Contraction of a mammalian cardiac ventricular myocyte is normally initiated by an action potential, which causes a rapid increase of intracellular [Ca] (the Ca transient) by triggering Ca release from the sarcoplasmic reticulum (SR) via Ca-induced Ca release (CICR). The Ca transient is temporally and spatially synchronised within the cell because of the presence of transverse (t-) tubules, invaginations of the cell membrane that form a complex network which carries excitation into the cell. The function of many of the proteins involved in excitation-contraction coupling and its regulation appears to be located predominantly at the t-tubules, including ~80% of L-type Ca current (ICa) and ~65% of Na/Ca exchange current (INCX; for review see Orchard et al., 2009). Synchronous release of Ca from the SR is ensured by the proximity of L-type Ca channels in the t-tubule membrane to ryanodine receptors clustered in the SR membrane at the dyad. Spontaneous Ca release can also occur, particularly in conditions of Ca overload. Such Ca release can occur either as localised release from a cluster of ryanodine receptors (Ca spark) or as waves of Ca propagated within the cell by CICR, either between, or independent of, normal Ca transients. Such Ca release can cause arrhythmias by activating Ca-dependent inward currents, such as INCX. Since t-tubules are the main site of SR Ca release and the location of the majority of NCX activity in normal ventricular myocytes it is likely that they play an important role in the genesis of such arrhythmias. Disruption of t-tubule structure, and an accompanying decrease in Ca transient synchrony, has been reported in pathological conditions, such as heart failure (HF; e.g. Louch et al., 2006). It is unclear whether localised changes in protein function also occur; for example, basal protein kinase A (PKA) activity is involved in localisation of ICa and INCX at the t-tubules (e.g. Chase et al., 2010), so that changes of PKA activity during HF may cause local changes in protein, and thus t-tubule, function. However, loss of t-tubules results in loss of action potential propagation into the cell. In consequence, Ca release is initiated at the cell surface and propagates towards the centre of the cell, rather than arising as a rapid and synchronous Ca transient. There is also a decrease in the frequency of Ca sparks, which occur predominantly at the peripheral cell membrane rather than throughout the cell as in intact myocytes (Brette et al., 2005). Such changes may alter the propensity to arrhythmias due to spontaneous Ca release. Loss of synchronous Ca release and decreased Ca extrusion into the t-tubules could provide a substrate for altered Ca propagation (Li et al., 2012) and thus regenerating waves of intracellular Ca, although the associated decrease in Ca spark frequency will decrease the probability of such waves occurring. In addition, loss of t-tubules may alter the probability of spontaneous Ca release causing arrhythmias, because: (i) INCX normally occurs predominantly at the t-tubules (i.e. at the site of SR Ca release); thus, following loss of t-tubules, there may be insufficient activation of INCX by spontaneous Ca release to cause arrhythmias, unless NCX increases in remaining cell membrane and/or its activity is increased, for example by PKA; interestingly, an increase in NCX activity has been reported in HF. (ii) The density of ICa and neuronal-type Na channels is greater in the t-tubules than in the peripheral membrane, whereas the density of ITO, IK and IK1 is the same at the two sites, and cardiac-type Na channels are located predominantly in the peripheral membrane. Changes in each of these currents associated with loss of t-tubules will alter excitability, but the net effect is difficult to predict. However, detubulation has little effect on resting membrane potential but decreases action potential duration (APD; Brette et al., 2006), implying that membrane currents in the t-tubules prolong APD. Computer models incorporating a t-tubule compartment and experimentally-determined distributions of membrane currents suggest that the decrease in APD is due predominantly to loss of ICa and INCX (Pasek et al., 2008). Shortening of APD, and thus of the refractory period, may increase susceptibility to arrhythmias generated by spontaneous Ca release. (iii) Computer modelling also suggests an activity-dependent increase of K, and decrease of Ca, in the t-tubule lumen which may alter susceptibility to arrhythmias caused by Ca overload (Pasek et al., 2008). Thus in normal myocytes the t-tubules may play an important role in the genesis of arrhythmias. However, the net effect of altered t-tubule morphology in conditions such as HF is unknown, and will depend on changes in the expression, distribution and activity of proteins normally located at the t-tubules.