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Aims Myocardial external efficiency (MEE) is the ratio of cardiac work in relation with energy expenditure. We studied MEE in patients with different aetiologies and stages of heart failure (HF) to discover the role and causes of deranged MEE. In addition, we explored the impact of patient characteristics such as sex, body mass index (BMI), and age on myocardial energetics. Methods and results Cardiac energetic profiles were assessed with 11C-acetate positron emission tomography (PET) and left ventricular ejection fraction (LVEF) was acquired with echocardiography. MEE was studied in 121 participants: healthy controls (n = 20); HF patients with reduced (HFrEF; n = 25) and mildly reduced (HFmrEF; n = 23) LVEF; and patients with asymptomatic (AS-asymp; n = 38) and symptomatic (AS-symp; n = 15) aortic stenosis (AS). Reduced MEE coincided with symptoms of HF irrespective of aetiology and declined in tandem with deteriorating LVEF. Patients with AS-symp and HFmrEF had reduced MEE as compared with controls (22.2 ± 4.9%, P = 0.041 and 20.0 ± 4.2%, P Conclusion MEE was reduced in patients with HFrEF, HFmrEF, and HF due to pressure overload and MEE may therefore constitute a treatment target in HF. Patients with LVH, advanced age, female sex, and low BMI had more pronounced reduction in MEE and personalized treatment within these patient subgroups could be relevant.

Background Heart failure (HF) classification based on left ventricular ejection fraction (LVEF) can vary because of changes in filling pressures, afterload, and contractile function. 11C-acetate positron emission tomography (PET) provides a load-independent measure of myocardial external efficiency (MEE) by simultaneous assessment of myocardial oxygen consumption (MVO2), cardiac work, left ventricular mass (LVM), end-systolic wall stress (ESWS), and myocardial blood flow (MBF). Purpose We aimed to characterize mechanoenergetic derangements in patients with HF and to study its interrelation with age, sex and obesity. Methods MEE was measured in 121 participants with 11C-acetate PET, and LVEF was acquired with echocardiography. We investigated healthy controls (n=20) and patients with HF and reduced LVEF Results MEE declined in tandem with reduced LVEF from HFpEF and HFmrEF to HFrEF (p=0.041, p Conclusions Mechanoenergetic uncoupling was evident in every clinical state within the HF syndrome and associated with left ventricular hypertrophy and progressive systolic dysfunction. Sex, age, and obesity impacted myocardial energetics. To date, the present study is the largest investigation of mechanoenergetic coupling across several categories of patients with heart failure. 11C-acetate PET extends our pathophysiological comprehension of the HF syndrome beyond LVEF. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Danish Heart FoundationThe Lundbeck Foundation Relationship between LVEF and MEEMyocardial energetics in heart failure

Supplemental Digital Content is available in the text., 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 (MVO2); 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 MVO2 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

AIMS: The present study tested the hypothesis that metformin treatment may increase myocardial efficiency (stroke work/myocardial oxygen consumption) in insulin-resistant patients with heart failure and reduced ejection fraction (HFrEF) without diabetes.METHODS AND RESULTS: Thirty-six HFrEF patients (ejection fraction 37 ± 8%; median age 66 years) were randomised to metformin (n = 19) or placebo (n = 17) for 3 months in addition to standard heart failure therapy. The primary endpoint was change in myocardial efficiency expressed as the work metabolic index (WMI), assessed by 11 C-acetate positron emission tomography and transthoracic echocardiography. Compared with placebo, metformin treatment (1450 ± 550 mg/day) increased WMI [absolute mean difference, 1.0 mmHg·mL·m-2 ·106 ; 95% confidence interval (CI) 0.1 to 1.8; P = 0.03], equivalent to a 20% relative efficiency increase. Patients with above-median plasma metformin levels displayed greater WMI increase (25% vs. -4%; P = 0.02). Metformin reduced myocardial oxygen consumption (-1.6 mL O2 ·100 g-1 ·min-1 ; P = 0.014). Cardiac stroke work was preserved (-2 J; 95% CI -11 to 7; P = 0.69). Metformin reduced body weight (-2.2 kg; 95% CI -3.6 to -0.8; P = 0.003) and glycated haemoglobin levels (-0.2%; 95% CI -0.3 to 0.0; P = 0.02). Changes in resting and exercise ejection fraction, global longitudinal strain, and exercise capacity did not differ between groups.CONCLUSION: Metformin treatment in non-diabetic HFrEF patients improved myocardial efficiency by reducing myocardial oxygen consumption. Measurement of circulating metformin levels differentiated responders from non-responders. These energy-sparing effects of metformin encourage further large-scale investigations in heart failure patients without diabetes.

