bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3448: Differences in the Associations between Various Ultrasound-Based Markers of Peripheral Atherosclerosis at Carotid and Femoral Levels and Risk factors in a general Middle-Aged Population
Authors: Yerly Patrick O , Rodondi Nicolas , Paccaud Fred , Vogt Pierre , Bovet Pascal
Published: July 2021

Introduction:
Ultrasound detection of sub-clinical atherosclerosis (ATS) is a useful mean to identify subjects at high risk of cardiovascular (CV) events. Most studies have evaluated intima-media thickness (IMT) at the carotid artery level, but plaque-based markers (plaque thickness, plaque area) as well as the femoral artery level have been proposed as valid alternatives. The superiority of one method upon the others has not been demonstrated. The aim of this study is to compare the relationships between five indicators of ATS (IMT, mean / maximal plaque thickness, mean / maximal plaque area) at both carotid and femoral levels and conventional cardiovascular risk factors (CVRF) in a population-based sample of middle-aged adults.

Methods:
High resolution B-mode ultrasound was performed in both right and left carotid and femoral arteries on 496 consecutive participants aged 45– 64 randomly selected from the general population. A plaque was defined as a focal IMT thickening ≥ 1.2 mm. CVRF included age, sex, current smoking, systolic blood pressure, LDL-cholesterol, HDL-cholesterol, and diabetes.

Results
: All CVRF were associated, independently of age, with each of the ATS markers at femoral level but only LDL-cholesterol and systolic blood pressure were consistently associated with ATS markers at carotid level. The table

shows the adjusted R-squared values in a multivariate model with all CVRF. Variance (adjusted

R
2

) in predicting any of the ATS markers was larger at femoral than carotid levels. At both carotid and femoral levels, the CVRF accounted for more variance in predicting plaque-based markers than IMT.

Conclusion:
The stronger association of CVRF with ATS markers at the femoral than carotid levels and with plaque-based markers than with IMT suggest that markers assessed at femoral level and based on plaque morphology might be the most useful tools for assessing cardiovascular risk. These findings need to be confirmed in prospective studies with CV events.
Abstract 3459: Human Atrial Natriuretic Peptide (ANP) Gene Is Associated With Metabolic Syndrome In The French Population
Authors: Roussel Ronan , Maimaitiming Suliya , Fumeron Frederic , Hadjadj Samy , Aubert Roberte , Balkau Beverley , Marre Michel
Published: July 2021

Background: ANP is important in hemodynamics, but also in lipolysis, particularly in overweight. Its plasmatic concentration is related to number of metabolic syndrome components. Its gene, NPPA, was considered as a candidate for susceptibility to metabolic disorders.

Aims-Methods: We assessed the effect of 3 Hapmap-tagged haplotypes-defining NPPA SNPs, G664A (rs5063), 708C>T (rs5064) and 2238T>C (rs5065) on metabolic parameters levels and metabolic syndrome and their interaction with overweight in a cohort study included 2,576 men and 2,636 women from the general population, followed for 9 years.

Results: In the whole population, there was a significant effect of the 708C>T SNP on waist girth (CC: 83.5 ± 0.1cm, CT: 83.1 ± 0.2 and TT: 81.2 ± 0.9, p=0.04) and HDL-C (CC: 1.63 ± 0.01 mM CT: 1.63 ± 0.01 and TT: 1.77 ± 0.03, p=0.04). The 708C>T SNP interacted with overweight on triglycerides (TG) and waist girth (p=0.002 and p=0.03 respectively for interaction) and in overweight subjects, was associated with TG (CC: 1.51 ± 0.03mM, CT: 1.37 ± 0.07 and TT: 1.13 ± 0.31, p=0.009) and waist girth (CC: 93.1 ± 0.2cm, CT: 92.1 ± 0.4 and TT: 89.1 ± 1.8, p=0.009). The 2238T>C SNP interacted with overweight on waist girth (p=0.08 for interaction) and in overweight subjects, was associated with waist girth (TT: 93.1 ± 0.2cm, TC: 92.4 ± 0.3 and CC: 91.1 ± 0.9, p=0.03). The overweight 708TT carriers and 2238CC carriers had a lower risk of metabolic syndrome (MS) during the 9-year follow-up (rare allele OR=0.74, p=0.043 and 0.75, p=0.017 respectively). No association was found with 664G>A. Haplotype GTC (carrying the minor allele of 708C>T) was significantly associated with lower waist girth level (p=0.007) and TG (p=0.02) in overweight subjects, and with a lower risk of developing MS during follow-up (p=0.02) in overweight subjects.

Conclusion: NPPA tagged SNPs and haplotypes are associated with cardiovascular risk in the general French population through association with lipids, waist girth levels and with incidence of MS in particular in overweight subjects.
Abstract 3481: A Prospective Comparison of NMR-Measured LDL Particle Number, Apolipoprotein B100, and Standard Lipids with Incident CHD in 27,673 Initially Healthy Women
Authors: Mora Samia , Otvos James , Buring Julie E , Rifai Nader , Ridker Paul M
Published: July 2021

Background While ATP-III recommends measurement of total and HDL cholesterol (HDL-C) as part of coronary risk assessment, measurement of LDL particle number (LDL-P) is not currently recommended.

