ABSTRACT
@#Objective To explore the possibility that GREM1, a bone morphogenetic protein (BMP) antagonist, is a mechanical explanation for BMP signal suppression in congenital heart disease associated pulmonary arterial hypertension (CHD/PAH) patients. Methods Systemic-to-pulmonary shunt induced PAH was surgically established in rats. At the postoperative 12th week, right heart catheterization and echocardiography evaluation were performed to evaluate hemodynamic indexes and morphology of right heart system. Right heart hypotrophy index and pulmonary vascular remodeling were evaluated. Changes of BMP signal pathway related proteins and GREM1 in lungs and plasma GREM1 concentration were detected. The effect of GREM1 on the proliferation and apoptosis of pulmonary arterial endothelial cells (PAECs) was also explored. Results The hypertensive status was successfully reproduced in rats with systemic-to-pulmonary shunt model. BMP signal pathway was suppressed but GREM1 was up-regulated with no change in hypoxia inducible factor-1 in lungs exposed to systemic-to-pulmonary shunt, while this trend was reversed by systemic-to-pulmonary shunt correction (P<0.05). Immunohistochemical staining demonstrated enhanced staining of GREM1 in remodeled pulmonary arteries. In vitro experiments found that BMP signal was down-regulated but GREM1 expression and secretion were up-regulated in proliferative PAECs (P<0.05). Furthermore, BMP2 significantly inhibited PAECs proliferation and promoted PAECs apoptosis (P<0.05), which could be antagonized by GREM1. In addition, plasma level of GREM1 in rats with systemic-to-pulmonary shunt was also increased and positively correlated with pulmonary hemodynamic indexes. Conclusion Systemic-to-pulmonary shunt induces the up-regulation of GREM1 in lungs, which promotes pulmonary vascular remodeling via antagonizing BMP cascade. These results present a new mechanical explanation for BMP pathway suppression in lungs of CHD/PAH patients.
ABSTRACT
Aim To determine the feasibility of transforming growth factor-a ( TGF-a ) as a diagnostic bio-marker for systemic-to-pulmonary shunts induced pulmonary arterial hypertension ( PAH ). Methods Systemic-to-pulmonary shunts induced PAH was built by combined surgery ( right pulmonary artery was ligated and a cervical shunt was established one week later). A total of 49 patients with congenital heart diseases were recruited, including 24 congenital heart disease patients without PAH(CHD) and 25 congenital heart disease patients with pulmonary arterial hypertension (CIID-PAH). Moreover, 20 healthy volunteers matched by age and sex were also included. Enzyme linked immunosorbent assay (EL1SA) was used to test TGF-a concentrations in plasma of systemic-to-pulmonary shunts induced PAH rats and CHD-PAH patients. Results ELISA results showed that TGF-a levels in plasma of systemic-to-pulmonary shunts induced PAH rats were significantly higher than those of sham operated group. Spearman correlation analysis showed that plasma TGF-a concentrations were positively associated with right ventricular systolic pressure, pulmonary arterial systolic pressure, mean pulmonary arterial pressure and right ventricular hypertrophy index. The plasma concentration of TGF-a in CHD-PAH patients was much higher than that of CHD patients and healthy vol- unteers ( CON); however, there was no significant difference between CHD group and CON group; Using 314 ng • L"1 as cutoff value of TGF-a for the diagnosis of CHD-PAH, the sensitivity, specificity and area under the cure was 0. 760, 0. 750 and 0. 895, respectively. Conclusions Plasma concentration of TGF-a increases with the progression of systemic-to-pulmonary shunt induced PAH; the level of TGF-a in plasma may be a potential biomarker for the diagnosis of systemic- to-pulmonary shunt induced PAII.
ABSTRACT
Objetivo - Avaliar o resultado pós-operatório imediato de crianças portadoras de cardiopatias congênitas com hipofluxo pulmonar, submetidas à derivaçäo sistêmico-pulmonar. Casuística e Métodos - Sessenta e quatro pacientes, 30 (46,8%) do sexo masculino, com idades entre 1 dia e 17 anos, divididos em: grupo I, 13 (20,3%) pacientes submetidos à operaçäo de Blalock-Taussig (B-T) clássica; grupo II, 46 (71,8%) pacientes submetidos à B-T modificada, sendo usados 2 tipos de enxertos, polytetrafluoroetylene (PTFE) em 34 casos e veia umbilical em 12; grupo III, em 5 (7,8%) pacientes submetidos à derivaçäo central com emprego de 3 tipos de enxertos, PTFE em 3, veia umbilical em 1 e artéria mamária bovina em 1. Os procedimentos associados foram ligadura do canal arterial persistente em 2 casos, ligadura de artérias brônquicas em 3, valvotomia pulmonar em 3, ampliaçäo de via de saída do ventrículo direito em 3 e apliaçäo de estenose de artéria pulmonar em outros 2 casos. Resultados - No grupo I houve 4 (30,7%) casos com obstruçäo da derivaçäo, tendo sido 2 reoperados, com mortalidade de 30,7%. No grupo II houve 4 (8,6%) casos com obstruçäo e 2 reoperaçöes com mortalidade de 15,2% (7 casos) e no grupo III houve 1 (20%) de obstruçäo e mortalidade de 80% (4 casos). A mortalidade relacionada exclusivamente à derivaçäo foi de 15,3%, 8,6% e 40% respectivamente. Conclusäo - A operaçäo de B-T modificada, realizada com maior freqüência, apresentou menor índice de obstruçäo e menor mortalidade, sendo recomendada como primeira escolha