bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract MP39:
FHL5
, A Novel Cofactor Associated With Coronary Artery Disease, Regulates Smooth Muscle Cell Function Through A Transcriptional Network Linking Multiple Risk Loci
Authors: Wong Doris , Turner Adam , Khan Mohammad Daud , Palmore Meredith , Perry Noah , kuppusamy maniselvan , Ottolini Matteo , Matic Ljubica , Hedin Ulf , Ma Lijiang , Sonkusare Swapnil K , Civelek Mete , Kovacic Jason C , Bjorkegren Johan , Miller Clint L
Published: May 2022

Introduction:
Coronary artery disease (CAD) is the leading cause of death worldwide with an estimated heritability of ~50%. The most recent genome wide association study (GWAS) for CAD and myocardial infarction (MI) identified over 200 loci. One such novel CAD/MI locus,
UFL1-FHL5
(P = 1.1E-8), is associated with additional vascular pathologies, including hypertension, migraines, and coronary calcification. We previously showed through statistical fine-mapping that
FHL5
is the top candidate causal gene underlying each of these vascular trait associations and highly enriched in the contractile mural cell populations in the artery. These preliminary studies motivate our hypothesis that FHL5 functions as a transcriptional regulator of SMC contractility to affect vascular disease risk.

Methods and Results:
Given the reported role of FHL5 as a cofactor, we mapped 17,201 candidate FHL5 binding sites in coronary artery SMCs using the Cleavage Under Targets and Release Using Nuclease (CUT&RUN) method. Binding sites were enriched for AP-1 family motifs and strongly overlapped CREB binding sites and H3K27ac enhancer marks. FHL5 target genes were functionally enriched in well characterized CAD pathways, such as extracellular matrix organization (P=5.2E-15, OR=2.1) and TGF-beta signaling (P=8.0E-5, OR=2.0). Interestingly, FHL5 binding sites were also enriched for CAD (P=1.8E-7, OR=2.3) and blood pressure (BP) risk variants (P=0.04, OR=1.2), thereby linking FHL5 with the regulation of multiple downstream CAD/BP loci. Weighted gene co-expression network and key driver analyses of human coronary artery transcriptomic data further support this regulatory role. Lastly, we validated these findings by performing confocal based calcium imaging and collagen gel contraction assays. Consistent with our functional genomic analyses, overexpression of FHL5 elevated intracellular calcium levels 2.5X and increased SMC contractility by ~45%.

Conclusion:
Taken together, our results provide evidence that
FHL5
may impact CAD risk by regulating a network of disease-associated genes mediating SMC functions. These findings further contribute to our understanding of the heritable risk for multiple vascular diseases.
Abstract MP42: Macrophage Chromatin Remodeling Complex Subunit Baf60a In Atherosclerosis
Authors: Zhao Yang , Liu Yuhao , Zhao Guizhen , Lu Haocheng , Chang Ziyi , Xue Chao , Chen Eugene , Zhang Jifeng
Published: May 2022

Objectives:
Atherosclerosis is a primary medical concern due to the increasing prevalence and lack of effective treatment that reverses the disease progression. While multiple genetic mutations/variations have been associated with atherosclerotic risk, the development of atherosclerosis in response to risk factors is also contributed by factors at the epigenetic and chromatin level. The SWI/SNF chromatin remodeling complex alters DNA accessibility and chromatin structure to modulate gene expression in response to external and internal cellular environments, potentially serving as an underexplored compartment of CVD and atherosclerosis development.

Approach and Results:
In an effort to identify key chromatin remodeling compartments involved in atherosclerotic foam cell formation, primary bone marrow-derived macrophages (BMDMs) were exposed to a pro-atherogenic environment, specifically to oxidized Low-density lipoprotein (oxLDL). We observed drastically and time-dependent decrease in the protein abundance of BAF60a, a transcription factor interacting subunit of the SWI/SNF chromatin remodeling complex. Macrophage-specific Baf60a deletion in ApoE deficient mice showed over 30% increase in aortic plaque formation after 16-weeks of western diet feeding (N=12, p=0.0097). Integrated analysis of RNA-seq and ATAC-seq regulatory network in oxLDL treated BAF60a deficient BMDMs identified a shift of chromatin accessibility, transcription factor footprint, and a reshape in gene expression patterns that regulate extracellular matrix organization, focal adhesion, integrin signaling, inflammation, and lead to foam cell formation which ultimately contribute to the atherosclerotic plaque build-up.

Conclusions:
Our data demonstrated the role of macrophage BAF60a in atherogenesis and suggested a potential therapeutic target to treat atherosclerosis, presumably by compensating for the loss of Baf60a.
Abstract P111: Effects Of Magnetic Field On Abca1-mediated Cellular Lipid Release And Adult Brain Cell Generation In Mice
Authors: Tsujita Maki , Takase Hiroshi , Kumamoto Natsuko , Ugawa Shinya , Furuie Yoshito , Tsubaki Motonari
Published: May 2022

Aim:
This project aims to explore a novel magnetic field (MF) health care based on the cholesterol metabolism.

Methods:
Mouse peritoneal macrophages foam cells were incubated in CO
2
-independent culture medium containing apoA-I and were exposed in a MF (0.4 T) using the electromagnet of EPR spectrometer. C57BL/6N mice (8 week-old) were peritoneally injected F-ara-EdU (133μg/g mouse body weight) then exposed to MF under the identical condition. Mouse plasma, cerebrospinal fluid, liver and brain were harvested on the 28
th
day. Lipoprotein profiles were examined enzymatic detection followed by a gel-permeable-HPLC (Skylight Biotech Inc.). Amyloid β40 and β42 levels were determined by WAKO ELISA kit. Fixed mouse brain sections (40um) were prepared by Leica CM1900 cryostat. Alexa fluor® 488 conjugates were link to F-ara-EdU by a click chemistry method and fluor positive nucleus images were captured by a confocal super resolution SpinSR10 (Olympus, Inc.).

