Cardiac autophagic vacuolation in severe X-linked myopathy with excessive autophagy

X-linked myopathy with excessive autophagy (XMEA), caused by mutations of the VMA21 gene, is a strictly skeletal muscle disease. Extensive studies in yeast established VMA21 as the master assembly chaperone of V-ATPase, the complex multisubunit proton pump that acidifies organelles and that is vital to all mammalian tissues. As such, skeletal muscle disease exclusivity in XMEA is highly surprising. We now show that the severest VMA21 mutation, c.164-6t>g, does result in XMEA-typical pathology with autophagic vacuolar changes outside skeletal muscle, namely in the heart. However, even patients with this mutation do not exhibit clinical extramuscular disease, including cardiac disease, despite extreme skeletal muscle wasting to the extent of ventilation dependence. Uncovering the unique skeletal muscle vulnerability to defective organellar acidification, and resultant tissue-destructive excessive autophagy, will be informative to the understanding of muscle physiology. Alternatively, understanding extramuscular resistance to VMA21 mutation might disclose heretofore unknown mammalian V-ATPase assembly chaperones other than VMA21. (C) 2016 Elsevier B.V. All rights reserved.Peer reviewe

Circulating N-terminal brain natriuretic peptide and cardiac function in response to acute systemic hypoxia in healthy humans

Background: As it remains unclear whether hypoxia of cardiomyocytes could trigger the release of brain natriuretic peptide (BNP) in humans, we investigated whether breathing normobaric hypoxic gas mixture increases the circulating NT-proBNP in healthy male subjects.Methods: Ten healthy young men (age 29 ± 5 yrs, BMI 24.7 ± 2.8 kg/m2) breathed normobaric hypoxic gas mixture (11% O2/89% N2) for one hour. Venous blood samples were obtained immediately before, during, and 2 and 24 hours after hypoxic exposure. Cardiac function and flow velocity profile in the middle left anterior descending coronary artery (LAD) were measured by Doppler echocardiography.Results: Arterial oxygen saturation decreased steadily from baseline value of 99 ± 1% after the initiation hypoxia challenge and reached steady-state level of 73 ± 6% within 20-30 minutes. Cardiac output increased from 6.0 ± 1.2 to 8.1 ± 1.6 L/min and ejection fraction from 67 ± 4% to 75 ± 6% (both p < 0.001). Peak diastolic flow velocity in the LAD increased from 0.16 ± 0.04 to 0.28 ± 0.07 m/s, while its diameter remained unchanged. In the whole study group, NT-proBNP was similar to baseline (60 ± 32 pmol/ml) at all time points. However, at 24 h, concentration of NT-proBNP was higher (34 ± 18%) in five subjects and lower (17 ± 17%), p = 0.002 between the groups) in f

Study of the Effect of Reconstruction Parameters for Myocardial Perfusion Imaging in PET With a Novel Flow Phantom

Myocardial perfusion imaging (MPI) with positron emission tomography (PET) allows quantitative temporal measurements of the radioactive tracer distribution in tissue. The quantification for myocardial blood flow (MBF) is conducted with kinetic modeling of the image-derived time-activity curves (TACs) allowing derivation for MBF in units of mL/min per gram of tissue. The ordered-subset expectation maximization (OSEM) reconstruction algorithm with time-of-flight (TOF) and point spread function (PSF) modeling is now routinely employed in cardiac imaging. However, the varying counting statistics of the MPI measurements conducted with short-lived tracers present a challenge for the PET image reconstruction methods. Thus, the effect of the reconstruction methods on the flow quantification needs to be evaluated in a standardized manner. Recently, a novel PET flow phantom modeling the MBF has been developed for investigation of the standardization of the MBF measurements. In this study, the effect of the reconstruction parameters on the image-derived flow values against a known reference flow of the flow phantom was studied with [O-15]H2O. The effects were studied by comparison of TACs and relative errors of the image-derived flow values with respect to the phantom-derived reference flow value using 5 repeated PET scans with fixed acquisition parameters using a digital Discovery MI PET/CT system. The reconstruction methods applied were OSEM using both TOF and PSF (OSEM-TOF-PSF) with several matrix sizes (128 x 128, 192 x 192, 256 x 256, 384 x 384), Gaussian filter sizes (4, 8 mm) and OSEM without TOF and PSF (OSEM), with TOF (OSEM-TOF) and with PSF (OSEM-PSF) in addition to recently introduced regularized reconstruction method based on Bayesian-penalized maximum likelihood (Q.Clear). Between repeated measurements, the image-derived flow values showed high repeatability with a SD less than 2 mL/min as well as high accuracy with the maximum error of 7% with respect to the reference flow for all reconstructions. Overall, reconstruction settings had only a small impact on the resulting flow values. In conclusion, due to the small differences detected, any of the implemented reconstruction algorithms on the system can be applied in MPI studies for accurate flow quantification

