bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 671: Glucagon-like Peptide-1 Inhibits Abdominal Aortic Aneurysm Development
Authors: Morimoto Keisuke , Okada Kenji , Yu Jie , Yu Zenhai , Okita Yutaka
Published: March 2022

Objective:
It has been shown that glucagon-like peptide-1 (GLP-1) signaling is protective effect in cardiovascular system. Thus, it is important to elucidate the underlying molecular mechanisms to develop a pharmacological treatment. We examined the effect of DPP-4 inhibitor (Alogliptin) and GLP-1 receptor analog (Lixisenatide) on AAA development.

Methods:
Thirty AAA model rats were divided into 2 groups: a control group (water) and alogliptin group (3 mg/kg/day). Alogliptin administration by gastric gavage was started at 7 days after aneurysm preparation. On day 14, plasma GLP-1 concentrations were measured with an ELISA. Furthermore we investigated the effect of lixisenatide to elucidate the role of GLP-1 signaling on AAA development, 42 rats were divided into 3 groups: a control group (saline), a low-dose group (10 μg/kg/day), and a high-dose group (100 μg/kg/day). Lixisenatide subcutaneous injection was started at 7 days after aneurysm preparation. Reactive oxygen species (ROS) expression in all groups was evaluated by dihydroethidium staining, and 8-hydroxydeoxyguanosine (8-OHdG) the oxidation product of DNA by immunochemical staining. The effect of GLP-1 signaling on the inflammatory response was also analyzed. Histopathological examinations were performed on day 28 and the AAA dilatation ratio was calculated.

Results:
On day 14, plasma GLP-1 concentrations were significantly increased by alogliptin (6.3 ± 0.8 pmol/L in Control group, 7.6 ± 0.9 pmol/L in Alogliptin group, p < 0.05). ROS expression and 8-OHdG-positive cells in aneurysm walls were significantly decreased by alogliptin and lixisenatide. They decreased ERK expression in Western blot analysis, and reduced mRNA expression of tumor necrosis factor-α and matrix metallo-proteinases. CD68 positive macrophages infiltration in aneurysm walls were also decreased with treatment. On day 28, alogliptin (199.2 ± 10.0 % in Control group, 155.1 ± 2.3 % in Alogliptin group, p < 0.01) and lixisenatide (188.0 ± 5.6 % in Control, 162.0 ± 6.0 % in Low-dose, and 151.5 ± 4.9 % in High-dose, p < 0.01) prevented aneurysm development.

Conclusion:
GLP-1 inhibits AAA development through anti-oxidant and anti-inflammatory effects, and it might be a potent pharmacological target for AAA treatment.
Abstract 687: Paracrine Function of Extracellular microRNA-191 in Diabetes Associated Impaired Wound Healing
Authors: Dangwal Seema , Stratmann Bernd , Bang Claudia , Lorenzen Johan M , Fiedler Jan , Kumarswamy Regalla , Falk Christine S , Scholz Claus J , Tschoepe Diethelm , Thum Thomas
Published: March 2022

MicroRNAs (miRNAs/miRs) stably circulate in blood and show biomarker potential under various pathological conditions. Additionally, miRNAs may exert paracrine effect upon cellular uptake.

This study profiles plasma miRNAs of diabetic patients and investigates the paracrine mechanism of miRNA mediated wound repair.

Plasma miRNAs and pro-inflammatory cytokines were profiled in type-2 diabetic patients with or without chronic wounds. Selected miRNA candidates were further validated in plasma samples obtained from controls (n=23), patients with PAD and chronic wound (PAD+W, n=27) or PAD alone (n=11) vs. that of 20 healthy controls by qRT-PCR. Inflammation mediated miRNA secretion and paracrine effects of released miRNAs on cellular functions were investigated in human endothelial or dermal cells respectively.

Differential levels of the circulating miRNAs in diabetic PAD+W patients were revealed in miRNA array profiling. Among 41 miRNA candidates, miR-191 levels significantly increased in PAD+W patients compared to diabetic controls, whereas lower levels were observed in diabetic vs. healthy controls. Circulating CRP and cytokine levels were also high in PAD+W patients compared to diabetic controls. miR-191 significantly correlated with CRP in diabetic patients.

Cytokine stimulation enhanced miR-191 secretion into culture supernatant from vascular endothelial cells. Moreover, co-culture assays maintained under pro-inflammatory stress demonstrated increased miR-191 levels in recipient dermal fibroblast cells when indirectly cultured with miRNA releasing endothelial cells compared to fibroblasts cultured alone. Luciferase reporter confirmed miR-191 binding to the 3’UTR of the ZO-1 transcript. miR-191 modulation in dermal fibroblasts inversely regulated ZO-1 expression and influenced scratch wound closure whereas in diabetic dermal microvascular endothelial cells, miR-191 overexpression compromised both tube formation and wound closure.

