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West J.D.,Vanderbilt University | West J.D.,Vanderbilt Vascular Biology Center | Austin E.D.,Vanderbilt University | Gaskill C.,Vanderbilt University | And 31 more authors.
American Journal of Physiology - Cell Physiology | Year: 2014

Understanding differences in gene expression that increase risk for pulmonary arterial hypertension (PAH) is essential to understanding the molecular basis for disease. Previous studies on patient samples were limited by end-stage disease effects or by use of nonadherent cells, which are not ideal to model vascular cells in vivo. These studies addressed the hypothesis that pathological processes associated with PAH may be identified via a genetic signature common across multiple cell types. Expression array experiments were initially conducted to analyze cell types at different stages of vascular differentiation (mesenchymal stromal and endothelial) derived from PAH patient-specific induced pluripotent stem (iPS) cells. Molecular pathways that were altered in the PAH cell lines were then compared with those in fibroblasts from 21 patients, including those with idiopathic and heritable PAH. Wnt was identified as a target pathway and was validated in vitro using primary patient mesenchymal and endothelial cells. Taken together, our data suggest that the molecular lesions that cause PAH are present in all cell types evaluated, regardless of origin, and that stimulation of the Wnt signaling pathway was a common molecular defect in both heritable and idiopathic PAH. © 2014 the American Physiological Society. Source

Butrous G.,Pulmonary Vascular Research Institute
Annals of Thoracic Medicine | Year: 2014

Schistosomiasis is caused by infection with the parasite Schistosoma, which is a flat-worm or fluke. The dominant species are Schistosoma mansoni, Schistosoma japonicum, and Schistosoma haematobium. Schistosomiasis is the third most common parasitic disease in the world after malaria and amoebiasis. It is endemic in more than 70 countries affecting about 200 million people worldwide, of whom 80% are in sub-Saharan Africa. There are pockets of infection in north-eastern Brazil, near the Yangtze River in China, and some pockets in south East Asia. In the East Mediterranean regions, the Schistosoma have been reported in Iraq and Egypt as well as in Sudan. The latter has the highest infection rate nowadays, particularly in the Al Jazeera area, due to the poor Schistosoma control program. In the Arabian peninsula, schistosomiasis has been reported in southwest part of Saudi Arabia, mainly in the Asir province and Jizan province, which lay in the southwest corner of Saudi Arabia and directly north of the border with Yemen. The efforts to control schistosomiasis have been very successful in Saudi Arabia due to the irrigation system control. However, the infection is prone in Yemen, where the schistosomiasis control is much less strict. Thus as a result, the problem still exists due to transmigration of the populations from both countries. As a cause of pulmonary arterial hypertension (PAH), schistosomiasis is still under diagnosed and undertreated. This article with give a highlight about the pathophysiology of the disease and both diagnostic and therapeutic strategies. Source

McLaughlin V.,University of Michigan | Channick R.N.,Massachusetts General Hospital | Ghofrani H.-A.,Justus Liebig University | Lemarie J.-C.,Effi Statistics | And 8 more authors.
European Respiratory Journal | Year: 2015

The safety and efficacy of adding bosentan to sildenafil in pulmonary arterial hypertension (PAH) patients was investigated. In this prospective, double-blind, event-driven trial, symptomatic PAH patients receiving stable sildenafil (≥20 mg three times daily) for ≥3 months were randomised (1:1) to placebo or bosentan (125 mg twice daily). The composite primary end-point was the time to the first morbidity/mortality event, defined as all-cause death, hospitalisation for PAH worsening or intravenous prostanoid initiation, atrial septostomy, lung transplant, or PAH worsening. Secondary/exploratory end-points included change in 6-min walk distance and World Health Organization functional class at 16 weeks, change in N-terminal pro-brain natriuretic peptide (NT-proBNP) over time, and all-cause death. Overall, 334 PAH patients were randomised to placebo (n=175) or bosentan (n=159). A primary endpoint event occurred in 51.4% of patients randomised to placebo and 42.8% to bosentan (hazard ratio 0.83, 97.31% CI 0.58-1.19; p=0.2508). The mean between-treatment difference in 6-min walk distance at 16 weeks was +21.8 m (95% CI +5.9-37.8 m; p=0.0106). Except for NT-proBNP, no difference was observed for any other end-point. The safety profile of bosentan added to sildenafil was consistent with the known bosentan safety profile. In COMPASS-2, adding bosentan to stable sildenafil therapy was not superior to sildenafil monotherapy in delaying the time to the first morbidity/mortality event. © ERS 2015. Source

