Age-matched Controls Research Articles

Limb-Specific Comparison of Flow-Mediated Dilation in Abdominal Obese Pre-menopausal Women

Abstract Purpose Normal aging can lead to arterial wall stiffening and development of atherosclerosis; however, the effects of overweight conditions can expedite the dysfunction of arterial health. In an earlier study, we identified in a group of abdominal obese pre-menopausal woman that during menses, these women had decreased vascular conductance of the brachial artery during dynamic hand-grip exercise. Endothelial function in abdominal obese (AO) premenopausal women could be associated with being highly sedentary which attenuates dilatory responses to FMD of both upper and lower limb vascular function. We hypothesized that the AO women would exhibit limb-specific differences in artery dilation with reduced dilation in the popliteal artery as compared to the brachial artery. Methods Artery dilatory responses in the brachial and popliteal arteries were assessed using flow-mediated dilation (FMD) in age-matched sedentary controls and AO groups during menses. Results Significant differences were found between groups including % BF, BMI, weight, waist to hip ratio, fasting blood glucose, and oxLDL. A between-group comparison revealed significantly lower percent dilation of the popliteal artery in AO participants compared to controls (p < 0.05) not present in the brachial arteries. Our results also indicate a difference in the time-to-peak (TP) of dilation between the control (33.38 ± 3.232) and AO (62.104 ± 5.813) groups (p < 0.01). Following FMD correction with shear rate as the covariate, significant differences in FMD between the brachial and popliteal artery were abolished. Conclusion We conclude that young, AO women show a limb-specific difference in dilation of the upper and lower extremities when compared to controls. Thus, reductions in FMD of the popliteal artery could be due to impaired dilation of the downstream resistance vasculature preventing increases in shear within the leg conduit arteries not as significantly in the arms.

Elevated Cerebrospinal Fluid Ubiquitin Carboxyl-Terminal Hydrolase Isozyme L1 in Asymptomatic C9orf72 Hexanucleotide Repeat Expansion Carriers.

To identify biochemical changes in individuals at higher risk of developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) via C9orf72 hexanucleotide repeat expansion (HRE) heterozygosity. Cross-sectional observational study of 48 asymptomatic C9orf72 HRE carriers, 39 asymptomatic non-carrier controls, 19 people with sporadic ALS, 10 with C9orf72 ALS, 14 with sporadic FTD, and 10 with C9orf72 FTD. Relative abundance of 30 pre-defined cerebrospinal fluid biomarkers of ALS and FTD were compared in asymptomatic C9orf72 HRE carriers and age-matched non-carrier controls. Differential abundance of these proteins was quantified using data independent acquisition mass spectrometry or electro chemiluminescent assay for neurofilament light chain. Unbiased analysis of the entire cerebrospinal fluid proteome was then carried out. Ubiquitin carboxyl-hydrolase isozyme L1 levels were higher in asymptomatic C9orf72 HRE carriers compared with age-matched non-carriers (log2fold change 0.20, FDR-adjusted p-value = 0.034), whereas neurofilament light chain levels did not significantly differ. Ubiquitin carboxyl-hydrolase isozyme L1 levels remained elevated after matching of groups by neurofilament levels (p = 0.011), and after adjusting for age, sex, and neurofilament levels. A significant difference was also observed when restricting analysis to younger participants (<37) matched by neurofilament level (p = 0.007). Elevated cerebrospinal fluid ubiquitin carboxyl-hydrolase isozyme L1 levels in C9orf72 HRE carriers can occur in the absence of increased neurofilament levels, potentially reflecting either compensatory or pathogenic mechanisms preceding rapid neuronal loss. This brings forward the window on changes associated with the C9orf72 HRE carrier state, with potential to inform understanding of penetrance and approaches to prevention. ANN NEUROL 2024.

Perifoveal Exudative Vascular Anomalous Complex (PEVAC): Retinal Vascular Density Findings

Objectives: This study aimed to describe the clinical, optical coherence tomography (OCT) and OCT angiography (OCTA) findings and characteristics in patients with perifoveal exudative vascular anomalous complex (PEVAC) and compare the macular vascular density with the age-matched control group. Methods: We conducted a case–control study to compare demographic information, clinical observations, and OCT/OCTA findings in eyes with PEVAC (n = 5 eyes in 5 patients) and a control group of subjects matched for age (n = 9). The Advanced Retina Imaging (ARI) network algorithms were utilized to evaluate OCTA observations. Statistical analysis was performed by the nonparametric Mann–Whitney U test. Results: Patients with PEVAC had a mean (±SD) age at presentation of 70 ± 12.6 years, the mean follow-up period was 7.8 ± 5.2 months, and unilateral disease was observed. Four out of the five patients in our cohort had a history of systemically treated hypertension and dyslipidemia. Three eyes had lesions in the inner temporal retinal zone, while the remaining two eyes had lesions in the inner inferior or central zone. Retina slab analysis using OCTA showed no significant difference in vascular density parameters between the PEVAC and control groups. Conclusions: Although limited by a small sample size, our study suggests that macular vessel density shows no significant difference between PEVAC cases and control eyes.

