Constance Jennings

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.

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 TGFβ/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.

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 patients systemic blood flow and clinical status improved significantly after the procedure, allowing her to be accepted as a candidate for lung transplantation.

Intercostal Lung Cyst Hernia in Idiopathic Pulmonary Hemosiderosis (Cyst Necessitans)

A 31-year-old woman had recurrent dyspnea, cough, hemoptysis, and diffuse alveolar infiltrates. Chest computed tomography showed bilateral interstitial and alveolar infiltrates and a dominant right-sided lung cyst. Serum protein electrophoresis and immunoglobulin levels were normal, and no autoantibodies were found. Open lung biopsy revealed patchy fibrosis, intra-alveolar and interstitial hemosiderin-laden macrophages, and no evidence of vasculitis. Idiopathic pulmonary hemosiderosis was diagnosed. Treatment with corticosteroids provided good results. Two years later, the patient presented with an intermittent-appearing lump on the right side of the chest, triggered by episodes of cough. Computed tomography showed a subcutaneous intercostal lung cyst herniation (left), which occurred sporadically through the biopsy incision (right, 1 week later), that was corrected surgically by excision. Intercostal lung hernia is a rare clinical entity, encountered mainly after chest trauma or surgery. A herniated lung cyst may rupture, with subsequent pneumothorax and subcutaneous emphysema. If such a cyst is recurrent or persistent, it should be corrected surgically.