T-Tubular Electrical Defects Contribute to Blunted Beta-Adrenergic Response in Heart Failure

Alterations of the -adrenergic signalling, structural remodelling, and electrical failure of T-tubules are hallmarks of heart failure (HF). Here, we assess the effect of -adrenoceptor activation on local Ca2+ release in electrically coupled and uncoupled T-tubules in ventricular myocytes from HF rats. We employ an ultrafast random access multi-photon (RAMP) microscope to simultaneously record action potentials and Ca2+ transients from multiple T-tubules in ventricular cardiomyocytes from a HF rat model of coronary ligation compared to sham-operated rats as a control. We confirmed that -adrenergic stimulation increases the frequency of Ca2+ sparks, reduces Ca2+ transient variability, and hastens the decay of Ca2+ transients: all these effects are similarly exerted by -adrenergic stimulation in control and HF cardiomyocytes. Conversely, -adrenergic stimulation in HF cells accelerates a Ca2+ rise exclusively in the proximity of T-tubules that regularly conduct the action potential. The delayed Ca2+ rise found at T-tubules that fail to conduct the action potential is instead not affected by -adrenergic signalling. Taken together, these findings indicate that HF cells globally respond to -adrenergic stimulation, except at T-tubules that fail to conduct action potentials, where the blunted effect of the -adrenergic signalling may be directly caused by the lack of electrical activity.