Bone microarchitecture evaluated by HR-pQCT in Chinese adolescent and pediatric patients with X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is the most common form of heritable hypophosphatemic rickets. Previous studies have found deteriorated bone microarchitecture in the XLH adults. Detailed studies on the skeletal microarchitecture of XLH adolescent and pediatric patients are still lacking. This study aimed to evaluate bone geometry, density, microarchitecture, stiffness in XLH adolescent and pediatric patients by using high-resolution peripheral quantitative computed tomography (HR-pQCT).Method: This study utilized HR-pQCT to assess bone geometry, density, microarchitecture, and stiffness in 106 Chinese adolescent and pediatric patients with XLH. Compared with the sex- and age-matched controls, XLH patients had significantly higher trabecular area (Tb.Ar), lower total volumetric bone mineral density (Tot.vBMD), lower cortical volumetric BMD (Ct.vBMD), and lower stiffness at both the distal radius and the tibia after adjusting for height and weight. Alkaline phosphatase Z score (ALP-Z), a marker to reflect the disease activity of rickets, was negatively correlated with Ct.vBMD and cortical thickness (Ct.Th) at the distal radius, and Ct.vBMD at the distal tibia, and positively correlated with cortical porosity (Ct.Po) at the distal tibia. We developed an online calculator to estimate Tb.Ar, Ct.vBMD, and stiffness of the distal tibia of XLH adolescent and pediatric patients based on clinical general characteristic and biochemical indicators. The bone microarchitecture of XLH adolescent and pediatric patients was deteriorated, and ALP-Z was negatively correlated with the skeletal quality of XLH adolescent and pediatric patients, especially in the cortical bone. HR-pQCT parameters can be estimated using clinical characteristics and biochemical indicators, which may assist physicians to monitor the disease progression in areas without HR-pQCT access.

Infants < 90 days of age with late-onset sepsis display disturbances of the microbiome-immunity interplay.

We hypothesized that previously healthy infants < 90 days of age with late-onset sepsis (LOS) have disturbances of the gut microbiome with yet undefined specific immunological patterns. We performed a prospective single-center convenience sample study between January 2019 and July 2021 in a case-control design. Routine diagnostics included conventional cultures (blood, cerebrospinal fluid, urine), PCRs and inflammatory markers in infants aged < 90 days with clinical LOS. We additionally analyzed blood lymphocyte subsets including CD4 + CD25 + forkhead box protein (FoxP3)+ Tregs and performed 16S rRNA sequencing of stool samples, both compared to age-matched healthy controls. Results were adjusted for potential confounders that may influence microbial composition. 51 infants with fever and clinical LOS were enrolled. Bacterial sepsis was diagnosed in n = 24 (47.1%) and viral infection in n = 13 (25.5%) infants, whereas in 14 (27.3%) infants the cause of fever remained undetermined. When compared to healthy controls, the gut microbiome of LOS infants at disease onset was characterized by a shift in community composition, specifically, decreased abundance of B. longum and an increase of Bacteroidia spp. Intriguingly, the abundance of B. longum negatively correlated with the frequency of blood CD4-positive cells in healthy controls but not in infants with LOS. At one year of age, we observed microbiome differences in infants with history of LOS when compared to healthy controls, such as an increased gut microbial diversity. Our data suggest potential signatures of the microbiome-immunity interplay in infants with LOS, which should be investigated further as possible targets for prevention.

Potential utility of anterior segment optical coherence tomography and biometry in differentiating plateau iris configuration from pupillary block

