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Purpose: Cardiac sympathetic nervous system (SNS) dysfunction is associated with poor prognosis in chronic heart failure patients. This study characterized the reproducibility and repeatability of [ 11 C]meta-hydroxyephedrine (HED) positron emission tomography (PET) quantification of cardiac SNS innervation, regional denervation, and myocardial blood flow (MBF)., Methods: Dynamic HED PET-CT scans were performed 47 ± 22 days apart in 20 patients with stable heart failure and reduced ejection fraction. Three observers, blinded to clinical data, used FlowQuant® to evaluate the test-retest repeatability and inter- and intra-observer reproducibility of HED tracer uptake and clearance rates to measure global (LV-mean) retention index (RI), volume of distribution (V T ), and MBF. Values were also compared with and without regional partial-volume correction. Regional denervation was quantified as %LV defect size of values < 75% of the LV-maximum. Test-retest repeatability and observer reproducibility were evaluated using intra-class-correlation (ICC) and Bland-Altman coefficient of repeatability (NPC)., Results: Intra- and inter-observer correlations of both V T and RI were excellent (ICC = 0.93-0.99). Observer reproducibility (NPC = 3-13%) was lower than test-retest repeatability (NPC = 12-61%). Both regional (%LV defect size) and global (LV-mean) measures of sympathetic innervation were more repeatable using the simple RI model compared to V T (NPC = 12% vs. 19% and 30% vs. 54%). Using either model, quantification of regional denervation (defect size) was consistently more reliable than the global LV-mean values of RI or V T . Regional partial-volume correction degraded repeatability of both the global and regional V T measures by 2-12%. Test-retest repeatability of MBF estimation was relatively poor (NPC = 30-61%) compared with the RI., Conclusions: Quantitative measures of global and regional SNS innervation were most repeatable using the simple RI method of analysis compared with the more complex V T . Observer variability was significantly lower than the test-retest repeatability using a highly automated analysis program. These results support the use of the simple RI method for reliable analysis of HED PET images in clinical research studies for future evaluation of new therapies and for risk stratification in patients with heart failure.

Background: Heart failure with reduced ejection fraction and obstructive sleep apnea (OSA), 2 states of increased metabolic demand and sympathetic nervous system activation, often coexist. Continuous positive airway pressure (CPAP), which alleviates OSA, can improve ventricular function. It is unknown whether this is due to altered oxidative metabolism or presynaptic sympathetic nerve function. We hypothesized that short-term (6-8 weeks) CPAP in patients with OSA and heart failure with reduced ejection fraction would improve myocardial sympathetic nerve function and energetics., Methods and Results: Forty-five patients with OSA and heart failure with reduced ejection fraction (left ventricular ejection fraction 35.8±9.7% [mean±SD]) were evaluated with the use of echocardiography and 11C-acetate and 11C-hydroxyephedrine positron emission tomography before and ≈6 to 8 weeks after randomization to receive short-term CPAP (n=22) or no CPAP (n=23). Work metabolic index, an estimate of myocardial efficiency, was calculated as follows: (stroke volume index×heart rate×systolic blood pressure÷Kmono), where Kmono is the monoexponential function fit to the myocardial 11C-acetate time-activity data, reflecting oxidative metabolism. Presynaptic sympathetic nerve function was measured with the use of the 11C-hydroxyephedrine retention index. CPAP significantly increased hydroxyephedrine retention versus no CPAP (Δretention: +0.012 [0.002, 0.021] versus -0.006 [-0.013, 0.005] min(-1); P=0.003). There was no significant change in work metabolic index between groups. However, in those with more severe OSA (apnea-hypopnea index>20 events per hour), CPAP significantly increased both work metabolic index and systolic blood pressure (P<0.05)., Conclusions: In patients with heart failure with reduced ejection fraction and OSA, short-term CPAP increased hydroxyephedrine retention, indicating improved myocardial sympathetic nerve function, but overall did not affect energetics. In those with more severe OSA, CPAP may improve cardiac efficiency. Further outcome-based investigation of the consequences of CPAP is warranted., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00756366., (© 2014 American Heart Association, Inc.)

