11C-acetate Positron Emission Tomography Research Articles

Abstract 4139188: Myocardial perfusion, oxidative metabolism and fibrosis in heart failure with preserved ejection fraction

Background: Cardiac remodeling among individuals with heart failure with preserved ejection fraction (HFpEF) and its risk factors is incompletely understood. Non-invasive cardiac imaging can reliably assess myocardial oxidative metabolism, perfusion, fibrosis, systolic and diastolic function. Nevertheless, the interrelationships between these, particularly with oxidative metabolism, remain unresolved from health to HFpEF as most human studies lack complementary multi-modality imaging. Methods: We performed a cross-sectional study using multi-modality cardiovascular imaging in healthy individuals (n=17), those with hypertension (n=15), and patients with HFpEF (n=8). We quantified myocardial oxidative metabolism (K mono ) with 11 C-acetate positron emission tomography (PET), coronary flow reserve (CFR) with 13 N-ammonia PET, fibrosis (extracellular volume [ECV], LVEF and mass with magnetic resonance imaging (MRI), and LV diastolic filling pressure (E/e’) by echocardiography. The associations between myocardial oxidative metabolism, perfusion, and fibrosis across clinical status (health, hypertension, and HFpEF) were examined in multivariable models. Results: From health to HFpEF, we found significant graded declines in oxidative metabolism indexed to workload (K mono /RPP) (β = -1.66 x 10 -6 [95%CI: -3.12 x 10 -6 to -2.10 x 10 -6 ]; p = 0.027) and CFR (β = -0.76 [95% CI: -1.36 to -0.16]; p = 0.021), along with increased fibrosis (ECV) (β = 2.12% [95% CI: 0.10 to 4.14%]; p = 0.041), independent of LVEF, LV mass, E/e’, age, sex, and body mass index. The decline in oxidative metabolism from health to HFpEF was also independent of ECV and CFR (β = -2.98 x 10 -6 [95% CI: -5.62 x 10 -6 to -3.41 x 10 -6 ], p = 0.015). In contrast, the decline in CFR from health to HFpEF was no longer significant (p = 0.30) with further adjustment for ECV. Conclusions: HFpEF and its development involves progressive declines in myocardial oxidative metabolism and perfusion reserve with increase in fibrosis. The decline in myocardial oxidative metabolism from health to HFpEF is independent of fibrosis and perfusion reserve, suggesting oxidative metabolism may be a target for the prevention and treatment of HFpEF.

Quantitation of mitral regurgitation using positron emission tomography

BackgroundCardiac positron emission tomography (PET) offers non-invasive assessment of perfusion and left ventricular (LV) function from a single dynamic scan. However, no prior assessment of mitral regurgitation severity by PET has been presented. Application of indicator dilution techniques and gated image analyses to PET data enables calculation of forward stroke volume and total LV stroke volume. We aimed to evaluate a combination of these methods for measurement of regurgitant volume (RegVol) and fraction (RegF) using dynamic 15O-water and 11C-acetate PET in comparison to cardiovascular magnetic resonance (CMR).ResultsTwenty-one patients with severe primary mitral valve regurgitation underwent same-day dynamic PET examinations (15O-water and 11C-acetate) and CMR. PET data were reconstructed into dynamic series with short time frames during the first pass, gated 15O-water blood pool images, and gated 11C-acetate myocardial uptake images. PET-based RegVol and RegF correlated strongly with CMR (RegVol: 15O-water r = 0.94, 11C-acetate r = 0.91 and RegF: 15O-water r = 0.88, 11C-acetate r = 0.84, p < 0.001). A systematic underestimation (bias) was found for PET (RegVol: 15O-water − 11 ± 13 mL, p = 0.002, 11C-acetate − 28 ± 16 mL, p < 0.001 and RegF: 15O-water − 4 ± 6%, p = 0.01, 11C-acetate − 10 ± 7%, p < 0.001). PET measurements in patients were compared to healthy volunteers (n = 18). Mean RegVol and RegF was significantly lower in healthy volunteers compared to patients for both tracers. The accuracy of diagnosing moderately elevated regurgitant volume (> 30mL) was 95% for 15O-water and 92% for 11C-acetate.ConclusionsLV regurgitation severity quantified using cardiac PET correlated with CMR and showed high accuracy for discriminating patients from healthy volunteers.

