Background: Myocardial utilization of 3-hydroxybutyrate (3-OHB) is increased in patients with heart failure and reduced ejection fraction (HFrEF). However, the cardiovascular effects of increased circulating plasma-3-OHB levels in these patients are unknown. Consequently, the authors’ aim was to modulate circulating 3-OHB levels in HFrEF patients and evaluate: (1) changes in cardiac output (CO); (2) a potential dose-response relationship between 3-OHB levels and CO; (3) the impact on myocardial external energy efficiency (MEE) and oxygen consumption (MVO ₂ ); and (4) whether the cardiovascular response differed between HFrEF patients and age-matched volunteers. Methods: Study 1: 16 chronic HFrEF patients (left ventricular ejection fraction: 37±3%) were randomized in a crossover design to 3-hour of 3-OHB or placebo infusion. Patients were monitored invasively with a Swan-Ganz catheter and with echocardiography. Study 2: In a dose-response study, 8 HFrEF patients were examined at increasing 3-OHB infusion rates. Study 3 to 4: 10 HFrEF patients and 10 age-matched volunteers were randomized in a crossover design to 3-hour 3-OHB or placebo infusion. MEE and MVO ₂ were evaluated using 11C-acetate positron emission tomography. Results: 3-OHB infusion increased circulating levels of plasma 3-OHB from 0.4±0.3 to 3.3±0.4 mM ( P <0.001). CO rose by 2.0±0.2 L/min ( P <0.001) because of an increase in stroke volume of 20±2 mL ( P <0.001) and heart rate of 7±2 beats per minute (bpm) ( P <0.001). Left ventricular ejection fraction increased 8±1% ( P <0.001) numerically. There was a dose-response relationship with a significant CO increase of 0.3 L/min already at plasma-3-OHB levels of 0.7 mM ( P <0.001). 3-OHB increased MVO ₂ without altering MEE. The response to 3-OHB infusion in terms of MEE and CO did not differ between HFrEF patents and age-matched volunteers. Conclusions: 3-OHB has beneficial hemodynamic effects in HFrEF patients without impairing MEE. These beneficial effects are detectable in the physiological concentration range of circulating 3-OHB levels. The hemodynamic effects of 3-OHB were observed in both HFrEF patients and age-matched volunteers. 3-OHB may potentially constitute a novel treatment principle in HFrEF patients.

White blood cells activated by either a pathogen or as part of a systemic inflammatory disease are characterized by high energy consumption and are therefore taking up the glucose analogue PET tracer FDG avidly. It is therefore not surprising that a steadily growing body of research and clinical reports now supports the use of FDG PET/CT to diagnose a wide range of patients with non-oncological diseases. However, using FDG PET/CT in patients with infectious or inflammatory diseases has some limitations and potential pitfalls that are not necessarily as pronounced in oncology FDG PET/CT. Some of these limitations are of a general nature and related to the laborious acquisition of PET images in patients that are often acutely ill, whereas others are more disease-specific and related to the particular metabolism in some of the organs most commonly affected by infections or inflammatory disease. Both inflammatory and infectious diseases are characterized by a more diffuse and less pathognomonic pattern of FDG uptake than oncology FDG PET/CT and the affected organs also typically have some physiological FDG uptake. In addition, patients referred to PET/CT with suspected infection or inflammation are rarely treatment naïve and may have received varying doses of antibiotics, corticosteroids or other immune-modulating drugs at the time of their examination. Combined, this results in a higher rate of false positive FDG findings and also in some cases a lower sensitivity to detect active disease. In this review, we therefore discuss the limitations and pitfalls of FDG PET/CT to diagnose infections and inflammation taking these issues into consideration. Our review encompasses the most commonly encountered inflammatory and infectious diseases in head and neck, in the cardiovascular system, in the abdominal organs and in the musculoskeletal system. Finally, new developments in the field of PET/CT that may help overcome some of these limitations are briefly highlighted.

Background: High levels of ketone bodies are associated with improved survival as observed with regular exercise, caloric restriction, and—most recently—treatment with sodium–glucose linked transporter 2 inhibitor antidiabetic drugs. In heart failure, indices of ketone body metabolism are upregulated, which may improve energy efficiency and increase blood flow in skeletal muscle and the kidneys. Nevertheless, it is uncertain how ketone bodies affect myocardial glucose uptake and blood flow in humans. Our study was therefore designed to test whether ketone body administration in humans reduces myocardial glucose uptake ( MGU ) and increases myocardial blood flow. Methods and Results: Eight healthy subjects, median aged 60 were randomly studied twice: (1) During 390 minutes infusion of Na‐3‐hydroxybutyrate ( KETONE ) or (2) during 390 minutes infusion of saline ( SALINE ), together with a concomitant low‐dose hyperinsulinemic–euglycemic clamp to inhibit endogenous ketogenesis. Myocardial blood flow was measured by ¹⁵ O‐H ₂ O positron emission tomography/computed tomography, myocardial fatty acid metabolism by ¹¹ C‐palmitate positron emission tomography/computed tomography and MGU by ¹⁸ F‐fluorodeoxyglucose positron emission tomography/computed tomography. Similar euglycemia, hyperinsulinemia, and suppressed free fatty acids levels were recorded on both study days; Na‐3‐hydroxybutyrate infusion increased circulating Na‐3‐hydroxybutyrate levels from zero to 3.8±0.5 mmol/L. MGU was halved by hyperketonemia ( MGU [nmol/g per minute]: 304±97 [ SALINE ] versus 156±62 [ KETONE ], P <0.01), whereas no effects were observed on palmitate uptake oxidation or esterification. Hyperketonemia increased heart rate by ≈25% and myocardial blood flow by 75%. Conclusions: Ketone bodies displace MGU and increase myocardial blood flow in healthy humans; these novel observations suggest that ketone bodies are important cardiac fuels and vasodilators, which may have therapeutic potentials.