ABSTRACT Clinical relevance Angle closure glaucoma is one of the most common blinding diseases encountered mainly in older age groups, although it may also occur at a younger age. Identifying the underlying cause of angle closure helps in designing specific treatment strategies essential for effective disease management. Background Primary angle closure disease, caused due to pupillary block (PB) and plateau iris configuration (PIC), necessitates different management strategies. This study assessed the potential utility of anterior segment optical coherence tomography (ASOCT) and optical biometry in distinguishing PIC from PB in primary angle closure disease of the young (PACDy). Methods Patients aged 20–40 years with PACDy and age-matched healthy controls were recruited. Ophthalmic examinations included gonioscopy, ultrasound biomicroscopy, ASOCT, and biometry. Anterior chamber depth, lens thickness, axial length, central corneal thickness, lens position, relative lens position, vitreous cavity length, lens vault, relative lens vault and angle opening distance, trabecular iris space area, and trabecular iris angle were measured. Receiver operating characteristics curve analysis evaluated the discriminative ability of these parameters. Results Of the 280 eyes, 128 were normal and 152 had PACDy. Of 128 PACDy, 88 had PIC, and 64 had PB. Both PIC and PB had significantly smaller ASOCT and biometric parameters than normal eyes. However, PIC had intermediate biometric values that fell between normal eyes and PB. All the aforementioned parameters, except central corneal thickness, showed excellent discriminating ability of PIC and PB from normal eyes; however, no single parameter can strongly differentiate PB from PIC. Axial length and relative lens vault had the highest, although weak, power for discriminating PB from PIC. Conclusion ASOCT and biometry effectively distinguish PIC and PB from normal eyes, but no single parameter reliably differentiates PIC from PB. Comprehensive gonioscopy and ultrasound biomicroscopy may be necessary for accurate diagnosis in PACDy.

A triad of gut dysbiosis, dysregulated immunity, and 'leaky' gut characterize HCMV associated neonatal cholestasis.

Gut microbiome dysbiosis and related immune dysfunction have been associated with the pathogenesis of Human Cytomegalovirus (HCMV) infection in infants with neonatal cholestasis (NC) as previously reported by us. However, the interaction of a perturbed microbiome, HCMV infection, and dysregulated immunity leading to exacerbation of disease severity has not been investigated so far. In this study, we examined the association of gut microbiome, host inflammatory and homeostatic markers that are likely to govern increased pathogenesis of NC in HCMV infected IgM positive infants (N = 15) compared to IgM negative (N = 15) individuals. Stool samples of HCMV infected infants and age-matched healthy controls (N = 10) were assessed for gut bacteria-derived metabolites like short-chain fatty acids (SCFAs), Lipopolysaccharide (LPS), cytokines and markers of gut barrier integrity. Data were correlated with previously determined gut microbiome composition and frequency of immune cell subsets. Finally, validation of clinical potential was undertaken by principal component analysis (PCA) of integrated data to delineate the spectrum of clinical pathology. Significantly lower levels of SCFAs and elevated fecal levels of soluble inflammatory mediators were observed in IgM positive HCMV infected infants. Further, increased plasma LPS levels and markers of gut permeability, suggestive of microbial translocation due to a 'leaky gut' were observed in HCMV infected IgM positive group. PCA of integrated data revealed clearly disparate profiles representative of IgM positive, IgM negative, and uninfected healthy states. Our results suggest the utility of an integrated approach involving dysregulated microbiome-immune axis for gaining a better understanding of pathogenesis associated with HCMV infection in NC.

Sexual dimorphism, altered hippocampal glutamatergic neurotransmission, and cognitive impairment in APP knock-in mice.

It is well established that glutamatergic neurotransmission plays an essential role in learning and memory. Previous studies indicate that glutamate dynamics shift with Alzheimer's disease (AD) progression, contributing to negative cognitive outcomes. In this study, we characterized hippocampal glutamatergic signaling with age and disease progression in a knock-in mouse model of AD (APPNL-F/NL--F). At 2-4 and 18+ months old, male and female APPNL/NL, APPNL-F/NL-F, and C57BL/6 mice underwent cognitive assessment using Morris water maze (MWM) and Novel Object Recognition (NOR). Then, basal and 70 mM KCl stimulus-evoked glutamate release was measured in the dentate gyrus (DG), CA3, and CA1 regions of the hippocampus using a glutamate-selective microelectrode in anesthetized mice. Glutamate recordings support elevated stimulus-evoked glutamate release in the DG and CA3 of young APPNL-F/NL-F male mice that declined with age compared to age-matched control mice. Young female APPNL-F/NL-F mice exhibited increased glutamate clearance in the CA1 that slowed with age compared to age-matched control mice. Male and female APPNL-F/NL-F mice exhibited decreased CA1 basal glutamate levels, while males also showed depletion in the CA3. Cognitive assessment demonstrated impaired spatial cognition in aged male and female APPNL-F/NL-F mice, but only aged females displayed recognition memory deficits compared to age-matched control mice. These findings confirm a sex-dependent hyper-to-hypoactivation glutamatergic paradigm in APPNL-F/NL-F mice. Further, data illustrate a sexually dimorphic biological aging process resulting in a more severe cognitive phenotype for female APPNL-F/NL-F mice than their male counterparts. Research outcomes mirror that of human AD pathology and provide further evidence of divergent AD pathogenesis between sexes.