Methods and Results In a prospective cohort of 27,673 initially healthy women, baseline LDL-P was measured by proton nuclear magnetic resonance spectroscopy, apolipoprotein B100 (ApoB) was measured using an immunoturbidimetric assay, and standard lipids were directly measured. LDL-P correlated with LDL cholesterol (LDL-C; r=0.62), ApoB (0.84), non HDL-C (0.74), and total:HDL-C ratio (0.80). During a mean follow-up of 11 years, 668 incident coronary heart disease (CHD) events occurred. Using the lowest quintile as the reference, and adjusting for age, smoking, blood pressure, diabetes, menopause, hormone use, and body mass index, the association of LDL-P with CHD was stronger than LDL-C (Table

), and comparable in magnitude to ApoB, non HDL-C and total:HDL-C ratio. In a subgroup analysis of women with LDL-C<100 mg/dL, elevations in LDL-P, ApoB, non HDL-C, or total:HDL-C ratio were all separately associated with higher CHD risk (P<0.001 for all). Both LDL-P and ApoB remained associated with CHD after additionally adjusting for total cholesterol, HDL-C, and triglycerides (hazard ratios for top vs bottom quintile: 2.03 [95% CI 1.27–3.24] for LDL-P, and 3.08 [95% CI 1.92– 4.93] for ApoB) overall, and similarly in women with LDL-C<100 mg/dL (2.77 [95%CI 1.05–7.29] for LDL-P and 2.62 [95%CI 0.97–7.05] for ApoB).

Conclusions In this large-scale prospective cohort, elevations in NMR-measured LDL particle number were significantly associated with incident CHD, with a magnitude of risk not substantially different from ApoB, non HDL-C, or total:HDL-C ratio. Among women with LDL-C <100mg/dL, elevations in LDL-P, ApoB, non HDL-C, and total:HDL-C ratio all carried higher CHD risk.

Risk Factor-Adjusted Hazard Ratios for Incident CHD
Abstract 3484: Dietary Patterns And The Risk Of Mortality From All-causes, Cardiovascular Disease, And Cancer In Women
Authors: Heidemann Christin , Schulze Matthias B , Franco Oscar H , van Dam Rob M , Mantzoros Christos S , Hu Frank B
Published: July 2021

Background: Few studies have investigated the impact of dietary patterns that reflect existing eating habits on the risk of all-cause or cause-specific mortality.

Objective: To prospectively examine the relation between major dietary patterns and the risk of all-cause and cause-specific mortality among women of the Nurses’ Health Study.

Methods: The participants included 72,113 women aged 35 to 55 years without a history of cancer, myocardial infarction, angina, coronary artery surgery, stroke, or diabetes at baseline. Dietary patterns were derived by factor analysis using information from five repeated, validated food frequency questionnaires that were administrated at baseline and every 2 to 4 years during the follow-up period (1984–2002). Cox proportional hazards regression was used to adjust for covariates including age, cigarette smoking, physical activity, body mass index, and further suspected risk factors.

Results: Two major dietary patterns were identified. High prudent pattern scores represented high intakes of vegetables, fruit, legumes, fish, poultry, and whole grains, whereas high western pattern scores represented high intakes of red meat, processed meat, refined grains, french fries, condiments, and sweets and desserts. During 18 years of follow-up (633,516 person-years), we ascertained 6,011 deaths, including 3,139 cancer deaths and 1,154 cardiovascular deaths. After adjustment for potential confounders, the prudent diet was inversely associated with all-cause mortality (relative risk [RR] = 0.83 for highest versus lowest quintile, 95% confidence interval [CI] = 0.76 – 0.90, p for trend < 0.0001) and cardiovascular mortality (RR = 0.72, 95% CI = 0.60 – 0.87, p for trend = 0.0007), but not with cancer mortality (RR = 0.99, 95% CI = 0.88 –1.11, p for trend = 0.87). The western pattern was directly associated with all-cause mortality (RR = 1.21, 95% CI = 1.11–1.32, p for trend < 0.0001), cardiovascular mortality (RR = 1.22, 95% CI = 1.00 –1.48, p for trend = 0.01), and cancer mortality (RR = 1.15, 95% CI = 1.02–1.29, p for trend = 0.004).

Conclusions: These data provide evidence that a high prudent pattern score and a low western pattern score may reduce the risk of total and cause-specific mortality.
Abstract 3486: Minimally Elevated Cardiac Troponin T Independently Predicts Death in Apparently Healthy Adults: Results from the Rancho Bernardo Study
Authors: Daniels Lori B , Laughlin Gail A , Clopton Paul , Maisel Alan S , Barrett-Connor Elizabeth
Published: July 2021

Background:
Minimally elevated levels of cardiac troponin T (TnT), a marker of cardiac myocyte injury, have been found in small subsets of the general population. The significance of these rare elevations is controversial. The purpose of this study was to determine the prognostic value of detectable TnT levels in a population of community-dwelling older adults.

Methods:
Prospective community-based study of 375 men and 584 women ages 60 to 97 (mean 77) who had plasma TnT measurements (Elecsys® Troponin T, Roche Diagnostics) at baseline (1997–99) and were followed for mortality through July 2006. Participants were divided into 2 groups based on TnT levels: Undetectable (n = 917) and Detectable (≥ 0.01 ng/ml, n = 39).

Results:
The 39 (4.1%) participants with detectable TnT levels were older and were more likely to be men (both p < 0.01) than those with undetectable TnT. Most of those with detectable TnT levels did not have known heart disease at baseline (79%, 95% C.I. 64 – 89%). During an average 6.3 year follow-up, 220 deaths occurred; 42% were cardiovascular (CV). In Cox proportional hazards regressions, participants with detectable TnT had increased risk of all-cause death (HR = 4.6, 95% CI 3.0 –7.1,

Figure

) and of CV death (HR = 5.6, 95% C.I. 3.0 –10.6). Adjusting for age, sex, lifestyle characteristics, and multiple CV risk factors, as well as exclusion of the 152 participants with known heart disease at baseline, did not materially change the TnT-mortality associations.

Conclusions:
Apparently healthy adults with detectable TnT, even at levels not currently considered abnormal, are at increased risk of death. The prognostic value of TnT persists for years.
Abstract 3499: Ethnic and Gender Differences in Large and Small Artery Elasticity: Results of the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Duprez Daniel A , Herrington David , Prime Darryl , Ouyang Pamela , Barr Graham R , Bluemke David A
Published: July 2021

Background: Arterial stiffness is a surrogate marker for cardiovascular morbidity and mortality; it may help account for ethnic and gender differences in cardiovascular risk.

