Pulmonary vascular adaptations to hypoxia in elite breath-hold divers.

Introduction: Elite breath-hold divers (BHD) possess several oxygen conserving adaptations to endure long dives similar to diving mammals. During dives, Bottlenose Dolphins may increase the alveolar ventilation (VA) to perfusion (Q) ratio to increase alveolar oxygen delivery. We hypothesized that BHD possess similar adaptive mechanisms during apnea. Methods and results: Pulmonary blood volume (PBV) was determined by echocardiography, 15O-H2O PET/CT, and cardiac MRi, (n = 6) during and after maximum apneas. Pulmonary function was determined by body box spirometry and compared to matched controls. After 2 min of apnea, the PBV determined by echocardiography and 15O-H2O-PET/CT decreased by 26% and 41%, respectively. After 4 min of apnea, the PBV assessed by echocardiography and cardiac MRi decreased by 48% and 67%, respectively (n = 6). Fractional saturation (F)O2Hb determined by arterial blood-gas-analyses collected after warm-up and a 5-minute pool-apnea (n = 9) decreased by 43%. Compared to matched controls (n = 8), spirometry revealed a higher total and alveolar-lung-capacity in BHD (n = 9), but a lower diffusion-constant. Conclusion: Our results contrast with previous studies, that demonstrated similar lung gas transfer in BHD and matched controls. We conclude that elite BHD 1) have a lower diffusion constant than matched controls, and 2) gradually decrease PBV during apnea and in turn increase VA/Q to increase alveolar oxygen delivery during maximum apnea. We suggest that BHD possess pulmonary adaptations similar to diving mammals to tolerate decreasing tissue oxygenation. New and noteworthy: This manuscript addresses novel knowledge on tolerance to hypoxia during diving, which is shared by elite breath-hold divers and adult diving mammals: Our study indicates that elite breath-hold divers gradually decrease pulmonary blood volume and in turn increase VA/Q, to increase alveolar oxygen delivery during maximum apnea to tolerate decreasing oxygen levels similar to the Bottlenose Dolphin.

A three-week ketogenic diet increases skeletal muscle insulin sensitivity in individuals with obesity - a randomized, controlled crossover trial.

A ketogenic diet (KD) can induce weight loss and improve glycemic regulation, potentially reducing the risk of developing type 2 diabetes. To elucidate the underlying mechanisms behind these beneficial effects of a KD, we investigated the impact of a KD on organ-specific insulin sensitivity (IS) in skeletal muscle, liver, and adipose tissue. We hypothesized that a KD would increase IS in skeletal muscle. The study included 11 individuals with obesity who underwent a randomized, crossover trial with two three-week interventions: 1) KD and 2) standard diet. Skeletal muscle IS was quantified as the increase in glucose disposal during a hyperinsulinemic-euglycemic clamp (HEC). Hepatic IS and adipose tissue IS were quantified as the relative suppression of endogenous glucose production (EGP) and the relative suppression of palmitate flux during the HEC. The KD led to a 2.2 kg weight loss, increased insulin-stimulated glucose disposal, whereas the relative suppression of EGP during the HEC was similar. In addition, the KD decreased insulin-mediated suppression of lipolysis. In conclusion, a KD increased skeletal muscle IS in individuals with obesity.

Improved Diagnostic Accuracy for Polymyalgia Rheumatica using FDG-PET/CT with Clinical Diagnosis or 2012 ACR/EULAR Classification Criteria.

PURPOSE: In routine care, clinicians may employ 2-[18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) computed tomography (CT) to validate their initial clinical diagnosis of polymyalgia rheumatica (PMR). Nevertheless, the diagnostic utility of combining FDG-PET/CT findings with clinical presentation has not been explored. Therefore, this study aimed to investigate whether the diagnostic accuracy for PMR could be enhanced by combining FDG-PET/CT findings with the clinical baseline diagnosis or the 2012 ACR/EULAR clinical classification criteria for PMR. METHODS: An investigation and a validation cohort were included from two countries, encompassing 66/27 and 36/21 PMR/non-PMR patients, respectively. The cohorts comprised treatment-naïve patients suspected of PMR, who initially received a clinical baseline diagnosis and underwent FDG-PET/CT scans. The FDG-PET/CT Leuven-score was applied to classify patients as either PMR or non-PMR and combined with the clinical baseline diagnosis. Final diagnoses were established through clinical follow-up after twelve or six months in the investigation and validation cohorts, respectively. RESULTS: In the investigation cohort, a clinical baseline diagnosis yielded a sensitivity/specificity of 94%/82%, compared with 78%/70% using the ACR/EULAR criteria. Combining the clinical baseline diagnosis with a positive Leuven-score showed a sensitivity/specificity of 80%/93%, compared with 80%/82% for an ACR/EULAR-Leuven-score. In the validation cohort, the baseline diagnosis revealed a sensitivity/specificity of 100%/91%, compared with 92%/76% using the ACR/EULAR criteria. Combining FDG-PET/CT with the baseline diagnosis demonstrated a sensitivity/specificity of 83%/95% compared with 89%/81% for the ACR/EULAR-Leuven-score. CONCLUSION: Combining FDG-PET/CT findings with the clinical baseline diagnosis or ACR/EULAR clinical classification criteria can improve the diagnostic specificity for PMR.