Results:
ABCA1-apoA-I mediated cellular cholesterol release was not affected or reduced by the exposure in the MF of 0.4 T. The
Pcsk9
expression showed significant reduction in the hepatocytes. Reduction of
Abca1
expression and increase of
Scarb1
were obtained non significantly. The newly generated hippocampal dentate gyrus cells in the control mice group and the MF exposed group were 1.6±1.17, and 0.47±0.62 cells per dentate gyrus section, respectively (P=0.003) despite bulk of new cells in olfactory bulbs in the both groups.

Discussions:
No substantial increase in cellular cholesterol export was observed by MF irradiation of mouse peritoneal macrophage cells. In addition, the lipoprotein profile showed a decrease in HDL cholesterol even after 28 days. As a result of gene expression in the liver, a decrease in ABCA1 expression and an increase in SR-BI expression inferred reduction of HDL. The number of new cells detected in the granular zone and the subgranular zone in the dentate gyrus of the hippocampus was significantly reduced in the mice subjected to the MF treatment. In the future, it is necessary to investigate in detail whether these newborn cells are neuron or glial cells.
Abstract P116: Exercise And Quercetin Synergistic Effects On Omega 3 And 6 Fatty Acids In Mice Livers
Authors: Ochin Chinedu C , Punch Emily , Mahini Halleh , Garelnabi Mahdi O
Published: May 2022

Synopsis:
omega 3 and omega 6 fatty acids are important precursors for the synthesis of other fatty acids and they play vital roles in many metabolic processes in health and diseases.

Objectives/Purpose:
Exercise and the use of antioxidants such as quercetin have been demonstrated to favorably modulate long chain fatty acid metabolism beneficial role in cardiovascular health. This study investigates the interactive effect of exercise and quercetin intake on hepatic omega-3 and omega-6 fatty acids.

Method:
Four groups of (10 each) C57BL6 LDLr -/- mice as follows; untreated control mice (NN), 100ug/day of Quercetin fed mice (NQ), exercise only mice (NE) and combined exercise with quercetin fed mice (EQ), were all fed an atherogenic diet for 30 days. The exercise groups were placed on an exercise regimen of 30 minute run for 5 days/week for 30 days. All animals were subsequently sacrificed, livers harvested and homogenized for lipid extraction and derivatization for GCMS analysis. The analysis was performed using a Shimadzu GCMS-QP2010 Plus instrument with an Agilent HP-5MS; 30m, 0.25mm, 0.25um column. Statistical analysis was performed using descriptive statistics, one-way and two-way ANOVA with statistical significance set at a p ≤ 0.05

Result:
There was statistically significant decrease of both omega 3 (p ≤ 0.0002) and omega 6 (p≤ 0.0001) fatty acids in all groups when compared to the control. The interaction effect of exercise administration and quercetin supplementation (EQ) on the combined reduction of liver ω 3 and ω 6 fatty acids was also statistically significant (p ≤0.009).

Conclusion:
The results demonstrate that the use of quercetin antioxidant, exercise or the combination reduces both hepatic ω3 and ω6 fatty acids accumulation in LDLr deficient animal models fed atherogenic diet. This reduction was accompanied with a 78% drop in the atherosclerotic plaque development in exercising group compared to non-exercising mice and also accompanied with changes in plasma lipids and inflammatory markers.
Abstract P133: Inflammatory Biomarkers As Predictors Of Adverse Outcome In Acute Myocardial Infarction
Authors: Kristono Gisela A , Holley Ana S , Hally Kathryn , Brunton-O'Sullivan Morgane M , Harding Scott , Larsen Peter
Published: May 2022

Introduction:
Inflammation contributes to the pathogenesis of major adverse cardiovascular events (MACE) after an acute myocardial infarction (AMI). However, the optimal way to characterise inflammation and predict risk is unclear. While various biomarkers have been used to examine the relationship between acute inflammation and MACE risk, results are inconsistent between studies. Using a range of inflammatory markers, we assessed their utility to predict MACE in AMI patients.

Hypothesis:
A combined inflammatory biomarker approach is superior to individual biomarkers for predicting MACE risk in AMI patients.

Methods:
We conducted a systematic review of multi-marker approaches to characterise inflammation following AMI. Through cohort studies, a case control study, and a time series, we also examined the relationship between inflammatory markers and MACE. The studies ranged in size from 23 to 860 patients, with an average MACE rate of 13 in 100 at one year follow up.

Results:
Our systematic review found four studies that attempted various combined cytokine approaches. All found statistical associations with MACE, and performed better than single markers. In our studies, we first explored simple methods of combining biomarkers (ratios of leukocyte counts, and simple addition of C-reactive protein, IL-6 and TNF-alpha). We found no independent associations with MACE when biomarkers were combined via simple methods. We then examined a more sophisticated approach for combining cytokines. We chose to use a mathematical technique (principal component analysis, PCA) that could deal with co-linearity within individual cytokine measurements and combine individual cytokine measurements into a score. We selected six cytokines, and a PCA score derived from these markers was associated with MACE on univariate analysis. Individually, IL-6 and IL-8 levels were univariate predictors of MACE. Combining these two into a PCA-derived score resulted in a stronger, independent association with MACE (odds ratio 2.77, p<0.05) than seen with either marker alone.

