In the liver, glutamine utilization may be limited by the rate of transport across the plasma membrane by the System N carrier. System N-mediated transport activity has been solubilized from rat ...liver plasma membrane, partially purified, and then reconstituted into proteoliposomes. To identify the System N carrier protein, monoclonal antibodies were generated against the protein fraction enriched for System N activity. Two antibodies , 3E1-2 and 1E7-3, inhibited System N activity in hepatocytes. These antibodies also immunoprecipitated System N activity from a mixture of solubilized proteins and were specific for antigen recognition in that neither immunoprecipitated System A activity. The antibody recognized a single protein of molecular size 100 kDa by immunoblot analysis. Recognition of this protein by the antibody increased in parallel with the enrichment of System N activity in solubilized membrane fractions. These data suggest that a 100-kDa plasma membrane protein mediates System N transport activity in rat hepatocytes.
Immune checkpoint blocker (ICB) associated myocarditis (ICB-myocarditis) may present similarly and/or overlap with other cardiac pathology including acute coronary syndrome presenting a challenge for ...prompt clinical diagnosis.
An international registry was used to retrospectively identify cases of ICB-myocarditis. Presence of coronary artery disease (CAD) was defined as coronary artery stenosis >70% in patients undergoing coronary angiogram.
Among 261 patients with clinically suspected ICB-myocarditis who underwent a coronary angiography, CAD was present in 59/261 patients (22.6%). Coronary revascularization was performed during the index hospitalisation in 19/59 (32.2%) patients. Patients undergoing coronary revascularization less frequently received steroids administration within 24 h of admission compared to the other groups (p = 0.029). Myocarditis-related 90-day mortality was 9/17 (52.7%) in the revascularised cohort, compared to 5/31 (16.1%) in those not revascularized and 25/156 (16.0%) in those without CAD (p = 0.001). Immune-related adverse event-related 90-day mortality was 9/17 (52.7%) in the revascularized cohort, compared to 6/31 (19.4%) in those not revascularized and 31/156 (19.9%) in no CAD groups (p = 0.007). All-cause 90-day mortality was 11/17 (64.7%) in the revascularized cohort, compared to 13/31 (41.9%) in no revascularization and 60/158 (38.0%) in no CAD groups (p = 0.10). After adjustment of age and sex, coronary revascularization remained associated with ICB-myocarditis-related death at 90 days (hazard ratio HR = 4.03, 95% confidence interval CI 1.84–8.84, p < 0.001) and was marginally associated with all-cause death (HR = 1.88, 95% CI, 0.98–3.61, p = 0.057).
CAD may exist concomitantly with ICB-myocarditis and may portend a poorer outcome when revascularization is performed. This is potentially mediated through delayed diagnosis and treatment or more severe presentation of ICB-myocarditis.
•ICB-myocarditis can clinically present similarly to acute coronary syndrome.•Diagnostic steps are similar; treatment of both entities is substantially different.•Delay in appropriate treatments of severe ICB-myocarditis should be avoided.
Survival after heart transplant has greatly improved, with median survival now over 12 years. Cardiac allograft vasculopathy (CAV) has become a major source of long-term morbidity and mortality. ...Single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is used for CAV surveillance, but there is limited data on its prognostic utility.
We retrospectively identified patients undergoing SPECT MPI for CAV surveillance at a single, large-volume center. Images were assessed with semiquantitative visual scoring (summed stress score SSS and summed rest score) and quantitatively with total perfusion defect (TPD).
We studied 503 patients (mean age 62.5, 69.3% male) at a median of 9.0 years post-transplant. During mean follow-up of 5.1 ± 2.5 years, 114 (22.6%) patients died. The diagnostic accuracy for significant CAV (ISHLT grade 2 or 3) was highest for SSS with an area under the curve of 0.650 and stress TPD (area under the curve, 0.648), with no significant difference between SSS and stress TPD (P = 0.061). Stress TPD (adjusted hazard ratio, 1.07; P = 0.018) was independently associated with all-cause mortality, while SSS was not (P = 0.064). The prognostic accuracy of quantitative assessment of perfusion tended to be higher compared with semiquantitative assessment, with the highest accuracy for stress TPD (area under the receiver operating curve 0.584).
