Reddy Sushma, Hu Dong-Qing, Zhao Mingming, Blay Eddie, Sandeep Nefthi, Ong Sang-Ging, Jung Gwanghyun, Kooiker Kristina B, Coronado Michael, Fajardo Giovanni, Bernstein Daniel
Department of Pediatrics, Division of Cardiology, Stanford University, Stanford, California, USA.
Department of Surgery, Temple University, Philadelphia, Pennsylvania, USA.
JCI Insight. 2017 May 4;2(9). doi: 10.1172/jci.insight.91625.
Combined pulmonary insufficiency (PI) and stenosis (PS) is a common long-term sequela after repair of many forms of congenital heart disease, causing progressive right ventricular (RV) dilation and failure. Little is known of the mechanisms underlying this combination of preload and afterload stressors. We developed a murine model of PI and PS (PI+PS) to identify clinically relevant pathways and biomarkers of disease progression. Diastolic dysfunction was induced (restrictive RV filling, elevated RV end-diastolic pressures) at 1 month after generation of PI+PS and progressed to systolic dysfunction (decreased RV shortening) by 3 months. RV fibrosis progressed from 1 month (4.4% ± 0.4%) to 3 months (9.2% ± 1%), along with TGF-β signaling and tissue expression of profibrotic miR-21. Although plasma miR-21 was upregulated with diastolic dysfunction, it was downregulated with the onset of systolic dysfunction), correlating with RV fibrosis. Plasma miR-21 in children with PI+PS followed a similar pattern. A model of combined RV volume and pressure overload recapitulates the evolution of RV failure unique to patients with prior RV outflow tract surgery. This progression was characterized by enhanced TGF-β and miR-21 signaling. miR-21 may serve as a plasma biomarker of RV failure, with decreased expression heralding the need for valve replacement.
联合性肺功能不全（PI）和狭窄（PS）是多种先天性心脏病修复术后常见的长期后遗症，会导致进行性右心室（RV）扩张和衰竭。对于这种前负荷和后负荷应激源组合背后的机制，人们知之甚少。我们建立了一种PI和PS（PI+PS）的小鼠模型，以确定疾病进展的临床相关途径和生物标志物。在PI+PS形成后1个月诱导舒张功能障碍（限制性RV充盈，RV舒张末期压力升高），并在3个月时进展为收缩功能障碍（RV缩短减少）。RV纤维化从1个月（4.4%±0.4%）进展到3个月（9.2%±1%），同时伴有TGF-β信号传导和促纤维化miR-21的组织表达。虽然血浆miR-21在舒张功能障碍时上调，但在收缩功能障碍开始时下调，与RV纤维化相关。PI+PS患儿的血浆miR-21遵循类似模式。联合RV容量和压力过载模型概括了既往RV流出道手术患者特有的RV衰竭演变过程。这种进展的特征是TGF-β和miR-21信号增强。miR-21可能作为RV衰竭的血浆生物标志物，其表达降低预示着需要进行瓣膜置换。