Outcome prediction by myocardial external efficiency from 11 C-acetate positron emission tomography in cardiac amyloidosis.

This study aimed to study the prognostic value of myocardial oxygen consumption (MVO2 ) and myocardial external efficiency (MEE) from 11 C-acetate positron emission tomography (PET) in cardiac amyloidosis (CA) patients. Forty-eight CA patients, both transthyretin (ATTR) and immunoglobulin light chain (AL) amyloidosis, and 20 controls were included. All subjects were examined with 11 C-acetate PET and echocardiography. MVO2 , forward stroke volume (FSV), and left ventricular mass (LVM) were derived from 11 C-acetate PET and used to calculate MEE. CA patients were followed for survival and the prognostic impact of clinical, echocardiographic, and 11 C-acetate PET parameters was analysed. MVO2 and MEE were reduced in CA compared with controls, but without significant difference between deceased and surviving CA patients. The ratio of 11 C-acetate PET-derived FSV and LVM was also reduced in CA and significantly lowered in deceased patients compared with survivors. In univariate analysis, New York Heart Association class, N-terminal pro-brain natriuretic peptide, and the 11 C-acetate PET parameters FSV/LVM and MEE were the strongest prognostic factors. Of the 11 C-acetate PET parameters, FSV/LVM was the strongest survival predictor with hazard ratio of 0.56 per 0.1mL/g (95% confidence interval 0.39-0.81, P=0.002) and independently prognostic in a multivariate model. MEE significantly separated deceased from surviving CA patients with the cut-off of 15.7% (P=0.032). Survival was significantly shorter with FSV/LVM below 0.27mL/g (P<0.001), also when separating AL- and ATTR-CA. Reduced MEE was associated with shorter survival in CA patients, but FSV/LVM was the strongest survival predictor and the only independently prognostic 11 C-acetate PET parameter in multivariate analysis.

Serial measurements of myocardial efficiency in patients with aortic valve stenosis: pathophysiological insights and prognostic information

Abstract Background In patients with aortic valve stenosis (AS), the pathophysiological abnormalities involved in the transition to symptomatic heart failure are unclear. During progression of chronic heart failure, the coupling between myocardial stroke work and myocardial oxygen consumption, i.e. myocardial external efficiency (MEE), deteriorates. However, in AS patients it is unknown whether changes in MEE over time are involved in disease progression and whether MEE has prognostic information. Purpose In patients with AS, we 1) investigated changes in MEE over time and 2) studied if MEE was associated with long-term prognosis. Methods In a prospective design, we studied 10 healthy controls and 38 patients with moderate-severe, asymptomatic AS (aortic valve area 0.5±0.1 cm2/m2, mean gradient 31±12 mmHg) and left ventricular ejection fraction ≥50%. The patient group was evaluated by serial 11C-acetate positron emission tomography, cardiovascular magnetic resonance imaging and echocardiography with a median follow-up period of 2.8 years. Furthermore, we conducted an extended follow-up of patients for a median of 5.2 years to detect clinical events (defined as symptoms due to AS, aortic valve replacement, hospitalization due to heart failure or cardiovascular death) and related them to MEE changes. Results During follow-up AS patients mean aortic valve pressure gradients increased by 13 mmHg (9 to 17; p&amp;lt;0.001) (mean (95% confidence interval)) and aortic valve opening area declined by −0.15 cm2 (−0.20 to −0.09; p&amp;lt;0.001). Global longitudinal strain worsened by 2.6% (1.8 to 3.5; p&amp;lt;0.001) and N-terminal pro-B-type natriuretic peptide increased by 162 ng/L (28 to 296; p=0.02) whereas left ventricular ejection fraction and cardiac index did not change significantly. MEE increased during follow-up by 4.3% (1.9 to 6.8; p=0.001) from 25.2% (24.0 to 26.5) to 29.5% (27.3 to 31.8) and was higher compared to healthy volunteers 19.9% (18.1 to 21.8; p&amp;lt;0.001). The changes in MEE were positively correlated to changes in end-diastolic volume (r=0.58, p=0.005) and wall stress (r=0.54, p=0.01). There were no changes in MVO2 0.0 mL/min/100g (−0.8 to 0.8; p=0.98) during follow-up. As compared to event-free patients, patients who experienced a clinical event during long-term follow-up (n=24, 63%) had higher baseline MEE 26.5% (24.3 to 28.6) vs 23.8% (22.6 to 25.1) (p=0.04) and did not increase MEE during follow-up 1.9% (−1.8 to 5.6; p=0.28) vs 5.9% (2.6 to 9.2; p=0.002). Conclusion In asymptomatic AS patients, MEE increased over time in tandem with increasing transvalvular gradients and wall stress. Thus, the myocardium displayed an inherent capacity to improve the coupling between oxidative metabolism and contractile function in response to pressure overload. High baseline MEE and blunted MEE increase predicted a poor prognosis. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Lundbeck FoundationArvid Nilssons Foundation

