Inflammation and fibrotic pathways induced heterogeneous cardiac conduction and arrhythmias including atrial fibrillation and ventricular tachycardias. However, the development of preventative therapies has been disappointing. We explored several inflammatory mediators and immune activation (such as heat shock proteins), and suggested their critical roles in the induction of arrhythmias.  Moreover, the myocardial MMP-9 knockout decreased ventricular arrhythmia attacks in the arrhythmia model of transgenic mice. CD36 is the substrate of MMP-9. MMP-9 deficiency prevented the proteolysis of CD36, the activation of protein kinase A and ryanodine receptors through pS2808. This prevented calcium leakage from the sarcoplasmic reticulum and reduced arrhythmia-like irregular calcium transients. The abnormal calcium leakage could be similarly prevented by MMP-9 inhibition in the human induced pluripotent stem cell-derived cardiomyocytes. Myocardial MMP-9 inhibition prevented ventricular arrhythmia through the modulation of calcium homeostasis and reduced calcium leakage. The MMP-9 inhibitor was identified for future clinical translation.