Measurement uncertainty quantification for myocardial perfusion using cardiac positron emission tomography imaging

Perfusion, the flow of blood, and hence oxygen, is essential to the functioning of the heart. Reduced perfusion (or ischemia), is a reliable indicator of the presence of significant obstructive coronary artery disease (CAD), which is one of the biggest causes of death in Europe. Myocardial perfusion imaging is a non-invasive technique used in the diagnosis, management and prognosis of CAD and is a key component in the triage of patients into treatment and non-treatment groups. Cardiac positron emission tomography (PET) is an imaging technique with high sensitivity and specificity to CAD, however perfusion measurements are difficult to calibrate against a common reference standard, and confidence in them is generally not quantified in terms of measurement uncertainty. There are a number of steps involved in measuring perfusion using cardiac PET-from patient preparation to data analysis-each associated with potential sources of uncertainty. The absence of measurement uncertainty quantification can lead to inaccuracies in measurement results, a lack of comparability between devices or scanning facilities, and is likely to be detrimental to a decision-making process. In this paper, we identify some of the sources of measurement uncertainty in the cardiac PET perfusion measurement pipeline. We assess their relative contribution by performing a sensitivity analysis using experimental data of a flow phantom acquired on a PET scanner. The results of this analysis will inform users of how parameter choices in their imaging pipeline affect the output of their measurements, and serves as a starting point to develop an uncertainty quantification method.</p

Atherosclerotic plaque characteristics on quantitative coronary computed tomography angiography associated with ischemia on positron emission tomography in diabetic patients

Patients with diabetes mellitus (DM) may show diffuse coronary artery atherosclerosis on coronary computed tomography angiography (CTA). The present study aimed at quantification of atherosclerotic plaque with CTA and its association with myocardial ischemia on positron emission tomography (PET) in DM patients. Of 922 symptomatic outpatients without previously known coronary artery disease who underwent CTA, 115 with DM (mean age 65 ± 8 years, 58% male) who had coronary atherosclerosis and underwent both quantified CTA (QCTA) and PET were included in the study. QCTA analysis was performed on a per-vessel basis and the most stenotic lesion of each vessel was considered. Myocardial ischemia on PET was based on absolute myocardial blood flow at stress ≤ 2.4 ml/g/min. Of the 345 vessels included in the analysis, 135 (39%) had flow-limiting stenosis and were characterized by having longer lesions, higher plaque volume, more extensive plaque burden and higher percentage of dense calcium (37 ± 22% vs 28 ± 22%, p = 0.001). On univariable analysis, QCTA parameters indicating the degree of stenosis, the plaque extent and composition were associated with presence of ischemia. The addition of the QCTA degree of stenosis parameters (x2 36.45 vs 88.18, p < 0.001) and the QCTA plaque extent parameters (x2 88.18 vs 97.44, p = 0.01) to a baseline model increased the association with ischemia. In DM patients, QCTA variables of vessel stenosis, plaque extent and composition are associated with ischemia on PET and characterize the hemodynamic significant atherosclerotic lesion.</p

Macrophage Hitchhiking Nanoparticles for the Treatment of Myocardial Infarction:An In Vitro and In Vivo Study

Myocardial infarction (MI) is the leading cause of death worldwide. However, current therapies are unable to restore the function of the injured myocardium. Advanced approaches, such as stimulation of cardiomyocyte (CM) proliferation are promising, but suffer from poor pharmacokinetics and possible systemic adverse effects. Nanomedicines can be a solution to the above-mentioned drawbacks. However, targeting the cardiac tissue still represents a challenge. Herein, a MI-selective precision nanosystem is developed, that relies on the heart targeting properties of atrial natriuretic peptide (ANP) and lin-TT1 peptide-mediated hitchhiking on M2-like macrophages. The system based on pH-responsive putrescine-modified acetalated dextran (Putre-AcDEX) nanoparticles, shows biocompatibility with cultured cardiac cells, and ANP receptor-dependent interaction with CMs. Moreover, treatment with nanoparticles (NPs) loaded with two pleiotropic cellular self-renewal promoting compounds, CHIR99021 and SB203580, induces a 4-fold increase in bromodeoxyuridine (BrdU) incorporation in primary cardiomyocytes compared to control. In vivo studies confirm that M2-like macrophages targeting by lin-TT1 peptide enhances the heart targeting of ANP. In addition, NP administration does not alter the immunological profile of blood and spleen, showing the short-term safety of the developed system in vivo. Overall, the study results in the development of a peptide-guided precision nanosystem for delivery of therapeutic compounds to the infarcted heart