The glucose-lowering drug metformin has recently been shown to reduce myocardial oxygen consumption and increase myocardial efficiency in chronic heart failure (HF) patients without diabetes. However, it remains to be established whether these beneficial myocardial effects are associated with metformin-induced alterations in whole-body insulin sensitivity and substrate metabolism.Eighteen HF patients with reduced ejection fraction and without diabetes (median age, 65 (interquartile range 55-68); ejection fraction 39 ± 6%; HbA1c 5.5 to 6.4%) were randomized to receive metformin (n = 10) or placebo (n = 8) for 3 months. We studied the effects of metformin on whole-body insulin sensitivity using a two-step hyperinsulinemic euglycemic clamp incorporating isotope-labeled tracers of glucose, palmitate, and urea. Substrate metabolism and skeletal muscle mitochondrial respiratory capacity were determined by indirect calorimetry and high-resolution respirometry, and body composition was assessed by bioelectrical impedance analysis. The primary outcome measure was change in insulin sensitivity.Compared with placebo, metformin treatment lowered mean glycated hemoglobin levels (absolute mean difference, - 0.2%; 95% CI - 0.3 to 0.0; p = 0.03), reduced body weight (- 2.8 kg; 95% CI - 5.0 to - 0.6; p = 0.02), and increased fasting glucagon levels (3.2 pmol LIncreased myocardial efficiency during metformin treatment is not mediated through improvements in insulin action in HF patients without diabetes.URL: https://clinicaltrials.gov . Unique identifier: NCT02810132. Date of registration: June 22, 2016.

Myocardial efficiency measured by 11C-acetate positron emission tomography (PET) has successfully been used in clinical research to quantify mechanoenergetic coupling. The objective of this study was to establish the repeatability of myocardial external efficiency (MEE) and work metabolic index (WMI) by non-invasive concepts. Ten healthy volunteers (63 ± 4 years) were examined twice, one week apart, using 11C-acetate PET, cardiovascular magnetic resonance (CMR), and echocardiography. Myocardial oxygen consumption from PET was combined with stroke work data from CMR, echocardiography, or PET to obtain MEE and WMI for each modality. Repeatability was estimated as the coefficient of variation (CV) between test and retest. MEECMR, MEEEcho, and MEEPET values were 21.9 ± 2.7%, 16.4 ± 3.7%, and 23.8 ± 4.9%, respectively, P

Levosimendan is an inotropic and vasodilator drug, which is known to improve cardiac function in animal models of right ventricular (RV) failure. The effects of levosimendan on oxygen consumption and myocardial efficiency in the failing RV is unknown. We investigated the effects of levosimendan on RV function, myocardial oxygen consumption, myocardial external efficiency (MEE), and myocardial metabolism in rats with RV hypertrophy and failure. RV hypertrophy and failure were induced by pulmonary trunk banding in rats. Rats were randomized to seven weeks of treatment with vehicle (n = 16) or levosimendan (3 mg/kg/day) (n = 13). Control animals without pulmonary banding received vehicle treatment (n = 11). RV MEE and RV metabolism were evaluated by echocardiography, 11C-acetate positron emission tomography (PET), 18F-FDG PET, and invasive pressure measurements. We found that levosimendan improved RV MEE (26 ± 3 vs. 14 ± 1%, P

Background. Liraglutide, a glucagon-like peptide-1 agonist, is used for treatment of type 2 diabetes and has beneficial cardiovascular properties. However, treatment increases heart rate (HR) and possibly the risk of cardiovascular events in chronic heart failure (CHF) patients. We investigated potential associations between HR changes and clinical, laboratory and echocardiographic parameters and clinical events in liraglutide treated CHF patients. Methods. This was a sub-study of the LIVE study. CHF patients (N = 241) with a left ventricular ejection fraction ≤45% were randomised to 1.8 mg liraglutide daily or placebo for 24 weeks. Electrocardiograms (N = 117) and readouts from cardiac implanted electronic devices (N = 20) were analysed for HR and arrhythmias. Results. In patients with sinus rhythm (SR), liraglutide increased HR by 8 ± 9 bpm (pulse measurements), 9 ± 9 bpm (ECG measurements) and 9 ± 6 bpm (device readouts) versus placebo (all p

