bluuebunny/crossref_metadata_2025 huggingface dataset:
Função social da propriedade ou especulação imobiliária? A aplicação dos instrumentos de ordenamento territorial no município de São Paulo entre 2014 e 2019
Authors: Alves José Diego Gobbo
Published: July 2021

Partindo da atuação dos diferentes agentes que produzem o espaço urbano, o propósito do artigo é analisar a aplicação dos instrumentos de gestão urbana no município de São Paulo, especificamente, o Parcelamento, Edificação ou Utilização Compulsórios (PEUC) e o Imposto sobre a Propriedade Predial e Territorial Urbana (IPTU) progressivo no período de 2014 e 2019. Para a realização do objetivo, foi elaborado um mapeamento da distribuição das notificações de imóveis considerados ociosos pela prefeitura, bem como uma revisão bibliográfica sobre o processo de especulação recente no município, visando subsidiar os resultados encontrados no mapeamento temático. Foram encontradas 1.425 notificações realizadas pelo poder público municipal à proprietários de lotes que no entender do poder público não cumpriam a função social da propriedade. Os territórios administrativos das prefeituras regionais da Sé, Mooca e Ipiranga, respectivamente, foram os que concentraram maior número de notificações. A hipótese resultante deste estudo é a de que, no período analisado, a aplicação dos instrumentos de ordenamento territorial no município contribuiu para o cumprimento da função social da propriedade e da cidade e, contraditoriamente, tendeu a estimular a atuação do capital imobiliário em áreas de recente atratividade de capital. Este artigo contribui para as discussões acerca das relações entre o poder público municipal e o capital imobiliário, principalmente, no que tange aos nexos territoriais que conectam e expressam as intencionalidades dos agentes produtores do espaço urbano.
Considerações sobre a gênese do vale suspenso do alto Rio Preto na borda da Bacia de Resende
Authors: Rezende Éric Andrade , Salgado André Augusto Rodrigues
Published: July 2021

O presente trabalho tem como objetivo investigar a gênese do vale suspenso do alto rio Preto, levando em conta seu posicionamento na borda de um rifte continental e sua proximidade com o divisor hidrográfico entre as bacias dos rios Grande e Paraíba do Sul. O alto curso do rio Preto localiza-se na Serra da Mantiqueira e estabelece a divisa entre os estados de Minas Gerais e Rio de Janeiro. A investigação teve foco na identificação de possíveis anomalias de drenagem ou controles litoestruturais e tectônicos que pudessem estar associados à formação do vale suspenso. Para isso, foi empregada a análise de modelos digitais de elevação em conjunto com perfis topográficos, mapas geológicos e observações de campo. Evidências geomorfológicas indicam que a depressão intramontana na qual se aloja o alto vale do rio Preto teve sua gênese associada primordialmente a causas erosivas e não a um escalonamento de origem tectônica que teria afetado a Serra da Mantiqueira. O vale suspenso pode ser interpretado como um produto da retração erosiva da borda de falha da Bacia de Resende, que localmente teria culminado em uma captura fluvial. Para a ocorrência do fenômeno, foi fundamental o paralelismo existente entre o rio Preto e a escarpa da Serra da Mantiqueira, assim como a presença de uma zona de falhas aproximadamente perpendicular à escarpa. A gênese do vale suspenso por meio de uma captura fluvial reafirma o relevante papel dos rearranjos de drenagem na evolução de flancos de rifte.
Melhoria da qualidade do cuidado à sífilis gestacional no município do Rio de Janeiro
Authors: Cerqueira Brena Gabriella Tostes de , Silva Eliane Pereira da , Gama Zenewton André da Silva
Published: July 2021

OBJETIVO Analisar o efeito de uma intervenção multifacetada no cuidado das gestantes com sífilis na atenção primária à saúde. MÉTODOS Trata-se de projeto de melhoria da qualidade realizado em 26 unidades básicas de saúde do município do Rio de Janeiro, entre janeiro e dezembro de 2017. O desenho foi quase-experimental misto, com análises anteriores, posteriores e de série temporal. Avaliou-se o cuidado prestado a todas as gestantes com sífilis e pré-natal encerrado no período, mediante dez critérios de qualidade e um indicador. A intervenção foi multifacetada, abrangendo educação permanente, melhoria dos registros e sistemas de informação, auditoria e feedback, educação do paciente, mudanças organizacionais e nos processos de trabalho. Estimaram-se as melhorias absoluta e relativa dos critérios e sua significância estatística (α = 5%). Os facilitadores e dificultadores da intervenção foram analisados segundo o Model for Understanding Success in Quality. RESULTADOS Após a intervenção, observou-se melhoria absoluta total de 6,7% (64,4% versus 71,0%) e relativa de 28,8% (p > 0,05). Oito dos dez critérios de qualidade tiveram melhoria, sendo esta significativa em quatro deles (p < 0,05). O indicador mensal de tratamento adequado também melhorou (p < 0,05), porém manteve baixo desempenho em todo o projeto. Destacou-se positivamente o aumento da conformidade do esquema de tratamento com o protocolo (91,4% versus 99,1%), porém as principais oportunidades de melhoria foram a testagem (42,8% versus 48,5%) e o tratamento das parcerias sexuais (42,8% versus 44,2%). Pressões regulatórias para melhorar o indicador mensal e a crise político-econômica vivenciada pelo município modularam o efeito da intervenção. CONCLUSÃO O projeto foi útil para identificar prioridades e orientar intervenções para a melhoria da qualidade da assistência à sífilis, embora ainda exista ampla margem para avanços. Os problemas identificados, bem como os moduladores contextuais do efeito, devem ser considerados em futuras intervenções.
Saúde do idoso e atenção primária: autonomia, vulnerabilidades e os desafios do cuidado
Authors: Carneiro Jeane Lima e Silva , Ayres José Ricardo de Carvalho Mesquita
Published: July 2021

