Abstract Body: Background: 50-85% of patients with metabolic syndrome (MeS) develop heart failure with preserved ejection fraction (HFpEF). Sudden cardiac death (SCD) is the most common cause of death in patients with HFpEF. Hypothesis: This study demonstrates a new link between ventricular tachycardia (VT), abnormalities of repolarization, autophagy and lysosomal dysfunction in the left ventricle (LV), and to identify unique therapeutic targets for metabolic heart disease. Methods: C57/B6 mice fed a high fat high sucrose (HFHS) diet for 7 months which develop obesity, hyperinsulinemia and HFpEF; programmed ventricular stimulation (PVST) of the heart, a reliable predictor of the predisposition to develop lethal arrhythmias and SCD in patients; spontaneous VT following coronary artery ligation and myocardial infarction (post-MI VT) using implantable EKG transmitters; Patch clamp recordings of the spatial distribution of repolarizing currents in site specific cardiomyocytes (CM) from LV epicardial and endocardial layers; RNA and protein for lysosomal TMEM175 channel, crucial for lysosome acidification, and phagophore protein LC3-II; rapamycin, an mTORC1 inhibitor and autophagy activator; MHY1485, an mTORC1 activator and autophagy inhibitor, and HpTX-2, an inhibitor of Ito,f (fast transient outward repolarizing K⁺ current). Results: HFHS-fed mice demonstrated a marked predisposition to inducible VT and spontaneous post-MI VT compared with mice fed a control diet. Site specific CM from these mice demonstrated decreased current density and disrupted spatial distribution of Ito,f vs. control. RNA and protein levels of TMEM175 were decreased and levels of LC3-II protein increased in the LV of HFHS mice consistent with decreased autophagy and lysosomal function. Rapamycin reduced inducible VT and HFpEF, restored density and spatial distribution of Ito/Ito,f, in HFHS-fed mice. Conversely, treatment of mice on a control diet with MHY1485, reduced lysosomal pH, decreased current density and restored spatial distribution of Ito/Ito,f. HpTX-2 lowered lysosomal pH, indicating that decreased Ito,f leads to lysosomal overacidification and impaired autophagy. Conclusions: A mouse model for MeS demonstrates marked predisposition to inducible and spontaneous VT, lysosomal overacidification and impaired autophagy. Rapamycin mitigates VT and restores abnormal early repolarization, supporting novel role for autophagy as a potential therapeutic target for SCD/HFpEF in MeS.