Myocardial Glucose Uptake Research Articles

Effect of Hyperketonemia on Myocardial Function in Patients with Heart Failure and Type 2 Diabetes.

We examined the effect of increased plasma ketones on left ventricular (LV) function, myocardial glucose uptake (MGU), and myocardial blood flow (MBF) in type 2 diabetes (T2DM) patients with heart failure (HF). Three groups (I,II,III) of T2DM (12 per group) with LV ejection fraction ≤50% received incremental infusions of β-OH-B for 3-6 hours to raise plasma β-OH-B concentration throughout the physiologic (Groups I and II) and pharmacologic (Group III) range. Cardiac MRI was performed at baseline and after each β-OH-B infusion to provide measures of cardiac function. On a separate day, Group II also received NaHCO3 infusion, thus serving as their own control for time, volume, and pH. Additionally, Group II underwent positron emission tomography study with 18F-fluoro-2-deoxyglucose to examine effect of hyperketonemia on MGU. Groups I, II, III achieved plasma β-OH-B levels of 0.7±0.3, 1.6±0.2, 3.2±0.2 mmol/L, respectively. Cardiac output, LVEF, and stroke volume increased significantly during β-OH-B infusion in Groups II (CO, 4.54 to 5.30; EF, 39.9 to 43.8; SV, 70.3 to 80.0) and III (CO, 5.93 to 7.16; EF, 41.1 to 47.5; SV, 89.0 to 108.4) and did not change with NaHCO3 infusion in Group II. The increase in LVEF was greatest in Group III (p<0.001 vs Group II). MGU and MBF were not altered by β-OH-B. In T2DM patients with LVEF≤50%, increased plasma β-OH-B significantly increased LV function dose-dependently. Since MGU did not change, the myocardial benefit of β-OH-B resulted from providing an additional fuel for the heart without inhibiting MGU.

Association between appendicular skeletal muscle mass and myocardial glucose uptake measured by 18F-FDG PET.

Low muscle mass is associated with high insulin resistance and an increased risk of cardiovascular disease. This study aims to determine whether low muscle mass affects the alterations in myocardial substrate metabolism that are associated with the development of cardiovascular disease. The study included 299 individuals (182 men and 117 women) who underwent examination at the Severance Health Check-up Center between January 2018 and February 2019. Myocardial glucose uptake was assessed using [18F]-fluorodeoxyglucose-positron emission tomography (18F-FDG PET/CT) scanning. Direct segmental bioimpedance analysis was used to measure appendicular skeletal muscle mass (ASM). We analysed men and women separately owing to sex-related body composition differences. ASM/Ht2 was significantly positively correlated with myocardial glucose uptake measured by 18F-FDG PET/CT [ln (SUVheart/liver)] only in men (r=0.154, P=0.038 in men; r=-0.042, P=0.652 in women, respectively). In men, myocardial glucose uptake was significantly associated with ASM/Ht2 even after adjusting for multiple confounders in a multivariable linear regression model (standardized β=0.397, P=0.004, in men; β=-0.051, P=0.698, in women). In women, age (β=-0.424 P=0.029) was independent determinants of myocardial glucose uptake. In men, ASM was strongly associated with myocardial glucose uptake as measured by 18F-FDG PET/CT. In women, age was significantly correlated with myocardial substrate utilization, but not with ASM.

Evaluation of Clinical Variables Affecting Myocardial Glucose Uptake in Cardiac FDG PET.

Cardiac 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography (FDG PET) is widely used to assess myocardial viability in patients with ischemic heart disease. While sufficient glucose uptake is a prerequisite for accurate interpretation of cardiac viability, there are a lack of data on which clinical variables have the most significant impact on myocardial glucose metabolism. Therefore, this study was designed to evaluate several clinical variables that could affect myocardial glucose metabolism. A total of 214 consecutive cases were retrospectively enrolled in this study. All subjects received 250 mg of acipimox and underwent glucose loading as preparation for cardiac FDG PET/CT. Three-dimensional regions of interest (ROIs) were drawn on PET/CT fusion images. Myocardial glucose uptake ratio (MGUR = SUVmax of LV myocardium/SUVmean of liver) was then calculated. Multiple clinical variables including body mass index (BMI), blood glucose levels at different times, administered insulin dosage, lipid profiles, and ejection fraction were measured and analyzed for correlation with myocardial glucose uptake. After dichotomizing the subjects based on a BMI of 25, each group's MGUR was compared. Myocardial uptake showed significant correlations with BMI (r = -0.162, p = 0.018), HbA1c (r = -0.150, p = 0.030), and triglyceride levels (r = -0.137, p = 0.046). No other clinical variables showed a significant correlation with myocardial glucose uptake. After multiple linear regression analysis, BMI (p = 0.032) and HbA1c (p = 0.050) showed a correlation with MGUR. In group analysis, after dividing patients based on BMI, the obese group showed significantly lower myocardial uptake than the non-obese group (3.8 ± 1.9 vs. 4.4 ± 2.1, p = 0.031). Among several clinical variables, BMI and HbA1c levels were related to myocardial glucose uptake. A prospective study would be needed to examine whether a protocol that additionally considers BMI and HbA1c levels is necessary for the current cardiac FDG PET protocol.