While SPECT MPI identified a cohort of higher risk patients, with quantitative analysis of perfusion demonstrating higher prognostic accuracy. However, the overall prognostic accuracy was modest and alternative noninvasive modalities may be more suitable for CAV surveillance.
The secondary active transport of glutamine into hepatocytes is mediated by the sodium-dependent System N amino acid transporter. In SV40-transformed fetal or adult hepatocytes, System N activity was ...increased by culturing the cells at the growth-permissive temperature of 33 degrees C compared with 40 degrees C. The sulfhydryl specific protein modification reagent p-chloromercuribenzene sulfonate (PCMBS) inactivated all of System N activity in fetal cells, whereas in the adult cells PCMBS inactivated only the elevated System N activity expressed at 33 degrees C; basal System N activity remained unaffected. Also, the inactivation of transport in the adult cells could be blocked by the presence of the substrate glutamine, whereas that in the fetal cells was completely resistant to protection. To characterize the System N transporter, murine monoclonal antibodies were generated. Two hybridomas (3E1-2 and 1E7-3) produced antibodies that inhibit System N activity in hepatocytes and can immunoprecipitate the activity from a solubilized protein fraction. Based on two-dimensional PAGE, the molecular size of the carrier protein has been shown to be -100 kDa
Background
Women with signs and symptoms of ischemia and no obstructive coronary artery disease (INOCA) are at risk of heart failure with preserved ejection fraction (HFpEF); however, the mechanism ...for HFpEF progression remains unclear. Studies in INOCA have largely focused on left ventricular function. The left atrium serves an important role in maintaining transmitral flow, and is impaired in HFpEF; however, it remains unclear if left atrial function is impaired in INOCA.
Hypothesis
Left atrial function is progressively worse in INOCA and HFpEF compared to controls.
Methods
We compared 39 reference control subjects to 64 women with INOCA and 22 subjects with HFpEF. Left atrial strain was assessed by feature tracking using magnetic resonance cine images.
Results
Peak left atrial strain was reduced in HFpEF compared to controls (22.9 ± 4.8% vs 25.9 ± 3.2%, P < .01), but similar in INOCA (24.8 ± 4.5%) compared to HFpEF and controls (P = .18). However, left ventricular end‐diastolic pressure (LVEDP) was elevated in 33% of INOCA participants, suggesting that left atrial stiffness (LVEDP/LA strain) is elevated in a large portion of women with INOCA.
Conclusions
Taken together, we interpret these data to support our working hypothesis that INOCA is a pre‐HFpEF state, with left atrial stiffness preceding overt left atrial dysfunction; representing a putative therapeutic target to prevent HFpEF progression in this at‐risk population.
The secondary active transport of glutamine into hepatocytes is mediated by the sodium-dependent System N amino acid transporter. In SV40-transformed fetal or adult hepatocytes, System N activity was ...increased by culturing the cells at the growth-permissive temperature of 33°C compared with 40°C. The sulfhydryl specific protein modification reagent p-chloromercuribenzene sulfonate (PCMBS) inactivated all of System N activity in fetal cells, whereas in the adult cells PCMBS inactivated only the elevated System N activity expressed at 33°C; basal System N activity remained unaffected. Also, the inactivation of transport in the adult cells could be blocked by the presence of the substrate glutamine, whereas that in the fetal cells was completely resistant to protection. To characterize the System N transporter, murine monoclonal antibodies were generated. Two hybridomas (3E1-2 and 1E7-3) produced antibodies that inhibit System N activity in hepatocytes and can immunoprecipitate the activity from a solubilized protein fraction. Based on two-dimensional PAGE, the molecular size of the carrier protein has been shown to be ∼100 kDa.
Non-invasive fractional flow reserve derived from coronary CT angiography (FFRCT) has been shown to be predictive of lesion-specific ischemia as assessed by invasive fractional flow reserve (FFR). ...However, in practice, clinicians are often faced with an abnormal distal FFRCT in the absence of a discrete obstructive lesion. Using quantitative plaque analysis, we sought to determine the relationship between an abnormal whole vessel FFRCT (V-FFRCT) and quantitative measures of whole vessel atherosclerosis in coronary arteries without obstructive stenosis.
