Heart failure (HF) is a leading cause of cardiovascular mortality and morbidity. While pump failure is a frequent cause of mortality, up to 50% of deaths are due to sudden cardiac death following lethal arrhythmias. Dysregulation in Ca²⁺ handling has emerged as a key mediator of these arrhythmias. The rhythmic contraction of cardiomyocytes necessary for the efficient pumping of the heart is mediated by the process of excitation contraction coupling (EC) whereby Ca²⁺ entering the cell via L-type Ca²⁺ channels during the action potential activates Ca²⁺ release through Ryanodine Receptor channels (RyR) on the Sarcoplasmic Reticulum (SR) Ca²⁺ store, which then engages the contractile machinery to induce cell contraction. This mechanism is highly dependent upon the synchronized release of Ca²⁺ from clusters of RyRs dispersed throughout the cytosol, predominantly at the Z lines. Ensuring the coupling of Ca²⁺ entry and SR Ca²⁺ release are T-tubular invaginations of the sarcolemma that bring its voltage gated channels into close proximity with RyRs on the SR at cell compartments termed dyads. During heart failure, T-tubules are lost leading to reduced coupling between L-type channels and RyRs, which in turn reduces Ca²⁺ release synchrony as well as increasing arrhythmogenic Ca²⁺ waves. We have identified increased expression of a second SR Ca²⁺ channel, the InsP₃ receptor (InsP₃R), in animal models of CV disease and in human heart failure. This channel is engaged by InsP₃ generated downstream of G-protein coupled receptors such as those liganded by the neurohormones endothelin-1 and Angiotensin, which are also elevated in disease. We find potent effects of InsP₃ on Ca²⁺ handling in voltage clamped cardiomyocytes isolated from failing human hearts in comparison to cardiomyocytes from age-matched non failing hearts. Specifically, in the presence of InsP₃, Ca²⁺ transient amplitude was reduced and frequency of elementary Ca²⁺ release events (Ca²⁺ sparks) via RyRs was increased. RyRs were required for the action of InsP₃, suggesting Ca²⁺ channel crosstalk, an observation that was supported by super resolution microscopy. The effects of InsP₃ were most prominent at RyRs that were not coupled to the T-tubular membrane at dyads. Mathematical modelling provided further evidence supporting the role of crosstalk between InsP₃R and RyRs and the potential for Ca²⁺ release via InsP₃Rs to sensitize RyRs to Ca²⁺. The increased spontaneous Ca²⁺ spark events contributed to the development of Ca²⁺ waves, which through engaging the sodium Ca²⁺ exchanger, led to cell depolarization and action potential generation. This arrhythmogenic activity was further established in a tissue wedge model where increased arrhythmic activity was detected when perfused with AngII to increase InsP₃. The effects of AngII were suppressed by the InsP₃R inhibitor 2-APB. Together, provide a new mechanistic basis for the action of InsP₃ mediated Ca²⁺ release in cardiomyocytes, whereby InsP₃Rs in the neighbourhood of RyRs act to tune their sensitivity to Ca²⁺ release. We further  identify InsP₃Rs as important players in the pathology of human heart where they promote arrhythmogenic activity and diminished Ca²⁺ transients.