Objective: We examined the large and small artery elasticity (LAE, SAE) according to ethnicity and gender in the large MESA cohort study.

Methods: A total of 3293 women and 3000 men aged 45– 84 years free of clinically recognized cardiovascular disease were recruited in 6 US communities from white, African American, Hispanic, and Chinese ethnicity. Pulse wave contour registration at the radial artery was performed in all subjects in a supine position using radial tonometry. LAE and SAE were derived from diastolic pulse contour analysis.

Results: A strong gradient of arterial elasticity was seen per decade of age, about 1.2 ml/mmHgx10 for LAE and 0.7 ml/mmHgx100 for SAE. Table 1

presents mean levels of LAE and SAE, both unadjusted and simultaneously adjusted by regression for age, race/ethnicity, gender, center and education. We also adjusted for variables used in the estimation of arterial elasticity (height, heart rate, blood pressure and BMI), thus examining the information unique to the pulse wave contour. Much of the gender difference in arterial elasticity is explained by the gender difference in height. After adjustment LAE did not differ by ethnicity, but African Americans had lower levels of SAE.

Conclusions: African Americans free of overt cardiovascular disease have lower SAE but not different LAE compared to white, Chines and Hispanic ethnicity. This reduced SAE may indicate earlier vascular disease in African Americans than in other groups.

Table 1
Abstract 3519: Modest Fat Gain Causes Endothelial Dysfunction In Lean Healthy Humans: A Randomized Blinded Controlled Trial
Authors: Corral Abel Romero , Sierra-Johnson Justo , Orban Marek , Gami Apoor S , Kuniyoshi Fatima H Sert , Pusalavidyasager Snigdha , Davison Diane , Huyber Christine M , Votruba Susanne M , Jensen Michael D , Somers Virend K
Published: July 2021

Background:
Endothelial dysfunction assessed by flow mediated dilation (FMD) of the brachial artery has been identified as an independent predictor of cardiovascular events. However, whether weight gain impairs endothelial function is unknown.

Methods:
A randomized blinded controlled-trial to assess the effects of weight gain on endothelial function. After a weight maintenance period supervised by an experience dietitian, volunteers were randomized to gain weight (4 kg) or maintain weight. We recruited lean (BMI 18.5–24.9 kg/m
2
) healthy volunteers (no diseases, medications and non-smokers) from the community. Using ultrasound, endothelial function was measured by FMD and non-flow mediated dilation (NFMD) of the brachial artery in the early morning (6:30 a.m.). Endothelial function was measured at baseline, after fat gain at 8 weeks and after weight loss at 16 weeks for fat-gainers and at baseline and follow-up (8 weeks) for weight maintainers. Body composition techniques to measure body fat %, such as dual x-ray absorptiometry and abdominal CT scans were performed.

Results:
We recruited 35 fat-gainers and 8 weight maintainers. Mean age was 29 ± 6 years and 18 (42 %) were women. There were no differences in age, anthropometric and body composition measurements, blood pressure, heart rate or apnea hypopnea index at baseline between both groups. After an average gain of 4 kg, the fat-gainer group significantly increased their total, visceral and subcutaneous fat. Brachial artery FMD and NFMD remained unchanged in weight maintainers. However, it decreaed in fat-gainers (FMD=9.1 ± 3 vs. 7.6 ± 3.2, p=0.003 and NFMD=12.0 ± 4.9 vs. 10.1 ± 6.0, p=0.01), but recovered to baseline after subjects shed the gained weight (basleline vs. recovery: FMD=9.1 ± 3 vs. 9.0 ± 3, p=NS and NFMD =12.0 ± 4.9 vs.12.6 ± 5.0, p=NS). Visceral fat gain, but not subcutaneous fat gain was significantly correlated with the decrease in brachial artery FMD (rho =−0.42, p=0.004 and rho =−0.22, p=0.15, respectively).

Conclusions:
In lean healthy young subjects, modest weight gain results in impaired endothelial function, even in the absence of changes in blood pressure. Endothelial funcion recovers after weight loss. Viscerar rather than subcutaneous fat predicts endothelial dysfunction.
Abstract 3555: Increased Fatness and Reduced Fitness are Associated with Aortic Stiffness in Persons with Type 2 Diabetes and Hypertension
Authors: Stewart Kerry J , George Brian H , Potrekus Kristina , Bacher Anita C , Silber Harry A , Wang Nae-Yuh , Shapiro Edward P , Ouyang Pamela
Published: July 2021

Background: Large artery stiffness, thought to be a marker of cardiovascular disease, is accelerated in persons with diabetes and hypertension. While reduced fatness and increased fitness are associated with lower BP, we tested the hypothesis that increased fatness and reduced fitness are each independently associated with greater aortic stiffness.

Methods: Sedentary subjects (M=60; F=29), mean (SD) age 57.1 (5.8) years, were examined at baseline as part of an exercise training study to reduce BP in persons with type 2 diabetes. Subjects were taking their usual medical therapy. For BP eligibility, subjects were required to have SBP between 120–159 and/or DBP between 80–99 mm Hg during 2 consecutive weekly visits. BP was the mean of the screening visits and a visit after qualification for the study. Aortic stiffness was assessed by carotid-to-femoral pulse wave velocity (PWV), using ultrasound probes simultaneously at each of these sites. General fatness was assessed by dual-energy x-ray absorptiometry (DEXA) and expressed as percent body fat. Abdominal fatness was assessed by magnetic resonance imaging at the level of the umbilicus and the areas for total, subcutaneous, and visceral fat were measured. Maximal oxygen uptake was obtained on a treadmill. The associations of PWV with BP, oxygen uptake, and abdominal fat were determined by stepwise regression analysis with adjustment for age and gender.

