Human cardiac metabolism.

The heart is the most metabolically active organ in the human body, and cardiac metabolism has been studied for decades. However, the bulk of studies have focused on animal models. The objective of this review is to summarize specifically what is known about cardiac metabolism in humans. Techniques available to study human cardiac metabolism are first discussed, followed by a review of human cardiac metabolism in health and in heart failure. Mechanistic insights, where available, are reviewed, and the evidence for the contribution of metabolic insufficiency to heart failure, as well as past and current attempts at metabolism-based therapies, is also discussed.

Effect of empagliflozin on ectopic fat stores and myocardial energetics in type 2 diabetes: the EMPACEF study.

BACKGROUND: Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that has demonstrated cardiovascular and renal protection in patients with type 2 diabetes (T2D). We hypothesized that empaglifozin (EMPA) could modulate ectopic fat stores and myocardial energetics in high-fat-high-sucrose (HFHS) diet mice and in type 2 diabetics (T2D). METHODS: C57BL/6 HFHS mice (n = 24) and T2D subjects (n = 56) were randomly assigned to 12 weeks of treatment with EMPA (30 mg/kg in mice, 10 mg/day in humans) or with placebo. A 4.7 T or 3 T MRI with 1H-MRS evaluation-myocardial fat (primary endpoint) and liver fat content (LFC)-were performed at baseline and at 12 weeks. In humans, standard cardiac MRI was coupled with myocardial energetics (PCr/ATP) measured with 31P-MRS. Subcutaneous (SAT) abdominal, visceral (VAT), epicardial and pancreatic fat were also evaluated. The primary efficacy endpoint was the change in epicardial fat volume between EMPA and placebo from baseline to 12 weeks. Secondary endpoints were the differences in PCr/ATP ratio, myocardial, liver and pancreatic fat content, SAT and VAT between groups at 12 weeks. RESULTS: In mice fed HFHS, EMPA significantly improved glucose tolerance and increased blood ketone bodies (KB) and ß-hydroxybutyrate levels (p < 0.05) compared to placebo. Mice fed HFHS had increased myocardial and liver fat content compared to standard diet mice. EMPA significantly attenuated liver fat content by 55%, (p < 0.001) but had no effect on myocardial fat. In the human study, all the 56 patients had normal LV function with mean LVEF = 63.4 ± 7.9%. Compared to placebo, T2D patients treated with EMPA significantly lost weight (- 2.6 kg [- 1.2; - 3.7]) and improved their HbA1c by 0.88 ± 0.74%. Hematocrit and EPO levels were significantly increased in the EMPA group compared to placebo (p < 0.0001, p = 0.041). EMPA significantly increased glycosuria and plasma KB levels compared to placebo (p < 0.0001, p = 0.012, respectively), and significantly reduced liver fat content (- 27 ± 23 vs. - 2 ± 24%, p = 0.0005) and visceral fat (- 7.8% [- 15.3; - 5.6] vs. - 0.1% [- 1.1;6.5], p = 0.043), but had no effect on myocardial or epicardial fat. At 12 weeks, no significant change was observed in the myocardial PCr/ATP (p = 0.57 between groups). CONCLUSIONS: EMPA effectively reduced liver fat in mice and humans without changing epicardial, myocardial fat or myocardial energetics, rebutting the thrifty substrate hypothesis for cardiovascular protection of SGLT2 inhibitors. Trial registration NCT, NCT03118336. Registered 18 April 2017, https://clinicaltrials.gov/ct2/show/NCT03118336.

Myocardial bioenergetic abnormalities in experimental uremia.

PURPOSE: Cardiac bioenergetics are known to be abnormal in experimental uremia as exemplified by a reduced phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio. However, the progression of these bioenergetic changes during the development of uremia still requires further study and was therefore investigated at baseline, 4 weeks and 8 weeks after partial nephrectomy (PNx). METHODS: A two-stage PNx uremia model in male Wistar rats was used to explore in vivo cardiac and skeletal muscles' bioenergetic changes over time. High-energy phosphate nucleotides were determined by phosphorus-31 nuclear magnetic resonance ((31)P-NMR) and capillary zone electrophoresis. RESULTS: (31)P-NMR spectroscopy revealed lower PCr/ATP ratios in PNx hearts compared to sham (SH)-operated animals 4 weeks after PNx (median values given ± SD, 0.64±0.16 PNx, 1.13±0.31 SH, P<0.02). However, 8 weeks after PNx, the same ratio was more comparable between the two groups (0.84±0.15 PNx, 1.04±0.44 SH, P= not significant), suggestive of an adaptive mechanism. When 8-week hearts were prestressed with dobutamine, the PCr/ATP ratio was again lower in the PNx group (1.08±0.36 PNx, 1.55±0.38 SH, P<0.02), indicating a reduced energy reserve during the progression of uremic heart disease. (31)P-NMR data were confirmed by capillary zone electrophoresis, and the changes in myocardial bioenergetics were replicated in the skeletal muscle. CONCLUSION: This study provides evidence of the changes that occur in myocardial energetics in experimental uremia and highlights how skeletal muscle bioenergetics mirror those found in the cardiac tissue and so might potentially serve as a practical surrogate tissue during clinical cardiac NMR investigations.