OBJETIVO: Compreender as relações entre a autonomia e processos de saúde-doença-cuidado do idoso no cotidiano da atenção primária à saúde. MÉTODOS: Investigação qualitativa desenvolvida em 2019, em uma unidade básica de saúde da região central da cidade de São Paulo, utilizando observação participante e entrevistas em profundidade com 16 profissionais de saúde e 8 idosos. A construção e interpretação das narrativas produzidas no estudo foram orientadas pela perspectiva da hermenêutica filosófica de Gadamer e a teoria da interpretação de Ricoeur. O quadro teórico da vulnerabilidade/Cuidadoᵃ, tal como proposto por Ayres, orientou a definição do desenho do estudo e das categorias interpretativas. RESULTADOS: Estreitamente relacionada às dificuldades, facilidades e estratégias de enfrentamento dos desafios diários na atenção à saúde do idoso, a autonomia mostrou-se um importante marcador de vulnerabilidade (interpessoal, social e programática), indicando áreas que requerem atenção especial, como dispensação de medicamentos, mobilidade urbana, isolamento social, fragilidades financeiras e adequação das rotinas dos serviços. CONCLUSÃO: Distintamente de um atributo individual, a autonomia revelou-se expressão de características relacionais, exigindo estratégias, técnicas e horizontes prático-morais plurais e flexíveis, embora sempre orientados pelo mesmo compromisso ético de respeito às necessidades singulares dos indivíduos.
Matrix Embedding Alters the Immune Response Against Endothelial Cells In Vitro and In Vivo
Authors: Methe Heiko , Nugent Helen M. , Groothuis Adam , Seifert Philip , Sayegh Mohamed H. , Edelman Elazer R.
Published: July 2021

Background—

Endothelial cell (EC) dysfunction represents the first manifestation of atherosclerotic disease. Restoration of endothelium via seeding or transfection is hampered by local alterations in flow, inflammation, and metabolic activation. Perivascular EC matrix implants are shielded from these forces and still control vascular repair. The host immune response to such implants, however, remains largely unknown. We investigated the effect of embedding of ECs within 3-dimensional matrices on host immune responses in vitro and in vivo.

Methods and Results—

We compared expression of major histocompatibility complex (MHC), costimulatory, and adhesion molecules by free aortic ECs or ECs embedded in Gelfoam matrices by flow-cytometry. T-cell proliferation was assessed by [
3
H] thymidine incorporation. Humoral immune response (ELISA and FACS analysis) and cellular (histopathology) infiltration were investigated after subcutaneous injection of free porcine aortic ECs (PAEs) or of a Gelfoam/EC block, or after concomitant injection of PAEs adjacent to Gelfoam in rats. Aortic ECs embedded in Gelfoam expressed lower levels of MHC class II, costimulatory, and adhesion molecules compared with free ECs (
P
<0.001), and induced 3-fold less proliferation of human CD4
+
T-cells (
P
<0.0005). Implantation of a Gelfoam/EC block in rats nearly abrogated the immune response with 1.75- to 9.0-fold downregulation in tumor necrosis factor-α, interleukin-6, monocyte chemotactic protein-1, and PAE-specific immunoglobulin G (
P
<0.005) and 3.3- to 4.5-fold reduction in leukocytic tissue infiltration. Injecting PAEs adjacent to Gelfoam induced a significant response comparable to that of free implanted PAEs.

Conclusions—

Embedding ECs within 3-dimensional matrices alters the host immune response by inhibiting expression of MHC class II, costimulatory, and adhesion molecules, offering the rationale to develop novel therapies for vascular diseases.
Abstract 128: Short-Term, High-Saturated and Trans Fatty Acid Diet Increases Expression of Key Intestinal Genes Involved in Lipoprotein Metabolism in Healthy Males
Authors: Tremblay André J , Lamarche Benoit , Guay Valerie , Lemelin Valery , Couture Patrick
Published: July 2021

Dietary saturated fat (SFA) and trans fatty acids (TFA) have been linked to an increased risk of cardiovascular disease mainly by increasing plasma LDL-C levels. The modulation of cholesterol and fatty acids homeostasis by SFA and TFA is thought to be mediated by changes in expression of key intestinal genes involved in lipid and lipoprotein metabolism. However, the short-term impact of dietary fat intake on expression of these genes has not been fully investigated. To test whether short-term changes in SFA and TFA intake affects expression of key intestinal genes involved in lipid and lipoprotein metabolism, we conducted a randomized, double-blind, cross-over study using an intensive dietary modification in 12 nonobese healthy men with normal plasma lipid profile. Participants were subjected to 2 isocaloric 3-day diets: 1) high-fat diet (37% energy from fat, 15% from SFA, 3.5% from TFA and 50% energy from carbohydrate) and 2) low-fat diet (25% energy from fat, 6% from SFA, 0% from TFA and 62% energy from carbohydrate) in random order, each separated by a two-week washout period. Fasting plasma lipid levels were determined and expression of key genes involved in lipid and lipoprotein metabolism was compared by real-time PCR quantification in duodenal biopsy specimens obtained in the fasted state after 3 days of feeding on each diet. Following the 3-day high-fat diet, plasma-C (+7.4%, P=0.02), LDL-C (+16.9%, P=0.005) and HDL-C (+9.3%, P=0.002) levels were significantly increased as compared to low-fat diet. Plasma triglycerides (-31.7%, P=0.001) and apolipoprotein B-48 (-39.6%, P=0.003) levels were significantly decreased after the high-fat diet relative to the low-fat diet. The high-fat diet also resulted in significant increases in intestinal mRNA expression levels of SREBP-2, HNF-4α, PPAR-α, PPAR-γ, NPC1L1, ABCG8, FABP-2, ACAC-α, SCD-1, ELOVL5, DGAT-2, apolipoprotein B, MTTP, SAR1β and LDL receptor. These findings suggest that short-term exposure to a high-SFA and TFA diet upregulates the expression of key genes involved in lipid and lipoprotein metabolism at the enterocyte level.
Abstract 134: A Double Heterozygote for LCAT and ABCA1 Mutations Accounts for Severe Hypoalphalipoproteinemia
Authors: Patel Shailesh B , McIntyre Adam , Hegele Robert A
Published: July 2021

