Qin Zihan, Bäck Magnus, Franco-Cereceda Anders, Pawelzik Sven-Christian
Translational Cardiology, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Heart and Vascular Center, Karolinska University Hospital, Stockholm, Sweden.
ESC Heart Fail. 2025 Apr;12(2):1469-1473. doi: 10.1002/ehf2.15132. Epub 2024 Oct 27.
Calcific aortic valve disease (CAVD) progresses over time to severe aortic stenosis and eventually heart failure. Recent evidence indicates that intraleaflet haemorrhage (ILH) strongly promotes CAVD progression. However, it remains poorly understood how it mechanistically contributes to valvular calcification.
ILH was identified as iron deposition by morphological analysis. To elucidate the underlying mechanism, human valvular interstitial cells (VIC) were cultured in the presence of fresh or senescent red blood cells (RBC), simulating ILH in vivo conditions.
ILH was common in aortic valves derived from patients with severe aortic stenosis. VIC undergo erythrophagocytosis of senescent RBC, leading to intracellular iron accumulation analogous to observed following exposure to extracellular iron. The presence of senescent RBC significantly intensified VIC calcification, which was significantly mitigated by ferroptosis inhibition.
Our results identify erythrophagocytosis by VIC, leading to iron accumulation and enhanced calcification through ferroptosis. This may be a crucial component of the pathophysiological mechanisms that links ILH to valvular calcification and accelerated aortic stenosis progression.
钙化性主动脉瓣疾病（CAVD）会随着时间的推移发展为严重的主动脉瓣狭窄，并最终导致心力衰竭。最近的证据表明，瓣叶内出血（ILH）强烈促进CAVD的进展。然而，其如何在机制上导致瓣膜钙化仍知之甚少。
通过形态学分析将ILH鉴定为铁沉积。为了阐明潜在机制，在新鲜或衰老红细胞（RBC）存在的情况下培养人瓣膜间质细胞（VIC），模拟体内ILH情况。
ILH在严重主动脉瓣狭窄患者的主动脉瓣中很常见。VIC会对衰老的RBC进行红细胞吞噬作用，导致细胞内铁积累，类似于暴露于细胞外铁后观察到的情况。衰老RBC的存在显著加剧了VIC钙化，而铁死亡抑制可显著减轻这种钙化。
我们的结果确定了VIC的红细胞吞噬作用，导致铁积累并通过铁死亡增强钙化。这可能是将ILH与瓣膜钙化及加速主动脉瓣狭窄进展联系起来的病理生理机制的关键组成部分。
