Khalid Arbab, Ahmed Abu-Bakr, Gill Randeep, Shaikh Taha, Khorsandi Joshua, Kia Ali
Department of Internal Medicine, Kirk Kerkorian School of Medicine, UNLV, Las Vegas, NV 89106, USA.
Kirk Kerkorian School of Medicine, UNLV, Las Vegas, NV 89106, USA.
Int J Mol Sci. 2025 Jun 15;26(12):5738. doi: 10.3390/ijms26125738.
The L-type calcium channels (LTCCs) function as the main entry points that convert myocyte membrane depolarization into calcium transients, which drive every heartbeat. There is increasing evidence to show that maladaptive remodeling of these channels is the cause of heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Recent experimental, translational, and clinical studies have improved our understanding of the roles LTCC expression, micro-domain trafficking, and post-translational control have in disrupting excitation-contraction coupling, provoking arrhythmias, and shaping phenotype specific hemodynamic compromise. We performed a systematic search of the PubMed and Google Scholar databases (2015-2025, English) and critically evaluated 17 eligible publications in an effort to organize the expanding body of work. This review combines existing data about LTCC density and T-tubule architecture with β-adrenergic and Ca⁺/calmodulin-dependent protein kinase II (CaMKII) signaling and downstream sarcoplasmic reticulum crosstalk to explain how HFrEF presents with contractile insufficiency and how HFpEF shows diastolic calcium overload and stiffening. Additionally, we highlight the emerging therapeutic strategies aimed at restoring calcium homeostasis such as CaMKII inhibitors, ryanodine receptor type 2 (RyR2) stabilizers, and selective LTCC modulators without compromising systolic reserve. The review establishes LTCC dysregulation as a single mechanism that causes myocardial dysfunction while remaining specific to each phenotype, thus offering clinicians and researchers a complete reference for current concepts and future precision therapy approaches in heart failure.
L型钙通道（LTCCs）作为主要的入口点，将心肌细胞膜去极化转化为钙瞬变，从而驱动每一次心跳。越来越多的证据表明，这些通道的适应性重塑是射血分数降低的心力衰竭（HFrEF）和射血分数保留的心力衰竭（HFpEF）的病因。最近的实验、转化和临床研究增进了我们对LTCC表达、微区转运和翻译后调控在破坏兴奋-收缩偶联、引发心律失常以及形成特定表型的血流动力学损害中所起作用的理解。我们对PubMed和谷歌学术数据库（2015 - 2025年，英文）进行了系统检索，并严格评估了17篇符合条件的出版物，以整理这一不断扩展的研究工作。本综述将关于LTCC密度和T管结构的现有数据与β-肾上腺素能和钙/钙调蛋白依赖性蛋白激酶II（CaMKII）信号传导以及下游肌浆网串扰相结合，以解释HFrEF如何表现为收缩功能不全，以及HFpEF如何表现为舒张期钙超载和僵硬。此外，我们强调了旨在恢复钙稳态的新兴治疗策略，如CaMKII抑制剂、2型兰尼碱受体（RyR2）稳定剂和选择性LTCC调节剂，同时不损害收缩储备。该综述将LTCC失调确立为导致心肌功能障碍的单一机制，同时对每种表型具有特异性，从而为临床医生和研究人员提供了关于心力衰竭当前概念和未来精准治疗方法的完整参考。
