Drug discovery focused on novel pathogenic proteins for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a fatal disease in which the wall thickening and narrowing of pulmonary microvessels progress due to complicated interactions among processes such as endothelial dysfunction, the proliferation of pulmonary artery smooth muscle cells (PASMCs) and adventitial fibrocytes, and inflammatory cell infiltration. Early diagnosis of patients with PAH is difficult and lung transplantation is the only last choice to save severely ill patients. However, the number of donors is limited. Many patients with PAH show rapid progression and a high degree of pulmonary arterial remodeling characterized by the abnormal proliferation of PASMCs, which makes treatment difficult even with multidrug therapy comprising pulmonary vasodilators. Thus, it is important to develop novel therapy targeting factors other than vasodilation, such as PASMC proliferation. In the development of PAH, inflammation and oxidative stress are deeply involved in its pathogenesis. Excessive proliferation and apoptosis resistance in PASMCs are key mechanisms underlying PAH. Based on those characteristics, we recently screened novel pathogenic proteins and have performed drug discovery targeting those proteins. To confirm the clinical significance of this, we used patient-derived blood samples to evaluate biomarker potential for diagnosis and prognosis. Moreover, we conducted high throughput screening and found several inhibitors of the pathogenic proteins. In this review, we introduce the recent progress on basic and clinical PAH research, focusing on the screening of pathogenic proteins and drug discovery.

Prevalence of Pulmonary Hypertension in Pediatric Patients With Obstructive Sleep Apnea and a Cardiology Evaluation: A Retrospective Analysis.

STUDY OBJECTIVES: Pulmonary hypertension (PH) has been reported as a serious complication of obstructive sleep apnea (OSA) in children; however, estimated prevalence rates vary widely (zero to 85%). The purpose of this study is to determine the prevalence of PH in children with OSA and identify factors that may predict an increased PH risk in children with OSA. METHODS: A retrospective review of all pediatric beneficiaries (88,058) in the San Antonio Military Health System with a diagnosis of OSA and a clinical evaluation by a pediatric cardiologist. OSA severity and nadir oxygen saturation were recorded from overnight polysomnography. Reason for referral, comorbid disorders, echocardiogram results, and cardiac diagnoses were obtained from cardiology records. RESULTS: OSA was identified in 2,020 pediatric patients (2.3%). A pediatric cardiology consultation was reported for 296 patients with OSA. After excluding 95 patients for incorrect OSA diagnoses, incomplete data, or OSA treatment before cardiology evaluation, 163 patients were included in the final analysis. A diagnosis of PH was found in 3 patients with OSA (1.8%). Two of these patients had obesity, and all three had comorbid cardiac disorders. CONCLUSIONS: Prevalence of PH in pediatric patients with OSA is low and none of the patients with PH had severe OSA. Current guidelines recommend PH screening in patients with severe OSA, yet OSA severity may not accurately predict risk. Factors evaluated in this study did not demonstrate an increased PH risk; additional research is necessary to improve screening in pediatric patients with OSA. CITATION: Burns AT, Hansen SL, Turner ZS, Aden JK, Black AB, Hsu DP. Prevalence of pulmonary hypertension in pediatric patients with obstructive sleep apnea and a cardiology evaluation: a retrospective analysis. J Clin Sleep Med. 2019;15(8):1081-1087.