Remodelling 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 and diastolic function. The clinical significance of T-tubules has become evident in that their remodelling is recognised 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 remodelling is particularly pronounced in HF with reduced ejection fraction (HFrEF), but not in HF with preserved ejection fraction, implying that T-tubule remodelling may play a crucial pathophysiologic role in HFrEF. While research on the functional importance of T-tubules is ongoing, T-tubule remodelling has been found to be reversible. That 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 remodelling, 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.