Results: PWV was 922.9 (300.0) msec, SBP was 126.9 (13.2) mm Hg, DBP was 71.8 (8.8) mm Hg, pulse pressure (PP) was 55.0 (10.4) mm Hg, percent body fat was 35.0 (6.5) %, and maximal oxygen uptake was 21.7 (5.0) ml/kg/min. In the final model, the variance in PWV was accounted for by increased PP, 8.9%; increased abdominal visceral fat accounted for an additional 6.2%; increased percent body fat, an additional 3%; and decreased maximal oxygen uptake, an additional 5.6%.

Conclusions: These data bring to light an independent relationship of aortic stiffness with increased fatness and reduced fitness. Though further work is needed to elucidate the mechanisms linking aortic stiffness, fatness, and fitness, these findings support the need for a therapeutic approach for reducing aortic stiffness that considers the potential benefits of weight reduction and exercise.
Abstract 3556: Diabetic Cardiac and Renal Complications are attenuated in Mice with Conditional Knockout of Endothelin-1 in Vascular Endothelial Cell
Authors: Widyantoro Bambang , Adiarto Suko , Iwasa Naoko , Nakayama Kazuhiko , Anggrahini Dyah W , Miyagawa Kazuya , Nonaka Hidemi , Suzuki Takashi , Kisanuki Yaz Y , Yanagisawa Masashi , Emoto Noriaki
Published: July 2021

High plasma endothelin-1 (ET-1) level has been associated with diabetic cardiovascular and renal complications, which remained prevalent despite good glycemic control. Since endothelial dysfunction, which is characterized by enhanced ET-1 secretion, plays an important role in mediating diabetic complication, we hypothesized that disruption of ET-1 in endothelial cell will be protective against cardiac and renal complication of diabetes. To test this hypothesis, we injected streptozotocin to Vascular Endothelial cell Specific Endothelin-1 Knockout (VEETKO) mice, of which ET-1 expression in major organs including heart and kidney were reduced by 60%, and to their wild type (WT) littermates. Six months of diabetes increased systolic blood pressure (SBP) similarly in both genotypes, with DM-VEETKO mice have remained lower SBP than DM-WT mice (124±1.08 vs. 131.33±1.33 mmHg, p<0.01, n=8 each). Diabetes also exaggerated the difference in cardiac ET-1 mRNA expression between both groups. The heart of DM-VEETKO mice showed lower area of interstitial fibrosis as compared to DM-WT mice, and this is associated with lower expression of fibrotic genes (TGF-β, CTGF and Collagen-1), higher capillary density (as measured by CD-31 staining) and higher VEGF mRNA expression. Furthermore, eight months of diabetes decreased cardiac systolic function of all mice, however, the decrease is significantly attenuated in DM-VEETKO mice (fractional shortening 45.67±0.61 vs. 38.27±2.2%, p<0.01, n=4 each). Similarly, DM-VEETKO mice also preserved renal function. Diabetes caused an increase in urinary protein excretion with the values in DM-VEETKO mice being approximately one fifth of DM-WT mice (30.12±10.09 vs. 170±23.19 mg/dl, p<0.01, n=6 each) Morphologically, DM-VEETKO mice have less glomerular fibrosis which is associated with lower expression of ICAM-1, and further leads to lower glomerular macrophage recruitment. In conclusion, these findings indicate that disruption of ET-1 in endothelial cell is significantly attenuated diabetic cardiovascular and renal complication in streptozotocin-induced diabetic mice model, and may provide additional basic rationales for the use of ET-1 blockade for the prevention of cardiac and renal complication of diabetes.
Abstract 3562: The Ala12 Variant of the
PPARG
Gene is Associated with Higher Polyunsaturated Fatty Acids in Adipose Tissue and Attenuates the Protective Effect of Polyunsaturated Fat Intake on the Risk of MI
Authors: Ruiz-Narvaez Edward , Kraft Peter , Campos Hannia
Published: July 2021

Background:
Intake of polyunsaturated fat is protective against development of coronary heart disease (CHD). Less is known about genetic variation modulating this association. The Ala12 allele of the
PPARG
gene decreases lipolysis of triacylglycerols in adipose tissue, resulting in accumulation of fatty acids in adipocytes.

Objective:
Determine whether the Pro12Ala polymorphism interacts with polyunsaturated fat intake to affect the risk of myocardial infarction (MI).

Design:
Cases (n=1805) with a first nonfatal acute MI and age, sex and area of residence matched population-based controls (n=1805) living in Costa Rica, were genotyped for the
PPARG
Pro12Ala genetic polymorphism. Polyunsaturated fat intake was determined by a validated food frequency questionnaire and by GC analysis in adipose tissue. Odds ratios (ORs) and 95% confidence intervals (95% CI) for MI were estimated using logistic regression.

Results:
The relative allele frequencies of the Ala12 allele were 10% in controls and 11% in cases. ORs (95% CI) for MI per each 5% increase of energy from polyunsaturated fat were 0.66 (0.53, 0.82) in Pro12/Pro12 subjects, and 0.93 (0.61, 1.42) in carriers of the Ala12 allele (p for interaction = 0.03). Increments (95% CI) of polyunsaturated fat in adipose tissue per 5% increment in dietary intake were 5.4% (4.9%, 5.9%) in Pro12/Pro12 homozygous, and 7.0% (6.0%, 8.0%) in carriers of the Ala12 variant (p for homogeneity of slopes = 0.02).