Background Myocardial external efficiency (MEE) is defined as the ratio of kinetic energy associated with cardiac work [forward cardiac output (FCO)*mean systemic pressure] and the chemical energy from oxygen consumed (MVO2) by the left ventricular mass (LVM). We developed a fully automated method for estimating MEE based on a single 11C-acetate PET scan without ECG-gating. Methods and Results Ten healthy controls, 34 patients with aortic valve stenosis (AVS), and 20 patients with mitral valve regurgitation (MVR) were recruited in a dual-center study. MVO2 was calculated using washout of 11C -acetate activity. FCO and LVM were calculated automatically using dynamic PET and parametric image formation. FCO and LVM were also obtained using cardiac magnetic resonance (CMR) in all subjects. The correlation between MEEPET-CMR and MEEPET was high (r = 0.85, P

Background— Currently, no pharmacological treatment can modify the natural history of aortic valve stenosis (AS). This underlines the critical need to explore novel treatment strategies, which could postpone or prevent the need for aortic valve replacement in patients with asymptomatic AS. The objectives of this study were to investigate whether metoprolol reduce the hemodynamic and metabolic burden imposed by AS. Methods and Results— In a double-blinded design, 40 patients with moderate-severe asymptomatic AS (aortic valve area, 0.5±0.1 cm 2 /m 2 ; peak gradient, 53±19 mm Hg) were randomized to placebo or metoprolol treatment for 22 weeks. Patients were evaluated by echocardiography, cardiovascular magnetic resonance, and 11 C-acetate positron emission tomography. Compared with placebo, metoprolol (100±53 mg/d) decreased heart rate; mean difference (95% confidence interval) −8 minute − 1 (−13, −3; P =0.003) and increased ejection time 26 ms (2, 50; P =0.03). Furthermore, metoprolol reduced aortic valve peak −7 mm Hg (−13, 0; P =0.05) and mean −4 mm Hg (−7, −1; P =0.03) gradients, without affecting stroke volume 3 mL/m 2 (−2, 8; P =0.16). Valvuloarterial impedance (ie, global afterload) and myocardial oxygen consumption were reduced by −11% and −12% ( P =0.03 and 0.01), respectively; and decreased heart rate correlated with lower valvuloarterial impedance, myocardial oxygen consumption, and improved myocardial efficiency defined as stroke work/myocardial oxygen consumption ( r =0.63–0.65; all P Conclusions— In patients with asymptomatic AS, metoprolol increases systolic ejection time and reduces aortic valve gradients, global afterload, and myocardial oxygen requirements. Thus, metoprolol displays favorable hemodynamic and metabolic effects and could improve outcome in patients with asymptomatic AS. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT02076711.

Background Myocardial oxygen consumption (MVO 2 ) and its coupling to contractile work are fundamentals of cardiac function and may be involved causally in the transition from compensated left ventricular hypertrophy to failure. Nevertheless, these processes have not been studied previously in patients with aortic valve stenosis (AS). Methods and Results Participants underwent 11 C‐acetate positron emission tomography, cardiovascular magnetic resonance, and echocardiography to measure MVO 2 and myocardial external efficiency (MEE) defined as the ratio of left ventricular stroke work and the energy equivalent of MVO 2 . We studied 10 healthy controls (group A), 37 asymptomatic AS patients with left ventricular ejection fraction ≥50% (group B), 12 symptomatic AS patients with left ventricular ejection fraction ≥50% (group C), and 9 symptomatic AS patients with left ventricular ejection fraction 2 did not differ among groups A, B, C, and D (0.105±0.02, 0.117±0.024, 0.129±0.032, and 0.104±0.026 mL/min per gram, respectively; P =0.07), whereas MEE was reduced in group D (21.0±1.6%, 22.3±3.3%, 22.1±4.2%, and 17.3±4.7%, respectively; P P 2 and MEE (area under the curve 0.98, 0.48, and 0.61, respectively; P Conclusions AS patients display a persistent ability to maintain normal MVO 2 and MEE (ie, the ability to convert energy into stroke work); however, patients with left ventricular ejection fraction