Characterization of myocardial oxidative metabolism and myocardial external efficiency in high-risk alcohol cardiotoxicity and alcoholic cardiomyopathy via dynamic 11C-Acetate positron emission tomography

IntroductionThe purpose of this study was to evaluate subjects with high-risk alcohol cardiotoxicity and patients with alcoholic cardiomyopathy (ACM) via dynamic 11C-Acetate positron emission tomography (PET) imaging as a myocardial oxidative metabolic probe. Methods and ResultsWe recruited 37 subjects with chronic alcohol consumption [18 with moderate consumption (MC), 19 with heavy consumption (HC)], 5 ACM patients, and 12 healthy controls to receive dynamic 11C-Acetate PET scans. PET imaging data were analyzed to calculate kinetic parameters (e.g., Kmono, K1 and k2) based on the mono-exponential and one-tissue compartmental models. Myocardial oxygen consumption (MVO2) and myocardial external efficiency (MEE) were then derived from these kinetic parameters. MVO2 was significantly lowered in the HC group and in ACM patients (0.121± 0.018 and 0.111 ± 0.017 mL·g−1·min−1, respectively) compared with those in healthy controls and MC subjects (0.144 ± 0.023 and 0.146 ± 0.027 mL·g−1·min−1, respectively; P < .01). MEE was significantly reduced in ACM patients (13.0% ± 4.3%) compared with those of healthy controls (22.4% ± 4.6%, P < .01), MC subjects (20.1% ± 4.5%, P < .05), and HC subjects (22.3% ± 4.5%, P < .001). ConclusionFunctional assessment via dynamic 11C-Acetate PET imaging may represent a clinically feasible probe for identifying cohorts with high-risk cardiotoxicity due to addictive alcohol consumption and ACM.

11C-acetate positron emission tomography is more precise than 18F-fluorodeoxyglucose positron emission tomography in evaluating tumor burden and predicting disease risk of multiple myeloma

The optimal method of tumor burden evaluation in newly diagnosed multiple myeloma (NDMM) is yet to be determined. This study aimed to compare the value of 11C-acetate positron-emission tomography (PET)/computed tomography (CT) (AC-PET and 18F-fluorodeoxyglucose PET/CT (FDG-PET) in the assessment of tumor burden in NDMM.This study evaluated 64 NDMM patients between February 2015 and July 2018. AC-PET and FDG-PET were used to assess myeloma lesions. The clinical data, imaging results, and their correlations were analyzed. Diffuse bone marrow uptake in AC-PET was significantly correlated with biomarkers for tumor burden, including serum hemoglobin (P = 0.020), M protein (P = 0.054), the percentage of bone marrow plasma cells (P < 0.001), and the Durie–Salmon stage of the disease (P = 0.007). The maximum standard uptake value (SUVmax) of focal lesions and high diffuse bone marrow uptake in AC-PET showed stronger correlations with high-risk disease (P = 0.017, P = 0.013) than those in FDG-PET. Moreover, the presence of diffuse bone marrow uptake, more than ten focal lesions, and an SUVmax of focal lesions of > 6.0 in AC-PET, but not in FDG-PET, predicted a higher probability of disease progression and shorter progression-free survival (P < 0.05). AC-PET outperformed FDG-PET in tumor burden evaluation and disease progression prediction in NDMM.

Myocardial efficiency in patients with different aetiologies and stages of heart failure.

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. 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 < 0.001 vs. 26.1 ± 5.8% in controls) and a further decline was observed in patients with HFrEF (14.7 ± 6.3%, P < 0.001). Disproportionate left ventricular hypertrophy was a major cause of reduced MEE. Female sex (P < 0.001), a lower BMI (P = 0.001), and advanced age (P = 0.03) were associated with a lower MEE. 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.

