricuspid regurgitation ranged from 1.6 to 4.5 m/s. The calculated PA ranged from 15 to 95 (mean±SD=30±14 mm Hg). Twelve patients (35% of the total cohort) had pulmonary hypertension defined as PA of 30 mm Hg or greater. Undiagnosed elevation of PA is common in patients with scleroderma. Noninvasive assessment of PA can be performed accurately in most patients independent of clinical signs of pulmonary hypertension. If successful treatment strategies are identified, it may be possible to identify patients early in the development of pulmonary hypertension and intervene before significant end-organ damage occurs.
The transcription of genes could be defined as the intricate molecular manoeuvres occurring in the nuclei of cells, which allow the translation of genetic information held in the DNA into the proteins required for life. Gene transcription is the dominant control point in the production of any protein, and is initiated and regulated through the combined activities of a highly specialised set of nuclear proteins. This review examines the role of these protein “transcription factors” in the production of messenger RNA, the information intermediary produced in the nucleus, and transferred to the cytoplasm to serve as a template for protein synthesis. In combination with RNA polymerase, an extraordinary and complex enzyme required to synthesise new RNA molecules, a multitude of transcription factors combine their activities to orchestrate and control this elegant process.,Approximately 10% of melanoma cases report a relative affected with melanoma, and a positive family history is associated with an increased risk of developing melanoma. Although the majority of genetic alterations associated with melanoma development are somatic, the underlying presence of heritable melanoma risk genes is an important component of disease occurrence. Susceptibility for some families is due to mutation in one of the known high penetrance melanoma predisposition genes: CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP and TERT. However, despite such mutations being implicated in a combined total of approximately 50% of familial melanoma cases, the underlying genetic basis is unexplained for the remainder of high-density melanoma families. Aside from the possibility of extremely rare mutations in a few additional high penetrance genes yet to be discovered, this suggests a likely polygenic component to susceptibility, and a unique level of personal melanoma risk influenced by multiple low-risk alleles and genetic modifiers. In addition to conferring a risk of cutaneous melanoma, some ‘melanoma’ predisposition genes have been linked to other cancers, with cancer clustering observed in melanoma families at rates greater than expected by chance. The most extensively documented association is between CDKN2A germ line mutations and pancreatic cancer, and a cancer syndrome including cutaneous melanoma, uveal melanoma and mesothelioma has been proposed for BAP1 germ line mutations. Other medium to high penetrance melanoma predisposition genes have been associated with renal cell carcinoma (MITF, BAP1) and glioma (POT1). These associations between melanoma and other cancers hint at the possibility of common pathways for oncogenesis, and better knowledge of these pathways may improve understanding of the genetic basis underpinning familial melanoma. It is likely that ‘melanoma’ risk genes will impact on mutation screening and genetic counselling not only for melanoma but also a range of other cancers.,The main problems in identifying Treponema pallidum in tissues are optical definition contrast, and specificity. In general, fluorochrome staining provides optical definition and contrast superior to that obtained by ordinary tinctorial staining, and in theory improved resolution. Specificity is lacking however, as with other stains. In contrast, immunofluorescence should combine the optical advantages of fluorochrome staining with the immunological advantages of specificity. Since the validity of such staining depends in part upon the integrity of the antigenic components of the micro-organisms, it is customary to avoid such drastic procedures as are involved in routine fixation and paraffin embedding. The manipulation, however, of unfixed cryostat material, in contrast with that of paraffin sections suffers from two disadvantagesnamely, friability and infectivity. Published and unpublished work has shown antigenic stability in T. pallidum to a variety of procedures, both physical and chemical. Consideration of these facts led in this work to successful immunofluorescent staining after routine formalin fixation and paraffin embedding of tissues infected with T. pallidum or Treponema pertenue. Optical definition and contrast, were superior to that obtained with silver methods, but it was not possible to differentiate between these two organisms. Nevertheless immunofluorescence applied as described to paraffin sections should supply a convenient safe, and sensitive means of reappraising the histopathology of treponemal disease in patients, necropsy material, and experimental animals.
Background. We describe the hemodynamic response to initiation and withdrawal of inhaled nitric oxide (NO) in infants with pulmonary hypertension after surgical repair of total anomalous pulmonary venous connection. Methods. Between January 1, 1992, and January 1, 1995, 20 patients underwent repair of total anomalous pulmonary venous connection. Nine patients had postoperative pulmonary hypertension and received a 15-minute trial of inhaled NO at 80 parts per million. Five of these patients received prolonged treatment with NO at 20 parts per million or less. Results. Mean pulmonary artery pressure decreased from 35.6 ± 2.4 to 23.7 ± 2.0 mm Hg (mean ± standard error of the mean) (p = 0.008), and pulmonary vascular resistance decreased from 11.5 ± 2.0 to 6.4 ± 1.0 U·m (p = 0.03). After prolonged treatment with NO, pulmonary artery pressure increased transiently in all patients when NO was discontinued. Conclusions. After operative repair of total anomalous pulmonary venous connection, inhaled NO selectively vasodilated all patients with pulmonary hypertension. Withdrawal of NO after prolonged inhalation was associated with transient rebound pulmonary hypertension that dissipated within 60 minutes. Appreciation of rebound pulmonary hypertension may have important implications for patients with pulmonary hypertensive disorders when interruption of NO inhalation is necessary or when withdrawal of NO is planned.