Relationship of Ketosis With Myocardial Glucose Uptake Among Patients Undergoing FDG PET/CT for Evaluation of Cardiac Sarcoidosis.

Fluorine-18 fluorodeoxyglucose (FDG) with positron emission tomography (PET) is the standard for detecting myocardial inflammation in cardiac sarcoidosis, requiring preparation with the ketogenic diet (KD) to achieve myocardial glucose suppression. Despite this, incomplete myocardial glucose suppression remains a significant issue, and strategies to reduce myocardial glucose uptake (MGU) and identify incomplete myocardial glucose suppression are required. This study sought to understand the relationship between point-of-care beta-hydroxybutyrate (BHB) and different patterns of MGU and between KD and fasting duration with MGU in patients undergoing evaluation for cardiac sarcoidosis. We prospectively included 471 outpatients who underwent FDG-PET for cardiac sarcoidosis evaluation, followed the KD for 1 (n=100), 2 (n=29), and ≥3 days (n=342), fasted for at least 12 hours, and had BHB levels measured immediately before FDG injection. Images were classified as (1) no MGU (negative), (2) focal/multifocal (positive), (3) diffuse (nondiagnostic), or (4) nonspecific uptake (NS-MGU). Cardiac FDG-PET scans were interpreted as the following: 376 (79.83%) negative; 61 (12.95%) positive; 14 (2.97%) diffuse; and 20 (4.25%) NS-MGU. There was a strong negative relationship between BHB levels and MGU (P<0.0001). BHB levels increased significantly with KD duration (P<0.0001) and fasting time (P=0.0067). The combined rate of diffuse, NS-MGU, and positive scans (34%, 28%, 16%) decreased inversely with KD duration (1, 2, and ≥3 days, respectively). However, MGU was not different across different fasting times (P=0.6). Blood glucose levels were not associated with MGU (P=0.17) and only weakly associated with BHB levels (R2=0.03; P<0.001). We observed a strong inverse relationship between ketosis and patterns of MGU. Longer KD and fasting durations are associated with higher ketosis. However, only KD duration was associated with lower rates of MGU. Measurement of BHB levels before FDG-PET using point-of-care testing is feasible and may facilitate the management of patients referred for myocardial inflammation.

Adropin Treatment Restores Cardiac Function and Metabolic Flexibility in Diabetic Cardiomyopathy

Background: Diabetic cardiomyopathy (DCM) is a major complication of diabetes, and has been recognized as a cause of heart failure independent of other common risk factors. Metabolic inflexibility is a hallmark feature, where increased free fatty acid availability and decreased myocardial glucose uptake lead to an over-reliance on fatty acid oxidation, reducing cardiac work effciency. Energetic ineffciency in diabetic hearts may have profound implications for cardiac function under conditions of increased workload, and therefore therapeutic approaches are warranted. Adropin is a liver- and brain-secreted peptide hormone shown to regulate fuel metabolism in the heart. Adropin levels are significantly reduced in obese and diabetic human subjects, and this decrease is linked to increased adiposity, insulin resistance, and impaired glucose tolerance. Our lab recently showed that acute adropin treatment restores glucose oxidation activity in the hearts of prediabetic obese mice. However, the effects of chronic adropin exposure in the heart remains unknown. Hypothesis: We hypothesize that adropin treatment will exhibit beneficial effects on cardiac fuel metabolism that may lead to long-term improvements in functional output. Methods: We used a preclinical model of DCM to investigate the effects of long-term adropin treatment on cardiac structural and metabolic remodeling. Mice were treated with adropin daily for four weeks, and subjected to echocardiography, glucose tolerance tests, histopathology, RNA-sequencing, and metabolomics. Results: We report that long-term adropin treatment restores normal cardiac structure and metabolic function in the diabetic heart, by inhibiting flux of non-oxidative glycolytic intermediates into the hexosamine biosynthetic pathway. Conclusions: Our findings highlight the therapeutic potential of adropin signaling to attenuate cardiac remodeling in DCM. The project described was supported by NIDDK 1F31DK134089 and NHLBI R01HL147861. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Standardized ketogenic dietary preparation for metabolic PET imaging in suspected and known cardiac sarcoidosis.