We report a family with extremely depressed high density lipoprotein (HDL) cholesterol (C) levels. The proband, a 27 year-old male of Asian Indian origin, was identified on routine lipid screening to have an HDL-C of 9mg/dL. His 24 year-old brother had an HDL-C of 6mg/dL and was therefore referred to a local lipid clinic in 1997. Both brothers were asymptomatic. The nuclear family was comprised of another brother and a mother living in India; their father had died previously from an undetermined cause. The parents were second cousins. Blood was obtained from members of the extended family and showed that the mother’s HDL-C was reduced at 29mg/dL, while the 3rd bother had a normal HDL-C at 54mg/dL. Based on the above scenario, a homozygous mutation most likely involving ABCA1 was presumed to be responsible for this lipoprotein profile. However, microsatellite marker analyses of the ABCA1 locus showed no homozygosity pattern in the two affected brothers. Further analyses of the APOA1-C3-A4 locus similarly failed to show homozygosity in the affected brothers. Plasma activities of both salt-stimulated paraoxanase and LCAT were at the low end of normal. Direct sequence analyses of the LCAT gene showed all three brothers were heterozygous for the Arg423His mutation, while the mother’s LCAT gene sequence was normal. No further work was pursued until 2011, when this family’s DNA was re-examined by direct sequencing. On this occasion, a heterozygous mutation in ABCA1 was found, namely Arg1270X in the 2 affected brothers and their mother. To our knowledge, this is the first report of ’double heterozygosity’ for LCAT and ABCA1 mutations producing severe hypoalphalipoproteinemia. Further, simple heterozygosity for the ABCA1 Arg1270X mutation had a co-dominant influence, moderately reducing HDL-C levels. In contrast, simple heterozygosity for the LCAT Arg423His mutation had no effect on HDL-C, but in the presence of ABCA1 Arg1270X it contributed to markedly reduced HDL-C. This case report highlights a potential pitfall in human genetic studies, namely assuming a particular inheritance pattern based upon family structure. It also highlights the value of perseverance by searching for causative mutations in more than one gene.
Abstract 141: APOA1, CETP, and CILP2 Variants Modify the Lipid Response to Fenofibrate: Genetics of Lipid Lowering and Diet Network
Authors: Aslibekyan Stella , Irvin Marguerite M , Frazier-Wood Alexis C , Straka Robert J , Borecki Ingrid B , Tiwari Hemant K , Tsai Michael Y , Hopkins Paul N , Ordovas Jose M , Mayer USDA HNRCA Jean , Arnett Donna K
Published: July 2021

Introduction:
Despite the widespread use of fibrates in treatment of dyslipidemia, the observed response is highly heterogeneous, suggesting a role for genetic determinants. Whether replicated variants associated with blood lipids identified by genome wide association studies (GWAS) are also associated with lipid response to fenofibrate is unknown.

Objectives:
To test if 95 genome-wide significant loci identified in a recent meta-analysis of blood lipids are associated with changes in high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, and triglycerides (TG) following 3 weeks of therapy with 160 mg of micronized fenofibrate.

Methods:
Using data from 861 European American Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) participants, we fit mixed linear models with baseline blood lipids and the post-to-pre fenofibrate treatment ratio of blood lipid levels as outcomes, the corresponding genetic markers from the published meta-analysis as predictors, and age, sex, pedigree, and ancestry as assessed by principal components as covariates. A Bonferroni correction was applied to adjust for multiple comparisons. Least square means were used to report the direction of fenofibrate-induced changes by genotype.

Results:
We observed statistically significant associations between
rs964184
, a variant near the APOA1 gene, and baseline HDL-C (P<0.0001) and baseline TG (P<0.0001), as well as with diminished response to fenofibrate as evidenced by a smaller increase in HDL-C (P<0.0001) and a smaller decrease in TG (P=0.0001) per each copy of the variant allele. Additionally, we report suggestive associations of rs3764261 locus in the CETP gene and the rs10401969 locus in the CILP2 gene with decreased fenofibrate response as measured by changes in LDL-C (P=0.0003 and 0.02, respectively) and non-HDL-C (P=0.004 and 0.005, respectively).

Conclusions:
We have identified several novel biologically relevant loci associated with baseline blood lipids and fenofibrate-induced changes in blood lipids.
Abstract 167: PLTP Acts in Concert with SAA to Reduce Plasma HDL Levels in Mice and Modulates Nascent HDL Formation in Hepatocytes
Authors: Ji Ailing , Wroblewski Joanne M , Webb Nancy R , van der Westhuyzen Deneys R
Published: July 2021

Phospholipid transfer protein (PLTP), which binds phospholipids and facilitates their transfer between lipoproteins in plasma, plays a key role in lipoprotein remodeling. PLTP levels increase during acute inflammation and increased PLTP activity is associated with the inflammatory markers C-reactive protein (CRP) and serum amyloid A (SAA) as seen in patients with type 2 diabetes and cardiovascular disease. SAA, an HDL apolipoprotein, is highly induced during inflammation. In this study we investigated whether HDL remodeling by PLTP is affected by SAA, and the significance of PLTP on HDL biogenesis. Over-expression of PLTP in mice using an adenoviral vector reduced HDL-C and phospholipid (PL) in a dose dependent manner with the liberation of lipid-poor apoA-I. Co-expression of PLTP and SAA produced a significantly greater reduction in HDL-C and PL than expression of either PLTP or SAA alone. Studies were carried out to examine the lipidation of apoA-I and formation of nascent HDL particles by primary mouse hepatocytes. Over-expression of PLTP in hepatocytes markedly affected the levels as well as the species of nascent HDL particles produced by cells. Although the formation of smaller nascent HDLs was reduced by PLTP, the formation of the larger HDLs was increased. PLTP expression in hepatocytes did not change ABCA1 levels. Co-expression of SAA with PLTP exerted only a modest effect on the levels and types of HDL generated in the presence of PLTP. Our findings suggest that the remodeling of plasma HDL by PLTP and SAA contributes to the reduced HDL-C levels observed during inflammation. PLTP also significantly affects apoA-I lipidation and nascent HDL biogenesis in hepatocytes.
Abstract 178: RCBTB1 Genotypes Modulate Smoking Effect on Carotid Intima-Media Thickness: A Finding from a Genome-Wide Interaction Analysis
Authors: Dong Chuanhui , Wang Liyong , Cabral Digna , Beecham Ashley , Blanton Susan H , Zhao Hongyu , Rundek Tatjana , Sacco Ralph L
Published: July 2021

