Defects in T-tubular electrical activity underlie local alterations of calcium release in heart failure

The plasma membrane of cardiac myocytes contains complex invaginations known as transverse tubules (T-tubules). In heart failure, T-tubule loss is a major contributor to Ca²⁺ transient abnormalities, leading to weaker and slower contraction. Current therapeutic strategies are often based on attempts to accelerate Ca²⁺ transients. Here, we demonstrate that T-tubular loss represents just one way by which T-tubule dysfunction leads to asynchronous Ca²⁺ release across the myocyte. In fact, we report that defects in T-tubular electrical activity may contribute to Ca²⁺-mediated arrhythmogenesis not only by favoring asynchronous Ca²⁺ release, but also by generating voltage-associated Ca²⁺ sparks. This work provides the first description to our knowledge of these novel proarrhythmogenic events that could help guide future therapeutic strategies.