Abstract Body:

Background: Sex differences in the predisposition to the development of VT and SCD remain poorly studied. DM has been associated with the development of metabolic heart disease, characterized in part by heart failure with preserved ejection fraction (HFpEF), affecting approximately 30 million adults worldwide. SCD is the most common cause of death in pts with HFpEF accounting for 40% of cardiovascular mortality. Women are 1.27 to 2 times more likely than men to develop HFpEF. Although men are more likely to experience SCD in the presence of significant heart disease, data suggest that women with SCD often have structurally normal-appearing hearts at postmortem, suggesting an arrhythmic etiology. The development of VT in response to programmed ventricular stimulation (PVST) of the heart is a reliable predictor of the predisposition to develop lethal arrhythmias and SCD in patients. Goals: To determine whether dietary fiber has a sex specific effect on the development of VT. Methods: C57/B6 mice fed a high fat high sucrose (HFHS) diet for 6-7 months, PVST, patch clamp and action potential recordings from isolated mouse ventricular cardiomyocytes (M), echocardiography, ovariectomy. Results: Male mice fed a HFHS diet develop obesity, insulin resistance and HFpEF characterized by increased isovolumetric relaxation time (IVRT) of 16 vs 10 in mice on control diet and E/A of 1.3 compared to 0.9 in controls consistent with metabolic syndrome and are highly inducible for VT. Ventricular myocytes (M) from these mice demonstrate action potential prolongation (APD) and decreased transient outward K currents (Ito). HFHS fed female mice were not inducible for VT, with normal APD. Ovariectomized mice were inducible for VT with prolonged APD. Female mice fed a HFHS diet deficient in fiber were highly inducible for VT, developed HFpEF and decreased Ito and changes in gut flora and gut permeability. Conclusions: Dietary fiber may play an important role in the development of a sex specific inducible VT and HFpEF in females. The mechanism of fiber protection in the female heart in metabolic disease might offer important insight into a previously unrecognized sex specific role of diet and obesity in metabolic heart disease.