Conclusion:
Multi-marker inflammatory scores may produce more consistent associations with MACE than single biomarkers. We suggest that PCA is a useful mathematical method for creating this type of score.
Abstract P142: B Cell Activating Factor Neutralization In High-Fat Diet-Induced Obese Mice Retains Adipose Tissue B Cells And Exacerbates Glucose Homeostasis
Authors: Lempicki Melissa D , Gray Jake , Paul Saikat , Bhowmick Debajit , Meher Akshaya K
Published: May 2022

Adults with type 2 diabetes have a two-to-three-fold increased risk of cardiovascular diseases. B cell activating factor (BAFF), a tumor necrosis superfamily member, is implicated both in diabetes and cardiovascular diseases. BAFF deficiency in mice retains glucose homeostasis despite high-fat diet-induced obesity. We examined if neutralization of BAFF with an anti-BAFF antibody improves glucose utilization in high-fat diet-induced obese mice. Male C57BL/6J mice fed with a high-fat diet (60% calories from fat) for 12 weeks were segregated into two groups based on their glucose intolerance (GI) determined by a glucose tolerance test (GTT). Each group received a total of 4 injections of anti-BAFF or an isotype control antibody, and GTT was performed every two weeks. BAFF neutralization was confirmed by depletion of B2 B cells in the blood two weeks after the first anti-BAFF antibody injection. Although GI increased after continuous feeding of a high-fat diet, no differences in GI was observed between the groups till 18 weeks on diet. At 20 weeks, GI was significantly higher in the anti-BAFF treated group compared to the control group. Extensive cellular phenotyping using flow cytometry revealed that BAFF neutralization depleted mature B2 B cells in the spleen and blood but did not affect the CD4+ T cells and CD8+ T cells. No differences were found in fat accumulation in the liver, whole body fat content, visceral adipose tissue (VAT) weight, or in the number of VAT-infiltrated M1 and M2 macrophages, eosinophils, natural killer T cells, CD4+ T cells, and CD8+ T cells. Unexpectedly, in the VAT of anti-BAFF antibody-treated mice, B2 cells were retained, whereas, the number of CD4+ T cells and dead adipocytes was higher. Real-time RT-PCR analysis of stromal vascular fraction from VAT revealed increased expression of both the M1 and M2 macrophage markers IL-1β, IL-6, IL-10, Arg1, and Mrc1 in the anti-BAFF treated mice. Altogether, these results suggest BAFF neutralization promotes inflammation in the VAT of obese mice and exacerbates systemic glucose intolerance. Furthermore, our results highlight the need for more studies on the use of anti-BAFF biologics for the treatment of systemic lupus erythematosus patients who are diabetic.
Abstract P154: Pgc1a Regulates The Endothelial Response To Fluid Shear Stress
Via
Telomerase Reverse Transcriptase Control Of Heme Oxygenase-1
Authors: Kant Shashi
Published: May 2022

Fluid shear stress (FSS) is known to mediate multiple phenotypic changes in the endothelium. Laminar FSS (undisturbed flow) is known to promote endothelial alignment to flow that is key to stabilizing the endothelium and rendering it resistant to atherosclerosis and thrombosis. The molecular pathways responsible for endothelial responses to FSS are only partially understood. Here we have identified peroxisome proliferator gamma coactivator-1α (PGC-1α) as a flow-responsive gene required for endothelial flow alignment
in vitro
and
in vivo
. Compared to oscillatory FSS (disturbed flow) or static conditions, laminar FSS (undisturbed flow) increased PGC-1α expression and its transcriptional co-activation. PGC-1α was required for laminar FSS-induced expression of telomerase reverse transcriptase (TERT)
in vitro
and
in vivo
via its association with ERRα and KLF4 on the
TERT
promoter. We found that TERT inhibition attenuated endothelial flow alignment, elongation, and nuclear polarization in response to laminar FSS
in vitro
and
in vivo
. Among the flow-responsive genes sensitive to TERT status was heme oxygenase-1 (HMOX1), a gene required for endothelial alignment to laminar FSS. Thus, these data suggest an important role for a PGC-1α-TERT-HMOX1 axis in the endothelial stabilization response to laminar FSS.
Abstract P156: Intimal And Medial Calcification Underlie Differential Molecular Mechanisms
Authors: Augusto Heuschkel Marina , Heyn Jonas , van der Vorst Emiel , Marx Nikolaus , Goettsch Claudia
Published: May 2022

Introduction:
Vascular calcification (VC) is a significant risk factor for cardiovascular morbidity and mortality. Based on the mineral deposition site in the arterial wall, VC classifies into intimal and medial calcification. We hypothesize that distinct in vitro mineralization methods promote specific intracellular signalling pathways in vascular smooth muscle cells (SMC), reflecting both VC types.

Methods and Results:
Human coronary artery SMCs were cultured in osteogenic medium (OM) or high calcium-phosphate medium (CaP) to induce calcification. OM resembles SMCs differentiation in intimal calcification - a key process in atherosclerotic plaque remodeling. CaP is associated with chronic kidney disease - a risk factor for medial calcification. Transcriptomics revealed a distinct gene expression profile of OM and CaP-calcifying SMCs, that share 6.9% and 11.3% of their genes, respectively. The 109 shared dysregulated genes between OM and CaP-calcifying SMCs highlighted enriched pathways related to SMC contraction and metabolism. Real-time extracellular efflux analysis demonstrated a different metabolic profile in OM and CaP-calcifying SMCs. We observed decreased mitochondrial respiration and glycolysis (-57,3% p=0.029) by CaP and increased mitochondrial respiration without altered glycolysis by OM. Subsequent kinome and in silico drug repurposing analysis (Connectivity Map) revealed a distinct role of protein kinase C (PKC). Validation using prostratin, a specific PKC activator, demonstrated differential effects on matrix mineralization that was decreased by OM (-69,3%, p<0.001) and increased by CaP (+69,6%, p=0.044).

