bluuebunny/crossref_metadata_2025 huggingface dataset:
Common Genetic Influences on fasting insulin and waist circumference: The Japanese American Family Study
Authors: Edwards Karen L. , Monks Stephanie A. , LeBoeuf Renee , Leonetti Donna , Talmud Philippa J. , Humphries Steve , Austin Melissa A. , Fujimoto Wilfred Y.
Published: March 2022

P13

The Insulin Resistance Syndrome (IRS) increases risk for both cardiovascular disease (CVD) and diabetes. While the underlying defect may be insulin resistance itself, others have suggested that central adiposity is the primary defect. Further, these risk factors are highly interrelated, but it is not known if genetic and/or environmental factors influence this relationship. The purpose of this analysis was to evaluate evidence for shared genetic and environmental effects on the covariation of fasting plasma insulin level (FI), a marker for insulin resistance, and waist circumference (WC) in 315 Japanese Americans with complete data (in 38 families) participating in the Japanese American Family Study, in Seattle. Subjects ranged in age from 18-94 (mean=54.8, SD=16), and 52% were female. Insulin was measured from a fasting blood sample, and waist circumference was self-measured using a tape measure and specific instructions provided to each participant. Quantitative genetic analysis was used to evaluate genetic (ρ

G

) and environmental (ρ

E

) correlations between FI and WC, adjusting for age, gender, and body mass index. A significant (p<0.05) proportion of the variance in each trait was attributable to additive genetic effects: heritability =0.29 and 0.23 for FI and WC, respectively. The strong and significant (p<0.01) ρ

G

=0.83 reflects shared genetic influences between FI and WC, indicating that the majority of genes that influence FI also influence WC. Further, ρ

G

was not significantly different from 1.0, suggesting the possibility of nearly complete genetic pleiotropy between these risk factors (i.e. that FI and WC share all their genes in common). Estimated ρ

E

=-0.08, but

was not significantly different from zero. These results are the first to suggest complete pleiotropy between FI and WC. Incorporating these results into future gene mapping studies should increase power to detect susceptibility genes for not only CVD and diabetes, but also central adiposity.
Apo E Effects on Blood Cholesterol Are Independent of Growth and Maturation in Adolescent Girls: Project HeartBeat!
Authors: Dai Shifan - , Fulton Janet E. , Grunbaum Jo Anne , Boerwinkle Eric , Labarthe Darwin R.
Published: March 2022

P15

Apolipoprotein E polymorphism (apo E) is a genetic determinant of lipid and lipoprotein levels and subsequent risk for CHD. We have previously demonstrated that girls with ε3/3 or ε3/4 genotypes had both higher total (TC) and LDL-cholesterol (LDL-C) throughout ages 8 to 18 compared with those with the ε2/3 genotype. The current analysis further explored potential confounding or interaction effects of physical growth, body composition, sexual maturation, and endocrine function with apo E. In Project HeartBeat!, a mixed longitudinal study of CVD risk factor development in children, apo E genotyping was performed among 331 girls aged 8, 11, and 14 years at baseline. Plasma lipid concentrations, weight, height, body mass index (BMI), skinfolds, fat free mass (FFM), percent body fat (%BF), Tanner stage (pubic hair, PH), and endocrine function (estradiol, EST) were determined by standard methods 3 times a year for up to 4 years. Analyses were restricted to 247 Caucasian girls. The numbers of measurements used ranged from 1090 to 1960 according to the combination of variables in different multilevel linear models. FFM, BMI, %BF, PH, and EST each showed a significant effect on TC and LDL-C whether tested alone or included in models containing age (age, age

2

, and age

3

), apo E (ε2/3, ε3/3, and ε3/4), and age-apo E interaction terms. Age, apo E, and age-apo E interaction terms were strong, independent determinants of TC and LDL-C. Except for a ε3/4-by-%BF interaction, all 2-way interaction effects between apo E and FFM, BMI, %BF, PH, and EST were not significant in either TC or LDL-C models (P>.05). We conclude that the apo E effects on age-related serial changes in TC and LDL-C are independent of physical growth, body composition, sexual maturation, and estradiol level in normal adolescent girls. Girls with ε3/3 or ε3/4 genotypes may be at higher risk for elevated TC and LDL-C later in life. These genotypes were found in 85% of the study population and may be important to identify in intervention studies or in clinical practice to evaluate responsiveness to lipid-lowering therapy.
Quantitative genetic analysis of lipoproteins in Finnish hyperlipidemic families
Authors: Edwards Karen L. , Pihlajamaki Jussi , Austin Melissa A. , Laakso Markku
Published: March 2022