Circulating miRNA patterns are influenced by underlying inflammation associated with chronic wounds in type-2 diabetic patients and miR-191 modulates essential cellular functions in a paracrine manner by targeting ZO-1 during wound healing.
Abstract 688: Trans-10, Cis-12 Conjugated Linoleic Acid Induces a Lipodystrophic Phenotype and Browning of White Adipose Tissue in a Mouse Model of the Metabolic Syndrome
Authors: den Hartigh Laura J , Wang Shari , Goodspeed Leela , Chait Alan
Published: March 2022

Trans-10, cis-12 conjugated linoleic acid (10,12 CLA) is a naturally occurring dietary trans fatty acid reported to promote weight loss by unknown mechanisms. 10,12 CLA is associated with reduced adiposity, while simultaneously promoting inflammation, insulin resistance, and dyslipidemia. Commercially available CLA supplements containing 10,12 CLA are used to facilitate weight loss, so opposing effects on body weight and inflammation could put consumers at risk for adverse health effects. We therefore examined how 10,12 CLA reduces adiposity in an obese mouse model of the metabolic syndrome. Ldlr-/- mice consuming a high fat high sucrose diet with added cholesterol (HFHSC) supplemented with 1% 10,12 CLA are resistant to weight gain, have reduced body fat, and express genes associated with fatty acid oxidation in adipose tissue. They exhibit substantial fat loss from subcutaneous but not visceral adipose depots, in stark contrast to weight matched calorically restricted mice that maintain subcutaneous fat. Further, mice consuming 10,12 CLA do not show the expected improvements in glucose metabolism or plasma lipids despite carrying significantly less fat, consistent with what is seen with lipodystrophy. Additionally, subcutaneous and brown adipose tissue contain more macrophages in 10,12 CLA-supplemented mice than in control mice, suggestive of a pro-inflammatory state. Mice supplemented with 10,12 CLA also show signs of white adipose tissue “browning” with better maintenance of core body temperature upon cold exposure, both of which were absent in the weight matched control group. In summary, 10,12 CLA induces a lipodystrophic phenotype in obese mice with fat loss specifically from subcutaneous depots, resulting in negligible improvements in glucose tolerance, plasma lipids, and adipose tissue inflammation compared to weight matched controls. Despite substandard improvements in metabolic health and the lipodystrophic phenotype seen with 10,12 CLA, the notion that such a readily available compound could increase browning of white adipose tissue has therapeutic potential, and future studies could provide insight into mechanisms by which this browning potential could be harnessed while minimizing the detrimental effects of 10,12 CLA.
Abstract 691:
Arv1
Deletion Alters Fat Storage via Adipose-Extrinsic Mechanisms
Authors: Jarrett Kelsey E , Gupta Rajat , Billheimer Jeffrey T , Lagor William R , Rader Daniel J
Published: March 2022

ARE2 Required for Viability 1 (ARV1) is a transmembrane protein of the endoplasmic reticulum (ER) that is believed to promote intracellular sterol transport in yeast. Deletion of
ARV1
in yeast causes lipid accumulation in the ER, altered membrane structure, and constitutive activation of the unfolded protein response. This protein is conserved in mammals, and human ARV1 is known to rescue the growth and viability defects in
ARV1
deficient yeast. In previous work, we found that germline deletion of Arv1 in mice results in a 25% reduction in body weight, greatly reduced fat mass, increased energy expenditure, andimproved glucose tolerance. In the present work, we sought to test the hypothesis that loss of ARV1 activity in white and brown fat is responsible for the metabolic changes we observed. To test this, we utilized two different adipose-selective Cre drivers:
Adiponectin-Cre
and
Ap2-Cre
.
Adiponectin-Cre
mediated deletion was robust and highly specific to the white and brown fat, and had no impact on fat storage or blood glucose. In contrast,
Ap2-Cre
resulted in a substantial 53% decrease in
Arv1
mRNA in the brain (p < 0.05), accompanied by reduced fat mass and markedly improved glucose tolerance. The data suggest that mammalian ARV1 controls metabolic rate and fat storage through non-adipocyte tissues, most likely involving the central nervous system.
Abstract 699: Mitochondrial Aldehyde Dehydrogenase (aldh-2) Protects Against Lipopolysaccharide-induced Myocardial Contractile Dysfunction by Suppression of ER Stress via Regulation of Autophagy
Authors: Pang Jiaojiao , Xu Xihui , Zhang Yingmei , Chen Yuguo , Ren Jun
Published: March 2022

Lipopolysaccharide (LPS), a constituent of the outer membrane of Gram-negative bacteria, is the principal culprit factor responsible for the development of multi-organ failure including septic heart failure - a major contributor to increased mortality in patients with sepsis. However, there is still no efficacious treatment for septic cardiomyophathy. ALDH2 is well-known for its distinct beneficial role in cardiac pathologies including heart failure, ischemia and reperfusion injury. Little is known with regards to its effect on septic cardiomyopathy and the underlying mechanism. This study was designed to examine whether ALDH2 affects LPS-induced myocardial dysfunction and the underlying mechanism involved with a focus on ER stress and autophagy.

WT and ALDH2 transgenic mice were subjected to LPS (4 mg/kg, 4 h). Myocardial mechanical and intracellular Ca2+ properties were examined in FVB wild-type and ALDH2 transgenic mice using echocardiography and IonOptix SoftEdge techniques. Protein markers for ER stress, autophagy and related signaling molecules were evaluated. LPS compromised cardiac contractile function shown as reduced fractional shortening, peak shortening, maximal velocity of shortening/relengthening, prolonged relengthening duration and impaired intracellular Ca2+ homeostasis, associated with overt ER stress, upregulated autophagy, suppressed phosphorylation of Akt and its downstream signal molecule mTOR, the effects of which were attenuated by ALDH2. In vitro study revealed that the ER stress inducer tunicamycin exacerbated LPS-induced myocardial dysfunction, which was abrogated by the ALDH2 activator Alda-1 and the autophagy inhibitor 3-MA. Interestingly, the beneficial effect of Alda-1 was obliterated by the autophagy inducer rapamycin, Akt inhibitor AktI and mTOR inhibitor RAD001.