A major limitation of cardiac positron emission tomography (PET) with F18-fluorodeoxyglucose (F18-FDG) for the evaluation of cardiac sarcoidosis (CS) is associated with physiologic myocardial glucose uptake. The optimal dietary protocol to suppress physiologic myocardial F18-FDG uptake is not well-established. We aimed to evaluate the diagnostic performance of a novel dietary preparation using a ketone-based infant formula. Between 2018 and 2021, consecutive studies using a ketogenic dietary preparation were identified (n = 198). The rate of non-diagnostic studies due to failure to suppress myocardial glucose was 7.1% (n = 14) with a similar incidence in diabetics (n = 6, 8.1%). Among studies reported to have no inflammation (n = 137), 130 studies (66%) had mean myocardial standardized uptake value (SUV) less than or equal to mean blood pool SUV. Patient preparation with a ketone-based infant formula resulted in low rate of inappropriate myocardial glucose suppression in patients undergoing F18-FDG cardiac PET to evaluate CS.

Left atrial glucose metabolism by 18F-FDG PET/CT in persistent atrial fibrillation and after return to sinus rhythm

Abstract Background Atrial Fibrillation (AF) is strongly associated with the development of Left Atrial (LA) remodeling. Animal studies pointed to an important role of metabolic deregulation in AF, yet few studies have assessed LA myocardial metabolism in vivo in patients with AF. 18-fluorodeoxyglucose (FDG) Positron Emission tomography (PET) has been widely used for evaluation of left ventricular (LV) metabolism, but its application to study metabolism of LA has not yet been explored. Purpose The aim of this study was to evaluate LA glucose metabolism and contractile efficiency in patients with persistent AF, following our successful implementation of a protocol enabling the acquisition of high-resolution PET images of the LA. Methods 36 nondiabetic patients (64±7 years, 29 men) with persistent non valvular AF (peAF) undergoing a first AF ablation and 5 healthy age matched volunteers (69±5 years, 3 men, p=0.114) without AF underwent FDG PET, speckle tracking echocardiography (STE) and cardiac MRI (cMR). PET was performed after overnight fasting and after administration of a nicotinic acid derivative (Acipimox 250 mg) to maximally stimulate myocardial glucose uptake. The 3 tests were repeated 3 months later in 26 patients in whom return to permanent sinus rhythm (SR) could be obtained after the ablation procedure. PET images were registered with cMR LA angiography, and the mean partial volume and spillover corrected standardized FDG uptake (SUV) in the whole LA, the left atrial appendage (LAA), and the left ventricle (LV) were computed. Measurements were compared to global Peak Atrial Longitudinal Strain (GPALS) and to left atrial ejection fraction (LAEF) measured by STE and LA contractile efficiency was computed as the ratio of LA SUV to LAEF. Results Hemodynamics (syst. BP mmHg: 128±11 vs 129±5 mmHg, p=0.663) and metabolic parameters (glycemia: 99±14 vs 96±7 mg/dl, p=0.480) were similar in peAF patients and healthy controls. While 18F-FDG SUV in the LV was comparable between pEAF patients and healthy controls, patients in peAF exhibited significantly increased SUV in LA and LAA compared to controls. Following a return to SR, LA-SUVmean and LAA-SUVmean in patients peAF decreased significantly after 3 months (20.3%, p&amp;lt;0.002 and 34.1%, p&amp;lt;0.001), whereas the LV-SUVmean remained unchanged (p=0.847). The Global Peak Atrial Longitudinal Strain (GPALS) increased by 54.2%(p&amp;lt;0.001), and the Left Atrial Ejection Fraction (LAEF) by 39.2% (p&amp;lt;0.001), post-restoration of SR. (Figure 1). Accordingly contractile efficiency of LA SUV/LAEF in peAF patients improved significantly upon their return to SR (47%, p&amp;lt;0.001). Conclusion LA glucose metabolism is significantly increased in peAF and return after restoration of SR. This could indicate oxygen wasting and reduced contractile efficiency of AF or metabolic shift towards preferred glucose metabolism in AF. These findings support the notion that LA glucose metabolism plays a role in the pathophysiology of AF.Figure 1Figure 2

Abstract 18692: Relationship Between Fasting Time on Ketogenic Diet and Myocardial Glucose Suppression in Patients Referred for Cardiac Sarcoidosis Evaluation on FDG-PET Imaging

