AimsInvaginations of the cellular membrane called t-tubules are essential for maintaining efficient excitation–contraction coupling in ventricular cardiomyocytes. Disruption of t-tubule structure during heart failure has been linked to dyssynchronous, slowed Ca2+ release and reduced power of the heartbeat. The underlying mechanism is, however, unknown. We presently investigated whether elevated ventricular wall stress triggers remodelling of t-tubule structure and function.Methods and resultsMRI and blood pressure measurements were employed to examine regional wall stress across the left ventricle of sham-operated and failing, post-infarction rat hearts. In failing hearts, elevated left ventricular diastolic pressure and ventricular dilation resulted in markedly increased wall stress, particularly in the thin-walled region proximal to the infarct. High wall stress in this proximal zone was associated with reduced expression of the dyadic anchor junctophilin-2 and disrupted cardiomyocyte t-tubular structure. Indeed, local wall stress measurements predicted t-tubule density across sham and failing hearts. Elevated wall stress and disrupted cardiomyocyte structure in the proximal zone were also associated with desynchronized Ca2+ release in cardiomyocytes and markedly reduced local contractility in vivo. A causative role of wall stress in promoting t-tubule remodelling was established by applying stretch to papillary muscles ex vivo under culture conditions. Loads comparable to wall stress levels observed in vivo in the proximal zone reduced expression of junctophilin-2 and promoted t-tubule loss.ConclusionElevated wall stress reduces junctophilin-2 expression and disrupts t-tubule integrity, Ca2+ release, and contractile function. These findings provide new insight into the role of wall stress in promoting heart failure progression.

Key points• The amount of force generated by heart cells is strongly influenced by feedback from the deformation of cardiac tissue, both from the changes in cell length and the rate at which cells are stretched.• We analysed the effect these cellular mechanisms have on whole heart function by making a computational model of mouse heart cells, and embedding this cellular model into a representation of the heart. • Unlike previous murine models, this model represents the heart at both body temperature and the high heart rates seen in these animals, allowing us to directly compare results from our computational model with experimental measurements.• Results show that effects from the rate of stretch are especially important for explaining the large differences observed between force generated by isolated cells and pressure measured experimentally.• The model also provides an important framework for future research focused on interpreting results from genetic manipulation experiments in mice.Abstract To investigate the effects of the coupling between excitation and contraction on whole-organ function, we have developed a novel biophysically based multiscale electromechanical model of the murine heart. Through comparison with a comprehensive in vivo experimental data set, we show good agreement with pressure and volume measurements at both physiological temperatures and physiological pacing frequencies. This whole-organ model was used to investigate the effects of material and haemodynamic properties introduced at the tissue level, as well as emergent function of our novel cell contraction model. Through a comprehensive sensitivity analysis at both the cellular and whole organ level, we demonstrate the sensitivity of the model's results to its parameters and the constraining effect of experimental data. These results demonstrate the fundamental importance of length-and velocity-dependent feedback to the cellular scale for whole-organ function, and we show that a strong velocity dependence of tension is essential for explaining the differences between measured single cell tension and whole-organ pressure transients.