Mechanoenergetic coupling in heart failure with preserved, mid-range and reduced left ventricular ejection fraction

Abstract 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 &amp;lt;40% (HFrEF; n=25), mid-range LVEF 40–49% (HFmrEF; n=23), as well as patients with asymptomatic aortic valve stenosis (AS) and LVEF ≥50% (AS-asymp; n=38), and symptomatic AS and LVEF ≥50% (defined as HF with preserved LVEF (HFpEF); n=15). Results MEE declined in tandem with reduced LVEF from HFpEF and HFmrEF to HFrEF (p=0.041, p&amp;lt;0.001, and p&amp;lt;0.001 versus control, respectively; Figure 1). Impaired MEE was aggravated with increasing LVM (p=0.001) due to a disproportionate increase in overall left ventricular MVO2. In a multivariate analysis, female sex (p&amp;lt;0.001), a lower body mass index (p&amp;lt;0.001), and advanced age (p=0.01) were associated with a lower MEE (Figure 2). HFpEF, HFmrEF, and HFrEF patients had distinct energetic profiles involving MEE, MVO2, MBF, ESWS, and LVM (Figure 2). 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

Myocardial efficiency in severe asymptomatic primary mitral regurgitation: relation to quantitative measures of regurgitation

Abstract Objectives To study the association of myocardial external efficiency (MEE) in mitral regurgitation (MR) towards routinely used quantitative indicators of disease severity and progression. Background Quantitative assessment of LV function and regurgitation in asymptomatic severe primary MR is crucial for management. MEE is a load-independent indicator of mechano-energetic coupling and can be measured non-invasively using 11C-acetate positron emission tomography (PET). The role of MEE in this setting has not been studied. Methods 48 asymptomatic patients with severe primary mitral regurgitation underwent PET, echo, and CMR on the same day. MEE was automatically derived from PET as the ratio of cardiac work (cardiac output * mean arterial pressure) and total left ventricular (LV) oxygen consumption (mean MVO2 * LV mass). LV function and mitral regurgitant volumes (RegVol) were measured by echo and CMR. MEE in MR was compared to healthy volunteers (n=9). MEE and parameters of regurgitation severity and of LV volumes and function were studied as predictors of outcome (valve surgery or death). Results MEE was reduced in MR (21.5±4.2%) vs healthy volunteers (32.0±5.6%, p&amp;lt;0.001) and showed weak but significant correlations (r2&amp;lt;0.25) with regurgitation severity and LV volumes. There were 23 cardiac events (valve surgery: 22; cardiovascular death: 1) during follow-up (median 2.7 years, IQR 1.9–3.2). Univariate Cox models showed that MEE, echocardiographic left atrial volume as well as RegVol and LV ventricular volumes from both echo and CMR were significant outcome predictors (all p&amp;lt;0.05), while LVEF and NT-pro-BNP were not (p&amp;gt;0.05). Prediction by MEE was not affected by age, sex or BMI. When categorically divided by the median MEE was a strong predictor in Kaplan-Meier analysis (log-rank p=0.0004, figure 1) and remained independently significant, compared to all other univariate predictors in bivariate Cox models. Conclusions This study suggests an important role of energetic insufficiency in progression of asymptomatic severe primary MR. Reduced MEE was linked to outcome independently of standard functional measures of regurgitation severity or left ventricular size and function. Strategies for improvement of myocardial energetics in MR are warranted. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swedish Heart-Lung Foundation Figure 1

Early Detection of Response to Radiotherapy Treatment with 11C-Acetate PET Imaging

11C-Acetate radiotracer with Positron Emission Tomography (PET) imaging is currently used in cardiovascular imaging for perfusion and oxygen consumption measurement. It is also used, among other diseases, for prostate cancer as this radiotracer does not accumulate in the bladder. The present study reports the assessment of the radiotherapy treatment by measuring the tumor perfusion and oxygenation before and at mid-treatment by imaging with dynamic 11C-Acetate in patients with head and neck cancer. A pre-treatment dynamic 11C-Acetate and a clinical static 18F-FDG PET were conducted before initiation of the treatment, and the second 11C-Acetate dynamic scan was performed after four weeks of radiotherapy (i.e., after a dose of 35 Gy for a total of 70 Gy). The two-tissue compartment model was applied to 11C-Acetate images to extract the perfusion and oxygen consumption. The results showed a reduction in tumor volume by more than 50% compared to the initial volume in patient-1. Besides, patient-2 has displayed a more reduced tumor volume after 4 weeks of treatment. The 11C-Acetate rate constant k2 representing oxygen consumption increased after radiotherapy dose in both patients. This increase of k2 could reflect the reoxygenation process inside the tumor, and it can reflect the early treatment response. In conclusion, 11C-Acetate could predict the early changes in the tumor perfusion and the oxidative metabolism to optimally adjust the treatment.