We conclude that ALDH2 protects against LPS-induced myocardial dysfunction possibly through suppression of ER stress and inhibition of autophagy.
Abstract 705: Coronary Artery Calcification and Cardiovascular Risk Factors in South Asians
Authors: Wang Serena , Mathur Ashish , Deo Vijaya , Kotrys Jeannette , Sathe Anita , Kakani Meena , Mehta Akhil , Molina César
Published: March 2022

Compared to other ethnic groups, South Asians are at higher risk for cardiovascular disease and diabetes mellitus. Traditional risk factor assessment, developed mainly in a white European-descent populations, may underestimate the incidence of cardiovascular disease in South Asians. Our study examined the relationship between coronary calcification, a strong predictor of cardiovascular events, and other traditional cardiovascular risk factors in South Asians. We analyzed the association of coronary calcification with both traditional and emerging factors commonly used to predict cardiovascular risk. These factors include the lipid panel (total cholesterol, LDL-C, HDL-C, and triglycerides), fasting blood glucose, high-sensitivity CRP, family history of coronary artery disease and diabetes, and the ACC/AHA-recommended atherosclerotic cardiovascular disease (ASCVD) risk score. We found that fasting blood glucose, glycated hemoglobin, insulin, BMI, and personal history of hypertension, hypercholesterolemia, and diabetes mellitus were all significantly associated with a non-zero calcium score. High-sensitivity CRP, the conventional lipid panel, the ASCVD risk score, and family history of coronary artery disease and diabetes were not. Because the lipid panel was not predictive while the glucose dysmetabolism risk factors were, the evaluation of South Asians should include and focus on pre-diabetic risk factors, such as fasting blood glucose, insulin, and hemoglobin A1c, and measurements of obesity.
Abstract 8: RNA-binding Protein Quaking Maintains Endothelial Barrier Function Through β-catenin and VE-cadherin
Authors: de Bruin Ruben G , Dane Martijn J , Lee Dae Hyun , Roeten Marko K , Schmidt Iris , Bijkerk Roel , van der Veer Eric P , de Boer Hetty C , Rabelink Ton J , van Zonneveld Anton Jan , van Gils Janine M
Published: March 2022

Endothelial barrier function plays a major role in the onset of atherosclerosis. This barrier is determined largely by adherens junctions. Remarkably little is known about their regulation at the post[[Unable to Display Character: ‐]]transcriptional level. We find that the RNA-binding protein Quaking (QKI), known for its function in embryonic blood vessel formation, is highly expressed in quiescent adult endothelial cells (EC) in vivo. In vitro, EC displayed increased levels of QKI when cultured under laminar atheroprotective flow. Using KLF2 overexpression and a human QKI promoter reporter gene, we found that KLF2 mediates this increase in QKI expression.

Subsequently we aimed to investigate the role of QKI in EC vascular integrity. Silencing of QKI markedly impaired (0.65 fold ±0.13; p<0.05) the capacity to form a high resistance endothelial monolayer, as measured using Electric cell-substrate impedance sensing. To confirm a role for QKI in maintaining EC barrier function in vivo, we measured Bradykinin-induced vascular leakage in QKI viable mice (QKIv), which express decreased levels of the QKI protein. Indeed, QKIv mice displayed a 20% (p<0.05) increase in extravascular accumulation of Evans blue-labeled albumin compared to wild type littermates. Interestingly, the mRNA of both β-catenin and VE-cadherin, the prime adhesion proteins in EC adherens junctions, contain conserved QKI-binding sites. Moreover the targeted reduction of QKI resulted in a reduction of β-catenin and VE-cadherin protein expression. Importantly, we identified a direct role for QKI in regulating mRNA biology of β-catenin and VE-cadherin, as RNA immunoprecipitation and luciferase-reporter assays revealed that QKI can directly bind to the mRNA and induces transcript translation, respectively. This effects was perturbed upon reduced QKI expression.

In conclusion, we show that QKI functions as a critical regulator of β-catenin and VE-cadherin in endothelial cells, and the modulation of QKI expression affects endothelial monolayer integrity, in vitro and in vivo. These studies provide novel insight into the importance of post-transcriptional regulation of components of the endothelial adherens junction, and may have wide ranging implications for the preservation of vascular integrity in disease.
Autosomal genomewide linkage scan for coronary artery calcification loci.
Authors: Lange Leslie A , Lange Ethan M , Bielak Lawrence F , Langefeld Carl D , Kardia Sharon L , Turner Steve T , Sheedy Patrick F , Boerwinkle Eric , Peyser Patricia A
Published: March 2022

P10

Coronary artery calcification (CAC), quantified by electron beam computed tomography, provides a measure of extent of coronary atherosclerosis in asymptomatic and symptomatic individuals. It is well recognized that coronary artery disease and CAC are complex processes that are influenced by many genetic and environmental factors. Several aspects of CAC quantity make genetic studies of it particularly challenging. These include the non-normality of CAC frequency distributions and the strong age- and sex-dependence of CAC levels. To search for regions that may contain genes influencing CAC quantity, a genome-wide scan was conducted on a sample enriched for hypertension from the Epidemiology of Coronary Artery Calcification Study. The genome-wide linkage scan was based on 370 anonymous markers spanning the 22 autosomal chromosomes in 29 families. The analysis sample consisted of 20 affected sib-pairs, 8 affected sib-trios and 1 family with 6 affected siblings. Here, affection status was defined as being above the 70th sex- and age-specific percentile based on a reference population. Mode-of-inheritance-free qualitative linkage analysis was used to analyze sib-pair data. Maximum multipoint lod scores were calculated using the computer software Genehunter-2. Weighted analyses were conducted using Holmans “possible triangle” constraint. The overall maximum lod scores were observed on chromosomes 6 (lod=2.22) and 10 (lod=3.24). Additional lod scores greater than 1.0 were observed on chromosomes 2, 14, 15 and 17. These results identify regions that may harbor genes involved in high sex- and age-specific levels of CAC (supported by HL46292).
Quantitative Genetics of Body Composition and Homeostasis Model Assessment (HOMA) Measures of Insulin Sensitivity and Beta-Cell Function
Authors: Towne Bradford , Rogers Nikki L. , Demerath Ellen W. , Czerwinski Stefan A. , Guo Shumei S. , Chumlea Wm. Cameron , Siervogel Roger M.
Published: March 2022