Introduction: FDG-PET imaging is standard for assessing myocardial inflammation for cardiac sarcoidosis (CS). Preparation with the ketogenic diet (KD) is required to suppress physiologic myocardial glucose uptake (MGU), thereby highlighting pathologic MGU. Incomplete physiologic myocardial glucose suppression (MGS) continues to limit FDG-PET. The effect of fasting time (FT) on MSG remains unexplored. Goal: To identify if FT is an independent predictor of MGS following a KD in patients undergoing FDG-PET imaging. Methods: We prospectively included 442 consecutive patients (59.2 ± 10.9 yrs, 39% female, 55% white) who underwent 590 FDG-PET scans for the evaluation of CS after following a KD at our institution between 2021 and 2023. Time from last meal to FDG injection was documented in all patients. Serum BHB levels were measured in 516 scans. FDG PET images were classified as 1) diagnostic (complete MGS) when there was either no MGU (negative) or multifocal uptake (positive), or 2) nondiagnostic (incomplete MGS) when there was either diffuse left ventricular or nonspecific uptake. Results: The KD was followed for 1, 2 or ≥3 days in 127 (22%), 61 (10%), and 402 (68%) of cases respectively. FDG-PET scans were interpreted as the following: 436 (74%) negative; 109 (18.3%) positive; 13 (2.2%) diffuse; 32 (5.4%) nonspecific uptake. Patients on the KD for only 1 day had higher rates of MGS with increased FT (β = 0.33 ± 0.11, p &lt;0.01); this correlation did not hold true for patients on KD for 2 days (β = -0.005 ± 0.09, p = 0.96) whereas, patients on the KD for 3 or more days showed lower rates of MGS with increased FT (β = -0.18 ±0.07, p&lt;0.01) ( Figure 1 ). When adjusting for BHB level, the correlation between MGS and FT held true (1 day: β = 0.35 ± 0.13, p &lt;0.01; 2 days: β = 0.26 ± 0.28, p = 0.35; 3 days: β = -0.17 ± 0.07, p = 0.02). Conclusion: Fasting time appears to be most beneficial in patients following the KD for 1-day only. Patients following the KD for 2 days or longer may not require overnight fasting.

Multifaceted Roles of GLP-1 and Its Analogs: A Review on Molecular Mechanisms with a Cardiotherapeutic Perspective.

Diabetes is one of the chronic metabolic disorders which poses a multitude of life-debilitating challenges, including cardiac muscle impairment, which eventually results in heart failure. The incretin hormone glucagon-like peptide-1 (GLP-1) has gained distinct recognition in reinstating glucose homeostasis in diabetes, while it is now largely accepted that it has an array of biological effects in the body. Several lines of evidence have revealed that GLP-1 and its analogs possess cardioprotective effects by various mechanisms related to cardiac contractility, myocardial glucose uptake, cardiac oxidative stress and ischemia/reperfusion injury, and mitochondrial homeostasis. Upon binding to GLP-1 receptor (GLP-1R), GLP-1 and its analogs exert their effects via adenylyl cyclase-mediated cAMP elevation and subsequent activation of cAMP-dependent protein kinase(s) which stimulates the insulin release in conjunction with enhanced Ca2+ and ATP levels. Recent findings have suggested additional downstream molecular pathways stirred by long-term exposure of GLP-1 analogs, which pave the way for the development of potential therapeutic molecules with longer lasting beneficial effects against diabetic cardiomyopathies. This review provides a comprehensive overview of the recent advances in the understanding of the GLP-1R-dependent and -independent actions of GLP-1 and its analogs in the protection against cardiomyopathies.

Progressive Cardiac Metabolic Defects Accompany Diastolic and Severe Systolic Dysfunction in Spontaneously Hypertensive Rat Hearts.

Background Cardiac metabolic abnormalities are present in heart failure. Few studies have followed metabolic changes accompanying diastolic and systolic heart failure in the same model. We examined metabolic changes during the development of diastolic and severe systolic dysfunction in spontaneously hypertensive rats (SHR). Methods and Results We serially measured myocardial glucose uptake rates with dynamic 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography in vivo in 9-, 12-, and 18-month-old SHR and Wistar Kyoto rats. Cardiac magnetic resonance imaging determined systolic function(ejection fraction) and diastolic function (isovolumetric relaxation time) and left ventricular mass in the same rats. Cardiac metabolomics was performed at 12 and 18 months in separate rats. At 12 months, SHR hearts, compared with Wistar Kyoto hearts, demonstrated increased isovolumetric relaxation time and slightly reduced ejection fraction indicating diastolic and mild systolic dysfunction, respectively, and higher (versus 9-month-old SHR decreasing) 2-[18F] fluoro-2-deoxy-d-glucose uptake rates (Ki). At 18 months, only few SHR hearts maintained similar abnormalities as 12-month-old SHR, while most exhibited severe systolic dysfunction, worsening diastolic function, and markedly reduced 2-[18F] fluoro-2-deoxy-d-glucose uptake rates. Left ventricular mass normalized to body weight was elevated in SHR, more pronounced with severe systolic dysfunction. Cardiac metabolite changes differed between SHR hearts at 12 and 18 months, indicating progressive defects in fatty acid, glucose, branched chain amino acid, and ketone body metabolism. Conclusions Diastolic and severe systolic dysfunction in SHR are associated with decreasing cardiac glucose uptake, and progressive abnormalities in metabolite profiles. Whether and which metabolic changes trigger progressive heart failure needs to be established.

