Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT 84112, USA.
Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA.
Int J Mol Sci. 2021 Feb 25;22(5):2299. doi: 10.3390/ijms22052299.
Since its first identification as a cardiac transverse tubule (t-tubule) protein, followed by the cloning of the cardiac isoform responsible for t-tubule membrane microdomain formation, cardiac bridging integrator 1 (cBIN1) and its organized microdomains have emerged as a key mechanism in maintaining normal beat-to-beat heart contraction and relaxation. The abnormal remodeling of cBIN1-microdomains occurs in stressed and diseased cardiomyocytes, contributing to the pathophysiology of heart failure. Due to the homeostatic turnover of t-tubule cBIN1-microdomains via microvesicle release into the peripheral circulation, plasma cBIN1 can be assayed as a liquid biopsy of cardiomyocyte health. A new blood test cBIN1 score (CS) has been developed as a dimensionless inverse index derived from plasma cBIN1 concentration with a diagnostic and prognostic power for clinical outcomes in stable ambulatory patients with heart failure with reduced or preserved ejection fraction (HFrEF or HFpEF). Recent evidence further indicates that exogenous cBIN1 introduced by adeno-associated virus 9-based gene therapy can rescue cardiac contraction and relaxation in failing hearts. The therapeutic potential of cBIN1 gene therapy is enormous given its ability to rescue cardiac inotropy and provide lusitropic protection in the meantime. These unprecedented capabilities of cBIN1 gene therapy are shifting the current paradigm of therapy development for heart failure, particularly HFpEF.
自首次被鉴定为心肌横管（t-小管）蛋白以来，随后克隆出负责 t-小管膜微区形成的心肌同工型，心脏桥连整合器 1（cBIN1）及其有组织的微区已成为维持正常心跳收缩和舒张的关键机制。在应激和患病的心肌细胞中，cBIN1-微区的异常重构导致心力衰竭的病理生理学改变。由于 t-小管 cBIN1-微区通过微泡释放到外周循环中的稳态周转，因此可以将血浆 cBIN1 作为心肌细胞健康的液体活检进行检测。已经开发出一种新的血液测试 cBIN1 评分（CS），作为一种无量纲的倒数指数，源自血浆 cBIN1 浓度，对射血分数降低或保留的心力衰竭稳定门诊患者的临床结局具有诊断和预后价值（HFrEF 或 HFpEF）。最近的证据进一步表明，通过腺相关病毒 9 为基础的基因治疗引入的外源性 cBIN1 可以挽救衰竭心脏的收缩和舒张。鉴于 cBIN1 基因治疗能够挽救心脏的收缩力并同时提供变力性保护，因此其治疗潜力巨大。cBIN1 基因治疗的这些前所未有的能力正在改变心力衰竭治疗的现有模式，尤其是 HFpEF。