P12

Insulin resistance and impaired glucose tolerance often co-occur with overweight. Measures of insulin and glucose metabolism, and of adiposity, also have significant heritable components, and studies suggest that there are pleiotropic effects of genes on measures of adiposity and fasting insulin and glucose levels. Because clinical tests of insulin resistance and glucose tolerance are time consuming and expensive, however, the Homeostasis Model Assessment (HOMA; Matthews et al., 1985) has been used as a surrogate for direct measures of insulin and glucose metabolism in population-based epidemiological studies. The computerized HOMA (Levy et al., 1998) yields indices of insulin sensitivity (%S) and beta-cell function (%B) based on fasting insulin and glucose values, and has been validated against clinical measures. The goal of this study was to evaluate the utility of %S and %B in elucidating the genetic architecture of insulin and glucose metabolism and body composition. Maximum likelihood methods were used to analyze familial data from 645 adults aged 18-70 years from 124 kindreds participating in the Fels Longitudinal Study. Heritability estimates were 0.30 for both %S and fasting insulin, 0.17 for %B, 0.16 for fasting glucose, and 0.50 for BMI. The genetic correlations were -0.61 between %S and BMI, 0.62 between fasting insulin and BMI, 0.35 between %B and BMI, and 0.44 between fasting glucose and BMI. Although different in sign, the genetic correlations between %S and BMI, and fasting insulin and BMI, are essentially identical in magnitude. This is explained by the complete (i.e., 1.0) genetic correlation between %S and fasting insulin. That is, %S and fasting insulin are influenced by the same set of genes. The genetic correlations between %B and fasting insulin, and between %B and fasting glucose, however, are less than 1.0, indicating that %B is not completely regulated by the same set of genes that regulate either fasting insulin or glucose. Thus, %B may be a useful adjunct parameterization of insulin and glucose homeostasis in genetic epidemiological studies of insulin and glucose metabolism and body composition.
Estrogen Receptor Polymorphisms Associated With Enhanced Response of HDL to Estrogen Replacement Therapy in Postmenopausal Women
Authors: Herrington David M. , Howard Timothy , Florance Allison , Xu Jianfeng , Bleecker Eugene R. , Meyers Deborah A.
Published: March 2022

P14

HDL levels in women are highly heritable and also modulated by endogenous and exogenous estrogen. Several estrogen receptor polymorphisms (ERPs) exist, however, their influence on estrogen’s effects on HDL are unknown. To determine if ERPs modify the HDL response to estrogen replacement, we studied ERP genotypes and pre/post HDL levels in 274 unrelated women (mean age 65 years, 82% white)in the Estrogen Replacement and Atherosclerosis (ERA) trial. Associations between alleles of two single nucleotide polymorphisms(XbaI and PvuII) and follow-up HDL levels were examined after adjustment for baseline levels of HDL and age, diabetes, BMI, exercise, and alcohol intake. Results. See

table. Both PvuII and XbaI are in H-W equilibrium. XbaI is only 50 base pairs from PvuII, is in strong linkage disequilibrium with XbaI (p<0.0000), and shows a similar association with changes in HDL levels. Conclusion. This association study suggests a drug-gene interaction between estrogen and ERPs with respect to HDL levels. Confirmation in other populations and functional genomic studies are needed to fully determine the functional and clinical significance of these polymorphisms.

Table 1.
Genetic analysis of blood pressure and blood pressure response to orthostatic stress: are the same genes involded in both traits?
Authors: Siervogel Roger M. , Czerwinski Stefan A. , Maynard Leah M. , Wilson Alexander F. , Demerath Ellen E. , Guo Shumei S. , Rogers Nikki , Towne Bradford
Published: March 2022

P20

Aim: Our aim was to investigate genetic involvement in systolic and diastolic blood pressure (SBP and DBP) responses to orthostatic stress.Methods: Data from 453 members of 4 large kindreds, each ascertained through a white male with essential hypertension, were used. Blood pressures were measured seated, supine (SBP mean = 111mmHg and DBP mean = 68 mmHg), and at 1-, 2- and 3- minutes of 70-degree head-up tilt. A variance components analytical approach implemented in the SOLAR statistical genetic analytical package was used. Sex, age and age squared were covariates in all of the models. Bivariate analyses were conducted to examine pleiotropy between supine blood pressures with those at 1-, 2-, and 3-minutes of tilt. Likelihood ratio tests were used to evaluate different genetic models. Results: For SBP the covariates explained 10 to 15 percent of the phenotypic variance. Significant heritabilities were observed for seated and supine blood pressures; e.g., 0.29 and 0.31 respectively for SBP. Blood pressures resulting from the baroreceptor reflex response to arterial pressure change induced by tilt had comparable heritabilities; e.g., at 1-, 2- and 3-minutes post-tilt they were 0.24, 0.29, and 0.36, respectively for SPB. Similarly, the blood pressure response, the change in blood pressure from supine to tilt, had modest heritabilities of 0.08 (n.s.), 0.16, and 0.19 respectively for SBP, and 0.13, 0.08 (n.s.), and 0.16 for DBP. For both SBP and DBP, the bivariate models testing for pleotropy between the supine pressure and the pressure at each minute of tilt showed that there was no evidence for differential gene expression for blood pressure in these two conditions. Conclusions: Resting levels of blood pressure, the levels reached in response to orthostatic stress, and the actual change in blood pressure resulting from that stress are heritable. The genes that are involved in establishing the control of resting supine blood pressure do not differ from those that are involved in mediating the first 3 minutes of blood pressure response to an orthostatic stress of 70-degree head-up tilt (i.e., there is complete pleiotropy for these traits).
Coronary Calcification Detected by Electron-Beam Computed Tomography and Coronary Heart Disease: The Rotterdam Study.
Authors: Vliegenthart Rozemarijn , Oudkerk Matthijs , Song Bin , de Feyter Pim J , van der Kuip Deirdre AM , Hofman Albert , Witteman Jacqueline CM
Published: March 2022