Background: Left heart failure is characterized by alterations in metabolic substrate utilization, and metabolic modulation may be a future strategy in the management of heart failure. Little is known about cardiac metabolism in the right ventricle and how it relates to other measures of right ventricular (RV) function. This study was designed to measure glucose metabolism in the right ventricle, as estimated by [(18)F]fluorodeoxyglucose (FDG) positron emission tomography imaging and to determine the relation between RV function and FDG uptake in patients with heart failure., Methods and Results: A total of 68 patients underwent cardiac [(18)F]FDG positron emission tomography scanning with measurement of RV FDG uptake as a standardized uptake value. Perfusion imaging was acquired at rest with rubidium-82 or [(13)N]ammonia. RV function was determined by equilibrium radionuclide ventriculography. Relative RV FDG uptake was determined as the ratio of RV to LV standardized uptake value. Fifty-five percent of these patients had ischemic cardiomyopathy. The mean LV and RV ejection fractions were 21±7% and 35±10%, respectively. There was a correlation between RV ejection fraction and the ratio of RV to LV FDG uptake whether the entire LV myocardium (r=-0.40, P<0.001) or LV free wall (r=-0.43, P<0.001) was used. This relation persisted in the subgroup with nonischemic cardiomyopathy (r=-0.37, P=0.04). RV FDG uptake was weakly related to increased RV systolic pressure but not related to LV size, function, or FDG uptake. The correlation between RV ejection fraction and RV/LV FDG was maintained after partial-volume correction (r=-0.68, P<0.001)., Conclusions: RV dysfunction is associated with an increase in RV FDG uptake, the magnitude of which may be correlated with severity.

Background: The relationship between minute ventilation and the rate of CO2 elimination (VE/VCO2 slope) is associated with mortality in patients with congestive heart failure (CHF). The VE/VCO2 slope > or =34 denotes a poor prognosis and has been proposed to reflect abnormalities in pulmonary perfusion., Aims: To study whether increased VE/VCO2 slope is associated with elevated right ventricular (RV) oxidative metabolism relative to the left ventricle (LV)., Methods: 21 patients with stable NYHA II-III CHF underwent symptom limited cardiopulmonary exercise testing. Dynamic [(11)C]acetate positron emission tomography (PET) was used to measure oxidative metabolism (k(mono)) of the LV and RV. Corrected RV oxidative metabolism (RVOx) was calculated as RV/LV k(mono) ratio., Results: Peak VO2 was 16.2+/-4.1 ml/min/kg and the VE/VCO2 slope was 33.4+/-6.1. LV and RV k(mono) were 0.046+/-0.009 and 0.037+/-0.007 min(-1), respectively, with a RVOx of 0.83+/-0.17. There was a good correlation between RVOx and the VE/VCO2 slope (r=0.61, p=0.0034). RVOx was 0.77+/-0.16 in patients with a VE/VCO2 slope <34 and 0.93+/-0.16 in patients with VE/VCO2 slope > or =34 (p=0.047)., Conclusion: RVOx correlates with VE/VCO2 slope in CHF patients. This supports the hypothesis that pulmonary vascular resistance is a determinant of the VE/VCO2 slope.

Objectives: We sought to examine the short-term and longer term (6-week) effects of continuous positive airway pressure (CPAP) on myocardial energetics., Background: Obstructive sleep apnea (OSA) and heart failure (HF) are both states of increased afterload and metabolic demand. Treatment with CPAP may initially reduce stroke volume but subsequently improves left ventricular function. However, it is not clear whether CPAP therapy favorably affects myocardial energetics and hence improves cardiac efficiency., Methods: Twelve patients with HF were divided into two groups: 7 patients with OSA were treated with CPAP (group I), and 5 patients without OSA served as a control group (group II). Oxidative metabolism was measured using the mono-exponential fit of the myocardial [(11)C] acetate positron emission tomography time-activity curve (k-mono). Myocardial efficiency was derived using the work metabolic index (WMI = [heart rate x stroke volume index x systolic blood pressure]/k-mono) measured at baseline, during short-term CPAP, and after 6 +/- 3 weeks of CPAP., Results: In group I, short-term CPAP tended to reduce SVI (p = 0.063) and reduced oxidative metabolism (p = 0.031). Work metabolic index did not change. However, longer term CPAP improved left ventricular ejection fraction (38.4 +/- 3.3% to 43.4 +/- 4.8%, p = 0.031), tended to reduce oxidative metabolism (0.047 +/- 0.012 to 0.040 +/- 0.008 min(-1), p = 0.078), and improved WMI (7.13 +/- 2.82 x 10(6) to 8.17 +/- 3.06 x 10(6) mm Hg.ml/m(2), p = 0.031). In group II (control), these parameters did not change., Conclusions: In this cohort of patients with HF and OSA, short-term CPAP decreased oxidative metabolism and tended to decrease SVI, but did not alter cardiac efficiency. Longer term CPAP improved cardiac efficiency, indicating an energy-sparing effect. These effects may contribute to the benefits of CPAP therapy.