Conclusions:
The protective effect of polyunsaturated fat intake on MI is attenuated in carriers of the Ala12 allele of the
PPARG
gene.
Abstract 3569: Genetic Contribution to Collagen-Induced Platelet Aggregation Following Low-Dose Aspirin in Families with Premature Coronary Artery Disease
Authors: Herrera-Galeano J. Enrique , Wilson Alexander F , Faraday Nauder , Yanek Lisa R , Moy Taryn F , Becker Diane M , Becker Lewis C
Published: July 2021

Background:
Lesser suppression by aspirin (ASA) of collagen-induced platelet aggregation predicts myocardial infarction and stroke. Variability in platelet aggregation to collagen was recently shown to be under genetic control; however, the specific genes that contribute to phenotypic variation are not known.

Methods

: We examined platelet function in 955 Caucasian (mean age 47+/−13.54, 52% female) and 541 African-American (mean age 45.71+/−12.7, 60% female) healthy subjects with a family history of early onset coronary artery disease (CAD). Collagen-induced platelet aggregation was measured by optical aggregometry after subjects were treated with low dose ASA (81 mg/day) for 2 weeks. 2638 single nucleotide polymorphisms (SNPs) from 191 candidate genes were evaluated using the Illumina platform. The ASSOC subroutine of SAGE was used to examine genotype-phenotype associations. To help discriminate true from false positive associations, while at the same time maintaining sensitivity, we propose a new approach in which SNPs are considered “significant” only when alpha < 0.05 in
both
whites and blacks, combined with a locus specific heritability (LSH) ≥1% in both groups.

Results:

Using the Bonferroni correction to establish a p value threshold, no SNPs were associated with the phenotype. However, SNPs in 8 genes (ITGA2G, ITGB2, MAPK10, RAP1A, RGS10, VAV1, PEAR1 (platelet endothelial aggregation receptor 1), and PAFAH1B (platelet-activating factor acetylhydrolase) met the criteria of having significant p values in both groups, and SNPs in only 2 of the genes (PEAR1 and PAFAH1B) also contributed 31% to LSH (Table

). For both genes, the allele associated with a decreased response to ASA was the major allele among Caucasians, but the minor allele among African-Americans.

Conclusions:

Variants in PEAR1 and PAFAH1B are associated with decreased response to ASA in both African-Americans and Caucasians. Each contributes more than 1% to the genetic variance.

Genotype Means and Variance contribution
Abstract 476: Attenuated Activities of Mitochondria in Vascular Endothelial Cells Exposed to Oxidized or Glycated Low Density Lipoprotein
Authors: Shen Garry X , Chowdhury Subir K Roy
Published: July 2021

Hyperglycemia and dyslipoproteinemia are two major biochemical markers of diabetes. Elevated low density lipoprotein (LDL) is a classical risk factor for atherosclerotic cardiovascular disease. Our previous studies demonstrated that oxidized LDL (ox-LDL) and glycated LDL (gly-LDL) increased the generation of reactive oxygen species (ROS) in vascular endothelial cells. ROS is implicated in endothelial dysfunction and diabetic vascular complications. Mitochondria are an important source of ROS in the body. We hypothesize that ox-LDL or gly-LDL might affect the activity of mitochondrial respiratory chain. We evaluated the activities of mitochondrial respiratory chain complexes in porcine aortic endothelial cells (PAEC) using OROBORS oxygraph. The oxygraph was used as a highly sensitive tool to evaluate mitochondrial complex activity in freshly harvested and digitonin-permeabilized PAEC (for Complex I, the rotenone-sensitive oxidation of glutamate + malate in the presence of ADP; Complex II, antimycin A-sensitive oxidation of succinate; Complex IV, potassium cyanide-sensitive oxidation of ascorbate + TMPD). The oxygen consumption in Complex I, II and IV of PAEC was significantly decreased by >12 h of incubation with LDL, ox-LDL or gly-LDL compared to control cultures. Attenuated activity of succinate cytochrome C reductase was detected in EC treated with LDL, ox-LDL or gly-LDL for 24 h. Decreased levels of respiratory control ratio were detected in EC treated with LDL or ox-LDL for 6 h, but not for 2 h, compared to control. Impaired activity of mitochondrial complexes can cause electron leakage in the respiratory chain and substantially increase ROS formation. The findings suggest that oxidized or glycated LDL attenuates mitochondrial activities in vascular EC, which may contribute to increased ROS generation and endothelial dysfunction induced by the atherogenic lipoproteins (supported by operating grants from Canadian Institute of Health Research and Canadian Diabetes Association).
Abstract 3584: The Prevalence and Factors Associated With 1-Year Angina among Post-MI Patients
Authors: Maddox Thomas M , Reid Kimberly J , Spertus John A , Parashar Susmita , Krumholz Harlan M , Ho P. Michael , Rumsfeld John S
Published: July 2021

Background: A primary goal of in-hospital treatment and outpatient care following myocardial infarction (MI) is the eradication of angina. However, the prevalence of angina and the factors associated with angina in the year after MI are unknown.

Methods: The primary outcome of the PREMIER multi-center prospective study was presence of angina, as measured by the Seattle Angina Questionnaire (SAQ), 1 year after MI hospitalization. Multivariable regression modeling identified the socio-demographic factors, clinical history, MI presentation, inpatient therapies and complications, and outpatient treatment characteristics associated with 1-year angina, adjusted for site. .

Results: Of 1957 patients in the cohort, 83 patients (4.2%) reported daily or weekly angina, and 306 patients (15.6%) reported less than weekly angina 1 year after their index MI. After multivariable analysis (figure

), angina 1 year after an index MI was associated with younger age, non-white race, baseline angina, history of CABG surgery, no inpatient revascularization, recurrent rest angina during MI hospitalization, persistent smoking after MI hospitalization, outpatient revascularization after MI hospitalization, and depressive symptoms (either as an inpatient or during the year after MI hospitalization).