Effective suppression of myocardial glucose uptake using predesigned low-carbohydrate boxed meals

BackgroundDietary preparation protocols are an effective means to suppress physiological myocardial 18F-fluorodeoxyglucose (FDG) uptake. This study aimed to investigate the efficacy of various carbohydrate-restricted diets using predesigned boxed meals. MethodsThe patients were divided into four groups to undergo different preparatory protocols as follows: a minimum 15-hour fast alone, two meals of high-fat, low-carbohydrate diet (HFLCD), two meals of high-animal-protein, low-carbohydrate diet (HAPLCD), and two meals of high-plant-based-protein, low-carbohydrate diet (HPPLCD). Boxed meals were prepared to meet the required carbohydrate restrictions. Myocardial SUVmax and SUVmean were measured and the suppression rate was analyzed. ResultsThe average myocardial SUVmax of fast alone, HFLCD, HAPLCD, and HPPLCD were 8.26 ± 5.85, 2.21 ± 1.50, 2.34 ± 1.88, and 4.10 ± 3.61, respectively, and the suppression rates were 36.6%, 93.3%, 93.3%, and 70%, respectively. The effectiveness of HFLCD, HAPLCD, and HPPLCD was all statistically superior to that of a 15-hour fast alone. SUVmax of HFLCD and HAPLCD showed no significant differences (p = 1), whereas HFLCD and HPPLCD had significant differences (p = .046). ConclusionsUsing the predesigned boxed meals based on carbohydrate restriction, HFLCD, HAPLCD, and HPPLCD can be administered to patients with different dietary needs while providing a substantial reduction in physiological myocardial FDG uptake.

Caloric restriction increases the resistance of aged heart to myocardial ischemia/reperfusion injury via modulating AMPK–SIRT1–PGC1a energy metabolism pathway

A large number of data suggest that caloric restriction (CR) has a protective effect on myocardial ischemia/reperfusion injury (I/R) in the elderly. However, the mechanism is still unclear. In this study, we created the I/R model in vivo by ligating the mice left coronary artery for 45 min followed by reperfusion. C57BL/6J wild-type mice were randomly divided into a young group fed ad libitum (y-AL), aged fed ad libitum (a-AL) and aged calorie restriction group (a-CR, 70% diet restriction), and fed for 6 weeks. The area of myocardial infarction was measured by Evan’s blue-TTC staining, plasma cholesterol content quantified by ELISA, fatty acids and glucose measured by Langendorff working system, as well as protein expression of AMPK/SIRT1/PGC1a signaling pathway related factors in myocardial tissue detected by immunoblotting. Our results showed that CR significantly reduced infarct size in elderly mice after I/R injury, promoted glycolysis regardless of I/R injury, and restored myocardial glucose uptake in elderly mice. Compared with a-AL group, CR significantly promoted the expression of p-AMPK, SIRT1, p-PGC1a, and SOD2, but decreased PPARγ expression in aged mice. In conclusion, our results suggest that CR protects elderly mice from I/R injury by altering myocardial substrate energy metabolism via the AMPK/SIRT1/PGC1a pathway.

The utility of beta-hydroxybutyrate in detecting myocardial glucose uptake suppression in patients undergoing inflammatory [18F]-FDG PET studies.

We evaluated whether serum beta-hydroxybutyrate (BHB) can identify adequate suppression of the left ventricle (LV) among patients undergoing [18F]-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET) for cardiac inflammatory/infectious studies. Consecutive patients who underwent [18F]-FDG PET imaging were included. Serum BHB levels were measured in all patients on the day of imaging prior to injecting [18F]-FDG. Myocardial [18F]-FDG suppression was defined if [18F]-FDG uptake in the walls of myocardium, measured using standardized uptake values (SUV), was lower than the blood pool. The optimal threshold of BHB to identify myocardial suppression was based on receiver operating characteristics (ROC) in a random 30% sample of the study population (derivation cohort) and tested in the remaining 70% of sample (validation cohort). A total of 256 images from 220 patients were included. Patients with sufficient LV suppression had significantly higher BHB levels compared to those with non-suppressed myocardium (median (IQR) BHB 0.6 (0.3-0.8) vs. 0.2 (0.2-0.3) mmol/l, p < 0.001, respectively). BHB level ≥ 0.335mmol/l had a sensitivity of 84.90% and a specificity of 92.60% to identify adequate LV suppression in the validation cohort. All patients (100%) with BHB ≥ 0.41mmol/l had adequate myocardial suppression compared to 29.63% of patients with BHB ≤ 0.20mmol/l. Serum BHB level can be used at the point of care to identify sufficient LV suppression in patients undergoing [18F]-FDG PET cardiac inflammatory/infectious studies. Central illustration (image to the right) shows representative cases of patient images and BHB and, in the image to the left, shows the sensitivity and specificity to identify left myocardial suppression using BHB in validation group.