P22

We examined the association between coronary calcification detected by electron-beam computed tomography (EBT) and the presence of myocardial infarction, stratified for gender and age. We performed a cross-sectional study among elderly subjects, participants from the population-based Rotterdam study. Baseline data were collected in 1990-1993. During the third examination phase (1998-2000), subjects were invited for EBT scanning to detect coronary calcification. Calcified lesions were quantified according to Agatston’s method. Calcium scores were available for 1874 of 2263 subjects who underwent EBT scanning. A history of myocardial infarction was defined as the occurrence of a myocardial infarction before baseline or during follow-up but before EBT scanning.Mean age (SD) of the 997 women and 877 men was 71 (5.7) years. The calcium score showed a graded association with the presence of myocardial infarction. Compared to the lowest calcium score category (0 - 100), the age-adjusted odds ratio for myocardial infarction in subjects with calcium score > 2000 was 9.2 (95% CI 4.7 - 18.3) for men, and 10.0 (95% CI 3.4 - 29.8) for women. Additional adjustment for cardiovascular risk factors hardly changed the estimates. The association remained present in subjects above 70 years of age. In conclusion, in this population-based study, a strong association between coronary calcification and myocardial infarction was present in both men and women, which remained present at high age. Although results from prospective data in unselected populations have to be awaited, this study suggests that EBT is a promising tool for the detection of subjects at high-risk of coronary events in the general population.
Aortic stiffness is associated with aortic and coronary calcification in older adults
Authors: Mackey Rachel H. , Sutton-Tyrrell Kim , Kuller Lewis H. , Naydeck Barbara L. , Newman Anne B.
Published: March 2022

P23

Aortic stiffness increases with age and blood pressure, even when the population prevalence of atherosclerosis is low. The extent to which atherosclerosis may exacerbate the aortic stiffening of aging remains unclear. Aortic stiffness was measured by carotid to femoral pulse wave velocity (PWV) and atherosclerosis by coronary artery calcification score (CCS) and aortic calcification score (ACS) by electron beam tomography in 484 participants (42% men, 23% black) aged 70-96 years (mean=79.4) from the Pittsburgh site of the Cardiovascular Health Study. The distributions of PWV (898, 851, 366-2183 cm/sec) (mean, median, range), CCS (676, 327, 0-4954) and ACS (5183, 3040, 0-57,950) were log-transformed when used as continuous variables. Median PWV and ACS were not different by gender but CCS was higher for men than women (median 637 vs. 187, p<0.01). Median PWV did not differ by race. Median CCS and ACS were higher in white participants (392 vs. 132; 3865 vs. 1154, p<0.01 for both). After adjustment for age and mean arterial pressure (MAP), PWV was higher for higher quartiles of CCS in women (792, 862, 854, 906, p for trend=0.02), but not men (879, 838, 888, 886, p for trend=0.67). Mean PWV was also higher by quartile of ACS (844, 918, 915, 942, p for trend=0.04) for the total group after adjustment for age, sex and MAP. When stratified by sex, the association was significant only for women (805, 861, 903, 933, p for trend=0.02), not men (910, 1021, 939, 966, p for trend=0.72). Similar results were found using linear regression with log CCS or log ACS as the independent variable, even after excluding participants with prevalent clinical disease. Race did not affect the associations. In these older adults, we found a cross-sectional association between aortic stiffness (PWV) and aortic and coronary calcification, independent of age and MAP, largely due to an association in women. The lack of association in these older men may be due to low power or survival bias. It will be important to determine whether aortic stiffness is an independent predictor of myocardial infarction and congestive heart failure, especially in conjunction with coronary calcification as a measure of atherosclerosis.
Continuous Relation in Risk Between Left Ventricular Mass and Cardiovascular Disease Incidence in African-Americans
Authors: Nunez Eduardo , Arnett Donna K. , Benjamin Emelia J. , Liebson Philip R. , Skelton Thomas N. , Tyroler H. A. , Taylor Herman , Szklo Moyses
Published: March 2022

P26

Objective: To determine the magnitude and the shape of the relation between left ventricular mass (LVM) and cardiovascular event (CVD) rates in African-Americans (AA). Background: Left ventricular hypertrophy on echocardiography is a powerful and independent CVD risk factor. Previous studies indicate a monotonic relation of increasing LVM index with increasing CVD rates in the general population (mostly whites). However, the relation between LVM index and incident CVD in AA has not been addressed. Methods: The Atherosclerosis Risk in Communities (ARIC) is an ongoing cohort study of CVD in 4 US communities. During the third visit, LVM was measured by echocardiography in AA from Jackson, MS (1,975 participants free of prevalent CVD, age range: 49-75, mean 58.9±1.5). Measurements were taken according to the ASE recommendations. LVM was calculated as (0.8[1.04((IVS+LVID+PWT)