Contribution of perfusion to the 11 C-acetate signal in brown adipose tissue assessed by DCE-MRI and 68 Ga-DOTA PET in a rat model.

Determine if dynamic contrast enhanced (DCE) -MRI and/or 68 gallium 1,4,7,10-tetraazacyclododecane N, N', N″, N‴-tretraacetic acid (68 Ga-DOTA) positron emission tomography (PET) can assess perfusion in rat brown adipose tissue (BAT). Evaluate changes in perfusion between cold-stimulated and heat-inhibited BAT. Determine if the 11 C-acetate pharmacokinetic model can be constrained with perfusion information to improve assessment of BAT oxidative metabolism. Rats were split into three groups. In group 1 (N=6), DCE-MRI with gadobutrol was compared directly to 68 Ga-DOTA PET following exposure to 10°C for 48h. 11 C-Acetate PET was also performed to assess oxidation. In group 2 (N=4), only 68 Ga-DOTA PET was acquired following exposure to 10°C for 48h. Finally, in group 3 (N=10), perfusion was assessed with DCE-MRI in rats exposed to 10°C or 30°C for 48h, and oxidation was measured with 11 C-acetate. Perfusion was quantified with a two-compartment pharmacokinetic model, while oxidation was assessed by a four-compartment model. DCE-MRI and 68 Ga-DOTA PET provided similar perfusion measures, but a decrease in the perfusion signal was noted with longer imaging sessions. Exposure to 10°C or 30°C did not affect the perfusion measures, but the 11 C-acetate signal increased in BAT at 10°C. Without prior information about blood volume, the 11 C-acetate compartment model overestimated blood volume and underestimated oxidation in 10°C BAT. Precise assessment of oxidation via 11 C-acetate PET requires prior information about blood volume which can be obtained by DCE-MRI or 68 Ga-DOTA PET. Since perfusion can change rapidly, simultaneous PET-MRI would be preferred.

Myocardial tissue and metabolism characterization in men with alcohol consumption by cardiovascular magnetic resonance and 11C-acetate PET/CT

BackgroundChronic alcohol consumption initially leads to asymptomatic left ventricular dysfunction, but can result in myocardial impairment and heart failure if ongoing. This study sought to characterize myocardial tissues and oxidative metabolism in asymptomatic subjects with chronic alcohol consumption by quantitative cardiovascular magnetic resonance (CMR) and 11C-acetate positron emission tomography (PET)/computed tomography (CT).MethodsThirty-four male subjects (48.8 ± 9.1 years) with alcohol consumption > 28 g/day for > 10 years and 35 age-matched healthy male subjects (49.5 ± 9.7 years) underwent CMR and 11C-acetate PET/CT. Native and post T1 values and extracellular volume (ECV) from CMR and Kmono and K1 from PET imaging were measured. Quantitative measurements by CMR and PET imaging were compared between subjects with moderate to heavy alcohol consumption and healthy controls, and their correlations were also analyzed.ResultsCompared to healthy controls, subjects with alcohol consumption showed significantly shorter native T1 (1133 ± 65 ms vs. 1186 ± 31 ms, p < 0.001) and post T1 (477 ± 42 ms vs. 501 ± 38 ms, p = 0.008) values, greater ECV (28.2 ± 2.2% vs. 26.9 ± 1.3%, p = 0.003), marginally lower Kmono (57.6 ± 12.1 min− 1 × 10− 3 vs. 63.0 ± 11.7 min− 1 × 10− 3, p = 0.055), and similar K1 (0.82 ± 0.13 min− 1 vs. 0.83 ± 0.15 min− 1, p = 0.548) after adjusting for confounding factors. There were no significant differences in CMR measurements and K1 between subjects with heavy and moderate alcohol consumption (all p > 0.05). In contrast, subjects with heavy alcohol consumption showed significantly lower Kmono values compared to those with moderate alcohol consumption (52.9 ± 12.1 min− 1 × 10− 3 vs. 63.7 ± 9.2 min− 1 × 10− 3, p = 0.012). Strong and moderate correlations were found between K1 and ECV in healthy controls (r = 0.689, p = 0.013) and subjects with moderate alcohol consumption (r = 0.518, p = 0.048), respectively.ConclusionAsymptomatic men with heavy alcohol consumption have detectable structural and metabolic changes in myocardium on CMR and 11C-acetate PET/CT. Compared with quantitative CMR, 11C-acetate PET/CT imaging may be more sensitive for detecting differences in myocardial damage among subjects with moderate to heavy alcohol consumption.

