Calcium handling remodeling in dilated cardiomyopathy: From molecular mechanisms to targeted therapies

Calcium ions play a crucial role in cardiac excitation-contraction (EC) coupling, and disruptions in Ca²⁺ homeostasis are a key factor in the development of dilated cardiomyopathy (DCM). This review aims to systematically analyze how structural and functional remodeling of Ca²⁺-handling proteins drives DCM progression and to evaluate therapeutic strategies targeting these pathways. The movement of intracellular Ca²⁺, which is regulated by transporters like SERCA2a, ryanodine receptor 2 (RYR2), and L-type Ca²⁺ channels, affects the heart's contraction and relaxation. In DCM, both structural and functional changes in the Ca²⁺-handling machinery-including t-tubule remodeling, modifications to RYR2, and dysregulation of SERCA2a and phospholamban (PLN)-disrupt Ca²⁺ cycling, worsening systolic dysfunction and ventricular dilation. For instance, reduced affinity of SERCA2a for Ca²⁺ due to imbalances in the PLN-SERCA2a interaction impairs the heart's ability to reuptake Ca²⁺ during diastole. Meanwhile, abnormalities in RYR2 contribute to arrhythmogenic Ca²⁺ leaks. Targeting these pathways for treatment has two main challenges: too much Ca²⁺ modulation can cause arrhythmias, while insufficient correction may fail to improve heart contractility. Precision interventions demand structurally resolved targets, such as stabilizing RYR2 closed states or enhancing SERCA2a activity via gene therapy, to address DCM's heterogeneous pathophysiology. Emerging strategies leveraging t-tubule restoration or isoform-specific L-type channel modulation show promise in normalizing Ca²⁺ transients and halting adverse remodeling. This review compiles evidence that connects changes in EC coupling components to the progression of DCM and emphasizes the potential benefits of restoring Ca²⁺ balance as a treatment. By integrating molecular insights with clinical phenotypes, structurally informed Ca²⁺-targeted therapies could pave the way for personalized DCM management, balancing efficacy with minimized off-target effects.