Dynamic cardiac positron emission tomography (PET) is used to quantify molecular processes in vivo. However, measurements of left-ventricular (LV) mass and volumes require electrocardiogram (ECG)-gated PET data. The aim of this study was to explore the feasibility of measuring LV geometry using non-gated dynamic cardiac PET. METHODS: Thirty-five patients with aortic-valve stenosis and 10 healthy controls (HC) underwent a 27-min 11C-acetate PET/CT scan and cardiac magnetic resonance imaging (CMR). HC were scanned twice to assess repeatability. Parametric images of uptake rate K1 and the blood pool were generated from non-gated dynamic data. Using software-based structure recognition the LV wall was automatically segmented from K1 images to derive mLV and wall thickness (WT). End-systolic (ESV) and end-diastolic (EDV) volumes were calculated using blood pool images and used to obtain stroke volume (SV) and LV ejection fraction (LVEF). PET measurements were compared with CMR. RESULTS: High and linear correlations were found for LV mass (r=0.95), ESV (r=0.93) and EDV (r=0.90), and slightly lower for SV (r=0.74), LVEF (r=0.81) and WT(r=0.78). Bland Altman analyses showed significant differences for mLV and WT only and an overestimation for LVEF at lower values. Intra- and inter-observer correlations were >0.95 for all PET measurements. PET repeatability accuracy in HC was comparable to CMR. CONCLUSION: LV mass and volumes are accurately and automatically generated from dynamic 11C-acetate PET without ECG-gating. This method can be incorporated in a standard routine without any additional workload and can, in theory, be extended to other PET tracers. Dynamic cardiac positron emission tomography (PET) is used to quantify molecular processes in vivo. However, measurements of left-ventricular (LV) mass and volumes require electrocardiogram (ECG)-gated PET data. The aim of this study was to explore the feasibility of measuring LV geometry using non-gated dynamic cardiac PET.METHODS: Thirty-five patients with aortic-valve stenosis and 10 healthy controls (HC) underwent a 27-min (11)C-acetate PET/CT scan and cardiac magnetic resonance imaging (CMR). HC were scanned twice to assess repeatability. Parametric images of uptake rate K1 and the blood pool were generated from non-gated dynamic data. Using software-based structure recognition the LV wall was automatically segmented from K1 images to derive mLV and wall thickness (WT). End-systolic (ESV) and end-diastolic (EDV) volumes were calculated using blood pool images and used to obtain stroke volume (SV) and LV ejection fraction (LVEF). PET measurements were compared with CMR.RESULTS: High and linear correlations were found for LV mass (r=0.95), ESV (r=0.93) and EDV (r=0.90), and slightly lower for SV (r=0.74), LVEF (r=0.81) and WT(r=0.78). Bland Altman analyses showed significant differences for mLV and WT only and an overestimation for LVEF at lower values. Intra- and inter-observer correlations were >0.95 for all PET measurements. PET repeatability accuracy in HC was comparable to CMR.CONCLUSION: LV mass and volumes are accurately and automatically generated from dynamic (11)C-acetate PET without ECG-gating. This method can be incorporated in a standard routine without any additional workload and can, in theory, be extended to other PET tracers.

