The mechanism by which SGLT2 inhibitors reduce cardiac events in diabetic patients remains unclear. Here, we examined the effects of an SGLT2 inhibitor on the acute survival rate after myocardial infarction (MI) in an animal model of type 2 diabetes mellitus (DM) and the possible involvement of modification of cardiac metabolomes and antioxidative proteins. MI was induced in DM Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) control rats. Treatment with empagliflozin (10 mg/kg per day, 14 days) before MI reduced blood glucose and increased blood and myocardial b-hydroxybutyrate (bOHB) levels in OLETF. Survival rate at 48 hours after MI was significantly lower in OLETF rats than in LETO rats (40% vs. 84%), and empagliflozin significantly improved the survival rate in OLETF rats to 70%, although the sizes of MI were comparable. Patterns of metabolomes and gene expression in the noninfarcted myocardium of OLETF rats were consistent with increased fatty acid oxidation and decreased glucose oxidation. The patterns were modified by empagliflozin, suggesting both increased glucose oxidation and ketone utilization in OLETF rats. Empagliflozin prevented reduction of ATP level in the noninfarcted myocardium after MI and significantly increased myocardial levels of Sirt3 and superoxide dismutase 2 in OLETF rats. Administration of bOHB partially mimicked the effects of empagliflozin in OLETF rats. The results suggest that empagliflozin prevents DM-induced increase in post-MI mortality, possibly by protective modification of cardiac energy metabolism and antioxidant proteins.

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AimsThe clinical outcome of heart failure (HF) is complicated by the presence of multiple comorbidities including malnutrition and cachexia, and prediction of the outcome is still difficult in each patient. Metabolomics including amino acid profiling enables detection of alterations in whole body metabolism. The aim of this study was to determine whether plasma amino acid profiling improves prediction of clinical outcomes in patients with HF. Methods and resultsWe retrospectively examined 301 HF patients (70 ± 15 years old; 59% male). Blood samples for measurements of amino acid concentrations were collected in a fasting state after stabilization of HF. Plasma amino acid concentrations were measured using ultraperformance liquid chromatography. Clinical endpoint of this study was adverse event defined as all-cause death and unscheduled readmission due to worsening HF or lethal arrhythmia. During a mean follow-up period of 380 ± 214 days, 40 patients (13%) had adverse events. Results of analyses of variable importance in projection score, a measure of a variable's importance in partial least squares-discriminant analysis (PLS-DA) showed that the top five amino acids being associated with adverse events were 3-methylhistidine (3-Me-His), β-alanine, valine, hydroxyproline, and tryptophan. Multivariate Cox-proportional hazard analyses indicated that a high 3-Me-His concentration and low β-alanine and valine concentrations were independently associated with adverse events. When HF patients were divided according to the cut-off values of amino acids calculated from receiver operating characteristic curves, Kaplan-Meier survival curves showed that event-free survival rates were lower in HF patients with high 3-Me-His than in HF patients with low 3-Me-His (68% vs. 91%, P < 0.01). In a subgroup with high 3-Me-His, HF patients with low β-alanine and those with low valine had significantly lower event-free survival rates than did HF patients with high β-alanine and those with high valine, respectively. On the other hand, Kaplan-Meier curves of event-free survival rates did not differ between HF patients with and those without low β-alanine and low valine in subgroups of patients with low 3-Me-His. Inclusion of both high 3-Me-His and low β-alanine or low valine into the adjustment model including N-terminal pro-brain natriuretic peptide improved the accuracy of prediction of adverse events after discharge. 3-Me-His concentration was associated with muscle mass and nutritional status. Conclusions Simple measurement of 3-Me-His with either β-alanine or valine improved the predictive ability for adverse events, indicating the utility of plasma amino acid profiling in risk stratification of hospitalized HF patients.

Objective Malnutrition is associated with an increased risk of mortality in heart failure (HF) patients. Here, we examined the hypothesis that assessment of energy intake in addition to nutritional status improves the stratification of mortality risk in elderly HF patients. Methods We retrospectively examined 419 HF patients aged ≥ 65 years (median 78 years, 49% female). Nutritional status was assessed by the Mini Nutritional Assessment Short Form (MNA-SF), and daily energy intake was calculated from intake during 3 consecutive days before discharge. Results During a median 1.52-year period (IQR 0.96–2.94 years), 110 patients (26%) died. Kaplan–Meier survival curves showed that patients with low tertile of daily energy intake had a higher mortality rate than did patients with high or middle tertile of daily energy intake. In multivariate Cox regression analyses, low daily energy intake was independently associated with higher mortality after adjustment for the model including age, sex, BNP, Charlson Comorbidity Index, history of HF hospitalization, and cachexia in addition to MNA-SF. Inclusion of both MNA-SF and energy intake into the adjustment model improved the accuracy of prediction of the mortality after discharge (continuous net reclassification improvement, 0.355, p = 0.003; integrated discrimination improvement, 0.029, p = 0.003). Results of a fully adjusted dose-dependent association analysis showed that risk of all-cause mortality was lowest among HF patients who consumed 31.5 kcal/kg/day of energy. Conclusions Energy intake during hospital stay is an independent predictor of the mortality in elderly HF patients, and its assessment together with established predictors improves the mortality risk stratification. Graphic abstract

Diabetes mellitus is a major risk factor for acute kidney injury (AKI). Here, we hypothesized that suppression of autophagic response underlies aggravation of renal ischemia/reperfusion (I/R) injury by type 2 diabetes mellitus (T2DM). In OLETF, a rat model of T2DM, and its non-diabetic control, LETO, AKI was induced by unilateral nephrectomy and 30-min occlusion and 24-h reperfusion of the renal artery in the contralateral kidney. Levels of serum creatinine and blood urea nitrogen and tubular injury score after I/R were significantly higher in OLETF than in LETO. Administration of chloroquine, a widely used autophagy inhibitor, aggravated I/R-induced renal injury in LETO, but not in OLETF. In contrast to LETO, OLETF exhibited no increase in autophagosomes in the proximal tubules after I/R. Immunoblotting showed that I/R activated the AMPK/ULK1 pathway in LETO but not in OLETF, and mTORC1 activation after I/R was enhanced in OLETF. Treatment of OLETF with rapamycin, an mTORC1 inhibitor, partially restored autophagic activation in response to I/R and significantly attenuated I/R-induced renal injury. Collectively, these findings indicate that suppressed autophagic activation in proximal tubules by impaired AMPK/ULK1 signaling and upregulated mTORC1 activation underlies T2DM-induced worsening of renal I/R injury.

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Heart failure (HF) is a major public health problem, with a prevalence of over 23 million worldwide, and is a leading cause of morbidity, mortality, and rehospitalization. 1,2 The prevalence of HF increases with aging: more than 80% of patients diagnosed with HF are >65 years of age. 3-5 In addition to establishing preven-