Objective:
Smoking is an established risk factor for atherosclerotic disease. However, the degree of the cigarette smoking-induced damage varies from individual to individual, partly due to the between-individual difference in genetic makeup. The aim of this study was to identify genetic loci influencing the effect of cigarette smoking on carotid intima-media thickness (IMT) by performing a genome-wide association smoking-by-SNP interaction analysis.

Methods and results:
Genome-wide genotyping was performed using the Affymetrix SNP array 6.0 among 1,010 individuals who underwent B-mode ultrasound examination of carotid IMT from the population-based Northern Manhattan Study. Cigarette pack-years was calculated as number of years smoked multiplied by number of cigarettes smoked per day, then divided by 20. After quality control, a total of 722,379 single nucleotide polymorphisms (SNPs) were included in the final analysis. Generalized linear modeling was conducted to look for smoking-by-SNP interaction on carotid IMT while controlling for age, sex, hypertension, diabetes, dyslipidemia, body mass index, waist-to-hip ratio, and the top 3 principal components estimated to capture ancestry by EIGENSTRAT. Ten SNPs near or within 5 genes showed an interactive effect with cigarette smoking on IMT with a p value <1.0E-5. Among them, 3 SNPs (including 1 exonic splice enhancer SNP rs3751283, P=8.3E-7) are near or within regulator of chromosome condensation and BTB domain containing protein 1 (RCBTB1) gene on 13q14. Specifically, for SNP rs3751283, the mean IMT was substantially increased among CC-carriers (0.70 mm, 0.76 mm, 0.81 mm for 0, <20, and ≥20 cigarette pack-years, respectively, P=2.6E-6), slightly increased with smoking pack-years among TC-carriers (0.72 mm, 0.74 mm, 0.75 mm for 0, <20, and ≥20 cigarette pack-years, respectively, P=0.03), but very similar (0.73 mm) among TT-carriers for the three smoking groups (P=0.84).

Conclusion:
Our genome-wide interaction analysis reveals multiple genes, especially RCBTB1, that may modify the effect of smoking on carotid IMT. These genes will be further evaluated in our full dataset with additional genotyping. Also, larger independent studies are needed to validate these findings.
Abstract 182: Mitogen-Activated Protein Kinase Phosphatase-1 and the Redox Regulation of Monocyte Adhesion and Migration
Authors: Kim Hong Seok , Ullevig Sarah , Zamora Debora , Lee Chi Fung , Asmis Reto
Published: July 2021

Monocytic adhesion and chemotaxis are regulated by mitogen-activated protein kinase (MAPK) pathways, which in turn are under the control of MAPK phosphatases (MKPs). MKPs have an oxidation-sensitive cysteine residue in their active site. We recently reported that thiol oxidative stress induced by metabolic disorders enhances monocyte recruitment into vascular lesions by increasing their responsiveness to chemoattractants. We therefore investigated whether the priming effect of metabolic stress on monocytes is mediated by inactivation of MKP-1. Blood monocytes isolated from diabetic mice showed a 55% reduction MKP-1 activity compared to non diabetic mice. Chronic exposure of human THP-1 monocytes to diabetic conditions induced by human LDL plus high glucose concentrations (LDL+HG) resulted in the loss of MKP-1 protein levels, the hyperactivation of Erk1/2 and p38 MAPK in response to MCP-1, and increased monocyte adhesion and chemotaxis. Knockdown of MKP-1 mimicked the priming effects of LDL+HG, including hyperactivation of Erk1/2 and p38 MAPK, and accelerated monocyte adhesion and chemotaxis, whereas MKP-1 overexpression protected monocytes from metabolic stress-induced priming. LDL+HG exposure also promoted S-glutathionylation of MKP-1. The proteasomal inhibitor MG132 prevented the loss of MKP-1 protein induced by metabolic stress, but increased levels of S-glutathionylated MKP-1, suggesting that S-glutathionylation targets MKP-1 for proteasomal degradation. Inhibiting LDL+HG-induced MKP-1 S-glutathionylation by overexpressing glutaredoxin 1 in monocytes prevented MKP-1 degradation and normalized monocyte adhesion and chemotaxis in response to MCP-1. Finally, transplantation of bone marrow from MKP-1-null mice into LDLR-null mice significantly increased macrophage recruitment into MCP-1-loaded Matrigel plugs implanted in these mice, mimicking the priming effects of metabolic disorders reported previously. In conclusion, metabolic stress promotes the inactivation of MKP-1 activity through S-glutathionylation and subsequent proteasomal degradation. Loss of MKP-1 activity primes blood monocytes and converts them into a hypermigratory, proinflammatory and proatherogenic phenotype.
Abstract 184: Aortic Pulse Wave Velocity Does Not Correlate with Flow Wave Velocity or Mean Arterial Pressure in Robust, in Vitro Cardiovascular Hemodynamic Simulation
Authors: Lillie Jeffrey , Mix Doran , Schwarz Karl , Chandra Ankur , Day Steven , Borkholder David
Published: July 2021

Introduction:
Arterial compliance is a marker for cardiac burden in atherosclerotic disease, with the pressure Pulse Wave Velocity (PWV) correlated to compliance. Current clinical practice employs pulsed wave Doppler to measure Flow Wave Velocity (FWV) as a surrogate of PWV. We hypothesized that PWV and FWV are not directly related and are affected by left ventricular ejection time (LVET). Furthermore, we proposed that aortic PWV is independent of mean arterial pressure (MAP) in the setting of isolated systolic hypertension.