P16

Familial combined hyperlipidemia (FCHL) is a common familial dyslipidemia associated with CVD risk. FCHL is characterized by higher levels of apolipoprotein B (ApoB),triglyceride (TG), smaller low-density lipoprotein particle size (LDL size) and lower high-density lipoprotein cholesterol (HDLC). The purpose of this analysis was to evaluate evidence for shared genetic effects between these fasting measurements in 365 subjects in 37 Finnish FCHL families. Mean age was 48 yrs (SD=16), 50% were male. Quantitative genetic analysis was used to evaluate the genetic (ρG) and environmental (ρE) correlations between each pair of risk factors (RF) adjusting for age and sex. Heritability was significant(p<0.02) for each RF. The ρG for each pair reflects shared genetic influences, i.e. genes that influence variation in both RF of the pair. The ρG’s for LDL size and both TG and HDLC suggest that these RF share a majority of genes in common. ρG for ApoB and TG shows that these RF also share genes in common, suggesting that at least two sets of genes influence the lipoprotein RF characterizing FCHL. Shared environmental (ρE) factors also contribute to the covariation in each pair. Using this information in mapping studies may improve power to detect genes underlying these lipoprotein abnormalities, and lead to a better understanding of genetic susceptibility to CVD in FCHL.

Table 1.
Is the Heat Labile Variant of Methylene Tetrahydrofolate Reductase (MTHFR-HL) Associated with Elevated Plasma Total Homocysteine (tHcy) and Premature Coronary Artery Disease (CAD)?
Authors: Hopkins Paul N. , Rozen Rima , Hunt Steven C. , Wu Lily L.
Published: March 2022

P18

Patients with premature CAD (onset ≤55 in males, ≤65 in females) generally have higher tHcy while MTHFR-HL has been inconsistently associated with CAD. To address this issue we determined MTHFR genotype (HL vs wild type = WT), and measured tHcy, plasma folate, vitamins B12 and B6, and standard risk factors in 224 (74% male, mean age 56.0 ± 6.0) patients with premature, familial CAD (cases) and in 146 controls (56% male, mean age 48.7 ± 6.5). As expected, tHcy was significantly higher in cases (p < 0.0001) and in subjects with low folate (<16 nmol/L, p <0.0001). Furthermore, there was a significant interaction between case status, MTHFR-HL homozygosity (HL/HL), and low folate as shown in the

figure (shown are least-square means ± 95% CI; p = 0.0072 for interaction term; “other” refers to WT/WT and WT/HL genotypes). However, the frequency of MTHFR-HL homozygosity was not different in cases (10.71%) versus controls (10.96%), nor was there an excess of risk associated with having both HL/HL and low folate though numbers were small (4.9% of cases versus 4.1% of controls). Thus, the MTHFR-HL variant may contribute to high tHcy in premature CAD cases with low folate status, but a direct effect of MTHFR-HL on CAD risk appears to be unlikely, at least in populations with sufficient folate intake.

Figure 1.
Plasma Concentration of Interleukin-6 and C-reactive Protein and the Risk of Developing Type 2 Diabetes Mellitus Among Healthy Middle-Aged Women
Authors: Pradhan Aruna D. , Manson JoAnn E. , Buring Julie E. , Ridker Paul M.
Published: March 2022

P02

Background Inflammation may play an important role in the development of type 2 diabetes mellitus. We studied whether plasma concentrations of the inflammatory markers, interleukin-6 (IL-6) and C-reactive protein (CRP), are related to the development of type 2 diabetes in women. Methods We conducted a prospective, nested case-control study among a cohort of middle-aged female health professionals free of diagnosed diabetes mellitus, cardiovascular disease, and cancer to assess the risk of incident type 2 diabetes over a four-year period associated with baseline levels of IL-6 and high-sensitivity CRP (hs-CRP). A diagnostic threshold of 6.5% for hemoglobin A1c (HbA1c) was used to exclude prevalent undiagnosed diabetes. Results Baseline levels of IL-6 (P<0.001) and hs-CRP (P<0.001) were significantly higher among women who subsequently developed diabetes mellitus compared to those who did not. The relative risks of future diabetes for women in the highest as compared to the lowest quartile of these inflammatory markers were 7.5 for IL-6 (95% CI, 3.7 to 15.4) and 15.7 for hs-CRP (95% CI, 6.5 to 37.9). These effects persisted after adjustment for body-mass index, family history of diabetes, smoking, exercise, use of alcohol and hormone replacement therapy; adjusted relative risks for the highest versus lowest quartile were 2.3 for IL-6 (95% CI, 0.9 to 5.6; P-trend = 0.066) and 4.2 for hs-CRP (95% CI, 1.5 to 12.0; P-trend = 0.001). Similar results were seen in analyses limited to individuals with HbA1c ≤ 6.0% and after adjustment for fasting insulin levels. Conclusions Plasma concentrations of interleukin-6 and C-reactive protein are associated with an increased risk of developing type 2 diabetes mellitus in middle-aged women. These data support the inflammatory hypothesis of diabetogenesis.
A Cross-Sectional Analysis of the Relationship Between Hormone Replacement Therapy and Coronary Artery Calcification
Authors: Gallagher Amy M. , Schisterman Enrique F. , Merz Noel Bairey , Lewin Howard C. , Hayes Sean W. , Friedman John D. , Miranda Romalisa S. , Ledesma Arlene , Berman Daniel S.
Published: March 2022