Conclusions:
In conclusion, OM and CaP-induced SMC calcification underlies differential mechanisms in vitro. Therefore, research should distinguish between the two aspects of VC and increased knowledge about the underlying pathophysiological mechanisms may open the possibility for preventing intimal and medial calcification.
Abstract P159: Induction Of Human Angiotensinogen In Hepatocytes And Human Renin In Renal Proximal Tubule Cells Does Not Accelerate Atherosclerosis In Mice
Authors: Amioka Naofumi , Kukida Masayoshi , Ye Dien , Howatt Deborah A , Moorleghen Jessica J , Daugherty Alan , Lu Hong
Published: May 2022

Objective:
Hepatocyte-produced angiotensinogen (AGT) can be filtered by glomeruli and retained in renal proximal tubules. Renin protein has also been detected in proximal tubules (PTC) of kidney. However, it is unknown whether AGT and renin in proximal tubules contribute to atherosclerosis. This study aimed to determine whether hepatocyte-derived AGT interacts with renin in proximal tubules to promote atherosclerosis.

Approach and Results:
Transgenic mice expressing human renin driven by a kidney androgen-related protein promoter (KAP-hREN) in an LDLR -/- background were administered subcutaneously with testosterone (15 mg/mouse, constant release for 60 days) to activate the human renin transgene in PTCs. To induce synthesis of human AGT in hepatocytes, adeno-associated viral (AAV; 3 x 10
10
genomic copies/mouse) vector containing human AGT with a liver-specific promoter was injected intraperitoneally. Three groups of male littermates were administered testosterone: (1) wild type mice administered null AAV (n=11), (2) KAP-hREN transgenic mice administered null AAV (n=7), and (3) KAP-hREN transgenic mice (n=8) administered AAV containing human AGT. Two weeks after administration of testosterone and AAVs (either null or human AGT), all mice were fed a Western diet for 6 weeks. Induction of human renin was confirmed by mRNA abundance of human renin in kidney of KAP-hREN transgenic mice. In mice administered human AGT AAV, presence of human AGT was detected in plasma with a human AGT ELISA kit. Induction of both human AGT in liver and human renin in proximal tubules did not affect plasma cholesterol concentrations or systolic blood pressure. Atherosclerotic lesion sizes, as quantified by percent lesion area using an
en face
method, were not different among the 3 groups (Group 1 vs 2 vs 3: 3.7 ± 0.4% vs 3.3 ± 0.9% vs 2.3 ± 0.3%; P = 0.19).

Conclusions:
Induction of human AGT in hepatocytes and human renin in proximal tubules does not augment atherosclerosis in hypercholesterolemic mice.
Abstract P166: Gsk3beta Shifts Osteoblast To Endothelial Differentiation To Reduce Osteogenesis
Authors: Zhang Daoqin , Yao Jiayi , Wu Xiuju , Qiao Xiaojing , Zhang Li , Ma Jocelyn , Cai Xinjiang , Bostrom Kristina I , Yao Yucheng
Published: May 2022

Transitions between cell fates commonly occur in development and disease. However, reversing an unwanted cell transition in order to treat disease remains an unexplored area. Here, we report a successful process of guiding ill-fated transitions toward normalization in vascular calcification. Vascular calcification is a severe complication that increases all-cause mortality of cardiovascular disease but lacks medical therapy. The vascular endothelium is a contributor of osteoprogenitor cells to vascular calcification through endothelial-mesenchymal transitions, in which endothelial cells (ECs) gain plasticity and ability to differentiate into osteoblast-like cells. We created a high throughput screening and identified SB216763, an inhibitor of glycogen synthase kinase 3 (GSK3), as an inducer of osteoblastic-endothelial transition. We demonstrated that SB216763 limits osteogenic differentiation in ECs at an early stage of vascular calcification. Lineage tracing showed that SB216763 redirected osteoblast-like cells to the endothelial lineage and reduced late-stage calcification. We also find that deletion of GSK3β in osteoblasts recapitulated osteoblastic-endothelial transition and reduced vascular calcification. Overall, inhibition of GSK3β promoted the transition of cells with osteoblastic characteristic to endothelial differentiation thereby ameliorating vascular calcification.
Abstract P168: Promising Diagnostic Biomarkers For Congenital Vascular Malformations
Authors: Abu-Hanna Jeries , Pang Calver , Valnarov-Boulter Alexander , Khurram Ruhaid , Papadopoulou Anthie , Lim Chung Sim , Brookes Jocelyn , Hamilton George , Tsui Janice
Published: May 2022

Background:
Congenital vascular malformations (CVMs) are vascular lesions that result from developmental errors during embryogenesis. They can occur anywhere in the body, causing pain, bleeding, ulcers, disfiguration, organ failure or limb loss. Depending on intralesional blood flow dynamics, CVMs can be broadly classified into low-flow (LF), which involve veins, lymphatics, capillaries or a mixture, and high-flow (HF), which involve arteries and veins. Accurate diagnosis and monitoring of LF and HF CVMs remains challenging and requires a wide range of imaging modalities.

Aim:
We sought to identify potential diagnostic serum biomarkers, particularly those pertaining to the processes of inflammation and angiogenesis.

Methods:
Sera were isolated from the peripheral bloods of consented healthy controls (
n
= 10) and patients diagnosed as having either LF (
n
= 10) or HF (
n
= 10) CVMs. Various mediators of inflammation and angiogenesis were analysed in the sera using the Inflammation 20-Plex and Angiogenesis 18-Plex Human ProcartaPlex™ Panels. The levels of these mediators in patients with LF or HF CVMs were compared with those in healthy controls using the Kruskall-Wallis test and correlated with lesion volumes and visual analogue scores for pain using the Spearman rank correlation test.

Results:
Compared to healthy controls, the inflammatory mediators E-selectin, IFNα, IFNγ, IL1β, IL4, IL12, IL17, MIP1α, MIP1β and TNFα were elevated in the sera of LF CVM patients, whereas only MIP1α was raised in the sera of HF CVM patients. None of the angiogenic mediators were altered in the sera of patients with LF or HF CVMs. Serum IFNα, IFNγ, IL4, IL12, TNFα, VEGFA, VEGFD and syndecan correlated positively with pain scores in patients with LF CVMs, whereas only IP10 did in patients with HF CVMs. Serum Ang1 and leptin correlated negatively with lesion volumes in patients with LF or HF CVMs, respectively.