Methods:
Using a physiologically accurate electromechanical cardiovascular simulator, two solid state manometer-tipped pressure transducers and two transit time flow sensors were located at the aortic root and at the aortic bifurcation. PWV and FWV were directly measured while individually varying contractility and thus LVET. The experiments were repeated at various systemic vascular resistances (SVR) and vascular compliances. Automated signal processing and data extraction techniques were used to calculate the key parameters.

Results:
As LVET increased, FWV decreased but PWV increased while MAP remained constant for a fixed SVR and compliance. (Figure 1) This trend held consistent at different SVR’s and compliances. The relationship of PWV and FWV with LVET appeared to be exponential and linear respectively. For a constant MAP, the associated PWV varied by up to 50m/s and FWV by up to 10m/s for a change in LVET of 225ms.

Conclusions:
In conclusion, our data shows that PWV and FWV appear to be inversely related. Our data also suggest that PWV and FWV are independent of MAP in the setting of isolated systolic hypertension. These findings suggest that FWV measured by pulsed wave Doppler may not be a simple surrogate for true PWV. Future work is needed to elucidate the hemodynamic principals governing the relationship between PWV and FWV.
Abstract 19: Single-Dose Extended-Release Niacin Acutely Attenuates HDL Reduction in the Setting of Experimental Oral Fat Challenge: A Possible Role of ANGPTL-3 and CETP Modulation
Authors: Usman M Haris U , Nakaya Kazuhiro , Qamar Arman , Nijjar Prabhjot , Gadi Ramprasad , Wolfe Megan , Nathanson Grace B , Rader Daniel J , Dunbar Richard L
Published: July 2021

Background:
High density lipoprotein (HDL-c) levels are inversely correlated with the development of atherosclerosis and are reduced postprandially. Niacin is the most potent elevator of fasting HDL-c but the mechanisms are not fully elucidated, and its effects on postprandial HDL-c are largely unknown.

Aim:
Our aim was to determine whether a single dose ER niacin before a fat challenge acutely attenuates the postprandial drop in HDL-c compared to placebo, and to determine whether angiopoeitin like protein 3 (ANGPTL3) and cholesterol ester transfer protein (CETP) contribute to increased postprandial HDL-c by niacin.

Method:
We conducted 2 postprandial studies in healthy volunteers: 1. a double-blinded, placebo-controlled, random-order crossover experiment comparing 2 grams of ER niacin to matching placebo, and 2. open-label administration of 1 gram of ER niacin compared to a fat load without niacin. Study drug was administered 1 hour prior to an oral fat load of heavy cream followed by serial plasma sampling for triglyceride (TG), apolipoprotein A-1 (Apo A-1), ANGPTL3, and CETP mass and activity, and HDL-c over 12 hours. Data are expressed as means (95% CI) for incremental (iAUC) or total (tAUC) area under the curve.

Results:
Study 1 involved 304 fat challenges in 152 subjects. As expected HDL-c dropped after the fat load alone, with an iAUC of -71.9 mg/dL*h (-65.1 to -78.6),whereas 1 gram ER niacin reduced the drop to -32.5 mg/dL*h (-25.6 to -39.3) a 55% difference (p<0.00001). In Study 2, 2 grams ER-Niacin mitigated the drop in HDLc more effectively: the iAUC was -19.0 (-35.7 to -2.3) on placebo vs. -2.1 (-18.8 to +14.6) mg/dL*h on niacin, an 89% difference ( p=0.047). ANGPTL3 iAUC was +2206 ng/mL*h (+1811 to +2602) on placebo vs. +2560 ng/mL*h (+2165 to +2955) on ER-niacin, a 16% rise (p=0.001). CETP activity decreased from an iAUC of +118.2 nmol/L*h (95%CI +90.5 to +146) to -15.7 nmol/L*h (95%CI -36.4 to +5.1) on niacin, so that the usual postprandial increase in CETP activity was abolished by niacin (p<0.00001). Postprandial TG tAUC was strongly inversely correlated with HDL tAUC (Spearman’s rho -0.62, p<0.00005).

Conclusions:
HDL-c decreases significantly in the setting of an experimental oral fat load. We found that one-time dosing with either 1 or 2 grams of ER-Niacin mitigated this decline in drug-naive subjects. Acute pharmacodynamic effects of ER-niacin including TG lowering, ANGPTL3 elevation and CETP suppression may play a mechanistic role in this process.
Abstract 192: A Hypothesis on Initiation of Coronary Atherosclerosis: The Role of Intimal Neovascularization and Proliferation. Do Lipoproteins Invade Coronary Tunica Intima from the Opposite Site?
Authors: Subbotin Vladimir M
Published: July 2021

Objectives
Tremendous success of statins in coronary atherosclerosis (CA) prevention offered great expectations for extended protection and effective therapeutics. However, stalled progress in pharmaceutical treatment gives a good reason to review whether the hypothesis underlining our efforts is consistent with undoubted facts on coronary artery in normal and diseased forms.