FFRCT was calculated in 155 consecutive patients undergoing coronary CTA with ≥25% but less than 70% stenosis in at least one major epicardial vessel. Semi-automated software was used to quantify plaque volumes (total plaque TP, calcified plaque CP, non-calcified plaque NCP, low-density non-calcified plaque LD-NCP), remodeling index RI, maximal contrast density difference CDD and percent diameter stenosis %DS. Abnormal V-FFRCT was defined as a minimum value of ≤0.75 across the vessel (at the most distal region where FFRCT was computed).
Vessels with abnormal V-FFRCT had higher per-vessel TP (554 vs 331 mm3), CP (59 vs 25 mm3), NCP (429 vs 295 mm3), LD-NCP (65 vs 35 mm3) volume and maximum CDD (21 vs 14%) than those with normal V-FFRCT (median, p < 0.05 for all). Using a multivariate analysis to adjust for CDD and %DS, all measures of plaque volume were predictive of abnormal V-FFRCT (OR 2.09, 1.36, 1.95, 1.95 for TP, CP, NCP and LD-NCP volume, respectively; p < 0.05 for all).
Abnormal V-FFRCT in vessels without obstructive stenosis is associated with multiple markers of diffuse non-obstructive atherosclerosis, independent of stenosis severity. Whole vessel FFRCT may represent a novel measure of diffuse coronary plaque burden.
Glutamine is an important amino acid because of its key role in the transfer of both carbon and nitrogen between tissues in the body. Specific tissues are usually associated with either net synthesis ...or net utilization of glutamine, but the liver plays a central role in glutamine homeostasis, in that it can shift to function in either capacity. This capability, along with the localization of urea biosynthesis in the periportal hepatocytes, focuses attention on the transport mechanisms in hepatocytes for uptake and release of glutamine. Active transport of glutamine by hepatocytes is mediated by a Na(+)-dependent activity termed system N, which exhibits a rather narrow substrate specificity mediating uptake of histidine and asparagine as well as of glutamine. This secondary active transport system allows for the net accumulation of glutamine against a concentration gradient and maintenance of intracellular concentrations of glutamine between 4 and 8 mM in the face of a plasma concentration of 0.6 mM. Utilization of the Na+ electrochemical gradient as a driving force ensures that the system N carrier catalyzes a unidirectional transport event favoring the cytoplasm. It is obvious from the glutamine gradient across the plasma membrane that efflux of this amino acid is typically slower than accumulation; measurement of saturable, Na(+)-independent glutamine transport by system L substantiates this proposal. However, it is clear that under certain metabolic conditions the liver represents a source of glutamine for other tissues in the body and net efflux must occur. The system N transport activity in hepatocytes is regulated by hormones such as insulin, glucagon, and glucocorticoids, as demonstrated both in vivo and in vitro.
Age- and gender-adjusted percentiles of coronary artery calcium (CAC) score are commonly reported to compare a patient's coronary atherosclerosis burden to that of others of the same age and gender. ...The number of calcified plaques (numCP) detected on CAC scanning, a measure of plaque diffusivity, is associated with increased cardiovascular risk and, in the intermediate CAC range, adds to the CAC score in predicting mortality. This study aims to develop adjusted percentiles for numCP to provide a better context for understanding CAC scan findings.
Using nonparametric modeling techniques, the distribution of numCP was analyzed in 70,320 consecutive, asymptomatic patients without prior clinically-diagnosed cardiovascular disease who were part of the Coronary Artery Calcium Consortium and supplemented by additional patients referred for clinical CAC scanning in a single center between 1998 and 2016. Nomograms for age-adjusted numCP percentiles for each gender were generated using quantile regression. The prevalence and average number of calcified coronary plaque were found to be higher in men than women. Distribution of numCP in women was found to closely mirror that of men approximately a decade younger. NumCP increased consistently across age groups in both men and women for each quantile category.
A nomogram for age and gender-adjusted percentiles for the numCP on CAC scans has been developed in a large population of asymptomatic patients studied across multiple centers. This numCP nomogram may provide an additional tool for refining physician recommendations regarding treatment and expressing to patients how their CAC findings relate to others of similar age and gender. The numCP percentiles may also provide a meaningful way to evaluate and report the rate of progression of CAC on serial studies.
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