#1315139: Cardiometabolic Effects of Elevated Plasma Ketones in Patients with Heart Failure and T2DM

This research study aims to discern the mechanism(s) responsible for the cardiac benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors. SGLT2 inhibitors induce systemic ketosis, but whether this is a mechanism of benefit in relation to improved cardiac function is currently unclear. To further elucidate this relationship, the effect of increased ketone concentration (with infusion of beta-hydroxybutyrate [BOHB]) on left ventricular (LV) function and myocardial glucose uptake (MGU) was done.

Abstract 10378: Metabolomic Signatures of Myocardial Glucose Uptake on FDG-PET

Introduction: FDG-PET is critical for evaluating myocardial inflammation, but requires preparation with a ketogenic diet (KD) to suppress physiologic myocardial glucose uptake (MGU). Even in monitored settings, incomplete suppression occurs in ~20% and remains the Achilles’ heel of the KD technique. We recently found in a crossover trial (NCT04275453; KEETO-CROSS) that despite achieving robust ketosis, ketone ester (KE) drink was inferior to KD to suppress MGU. We sought to understand whether a common metabolite signature might predict myocardial glucose suppression (MGS) irrespective of technique to ensure adequate myocardial preparation. Methods: Twenty healthy participants were first randomly assigned to acute KE ingestion or KD (24/72 hour visits) with subsequent crossover. Targeted plasma metabolomic profiling of 61 metabolites was performed at these 3 visits paired with FDG-PET. The association between metabolites and MGU was assessed using mixed effects linear regression. Results: The mean age of the participants was 30±7 years (50% women and 45% non-white). The Figure shows volcano plots for the relationship between metabolites and MGU. In both arms, two C4-OH carnitine species (markers of ketone/fatty acid oxidation) were strongly and inversely associated with MGU. Both species (C4-OH isobutyrylcarnitine and C4-OH butyrylcarnitine) were predictive of MGS in all patients (c-statistic 0.83, 95% CI 0.65-1.00 and 0.81, 95% CI 0.70-0.92, respectively) and much stronger than ketone/fatty acid levels. C4-OH isobutyrylcarnitine levels were higher during 24/72 hour KD visits than KE (p=0.018 and p=0.003). Conclusions: Metabolite markers of ketone and fatty acid oxidation strongly predict MGS, have robust discriminatory value, and may be used upstream of FDG-PET to reduce false positive scans. Strategies to enhance ketone/fatty acid oxidation (rather than circulating ketone/fatty acid levels) may improve MGS.

Impact of metabolic substrate modification on myocardial efficiency in a rat model of obesity and diabetes

Abstract Background Congenic leptin receptor deficient rat generated by introgression of the Koletsky leptin receptor mutation into BioBreeding Diabetes Resistant rat (BBDR.lepr−/−) is a novel animal model combining obesity, systemic insulin resistance and diabetes. Systemic insulin resistance is associated with reduced myocardial glucose utilization, but its effect on myocardial external efficiency, i.e. the ability of the myocardium to convert energy into external stroke work, remains uncertain. Purpose To characterize cardiac energy metabolism and function in BBDR.lepr−/− rats and to study the effect of dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin in this model. Methods Cardiac phenotype was evaluated in six-month-old male BBDR.lepr−/− rats (n=11) and age-matched male non-diabetic lean control littermates (BBDR.lepr+/− or BBDR.lepr+/+ rats, n=14). Of these, 7 BBDR.lepr−/− rats and 6 controls underwent cardiac ultrasound, 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT), and [11C]acetate PET in order to evaluate cardiac structure and function as well as glucose and oxidative metabolism. In the remaining rats, fatty acid metabolism was evaluated by [18F]fluorothia-6-heptadecanoic acid ([18F]FTHA) PET/CT. In the linagliptin intervention study, 25 BBDR.lepr−/− male rats were randomly divided into control group (n=11) that received regular chow diet and linagliptin group (n=14) that received linagliptin (10mg/kg/d) mixed in the chow diet for three months. After the intervention, the rats underwent cardiac ultrasound, [18F]FDG PET/CT, and [11C]acetate PET. Results Compared with controls, BBDR.lepr−/− rats showed increased left ventricle (LV) mass (∼40%, p&amp;gt;0.001) and higher systolic blood pressure (∼10%, p=0.02). However, fractional shortening and cardiac output were similar in both groups. Myocardial fractional uptake rate of glucose measured with [18F]FDG PET was significantly reduced (∼86%, p=0.004) (Fig. 1A, E), whereas myocardial fatty acid uptake measured by [18F]FTHA PET was not significantly increased (free fatty acid (FFA) corrected standardized uptake value (SUV) ∼21%, p=0.54) (Fig. 1B) in BBDR.lepr−/− compared to controls. Myocardial oxygen consumption assessed by [11C]acetate PET was similar in both groups (Fig. 1C, E), but LV work per gram of myocardium was reduced (∼28%, p=0.001) resulting in reduced myocardial external efficiency (∼21%, p=0.03) (Fig. 1D) in BBDR.lepr−/− compared to controls. Treatment with linagliptin significantly enhanced myocardial fractional uptake rate of glucose (∼166%, p=0.006) (Fig. 2A, C), but had no effect on efficiency of cardiac work (Fig. 2B). Conclusions Obese and diabetic BBDR.lepr−/− rats demonstrate LV hypertrophy and markedly reduced myocardial glucose utilization associated with impaired myocardial external efficiency despite normal LV systolic function. Enhancement of myocardial glucose uptake by linagliptin did not improve efficiency of cardiac work. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): IMI-SUMMIT