Myocardial Blood Flow by Magnetic Resonance in Patients With Suspected Coronary Stenosis: Comparison to PET and Invasive Physiology.

BACKGROUND: Despite recent guideline recommendations, quantitative perfusion (QP) estimates of myocardial blood flow from cardiac magnetic resonance (CMR) have only been sparsely validated. Furthermore, the additional diagnostic value of utilizing QP in addition to the traditional visual expert interpretation of stress-perfusion CMR remains unknown. The aim was to investigate the correlation between myocardial blood flow measurements estimated by CMR, positron emission tomography, and invasive coronary thermodilution. The second aim is to investigate the diagnostic performance of CMR-QP to identify obstructive coronary artery disease (CAD). METHODS: Prospectively enrolled symptomatic patients with >50% diameter stenosis on computed tomography angiography underwent dual-bolus CMR and positron emission tomography with rest and adenosine-stress myocardial blood flow measurements. Subsequently, an invasive coronary angiography (ICA) with fractional flow reserve and thermodilution-based coronary flow reserve was performed. Obstructive CAD was defined as both anatomically severe (>70% diameter stenosis on quantitative coronary angiography) or hemodynamically obstructive (ICA with fractional flow reserve ≤0.80). RESULTS: About 359 patients completed all investigations. Myocardial blood flow and reserve measurements correlated weakly between estimates from CMR-QP, positron emission tomography, and ICA-coronary flow reserve (r<0.40 for all comparisons). In the diagnosis of anatomically severe CAD, the interpretation of CMR-QP by an expert reader improved the sensitivity in comparison to visual analysis alone (82% versus 88% [P=0.03]) without compromising specificity (77% versus 74% [P=0.28]). In the diagnosis of hemodynamically obstructive CAD, the accuracy was only moderate for a visual expert read and remained unchanged when additional CMR-QP measurements were interpreted. CONCLUSIONS: CMR-QP correlates weakly to myocardial blood flow measurements by other modalities but improves diagnosis of anatomically severe CAD. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481712.

Hemoglobin concentration and blood shift during dry static apnea in elite breath hold divers.

Introduction: Elite breath-hold divers (BHD) enduring apneas of more than 5 min are characterized by tolerance to arterial blood oxygen levels of 4.3 kPa and low oxygen-consumption in their hearts and skeletal muscles, similar to adult seals. Adult seals possess an adaptive higher hemoglobin-concentration and Bohr effect than pups, and when sedated, adult seals demonstrate a blood shift from the spleen towards the brain, lungs, and heart during apnea. We hypothesized these observations to be similar in human BHD. Therefore, we measured hemoglobin- and 2,3-biphosphoglycerate-concentrations in BHD (n = 11) and matched controls (n = 11) at rest, while myocardial mass, spleen and lower extremity volumes were assessed at rest and during apnea in BHD. Methods and results: After 4 min of apnea, left ventricular myocardial mass (LVMM) determined by 15O-H2O-PET/CT (n = 6) and cardiac MRI (n = 6), was unaltered compared to rest. During maximum apnea (∼6 min), lower extremity volume assessed by DXA-scan revealed a ∼268 mL decrease, and spleen volume, assessed by ultrasonography, decreased ∼102 mL. Compared to age, BMI and VO2max matched controls (n = 11), BHD had similar spleen sizes and 2,3- biphosphoglycerate-concentrations, but higher total hemoglobin-concentrations. Conclusion: Our results indicate: 1) Apnea training in BHD may increase hemoglobin concentration as an oxygen conserving adaptation similar to adult diving mammals. 2) The blood shift during dry apnea in BHD is 162% more from the lower extremities than from the spleen. 3) In contrast to the previous theory of the blood shift demonstrated in sedated adult seals, blood shift is not towards the heart during dry apnea in humans.