3

-LVID

3

)]+ 0.6 g) and normalized by height

2.7

. Results: At a mean follow up of 2.95 years, range (0.03-4.4) there were 63 cardiovascular events (non-fatal MI= 19, fatal CHD= 8, non-fatal/fatal stroke= 30/8 and cardiac procedure= 4; 8 participants had more than one type of event) corresponding to an event rate of 1.08/100 patient-years. In the four quartiles of LVM index distribution (partition values: 38, 47, 57, and 162 g/m

2.7

), CVD rates were 0.33, 0.80, 0.83, and 2.51 per 100 patient-years respectively (p-value for trend= 0.002). After adjustment for traditional risk factors (age, gender, smoking, diabetes, hypertension, obesity and education level), the relative risk of developing CVD increased progressively along a continuum of LVM index values (RR 1.24/per each 10 g/m

2.7

, 95%CI 1.10-1.39). Conclusion: Our findings showed a linear, powerful, and independent relation between LVM index and cardiovascular risk in AA who were free from overt cardiovascular disease at the time of the exam. Echocardiographic estimation of LVM index may be a useful tool for assessment of total CVD risk in AA.
Periodontal Disease Was Mildly Associated With an Increased Mortality in 88,882 Men.
Authors: Lopez-Jimenez Francisco , Sesso Howard , Buring Julie , Gaziano J Michael
Published: March 2022

P32

We sought to investigate the association between periodontal disease (PD) and total and cardiovascular (CV) mortality in a large cohort of men. Methods: Of 104,388 men in the Physician s Health Study enrollment cohort, 88,882 who had no history of cancer, myocardial infarction, stroke or liver disease and provided information on PD were included in this analysis. A total of 10,264 patients reported history of PD. Results: During a mean follow-up of 5 years, 2,921 patients died, from which 1,461 had a CV death. The crude, age adjusted RR, showed an association between PD and total mortality (RR=1.31, C.I. 1.2-1.4, p<0.0001). Men with PD were more likely to have history of diabetes, hypertension, stable angina, diabetes, and past or current smoking, all with p<0.001. The association between PD and total mortality was substantially attenuated after adjustment for potential confounders (RR=1.14, C.I. 1.02-1.26, p=0.02). Smoking appeared to be an effect modifier because the crude RR between PD and mortality in current or past smokers (RR=1.33, C.I. 1.2-1.5, p<0.0001) was not significantly attenuated after adjustment for potential confounders (RR=1.25, C.I. 1.1-1.4, p<0.0005). A similar association was found with CV mortality, see

table. Conclusion: This prospective cohort study suggests that PD is associated with increased mortality, particularly among smokers. However, whether this mild association is real or only due to residual confounding remains to be clarified.

Table 1.
Menopausal status and current usage of oral contraceptives and hormone replacement therapy in relationship to soluble concentrations of adhesion molecules
Authors: Demerath Ellen W , Zeller Christine , Towne Bradford , Guo Shumei S , Chumlea Wm. Cameron , Siervogel Roger M
Published: March 2022

P35

Epidemiological studies have shown that hormone replacement therapy (HRT) generally reduces coronary heart disease mortality in post-menopausal women. A smaller number of reports also indicate that oral contraceptive (OC) use provides some cardioprotective effects. However, the mechanisms by which these commonly-used exogenous hormones affect the vascular system are not entirely known and comparisons to males are not always made. We measured the circulating concentrations of four inflammatory markers [intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin (ESEL), and P-selectin (PSEL)] in 281 healthy men and 307 healthy women (204 pre-menopausal, 103 post-menopausal) aged 18-85 years. Individuals were grouped according to sex, and in women, menopausal status (pre/post), OC use (yes/no), and HRT use (yes/no). The effects of these variables on adhesion molecule concentrations were examined using analysis of variance, adjusting for smoking, age, body mass index, and waist-hip ratio. The means shown are ± standard error and the values are in ng/ml. We found significantly higher mean ICAM-1 concentrations in post-menopausal women (358±15) than in pre-menopausal women (317±15) and men (295±10), p<0.01. ESEL was significantly higher in men (61±2) and post-menopausal women (63±3) than in pre-menopausal women (54±2), p<0.05. Similarly, there was a tendency for VCAM-1 and PSEL to be higher in post-menopausal women and men compared to pre-menopausal women, although these contrasts were not statistically significant. Among pre-menopausal women, OC users (N=59) had lower mean VCAM-1 and E-SEL concentrations than those not using OC (N=145)(VCAM-1: 494±47 vs. 644±29, p<0.001 and ESEL 42±4 vs..54±2, p<0.005). Among post-menopausal women, those using HRT (N=52) had lower ICAM-1 and VCAM-1 than those not using HRT (N=51) (ICAM-1: 342±26 vs. 408±24, p<0.05 and VCAM-1: 682±89 vs. 790±82, p=0.15). We conclude that current use of OC and HRT is associated with a beneficial effect on the expression of certain inflammatory markers.
White Blood Cell Count and Incidence of Coronary Heart Disease and Ischemic Stroke, and Mortality from Cardiovascular Disease in African-American and White Men and Women: The Atherosclerosis Risk in Communities Study
Authors: Lee Chong D , Folsom Aaron R , Nieto F J , Chambless Lloyd E , Shahar Eyal , Wolfe Douglas A
Published: March 2022

