ABSTRACT
Bronchopulmonary dysplasia (BPD) is a combined pulmonary vascular and parenchymal disease, representing the most common cause of chronic lung disease (CLD) in infancy. Pulmonary hypertension (PH) is frequently associated with BPD and-if persistent-substantially increases mortality. We report on a 4-month-old, former preterm infant with BPD, severe PH and right heart failure who greatly and rapidly improved clinical status and right ventricular (RV) function by means of blood biomarkers [N-terminal prohormone of brain natriuretic peptide (NT-pro-BNP), cardiac troponin T] and transthoracic echocardiography, following the addition of spironolactone and hydrochlorothiazide to the treatment regimen.
ABSTRACT
OBJECTIVES: We investigated whether concentrations of circulating microRNAs differ across the hypertensive right ventricle and pulmonary circulation, and correlate with hemodynamic/echocardiographic variables in patients with pulmonary arterial hypertension versus nonpulmonary arterial hypertension controls. DESIGN: Prospective blood collection during cardiac catheterization from the superior vena cava, pulmonary artery, and ascending aorta in 12 children with pulmonary arterial hypertension and nine matched nonpulmonary arterial hypertension controls, followed by an unbiased quantitative polymerase chain reaction array screen for 754 microRNAs in plasma. SETTING: Children's hospital at a medical school. PATIENTS: Twelve pulmonary arterial hypertension patients included as follows: idiopathic pulmonary arterial hypertension (5), pulmonary arterial hypertension (2), pulmonary arterial hypertension-repaired congenital heart disease (4), portopulmonary pulmonary hypertension (1). Nine nonpulmonary arterial hypertension controls included as follows: mild/moderate left ventricular outflow tract obstruction (7), mediastinal teratoma (1), portal vein stenosis (1). INTERVENTIONS: Standard pulmonary arterial hypertension treatment. MEASUREMENTS AND MAIN RESULTS: Analysis of differential concentrations (false discovery rate < 0.05) revealed two trans-right-ventricle microRNA gradients (pulmonary artery vs superior vena cava): miR-193a-5p (step-up in pulmonary arterial hypertension and step-down in control) and miR-423-5p (step-down in pulmonary arterial hypertension and step-up in control) and two transpulmonary microRNA gradients (ascending aorta vs pulmonary artery): miR-26b-5p (step-down only in control) and miR-331-3p (step-up only in pulmonary arterial hypertension). Between-group comparison revealed miR-29a-3p, miR-26a-5p, miR-590-5p, and miR-200c-3p as upregulated in pulmonary arterial hypertension-superior vena cava and miR-99a-5p as downregulated in pulmonary arterial hypertension-pulmonary artery. The differential microRNA-concentrations correlated with prognostic hemodynamic variables (pulmonary vascular resistance, tricuspid annular plane systolic excursion, etc.). CONCLUSIONS: We identified for the first time in human disease (pulmonary arterial hypertension) trans-right-ventricle and transpulmonary microRNA gradients in blood plasma. Several of these microRNAs regulate transcripts that drive cardiac remodeling and pulmonary arterial hypertension and are now emerging as epigenetic pulmonary arterial hypertension biomarkers and targets for therapy.
Subject(s)
MicroRNAs , Pulmonary Arterial Hypertension , Child , Familial Primary Pulmonary Hypertension , Heart Ventricles/diagnostic imaging , Humans , MicroRNAs/genetics , Prospective Studies , Vena Cava, SuperiorABSTRACT
A population of monocytes, known as Ly6C(lo) monocytes, patrol blood vessels by crawling along the vascular endothelium. Here we show that endothelial cells control their origin through Notch signalling. Using combinations of conditional genetic deletion strategies and cell-fate tracking experiments we show that Notch2 regulates conversion of Ly6C(hi) monocytes into Ly6C(lo) monocytes in vivo and in vitro, thereby regulating monocyte cell fate under steady-state conditions. This process is controlled by Notch ligand delta-like 1 (Dll1) expressed by a population of endothelial cells that constitute distinct vascular niches in the bone marrow and spleen in vivo, while culture on recombinant DLL1 induces monocyte conversion in vitro. Thus, blood vessels regulate monocyte conversion, a form of committed myeloid cell fate regulation.