Splenic switch-off in [15O]H2O-positron emission tomography myocardial perfusion imaging using parametric blood flow images.

BACKGROUND: Evaluation of sufficient adenosine response constitutes a significant challenge in myocardial perfusion imaging (MPI). Splenic switch-off in MPI studies denotes a visually (qualitatively) reduced splenic radiotracer signal during adenosine stress and is considered indicative of sufficient cardiac vasodilation. In this study, we examined semi-quantitative and quantitative approaches to splenic switch-off assessment using [15O]H2O-PET with either summed activity images or calculated parametric splenic blood flow images. METHODS: Cohort 1: 90 clinical patients undergoing [15O]H2O MPI in whom adenosine response was considered clinically adequate were identified to characterize the corresponding splenic switch-off. Spleen stress/rest-ratio (SSR-ratio) was calculated as spleen stress signal intensity/spleen rest signal intensity on both summed activity and parametric blood flow images. Cohort 2: Twenty-five patients with repeat MPI due to suspected insufficient adenosine response were identified to observe if splenic switch-off on the initial MPI could predict the outcome of the repeat MPI. Cohort 3: Fifty-four patients who were considered adenosine responders on MPI and who had a coronary angiogram (CAG) follow-up within 3 months after MPI served as a separate validation group. RESULTS: Splenic switch-off was present in most patients with a clinically sufficient adenosine response (Cohort 1), illustrated by both visual (74.4%-86.7%), semi-quantitative (summed activity images) (85.6%), and quantitative (parametric blood flow images) (92.2%) evaluation, which corresponds to the distribution in patients with sufficient adenosine response and follow-up CAG (Cohort 3). In patients suspected of insufficient adenosine response on the initial MPI (Cohort 2), the repeat MPI only yielded different myocardial blood flow (MBF) results if the initial SSR-ratio was >0.90 on splenic parametric blood flow images. CONCLUSION: quantitative splenic switch-off assessment on parametric blood flow images was superior to the semi-quantitative splenic switch-off approach. Patients with a suspected insufficient initial adenosine response and SSR-ratio >0.90 can benefit from a repeat MPI. Thus, the integration of quantitative splenic switch-off using parametric blood flow images in the evaluation of adenosine response may support future clinical decision-making.

Enantiomer-Specific Cardiovascular Effects of the Ketone Body 3-Hydroxybutyrate.

BACKGROUND: The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output (CO) by 35% to 40% in healthy people and people with heart failure. The mechanisms underlying the effects of 3-OHB on myocardial contractility and loading conditions as well as the cardiovascular effects of its enantiomeric forms, D-3-OHB and L-3-OHB, remain undetermined. METHODS AND RESULTS: Three groups of 8 pigs each underwent a randomized, crossover study. The groups received 3-hour infusions of either D/L-3-OHB (racemic mixture), 100% L-3-OHB, 100% D-3-OHB, versus an isovolumic control. The animals were monitored with pulmonary artery catheter, left ventricle pressure-volume catheter, and arterial and coronary sinus blood samples. Myocardial biopsies were evaluated with high-resolution respirometry, coronary arteries with isometric myography, and myocardial kinetics with D-[11C]3-OHB and L-[11C]3-OHB positron emission tomography. All three 3-OHB infusions increased 3-OHB levels (P<0.001). D/L-3-OHB and L-3-OHB increased CO by 2.7 L/min (P<0.003). D-3-OHB increased CO nonsignificantly (P=0.2). Circulating 3-OHB levels correlated with CO for both enantiomers (P<0.001). The CO increase was mediated through arterial elastance (afterload) reduction, whereas contractility and preload were unchanged. Ex vivo, D- and L-3-OHB dilated coronary arteries equally. The mitochondrial respiratory capacity remained unaffected. The myocardial 3-OHB extraction increased only during the D- and D/L-3-OHB infusions. D-[11C]3-OHB showed rapid cardiac uptake and metabolism, whereas L-[11C]3-OHB demonstrated much slower pharmacokinetics. CONCLUSIONS: 3-OHB increased CO by reducing afterload. L-3-OHB exerted a stronger hemodynamic response than D-3-OHB due to higher circulating 3-OHB levels. There was a dissocitation between the myocardial metabolism and hemodynamic effects of the enantiomers, highlighting L-3-OHB as a potent cardiovascular agent with strong hemodynamic effects.