A randomised, double-blind, placebo-controlled trial of metformin on myocardial efficiency in insulin-resistant chronic heart failure patients without diabetes.

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. 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. 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.

Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients.

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. 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. 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 MVO2 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. 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.

Test–retest repeatability of myocardial oxidative metabolism and efficiency using standalone dynamic 11C-acetate PET and multimodality approaches in healthy controls

BackgroundMyocardial 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. Methods and ResultsTen 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 < .001. WMICMR, WMIEcho, and WMIPET values were 4.42 ± 0.90, 4.07 ± 0.63, and 4.58 ± 1.13 mmHg × mL/m2 × 106, respectively, P = .45. Repeatability for MEECMR was superior compared with MEEEcho but did not differ significantly compared with MEEPET (6.3% vs 12.9% and 9.4%, P = .04 and .25). CV values for WMICMR, WMIEcho, and WMIPET were 10.0%, 14.8%, and 12.0%, respectively, (P = .53). ConclusionsNon-invasive measurements of MEE using 11C-acetate PET are highly repeatable. A PET-only approach did not differ significantly from CMR/PET and might facilitate further clinical research due to lower costs and broader applicability.

Repeatable and reproducible measurements of myocardial oxidative metabolism, blood flow and external efficiency using 11C-acetate PET

BackgroundNon-invasive approaches to investigate myocardial efficiency can help track the progression of heart failure (HF). This study evaluates the repeatability and reproducibility of 11C-acetate positron emission tomography (PET) imaging of oxidative metabolism. Methods and resultsDynamic 11C-acetate PET scans were performed at baseline and followup (47 ± 22 days apart) in 20 patients with stable HF with reduced ejection fraction. Two observers blinded to patients’ clinical data used FlowQuant® to evaluate test–retest repeatability, as well as intra- and inter-observer reproducibility of 11C-acetate tracer uptake and clearance rates, for the measurement of myocardial oxygen consumption (MVO2), myocardial external efficiency (MEE), work metabolic index (WMI), and myocardial blood flow. Reproducibility and repeatability were evaluated using intra-class-correlation (ICC) and Bland–Altman coefficient-of-repeatability (CR). Test–retest correlations and repeatability were better for MEE and WMI compared to MVO2. All intra- and inter-observer correlations were excellent (ICC = 0.95-0.99) and the reproducibility values (CR = 3%-6%) were significantly lower than the test–retest repeatability values (22%-54%, P < 0.001). Repeatability was improved for all parameters using a newer PET–computed tomography (CT) scanner compared to older PET-only instrumentation. Conclusion11C-acetate PET measurements of WMI and MEE exhibited excellent test–retest repeatability and operator reproducibility. Newer PET–CT scanners may be preferred for longitudinal tracking of cardiac efficiency.

Hyperpolarized [1-13C]-acetate Renal Metabolic Clearance Rate Mapping

11C-acetate is a positron emission tomography (PET) tracer of oxidative metabolism, whereas hyperpolarized 13C-acetate can be used in magnetic resonance imaging (MRI) for investigating specific metabolic processes. The aims of this study were to examine if the kinetic formalism of 11C-acetate PET in the kidneys is comparable to that of 13C-acetate MRI, and to compare the dynamic metabolic information of hyperpolarized 13C-acetate MRI with that obtained with 11C-acetate PET. Rats were examined with dynamic hyperpolarized 13C-acetate MRI or 11C-acetate PET before and after intravenous injection of furosemide, a loop diuretic known to alter both the hemodynamics and oxygen consumption in the kidney. The metabolic clearance rates (MCR) were estimated and compared between the two modalities experimentally in vivo and in simulations. There was a clear dependency on the mean transit time and MCR for both 13C-acetate and 11C-acetate following furosemide administration, while no dependencies on the apparent renal perfusion were observed. This study demonstrated that hyperpolarized 13C-acetate MRI is feasible for measurements of the intrarenal energetic demand via the MCR, and that the quantitative measures are correlated with those measured by 11C-acetate PET, even though the temporal window is more than 30 times longer with 11C-acetate.

