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miR-21 is associated with fibrosis and right ventricular failure
Sushma Reddy, … , Giovanni Fajardo, Daniel Bernstein
Sushma Reddy, … , Giovanni Fajardo, Daniel Bernstein
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e91625. https://doi.org/10.1172/jci.insight.91625.
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Research Article Cardiology

miR-21 is associated with fibrosis and right ventricular failure

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Abstract

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.

Authors

Sushma Reddy, Dong-Qing Hu, Mingming Zhao, Eddie Blay Jr., Nefthi Sandeep, Sang-Ging Ong, Gwanghyun Jung, Kristina B. Kooiker, Michael Coronado, Giovanni Fajardo, Daniel Bernstein

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Figure 1

Clinical and histologic characteristics recapitulate the clinical progression of PI+PS.

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Clinical and histologic characteristics recapitulate the clinical progre...
Sham-operated mice and mice with PI+PS were assessed using echocardiogram, cardiac catheterization, and exercise testing at 1, 2, and 3 months. Early RV diastolic dysfunction manifested as an increase in (A and B) tricuspid inflow E/A ratio by echocardiogram and (C) RV end diastolic pressures (RVEDp) by cardiac catheterization. Late RV systolic dysfunction characterized by (D) progressive decline in exercise duration by modified treadmill testing, (E) decrease in RV outflow tract (RVOT) shortening fraction (SF) by echocardiogram at 3 months, and (F) decrease in dP/dt by RV catheterization after an early increase. (G and H) Development of overt heart failure compared with generalized edema. (I and J) Histologic progression: A progressive increase in myocyte cell area was seen by wheat germ agglutinin staining of the cell wall in green, during the stage of diastolic dysfunction (1 month and 2 months) and plateaued with systolic dysfunction (3 months). Scale bar: 50 μm. (K and L) Progressive increase in subendocardial fibrosis was seen with trichrome staining. n = 6–9 sham for each time point at 1, 2, and 3 months; n = 4–10 PI+PS for each time point at 1, 2, and 3 months. Scale bar: 100 μm. PI+PS, pulmonary insufficiency and pulmonary stenosis; RV, right ventricle. Data represent mean ± SEM and were analyzed using ANOVA with multiple testing correction. *P < 0.05, **P < 0.01, ***P < 0.001.

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