Motor learning is modulated by dopamine availability in the sensorimotor putamen

Abstract Successful motor skill acquisition requires the dynamic interaction of multiple brain regions, with the striatum playing a critical role in this network. Animal studies suggest that dopaminergic mechanisms are involved in the regulation of motor learning-associated striatal plasticity. In humans, however, the contribution of nigrostriatal dopaminergic transmission to motor learning remains elusive beyond its well-characterized role in initiation and fluent execution of movements. In this prospective observational study, we investigated motor sequence learning in individuals who had undergone 123I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single-photon emission computed tomography for the differential diagnosis of Parkinson's disease (n=41) and age-matched healthy controls (n=20). We found that striatal dopamine transporter (DaT) depletion exhibited distinct spatial patterns that were associated with impairments in motor sequence learning and the manifestation of Parkinsonian motor symptoms, respectively. Specifically, significant associations between striatal DaT depletion and impairments in motor sequence learning were confined to posterior putaminal regions, whereas significant associations of striatal DaT depletion with Parkinsonian motor symptom severity showed a widespread spatial pattern across the entire striatal volume with an anterior maximum. Normative functional connectivity analysis revealed that both behavioral domains shared largely overlapping connectivity patterns with the basal ganglia and supplementary motor area. However, apart from connectivity with more posterior parts of the supplementary motor area, significant functional connectivity with primary motor cortical areas was only present for striatal DaT availability-related modulation of online motor learning. Our findings indicate that striatal dopaminergic signaling plays a specific role in motor sequence learning beyond its influence on mere motor execution, implicating learning-related sensorimotor striatum recruitment and cortico-striatal plasticity as dopamine-dependent mechanisms.

Does environmental enrichment mitigate the adverse effects of chronic low dose-rate radiation exposure on mice?

The purpose of the study was to determine whether environmental enrichments (EE) can mitigate the adverse effects of chronic low-dose-rate radiation exposure in mice. Female B6C3F1 mice were continuously exposed to 20mGyd-1 gamma-rays under specific-pathogen-free conditions since 8weeks of age for 400d. After completion of the radiation exposure, OV3121 cells, derived from an ovarian granulosa cell tumor, were inoculated subcutaneously alongside age-matched non-irradiated control mice. Irradiated mice were shown to have a significantly reduced ability to eliminate inoculated tumors. The results indicate that EE may be able to mitigate the adverse effects of low-dose-rate radiation exposure, but the effects vary greatly and are complex depending on the type of EE.

Do white-footed mice, the main reservoir of the Lyme disease pathogen in the United States, clinically respond to the borrelial tenancy?

As white-footed mice, Peromyscus leucopus, are considered the primary animal reservoir of Borreliella burgdorferi sensu stricto (Bb), the main agent of Lyme disease (LD) in the United States, these animals represent the most relevant model to study borrelial spirochetes in the context of their natural life cycle. Previous studies have consistently demonstrated that although white-footed mice respond immunologically to the invasion of the Lyme pathogen, P. leucopus adults do not develop a clinically detectable disease. This tolerance, which is common for mammalian reservoirs of different pathogens, contrasts with detrimental anti-borrelial responses of C3H mice, a widely used animal model of LD, which always result in a clinical manifestation (e.g., arthritis). The current investigation is a follow-up of our recent study that already showed a relative quiescence of the spleen transcriptome for Bb-infected white-footed mice compared to the infected C3H mice. In an effort to identify the mechanism behind this tolerance, in this study, we have evaluated an extensive list of hematological and biochemical parameters measured in white-footed mice after their 70-day-long borrelial infection. Despite missing reference intervals for Peromyscus mice, our sex- and age-matched uninfected controls allowed us to assess the blood and serum parameters. In addition, for our assessment, we also utilized behavioral, immunological, and histological analyses. Collectively, by using the metrics reported herein, the present results have demonstrated clinical unresponsiveness of P. leucopus mice to the borrelial infection, presenting no restriction to a long-term host-pathogen co-existence.