P24

Background: There is evidence that estrogen affects the vascular wall, independent of modifications to plasma lipoproteins, by accelerating reendothelialization of damaged blood vessels and by inhibiting smooth muscle cell proliferation. Therefore, we intended to investigate the relationship between hormone replacement therapy (HRT) use and prevalence of coronary calcium (CC) in postmenopausal women. Methods: Cardiac electron beam computed tomography (EBCT) was performed on 793 postmenopausal women participating in the Cedars-Sinai Cardiovascular Observational Study. At the time of their EBCT, 509 women were receiving HRT and 284 were not receiving HRT. The total coronary calcium score was determined using the Agatston method. A self-report of HRT use was assessed in all participants, as well as measurements of other known cardiovascular risk factors. Results: Independent sample t-tests identified the means of the following variables as significantly different between the two groups of women: age, LDL, HDL, and BMI. Self reports of hypertension, smoking, exercise and diet were similar between the two groups. Analysis of variance, controlling for confounders, showed a significant difference (p<.001) between the marginal means (MM) of the two HRT groups for total coronary calcium score, total number of calcified lesions, and total volume of calcium. The MM total CC score was 96.40 (±256.39) for HRT users and 150.97 (±362.54) for non-users. The MM number of lesions for users was 2.16 (±3.37) and 3.36 (±4.75) for non-users. The MM volume of calcium for users was 0.078 (±0.20) and 0.122 (±0.29) for non-users. Conclusions: Total coronary calcium score, total lesions, and total volume were found to be significantly lower in postmenopausal women receiving HRT than for those not receiving HRT. These findings support the hypothesis that hormone replacement therapy is associated with a lower prevalence of coronary calcium in postmenopausal women, which may be due to the independent effects of estrogen on coronary vessel walls.
Long-term Survival of Hospitalized Patients with a Heart Failure Discharge Code: Early Experience of a Community-Based Study
Authors: Kim Joseph , Shahar Eyal , McGovern Paul G. , Barber Cheryl , Duval Sue , Luepker Russell V.
Published: March 2022

P47

Survival after hospitalization for heart failure (HF) is poorly described in the community setting, particularly after accounting for the type of admission. We performed an interim analysis (n=3,627) of data gathered from a 50% random sample of patients 35-84 years old who were discharged in 1995 from Twin Cities area hospitals with an ICD9 428 code (HF). Patients were classified by case-type: I (incident case, admitted for HF), II (prevalent case, admitted for HF), III (incident case, developed HF during hospitalization), IV (prevalent case, HF progression during hospitalization), and V (prevalent case, hospitalization unrelated to HF). Follow-up through 1998 was performed using a statewide death certificate registry. The

table below shows heterogeneity of short and long-term survival by case-type. Prevalent cases with evidence of HF progression on admission (case-type II) or during hospitalization (case-type IV) had the worst 3-year survival. Patients with evidence of HF progression after an admission that was unrelated to HF (case-types III and IV) had a higher 28-day mortality than those admitted for HF (case-types I and II); however, these differences dissipated after 3 years of follow-up. A hospital-based perspective of the epidemiology of HF should consider the five different case-types behind a HF discharge code.

Table 1.
Left Ventricular Ejection Fraction Assessment in Patients with Congestive Heart Failure
Authors: Larson Jane M , Harper Carolyn V , Redberg Rita
Published: March 2022

P48

Background: The US Agency for Health Care Policy and Research guidelines state that any patient with suspected heart failure should have ejection fraction assessment performed. This study describes factors associated with left ventricular ejection fraction (LVEF) assessment in patients with congestive heart failure (CHF). Methods: A random sample of 1608 patients aged 65 and older were selected from all fee-for-service Medicare beneficiaries discharged from California hospitals in 1998 with a principal diagnosis of CHF. Patients were excluded if a diagnosis of CHF was not confirmed, if the patient died, was transferred to another acute care facility, left against medical advice, or had a procedure code for dialysis. The outcome measure was LVEF assessment. Results: After exclusions, 1562 patients remained of whom 1000 (64%) had LVEF either assessed during this hospitalization, prior to this hospitalization, or had a documented plan for LVEF evaluation after discharge. In multivariate analysis, controlling for age, gender, race, and past history of CHF, patients who did not have a LVEF assessment were less likely to have been prescribed an angiotensin converting enzyme (ACE) inhibitor (Odds Ratio=0.25, 95% Confidence Interval=0.20-0.31). Patients age 85 years and older were less likely to have LVEF assessed (OR=1.52, 95% CI=1.13-2.05). Conclusion: CHF patients who do not have a LVEF assessment are much less likely to receive an ACE inhibitor. Over one third of CHF patients do not undergo LVEF assessment, contributing to under-prescription of ACE inhibitors in CHF. Efforts to improve quality of care for CHF patients may need to promote LVEF assessment as a first step in CHF management.
Leptin in Relation to Hypertension: The Role of Obesity in the Insulin Resistance Atherosclerosis Study (IRAS)
Authors: Smith Sharon M , Mayer-Davis Elizabeth J
Published: March 2022