The effect of prednisolone and a short-term prednisolone discontinuation for the diagnostic accuracy of FDG-PET/CT in polymyalgia rheumatica-a prospective study of 101 patients.

PURPOSE: 2-[18F]Fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) has been suggested as an imaging modality to diagnose polymyalgia rheumatica (PMR). However, the applicability of FDG-PET/CT remains unclear, especially following glucocorticoid administration. This study aimed to investigate the diagnostic accuracy of FDG-PET/CT before and during prednisolone treatment, as well as following short-term prednisolone discontinuation. METHODS: Treatment naïve suspected PMR patients were clinically diagnosed at baseline and subsequently had an FDG-PET/CT performed. Patients diagnosed with PMR were administered prednisolone following the first FDG-PET/CT and had a second FDG-PET/CT performed after 8 weeks of treatment. Subsequently, prednisolone was tapered with short-term discontinuation at week 9 followed by a third FDG-PET/CT at week 10. An FDG-PET/CT classification of PMR/non-PMR was applied, utilizing both the validated Leuven score and a dichotomous PMR score. The final diagnosis was based on clinical follow-up after 1 year. RESULTS: A total of 68 and 27 patients received a final clinical diagnosis of PMR or non-PMR. A baseline FDG-PET/CT classified the patients as having PMR with a sensitivity/specificity of 86%/63% (Leuven score) and 82%/70% (dichotomous score). Comparing the subgroup of non-PMR with inflammatory diseases to the PMR group demonstrated a specificity of 39%/54% (Leuven/dichotomous score). After 8 weeks of prednisolone treatment, the sensitivity of FDG-PET/CT decreased to 36%/41% (Leuven/dichotomous score), while a short-term prednisolone discontinuation increased the sensitivity to 66%/60%. CONCLUSION: FDG-PET/CT has limited diagnostic accuracy for differentiating PMR from other inflammatory diseases. If FDG-PET/CT is intended for diagnostic purposes, prednisolone should be discontinued to enhance diagnostic accuracy. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04519580). Registered 17th of August 2020.

Incidental [18F]FDG-avid focuses in parotid glands on PET/CT.

BACKGROUND: The number of unexpected focal [18F]FDG-avid findings (incidentalomas) within the parotid gland (PGI) continues to increase with the expanding use of PET/CT scanning. The prevalence of malignancy in PGIs is uncertain and appropriate management is unsettled. AIMS: We aimed to explore the underlying pathologies associated with PGI. MATERIALS AND METHODS: A retrospective review of all patients with parotid gland incidentaloma(s) treated at the Ear-Nose-Throat Department, Aarhus University Hospital, Denmark in the period 2012-2021, was performed. RESULTS: In total, 94 patients with one (n = 86) or two (n = 8) PGI(s) were included. In patients with one PGI, 72 (84%) focuses were benign, two (2%) focuses were malignant (both malignant melanoma metastases), and 12 (14%) focuses were undiagnosed. In patients with two PGIs, all 12 lesions with pathological examinations were benign (4 PGIs were undiagnosed). The median SUVmax found in benign lesions was higher (12.0) compared to malignant lesions (5.5) (p = .043). CONCLUSIONS AND SIGNIFICANCE: The prevalence of malignancy was low (2/94, 2.4%) in PGIs. Based on our findings, PGI in patients without a history of parotid malignancy, who undergo PET/CT scanning for reasons other than head and neck cancer (including malignant melanoma), may be managed similarly to patients with asymptomatic parotid gland tumors.

Guiding early revascularization using [15O]H2O positron emission tomography myocardial perfusion imaging: impact of atrial fibrillation.