P53 and the E3 Ubiquitin Ligase MDM2 in Glaucomatous Lamina Cribrosa Cells

Lamina cribrosa (LC) cells play an integral role in extracellular matrix remodeling and fibrosis in human glaucoma. LC cells bear similarities to myofibroblasts that adopt an apoptotic-resistant, proliferative phenotype, a process linked to dysregulation of tumor suppressor-gene p53 pathways, including ubiquitin-proteasomal degradation via murine-double-minute-2 (MDM2). Here, we investigate p53 and MDM2 in glaucomatous LC cells. Primary human LC cells were isolated from glaucomatous donor eyes (GLC) and age-matched normal controls (NLC) (n = 3 donors/group). LC cells were cultured under standard conditions ± 48-h treatment with p53-MDM2-interaction inhibitor RG-7112. Markers of p53-MDM2, fibrosis, and apoptosis were analyzed by real-time polymerase chain reaction (qRT-PCR), western blotting, and immunofluorescence. Cellular proliferation and viability were assessed using colorimetric methyl-thiazolyl-tetrazolium salt assays (MTS/MTT). In GLC versus NLC cells, protein expression of p53 was significantly decreased (p &lt; 0.05), MDM2 was significantly increased, and immunofluorescence showed reduced p53 and increased MDM2 expression in GLC nuclei. RG-7112 treatment significantly increased p53 and significantly decreased MDM2 gene and protein expression. GLC cells had significantly increased protein expression of αSMA, significantly decreased caspase-3 protein expression, and significantly increased proliferation after 96 h. RG-7112 treatment significantly decreased COL1A1 and αSMA, significantly increased BAX and caspase-3 gene expression, and significantly decreased proliferation in GLC cells. MTT-assay showed equivocal cellular viability in NLC/GLC cells with/without RG-7112 treatment. Our data suggests that proliferation and the ubiquitin-proteasomal pathway are dysregulated in GLC cells, with MDM2-led p53 protein degradation negatively impacting its protective role.

PTSD Is Associated with Self-Perceived Hearing Handicap: An Evaluation of Comorbidities in Veterans Without Measured Hearing Loss.

Cases of self-reported hearing difficulty despite no traditionally measured hearing loss (pure tone audiometric thresholds ≤ 25 dB HL from 250 Hz through 8000 Hz) have risen with the return of Veterans from recent conflicts in Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn. Auditory outcomes improved despite low compliance among those receiving treatment. Medical chart data appeared more comprehensive for Veterans with, rather than without, auditory complaints. One possibility is that self-reported hearing problems are associated with a subset of these comorbidities, the treatment of which improved auditory outcomes. This study examined the relationships between Veterans' self-reported auditory problems and other diagnosed medical conditions. A retrospective chart review was used. Participants were 286 Veterans, aged 21 to 52 years with pure-tone audiometric thresholds ≤ 25 dB HL at all measured frequencies in both ears. Veterans were dichotomized into a group with either self-reported hearing complaints (n = 143) or an age-matched control group with no auditory complaints (n = 143). A query of the Computerized Patient Record System was performed with the date range restricted to 2009 to 2018. Metrics of self-perceived hearing handicap, auditory processing disorder testing, and hearing aid use were collected. All diagnoses and related symptoms were recorded. A best subsets regression with principled model selection was performed to investigate the role of these comorbidities on self-perceived hearing loss. The self-report group had 16 comorbidities that were classified as prevalent, having occurred in ≥33.3% of the group, compared with the age-matched control group, which had 2 comorbidities. The number of diagnosed medical conditions was associated with self-perceived hearing impairment. Specifically, posttraumatic stress disorder (PTSD) and related symptom clusters constituted the largest group of comorbidities that were significantly associated with self-reported hearing problems. The significant association between PTSD and self-perceived hearing impairment warrants investigations on whether treatment of PTSD would reduce perceived hearing handicap severity. Further, PTSD assessments could be useful for audiologists to identify potential candidates for auditory complaints without measured hearing loss.

Abstract 4141445: Long-Term Predictive Value of 4D Flow MRI in Bicuspid Aortic Valve Patients: A 10-Year Assessment for Aortic Surgery Risk

Introduction: Bicuspid aortic valve (BAV) is associated with progressive ascending aorta (AAo) dilation, often leading to aneurysms, dissections, and ruptures. Thus, current guidelines recommend preventive surgery for AAo dilation. Recent 4D flow MRI studies show that BAV morphology causes abnormal transvalvular flow patterns, increasing wall shear stress (WSS), a trigger of aortic growth. Further studies have delineated areas of abnormally high WSS by comparing to estimates of matched controls, and show promise in detecting risk for aortic growth. However, since the long-term prognostic significance of this marker is unclear, we aimed to quantify WSS in BAV patients to assess its value in predicting the need for aortic surgery up to 10 years post-4D flow MRI acquisition. Methods: BAV patients without prior surgical intervention scanned before April 1, 2014 were identified. Using medical records, patients were categorized as ‘operated’ if they underwent aortic surgery post-scan and ‘non-operated’ if they were surgery-free for at least 10 years post-scan. 4D flow MRIs were processed with an AI pipeline, including 3D segmentation of the aorta, followed by peak velocity (PV) and WSS quantification in the AAo (Fig. 1A-C). Patient-specific WSS heatmaps were computed relative to a map based on the WSS of 10 or more sex and age-matched controls. Relative areas of elevated WSS in the AAo were then calculated (Fig. 1D-F). Results: 115 patients were included, with 73 non-operated (age: 42.5±11.5y, 49M) and 42 operated patients (age: 53.5±12.1y, 34M). The mean baseline mid-AAo diameters for non-operated and operated patients were 3.8±0.6 cm and 4.1±0.5 cm, respectively. Among operated patients, the mean scan to surgery time was 5.7±3.3y. All three 4D flow metrics were significantly higher in operated compared to non-operated patients: PV: 2.6±0.6 vs. 1.7±0.4 m/s (p&lt;0.01); WSS: 2.2±0.5 vs. 1.6±0.4 Pa (p&lt;0.01); relative area of high WSS on heatmaps: 31±12 vs. 15±13% (p&lt;0.01). Conclusions: 4D flow MRI parameters provide long-term predictive value in BAV patients, as elevated peak velocity, wall shear stress, and relative area of high wall shear stress on heatmaps are associated with subsequent aortic surgery within 10 years post-scan.

