Brown adipose tissue (BAT) is an energy-dispensing thermogenic tissue that plays an important role in balancing energy metabolism. Lineage-tracing experiments indicate that brown adipocytes are ...derived from myogenic progenitors during embryonic development. However, adult skeletal muscle stem cells (satellite cells) have long been considered uniformly determined toward the myogenic lineage. Here, we report that adult satellite cells give rise to brown adipocytes and that microRNA-133 regulates the choice between myogenic and brown adipose determination by targeting the 3′UTR of Prdm16. Antagonism of microRNA-133 during muscle regeneration increases uncoupled respiration, glucose uptake, and thermogenesis in local treated muscle and augments whole-body energy expenditure, improves glucose tolerance, and impedes the development of diet-induced obesity. Finally, we demonstrate that miR-133 levels are downregulated in mice exposed to cold, resulting in de novo generation of satellite cell-derived brown adipocytes. Therefore, microRNA-133 represents an important therapeutic target for the treatment of obesity.
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► Satellite cells can differentiate into brown adipocytes ► MicroRNA-133 targets Prdm16 3′UTR and controls brown adipose determination ► MicroRNA-133 antagonism induces active brown adipocytes within regenerating muscle ► MicroRNA-133 antagonism impedes the development of obesity
Objectives We evaluated the prognostic value of myocardial flow reserve (MFR) using rubidium-82 (82 Rb) positron emission tomography (PET) in patients assessed for ischemia. Background The clinical ...value of MFR quantification using82 Rb PET beyond relative myocardial perfusion imaging remains uncertain. Methods We prospectively enrolled 704 consecutive patients; 677 (96%) completed follow-up (median 387 days interquartile range: 375 to 416 days). Patients were divided into 4 groups: I, normal summed stress score (SSS) (<4) and normal myocardial flow reserve (MFR) (>2); II, normal SSS and MFR <2; III, SSS ≥4 and MFR ≥2; IV, SSS ≥4 and MFR <2. Results For patients with a normal SSS and those with an abnormal SSS, there were significant differences in outcomes for hard events (cardiac death and myocardial infarction) between patients with MFR ≥2 and those with MFR <2 (I: 1.3% vs. II: 2% p = 0.029; III: 1.1% vs. IV: 11.4% p = 0.05) and for major adverse cardiac events (MACE) (p = 0.003 and p < 0.001, respectively). In the adjusted Cox model, MFR was an independent predictor of hard events (hazard ratio: 3.3; 95% confidence interval: 1.1 to 9.5; p = 0.029) and MACE (hazard ratio: 2.4, 95% confidence interval: 1.4 to 4.4, p = 0.003). The incremental prognostic value of the MFR over the SSS was demonstrated by comparing the adjusted SSS model with and without the MFR for hard events (p = 0.0197) and MACE (p = 0.002). Conclusions MFR quantified using82 Rb PET predicts hard cardiac events and MACE independent of the SSS and other parameters. Routine assessment of82 Rb PET–quantified MFR could improve risk stratification for patients being investigated for ischemia.
Objectives The PAREPET (Prediction of ARrhythmic Events with Positron Emission Tomography) study sought to test the hypothesis that quantifying inhomogeneity in myocardial sympathetic innervation ...could identify patients at highest risk for sudden cardiac arrest (SCA). Background Left ventricular ejection fraction (LVEF) is the only parameter identifying patients at risk of SCA who benefit from an implantable cardiac defibrillator (ICD). Methods We prospectively enrolled 204 subjects with ischemic cardiomyopathy (LVEF ≤35%) eligible for primary prevention ICDs. Positron emission tomography (PET) was used to quantify myocardial sympathetic denervation (11 C-meta-hydroxyephedrine 11 C-HED), perfusion (13 N-ammonia) and viability (insulin-stimulated18 F-2-deoxyglucose). The primary endpoint was SCA defined as arrhythmic death or ICD discharge for ventricular fibrillation or ventricular tachycardia >240 beats/min. Results After 4.1 years follow-up, cause-specific SCA was 16.2%. Infarct volume (22 ± 7% vs. 19 ± 9% of left ventricle LV) and LVEF (24 ± 8% vs. 28 ± 9%) were not predictors of SCA. In contrast, patients developing SCA had greater amounts of sympathetic denervation (33 ± 10% vs. 26 ± 11% of LV; p = 0.001) reflecting viable, denervated myocardium. The lower tertiles of sympathetic denervation had SCA rates of 1.2%/year and 2.2%/year, whereas the highest tertile had a rate of 6.7%/year. Multivariate predictors of SCA were PET sympathetic denervation, left ventricular end-diastolic volume index, creatinine, and no angiotensin inhibition. With optimized cut-points, the absence of all 4 risk factors identified low risk (44% of cohort; SCA <1%/year); whereas ≥2 factors identified high risk (20% of cohort; SCA ∼12%/year). Conclusions In ischemic cardiomyopathy, sympathetic denervation assessed using11 C-HED PET predicts cause-specific mortality from SCA independently of LVEF and infarct volume. This may provide an improved approach for the identification of patients most likely to benefit from an ICD. (Prediction of ARrhythmic Events With Positron Emission Tomography PAREPET; NCT01400334 )
Cardiac sarcoidosis is a potentially fatal complication of sarcoidosis. The 1993 guidelines of the Ministry of Health, Labour, and Welfare (MHLW) of Japan have been used as the diagnostic gold ...standard and for comparison with imaging modalities. (18)F-FDG PET is not currently included in the guidelines. However, studies have shown promising data using (18)F-FDG PET. We conducted a systematic review of studies that evaluated the accuracy of (18)F-FDG PET for the diagnosis of cardiac sarcoidosis compared with MHLW guidelines. Data from a prospective Ontario provincial registry are also reported and included in the metaanalysis.
PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies that satisfied predetermined criteria. Quality evaluation using the Quality Assessment for Diagnostic Accuracy Studies was performed by 2 independent masked observers. Data were extracted and analyzed to measure study-specific and pooled accuracy for (18)F-FDG PET compared with the MHLW as the reference.
A total of 519 titles was identified; 7 studies, including the Ontario registry, were selected for inclusion. Metaanalysis of these 7 studies was conducted, with a total of 164 patients, most of whom had been diagnosed with systemic sarcoidosis. The prevalence of cardiac sarcoidosis was 50% in the whole population. Pooled estimates for (18)F-FDG PET yielded 89% sensitivity (95% confidence interval CI, 79%-96%), 78% specificity (95% CI, 68%-86%), a 4.1 positive likelihood ratio (95% CI, 1.7-10), and a 0.19 negative likelihood ratio (95% CI, 0.1-0.4). The overall diagnostic odds ratio was 25.6 (95% CI, 7.3-89.5), and the area under the summary receiver operator characteristic curve was 93% ± 3.5. The Ontario study yielded sensitivity and specificity of 79% and 70%, respectively.
The high diagnostic accuracy determined for (18)F-FDG PET in this metaanalysis suggests potential value for diagnosis of cardiac sarcoidosis compared with the MHLW guidelines. These results may affect patient care by providing supportive evidence for more effective use of (18)F-FDG PET in the diagnosis of cardiac sarcoidosis. Large-scale multicenter studies are required to further evaluate this role.
Absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR) provide incremental diagnostic and prognostic information over relative perfusion alone. Recent development of dedicated cardiac ...SPECT cameras with better sensitivity and temporal resolution make dynamic SPECT imaging more practical. In this study, we evaluate the measurement of MBF using a multipinhole dedicated cardiac SPECT camera in a pig model of rest and transient occlusion at stress using 3 common tracers: (201)Tl, (99m)Tc-tetrofosmin, and (99m)Tc-sestamibi.
Animals (n = 19) were injected at rest/stress with (99m)Tc radiotracers (370/1,100 MBq) or (201)Tl (37/110 MBq) with a 1-h delay between rest and dipyridamole stress. With each tracer, microspheres were injected simultaneously as the gold standard measurement for MBF. Dynamic images were obtained for 11 min starting with each injection. Residual resting activity was subtracted from stress data and images reconstructed with CT-based attenuation correction and energy window-based scatter correction. Dynamic images were processed with kinetic analysis software using a 1-tissue-compartment model to obtain the uptake rate constant K(1) as a function of microsphere MBF.
Measured extraction fractions agree with those obtained previously using ex vivo techniques. Converting K(1) back to MBF using the measured extraction fractions produced accurate values and good correlations with microsphere MBF: r = 0.75-0.90 (P < 0.01 for all). The correlation in the MFR was between r = 0.57 and 0.94 (P < 0.01).
Noninvasive measurement of absolute MBF with stationary dedicated cardiac SPECT is feasible using common perfusion tracers.
Cardiac allograft vasculopathy (CAV) is a leading cause of graft failure and death after heart transplantation. Absolute myocardial blood flow (MBF) quantification using rubidium 82 (Rb-82) positron ...emission tomography (PET) could enable evaluation of diagnostically challenging diffuse epicardial and microvascular disease in CAV.
The authors aimed to evaluate Rb-82 PET detection of CAV.
Consecutive transplant recipients undergoing coronary angiography were prospectively evaluated with PET, multivessel intravascular ultrasound (IVUS), and intracoronary hemodynamics. CAV was defined as International Society of Heart and Lung Transplantation CAV1–3 on angiography and maximal intimal thickness ≥0.5 mm on IVUS.
Forty patients (mean age 56 years, 4.8 years post-transplant) completed evaluation. CAV was detected in 32 patients (80%) by IVUS and 14 (35%) by angiography. PET correlated significantly with invasive coronary flow indices: r = 0.29, rate-pressure product–adjusted myocardial flow reserve (cMFR) versus coronary flow reserve; r = 0.28, relative flow reserve versus fractional flow reserve; and r = 0.37, coronary vascular resistance (CVR) versus index of microcirculatory resistance. Patients with CAV or microvascular dysfunction had reduced cMFR and stress MBF and increased CVR. Receiver operator characteristic curves demonstrated good accuracy of PET for CAV on IVUS (area under the curve 0.77 to 0.81) and optimal diagnostic cutoffs of cMFR <2.9, stress MBF <2.3, and CVR >55. Combined PET assessment for CAV yielded excellent >93% sensitivity (>65% specificity) for 1 abnormal parameter and >96% specificity (>55% sensitivity) for 2 abnormal parameters.
Rb-82 PET flow quantification has high diagnostic accuracy for CAV, with potential for noninvasive evaluation after heart transplantation.
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