AIMS: Myocardial perfusion imaging (MPI) using [15O]H2O positron emission tomography (PET) is used to guide the selection of patients with angina for invasive angiography and possible revascularization. Our study evaluated (i) whether atrial fibrillation (AF) reduces global hyperaemic myocardial blood flow (MBF) and (ii) whether [15O]H2O PET MPI effectively guides revascularization procedures for patients with ongoing AF. METHODS AND RESULTS: We prospectively recruited 346 patients with angina and persistent or paroxysmal AF referred for baseline/hyperaemic [15O]H2O PET MPI. The primary outcome was revascularization within 3 months of MPI. In the analyses, patients were divided into four groups based on whether they had ongoing AF or sinus rhythm (SR) and whether they had previously documented coronary artery disease (CAD) or not. Thus, four groups were compared: SR-noCAD, AF-noCAD, SR-CAD, and AF-CAD. Hyperaemic MBF was affected by both ongoing AF and prior CAD [MBF (mL/min/g): 2.82 (SR-noCAD) vs. 2.12 (AF-noCAD) vs. 2.22 (SR-CAD) vs. 1.80 (AF-CAD), two-way analysis of variance P < 0.0001]. In multiple linear regression, ongoing AF was independently associated with reduced hyperaemic MBF. Every 0.1 mL/min/g decrease in hyperaemic MBF was associated with a 23% increase in odds of early revascularization. Receiver operating characteristic (ROC) analysis of vessel-specific hyperaemic MBF to predict early revascularization yielded the following areas under the ROC curve: SR-noCAD: 0.95 (P < 0.0001); AF-noCAD: 0.79 (P < 0.0001); SR-CAD: 0.78 (P < 0.0001); and AF-CAD: 0.88 (P < 0.0001). CONCLUSION: Ongoing AF is associated with 19-25% reduced global hyperaemic MBF as measured by [15O]H2O MPI PET. Regardless, vessel-specific hyperaemic MBF still predicts early revascularization in patients with AF.

A ketogenic diet lowers myocardial fatty acid oxidation but does not affect oxygen consumption: a study in overweight humans.

OBJECTIVE: A ketogenic diet (KD) characterized by very low carbohydrate intake and high fat consumption may simultaneously induce weight loss and be cardioprotective. The "thrifty substrate hypothesis" posits that ketone bodies are more energy efficient compared with other cardiac oxidative substrates such as fatty acids. This work aimed to study whether a KD with presumed increased myocardial ketone body utilization reduces cardiac fatty acid uptake and oxidation, resulting in decreased myocardial oxygen consumption (MVO2 ). METHODS: This randomized controlled crossover trial examined 11 individuals with overweight or obesity on two occasions: (1) after a KD and (2) after a standard diet. Myocardial free fatty acid (FFA) oxidation, uptake, and esterification rate were measured using dynamic [11 C]palmitate positron emission tomography (PET)/computed tomography, whereas MVO2 and myocardial external efficiency (MEE) were measured using dynamic [11 C]acetate PET. RESULTS: The KD increased plasma ß-hydroxybutyrate, reduced myocardial FFA oxidation (p < 0.01) and uptake (p = 0.03), and increased FFA esterification (p = 0.03). No changes were observed in MVO2 (p = 0.2) or MEE (p = 0.87). CONCLUSIONS: A KD significantly reduced myocardial FFA uptake and oxidation, presumably by increasing ketone body oxidation. However, this change in cardiac substrate utilization did not improve MVO2 , speaking against the thrifty substrate hypothesis.

Impact of Absolute Myocardial Blood Flow Quantification on the Diagnostic Performance of PET-Based Perfusion Scans Using 82Rubidium.

BACKGROUND: Guidelines propose the inclusion of quantitative measurements from 82Rubidium positron emission tomography (RbPET) to discriminate obstructive coronary artery disease (CAD). However, the effect on diagnostic accuracy is unknown. The aim was to investigate the optimal RbPET reading algorithm for improved identification of obstructive CAD. METHODS: Prospectively enrolled patients (N=400) underwent RbPET and invasive coronary angiography with fractional flow reserve and quantitative coronary angiography. Quantitative measurements (myocardial blood flow (MBF), MBF reserve, transient ischemic dilatation) by RbPET were step-wisely added to a qualitative assessment by the summed stress score based on their diagnostic accuracy of obstructive CAD by invasive coronary angiography-fractional flow reserve. Prespecified cutoffs were summed stress score ≥4, hyperemic MBF 2.00 mL/g per min, and MBF reserve 1.80, respectively. Hemodynamically obstructive CAD was defined as >90% diameter stenosis or invasive coronary angiography-fractional flow reserve ≤0.80, and sensitivity analyses included a clinically relevant reference of anatomically severe CAD (>70% diameter stenosis by invasive coronary angiography-quantitative coronary angiography). RESULTS: Hemodynamically obstructive CAD was present in 170/400 (42.5%) patients. Stand-alone summed stress score showed a sensitivity and specificity of 57% and 93%, respectively, while hyperemic MBF showed similar sensitivity (61%, P=0.57) but lower specificity (85%, P=0.008). With increased discrimination by receiver-operating characteristic curves (0.78 versus 0.85; P<0.001), combining summed stress score, MBF and MBF reserve showed the highest sensitivity of 77% but lower specificity of 74% (P<0.001 for both comparisons). Against anatomically severe CAD, all measures independently yielded high discrimination ≥0.90 with increased sensitivity and lower specificity by additional quantification. CONCLUSIONS: The inclusion of quantitative measurements to a RbPET read increases in the identification of obstructive CAD. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481712.