Conclusions: Angina 1 year after MI hospitalization is associated with several modifiable factors, including persistent smoking and depressive symptoms in the year after MI discharge. Recognition of these relationships will be important in monitoring and treating at-risk patients for post-MI angina.
Abstract 3603: Extreme Lipoprotein(a) Levels Predict a 3–4 Fold Increase in Risk of Myocardial Infarction in the General Population
Authors: Kamstrup Pia R , Benn Marianne , Hansen Anne Tybjćrg , Nordestgaard Børge G
Published: July 2021

Background:
Elevated lipoprotein(a) levels associate with increased risk of myocardial infarction in some, but not all studies. Limitations of previous studies include lack of risk estimates for extreme lipoprotein(a) levels, measurements in long-term frozen samples and no correction for regression dilution bias. We tested the hypothesis that extreme lipoprotein(a) levels predict myocardial infarction in the general population, measuring levels shortly after sampling and correcting for regression dilution bias.

Methods and Results:
We examined 9330 men and women from the Danish general population, The Copenhagen City Heart Study. During 10 years follow-up, 498 participants developed myocardial infarction. In women, multifactorially adjusted hazard ratios for myocardial infarction for elevated lipoprotein(a) levels were 1.1(95% confidence interval 0.6 –1.9) for 5–29 mg/dL, 1.7(1.0 –3.1) for 30 – 84 mg/dL, 2.6(1.2–5.9) for 85–119 mg/dL (>90
th
percentile), and 3.6(1.7–7.7) for ≥120 mg/dL (>95
th
percentile) versus levels <5 mg/dL (figure

, p-values are test for trend of hazard ratios). Equivalent values in men were 1.5(0.9 –2.3), 1.6(1.0 –2.6), 2.6(1.2–5.5), and 3.7(1.7– 8.0).

Conclusions:
We observed a stepwise increase in risk of myocardial infarction with increasing levels of lipoprotein(a) in both genders, with no evidence of a threshold effect. Extreme lipoprotein(a) levels predict a 3– 4 fold increase in risk of myocardial infarction in the general population.

Figure.

Risk of myocardial infarction by levels of lipoprotein(a)
Abstract 3610: Comparative Effects of 3 Popular Diets on Lipids, Endothelial Function and Biomarkers of Atherothrombosis in the Absence of Weight Loss
Authors: Miller Michael , Beach Valerie , Mangano Charles , Rhyne Jeffrey , Dobmeier Christina , Novacic Danica , Vogel Robert A
Published: July 2021

Background
: While the effect of popular diets on weight loss has been extensively studied, less is known in the absence of weight loss. We hypothesized that a diet high in total and saturated fat would be associated with adverse effects on LDL-C, endothelial function and biomarkers of atherothrombosis compared to lower fat diets.

Methods
: We tested 3 popular diets, including Atkins (50% fat), South Beach (30% fat) and Ornish (10% fat) in a randomized and counterbalanced, crossover study. Subjects completed each of the three 4-week dietary intervention phases followed by a 4-week washout period. They were weighed weekly and caloric adjustments made if weight change exceeded 1 kg. At the completion of each dietary phase, 3-day food records were analyzed, fasting blood was sampled and brachial artery reactivity testing (BART) performed.

Results
: Eighteen of 26 adults (mean age: 30.6 ± 9.6 yrs, 50% female) completed all 3 dietary phases. There were no changes in weight at the conclusion of each phase. However, non-significant increases in LDL-C occurred during the Atkins phase (pre: 96.5, post: 112.9 mg/dL;
P=0.12
), whereas LDL-C was reduced during the Ornish (pre: 110.1, post: 84.6 mg/dL;
P=0.006
) and South Beach phases (pre: 101.7, post: 91.5 mg/dL;
P=0.01
). BART testing revealed a significant inverse correlation between flow-mediated vasodilation and intake of total fat (r
2
=−0.29;
P=0.03
), saturated fat (r
2
=−0.31;
P=0.02
) and monounsaturated fat (r
2
=−0.35;
P=0.01
). Microarray analysis demonstrated increased expression of several leukocyte biomarkers including, ICAM2 (37%;
P=0.002
), SELL (26%;
P=0.007
) and SOD1 (42%;
P=0.04
) at the completion of the Atkins diet compared to baseline. In contrast, expression of atherothrombotic biomarkers was not increased after the South Beach or Ornish phase.

Conclusions:
In the absence of weight loss, the high fat Atkins diet is associated with increased LDL-C, reduced endothelial vasoreactivity and increased expression of biomarkers of atherothrombosis. As such, these data suggest that isocaloric conversion to the Atkins diet may negatively impact cardiovascular health as compared to the South Beach or Ornish Diet.
Abstract 3613: Lipid Biomarkers, Hormone Therapy, and the Risk of Unprovoked Venous Thromboembolism in Women
Authors: Everett Brendan M , Glynn Robert J , Buring Julie E , Ridker Paul M
Published: July 2021

Background
: Published reports of a relationship between lipid biomarkers and venous thromboembolism (VTE) are inconsistent and controversial, and many do not account for potential effect modifiers such as hormone therapy (HT).

Methods and Results
: Among 27,082 initially healthy women followed prospectively (median, 11.4 years) for incident unprovoked VTE, we measured a full panel of lipid biomarkers, including total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, triglycerides, and apolipoproteins A-I (apo A-I) and B100. In analyses adjusted for age and body mass index (kg/m
2
), only HDL-C and apo A-I showed any association with VTE (N=158; hazard ratio (95% CI) per 1 unit SD, 1.17 (1.00 –1.37) and 1.29 (1.11–1.51), respectively). However, after stratifying by HT use at the time of blood collection, none of the lipid biomarkers was associated with future VTE (N=80) in non-users, while higher levels of HDL-C and apo A-I were associated with increased risk of VTE (N=78) among users. Specifically, among HT users the adjusted hazard ratios for future VTE were 1.29 (1.05–1.58) and 1.41 (1.13–1.75) per 1 unit SD increase in HDL-C and apo A-I, respectively (each P≤0.01; Table

). In models further adjusted for factor V, prothrombin, and methylenetetrahydrofolate reductase genotypes, risk estimates did not change substantially, suggesting that the differences seen with HT were not due to any confounding by these genotypes.