P36

Objective: To investigate the association between white blood cell (WBC) count and incidence of coronary heart disease (CHD) and ischemic stroke, and mortality from cardiovascular disease (CVD) in African-American and White men and women. Methods: We followed 13,555 African-American and white men and women, ages 45 to 64 years, who had a WBC count assessed at baseline. There were 488 incident CHD events, 220 incident strokes, and 258 deaths from CVD during an average of 8 years of follow-up. Results: After adjustment for age, sex, and ARIC field center, there was a direct association between WBC count and incidence of CHD (P <0.001 for trend) and stroke (P for trend <0.001), and mortality from CVD (P for trend <0.001) in African Americans. This association remained but was attenuated after further adjustment for multiple risk factors. The African Americans in the highest quartile of WBC count (≥7,000 cells/mm

3

) had 1.9 times the risk of incident CHD (95% CI, 1.19, 3.09, P = 0.008), 1.9 times the risk of incident ischemic stroke (95% CI, 1.03, 3.34, P = 0.04), and 2.3 times the risk of CVD mortality (95% CI, 1.38, 3.72, P = 0.001) than did their counterparts in the lowest quartile of WBC count (<4,800 cells/mm

3

). These associations were similar in whites and in never-smokers. Conclusions: An elevated WBC count is directly associated with increased incidence of CHD and ischemic stroke, and mortality from CVD in African-American and White men and women.
Thrombolytic therapy and secular trends (1985-1995) in long-term survival following acute myocardial infarction: the Minnesota Heart Survey
Authors: Duval Sue , Shahar Eyal , McGovern Paul G , Jacobs David R , Berger Alan K , Luepker Russell V
Published: March 2022

P38

Both short-term and long-term survival of acute myocardial infarction (AMI) patients have improved remarkably during the 1980s and 1990s. We investigated the contribution of greater utilization of thrombolytic therapy to these secular trends, and compared the survival trends among AMI patients who received thrombolytic therapy to survival trends among their counterparts who did not. The sample included 4,515 patients aged 30-74 years (2743 men, 1772 women) who were discharged from Minneapolis-St. Paul hospitals in 1985, 1990, or 1995 and determined to have had a definite AMI by the study criteria. Age-adjusted three-year mortality following hospitalized AMI decreased significantly over that period from 30% in 1985 to 25% in 1990 to 20% in 1995, with no evidence of heterogeneity of the secular trend by gender. The regression-derived hazard ratio of death - adjusted for age, gender, and history of MI - was 0.61 (95% CI: 0.52,0.71) for AMI patients in 1995 as compared with their counterparts in 1985. The frequency of administration of thrombolytic therapy increased dramatically from 1985 to 1990 (13% to 28%) but did not increase further in 1995 (27%). We estimated the contribution of more frequent administration of thrombolytic therapy to the time trend by modeling an indicator variable for thrombolytic therapy use and computing the percentage decrease in the coefficient for the “year effect” (1995 vs 1985). According to this method, only 11% of the secular trend in AMI mortality could be attributed to greater use of thrombolytic therapy. There was no statistical evidence of differential secular trend by thrombolytic therapy status (p=0.57). However, the estimated reduction in three-year mortality (1995 vs 1985) was larger among AMI patients who did not receive thrombolytic therapy treatment (31% to 22%) than among their counterparts who received that therapy (21% to 16%). Although more frequent use of thrombolytic therapy accounted for some of the favorable trend in AMI survival, other components of AMI care and secondary prevention measures appear to have played an important role.
Impact of Risk Factor Changes in a Population
Authors: Wu Lambert A , Kottke Thomas E , Brekke Lee N , Brekke Mark J
Published: March 2022

P39

Background: Risk factor trends in the United States are not favorable. We determined the potential population impact of risk factor trends versus achieving Healthy People 2010 goals. Methods: Four possible risk factor scenarios were defined for the year 2020. Scenarios were based on current and past risk factor levels and current national goals: 1) Current risk factor levels in Olmsted County, MN; 2) Continued rise in diabetes and smoking rates; 3) #2 plus loss of blood pressure and cholesterol control; 4)Population meets Healthy People 2010 goals. Risk factors were assigned stochastically to the year 2000 Olmsted County, MN population, ages 30-83. Framingham-based risk functions were then used to calculate cardiovascular (CVD) event rates under each scenario. Conclusions: If diabetes and smoking continue to rise, and hypertension and cholesterol rise to historically high levels, CVD rates could rise as much as 75%. In contrast, meeting Healthy People 2010 goals would reduce CVD rates by 49%.

Table 1.
Relation of insulin resistance and body size in adolescence to birthweight
Authors: Murtaugh Maureen A , Jacobs David R , Schmitz Kathryn H , Moran Antionnette , Steinberger Julia , Sinaiko Alan R.
Published: March 2022

P04

A relationship between birthweight (BW) and the insulin resistance syndrome has been reported in adults but has not been defined in adolescents. Data were analyzed in 287 children (124 girls, 163 boys) mean age 15.0 ±1.2 yrs undergoing euglycemic insulin clamp studies (intravenous administration of 1mU/kg/min of insulin balanced by a variable infusion of 20% glucose to maintain blood glucose at 100 mg/dl). Insulin sensitivity (M) was determined by glucose uptake during the final 40 minutes of the 3 hr clamp per kg body weight. BW was reported by parents. BW ranged from 1021-4848g (mean, 3403 ±573), with 5.4% of BW < 2500g. Height increased with BW (r=0.3, p<0.0001). Fat mass and BMI had U-shaped relations with BW after adjustment for ethnicity, age, sex, and blood pressure, but lean body mass was not signficantly different between BW quartiles (