Analysis
An accepted hypothesis states that CA is initiated by endothelial dysfunction due to inflammation and high levels of LDL, followed by lipids and macrophage penetration into arterial intima and plaque formation. It is crucial to highlight that normal coronary
intima
is not a single-layer endothelium covering thin acellular compartment, as is commonly claimed in most publications, but always appears as a multi-layer cellular compartment, or diffuse intimal thickening (DIT), where cells are arranged in a few dozens layers. Since it is unanimously agreed that LDL invade DIT from lumen, the initial depositions ought to be most proximal to blood, i.e. in inner DIT layers. The facts show that the opposite is true, and lipids are deposited in the outer DIT. This contradiction is resolved by noting that normal DIT is always avascular, receiving oxygen and nutrients by diffusion from lumen, whereas in CA outer DIT is always neovascularized from adventitial
vasa vasorum
. Proteoglycan biglycan, confined to outer DIT of normal and diseased coronary, has high binding capacity for LDL. However, normal DIT is avascular, whereas in CA biglycan of outer DIT layers appears in direct contact with blood and extract lipoproteins. These facts explain patterns and mechanisms of CA initiation, which is not unique: normally avascular cornea accumulates lipoproteins after neovascularization, resulting in lipid keratopathy. The author offers a hypothesis on neovascularization. Cells in coronary DIT possess high proliferative capacity. Excessive cell replication increases DIT thickness, impairs diffusion, resulting in hypoxia of outer DIT. Hypoxia induces neovascularization of outer DIT layers, where biglycan extracts LDL from newly formed capillary bed, initiating CA.

Conclusion
Controls of cell proliferation and neovascularization in coronary DIT should be a priority of our research.
Abstract 220: Interleukin 17 Promotes Endothelial Activation and Neutrophil Recruitment Through Synergistic Action with Tumor Necrosis Factor α
Authors: Griffin Gabriel K , Newton Gail , Tarrio Margarite , Bu De-Xiu , Maganto-Garcia Elena , Grabie Nir , Luscinskas Francis W , Croce Kevin J , Lichtman Andrew H
Published: July 2021

Introduction:
Interleukin 17 (IL-17) is the signature cytokine produced by TH17 cells, a novel subset of pro-inflammatory CD4+ T cells. Prior studies have noted elevated serum IL-17 in patients presenting with acute coronary syndrome but little is known regarding the effect of IL-17 on endothelial (EC) activation, a key step in thrombosis and the process of leukocyte and platelet recruitment to sites of inflammation.

Methods and results:
We tested the hypothesis that IL-17 would induce a distinct pattern of EC activation and leukocyte recruitment when compared to the TH1 cytokine IFNγ. We found that activation of mouse heart EC with the combination of TNFα and IL-17 but not IFNγ had a synergistic effect on mRNA expression of P-selectin (2.6 fold over TNFα alone, p<0.01) and E-selectin (4.0 fold, p<0.01); as well as the CXCR2-ligands CXCL1 (29.0 fold, p<0.01), CXCL2 (15.2 fold, p<0.01), and CXCL5 (53.4 fold, p<0.05), which are highly chemotactic for neutrophils (PMN). Furthermore, EC activation with TNFα and IL-17 but not IFNγ had a synergistic effect on the level of PMN transmigration (46.9% versus 9.1% for TNFα alone, p<0.01) in a parallel-plate flow chamber model, which was prevented upon perfusion of PMN from CXCR2 (-/-) mice. In addition, TNFα and IL-17 had a synergistic effect on microvascular inflammation in vivo as determined by intravital microscopy of cremasteric leukocyte rolling velocity (8.9 μm/s versus 23.9 μm/s for TNFα alone, p<0.01) and perivascular infiltration (22.4 cells/field versus 13.9 cells/field, p<0.01) at 16hr after cytokine injection. By contrast, treatment with TNFα and IFNγ but not IL-17 induced the expression of ICAM1 (2.0 fold over TNFα alone, p<0.05) and VCAM1 (1.6 fold, p<0.01), as well as the T-cell chemokines, CXCL9 (187.4 fold, p<0.01), CXCL10 (2.9 fold, p<0.01), and CCL5 (2.6 fold, p<0.01). Accordingly, treatment with TNFα and IFNγ but not IL-17 preferentially enhanced the transmigration of effector CD4+ T cells under shear flow (41.9% versus 29% for TNFα alone, p<0.01).

Conclusion:
IL-17 and TNFα act in a synergistic manner to induce a pattern of EC activation that favors selective PMN recruitment to sites of inflammation, providing a potential link between IL-17 and risk of atherosclerotic plaque rupture and thrombosis.
Abstract 233: Quantification of Histological and Biomechanical Properties of Tissue-Engineered Vascular Graft in Inferior Vena Cava
Authors: Naito Yuji , Lee Yong-Ung , Yi Tai , Church Spencer N , Solomon Daniel , Humphrey Jay D , Shinoka Toshiharu , Breuer Christopher K
Published: July 2021

Background:
We developed the first tissue engineered vascular graft (TEVG) for use in congenital heart surgery and confirmed its significant potential via an initial clinical trial (Shinoka et al., JTCVS 2005). The primary complication of TEVG at medium term was stenosis attributed to suboptimal neovessel remodeling, which necessitated an investigation of the mechanics and mechanobiology to predict diverse aspects of the neovessel formation. Here we present the novel tools to investigate the evolving biomechanical properties of TEVG in a mouse inferior vena cava (IVC) replacement model.

Hypothesis:
The biomechanical properties of a TEVG evolve nonlinearly in time from a construct-dominated stiffness to a neovessel dominated stiffness. Novel biaxial biomechanical tests are required to quantify such changes rigorously.

Method:
Thirty-six CB17 SCID/beige mice were implanted with TEVG (PGA + P[CL/LA]) as IVC interposition graft. Twelve tissue engineered neovessels were harvested at 2, 6, and 12 weeks after implantation. Neovessels were characterized biomechanically using a custom, computer-controlled biaxial testing device, and compared with native veins. Extracellular matrix (ECM) remodeling of the neovessel was characterized histologically, biochemically, and molecular biologically.