Aging and diseases generally result from tissue inability to maintain homeostasis through adaptation. The adult heart is particularly vulnerable to disequilibrium in homeostasis because its regenerative abilities are limited. Here, we report that MLIP (muscle enriched A-type lamin-interacting protein), a unique protein of unknown function, is required for proper cardiac adaptation. Mlip(-/-) mice exhibited normal cardiac function despite myocardial metabolic abnormalities and cardiac-specific overactivation of Akt/mTOR pathways. Cardiac-specific MLIP overexpression led to an inhibition of Akt/mTOR, providing evidence of a direct impact of MLIP on these key signaling pathways. Mlip(-/-) hearts showed an impaired capacity to adapt to stress (isoproterenol-induced hypertrophy), likely because of deregulated Akt/mTOR activity. Genome-wide association studies showed a genetic association between Mlip and early response to cardiac stress, supporting the role of MLIP in cardiac adaptation. Together, these results revealed that MLIP is required for normal myocardial adaptation to stress through integrated regulation of the Akt/mTOR pathways.

Neprilysin, also known as neutral endopeptidase, is a cell surface membrane metalo‐endopeptidase that cleaves various peptides. Altered neprilysin expression has been correlated with various cancers and cardiovascular diseases. In this work, we present the radiosynthesis of the novel O‐11C‐methylated derivative of LBQ657 (a potent neprilysin inhibitor). (2R,4S)‐5‐(Biphenyl‐4‐yl)‐4‐[(3‐carboxypropionyl)amino]‐2‐methylpentanoic acid [11C]methyl ester ([11C]MeOLBQ) is an analog of sacubitril where the alkyl ester is a 11C‐methyl instead of an ethyl. [11C]MeOLBQ was produced in a one‐pot two‐step synthesis. The O‐11C‐methylation of the pentanoic acid part was done with [11C]methyl triflate followed by the deprotection of the tert‐butyl ester precursor in acidic conditions. [11C]MeOLBQ ([11C]7) was produced in 9.5 ± 2.5% RCY (25 ± 6% decay‐corrected from [11C]CO2, n = 3) high molar activity 348 ± 100 GBq/μmol (9425 ± 2720 mCi/μmol) at EOS, in high chemical (>95%) and radiochemical (>99%) purities. The total synthesis time including HPLC purification and reformulation was 29 minutes. To our knowledge, this is the first PET‐labeled analog of the clinically used NEP inhibitor sacubitril. [ABSTRACT FROM AUTHOR]

Background: Altered myocardial energy metabolism has been linked to worsening of RV function in pulmonary arterial hypertension (PAH). The aim of this study was to evaluate RV glucose and fatty acid metabolism in vivo in a rat model of PAH using positron emission tomography (PET) and investigate the effects of Macitentan on RV substrate utilization.Methods: PAH was induced in male Sprague-Dawley rats by a single subcutaneous injection of Sugen 5416 (20 mg/kg) followed by 3 weeks of hypoxia (10% oxygen). At week 5 post-injection, the PAH rats were randomized to Macitentan (30 mg/kg daily) treatment or no treatment. Substrate utilization was serially assessed 5 and 8 weeks post-injection with 2-[18F]fluoro-2-deoxyglucose (FDG) and 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (FTHA) PET for glucose and fatty acid metabolism respectively and correlated with in vivo functional measurements.Results: PAH induction resulted in a 2.5-fold increase in RV FDG uptake (standardized uptake value (SUV) of normal control: 1.6 ± 0.4, week 5: 4.1 ± 1.9, week 8: 4.0 ± 1.6, P < 0.05 for all groups vs. control). RV FTHA showed twofold increased uptake at week 5 (SUV control: 1.50 ± 0.39, week 5: 3.06 ± 1.10, P = 0.03). Macitentan significantly decreased RV FDG uptake at 8 weeks (SUV: 2.5 ± 0.9, P = 0.04), associated with improved RV ejection fraction and reduced RV systolic pressure, while FTHA uptake was maintained.Conclusion: PAH is associated with metabolic changes in the RV, characterized by a marked increase in FDG and FTHA uptake. Macitentan treatment reduced PAH severity and was associated with a decrease in RV FDG uptake and improved RV function. [ABSTRACT FROM AUTHOR]

