Growing With the Flow

Q: What is the clinical evidence from this study?

Study design: Editorial. Population: Endocardial fibroelastosis (EFE). Intervention: Losartan vs. Untreated abnormal flow conditions (static and regurgitation flow). Primary outcome: Fibrotic area in the left ventricular endocardium and endothelial-to-mesenchymal transition (EndoMT) phenotypes.

Q: What does this research mean for the field?

Losartan treatment significantly reduces left ventricular endocardial fibrotic area and reverses endothelial-to-mesenchymal transition phenotypes in rodent models of endocardial fibroelastosis. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Nicole Min Qian Pek; Mingxia Gu

doi:10.1016/j.jacbts.2021.09.007

December 1, 2021JACC Basic to Translational ScienceOpen Access

Growing With the Flow

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Graphical abstract published by JACC Basic to Translational Science — Graphical abstract · Published by JACC Basic to Translational Science · CC BY-NC-ND

Why the study?

Does losartan reduce flow-mediated endocardial fibrosis and endothelial-to-mesenchymal transition in a preclinical model of endocardial fibroelastosis?

Key Points

Discuss the pathogenic role of altered hemodynamic flow profiles in driving endocardial fibroelastosis through endothelial-to-mesenchymal transition and evaluate losartan as an antifibrotic therapy.
Reviewed neonatal rat heterotopic heart transplantation models establishing static (unloaded), regurgitation, and normal (loaded) left ventricular flow profiles verified by echocardiogram.
Evaluated the effect of 7 days of losartan treatment on fibrotic area and molecular markers in the surgical rat model.
Assessed transcriptomic changes using bulk RNA-sequencing in human endocardial endothelial cells exposed to laminar shear stress versus static conditions.
At 7 days post-transplantation, hearts exposed to static and regurgitation flow developed endocardial thickening, profound collagen deposition, and elevated EndoMT markers SNAIL, SLUG, and αSMA alongside down-regulated CD31 and VE-cadherin.
Treatment with losartan for 7 days significantly reduced fibrotic area in the left ventricular endocardium of unloaded rat hearts and reversed several EndoMT phenotypes, though it did not restore endothelial cell marker expression.
Human endocardial endothelial cells subjected to laminar shear stress showed suppression of genes linked to mesenchymal cell differentiation, heart valve development, and Notch signaling relative to static controls.

Structured PICO

Does losartan reduce flow-mediated endocardial fibrosis and endothelial-to-mesenchymal transition in a preclinical model of endocardial fibroelastosis?

P

Population

Editorial commentary discussing a neonatal rodent heterotopic heart transplantation surgical model of endocardial fibroelastosis and isolated human endocardial endothelial cells from 3 patients with congenital heart disease.

I

Intervention

Losartan (angiotensin II receptor blocker) treatment for 7 days in the rat model; laminar shear stress (LSS) in isolated human endocardial endothelial cells

C

Comparator

Static (unloaded) and regurgitation blood flow conditions vs normal (loaded) flow

O

Outcome

Left ventricular endocardial thickening, fibrotic area, collagen deposition, and endothelial-to-mesenchymal transition (EndoMT) phenotypessurrogate

Limitations

Losartan treatment did not restore endothelial cell marker expression.
Human endocardial endothelial cells were obtained from 3 patients with existing congenital heart diseases, which may contain genetic mutations introducing heterogeneity.
Lack of coculture experiments with cardiomyocytes and fibroblasts to evaluate the roles of other cell types in flow-mediated EndoMT.
Difficulty in performing lineage tracing in rat models leaves unresolved whether EndoMT or epicardial-to-mesenchymal transition (EpiMT) is the primary driver of fibrosis.
Losartan treatment did not restore endothelial cell marker expression
HUEECs were isolated from only 3 patients with existing congenital heart diseases, potentially introducing genetic heterogeneity
In vitro HUEEC experiments lacked coculture with cardiomyocytes and fibroblasts
Lack of lineage tracing in the rat model leaves the EndoMT versus EpiMT debate unresolved

Implication

This editorial highlights preclinical evidence that abnormal blood flow drives endocardial fibroelastosis via TGF-beta-mediated endothelial-to-mesenchymal transition and identifies losartan as a potential antifibrotic therapy warranting further translational investigation.

Abstract

[Figure: see text]

Discussion

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Cite This Study

Pek et al. (2021) conducted an editorial in Endocardial fibroelastosis (EFE). Losartan vs. Untreated abnormal flow conditions (static and regurgitation flow) was evaluated on Fibrotic area in the left ventricular endocardium and endothelial-to-mesenchymal transition (EndoMT) phenotypes.

synapsesocial.com/papers/6a73b13f14e943abc869ed66 https://doi.org/10.1016/j.jacbts.2021.09.007

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Growing With the Flow

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

Growing With the Flow

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

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