Result:
The biaxial data revealed an improved compliance of the neovessel over time. Similarly, the axial stretch response of the TEVG became more like the native vein at 12 weeks. This response was quantified as a ratio of neo-vessel to native vein and improved to reach 52% at 12 weeks from 11% at 2 weeks. Scaffold mass in vivo, estimated by remaining scaffold on histology, showed a significant decline at 6 and 12 weeks. Gene expression of both type I and III collagen peaked at 2 weeks, and total collagen mass quantified by a Sircol™ assay revealed that total collagen peaked at 2 weeks but decreased gradually to the level of native vein. Gene expression of both tropoelastin and fibrillin-1 peaked at 2 weeks, whereas elastin mass quantified by Fastin™ assay showed a delayed peak level of elastin at 6 weeks. Gene expression of MMP-2 and 9 peaked at 6 and 2 weeks, respectively, implicating robust ECM remodeling at early time points.

Conclusion:
Our novel histo-mechanical approach is the first to show that neovessel formation is a dynamic process characterized by progressive degradation of the scaffold and increased ECM remodeling, which yields biomechanical properties of the TEVG similar to native vessel within 12 weeks in vivo.
Abstract 234: MyD88 and TRIF Mediate Divergent Responses Following Skeletal Muscle Ischemia
Authors: Sachdev Ulka , Cui Xiangdong , McEnaney Ryan , Tzeng Edith
Published: July 2021

Introduction:
We have shown that TLR2 mediates muscle regeneration and angiogenesis after muscle ischemia, independent of TLR4. Downstream signaling of TLR2 and TLR4 include MyD88 (TLR2 and 4) and TRIF (TLR4 and 3) pathways. We hypothesize that MyD88 is required for normal angiogenesis and muscle regeneration following ischemia while TRIF is not.

Methods:
MyD88
-/-
(KO), TRIF KO and control C57B6 mice (WT) (N=4-7) underwent femoral artery ligation on the right hindlimb, and sham operation on the left. LDPI was performed at day 14 and anterior tibialis muscle was collected to quantify muscle necrosis and regeneration. Vascular structures were identified with CD31 staining.

Results:
MyD88 KO and WT mice demonstrated partial perfusion recovery by 14 days while TRIF KO had minimal recovery. Despite this, there were significantly fewer vascular structures in MyD88 KO mice while TRIF KO had the greatest (17.9±1.5 MyD88 KO; 55.3±6.8 WT; 69.1±5.2 TRIF KO; p<0.01). TRIF KO exhibited marked muscle necrosis (43.1±19.9%) while WT and MyD88 KO had none (p<0.01) (Figure). Instead, WT had large areas of regenerating myocytes (95.8 ± 0.96%; p <0.01). Strikingly, MyD88 KO had almost no histologic evidence of ischemic injury with essentially normal muscle (85.3±12.6%, p<0.01).

Conclusions:
Contrary to our hypothesis, TRIF appears to be required for normal muscle regeneration and functional angiogenesis after ischemia, while MyD88 is an important mediator of hypoxic injury. These results, along with our prior findings that muscle regeneration is independent of TLR4, suggest that TLR3 may play a key role in ischemic muscle recovery independent of angiogenesis.
Abstract 246: Evaluation of 2-Dimensional Aortic Arch Motion at the Origin of the Left Subclavian Artery: Importance of Respiratory Motion
Authors: Arko Frank R , Perkins Keith D , Murphy Erin H , Corwin Lisa M , Curran Padraig M
Published: July 2021

Introduction:
Interactions between components of branched thoracic main stent grafts (MSG) and branch stent grafts (BSG) in the arch have not yet been evaluated. As the chest is subject to both cardiac and respiratory motion, the purpose of this study is to evaluate the cardiac and respiratory effects on interactions between components in the aortic arch.

Methods:
Two swine had a BSG alone placed in the LSA and two had an MSG/BSG system placed in the LSA. Frames representing the extreme positions of the BSG due to cardiac imposed motion during apnea and through the respiratory cycle were identified in 2-D cines. These images were overlaid as layers, using external reference markers common to each image for accurate overlay positioning. The BSG’s were traced and magnitudes of horizontal and vertical bulk displacements were quantified to evaluate cardiac (CM) and respiratory (RM) [deep inspiration (30 mmHg)]. Relative motion was extracted from bulk motion by comparing displacements at the top and bottom of the BSG.

Results:
RM resulted in significant difference in bulk horizontal motion compared to CM for the BSG [5.65
+
/
-
0.07 versus 3.15
+
/
-
0.63mm, (p=0.002)] and was nearly significant for the MSG /BSG system [4.25
+
/
-
0.07 versus 2.3
+
/
-
0.42mm, (p=0.061)]. RM resulted in significant difference in bulk vertical movement compared to CM for the BSG [2.2
+
/
-
0.28 versus 0.85
+
/
-
0.35mm, (p=0.026)] and the MSG/BSG system [2.05
+
/
-
0.07 versus 0.6
+
/
-
0 (p=0.000001)]. The MSG presence significantly dampened bulk horizontal movement for RM [4.25
+
/
-
0.07 versus 5.65
+
/
-
0.07mm, (p=0.0013)] but had no effect on vertical movement [2.05
+
/
-
0.07 versus 2.2
+
/
-
0.28mm, (p=0.15)]. RM resulted in significant difference in relative horizontal motion compared to CM for the BSG [4.25
+
/
-
0.49 versus 2.7
+
/
-
0.28mm, (p=0.014)] and the MSG/BSG system [1.85
+
/
-
0.07 versus 0.95
+
/
-
0.35mm, (p=0.0048)]. RM resulted in significant difference in relative vertical movement compared to CM for the BSG [1.25
+
/
-
0.07 versus 0.3
+
/
-
0.28mm, (p=0.002)] and MSG/BSG system [0.7
+
/
-
0.14 versus 0.25
+
/
-
0.21mm, (p=0.03)]. The MSG presence significantly dampened relative horizontal and vertical movement for RM [1.85
+
/
-
0.07 versus 4.75
+
/
-
0.49mm, (p=0.0004)] and [0.7
+
/
-
0.14 versus1.25
+
/
-
0.07mm, (p=0.02)], respectively.

