Impact of ultrastructural left-ventricular Ca2+ release unit remodeling in hemodynamic subtypes of severe aortic stenosis

Aortic valve stenosis (AS) frequently causes heart disease in elderly patients and is characterized by a broad spectrum of hemodynamic phenotypes, some with life-threatening arrhythmias, and increased risk of death. The guideline for management of severe AS in patients is to improve quality of life by transaortic catheter-based valve replacement (TAVR). However, the mechanisms underlying different AS-associated hemodynamic phenotypes remain poorly understood. Proteome profiling by data-independent acquisition mass spectrometry in individual left-ventricular biopsies quantified 2.273 proteins. 160 showed statistically significant abundance changes in AS hearts compared to non-failing samples. Unbiased hierchical clustering identified four different proteotypes which broadly corresponded to hemodynamic phenotypes. As adult cardiomyocytes undergo distinct stages of subcellular remodeling, we used quantitative superresolution microscopy of candidate proteins in left-ventricular biopsies to determine the consequences of dyadic RyR2 protein changes on AS dysfunction in vivo.主动脉瓣狭窄（Aortic valve stenosis, AS）是老年患者心脏疾病的常见诱因，其具有广泛的血流动力学表型谱，部分患者可出现致命性心律失常，且死亡风险显著升高。目前针对重度AS患者的临床管理指南推荐采用经主动脉导管瓣膜置换术（Transaortic catheter-based valve replacement, TAVR）以改善患者生活质量。然而，不同AS相关血流动力学表型背后的潜在分子机制仍未得到充分阐明。本研究通过数据非依赖采集质谱（data-independent acquisition mass spectrometry）对单个左心室活检标本进行蛋白质组分析，共定量得到2273种蛋白质；其中相较于非衰竭心脏样本，AS患者心脏样本中有160种蛋白质的丰度变化具有统计学显著性。通过无偏层次聚类分析，鉴定出四种不同的蛋白质组型，其大致对应于上述血流动力学表型。鉴于成年心肌细胞会经历不同阶段的亚细胞重塑，本研究利用左心室活检标本中候选蛋白质的定量超分辨显微镜成像，探究了二联结构兰尼碱受体2（RyR2）蛋白变化对体内AS相关心功能障碍的影响。