Conclusions
: We observed little evidence that any lipid marker predicted risk of future VTE among non-users of HT. The observation that among HT users high levels of HDL-C and apo A-I relate to risk of VTE likely reflects concomitant prothrombotic effects of hormone therapy, rather than direct effects of HDL-C or apo A-I.

Table.

Risk of Future Unprovoked Venous Thromboembolism
Abstract 484: Nitrosative Stress Enhances S-nitrosation Of Peroxiredoxins In The Heart
Authors: Reinartz Michael , Ding Zhaoping , Gödecke Axel , Schrader Jürgen
Published: July 2021

Nitric oxide (NO) is produced by different isoforms of NO-synthases and operates as a mediator of important cell signaling pathways. To explore thiol-based protein modifications in a situation of nitrosative stress, two transgenic mouse models recently generated in our laboratory were used:

Cardiac specific overexpression of inducible nitric oxide synthase (iNOS) (tg-iNOS
+
) and

tg-iNOS
+
with concomitant myoglobin-deficiency (tg-iNOS
+
/myo
−/−
).

Protein S-nitrosation, an important redox-based posttranslational modification, revealed no differences between WT and tg-iNOS
+
hearts as measured by the biotin-switch assay and 2-D PAGE. Even in the absence of myoglobin - an efficient endogenous NO-oxidase - the protein S-nitrosation pattern for nearly all the detected proteins (>40) remained unchanged in the tg-iNOS
+
/myo
−/−
hearts, with the exception of three proteins. Tandem mass spectrometry uncovered these proteins as peroxiredoxins (Prx II, III, VI), which are known to possess peroxidase activity, whereby hydrogen peroxide, peroxynitrite and a wide range of organic hydroperoxides are reduced and detoxified. To prove whether the higher abundance of the Prxs was due to enhanced S-nitrosation or due to changes in their basal expression levels, immunoblotting with specific antibodies was applied and revealed upregulation of Prx VI in tg-iNOS
+
/myo
−/−
hearts. The other proteins found to be S-nitrosated were identified as well. Data mining indicated a significant overlap of these proteins with proteins becoming glutathiolated. Protein glutathiolation detected by immunoblotting was enhanced in the tg-iNOS
+
hearts and even more so in the tg-iNOS
+
/myo
−/−
hearts. We conclude that protein glutathiolation in our transgenic model of nitrosative stress is important to protect protein thiols from irreversible oxidation. The upregulation of antioxidant proteins like Prx VI appears to be an additional mechanism to antagonize an excess of reactive oxygen/nitrogen species. Enhanced S-nitrosation of the Prxs may serve a new function in the signalling cascade coping with nitrosative stress.
Abstract 3646: Supplement with Omega-3 Fatty Acids Lowers Pulse Wave Velocity in Obese Adolescents
Authors: Dangardt Frida , Osika Walter , Chen Yun , Gronowitz Eva , Strandvik Birgitta , Friberg Peter
Published: July 2021

Introduction:
Compared with normal-weight adolescents, obese adolescents show higher ratio between omega-6 (n6) and omega-3 (n3) polyunsaturated fatty acids (PUFA) in plasma phospholipids. They also show increased arterial stiffness, which is related to development of atherosclerosis. Regular diet and lifestyle interventions have low compliance, while a standardized supplement of fish-oil is easy to define and administer.

Hypothesis:
Supplementation of n3 lowers the plasma n6/n3 PUFA ratio and lowers arterial stiffness measured by pulse wave velocity (PWV) in obese adolescents.

Methods:
25 obese adolescents (13 females, 12 males, age 15.4 ±1.1 yrs, BMI 34.1 ±4.3) were recruited and randomized to intake of capsules containing either n3 (186 mg eicosapentaenoic acid and 58 mg docosahexaenoic acid), or placebo (palmitic acid), 2x5 capsules, for 3 months. The study was performed in a double-blind, cross-over design with 6 weeks washout period. Weight, height, waist, hip and blood pressure measurements as well as fasting blood samples were obtained before and after each treatment period. PWV was measured after each respective treatment period.

Results:
The plasma n6/n3 PUFA ratio was reduced by 43 % from 6.8 ± 2.1 (p<0.0001) with n3 treatment, and was not affected by placebo treatment. The plasma triglycerides were reduced by 21% from 1.2 ±0.5 (p=0.001) with n3 treatment, but not placebo. The plasma n6/n3 PUFA ratio difference between n3 and placebo treatment was correlated to the difference in PWV (r=0.43, p=0.03) indicating that the lowering of n6/n3 ratio results in lowering PWV. There were no changes in weight, height, waist, hip or blood pressure.

Conclusion:
Supplementation with n3 capsules of 5 g/day decreases the ratio between n6/n3 PUFA and triglycerides in plasma and is associated with a lowering of arterial stiffness in obese adolescents.
Abstract 3652: Coronary Heart Disease Prevention in Women: The Prognostic Significance of Subclinical Atherosclerosis by Carotid Ultrasound
Authors: Akosah Kwame O , McHugh Vicki L , Mathiason Michelle A
Published: July 2021

Background
: The difficulty of coronary heart disease (CHD) prevention in women is recognized. Reasons include gender disparities in accuracy rates of current diagnostic tests and clinical presentation.

Objective
: Assess the utility and prognostic significance of carotid atherosclerosis in predicting CHD in women.