P53

Background: Leptin, a protein secreted by adipose tissue, has actions that may affect blood pressure via energy balance, insulin sensitivity and/ or the central nervous system. Purpose: The purpose of this abstract is to evaluate the association between leptin level and blood pressure in the multi-center, tri-ethnic Insulin Resistance Atherosclerosis Study (IRAS) population. Methods: IRAS participants (n=1507) were age 40-69 years; 56% female; mean body mass index (BMI)= 29 kg/m2; and 39% hypertensive. Main exposure: multi species leptin radioimmunoassay was used to quantify leptin concentrations (Linco Research Inc., St. Louis, MO; range 0-122.19ng/ml). Main outcome: Main outcome was hypertension (Yes/No), defined as a systolic >=140mm Hg and/ or a diastolic reading of >=90mm Hg or taking antihypertensive medication. Analysis: Logistic regression was used to analyze the relationship between leptin and hypertension, while adjusting for age, dietary fat, gender, activity, ethnicity and clinic. Final models evaluated the role of obesity. Results: The proportion of individuals that were hypertensive by quartile was 28%, 40%, 40% and 49%, respectively. The odds of being hypertensive was 1.60 (p=0.0001) times higher for every 16ng/ml (1 SD) change in leptin after adjusting for age, gender, dietary fat, ethnicity and clinic site, and energy expended (n=1507). The role of BMI (leptin*BMI) was considered, resulting in a reduction of leptin’s effect on hypertension (p=0.02 for the interaction term). The overall odds ratio for being hypertensive per 16ng/ml (1 SD) change was 1.80 (p=0.04) with an attenuation of the effect as BMI increased (estimated OR for BMI of 22, 27 and 32 was 1.23, 1.14, and 1.05 respectively). Analysis were repeated excluding those with diabetes (n=999) and results were essentially unchanged. Conclusion: Increased leptin is associated with increased occurrence of hypertension and its effect is attenuated by increasing BMI. Future work is necessary to confirm and explain these results.
Characterization of Stroke Signs and Symptoms: Findings from the Atherosclerosis Risk in Communities Study
Authors: Rathore Saif S , Rosamond Wayne D , Cooper Lawton S , Chambless Lloyd E , Tyroler Herman A , Hinn Albert R
Published: March 2022

P59

Background: Although patterns of stroke occurrence and mortality have been well studied, little epidemiologic data are available regarding the clinical characteristics of stroke events. Methods: We evaluated hospitalized stroke events reported in the Atherosclerosis Risk in Communities Study to describe the clinical characteristics of incident stroke. Incident confirmed stroke cases (n=474) were evaluated for stroke symptoms including headache, vertigo, gait disturbance, and convulsions. Cases were also evaluated for stroke signs including hemianopia, diplopia, speech deficits, paresis, and parasthesia/sensory deficits. Stroke characteristics were also evaluated for univariate associations with race, gender, and stroke subtype. Results: Over an average follow-up of 9.2 years, 407 (86%) ischemic and 67 (14%) hemorrhagic strokes occurred. Stroke symptoms in order of decreasing frequency (95% confidence intervals) were headache (27.4%, 23.4%-31.4%), gait disturbance (10.8%, 7.9%-13.6%), convulsions (4.4%, 2.6%-6.3%), and vertigo (2.1%, 0.8%-3.4%). Speech deficits occurred in 64.1% (59.8%-68.5%), hemianopia in 14.6% (11.4%-17.7%), and diplopia in 5.5% (3.4%-7.5%) of cases. Most cases involved paresis (81.6%, 78.1%-85.1%), predominantly of the arms (75.5%, 71.6%-79.4%). Fewer subjects experienced sensory deficits (44.5%, 40.0%-49.6%), predominantly in the arms (38.6%, 34.2%-43.0%). Blacks were more likely than whites to experience paresis (85.8% vs 77.9%, p=0.03). Men were more likely than women to experience a gait disturbance (14.3% vs 6.7%, p=0.001). As expected, persons with hemorrhagic strokes had a higher proportion of headaches (59.7% vs 22.1%, p=0.001) and convulsions (11.9% vs 3.2%, p=0.001) than those with ischemic events, while speech deficits were more common in ischemic strokes (68.1% vs 40.3%, p=0.001). Conclusions: We present epidemiologic data concerning the clinical characteristics of incident stroke in a population-based cohort. While minor differences by race, gender, and stroke subtype were observed, data from additional follow-up is required to confirm observed variation.
Self-reported Asthma is Associated with Increased Risk of Hospitalization and/or Death Due to Coronary Heart Disease among Never Smoking Men and Women.
Authors: Iribarren Carlos , Eisner Mark D , Go Alan S , Sidney Stephen , Klatsky Arthur L
Published: March 2022

