Background Perturbations in myocardial substrate utilization have been proposed to contribute to the pathogenesis of cardiac dysfunction in diabetic subjects. The failing heart in nondiabetics tends to decrease reliance on fatty acid and glucose oxidation, and increases reliance on ketone body oxidation. In contrast, little is known regarding the mechanisms mediating this shift among all 3 substrates in diabetes mellitus. Therefore, we tested the hypothesis that changes in myocardial glucose utilization directly influence ketone body catabolism. Methods and Results We examined ventricular‐cardiac tissue from the following murine models: (1) streptozotocin‐induced type 1 diabetes mellitus; (2) high‐fat‐diet–induced glucose intolerance; and transgenic inducible cardiac‐restricted expression of (3) glucose transporter 4 (transgenic inducible cardiac restricted expression of glucose transporter 4); or (4) dominant negative O ‐GlcNAcase. Elevated blood glucose (type 1 diabetes mellitus and high‐fat diet mice) was associated with reduced cardiac expression of β‐hydroxybutyrate‐dehydrogenase and succinyl‐CoA:3‐oxoacid CoA transferase. Increased myocardial β‐hydroxybutyrate levels were also observed in type 1 diabetes mellitus mice, suggesting a mismatch between ketone body availability and utilization. Increased cellular glucose delivery in transgenic inducible cardiac restricted expression of glucose transporter 4 mice attenuated cardiac expression of both Bdh1 and Oxct1 and reduced rates of myocardial BDH1 activity and β‐hydroxybutyrate oxidation. Moreover, elevated cardiac protein O ‐GlcNAcylation (a glucose‐derived posttranslational modification) by dominant negative O ‐GlcNAcase suppressed β‐hydroxybutyrate dehydrogenase expression. Consistent with the mouse models, transcriptomic analysis confirmed suppression of BDH1 and OXCT1 in patients with type 2 diabetes mellitus and heart failure compared with nondiabetic patients. Conclusions Our results provide evidence that increased glucose leads to suppression of cardiac ketolytic capacity through multiple mechanisms and identifies a potential crosstalk between glucose and ketone body metabolism in the diabetic myocardium.

No abstract

African Americans (AA) have an elevated risk for cardiovascular diseases compared to Caucasian Americans (CA), including heart failure (HF). Type 2 diabetes (T2D) is a major risk factor for HF that also disproportionately affects AA. These health disparities and others reduce life expectancy ~3.5 y for AA compared to CA. While prior studies have explored the connection between diabetes and heart failure, the current understanding of HF pathogenesis is based almost exclusively from studies of CA, whereas those considering race have been either epidemiologic or narrow in focus. The purpose of this study was to examine things from a different angle through the use of genome-wide RNA-sequencing to uncover how diabetes differentially or similarly affects end-stage heart failure in AA vs CA. To accomplish this, human biopsy samples were obtained from 32 age and diabetes status (T2D or non-diabetic (ND)) matched male patients undergoing left ventricle assist device surgeries (n = 8: CA-ND, CA-T2D, AA-ND, AA-T2D). Differential expression analysis was then performed using generalized linear modeling to control for clinical covariates including hypertension and coronary artery disease. Results of T2D vs ND in AA patients showed a greater number of differentially expressed genes (DEGs, P < 0.05,

Cardiovascular diseases, including ischemic heart failure (IHF), are the leading cause of mortality worldwide; furthermore, African Americans (AA) have 30% higher mortality than Caucasian Americans (CA). Our recent study correlates racial differences in socioeconomic status with DNA methylation (DNAm), altered gene expression, and mortality in HF independent of etiology. The current analysis focused on etiology-specific differences in DNAm with a specific focus on IHF, the related changes in gene expression, within self-reported race. RNA-seq expression ( P < 0.05, ±1.5-fold) and array-based methylation ( P < 0.05, ±5%) profiles were examined using cardiac biopsies from non-IHF (NIHF) and IHF AA (n = 9/5) and CA (n = 10/5) male patients. Network clusters were identified with MCODE (v2.0) and top hub genes identified via Cytohubba (v0.1). Both AA and CA patients showed similar numbers of IHF-specific differentially expressed genes (DEG) (591/365 AA; 439/486 CA; up/down). However, CA-specific methylation changes (29703/22703; up/down) were more abundant compared to AA (2904/2897; up/down). PPI network construction of these changes identified clusters unique to each group. The AA-specific upregulated cluster included AGPAT2, PPARG, and 10 other DEG associated with the fatty acid metabolism, while BMP2, SMAD6, and 4 other DEG that regulate BMP signaling and SMAD phosphorylation were downregulated. The CA-specific upregulated cluster included EZH2, CCNA1, and 18 other DEG that regulate mitotic sister chromatic separation, while EGFR, TNF, and 12 other DEG important for chronic inflammatory response formed the top downregulated cluster. Consistent with greater changes in DNAm the majority of DEGs in CA-specific clusters were also differentially methylated (58%) while fewer were in AA-specific clusters (17%). Within AA-specific PPI networks, PPARG/BMP2 (up/down) were the top ranked hub genes and KIF20A/KIT (up/down) in CA-specific networks. These racially distinct hub genes suggest altered regulatory mechanisms. Our analysis identified racially distinct clusters associated with specific pathways, which may connect the regulators of DNAm to gene expression and IHF, supporting the potential to use this information as prognostic biomarkers.