Although thrombosis is a prominent finding in lung vessels from patients with primary and secondary pulmonary hypertension, to our knowledge, plasma coagulation factors that might contribute to a hypercoagulable state have not been fully investigated. We hypothesized that the local coagulation environment in the lung vasculature is important to progression if not initiation of pulmonary hypertension. Quasi−experimental cross−sectional design with concurrent controls. Referral clinics and inpatient services of a University Hospital and a Veterans Administration Medical Center. To investigate the role of plasma coagulation factors in severe pulmonary hypertension, we sampled plasma from patients with primary pulmonary hypertension, patients with pulmonary hypertension secondary to a discernible etiology, and normal adult control subjects. We detected abnormalities of the thrombomodulin/protein C anticoagulant system, evidenced by a decrease in soluble thrombomodulin, in patients with primary pulmonary hypertension. In the patients with primary pulmonary hypertension, we found impaired fibrinolytic activity, with a rise in the fibrinolytic inhibitor plasminogen activator 1 and elevated euglobulin lysis time. Lower fibrinolytic activity correlated with high mean pulmonary artery pressure. In contrast, in patients with secondary pulmonary hypertension, von Willebrand factor antigen and fibrinogen levels were increased, and fibrinolytic activity decreased. Different patterns of coagulation and fibrinolytic abnormalities are apparent in plasma from patients with primary and secondary pulmonary hypertension. Although we are unable to address causality with this study, we speculate that abnormalities of these coagulation mechanisms may initiate or play a role in perpetuation of pulmonary hypertension.
Long-standing pulmonary hypertension (PH) leads to structural alterations of the pulmonary vasculature and its endothelium, and occlusion of small vessels by microthrombi. In patients with PH, the search for factors inducing or worsening endothelium damage and in situ thrombi is still ongoing. Thrombomodulin (TM), an endothelial cell membrane protein, is a receptor for thrombin and a major anticoagulant proteoglycan. To analyze plasma TM levels in patients with different forms of severe PH. We prospectively studied 32 consecutive patients with PH referred for heart, lung, or heart-lung transplantation: 11 patients with primary PH (group 1), 11 patients with secondary precapillary PH (Eisenmenger's syndrome, group 2) and 10 patients with secondary postcapillary PH due to congestive heart failure (group 3). Thirty-eight healthy subjects were also studied as a control group. Plasma concentrations of TM were measured by an immunoenzymatic technique that uses two anti-TM monoclonal antibodies that have a strong avidity and react with different epitopes of the molecule. Thrombomodulin plasma levels decreased in all patients with precapillary PH, and this decrease was highly significant compared with controls (26 ± 2 versus 44 ± 2 ng/mL, = 0.0001). In primary PH, the TM decrease was only significant in males whereas in the Eisenmenger's syndrome TM values were the lowest of all the patients studied, with mean values twice as low as controls (22 ± 2 versus 44 ± 2 ng/mL, = 0.0001). In contrast, in postcapillary PH, studied only in males, TM levels were increased (85 ± 17 versus 54 ± 3 ng/mL, = 0.02). Patients with precapillary PH had more severe disease than patients with postcapillary PH, with higher pulmonary artery pressure and pulmonary vascular resistance ( < 0.001). There was no correlation between TM plasma levels and all hemodynamic variables. We found low levels of plasma TM in patients with precapillary PH but not in postcapillary PH compared with healthy controls. This may be related to the severity of PH and may contribute to the initiation or worsening of in situ thromboses frequently found in pulmonary hypertension. Further studies should analyze whether other markers of endothelial cell damage are correlated with plasma TM levels in patients with precapillary pulmonary hypertension.
Management of pulmonary hypertension, a potentially fatal complication of operations to correct congenital heart disease, has evolved through the last 15 years. Monitoring of pulmonary arterial pressure and mixed venous saturation became available, and prophylactic use of α-blockers and other vasodilators increased. This study examines risk factors for morbidity and mortality from pulmonary hypertension after operations to correct congenital heart disease and evaluates the impact of management changes on outcomes. By means of multivariable logistic regression analysis, 880 high-risk patients with congenital heart disease (of 2484 patients undergoing cardiopulmonary bypass between January 1980 and December 1994) were analyzed to determine which were at risk for postoperative pulmonary hypertension and its associated morbidity and mortality. Patients with atrioventricular canal ( = 182), truncus arteriosus ( = 47), total anomalous pulmonary venous connection ( = 90), transposition of great arteries ( = 97), hypoplastic left heart syndrome ( = 50), and ventricular septal defect ( = 414) demonstrated a higher risk of postoperative pulmonary hypertension. By multivariable logistic regression, preoperative pulmonary hypertension ( < 0.0001), absence of mixed venous saturation monitoring ( < 0.0001), and absence of prophylactic α-blockade ( = 0.0004) significantly increased postoperative pulmonary hypertension. Preoperative pulmonary hypertension ( < 0.001) and absence of prophylactic α-blockers ( = 0.0004) were significant risk factors for in-hospital death related to pulmonary hypertension. Repair at older age (except in the case of total anomalous pulmonary venous connection) was a significant risk for postoperative pulmonary hypertension ( = 0.03). Mixed venous saturation monitoring and α-receptor blockade reduced the incidence of pulmonary hypertension after operations for congenital heart disease. Early definitive repair reduced morbidity and mortality from postoperative pulmonary hypertension. (J T C S 1996;112:1600-9)