The goal of this study was to assess the real-world clinical utility of fractional flow reserve (FFR) derived from coronary computed tomography angiography (FFRCT) for decision-making in patients with stable coronary artery disease (CAD). FFRCT has shown promising results in identifying lesion-specific ischemia. The real-world feasibility and influence on the diagnostic work-up of FFRCT testing in patients suspected of having CAD are unknown. We reviewed the complete diagnostic work-up of nonemergent patients referred for coronary computed tomography angiography over a 12-month period at Aarhus University Hospital, Denmark, including all patients with new-onset chest pain with no known CAD and with intermediate-range coronary lesions (lumen reduction, 30% to 70%) referred for FFRCT. The study evaluated the consequences on downstream diagnostic testing, the agreement between FFRCT and invasively measured FFR or instantaneous wave-free ratio (iFR), and the short-term clinical outcome after FFRCT testing. Among 1,248 patients referred for computed tomography angiography, 189 patients (mean age 59 years; 59% male) were referred for FFRCT, with a conclusive FFRCT result obtained in 185 (98%). FFRCT was ≤0.80 in 31% of patients and 10% of vessels. After FFRCT testing, invasive angiography was performed in 29%, with FFR measured in 19% and iFR in 1% of patients (with a tendency toward declining FFR-iFR guidance during the study period). FFRCT ≤0.80 correctly classified 73% (27 of 37) of patients and 70% (37 of 53) of vessels using FFR ≤0.80 or iFR ≤0.90 as the reference standard. In patients with FFRCT >0.80 being deferred from invasive coronary angiography, no adverse cardiac events occurred during a median follow-up period of 12 (range 6 to 18 months) months. FFRCT testing is feasible in real-world symptomatic patients with intermediate-range stenosis determined by coronary computed tomography angiography. Implementation of FFRCT for clinical decision-making may influence the downstream diagnostic workflow of patients. Patients with an FFRCT value >0.80 being deferred from invasive coronary angiography have a favorable short-term prognosis.

Metformin is the most widely prescribed oral anti-glycemic drug with few adverse effects. However, surprisingly little is known about its human biodistribution and target tissue metabolism. In animal experiments we have shown that metformin can be labelled by ¹¹C and that ¹¹C-metformin Positron emission tomography (PET) can be used to measure renal function. Here, we extend these pre-clinical findings by a first-in-human ¹¹C-metformin PET dosimetry, biodistribution and tissue kinetics study. Methods: Nine subjects (three women, six men) participated in two studies: In the first study, human radiation dosimetry and biodistribution of ¹¹C-metformin were estimated in 4 subjects (two women and two men) by whole-body PET. In the second study, ¹¹C-metformin tissue kinetics were measured in response to both intravenous and oral radiotracer administration. A dynamic PET scan with a field-of-view covering target tissues of metformin (liver, kidneys, intestines and skeletal muscle) was performed for 90 (intravenous) and 120 (oral) minutes. Results: Radiation dosimetry was acceptable with effective doses 9.5 (intravenous) and 18.1 μSv/MBq (oral) administrations. Whole body PET revealed, that ¹¹C-metformin was primarily taken up by the kidneys, urinary bladder and liver but also to a lesser extent in salivary glands, skeletal muscle and intestines. Reversible 2-tissue compartment kinetics was observed in the liver and volume of distribution (Vd) was calculated to be 2.45 ml/ml (arterial input) or 2.66 ml/ml (portal and arterial input). In the kidneys, compartmental models did not adequately fit the experimental data and Vd was therefore estimated by a linear approach to be 6.83 ml/ml. Skeletal muscle and intestinal tissue kinetics were best described by 2-tissue compartment kinetics and showed only discrete tracer uptake. Liver ¹¹C-metformin uptake was pronounced after oral administration of the tracer with tissue-to-blood ratio double what was observed after intravenous administration. Only slow accumulation of ¹¹C-metformin was observed in muscle. There was no elimination of ¹¹C-metformin through the bile both during the intravenous and the oral part of the study. Conclusion: ¹¹C-metformin is suitable for imaging metformin uptake in target tissues and may prove a valuable tool to assess the impact of metformin treatment in patients with varying metformin transport capacity.