Methods
: Women (n=140) scheduled for elective coronary angiography underwent carotid ultrasound and fasting lipid analysis. Subjects were excluded for age (≥ 65), prior history of CHD, and anti-lipid therapy. Severe coronary artery disease (CAD) was defined as stenosis ≥ 50%. Carotid atherosclerosis was defined as IMT ≥ 1 mm in the main body or focal plaque in the main body or bulb. Subjects were followed for a median of 50 months. Future cardiovascular events (CVEs) were defined as Major (death, MI, and stroke), and Any event (Major, revascularization, and new onset heart failure).

Results:
136 women (mean age 53 ± 8) had all data available. 80% (n=108) of subjects were classified as low risk and 1% (n=2) as intermediate risk per Framingham score, with an additional 19% (n=26) having CHD equivalent conditions. Severe CAD was present in 39 (28%) subjects. Carotid atherosclerosis had a sensitivity of 74%, specificity of 49%, and negative predictive value of 83% for CAD. Subjects were categorized into Group 1 (Carotid atherosclerosis, n=79) and Group 2 (no carotid atherosclerosis, n=57). After median follow-up of 50 months, 6 women experienced Major CVEs (Group 1 n = 5; Group 2 n=1). Major event rate for Group 1 was 6.3% vs. 1.8% for Group 2. For Any event, the rates were 22% for Group 1 compared to 9% for Group 2 (p=0.046). The event rates were similar between high-risk (3.8%) and low-risk (3.7%) for Major and 12% vs. 16 % for Any event. Kaplan-Meier survival analysis reveals that women without diagnosis of carotid atherosclerosis enjoyed significantly better event free survival. Negative predictive values for carotid atherosclerosis in predicting angiographic disease, Major events and Any event were 83%, 91% and 98%, respectively.

Conclusion
: Carotid atherosclerosis predicts CVEs in young to middle-aged women without high-risk clinical scores. Women without diagnosis of carotid atherosclerosis enjoy excellent long-term event free survival.
Abstract 3655: Esimating Lifetime Risk for Cardiovascular Disease in Men and Women: How well does the Framingham Risk Score Add Up?
Authors: Berry Jarett D , Lloyd-Jones Donald M
Published: July 2021

Background

: The AHA and ACC recommend summing sequential 10-year risk estimates as a surrogate for direct lifetime risk estimation. Because the accuracy of this method is unknown, we sought to compare this indirect method with a direct estimate of lifetime risk.

Methods and Results

: We defined five mutually exclusive risk strata (all optimal risk factors, ≥1 not-optimal risk factor, ≥1 elevated risk factor, 1 major risk factor, or ≥ 2 major risk factors) based on a previously published algorithm for men and women at age 50 years. We entered combinations of risk factors corresponding to the definition of each stratum into the online Adult Treatment Panel III risk assessment tool. We created an indirect lifetime risk estimate for each risk stratum by summing the 10-year risk at ages 50-, 60-, and 70 years, comparing it to our previously published direct estimate of lifetime risk at age 50 years. Summed versus directly estimated lifetime risks for men in the 5 strata were: 30% vs 5%; 36% vs 36%; 46% vs 47%; 47% vs 50%; and 83% vs 69%. In women, the summing method substantially under-estimated remaining lifetime risks in most strata: 5% vs 8%; 7% vs 27%; 11% vs 39%; 12% vs 39%; and 32% vs 50%. Representative data from women are shown in figure

.

Conclusions

: The indirect approach of summing 10-year risk estimates overestimated lifetime risk in men with low risk factor burden, but was generally accurate in men at higher risk. In contrast, the indirect approach substantially underestimated lifetime risk in women with any risk factors above optimal levels.

Figure:

Comparison of Summed vs. Lifetime Risk Estimates in Women
Abstract 3660: Cardioprotective Effect of Eicosapentaenoic Acid, an Important Fish Oil, through Suppression of Endothelin-1-induced Cardiomyocyte Hypertrophy via PPAR-α
Authors: Shimojo Nobutake , Jesmin Subrina , Soma Masaaki , Maeda Seiji , Miyauchi Takashi , Aonuma Kazutaka
Published: July 2021

A growing body of evidences report the cardiovascular benefit of fish oil including eicosapentaenoic acid (EPA) in humans and experimental animals. While many studies link EPA to cardiac protection, the effect of EPA on endothelin (ET)-1-induced cardiomyocyte hypertrophy is unknown. On the other hand, the previous study demonstrated peroxisomal proliferator-activated receptor (PPAR) -α ligand (fenofibrate) prevents ET-1-induced cardiomyocyte hypertrophy. Though EPA is one of the lignads of PPAR-α, there was no study linking relationship between EPA and PPAR-α on hypertrophied cadiomyocyte. The present study investigated whether ET-1-induced cardiomyocyte hypertrophy could be prevented by the pre-treatment of EPA. Cardiomyocytes were accumulated from neonatal rat heart, cultured and at day 4 of culture, the cardiomyocytes were divided into three groups: control, ET-1 (0.1nM) treated and EPA-pre-treated (10μM) ET-1 groups. A 90% increase in cardiomyocyte surface area, a 75% increase in protein synthesis rate and an elevated actinin expression in cardiomyocyte were observed after ET-1 administration and these changes were greatly prevented by EPA pre-treatment. ET-1-induced hypertrophied cardiomyocytes showed a 2.3-fold and 2.1-fold increase in ANP and BNP mRNA expression, respectively, which were also suppressed by EPA pre-treatment. Pre-treatment of EPA could also attenuate phosphorylated JNK (an important component of MAPK cascade), c-Jun and PPAR-α in ET-1-induced hypertrophied cardiomyocytes. In conclusion, the present study showed that ET-1 can induce significant hypertrophic changes in cardiomyocytes with upregulation of important hypertrophic markers, and that this remodeling was effectively prevented by the pre-administration of EPA through suppressing PPAR-α, phosporylated JNK, and c-Jun.