Abstract 19080: The Ketogenic Diet Aggravates the Ischemic Response in Mouse Hearts

Abstract

Ketone bodies, particularly beta-hydroxybutyrate (B-OHB), have been identified as an important fuel source during physiological and pathological stress. Although controversial, consumption of a ketogenic diet (KD) may be used as a method to increase B-OHB availability. Since the KD is a high-fat, low carbohydrate diet, the diet may have harmful effects on the heart especially during ischemic injury. Therefore, the objective of this study was to investigate the effects of short- term consumption of the KD on cardiac ischemia-reperfusion injury. Male (n=14) and female (n=13) were randomly assigned to KD (90% calories from fat) or normal chow diet. Serum B-OHB and cholesterol were significantly higher in both male and females fed the KD. KD did not increase body weight in male and female mice but significantly increased adipose tissue mass by 2.7 and 1.9 fold, respectively. KD increased hepatic triglyceride content in both males and females and increased cardiac triglycerides only in male mice. Cardiac function was assessed in isolated perfused hearts on a mixed substrate buffer consisting of 0.4mM fatty acids, 5.5mM glucose, 50uU/ml insulin, 1.2mM lactate, and 0.5mM B-OHB. Baseline function was monitored for 15 minutes followed by 18 minutes of global ischemia and 36 minutes of reperfusion. Baseline LV developed pressure (LVDevP) and heart rate (HR) were not affected by the KD in either male or female mice. During ischemia, the end diastolic pressure (EDP) was significantly higher in both male and female KD hearts. Time to peak contracture was accelerated in male and female KD hearts (P<0.05 vs chow), with a delay in female hearts (13.12 ± 1.06 vs. 9.27 ± 0.80 min, P<0.05 vs KD male). At the end of reperfusion, rate pressure product (RPP, the product of LVDevP and HR) was lower in male KD vs male chow (P<0.05) whereas RPP was similar in female KD and female chow. Moreover, RPP in female KD was significantly higher than male KD (6190 ± 929 vs 2133 ± 533 mmHg/min). These findings suggest that the KD may increase vulnerability of the heart to ischemia and may reduce recovery from ischemia, particularly in males. Overall, this study highlights potential sex differences and negative consequences of short-term consumption of the KD.