Conclusion:
Serum inflammatory mediators could be used as biomarkers to distinguish LF from HF CVMs and their expression seemed to be associated with pain severity in patients with LF CVMs. The angiogenic mediators Ang1 and leptin were associated with lesion volumes in patients with LF or HF CVMs, respectively.
Abstract P169: β-catenin C-terminal Domain/Sphingosine-1-Phosphate Receptor 1 Axis Drives Neointima Formation After Carotid Injury
Authors: Oliveira De Paula Gustavo H , Almonte Vanessa , Valenta Tomas , Basler Konrad , Riascos-Bernal Dario , Sibinga Nicholas
Published: May 2022

Introduction:
The β-catenin C-terminal domain (CTD) is required for artery formation during embryogenesis, but its role in vascular remodeling in adulthood is unknown. Inhibitors targeting specifically the CTD of β-catenin have been developed, but their use in obstructive vascular disease is not yet justified because of this gap of knowledge. Loss of β-catenin in mouse aortic smooth muscle cells (MASMCs) decreases the transcript levels of sphingosine-1-phosphate receptor 1 (S1PR1). However, no studies have evaluated the crosstalk between these proteins in vascular remodeling.

Hypothesis:
We hypothesized that the CTD of β-catenin promotes neointima formation after vascular injury, and that it acts by inducing S1PR1 expression.

Methods:
We studied mice bearing a knockin mutant β-catenin allele (ΔC) that lacks β-catenin CTD transcriptional activity. Mice expressing the SMC-specific SMA-CreERT2 and bearing one floxed and one mutant β-catenin allele were treated with tamoxifen to inactivate the floxed allele, leaving the mutant allele as the only source of β-catenin in SMC (SMβCΔC mice). Carotid artery ligation was performed to induce vascular injury. MASMCs were isolated from SMβCΔC mice (βCΔC cells).

Results:
We found reduced neointima formation after injury in SMβCΔC male (SMβCWT/-: 0.52±0.09
vs
SMβCΔC: 0.16±0.05; n=10; P<0.05) and female (SMβCWT/-: 0.56±0.11
vs
SMβCΔC: 0.17±0.04; n=10; P<0.05) mice. These findings were associated with reduced SMC proliferation, increased SMC apoptosis, and prevention of loss of SMC markers. In vitro, βCΔC MASMCs showed reduced growth compared to control cells (n=6; P<0.05). βCΔC MASMCs also showed reduced S1PR1 expression and decreased
S1pr1
promoter activity, which were both rescued by the transfection of a constitutively active form of β-catenin. Interestingly, overexpression of S1PR1 restored βCΔC MASMC growth towards control levels (n=6; P<0.05). In vivo, we found reduced S1PR1 expression in SMCs of injured arteries from SMβCΔC mice.

Conclusion:
Our results define an essential SMC β-catenin CTD-S1PR1 axis that drives neointima formation after arterial injury, and point to multiple points for potential therapeutic intervention to control vascular remodeling in disease.
Abstract 12490: In a World Full of Talk, No One Wants to Discuss Death: An International Analysis of End-of-Life Discussions With Implantable Cardioverter Defibrillator Recipients
Authors: Thompson Jessica H , Chung Misook L , Miller Jennifer , Thylen Ingela , Ski Chantal , David Thompson , Fitzsimons Donna , Hill Loreena , McKee Gabrielle , O'Donnell Sharon A , O'Brien Frances , Mooney Mary , Lee Kyoung S , Hwang Seon Y , Moser Debra K
Published: May 2022

Introduction:
End-of-life (EOL) decision making in implantable cardioverter defibrillator (ICD) recipients is a difficult process that requires input from patients, families, and providers. International guidelines advise providers to discuss EOL scenarios with patients prior to ICD implantation, and throughout the life of the patient. Healthcare systems and culture differ across countries and may determine whether these conversations occur. The purpose of this study was to determine if country of origin affected whether an ICD recipient had engaged in a conversation with their provider or next-of-kin about EOL decisions related to the ICD.

Methods:
Participants (N = 682) from six countries—United States (US), Australia, Northern Ireland, Republic of Ireland, Sweden, and South Korea—completed demographic information, and an EOL questionnaire. Binomial logistic regression was used to examine if country of origin predicted whether patients had discussed EOL with an ICD with their providers or next of kin controlling for demographic (age and gender) and clinical (having a cardiac resynchronization therapy device, history of myocardial infarction and having received a shock from the ICD) variables.

Results:
Overall, 21% of participants had an EOL discussion with their provider, and 15% had an EOL discussion with their next-of-kin. Country of origin was a significant predictor of having had an EOL discussion with a provider (p=0.003) and next-of-kin (p=0.005). Significant differences were found between the US and Korea for discussions with providers (OR=0.265, p<0.001) and next-of-kin (OR=0.301, p=0.003), and the US and Sweden for discussions with providers (OR=0.614, p=0.040) and next-of-kin (OR=0.537, p=0.021), with the US being the reference group. Having received a shock in the past was a significant predictor of having an EOL with providers (OR=2.275, p<0.001) and next-of-kin (OR=1.692, p=0.019).