Metformin Improves the Prerequisites for FGF21 Signaling in Patients With Type 2 Diabetes.

CONTEXT: Fibroblast growth factor (FGF) 21 acts as a metabolic regulator and its therapeutic use is under investigation. FGF21 signaling requires binding to surface receptors, FGFR1c and ß-klotho. FGF21 resistance is observed in metabolic diseases and FGF21 signaling is regulated by fibroblast activation protein (FAP). Metformin is reported to influence expression and secretion of FGF21 in preclinical models, but the effect of metformin on FGF21 in a clinical trial remains unknown. OBJECTIVE: To investigate how 12 weeks of treatment with metformin affects the FGF21 signaling pathway in patients with type 2 diabetes (T2D). METHODS: Randomized, placebo-controlled study in patients with T2D (n = 24) receiving either metformin (1000 mg twice daily) or placebo. A control group of body mass index- and age-matched healthy individuals (n = 12) received a similar dose of metformin. Blood samples and muscle and fat biopsies were collected at study entry and after 12 weeks. METHODS: Plasma levels of FGF21 (total and intact) and FAP (total and activity) were measured. Muscle and fat biopsies were analyzed for mRNA and protein expression of targets relevant for activation of the FGF21 signaling pathway. RESULTS: Circulating FAP activity decreased after metformin treatment compared with placebo (P = .006), whereas FGF21 levels were unchanged. Metformin treatment increased gene and protein expression of ß-klotho, FGFR1c, and pFGFR1c in adipose tissue. FGF21 mRNA expression increased in muscle tissue after metformin and the FGF21 protein, but not mRNA levels, were observed in adipose tissue. CONCLUSION: Our findings suggest that metformin suppresses the circulating FAP activity and upregulates the expression of FGFR1c and ß-klotho for increased FGF21 signaling in adipose tissue, thus improving peripheral FGF21 sensitivity.

A rare case of sarcoid myelitis complicating Löfgren's syndrome.

Neurosarcoidosis is a rare and serious condition. Rapid diagnosis and treatment are crucial to prevent morbidity and mortality. When neurological symptoms are not present at the time of diagnosis, CNS involvement can be undetected. We present a case of neurosarcoidosis complicating Löfgren's syndrome and discus the challenges in diagnostics and treatment, that can be encountered.

Danish study of Non-Invasive Testing in Coronary Artery Disease 3 (Dan-NICAD 3): study design of a controlled study on optimal diagnostic strategy.

INTRODUCTION: Current guideline recommend functional imaging for myocardial ischaemia if coronary CT angiography (CTA) has shown coronary artery disease (CAD) of uncertain functional significance. However, diagnostic accuracy of selective myocardial perfusion imaging after coronary CTA is currently unclear. The Danish study of Non-Invasive testing in Coronary Artery Disease 3 trial is designed to evaluate head to head the diagnostic accuracy of myocardial perfusion imaging with positron emission tomography (PET) using the tracers 82Rubidium (82Rb-PET) compared with oxygen-15 labelled water PET (15O-water-PET) in patients with symptoms of obstructive CAD and a coronary CT scan with suspected obstructive CAD. METHODS AND ANALYSIS: This prospective, multicentre, cross-sectional study will include approximately 1000 symptomatic patients without previous CAD. Patients are included after referral to coronary CTA. All patients undergo a structured interview and blood is sampled for genetic and proteomic analysis and a coronary CTA. Patients with possible obstructive CAD at coronary CTA are examined with both 82Rb-PET, 15O-water-PET and invasive coronary angiography with three-vessel fractional flow reserve and thermodilution measurements of coronary flow reserve. After enrolment, patients are followed with Seattle Angina Questionnaires and follow-up PET scans in patients with an initially abnormal PET scan and for cardiovascular events in 10 years. ETHICS AND DISSEMINATION: Ethical approval was obtained from Danish regional committee on health research ethics. Written informed consent will be provided by all study participants. Results of this study will be disseminated via articles in international peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04707859.