Qadar Pasha M.A.,Institute of Genomics and Integrative Biology | Qadar Pasha M.A.,Pulmonary Vascular Research Institute | Newman J.H.,Vanderbilt University | Newman J.H.,Pulmonary Vascular Research Institute
Chest | Year: 2010

Globally, it is estimated that > 140 million people live at a high altitude (HA), defined as > 2,500 m (8,200 ft), and that countless others sojourn to the mountains for work, travel, and sport. The distribution of exposure to HA is worldwide, including 35 million in the Andes and > 80 million in Asia, including China and central Asia. HA stress primarily is due to the hypoxia of low atmospheric pressure, but dry air, intense solar radiation, extreme cold, and exercise contribute to acute and chronic disorders. The acute disorders are acute mountain sickness (also known as soroche), HA cerebral edema, and HA pulmonary edema (HAPE). Of these, HAPE is highly correlated with acute pulmonary hypertension. The first chronic syndrome described in HA dwellers in Peru was chronic mountain sickness (Monge disease), which has a large component of relative hypoventilation and secondary erythrocytosis. The prevalence of chronic mountain sickness in HA dwellers ranges from 1.2% in native Tibetans to 5.6% in Chinese Han; 6% to 8% in male residents of La Paz, Bolivia; and 15.6% in the Andes. Subacute mountain sickness is an exaggerated pulmonary hypertensive response to HA hypoxia occurring over months, most often in infants and very young children. Chronic pulmonary hypertension with heart failure but without hypoventilation is seen in Asia. Not only does HA pulmonary hypertension exact health consequences for the millions affected, but also the mechanisms of disease relate to pulmonary hypertension associated with multiple other disorders. Genetic understanding of these disorders is in its infancy. © 2010 American College of Chest Physicians. Source

Graham B.B.,University of Colorado at Denver | Graham B.B.,Pulmonary Vascular Research Institute | Bandeira A.P.,University of Pernambuco | Bandeira A.P.,Pulmonary Vascular Research Institute | And 6 more authors.
Chest | Year: 2010

Inflammation is likely a critical underlying etiology in many forms of severe pulmonary hypertension (PH), and schistosomiasis-associated PH, one of the most common causes of PH worldwide, is likely driven by the host response to parasite antigens. More than 200 million people are infected with schistosomiasis, the third most common parasitic disease, and approximately 1% of those chronically infected develop PH. Acute cutaneous infection causes inflammation at the site of parasite penetration followed by a subacute immune complex-mediated hypersensitivity response as the parasite migrates through the lungs. Chronic schistosomiasis infection induces a granulomatous inflammation around ova deposited in the tissue. In particular, Schistosoma mansoni migrates to the portal venous system and causes preportal fibrosis in a subset of individuals and appears to be a prerequisite for PH. Portal hypertension facilitates shunting of ova from the portal system to the pulmonary arterial tree, resulting in localized periovular pulmonary granulomas. The pulmonary vascular remodeling is likely a direct consequence of the host inflammatory response, and portopulmonary hypertension may be a significant contributor. New specific therapies available for PH have not been widely tested in patients with schistosomiasis and often are unavailable for those infected in resource-poor areas of the world where schistosomiasis is endemic. Furthermore, the current PH therapies in general target vasodilation rather than vascular remodeling and inflammation. Further research is needed into the pathogenic mechanism by which this parasitic infection results in pulmonary vascular remodeling and PH, which also may be informative regarding the etiology of other types of PH. © 2010 American College of Chest Physicians. Source

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