BMPR2 mutation in a patient with pulmonary arterial hypertension and suspected hereditary hemorrhagic telangiectasia.

Pulmonary arterial hypertension (PAH) and hereditary hemorrhagic telangiectasia (HHT) are distinct clinical entities caused by germline mutations in genes encoding members of the TGFbeta/BMP superfamily: BMPR2 in PAH and ACVRL1, ENG, or SMAD4 in HHT. When PAH and HHT occasionally co-exist within the same family, ACVRL1 mutations predominate. We report a 36-year-old woman initially diagnosed with PAH at age 24. At 35, following massive hemoptysis, multiple pulmonary arteriovenous malformations were discovered, prompting evaluation for HHT. She met the Curaçao diagnostic criteria for suspected HHT based on additional findings of nasal telangiectases and epistaxis. Mutation analysis of ACVRL1, ENG, and SMAD4 was normal, but a germline nonsense mutation in BMPR2 was identified. This is the first known report of HHT features, particularly pulmonary AVMs, associated with a BMPR2 mutation. It adds further weight to a common molecular pathogenesis in PAH and HHT, and highlights that BMPR2 gene analysis is indicated in patients affected with both HHT and PAH.

Alterations of cellular bioenergetics in pulmonary artery endothelial cells.

Idiopathic pulmonary arterial hypertension (IPAH) is pathogenetically related to low levels of the vasodilator nitric oxide (NO). Because NO regulates cellular respiration and mitochondrial biogenesis, we hypothesized that abnormalities of bioenergetics may be present in IPAH. Evaluation of pulmonary artery endothelial cells from IPAH and control lungs in vitro revealed that oxygen consumption of IPAH cells was decreased, especially in state 3 respiration with substrates glutamate-malate or succinate, and this decrease paralleled reduction in Complex IV activity and IPAH cellular NO synthesis. IPAH pulmonary artery endothelial cells had decreased mitochondrial dehydrogenase activity and lowered mitochondrial numbers per cell and mitochondrial DNA content, all of which increased after exposure to NO donors. Although IPAH/pulmonary artery endothelial cells' ATP content was similar to control under normoxia, cellular ATP did not change significantly in IPAH cells under hypoxia, whereas ATP decreased 35% in control cells, identifying a greater dependence on cellular respiration for energy in control cells. Evidence that glucose metabolism was subserving the primary role for energy requirements of IPAH cells was provided by the approximately 3-fold greater glycolytic rate of IPAH cells. Positron emission tomography scan with [18F]fluoro-deoxy-D-glucose performed on IPAH patients and healthy controls revealed significantly higher uptake in IPAH lungs as compared with controls, confirming that the glycolytic rate was increased in vivo. Thus, there are substantial changes in bioenergetics of IPAH endothelial cells, which may have consequences for pulmonary hypertensive responses and potentially in development of novel imaging modalities for diagnosis and evaluation of treatment.

Atrial septostomy using a butterfly stent in a patient with severe pulmonary arterial hypertension.

We describe a patient with severe pulmonary artery hypertension and refractory right heart failure who underwent "butterfly" stent atrial septostomy guided by intracardiac ultrasound. This technique may be superior to previously reported blade and balloon septostomy because it allows creation of an atrial septal defect of a precise predetermined diameter. The patient's systemic blood flow and clinical status improved significantly after the procedure, allowing her to be accepted as a candidate for lung transplantation.

Detection of lung cancer by sensor array analyses of exhaled breath.