Intravenous and oral whole body ketone dosimetry, biodistribution, metabolite correction and kinetics studied by (R)-[1-11C]ß-hydroxybutyrate ([11C]OHB) PET in healthy humans.

BACKGROUND: Ketones are increasingly recognized as an important and possibly oxygen sparing source of energy in vital organs such as the heart, the brain and the kidneys. Drug treatments, dietary regimens and oral ketone drinks designed to deliver ketones for organ and tissue energy production have therefore gained popularity. However, whether ingested ketones are taken up by various extra-cerebral tissues and to what extent is still largely unexplored. It was therefore the aim of this study to use positron emission tomography (PET) to explore the whole body dosimetry, biodistribution and kinetics of the ketone tracer (R)-[1-11C]ß-hydroxybutyrate ([11C]OHB). Six healthy subjects (3 women and 3 men) underwent dynamic PET studies after both intravenous (90 min) and oral (120 min) administration of [11C]OHB. Dosimetry estimates of [11C]OHB was calculated using OLINDA/EXM software, biodistribution was assessed visually and [11C]OHB tissue kinetics were obtained using an arterial input function and tissue time-activity curves. RESULTS: Radiation dosimetry yielded effective doses of 3.28 [Formula: see text]Sv/MBq (intravenous administration) and 12.51 [Formula: see text]Sv/MBq (oral administration). Intravenous administration of [11C]OHB resulted in avid radiotracer uptake in the heart, liver, and kidneys, whereas lesser uptake was observed in the salivary glands, pancreas, skeletal muscle and red marrow. Only minimal uptake was noted in the brain. Oral ingestion of the tracer resulted in rapid radiotracer appearance in the blood and radiotracer uptake in the heart, liver and kidneys. In general, [11C]OHB tissue kinetics after intravenous administration were best described by a reversible 2-tissue compartmental model. CONCLUSION: The PET radiotracer [11C]OHB shows promising potential in providing imaging data on ketone uptake in various physiologically relevant tissues. As a result, it may serve as a safe and non-invasive imaging tool for exploring ketone metabolism in organs and tissues of both patients and healthy individuals. Trial registration Clinical trials, NCT0523812, Registered February 10th 2022, https://clinicaltrials.gov/ct2/show/NCT05232812?cond=NCT05232812&draw=2&rank=1 .

Diagnostic performance of clinical likelihood models of obstructive coronary artery disease to predict myocardial perfusion defects.

AIMS: Clinical likelihood (CL) models are designed based on a reference of coronary stenosis in patients with suspected obstructive coronary artery disease. However, a reference standard for myocardial perfusion defects (MPDs) could be more appropriate. We aimed to investigate the ability of the 2019 European Society of Cardiology pre-test probability (ESC-PTP), the risk-factor-weighted (RF-CL) model, and coronary artery calcium score-weighted (CACS-CL) model to diagnose MPDs. METHODS AND RESULTS: Symptomatic stable de novo chest pain patients (n = 3374) underwent coronary computed tomography angiography and subsequent myocardial perfusion imaging by single-photon emission computed tomography, positron emission tomography, or cardiac magnetic resonance. For all modalities, MPD was defined as coronary computed tomography angiography with suspected stenosis and stress-perfusion abnormality in ≥2 segments. The ESC-PTP was calculated based on age, sex, and symptom typicality, and the RF-CL and CACS-CL additionally included a number of risk factors and CACS. In total, 219/3374 (6.5%) patients had an MPD. Both the RF-CL and the CACS-CL classified substantially more patients to low CL (<5%) of obstructive coronary artery disease compared with the ESC-PTP (32.5 and 54.1 vs. 12.0%, P < 0.001) with preserved low prevalences of MPD (<2% for all models). Compared with the ESC-PTP [area under the receiver-operating characteristic curve (AUC) 0.74 (0.71-0.78)], the discrimination of having an MPD was higher for the CACS-CL model [AUC 0.88 (0.86-0.91), P < 0.001], while it was similar for the RF-CL model [AUC 0.73 (0.70-0.76), P = 0.32]. CONCLUSION: Compared with basic CL models, the RF-CL and CACS-CL models improve down classification of patients to a very low-risk group with a low prevalence of MPD.