P61

Inflammation is thought to play a crucial role in the pathogenesis of coronary atherosclerosis. Asthma is a chronic inflammatory disease and a major cause of pulmonary morbidity and mortality. However, very few prospective studies exist evaluating the question of whether asthma is related to increased risk of cardiovascular diseases, and none were restricted to never smokers. We examined the prospective association between self-reported asthma diagnosis and risk of hospitalization and/or death due to coronary heart disease (CHD, ICD-9 codes 410-414) in a large population-based sample. Data on self-reported health conditions, including asthma, and cardiovascular risk factors were collected at a health maintenance organization (HMO) in the San Francisco Bay Area between 1979 and 1985. The sample included 14,047 never smoking women and 7,989 never smoking men aged 35-89 years (mean ± SD, 50.4 ± 11.9 years), 56% Caucasian, who were free of known CHD at baseline. Of those, 652 women (4.6%) and 410 men (5.1%) self-reported physician-diagnosed asthma. Follow-up for hospitalization and/or death was available through the end of 1998 (median=13.4 years). Using Cox proportional hazards regression, we censored persons leaving the health plan at their last known date of HMO membership. Compared to subjects with no-known history of asthma, and after adjustment for age, sex, race, education level, alcohol consumption, body mass index, serum cholesterol, systolic blood pressure and diabetes, self-reported asthma was significantly associated with higher risk of hospitalization and /or death due to CHD (RR=1.33; 95% CI=1.05-1.67; p=0.02). Also in multivariate analysis, asthma under treatment at the time of the baseline examination was more strongly associated with CHD risk (RR=1.82; 95% CI=1.23-2.69; p=0.003). No interactions were found between self-reported asthma or asthma under treatment and patient sex. We conclude that, in a large representative population-based sample of non-smokers, self-reported asthma was associated with increased risk of coronary heart disease.
The impending epidemic: insulin resistance syndrome (IRS) in a representative sample of youth in Quebec, Canada.
Authors: Paradis Gilles , Lambert Marie , O’Loughlin Jennifer L , Lavallee Claudette , Levy Emile , Delvin Edgar
Published: March 2022

P69

Background: Although its prevalence is increasing in adults, there are no data available on precursors of type 2 diabetes, particularly IRS, from representative samples of children in North America. Methods: The Quebec Youth Heart Survey was designed to study the behavioral, biological and genetic correlates of CVD risk factors in a representative probability sample of Quebec youth surveyed with an age-specific questionnaire, standardized clinical measurements and a blood draw during Winter 1999. We studied the correlates of IRS among 735, 773 and 842 individuals aged 9, 13 and 16 years respectively (79.6% French-Canadians). Response rates were 80% for questionnaire and clinical measures and 58.4% for blood draw. Those who declined blood draw were not significantly different for gender, blood pressure (BP), weight, smoking status, urban or rural residence or parental income or education. All biochemical measures were CDC-standardized. Results: In all age-sex categories, HDL-C levels decreased significantly across insulin quartiles while triglycerides (TG), glucose, BMI, tricipital and subscapular skinfolds and BP increased (all p < 0.01). In contrast, no consistent association was observed between insulin quartiles and total cholesterol, LDL-C and apoB. In all age-sex categories, the number of other CVD risk factors (glucose ≥ 6.1 mmol/L, BMI ≥ 85th percentile, systolic BP ≥ 90th percentile, and dyslipidemia (upper quartile for TG and lower quartile for HDL-C) increased significantly across insulin quartiles (all p < 0.001). The prevalence of IRS (defined as 3 or more of hyperinsulinemia (upper quartile) or other CVD risk factors listed above) was as follows: 5.2% and 5.1% of 9-year old boys and girls, 6.9% and 6.7% of 13-year old boys and girls, 9.0% and 5.8% of 16-year old boys and girls, respectively. The prevelence of IRS was similar in French-Canadians and those of other ethnic origins. Conclusion: IRS is highly prevalent in youth, even among children as young as 9 years old and is associated with an atherogenic profile which, if it persists in adulthood, could be associated with a substantial public health burden in the near future.
Joint Linkage and Association Analysis of Hepatic Lipase Promoter Polymorphism and Lipoprotein Size Phenotypes
Authors: Almasy Laura , Rainwater David L. , Cole Shelley , Mahaney Michael , VandeBerg John , Hixson James E. , Stern Michael P. , MacCluer Jean W. , Blangero John
Published: March 2022

P07

The hepatic lipase gene (LIPC) has repeatedly been implicated as a potential regulator of HDL cholesterol concentration and HDL and LDL particle size. Association studies have centered on a C to T transition in the promoter of LIPC, 514 base-pairs upstream of the transcription initiation site. We performed a genome-wide linkage screen for several lipoprotein size phenotypes and tested for association of these traits with LIPC -514C->T in 798 individuals from 23 families in the San Antonio Family Heart Study. Median diameter was measured for HDL particles stained for apoAI (A1), apoAII (A2), unesterified (UC), and esterified (EC) cholesterol as well as for LDLs stained for EC. A subset of 479 people in 10 of the largest families was genotyped for a 10 cM genetic map, including 19 markers on chromosome 15. Variance component-based multipoint linkage analyses (using all available markers), measured genotype association analyses (with LIPC -514C->T), and joint linkage/association analyses were performed with SOLAR. Median diameter of HDL-A1 and HDL-UC exhibited significant evidence of linkage to the LIPC region (LODs = 3.79 and 3.56 respectively) whereas HDL-A2, HDL-EC, and LDL-EC sizes showed suggestive evidence of linkage (LODs of 1.78 to 2.71). Association with -514C->T was detected for HDL-A1, HDL-A2, HDL-UC, and HDL-EC median diameters (p < 0.001) but not for LDL-EC median diameter. If -514C->T is the functional site within LIPC responsible for the observed linkages and associations, the LOD score will drop to 0 when -514C->T is included in the trait model. Conversely, if -514C->T is in linkage disequilibrium with another site or is one of several functional sites, evidence for linkage will remain in the joint analyses. Linkage analyses of HDL-A1 and HDL-UC sizes conditional on -514C->T reduced the LOD scores in the LIPC region only slightly (LODs of 3.16 and 3.49 respectively). This suggests that the -514C->T polymorphism can not explain the observed linkage of lipoprotein size phenotypes to the LIPC region and, therefore, that there are one or more additional functional mutations in or near LIPC influencing HDL, and potentially LDL, size variation.
Is the Relationship Between Serum β-carotene and Cardiovascular Disease (CVD) Risk Confounded by Inflammation?
Authors: Erlinger Thomas P. , Guallar Eliseo , Stolzenberg-Solomon Rachael , Miller Edgar R. , Appel Lawrence J.
Published: March 2022