Levosimendan improves cardiac function and myocardial efficiency in rats with right ventricular failure

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 < 0.01) by increasing RV external work (0.62 ± 0.06 vs. 0.30 ± 0.03 mmHgċmL, P < 0.001) without affecting RV myocardial oxygen consumption (P = 0.64). The improvement in RV MEE was not associated with a change in RV myocardial glucose uptake (1.3 ± 0.1 vs. 1.0 ± 0.1 µmol/g/min, P = 0.44). In conclusion, in the hypertrophic and failing RV of the rat, levosimendan improves RV function without increasing myocardial oxygen consumption leading to improved MEE. The improvement in RV MEE was not associated with a change in myocardial glucose uptake. This study emphasizes the potential therapeutic value of chronic levosimendan treatment RV failure. It extends previous observations on the effect profile of levosimendan and motivates clinical testing of levosimendan in RV failure.

Targeting High Oxygen Consumption to Prevent Cardiac Dysfunction in Patients With Aortic Valve Stenosis

In the aging population, an increasing number of people experience aortic valve stenosis (AS) and develop severe concentric hypertrophy in response to pressure overload of the left ventricle.1 Although aortic valve replacement (AVR) prevents worsening of cardiac disease, there is currently no treatment that effectively prevents the transition from compensatory hypertrophy to failure of the ventricle in patients with AS. Initially, the hypertrophic response of the ventricle in response to increased pressure is compensatory to preserve wall stress and systolic function. However, chronic overload of the ventricle induces pathological changes that ultimately cause failure of the ventricle. Defining the pathophysiologic mechanisms that underlie the transition from a compensatory to a failing hypertrophied ventricle is key to finding pharmacological treatment options for patients with AS. Imaging studies combining cardiovascular magnetic resonance and 11C-acetate positron-emission tomography to assess myocardial external efficiency (MEE), that is, the ratio between external work and myocardial oxygen consumption (MVO2), revealed reduced MEE in patients with AS compared with controls.2 The hypertrophied ventricle of patients with symptomatic AS is characterized by high MVO2,2,3 indicative of high metabolic demand. To match …

Imaging of primary liver tumors with positron-emission tomography

The use of positron-emission tomography (PET) with fluorodeoxyglucose (FDG), 11C-acetate and radio-labelled choline such as 11C-choline or 18F-fluorocholine in the diagnosis of hepatocellular carcinoma (HCC), for risk stratification or therapy monitoring has emerged. This review aims to summarize the published results dealing with this issue. PubMed database was searched until February 2017. Sensitivities, specificities, progression-free survival (PFS), survival and hazard ratios (HR) are reported. Seventy-one studies were included. Most studies are dealing with the diagnostic value of FDG PET (N.=21), 11C-acetate PET (N.=11), and choline PET (N.=8). The results indicate a homogenously higher sensitivity for 11C-acetate and choline PET as compared to FDG PET in the diagnosis of primary or recurrent HCC. This is particularly true for well differentiated HCC, which tend to have higher uptake of 11C-acetate and radio-labelled choline. Contrary, poorly differentiated HCC are more often FDG-positive than well differentiated HCC. Sixteen studies are evaluating the prognostic value of FDG PET for surgery or liver transplantation. The studies found a significant worse prognosis in terms of time to recurrence, PFS, and survival in FDG-positive HCC as compared to FDG-negative ones. Sixteen studies are reporting about the prognostic value of FDG PET and one about 18F-fluoroethylcholine PET for palliative treatment. Most of these studies indicate a significant shorter PFS and survival in FDG-positive HCC for various treatments. Whereas FDG PET has only a limited role in the diagnosis of HCC, it provides valuable prognostic information for liver surgery, transplantation and palliative treatment. 11C-acetate and choline PET have a higher sensitivity in the diagnosis of HCC.