Remodeling of T-Tubules and Associated Calcium Handling Dysfunction in Heart Failure: Mechanisms and Therapeutic Insights

Abstract

In cardiomyocytes, transverse tubules (T-tubules) are sarcolemmal invaginations that facilitate excitation-contraction coupling (ECC) and diastolic function. The clinical significance of T-tubules has become evident as their remodeling is recognized as a hallmark feature of heart failure (HF) and a key contributor to disrupted Ca2+ homeostasis, compromised cardiac function, and arrhythmogenesis. Further investigations have revealed that T-tubule remodeling is particularly pronounced in HF with reduced ejection fraction (HFrEF), but not in HF with preserved ejection fraction (HFpEF), implying that T-tubule remodeling may play a crucial pathophysiological role in HFrEF. While research on the functional importance of T-tubules is ongoing due to their complexity, T-tubule remodeling has been found to be reversible. Such finding has triggered a surge in studies aimed at identifying specific therapeutic approaches for HFrEF. This review discusses the functional importance of T-tubules and their microdomains, the pathophysiology of T-tubule remodeling, and the potential mechanisms of current HFrEF therapeutic approaches in reversing T-tubule alterations. We also highlight discrepancies regarding the roles of T-tubule proteins in the recovery process across studies to offer valuable insights for future research.