Deletion of cardiac calsequestrin (Casq2) causes VT in mice akin to CASQ2 mutations. However, other sarcoplasmic reticulum (SR) proteins (triadin-1/junctin) are also reduced in homozygous ( Casq2 & minus;/− ) mice and may contribute to their arrhythmia phenotype. Furthermore, it is unknown if Casq2 regulates SR Ca 2+ -release directly or indirectly by buffering SR luminal Ca 2+ . To address both questions, we examined heterozygous ( Casq2 +/ − ) mice with a 25% reduction in Casq2, but no decrease in other SR proteins. Results: Casq2 +/ − mice (n=35) challenged with isoproterenol displayed 3-fold higher rates of ventricular ectopy than Casq2 +/+ mice (n=31; p<0.05). Programmed stimulation induced significantly more VT in Casq2 + / − mice. Field-stimulated Ca 2+ transients, cell shortening, L-type Ca 2+ current and SR volume were not different between the 2 groups. However, in presence of isoproterenol, SR Ca 2+ leak was significantly higher in Casq2 + / − myocytes ( Casq2 +/− 0.18±0.02 F ratio vs Casq2 +/+ 0.11±0.01 F ratio , n=57, 60; p=0.01), resulting in a significantly higher rate of spontaneous SR Ca 2+ -releases/triggered beats ( Casq2 +/− 0.38±0.07 vs Casq2 +/+ 0.12±0.06, n=47, 34; p=0.007). Luminal SR Ca 2+ was not significantly different between the 2 groups. However, on plotting SR Ca 2+ leak as a function of luminal SR Ca 2+, leak remained significantly higher in Casq2 +/− myocytes (figure ). Conclusion: Even modest reductions in Casq2 increase SR Ca 2+ leak and cause VT susceptibility under stress, which could explain increased risk for VT in CASQ2 +/− mutations. The underlying mechanism is likely the direct modulation of SR Ca 2+ -release by Casq2 rather than decreased Ca 2+ buffering in the SR lumen.