Ketogenic diet modulates cardiac metabolic dysregulation in streptozocin-induced diabetic rats

The ketogenic diet (KD) might improve cardiac function in diabetic cardiomyopathy, but the mechanisms remain unclear. This study investigated the effects of KD on myocardial fatty acid (FA), glucose, and ketone metabolism in diabetic cardiomyopathy. Echocardiograms, biochemistry, and micro-positron emission tomography were performed to evaluate cardiac function and glucose uptake in control rats and streptozotocin-induced diabetes mellitus (DM) rats with normal diet (ND) or KD for 6 weeks. Histopathology, adenosine triphosphate measurement, and Western blot were performed in the ventricular myocytes to analyze fibrosis, FA, ketone body, and glucose utilization. The ND-fed DM rats exhibited impaired left ventricular systolic function and increased chamber dilatation, whereas control and KD-fed DM rats did not. The KD reduced myocardial fibrosis and apoptosis in the DM rats. Myocardial glucose uptake in the micro-positron emission tomography was similar between ND-fed DM rats and KD-fed DM rats and was substantially lower than the control rats. Compared with the control rats, ND-fed DM rats had increased phosphorylation of acetyl CoA carboxylase and higher expressions of CD-36, carnitine palmitoyltransferase-1β, tumor necrosis factor-α, interleukin-1β, interleukin6, PERK, and e-IF2α as well as more myocardial fibrosis and apoptosis (assessed by Bcl-2, BAX, and caspase-3 expression); these increases were attenuated in the KD-fed DM rats. Moreover, ND-fed DM rats had significantly lower myocardial adenosine triphosphate, BHB, and OXCT1 levels than the control and KD-fed DM rats. The KD may improve the condition of diabetic cardiomyopathy by suppressing FA metabolism, increasing ketone utilization, and decreasing endoplasmic reticulum stress and inflammation.

Dapagliflozin improves myocardial flow reserve in patients with type 2 diabetes: the DAPAHEART Trial: a preliminary report

ObjectiveCardiovascular (CV) outcome trials have shown that in patients with type 2 diabetes (T2D), treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) reduces CV mortality and hospital admission rates for heart failure (HF). However, the mechanisms behind these benefits are not fully understood. This study was performed to investigate the effects of the SGLT-2i dapagliflozin on myocardial perfusion and glucose metabolism in patients with T2D and stable coronary artery disease (coronary stenosis ≥ 30% and < 80%), with or without previous percutaneous coronary intervention (> 6 months) but no HF.MethodsThis was a single-center, prospective, randomized, double-blind, controlled clinical trial including 16 patients with T2D randomized to SGLT-2i dapagliflozin (10 mg daily) or placebo. The primary outcome was to detect changes in myocardial glucose uptake (MGU) from baseline to 4 weeks after treatment initiation by [(18)F]2-deoxy-2-fluoro-D-glucose (FDG) PET/CT during hyperinsulinemic euglycemic clamp. The main secondary outcome was to assess whether the hypothetical changes in MGU were associated with changes in myocardial blood flow (MBF) and myocardial flow reserve (MFR) measured by 13N-ammonia PET/CT. The study was registered at eudract.ema.europa.eu (EudraCT No. 2016-003614-27) and ClinicalTrials.gov (NCT 03313752).Results16 patients were randomized to dapagliflozin (n = 8) or placebo (n = 8). The groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, renal and heart function). There was no significant change in MGU during euglycemic hyperinsulinemic clamp in the dapagliflozin group (2.22 ± 0.59 vs 1.92 ± 0.42 μmol/100 g/min, p = 0.41) compared with the placebo group (2.00 ± 0.55 vs 1.60 ± 0.45 μmol/100 g/min, p = 0.5). Dapagliflozin significantly improved MFR (2.56 ± 0.26 vs 3.59 ± 0.35 p = 0.006 compared with the placebo group 2.34 ± 0.21 vs 2.38 ± 0.24 p = 0.81; pint = 0.001) associated with a reduction in resting MBF corrected for cardiac workload (p = 0.005; pint = 0.045). A trend toward an increase in stress MBF was also detected (p = 0.054).ConclusionsSGLT-2 inhibition increases MFR in T2D patients. We provide new insight into SGLT-2i CV benefits, as our data show that patients on SGLT-2i are more resistant to the detrimental effects of obstructive coronary atherosclerosis due to increased MFR, probably caused by an improvement in coronary microvascular dysfunction.Trial registration EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752