P80

Background: In observational studies, low serum β-carotene levels have been associated with an increased risk of CVD and cancer. However, in clinical trials, supplementation of diet with β-carotene has had no benefit. This pattern of findings raises the possibility that confounding with other factors may explain the association of serum β-carotene with disease risk. Objective: To determine the association between serum β-carotene levels and markers of inflammation. Setting: 14,470 participants, ages 17 years and older, in NHANES III. Results: In multivariate models that adjusted for β-carotene intake and other factors associated with serum β-carotene, the geometric means of serum β-carotene for those with undetectable (<0.22 mg/dl), mildly elevated (0.22-0.99 mg/dl) and clinically elevated (≥ 1.0 mg/dl) CRP were 18.0, 16.1 and 13.6 μg/dl in never smokers (P-value for trend < 0.001), 18.1, 15.7 and 13.9 μg/dl in ex-smokers (P-value for trend < 0.001), and 11.3, 10.2 and 9.4 ìg/dl in current smokers (P-value for trend < 0.001). In corresponding analyses, WBC count was inversely related to serum β-carotene (P-value for trend <0.05 in each group). Conclusions: Serum β-carotene is strongly and inversely related to systemic inflammation. These results suggest that the relationship between serum β-carotene and disease risk is confounded by inflammation, which itself is a risk factor for CVD and perhaps cancer. More broadly, these results highlight the potential limitations of using serum nutrient levels as a surrogate for dietary intake.

Figure 1.
Dietary Fiber Intake and Reduced Risk of Coronary Heart Disease in US Men and Women
Authors: He Jiang , Bazzano Lydia A , Ogden Lorraine G , Loria Catherine M , Myers Leann , Whelton Paul K
Published: March 2022

P81

We examined the relationship between dietary fiber intake and the risk of coronary heart disease (CHD) in 3,745 men and 6,031 women who participated in the NHANES I Epidemiologic Follow-up Study and were free of cardiovascular disease (CVD) at their baseline examination. A 24-hour dietary recall was administered at the participant’s baseline examination and nutrient intakes were recalculated using the ESHA databases. Other important risk factors for CVD including age, sex, race, serum cholesterol level, blood pressure, body mass index, history of diabetes, level of education, physical activity, cigarette smoking, and alcohol consumption were also measured at baseline. These risk factors and dietary intakes of saturated fat and total energy were used for adjustment in multivariate analyses. Data for estimation of CVD incidence were obtained from medical records and death certificates. Cox proportional hazard models were used to examine the relationship between dietary fiber intake and risk of CVD. Over an average of 19 years of follow-up, we documented 1,843 CHD events (668 fatal) and 3,762 CVD events (1,198 fatal). Compared with those in the lowest quartile of total dietary fiber intake (median, 4.6 g/d), participants in the highest quartile (median, 20.6 g/d) had an adjusted relative risk (RR) of 0.81 (95% confidence interval [CI], 0.67−0.97, p=.008 for trend) for CHD events and 0.85 (95% CI: 0.76−0.95, p=.001 for trend) for CVD events. The corresponding adjusted RR for those in the highest (median, 5.4 g/d) compared with those in the lowest (median, 0.7 g/d) quartile of water-soluble dietary fiber intake was 0.81 (95% CI, 0.71−0.93, p=.004 for trend) for CHD events and 0.88 (95% CI, 0.80−0.96, p=.02 for trend) for CVD events. Our findings support the hypothesis that a higher intake of dietary fiber, particularly water-soluble fiber, reduces the risk of CHD. Furthermore, our findings suggest that increasing dietary fiber intake may be an important component of dietary approaches to prevention of CHD in the community.
Controlled Comparison of L-Folinic Acid Versus Folic Acid for the Treatment of Hyperhomocysteinemia in Hemodialysis Patients
Authors: Yango Angelito , Shemin Douglas , Dworkin Lance , Jacques Paul F , Selhub Jacob , Bostom Andrew G
Published: March 2022