Conclusions:
End-of-life decision making is a complicated process, and a person’s cultural beliefs, along with healthcare system may play a role. These factors should be considered when creating interventions and policy to improve EOL discussions for patients with an ICD in order to improve quality of EOL care.
Abstract 13159: Subclinical Cardiac Magnetic Resonance Imaging Reveals Subtle Myocardial Tissue Abnormalities in Individuals With Arrhythmogenic Cardiomyopathy-Associated Genetic Variants
Authors: Carruth Eric D , Fielden Sam , Alsaid Amro , Fornwalt Brandon , Haggerty Christopher M
Published: May 2022

Introduction:
With expanding genomic sequencing, incidental identification of patients with disease-causing variants who do not have overt disease is increasingly common. For example, secondary findings of desmosome gene variants associated with arrhythmogenic cardiomyopathy (ACM) are recommended for clinical return but exhibit low penetrance. Additional biomarkers, such as myocardial tissue characteristics, are needed to uncover early disease in patients with genetic risk.

Hypothesis:
Patients with desmosome variants (G
+
) but no clinical phenotype have abnormal ventricular volumes, left ventricular (LV) mass, native T1, T2, post-contrast T1, synthetic extracellular volume (sECV), and late gadolinium enhancement (LGE) via cardiac MRI.

Methods:
G
+
individuals were ascertained after clinical confirmation of likely pathogenic/pathogenic desmosome variants from 64548 sequenced Geisinger MyCode patients. MRI studies with myocardial mapping from a single scanner were included. Controls were identified from clinical MRI studies read as having normal biventricular structure and function. Patients who met diagnostic criteria for any cardiomyopathy were excluded from both groups. Ventricular volumes, mass, and tissue properties were defined by manual segmentation.

Results:
Qualifying studies were identified for 18 G
+
and 19 genotype unknown (G
+
) controls, with similar age and sex. Biventricular volumes and function, as well as LV mass, were similar (Figure). Native T1 was elevated (mean±SEM 1027±9 ms G
+
vs. 979±15 ms G
+
; p = 0.04). No significant differences were found in post-contrast T1, sECV, or native T2. Atypical LGE patterns were noted in 5/18 G
+
vs. 0/19 G
+
(p = 0.02).

Conclusion:
Elevated native T1 and atypical LGE, perhaps due to subclinical fibrosis, were detected in G
+
patients with normal mass and volume and no overt clinical cardiomyopathy. Longitudinal follow up with larger cohorts will help assess the prognostic significance of these findings.
Combined Associations of Physical Activity and Particulate Matter With Subsequent Cardiovascular Disease Risk Among 5‐Year Cancer Survivors
Authors: Choi Daein , Choi Seulggie , Kim Kyae Hyung , Kim Kyuwoong , Chang Jooyoung , Kim Sung Min , Kim Seong Rae , Cho Yoosun , Lee Gyeongsil , Son Joung Sik , Park Sang Min
Published: May 2022

Background

The combined associations of physical activity and particulate matter (PM) with subsequent cardiovascular disease (CVD) risk is yet unclear.

Methods and Results

The study population consisted of 18 846 cancer survivors who survived for at least 5 years after initial cancer diagnosis from the Korean National Health Insurance Service database. Average PM levels for 4 years were determined in administrative district areas, and moderate‐to‐vigorous physical activity (MVPA) information was acquired from health examination questionnaires. A multivariable Cox proportional hazards model was used to evaluate the risk for CVD. Among patients with low PM with particles ≤2.5 µm (PM2.5; (19.8–25.6 μg/m
3
) exposure, ≥5 times per week of MVPA was associated with lower CVD risk (adjusted hazard ratio [aHR], 0.77; 95% CI, 0.60–0.99) compared with 0 times per week of MVPA. Also, a higher level of MVPA frequency was associated with lower CVD risk (
P
for trend=0.028) among cancer survivors who were exposed to low PM2.5 levels. In contrast, ≥5 times per week of MVPA among patients with high PM2.5 (25.8–33.8 μg/m
3
) exposure was not associated with lower CVD risk (aHR, 0.98; 95% CI, 0.79–1.21). Compared with patients with low PM2.5 and MVPA ≥3 times per week, low PM2.5 and MVPA ≤2 times per week (aHR, 1.26; 95% CI, 1.03–1.55), high PM2.5 and MVPA ≥3 times per week (aHR, 1.34; 95% CI, 1.07–1.67), and high PM2.5 and MVPA ≤2 times per week (aHR, 1.38; 95% CI, 1.12–1.70) was associated with higher CVD risk.

Conclusions

Cancer survivors who engaged in MVPA ≥5 times per week benefited from lower CVD risk upon low PM2.5 exposure. High levels of PM2.5 exposure may attenuate the risk‐reducing effects of MVPA on the risk of CVD.
Obesity, Galectin‐3, and Incident Heart Failure: The ARIC Study
Authors: Florido Roberta , Kwak Lucia , Echouffo‐Tcheugui Justin B. , Zhang Sui , Michos Erin D. , Nambi Vijay , Goldberg Ronald B. , Hoogeveen Ron C. , Lazo Mariana , Gerstenblith Gary , Post Wendy S. , Blumenthal Roger S. , Coresh Josef , Folsom Aaron R. , Selvin Elizabeth , Ballantyne Christie , Ndumele Chiadi E.
Published: May 2022

Background

Laboratory data suggest obesity is linked to myocardial inflammation and fibrosis, but clinical data are limited. We aimed to examine the association of obesity with galectin‐3, a biomarker of cardiac inflammation and fibrosis, and the related implications for heart failure (HF) risk.

Methods and Results

We evaluated 8687 participants (mean age 63 years; 21% Black) at ARIC (Atherosclerosis Risk in Communities) Visit 4 (1996–1998) who were free of heart disease. We used adjusted logistic regression to estimate the association of body mass index (BMI) categories with elevated galectin‐3 (≥75th sex‐specific percentile) overall and across demographic subgroups, with tests for interaction. We used Cox proportional hazards models to assess the combined associations of galectin‐3 and BMI with incident HF (through December 31, 2019). Higher BMI was associated with higher odds of elevated galectin‐3 (odds ratio [OR], 2.32; 95% CI, 1.88–2.86) for severe obesity ([BMI ≥35 kg/m
2
] versus normal weight [BMI 18.5‐<25 kg/m
2
]). There were stronger associations of BMI with elevated galectin‐3 among women versus men and White versus Black participants (both
P
‐for‐interaction <0.05). Elevated galectin‐3 was similarly associated with incident HF among people with and without obesity (HR, 1.49; 95% CI, 1.18–1.88; and HR, 1.71; 95% CI, 1.38–2.11, respectively). People with severe obesity and elevated galectin‐3 had >4‐fold higher risk of HF (HR, 4.19; 95% CI, 2.98–5.88) than those with normal weight and galectin‐3 <25th percentile.