Hybrid PET/MRI for inflammatory cardiomyopathy

HintergrundDie Myokarditis und die inflammatorische Kardiomyopathie sind aufgrund ihrer unterschiedlichen Auslöser, Phänotypen und Stadien diagnostisch häufig schwer zu diagnostizieren.Methodische Innovationen und ProblemeDie kardiale Positronen-Emissions-Tomographie/Magnetresonanztomographie (PET/MRT) zeichnet sich neben der myokardialen Gewebecharakterisierung mittels MRT durch den möglichen Nachweis einer aktiven myokardialen Entzündung (Inflammation) mittels PET aus. Die Kombination von MRT und PET ist somit eher synergistisch als rein summativ: Die möglicherweise in der MRT vorhandenen kardialen Veränderungen lassen sich durch die PET in aktive inflammatorische (und somit noch potenziell reversible) Prozesse oder ältere chronische (irreversible) Narben unterscheiden. Die kardiale Sarkoidose mit einem potenziellen Nebeneinander von aktiven und chronischen Veränderungen bietet sich an, um die Stärken einer hybriden PET/MRT zur Geltung bringen zu lassen. Wichtig für eine aussagekräftige kardiale PET ist eine gute Vorbereitung mit Low-Carb-Diät, um eine suffiziente Suppression der myokardialen Glukoseaufnahme zu gewährleisten.EmpfehlungenDie Diagnostik einer inflammatorischen Herzerkrankung sowie deren Charakterisierung in akut vs. chronische Prozesse gelingt mit der kardialen Hybrid-PET/MRT, wie am Beispiel der kardialen Sarkoidose gezeigt werden konnte.

Interaction of ARRDC4 With GLUT1 Mediates Metabolic Stress in the Ischemic Heart.

An ancient family of arrestin-fold proteins, termed alpha-arrestins, may have conserved roles in regulating nutrient transporter trafficking and cellular metabolism as adaptor proteins. One alpha-arrestin, TXNIP (thioredoxin-interacting protein), is known to regulate myocardial glucose uptake. However, the in vivo role of the related alpha-arrestin, ARRDC4 (arrestin domain-containing protein 4), is unknown. We first tested whether interaction with GLUTs (glucose transporters) is a conserved function of the mammalian alpha-arrestins. To define the in vivo function of ARRDC4, we generated and characterized a novel Arrdc4 knockout (KO) mouse model. We then analyzed the molecular interaction between arrestin domains and the basal GLUT1. ARRDC4 binds to GLUT1, induces its endocytosis, and blocks cellular glucose uptake in cardiomyocytes. Despite the closely shared protein structure, ARRDC4 and its homologue TXNIP operate by distinct molecular pathways. Unlike TXNIP, ARRDC4 does not increase oxidative stress. Instead, ARRDC4 uniquely mediates cardiomyocyte death through its effects on glucose deprivation and endoplasmic reticulum stress. At baseline, Arrdc4-KO mice have mild fasting hypoglycemia. Arrdc4-KO hearts exhibit a robust increase in myocardial glucose uptake and glycogen storage. Accordingly, deletion of Arrdc4 improves energy homeostasis during ischemia and protects cardiomyocytes against myocardial infarction. Furthermore, structure-function analyses of the interaction of ARRDC4 with GLUT1 using both scanning mutagenesis and deep-learning Artificial Intelligence identify specific residues in the C-terminal arrestin-fold domain as the interaction interface that regulates GLUT1 function, revealing a new molecular target for potential therapeutic intervention against myocardial ischemia. These results uncover a new mechanism of ischemic injury in which ARRDC4 drives glucose deprivation-induced endoplasmic reticulum stress leading to cardiomyocyte death. Our findings establish ARRDC4 as a new scaffold protein for GLUT1 that regulates cardiac metabolism in response to ischemia and provide insight into the therapeutic strategy for ischemic heart disease.