Expression pattern of long non-coding RNAs in treatment-naïve and medicated schizophrenia patients.

Schizophrenia is a disabling mental disorder that affects 1% of people over their lifetime. The etiology and mechanism of schizophrenia are very complex, and many genes are involved in many different signaling pathways in the etiology of this disease. According to recent studies, one of the important mechanisms altered in this disorder is the regulation of immune system and the inflammation mechanism. In the present study, we evaluated the peripheral blood expression pattern of four lncRNAs and three protein-coding genes in the treatment- naïve patients, and medicated patients compared with sex and age-matched controls. In the medicated-patients, expression levels of IFNG, IL18RAP, AC007278.2 were significantly up-regulated (P < 0.05); and the expression level of IFNG-AS1-001 was significantly down-regulated compared to healthy controls (P < 0.05). However, levels of IL18R1, AC007278.3 and IFNG-AS1-003 were not different between these groups. In the treatment-naïve patients, IFNG, IL18R1, IL18RAP, IFNG-AS1-001, AC007278.2, and AC007278.3 were significantly up-regulated compared to controls. On the other hand, IFNG-AS1-003 was significantly down-regulated in the treatment-naïve patients compared to controls. Based on the Spearman correlation matrix, there was a significant correlation between genes in the treatment-naïve patients. We also showed the high sensitivity and specificity of IFNG-AS1-003, IFNG, IL18R1, and AC007278.3 in the identification of treatment-naïve patients from controls. The current study contributes further evidence to the understanding of the role of lncRNAs in the pathogenesis of schizophrenia. Future research is necessary to establish the validity of lncRNAs as peripheral markers for this condition.

Abstract 4145828: The Interplay Between Exercise Load, Myocardial fibrosis, Ventricular Systolic Dysfunction and Ventricular Arrhythmias

Background: An increased prevalence of myocardial ventricular fibrosis, ventricular dysfunction and arrhythmias has been reported amongst highly trained endurance athletes, but trials investigating these adverse phenotypes in adequately sized and accurately phenotyped cohorts are largely lacking. We aimed to define the prevalence of ventricular fibrosis, ventricular systolic dysfunction, arrhythmia and their interplay in healthy endurance athletes. Methods: We analysed a male cohort of 244 young elite endurance athletes (20yr), 134 middle-aged recreational athletes (56yr) and 65 middle-aged non-athletic controls (55yr). CMR assessed for non-hinge point and hinge point late gadolinium enhancement (NH-LGE and H-LGE) and LVEF and RVEF. 24-hour Holter was performed to assess ventricular arrhythmia. Complex arrhythmia was defined as couplets, triplets and NSVT. Exercise load was based on questionnaires. Multiple logistic regression assessed the relationship between exercise load, LGE, ventricular systolic dysfunction and ventricular arrhythmia. Results: Middle-aged athletes had more NH-LGE (19.4% vs 9.2% vs 4.5%, p&lt;0.001) and H-LGE (29.9% vs 13.8% vs 15.6%, p=0.002) than middle-aged controls and young athletes respectively. Lifetime hours of endurance exercise and age increased the odds of NH-LGE (OR 1.034, 95% CI 1.001-1.069, p=0.044 and OR 1.032, 95% CI 1.006-1.058, p=0.014). A LVEF&lt;50% and/or RVEF&lt;45% was more prevalent in middle-aged and young athletes compared to controls (23.1% % vs 20.5% vs 7.7%, p=0.029). A higher lifetime training load increased the odds of RVEF&lt;45% (OR 1.059, 95% CI 1.014-1.105, p=0.009). LGE did not predict LVEF&gt;50% or RVEF&lt;45%. Both complex arrhythmia and a burden of &gt;0.1% VPB were more prevalent in middle-aged athletes compared to young athletes but not compared to controls (26.1% vs 9.8% vs 12.3%, p&lt;0.001 and 13.6% vs 4.9% vs 7.7%, p=0.012 respectively). NH-LGE and RVEF&lt;45% increased the odds of VPB burden &gt;0.1%. (OR 3.845, 95% CI 1.465-10.089, p=0.006 and OR 5.230, 95% CI 1.698-16.106, p=0.004 respectively). Conclusion: NH-LGE is associated with exercise load and more prevalent in middle-aged athletes compared to younger athletes and age-matched controls. When present, LGE is not associated with a reduced ventricular function. On the other hand, NH-LGE and reduced RVEF are risk factors for increased ventricular ectopic burden and middle-aged athletes show significantly more complex arrhythmia compared to younger athletes.