RATIONALE: Electronic noses are successfully used in commercial applications, including detection and analysis of volatile organic compounds in the food industry. OBJECTIVES: We hypothesized that the electronic nose could identify and discriminate between lung diseases, especially bronchogenic carcinoma. METHODS: In a discovery and training phase, exhaled breath of 14 individuals with bronchogenic carcinoma and 45 healthy control subjects or control subjects without cancer was analyzed. Principal components and canonic discriminant analysis of the sensor data was used to determine whether exhaled gases could discriminate between cancer and noncancer. Discrimination between classes was performed using Mahalanobis distance. Support vector machine analysis was used to create and apply a cancer prediction model prospectively in a separate group of 76 individuals, 14 with and 62 without cancer. MAIN RESULTS: Principal components and canonic discriminant analysis demonstrated discrimination between samples from patients with lung cancer and those from other groups. In the validation study, the electronic nose had 71.4% sensitivity and 91.9% specificity for detecting lung cancer; positive and negative predictive values were 66.6 and 93.4%, respectively. In this population with a lung cancer prevalence of 18%, positive and negative predictive values were 66.6 and 94.5%, respectively. CONCLUSION: The exhaled breath of patients with lung cancer has distinct characteristics that can be identified with an electronic nose. The results provide feasibility to the concept of using the electronic nose for managing and detecting lung cancer.

Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH), a fatal disease of unknown etiology characterized by impaired regulation of pulmonary hemodynamics and vascular growth, is associated with low levels of pulmonary nitric oxide (NO). Based upon its critical role in mediating vasodilation and cell growth, decrease of NO has been implicated in the pathogenesis of PAH. We evaluated mechanisms for low NO and pulmonary hypertension, including NO synthases (NOS) and factors regulating NOS activity, i.e. the substrate arginine, arginase expression and activity, and endogenous inhibitors of NOS in patients with PAH and healthy controls. PAH lungs had normal NOS I-III expression, but substrate arginine levels were inversely related to pulmonary artery pressures. Activity of arginase, an enzyme that regulates NO biosynthesis through effects on arginine, was higher in PAH serum than in controls, with high-level arginase expression localized by immunostaining to pulmonary endothelial cells. Further, pulmonary artery endothelial cells derived from PAH lung had higher arginase II expression and produced lower NO than control cells in vitro. Thus, substrate availability affects NOS activity and vasodilation, implicating arginase II and alterations in arginine metabolic pathways in the pathophysiology of PAH.

Nitric oxide and pulmonary arterial pressures in pulmonary hypertension.

Decreased production of vasodilator substances such as nitric oxide (NO) has been proposed as important in development of pulmonary arterial hypertension (PAH). We hypothesize that NO measured over time serves as a non invasive marker of severity of PAH and response to therapy. We prospectively and serially measured exhaled NO and carbon monoxide (CO), a vasodilator and anti-inflammatory product of heme oxygenases, in 17 PAH patients in conjunction with hemodynamic parameters over 2 years. Although pulmonary artery pressures and NO were similar in all patients at entry to the study, NO increased in the 12 individuals who survived to complete the study, and correlated with change in pulmonary artery pressures. In contrast, CO did not change or correlate with hemodynamic parameters. Investigation of NO-oxidant reaction products in PAH in comparison to controls suggests that NO synthesis is impaired in the lung and that reactive oxygen species may be involved in the pathophysiology of pulmonary hypertension. Endogenous NO is inversely related to pulmonary artery pressure in PAH, with successful therapy of PAH associated with increase in NO.

Diagnosis and evaluation of pulmonary hypertension.

The diagnosis of pulmonary hypertension (PH) relies on a high index of suspicion. In patients with symptoms or chest radiographic findings suggestive of PH, a detailed history and physical examination followed by early assessment with a transthoracic echocardiogram, ventilation-perfusion scanning, chest computed tomography, pulmonary function testing, and nocturnal oximetry screening can provide valuable information about etiology and severity. Right heart catheterization should follow in patients who are symptomatic or who demonstrate moderate to severe PH by echocardiography and are candidates for treatment. Patients at risk for developing PH should undergo serial echocardiography and pulmonary function testing to assess for disease development and progression. Genetic testing is not currently recommended in the routine evaluation of patients with a diagnosis of primary pulmonary hypertension.

Failure of a predictive scale in identifying patients who may benefit from a pain management program: follow-up data.

A 7-item scale to identify patients who may benefit from a pain management program was prospectively studied. The patient group consisted of 217 patients. The duration of follow-up was 2-3 years. Although an item-by-item analysis revealed some differences between successes, partial successes, and failures, the overlap was such that the total score was not predictive of outcome. Although this finding precludes clinical use of the 7-item scale in its present form, future modifications are suggested that may improve its predictive ability.