Conclusions

Obesity is strongly associated with elevated galectin‐3. Additionally, the combination of obesity and elevated galectin‐3 is associated with marked HF risk, underscoring the importance of elucidating pathways linking obesity with cardiac inflammation and fibrosis.
IV Sotalol Use in Pediatric and Congenital Heart Patients: A Multicenter Registry Study
Authors: Malloy‐Walton Lindsey E. , Von Bergen Nicholas H. , Balaji Seshadri , Fischbach Peter S. , Garnreiter Jason M. , Asaki S. Yukiko , Moak Jeffrey P. , Ochoa Luis A. , Chang Philip M. , Nguyen Hoang H. , Patel Akash R. , Kirk Christa , Sherman Ashley K. , Avari Silva Jennifer N. , Saul J. Philip
Published: May 2022

Background

There is limited information regarding the clinical use and effectiveness of IV sotalol in pediatric patients and patients with congenital heart disease, including those with severe myocardial dysfunction. A multicenter registry study was designed to evaluate the safety, efficacy, and dosing of IV sotalol.

Methods and Results

A total of 85 patients (age 1 day–36 years) received IV sotalol, of whom 45 (53%) had additional congenital cardiac diagnoses and 4 (5%) were greater than 18 years of age. In 79 patients (93%), IV sotalol was used to treat supraventricular tachycardia and 4 (5%) received it to treat ventricular arrhythmias. Severely decreased cardiac function by echocardiography was seen before IV sotalol in 7 (9%). The average dose was 1 mg/kg (range 0.5–1.8 mg/kg/dose) over a median of 60 minutes (range 30–300 minutes). Successful arrhythmia termination occurred in 31 patients (49%, 95% CI [37%–62%]) with improvement in rhythm control defined as rate reduction permitting overdrive pacing in an additional 18 patients (30%, 95% CI [19%–41%]). Eleven patients (16%) had significant QTc prolongation to >465 milliseconds after the infusion, with 3 (4%) to >500 milliseconds. There were 2 patients (2%) for whom the infusion was terminated early.

Conclusions

IV sotalol was safe and effective for termination or improvement of tachyarrhythmias in 79% of pediatric patients and patients with congenital heart disease, including those with severely depressed cardiac function. The most common dose, for both acute and maintenance dosing, was 1 mg/kg over ~60 minutes with rare serious complications.
Age‐Related Associations of Low‐Density Lipoprotein Cholesterol and Atherosclerotic Cardiovascular Disease: A Nationwide Population‐Based Cohort Study
Authors: Jung Han Na , Kim Min‐Ju , Kim Hwi Seung , Lee Woo Je , Min Se Hee , Kim Ye‐Jee , Jung Chang Hee
Published: May 2022

Background

The relationship between low‐density lipoprotein cholesterol (LDL‐C) and atherosclerotic cardiovascular disease (ASCVD) according to age remains undetermined. Thus, this study aimed to investigate the age‐related association of LDL‐C and ASCVD.

Methods and Results

Data from the Korean NHIS‐HEALS (National Health Insurance Service‐National Health Screening Cohort) were analyzed. Individuals previously diagnosed with cardiovascular disease or taking lipid‐lowering drugs were excluded. Age‐specific association between LDL‐C and ASCVD was calculated using adjusted Cox proportional hazards models. During a median follow‐up of 6.44 years for 285 119 adults, ASCVD developed in 8996 (3.2%). All age groups showed positive associations between LDL‐C and ASCVD risk, mostly with statistical significance from LDL‐C of 160 mg/dL onward. ASCVD risk did not differ significantly between the age groups (
P
for interaction=0.489). Correspondingly, subgroup analysis in type 2 diabetes exhibited no difference in the age‐specific association of LDL‐C and ASCVD (
P
for interaction=0.784).

Conclusions

The study demonstrated that people aged ≥75 years with higher LDL‐C at baseline still presented increased ASCVD risk, which was not significantly different from the younger groups. These findings support the importance of managing LDL‐C for the prevention of primary ASCVD in the growing elderly population.
New species and records of Caenidae Newman, 1853 (Insecta: Ephemeroptera) from Northeastern Brazil
Authors: NASCIMENTO STÊNIO R. S. , RODRIGUES JACKSON A. O. , ALE-ROCHA ROSALY , LIMA LUCAS R. C.
Published: May 2022

New distributional records for four species and the description of a new species of Caenis Stephens from Parnaíba River Basin, in a semiarid region of the state of Piauí, Northeastern Brazil are given. Characters and illustrations to distinguish Caenis marataoan sp. nov. from all other species in Caenis are provided. The new species can be distinguished by the following combination of characters: 1) body length of male 1.5–2.0 mm, female 2.5–2.8 mm; 2) base of antennal flagellum not dilated; 3) forceps apically rounded, covered with trichomes and with 2–3 minute spines at apex; 4) styliger plate short with posterior margin convex; 5) penis fused and not laterally projected; 6) eggs oval-shaped; micropyle linear with narrow and long micropylar canal, preceded by an oval sperm guide.
Importance of Mesoscale Currents in AMOC Pathways and Timescales
Authors: Kamenkovich Igor , Garraffo Zulema
Published: May 2022