Table). Fasting insulin was positively, and M inversely, related to fat mass (r=0.55,and r=-0.45 respectively p<0.0001). After further adjustment for body weight, fasting insulin was highest (p= 0.009) and M lowest (p=0.17) in the lowest BW quartile. Triglycerides, HDL-C, LDL-C and blood pressure were unrelated to BW. In these data, insulin resistance in adolescence is higher with low BW and increased body fat. In addition, fat mass is increased in both high and low BW in adolescence. Thus both high and low BW are potential risk factors for the development of adult cardiovascular disease and insulin resistance syndrome.

Table 1.
Temporal Trends (1986-1997) in Cholesterol Assessment and Management Practices in Patients Hospitalized with Acute Myocardial Infarction: A Population-Based Perspective
Authors: Yarzebski Jorge L , Spencer Frederick A , Goldberg Robert J , Lessard Darleen , Gore Joel M
Published: March 2022

P42

Background: Elevated serum cholesterol levels are associated with increased risk of acute myocardial infarction (AMI) and adverse patient outcomes. It is unclear what proportion of patients have their serum cholesterol measured during hospitalization for AMI and are treated with lipid lowering therapy. The objectives of this longitudinal study were to examine trends over a decade long experience in serum cholesterol ordering practices during hospitalization for AMI and use of lipid lowering therapy. Methods: Observational study of 5204 residents of the Worcester, MA, metropolitan area hospitalized with validated AMI in all greater Worcester hospitals in seven one-year periods between 1986 and 1997. Results: Increases in the measurement of serum cholesterol levels during hospitalization for AMI were observed between 1986 and 1991 after which time there was a progressive decrease; only 24% of AMI patients in 1997 underwent cholesterol testing. Younger age, male sex, and absence of a history of cardiovascular disease were associated with an increased likelihood of serum cholesterol being measured. While the relative use of lipid lowering therapy increased significantly over time (0.4% in 1986; 10.7% in 1997), the absolute rate of utilization of lipid lowering therapy remained low. In patients with an elevated serum cholesterol (>240 mg/dL), 1.9% received lipid lowering therapy in 1986 and 36.6% in 1997. Conclusions: These findings suggest recent declines in the assessment of total cholesterol levels in patients hospitalized with AMI. While the use of lipid lowering therapy during hospitalization for AMI has increased over time, considerable room for improvement remains.
Secondary prevention of coronary heart disease in a sample of primary care practices in eastern England: evidence of unmet need
Authors: Wild Sarah H , Macleod Christine A
Published: March 2022

P44

Objective: To investigate prevalence of risk factors and use of secondary prevention strategies for recurrent coronary heart disease (CHD) in primary care. Design: Cross-sectional study of a 50% sample of medical records. Subjects: Patients aged 35-75 years with a record of coronary heart disease from 13 primary care practices in eastern England. Main outcome measures: Recorded prevalence of smoking, body mass index and use of aspirin, beta-blockers and statins. Results: Records were reviewed for 1205 patients with CHD of whom 76% were over 60 years of age and 34% were women. Crude age-specific prevalence of CHD was 4.1%. CHD was categorised as angina (52% of subjects), past myocardial infarction (33% of subjects) and history of coronary revascularisation (15% of subjects). Prevalence of smoking and obesity (body mass index >30kg/m

2

) was based on available data for 1080 and 973 subjects and was 23% and 31% respectively. Seventy percent of all subjects were recorded as receiving aspirin, 40% were being prescribed beta-blockers and 37% were being prescribed statins. These proportions varied by age, sex and category of CHD. Conclusion: Despite evidence of effectiveness most strategies for reducing risk of recurrent coronary heart disease are still not widely used in primary care. Possible explanations include absence of systematic care for CHD patients, limited availability of behavioral interventions and concerns over the cost of treatment. National guidelines for secondary prevention of CHD in primary care are being developed.
Plasma Concentration of Cystatin-C and Mannose Binding Protein and the Risk of Developing Peripheral Vascular Disease
Authors: Albert Michelle A , Rifai Nader , Ridker Paul M
Published: March 2022

P05

Background- Cystatin-C, a cysteine protease inhibitor, and mannose binding lectin, an innate defense protein involved in microbial clearance, have both been hypothesized to mediate atherosclerotic plaque progression. However, little prospective data are available evaluating whether levels of these proteins in healthy individuals are associated with incident cardiovascular disease. Methods and Results-Employing a prospective, nested, case control study design, baseline levels of cystatin-C and mannose binding protein were evaluated among 133 apparently healthy men who subsequently developed symptomatic peripheral arterial disease (cases) and among 133 age and smoking matched controls who remained free of reported vascular disease during a 5 year follow-up period. Overall, median baseline levels of cystatin-C were virtually identical among case and control subjects (0.83mg/L, p=0.84). Similarly, median baseline levels of mannose binding protein among cases and controls were 2.32mg/L and 2.2mg/L,(p=0.69). We found no evidence of association between either cystatin-C or mannose binding protein and the development of peripheral vascular disease in analyses evaluating for linear trends or for threshold effects (all p values >0.05). Conclusion-In contrast to prior retrospective and cross-sectional studies, we found no evidence in this prospective evaluation that baseline levels of cystatin-C or mannose binding protein are associated with increased risk of future vascular disease.