Conclusions:
RM adds considerably to bulk and relative motion, with horizontal motion dominating. Relative motion accounts for high percentage of bulk motion. The presence of the MSG dampens motion considerably. This is the first study to account for the effects of respiratory motion on branched endografts in the aortic arch. This movement should be taken into account when developing a MSG/BSG for the therapy of aortic arch aneurysms.
Abstract 258: High-Efficiency Enrichment of Oxidized Phospholipid-Modified Peptides with C18 Solid Phase Extraction Column Facilitates Detection of Covalent Interaction Between Oxidized Phospholipids and Proteins
Authors: Gao Detao , Podrez Eugene
Published: July 2021

Oxidized phospholipids accumulate at sites of oxidative stress and contribute significantly to atherosclerosis, acute inflammation, lung injury and ischemia. Most of the oxidized phospholipids have electrophilic substituents and are highly likely to form covalent adducts with proteins thus compromising protein function. Detection of covalent interaction between oxidized phospholipids and proteins could provide important information about proteins preferentially modified by oxidized phospholipids in a relevant biological system, as well as, shed light on the mechanism of interaction between proteins and oxidized phospholipids. However, due to the relatively low levels of phospholipid protein adducts compared to unmodified proteins, such studies are challenging. We developed a high efficiency enrichment method for oxidized phospholipid-modified peptides that employs a C18 SPE column. Using this approach, in combination with LC-MS analysis, we studied the interaction of a synthetic oxidized phospholipid (9-keto-12-oxo-10-dodecenoic acid esters of 2-lysoPC, KODA-PC) with Apo-AI in HDL. We found that Lys45, His162, His193 and Lys208 are the major residues for covalent modification by oxidized phospholipids. According to the double superhelix model of HDL, these residues are located at both terminals of the double superhelix of Apo-AI. Thus the present study, for the first time, successfully detected oxidized phospholipids adducts of ApoA-I in HDL.
Abstract 273: Phenotypic Differences Between Human Subcutaneous and Perivascular Adipose Tissues
Authors: Mauro Christine R , Ilonzo Godfrey , Nguyen Binh , Yu Peng , Tao Ming , Gao Ian , Seidman Michael A , Nguyen Louis L , Ozaki C K
Published: July 2021

Objective:
Human adipose lies in specific anatomic depots. Peri-vascular adipose appears unique and impacts blood vessel biology, but direct human data is limited. In view of their theorized roles, we tested the hypothesis that human peri-vascular and subcutaneous adipose tissue hold distinct phenotypic signatures. We also evaluated the impact of clinical parameters on adipose phenotype.

Methods:
Fresh human peri-vascular and subcutaneous adipose tissues were collected intra-operatively from patients undergoing major lower extremity amputation (n=27) and assayed for protein levels of the adipose-associated mediators IL-6, IL-8, leptin, TNF-α, MCP-1, adiponectin, resistin and PAI-1.

Results:
Leptin (2.4 fold, p=0.045) and adiponectin (1.8 fold, p=0.007) were significantly more abundant in subcutaneous compared to peri-vascular adipose (Table I). Clinical data were used to model associations between clinical characteristics and mediator levels. Age positively correlated with peri-vascular PAI-1 expression (β=0.64, p=0.042), and hyperlipidemia negatively correlated with peri-vascular adipose adiponectin (β=-1.18, p=0.039).

Conclusions:
While significant similarity was observed between subcutaneous and peri-vascular adipose from leg amputation patients, the differential in adipose derived hormones leptin and adiponectin provides direct human evidence that these tissue compartments hold distinct biologic roles. Further investigation into the unique nature of peri-vascular adipose may provide meaningful guidance in managing peripheral vascular disease.
Abstract 279: Vitamin D3 Attenuates ADAM-12--Mediated Shedding of EGFR in Carotid Artery Smooth Muscle Cells of Hypercholesterolemic Swine
Authors: Kansal Vikash , Sur Swastika , Rao Velidi H , Agrawal Devendra K
Published: July 2021

Deficiency of Vitamin D is linked to an increased risk of hypertension, peripheral artery disease, and myocardial infarction and is a major risk factor for the development of human atherosclerosis. Atheromatous cytokines, including TNF-α, IL-6 and IFN-γ, and EGF receptor family growth factors are released at the site of atherosclerosis and act on proteolytic enzymes, MMPs (matrix metalloproteinases), ADAMs (a disintegrin and metalloproteinases), and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs). ADAM-12 activates EGFR resulting in increased migration and proliferation of smooth muscle cells (SMCs). The aim of this study was to examine the effect of vitamin D on IL-6-induced ADAM-12 expression and SMC migration and proliferation. Micro-swine were fed with either vitamin D-deficient high cholesterol diet or high cholesterol diet containing 900 IU of vitamin D for 6 months. After six months when serum cholesterol levels ranged from 500-600 mg/dL, vitamin D-deficient group continued on the same deficient diet, whereas the other group received supplementation of vitamin D (1,000 IU/d) for 6 months. The mRNA expression of ADAM-12 and EGFR in whole carotid artery and in IL-6-treated SMCs was quantified by qPCR. The proliferation was assayed by CyQuant NF cell proliferation assay. The mRNA transcripts of ADAM-12 and EGFR were significantly increased in carotid arteries from Vitamin D-deficient than in vitamin D- supplemented swine. Treatment of SMCs with IL-6 also increased the mRNA transcripts of ADAM-12 and EGFR in vitamin D-deficient swine SMCs compared to vitamin D-supplemented swine SMCs. The cell proliferation was higher in SMCs isolated from Vitamin D-deficient swine carotid artery compared to vitamin D- supplemented swine carotid artery. Together, these results suggest that Vitamin D regulates ADAM-12-mediated activation of EGFR and vitamin D deficiency further enhances proliferation of SMCs, which is potentiated by atheromatous cytokines.