The article discusses cardiac metabolism of the right ventricle and its function in patients with heart failure. Glucose metabolism in the right ventricle was quantified using fluorodeoxyglucose (FDG) positron emission tomography imaging. Findings showed that an increased absorption of right ventricular (RV) FDG is associated with RV malfunctions, and that FDG uptake varies according to the intensity of the disease.

The O -[11C]methylated derivatives of the clinically used neprilysin inhibitor (NEPi) sacubitril ([11C]SacOMe, (2 R ,4 S)-ethyl 5-([biphenyl]-4-yl)-4-(4-[11C]methoxy-4-oxobutanamido)-2-methylpentanoate) and LBQ657 ([11C]MeOLBQ, (2 R ,4 S)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid [11C]methyl ester and [11C]LBQOMe, (2 R ,4 S)-5-(biphenyl-4-yl)-4-[(4-[11C]methoxy-4-oxobutanamido)]-2-methylpentanoic acid) were evaluated to determine their potential as PET imaging tracers and investigate the effect of such labeling esterification on neprilysin (NEP) binding. [11C]MeOLBQ, [11C]SacOMe and [11C]LBQOMe were synthesized by O -[11C]methylation using [11C]methyl triflate. Binding of these radiolabeled derivatives (5 nM) were assessed by autoradiography on rat neprilysin rich kidney slices with or without 10 μM NEPi (thiorphan or sacubitril) for 20 min at 37 °C. [11C]LBQOMe was further tested for binding selectivity in the presence of 10 μM of angiotensin-converting enzyme inhibitor (ACEi, captopril) or angiotensin II AT 1 receptor blocker (AT1R, losartan). Radioligands were evaluated for their in vitro stability up to 20 min after incubation at 37 °C in rat and human plasma by reverse-phase column-switch HPLC. Non-radioactive SacOMe incubated in rat and human plasma was analyzed by HPLC-coupled with high resolution mass spectrometry (HRMS) to confirm the metabolites' identity. [11C]SacOMe main labeled metabolite was further analyzed by HPLC after incubation in rat kidney slices at 37 °C. The novel [11C]SacOMe and [11C]LBQOMe were produced in 32 ± 3% RCY and 15 ± 6% at EOS (decay-corrected from [11C]CO 2 , n = 3), high molar activity (407 ± 92 GBq/μmol and 260 ± 92 GBq/μmol), and high chemical (≥90%) and radiochemical (≥99%) purities in a total synthesis time of 31 and 34 min, respectively. High accumulation of [11C]SacOMe and [11C]LBQOMe in kidneys was completely blocked (>99.9%) by pre-incubation with NEPi, whereas [11C]MeOLBQ displayed negligible uptake in autoradiography studies. [11C]LBQOMe binding was not affected by saturating doses of losartan or captopril indicating binding selectivity for NEP. While [11C]SacOMe and [11C]LBQOMe were stable in human plasma (>92%) even after 20 min incubation at 37 °C, rat plasma analyses exhibited >95% biotransformation of [11C]SacOMe, 40% of [11C]LBQOMe and >80% loss of the 11C-methyl group of [11C]MeOLBQ after 5 min of incubation. Comparable results using the non-radioactive SacOMe were obtained by HPLC-HRMS. Radio-HPLC analysis of the extracted activity of rat kidney slices incubated with [11C]SacOMe demonstrated that >95% of the radioactive signal corresponded to [11C]LBQOMe as the main metabolite. The desethyl active metabolite of [11C]SacOMe, [11C]LBQOMe, displayed stability in human plasma, binding selectivity for neprilysin over ACE or AT1R in rat kidney slices. Rapid plasmatic dealkylation at the 2-methylbutanoic acid position is in line with the necessity of incorporating the labeling group on oxobutanoic acid side in the strategy to develop a stable O -alkylated labeled derivative of sacubitril. [Display omitted] [ABSTRACT FROM AUTHOR]