The Atlantic meridional overturning circulation (AMOC) plays a key role in climate due to uptake and redistribution of heat and carbon anomalies. This redistribution takes place along several main pathways that link the high-latitude North Atlantic with midlatitudes and the Southern Ocean and involves currents on a wide range of spatial scales. This numerical study examines the importance of mesoscale currents (“eddies”) in these AMOC pathways and associated time scales, using a highly efficient offline tracer model. The study uses two boundary impulse response (BIR) tracers, which can quantify the importance of the Atlantic tracer exchanges with the high-latitude atmosphere in the north and with the Southern Ocean in the south. The results demonstrate that mesoscale advection leads to an increase in the overall BIR inventory during the first 100 years and results in a more efficient and spatially uniform ventilation of the deep Atlantic. Mesoscale currents also facilitate meridional spreading of the BIR tracer and thus assist the large-scale advection. The results point toward the importance of spatial inhomogeneity and anisotropy of the eddy-induced mixing in several mixing “hotspots,” as revealed by an eddy diffusivity tensor. Conclusions can be expected to assist evaluations of eddy-permitting simulations that stop short of full resolution of mesoscale, as well as development of eddy parameterization schemes.
How do trade unions manage themselves? A study of Australian unions’ administrative practices
Authors: Bamber Greg J , Jerrard Marjorie A , Clark Paul F
Published: May 2022

Dedication

We gratefully acknowledge the invaluable contributions to the research that we discuss here by our dear friend and colleague the late Dr Sandra Cockfield; we miss her greatly. We dedicate this article to her. For a tribute to her see www.monash.edu/vale/home/articles/vale-dr-sandra-cockfield .

The article discusses issues rarely addressed in research on Australian unions: the internal management policies and practices of unions, including human resource management, budgeting and strategy formulation. Management matters because it creates processes and systems that focus activity on whatever objectives a union or other organisation wishes to achieve. Our main research question is ‘how do Australian unions manage their employees, budgets, and strategies?’ Our study builds on earlier studies of US, UK and Canadian unions by adapting a survey instrument used in these countries. The Australian Council of Trade Unions (ACTU) asked national and branch unions to complete our online surveys. Of the unions surveyed, a majority of respondents use systematic human resource management policies and practices. They have also adopted strategic planning and budgeting practices. Echoing international findings, Australian unions have increasingly professionalised their administration. These findings are important since they have implications for how Australian unions deal with the challenges they face, including their revitalisation efforts and their responses to changing regulatory contexts.
A Brief Relationship Education Pilot Intervention for Men Post Release
Authors: Negash Sesen , Roberson Patricia N. E. , Tadros Eman , DeJesus Shannon Y.
Published: May 2022

Romantic relationships are often fraught with challenges for individuals post-release. Yet, few relationships-focused services are offered during this important and complex transitional period. Using pre- and post-test survey data, this pilot study of 63 men living in a residential substance treatment facility post release evaluated the impact of a 20-h individual-oriented relationship education (RE) program (Within My Reach) on attitudes toward intimate partner violence (IPV), sexist beliefs, attitudes toward infidelity, relational efficacy, and relationship decision making. Results showed a significant decrease in support of IPV at pre- and post-test even after controlling for education, number of children, and relationship status.
Relationship Expectations, Behavior Interactions and Commitment: A Dyadic Study Among Dual-Earner Couples
Authors: Harel Tal , Koslowsky Meni
Published: May 2022

Previous researchers have analyzed the links between relationship expectations and commitment in cohabiting and married couples. The present study examines a dyadic model where couple’s reported behavior interactions (RBI) are suggested as potential mediators and Work-Family Conflict (WFC) as a moderator. The association among these variables was tested by recruiting 111 ( N = 222) dual-earner couples to complete questionnaires. To examine the dyadic model, we used the Actor-Partner Interdependence Model on the hypothesized model. The results showed that actor’s RBI was seen as a significant mediator of the associations between relationship expectations and both partner’s commitment. The partner’s affective behavior interactions emerged as a significant mediator between the actor’s expectations-actor’s commitment link but not with the partner’s commitment. In addition, actor’s WFC significantly moderated the effect of partner’s RBI on their commitment. These findings extended our knowledge of possible factors that play a role in promoting relationship commitment among dual-earners couples in long-term relationships. Through the integration of the Investment Model this study illuminates the pathways by which relationship expectations affect commitment via RBI of married and cohabiting couples. Furthermore, the study elucidates the behavioral component of cohabiting couples in long-term relationships from a dyadic perspective. From a practical perspective, clinicians and counselors working with couples experiencing relational difficulties, may want to inquire as to their clients’ relationship expectations and behavior interactions for better understanding commitment among couples.
Introduction: Generating concepts of ‘the urban’ through comparative practice
Authors: Robinson Jennifer
Published: May 2022

This Introduction to the special issue, ‘ Comparative Methods for Global Urban Studies’, outlines the basis for a reformatted comparative method inspired by the complex spatialities of the urban world. The articles in the volume each bring forward innovative approaches to comparative methods which support wider conceptualisations of urban processes and urban experiences. The articles in this volume consider a wide range of urban contexts and collectively move beyond geopolitically imprecise propositions of ‘southern’ urbanism to embrace the wider comparative agenda of thinking with both the diversity and the profound interconnectedness of the urban globally. The articles contribute to decentring urban studies, opening conceptualisation to a range of different contexts and differently positioned writers. They also speak to the analytical and methodological challenges posed by current trends in global urbanisation, as dispersed, fragmented and extending over vast territories. Thinking with the multiple elsewheres of any urban context invites a comparative imagination – this introduction draws together the creative ways in which authors in this volume have responded to this potential. Processes of conceptualisation both emerge from and more acutely reveal the spatiality and nature of the global urban: comparative method, then, also proposes a certain mode of theorisation of the urban.