Abstract 4131736: Myocardial Work in Patients with Systemic Arterial Hypertension: Correlation with Left Ventricular Mass and Aortic Strain Lidia Capotosto 1,2 , Enrico Mangieri 2 , Gaetano Tanzilli 2 , Giuseppe Placanica 2 , Attilio Placanica 2 , Fabio Miraldi 2 , Antonio Vitarelli 1,21 Department of Echocardiography, Cardiodiagnostica CS, Rome, Italy, 2 Department of Cardiology and Cardiac Surgery, Sapienza

Background: Myocardial work (MW) is a new echocardiography-based diagnostic tool, which allows to quantify left ventricular performance based on pressure-strain loops and has been validated against invasively derived pressure-volume measurements. The purpose of the present study was to analyze whether systemic arterial hypertension is associated with abnormal left ventricular (LV) function assessed by myocardial work and how these changes are related to left ventricular hypertrophy (LVH) and aortic strain. Methods: We examined 86 hypertensive (mean age, 66±14 years, 51% male) and 86 sex- and age-matched healthy controls (mean age, 64±15 years, 53% male). Hypertensive patients were divided into two groups: patients without LVH (group-A) and patients with LVH (group-B, LVMI&gt;115g/m2 men, LVMI&gt;95g/m2 women). All of them had preserved LV ejection fraction. Global LV longitudinal strain (GLS) was calculated by speckle tracking echocardiography. The following indices of MW were assessed: global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE). Corrected circumferential aortic strain (Ao-S) was calculated in the ascending aorta by two-dimensional speckle tracking echocardiography as global aortic strain /pulse pressure. Data analysis was performed offline (GE EchoPAC). Results: GWI and GCW were increased in group-A compared to controls (p&lt;0.05) and decreased in group-B (p=0.04). GWW was increased in group-A(p=0.02) and group-B(p&lt;0.001). GWE was decreased in group-A(p&lt;0.01) and group-B(p&lt;0.005). There was a positive correlation between GWE and Ao-S(r=0.51,p=0.03). GWE was independently associated with GLS(β=0.26,p=0.034), LV mass(β=0.31,p=0.02) and Ao-S(β=0.37,p=0.01) in the whole hypertensive population. At the receiver operating characteristic (ROC) analysis, optimal cutoff values of GWI, GLS, Ao-S, GWE and (GWE+Ao-S) discriminating LV hypertrophy were 0.7329, 0.7613, 0.8011, 0.8442 and 0.8986, respectively. Conclusions: Decreased GWE in systemic hypertension was related to aortic strain and occurred even in the absence of LV hypertrophy. Additional assessment of aortic strain improved the ability of myocardial work variables to differentiate patients with LVH, patients without LVH, and control subjects.

Abstract 4137985: Impaired Skeletal Muscle Condition and Stroke Volume Reserve Characterize Poor Exercise Performance in Childhood Cancer Survivors