P85

Background:The hyperhomocysteinemia found in most hemodialysis patients is refractory to combined oral B-vitamin supplementation featuring supraphysiological doses of folic acid. We evaluated whether a high dose L-folinic acid based regimen provided improved total homocysteine (tHcy) -lowering efficacy in chronic hemodialysis patients, as suggested by a recent uncontrolled report. Methods and Results: We block randomized 48 chronic, stable hemodialysis patients based on their screening pre-dialysis tHcy levels, sex, and dialysis center, into 2 groups of 24 subjects treated for 12-weeks with oral folic acid (FA) at 15 mg/day, or an equimolar amount (20 mg/day) of oral L-folinic acid(FNA)[L-5-formyltetrahydrofolate]. All 48 subjects also received 50 mg/day of oral vitamin B6, and 1.0 mg/day of oral vitamin B12. The mean percent (%) reductions (with 95% confidence intervals) in pre-dialysis tHcy were not significantly different: FNA= 22.1% (11.8-31.4%) ; FA=20.7% (11.7-30.5%) ; P= 0.950 by paired t-test. Final on-treatment values (mean with 95% confidence interval) were, FNA: 15.9 μmol/L (14.0-18.0); FA: 16.9 μmol/L (14.8-18.8). Moreover, in those subjects with baseline tHcy levels ≥14 μmol/L, neither treatment resulted in normalization of tHcy levels (i.e., final on-treatment values < 12 μmol/L) among a significantly different, or clinically meaningful number of patients: FNA= 2/22 (9.1%); FA= 2/24 (8.3%); Fisher s exact test of between groups difference, P=1.000. Conclusions: Relative to high dose folic acid, high dose oral L-folinic acid -based supplementation does not afford improved tHcy-lowering efficacy in hemodialysis patients. The preponderance of hemodialysis patients (i.e., > 90%) exhibit mild hyperhomocysteinemia refractory to treatment with either regimen.
Predictors of seven-year change in homocysteine concentrations in the Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Loria Catherine M , Roseman Jeffrey M , Hilner Joan E , Cornwell Phillip E , Schreiner Pamela J , Siscovick David S
Published: March 2022

P87

While blood level of total homocysteine (tHcy) is inversely related to folate intake in cross-sectional studies, few prospective studies have examined changes in tHcy, folate intake, and cardiovascular disease (CVD) risk factors. Serum tHcy was measured on 755 18-30 year old participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study using stored samples from 1985-86 (baseline) and 1992-93 (Year 7), collected prior to food fortification with folic acid. Geometric mean tHcy did not differ by race at baseline (p>0.05). However by Year 7, mean tHcy was higher in blacks than whites (14.3, 13.3, 11.9, 10.9 μmol/L in black men, white men, black women, white women, respectively; p=0.001). Arithmetic mean change in tHcy differed from zero among blacks (1.3-1.4 μmol/L; p<0.001) but not among whites ( -0.3-0.2 μmol/L). Mean folate intake (from diet and supplements) at baseline was higher among whites than blacks within each sex (384, 439, 291, 349 μg, respectively; p=0.001). Although mean folate intake increased in all groups by Year 7, intake was higher among black than white men but the reverse was found among women (517, 496, 339, 421 μg; p for interaction=0.002). In multivariate models, change in tHcy was associated inversely with change in total folate intake in all race-sex groups; changes in smoking status among black men, in serum cholesterol level among whites, and in body mass index among white men were also independent predictors. Thus, tHcy increased over 7 years in blacks by 1.3-1.4 μmol/L (about 1 s.d.) on average, despite increases in folate intake. Changes in CVD risk factor status may help explain this contradictory finding.
Benefits of MEDPED Treatment Support Program (TSP) for Patients with Familial Hypercholesterolemia
Authors: Hopkins Paul N. , Stephenson Susan H. , Larrinaga-Shum Stacey
Published: March 2022

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As prior experience had shown treatment of heterozygous FH was often unsatisfactory, the U.S. MEDPED (Make Early Diagnoses to Prevent Early Deaths) team developed the TSP to empower FH patients to ensure the adequacy of their own care. The TSP consisted of mailed educational materials, baseline and follow-up questionnaires on lipids and medications, and individualized mailed feedback on NCEP goals and medications. There were 386 patients reporting 2 or more lipid levels. There were 6.03 contacts per patient including the baseline, 7.6 months apart. 40% of patients had initial total cholesterol under 240 mg/dl. These showed little additional benefit with follow-up. For the remainder, benefits of TSP participation were substantial as shown in the

table. In repeated measures analysis, major determinants of lipid change were baseline level (p <0.0001), number of contacts with TSP staff (p <0.0001) and an interaction term between these two variables (p=0.05 total-C; p<0.0001 LDL-C) such that patients with higher baseline values saw greater benefit with more contacts. There was a 39% to 45% reduction of total or LDL cholesterol (p <0.0001) in those with the highest quintiles of initial total cholesterol (mean 388 mg/dl) and number of contacts (8 or more).