Background The aim of this study was to develop and validate an automated method for extracting forward stroke volume (FSV) using indicator dilution theory directly from dynamic positron emission tomography (PET) studies for two different tracers and scanners. Methods 35 subjects underwent a dynamic 11 C-acetate PET scan on a Siemens Biograph TruePoint-64 PET/CT (scanner I). In addition, 10 subjects underwent both dynamic 15 O-water PET and 11 C-acetate PET scans on a GE Discovery-ST PET/CT (scanner II). The left ventricular (LV)-aortic time-activity curve (TAC) was extracted automatically from PET data using cluster analysis. The first-pass peak was isolated by automatic extrapolation of the downslope of the TAC. FSV was calculated as the injected dose divided by the product of heart rate and the area under the curve of the first-pass peak. Gold standard FSV was measured using phase-contrast cardiovascular magnetic resonance (CMR). Results FSV PET correlated highly with FSV CMR (r = 0.87, slope = 0.90 for scanner I, r = 0.87, slope = 1.65, and r = 0.85, slope = 1.69 for scanner II for 15 O-water and 11 C-acetate, respectively) although a systematic bias was observed for both scanners (p BACKGROUND: The aim of this study was to develop and validate an automated method for extracting forward stroke volume (FSV) using indicator dilution theory directly from dynamic positron emission tomography (PET) studies for two different tracers and scanners.METHODS: 35 subjects underwent a dynamic (11)C-acetate PET scan on a Siemens Biograph TruePoint-64 PET/CT (scanner I). In addition, 10 subjects underwent both dynamic (15)O-water PET and (11)C-acetate PET scans on a GE Discovery-ST PET/CT (scanner II). The left ventricular (LV)-aortic time-activity curve (TAC) was extracted automatically from PET data using cluster analysis. The first-pass peak was isolated by automatic extrapolation of the downslope of the TAC. FSV was calculated as the injected dose divided by the product of heart rate and the area under the curve of the first-pass peak. Gold standard FSV was measured using phase-contrast cardiovascular magnetic resonance (CMR).RESULTS: FSVPET correlated highly with FSVCMR (r = 0.87, slope = 0.90 for scanner I, r = 0.87, slope = 1.65, and r = 0.85, slope = 1.69 for scanner II for (15)O-water and (11)C-acetate, respectively) although a systematic bias was observed for both scanners (p CONCLUSIONS: FSV can be obtained automatically using dynamic PET/CT and cluster analysis. Results are almost identical for (11)C-acetate and (15)O-water. A scanner-dependent bias was observed, and a scanner calibration factor is required for multi-scanner studies. Generalization of the method to other tracers and scanners requires further validation.

A 64-year-old previously healthy woman consulted her general practitioner because of recurrent episodes of right-sided monocular transient visual loss (ie, amaurosis fugax). At first, these symptoms were followed over time, but as the attacks worsened, and were accompanied by dizziness and general discomfort, the patient was admitted to the department of neurology for further investigations. CT of the brain was normal; however, during admission, the patient developed rapid atrial fibrillation and was transferred to the department of cardiology. Transthoracic echocardiography revealed a massive tumour on the atrial side of the anterior mitral valve leaflet, partly obstructing the mitral valve inflow. The tumour was excised and a biological prosthetic mitral valve inserted. The tumour was histologically determined to be a highly malignant dedifferentiated chondrosarcoma. After 6 months, the tumour relapsed and expanded aggressively to completely obstruct the mitral valve inflow, ultimately leading to cardiac arrest and death.

A previously healthy 29-year-old man was admitted with palpitations, dizziness, and near-syncope after he had recently started taking weight loss pills purchased on the internet. The pills contained caffeine and ephedrine. An electrocardiogram and telemetry revealed multiple episodes of non-sustained monomorphic ventricular tachycardia, which was successfully treated with amiodarone. In conclusion, unauthorized weight loss pills can be harmful. In particular, ephedrine-containing drugs carry a risk of ventricular tachycardia and should be discouraged.

Objectives: Dynamic PET with 11C-acetate can be used to quantify myocardial blood flow and oxidative metabolism, the latter of which is used to calculate myocardial external efficiency (MEE). Calculation of MEE requires forward stroke volume (FSV) data. FSV is affected by cardiac loading conditions, potentially introducing bias if measured with a separate modality. The aim of this study was to develop and validate methods for automatically extracting FSV directly from the dynamic PET used for measuring oxidative metabolism. Methods: 16 subjects underwent a dynamic 27 min PET scan on a Siemens Biograph TruePoint 64 PET/CT scanner after bolus injection of 399±27 MBq of 11C-acetate. The LV-aortic time-activity curve (TAC) was extracted automatically from dynamic PET data using cluster analysis. The first-pass peak was derived by automatic extrapolation of the down-slope of the TAC. FSV was then calculated as the injected dose divided by the product of heart rate and the area under the curve of the first-pass peak. Gold standard FSV was measured in the left ventricular outflow tract by cardiovascular magnetic resonance using phase-contrast velocity mapping within two weeks of PET imaging. Results: Cluster analysis could be performed successfully in all patients. Heart rate varied by 5±4 beats/min between scans. FSV-PET was highly correlated with FSV-MRI (PET=0.92*MRI+18 mL, r = 0.88, p < 0.001) although obtained values were significantly higher (bias of 14±13%, 95% confidence interval -11:40%, p = 0.001). Conclusions: FSV can be obtained automatically and reliably using dynamic 11C-acetate PET/CT and cluster analysis, although a small overestimation is observed when compared to FSV determined from MRI. This method could potentially be generalized to other tracers, although this requires further validation.