Background: Childhood cancer survivors (CCS) frequently show poor exercise performance, but its pathophysiology and clinical significance are poorly understood. Methods: Poor exercise performers, defined as peak oxygen consumption (VO2)/kg &lt; 80% of predicted maximum VO2/kg, were enrolled, including 40 CCS (20 males, 20 females) and 32 controls (15 males, 17 females) from 79 CCS and 147 age-matched controls, respectively. Peak and submaximal CPET parameters were compared between CCS and controls with poor exercise performance. Submaximal slope parameters represent a trend up to anaerobic threshold (AT). Results: Ages and anthropometric measurements (weight, height, and body mass index) were comparable between CCS and controls in both sexes (Table 1). Both resting and peak heart rate (HR) were significantly higher in CCS than in controls in males. There was no significant difference in peak VO2/kg, peak oxygen pulse (OP)/kg, peak respiratory exchange ratio, or VO2/kg at AT (VAT/kg) between CCS and controls in both sexes. Peak work rate (WR/kg) was significantly lower in CCS compared with that in controls in both sexes, suggesting reduced muscle strength in CCS. Figure 1 demonstrates decreased muscle mass/strength in CCS than in controls. In males, Δ[VO2/kg]/ ΔHR was significantly lower in CCS than in controls, indicating limited stroke volume reserve (SVR) in male CCS. In female, although there was no significant difference in Δ[VO2/kg]/ΔHR between CCS and controls, HR-dependency expressed by ΔHR/Δ[WR/kg] was significantly higher in CCS than in controls, suggesting impaired SVR. ΔVO2/ΔWR, a marker for physical conditioning, was comparable between CCS and controls in both sexes. Conclusions: Poor exercise performance in CCS is characterized mainly by decreased muscle mass/strength and impaired SVR for both sexs. Impaired SVR may be an early sign of subclinical cardiotoxicity. Poor exercise performance in CCS should be improved to prevent future cardiovascular complications.

Abstract 4137337: Targeting Macrophage NCOR1 to Alleviate Inflammation in Heart Failure with Preserved Ejection Fraction

Background: Inflammatory response is a key player in heart failure with preserved ejection fraction, however the underlying mechanisms remain unclear. Recent evidence indicates that macrophage inflammation driven by the transcriptional coregulatory protein NCOR1 could play a pivotal role in disease states. Hypothesis: NCOR1 orchestrates macrophage inflammation and cardiac dysfunction in HFpEF. Methods: HFpEF was induced in mice using a validated model combining high-fat diet and L-NAME for 15 weeks. Cardiac function was assessed using high-resolution ultrasound imaging and LV samples were used to study macrophage polarization and inflammation by FACS. We generated myeloid-specific NCOR1-KO mice to investigate the in vivo effects of macrophage NCOR1 depletion on HFpEF. In vitro experiments included RAW 264.7 cells polarization and the assessment of macrophage phenotype switching in the presence or the absence of NCOR1. To study the crosstalk of macrophages with the surrounding cardiac cells, cardiomyocytes (H9c2) and endothelial cells (HAECS) were exposed to conditioned media from cultured RAW. Results: The expression of macrophage markers in human LV specimens showed an increase in pro-inflammatory macrophages (M1) and a decrease in regulatory macrophages (M2) as compared to age-matched control mice. HFpEF mice showed increased expression of vascular adhesion molecules (ICAM1, ICAM2, E-selectin) and a significant recruitment of M1 macrophages as proved by qPCR, WB, and flow cytometry analysis. Of interest, diastolic dysfunction - assessed by E/A ratio and isovolumic relaxation time (IVRT) – and lung congestion were significantly reduced in mice with macrophage NCOR1 deletion as compared to WT littermates, while exercise tolerance was significantly improved. These findings were associated with a reduction of myocardial inflammation (TNF-a, IL6, IL-1b) in Ncor1-KO mice. In vitro assays showed that stimulation of macrophages with PA induced M1 type switch and increased NCOR1, TNF-a, IL-6, and IL-1b levels, whereas NCOR1 depletion prevented detrimental changes of macrophage conditional medium (Fig.1). Conclusion: Targeting macrophage NCOR1 could represent a promising approach to blunt myocardial inflammation in HFpEF.

ASC specks as a single-molecule fluid biomarker of inflammation in neurodegenerative diseases.

Immunotherapeutic strategies for Alzheimer's and Parkinson's disease would be facilitated by better measures of inflammation. Here we established an ultra-sensitive single-molecule pull-down immunoassay combined with direct stochastic optical reconstruction microscopy (dSTORM) to measure the number, size and shape of individual extracellular inflammasome ASC specks. We assayed human post-mortem brain, serum and cerebrospinal fluid of patients with Parkinson's and Alzheimer's as well as healthy elderly. The number of ASC specks increased and showed altered morphology in the blood of early-stage Parkinson's and Alzheimer's patients compared to controls, mimicking those found in the brain and cerebrospinal fluid. In serum samples we also measured the number of Aβ, p-tau and α-syn aggregates and formed a composite biomarker of (ASC + p-tau)/Aβ and (ASC + α-syn)/Aβ ratios that distinguished age-matched healthy controls from patients with early-stage Alzheimer's with AUC of 92% and early-stage Parkinson's with AUC of 97%. Our findings confirm ASC specks as a fluid candidate biomarker of inflammation for neurodegenerative diseases with blood being the main focus for further development as convenient sample for diagnostics and clinical trials.