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Stress-induced remodelling of the mitral valve: a model for leaflet thickening and superimposed tissue formation in mitral valve disease.
Cardiovascular Research ( IF 10.8 ) Pub Date : 2019-09-08 , DOI: 10.1093/cvr/cvz204 Boudewijn P T Kruithof 1, 2, 3 , Laura Paardekooper 2 , Yasmine L Hiemstra 1 , Marie-José Goumans 2 , Meindert Palmen 4 , Victoria Delgado 1 , Robert J M Klautz 4 , Nina Ajmone Marsan 1
Cardiovascular Research ( IF 10.8 ) Pub Date : 2019-09-08 , DOI: 10.1093/cvr/cvz204 Boudewijn P T Kruithof 1, 2, 3 , Laura Paardekooper 2 , Yasmine L Hiemstra 1 , Marie-José Goumans 2 , Meindert Palmen 4 , Victoria Delgado 1 , Robert J M Klautz 4 , Nina Ajmone Marsan 1
Affiliation
AIMS
In mitral valve prolapse (MVP), leaflet thickening has recently been suggested to be due, in addition to a myxomatous degeneration, to the presence of a superimposed tissue (SIT), defined as an additional fibrous layer on top of the original leaflet. The mechanisms of SIT formation are currently unknown. We hypothesized that SIT formation would result from excessive leaflet stress and we used a unique ex vivo model to assess the correlation between leaflet remodelling and the type and location of mechanical stress and to elucidate the mechanisms underlying SIT formation.
METHODS AND RESULTS
Human diseased mitral valves (MVs; n = 21) were histologically analysed for SIT formation and original leaflet thickening. The SIT comprised of various compositions of extracellular matrix and could reach more than 50% of total leaflet thickness. Original leaflet and SIT thickness did not show significant correlation (r = -0.27, P = 0.23), suggesting different regulatory mechanisms. To study the role of the mechanical environment on MV remodelling, mouse MV were cultured in their natural position in the heart and subjected to various haemodynamic conditions representing specific phases of the cardiac cycle and the MVP configuration. SIT formation was induced in the ex vivo model, mostly present on the atrial side, and clearly dependent on the duration, type, and extent of mechanical stress. Specific stainings and lineage tracing experiments showed that SIT comprises of macrophages and myofibroblasts and is associated with the activation of the transforming growth factor-beta and bone morphogenetic protein signalling pathways. Migration of valvular interstitial cells and macrophages through breakages of the endothelial cell lining contributed to SIT formation.
CONCLUSIONS
Mechanical stresses induce specific cellular and molecular changes in the MV that result in SIT formation. These observations provide the first insights in the mechanism of SIT formation and represent an initial step to identify potential novel and early treatment for MVP.
中文翻译:
应力诱发的二尖瓣重塑:二尖瓣疾病中小叶增厚和组织重叠形成的模型。
目的在二尖瓣脱垂(MVP)中,最近提出了小叶增厚的原因是粘液变性,还包括叠加组织(SIT)的存在,该组织被定义为原始小叶顶部的附加纤维层。SIT形成的机制目前尚不清楚。我们假设SIT的形成将由过度的小叶压力引起,我们使用了独特的离体模型来评估小叶重塑与机械应力的类型和位置之间的相关性,并阐明SIT形成的潜在机制。方法和结果对人患二尖瓣(MVs; n = 21)进行了组织学分析,以了解SIT形成和原始小叶增厚。SIT由细胞外基质的各种成分组成,可以达到小叶总厚度的50%以上。原始的传单和SIT厚度没有显示出显着的相关性(r = -0.27,P = 0.23),表明不同的调节机制。为了研究机械环境在MV重塑中的作用,将小鼠MV以其在心脏中的自然位置进行培养,并使其经受各种血液动力学条件的影响,这些条件代表心动周期的特定阶段和MVP构型。SIT的形成是在离体模型中诱导的,主要存在于心房一侧,并且明显取决于机械应力的持续时间,类型和程度。特定的染色和谱系追踪实验表明,SIT包含巨噬细胞和成肌纤维细胞,并与转化生长因子-β和骨形态发生蛋白信号通路的激活有关。瓣膜间质细胞和巨噬细胞通过内皮细胞壁破裂的迁移有助于SIT的形成。结论机械应力引起MV中特定的细胞和分子变化,从而导致SIT形成。这些观察结果提供了关于SIT形成机制的初步见解,并代表了确定MVP的潜在新颖和早期治疗的第一步。
更新日期:2020-04-17
中文翻译:
应力诱发的二尖瓣重塑:二尖瓣疾病中小叶增厚和组织重叠形成的模型。
目的在二尖瓣脱垂(MVP)中,最近提出了小叶增厚的原因是粘液变性,还包括叠加组织(SIT)的存在,该组织被定义为原始小叶顶部的附加纤维层。SIT形成的机制目前尚不清楚。我们假设SIT的形成将由过度的小叶压力引起,我们使用了独特的离体模型来评估小叶重塑与机械应力的类型和位置之间的相关性,并阐明SIT形成的潜在机制。方法和结果对人患二尖瓣(MVs; n = 21)进行了组织学分析,以了解SIT形成和原始小叶增厚。SIT由细胞外基质的各种成分组成,可以达到小叶总厚度的50%以上。原始的传单和SIT厚度没有显示出显着的相关性(r = -0.27,P = 0.23),表明不同的调节机制。为了研究机械环境在MV重塑中的作用,将小鼠MV以其在心脏中的自然位置进行培养,并使其经受各种血液动力学条件的影响,这些条件代表心动周期的特定阶段和MVP构型。SIT的形成是在离体模型中诱导的,主要存在于心房一侧,并且明显取决于机械应力的持续时间,类型和程度。特定的染色和谱系追踪实验表明,SIT包含巨噬细胞和成肌纤维细胞,并与转化生长因子-β和骨形态发生蛋白信号通路的激活有关。瓣膜间质细胞和巨噬细胞通过内皮细胞壁破裂的迁移有助于SIT的形成。结论机械应力引起MV中特定的细胞和分子变化,从而导致SIT形成。这些观察结果提供了关于SIT形成机制的初步见解,并代表了确定MVP的潜在新颖和早期治疗的第一步。