Spontaneous Ca²⁺ release (SCR) events can cause triggered activities and initiate arrhythmias during disease remodeling. SCR events are traditionally studied by single cell or whole heart electrophysiology, but these techniques alone are limited in providing in-depth insights into complex cell-cell interactions and tissue microarchitecture. In our laboratory, a collection of data ranging from single cell level, multicellular tissue preparations up to in vivo animal models have shaped our current view as how SCR can contribute to arrythmia initiation. We have studied spontaneous loss of sarcoplasmic reticulum Ca²⁺ through ryanodine receptors (RyRs) at the subcellular level and found hyperactive RyRs being located in a microdomain outside the dyadic cleft in diseased myocytes. Single cell studies paired with in vivo observations from a large animal model with myocardial infarction suggested that these hyperactive RyRs can generate a substrate for arrhythmia and are a local initiator of triggered activities in the peri-infarct region. Also, work in multicellular tissue preparations showed a significant increase of SCR events and their propagation in living cardiac tissue slices from human heart failure patients. Collectively, complementary tools are used to dissect arrhythmia at the different multitude from aberrant SR Ca²⁺ release at the single cardiac myocyte level to the manifestation at the whole heart.