Table 1.
Effects of Dietary and Exercise Intervention on Progression of Carotid Intima-Media Thickness
Authors: Sutton-Tyrrell Kim , Newman Anne B. , Holubkov Richard , Liebenauer Laura , Simkin-Silverman Laurey , Kuller Lewis H
Published: March 2022

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The Women’s Healthy Lifestyle clinical trial has reported that a dietary and exercise intervention results in the prevention of weight gain and LDL cholesterol rise over a 54 month follow-up in pre-menopausal women approaching menopause (average age 47 at baseline and 52 at final follow-up). During this trial, serial carotid ultrasound was performed in 234 women with an average of 3.5 years between scans. Intima-Media Thickness (IMT) was the mean of measures taken in the right and left common, bulb and internal carotid arteries. The average change in carotid IMT over time was +0.033 mm. Change in IMT was higher among the control than the intervention group (.039 mm vs. .027 mm, p = .172). Among 109 women who had reached menopause by the end of the study, average IMT progression was .058 mm among controls vs. .017 mm among the intervention group (p=.003, a difference of .041 mm). Among HRT users, IMT progression was .037 mm greater among control vs intervention women (N= 60, p = .040) and this difference was .047 mm among HRT non-users (N= 46, p=.035). Linear regression was used to determine whether the treatment effect was independent of minor differences between treatment groups at baseline and changes in vessel diameter over follow-up. After controlling for age, baseline IMT, baseline adventitial diameter, change in adventitial diameter, hysterectomy status, smoking, baseline waist girth and baseline energy expenditure, the treatment effect remained significant (p=.005). Among these postmenopausal women, the control group had greater increases in weight, waist circumference and LDL, and a lower increase in Kilocalories of energy expenditure over follow-up in comparison to the intervention group (p < .01 for all but LDL). When change in each risk factor was tested in the model above, only change in waist girth modified the treatment effect. Increase in waist girth was positively associated with IMT progression (p=.04) and the p-value associated with the treatment effect was reduced from .005 to .04. We conclude that among women entering menopause, a successful dietary and exercise intervention was associated with measurable slowing of atherosclerosis progression.
Home Monitoring Service Improves Mean Arterial Pressure in Patients with Essential Hypertension: A Randomized Controlled Trial
Authors: Rogers Mary A. M. , Small David , Buchan Debra A. , Butch Carl A. , Stewart Christine M. , Krenzer Barbara E. , Husovsky Harold L.
Published: March 2022

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While the use of telecommunication systems in medicine has been increasing, there have been few trials to assess the efficacy of such technology for improving blood pressure (BP) in patients with essential hypertension. A randomized controlled trial (RCT) was conducted to assess the efficacy of an home monitoring service which utilized automatic transmission of BP data over telephone lines, conversion of the data into report form by computer, and facsimile transmission of the form weekly to physicians and patients. One hundred and eleven patients were randomized to either home service or usual care and followed for a median of 11 weeks. The primary endpoint was change in mean arterial pressure (MAP) which was assessed using a 24-hour ambulatory blood pressure monitoring (ABPM) device at both baseline and exit. There was a 3.0 mm Hg decline in MAP from baseline to exit for patients using the home service and a 1.5 mm Hg increase in MAP for patients receiving usual care (p=0.0139). There was a 2.1 mm Hg decline in average diastolic BP (DBP) in the home service group and a 2.3 mm Hg increase in the usual care group (p=0.0120). In addition, the proportion of 24-hour DBP readings above target levels decreased by 6.8% in patients receiving home service, but increased by 6.2% in patients receiving usual care (p=0.0057). The reduction in BP was evident for both genders, for each ethnic group, and for both younger and older patients. For African-Americans, MAP declined by 9.6 mm Hg for those receiving the home service and increased by 5.25 mm Hg for those receiving usual care (p=0.0469). The difference in MAP between the two study arms remained significant after adjustment for patient characteristics. The decrease in BP for home service was, in part, due to more frequent changes in dose and/or type of medication during the course of the trial. This was the first RCT of a home BP service that did not rely on patient self-report and which used 24-hour ABPM at baseline and at exit to assess usual BP. It is recommended that patients with essential hypertension, who are in the process of evaluation for a change in antihypertensive therapy, utilize a home monitoring service.
Relation between Dietary Linolenic Fatty Acid and Coronary Heart Disease in the NHLBI Family Heart Study
Authors: MA  , Pankow James S , Eckfeldt John H , Folsom Aaron R , Hopkins Paul N , Ellison R Curtis
Published: March 2022

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Epidemiologic studies suggest that higher consumption of alpha linolenic acid, eicosapentaenoic acid, and docosahexanoic acid is associated with lower risk of coronary heart disease (CHD). Little is known about the influence of the linoleic-to-linolenic ratio on the relation of linolenic acid to CHD. We used data collected on 4,406 participants of the NHLBI Family Heart Study (mean age of 52 years)to examine the relation between dietary linolenic acid and prevalent coronary heart disease and to determine if such a relation was influenced by fish consumption and linoleic-to-linolenic ratio. Dietary linolenic acid was assessed by semiquantitative food frequency questionnaire. We used generalized estimating equations to estimate the odds ratios of coronary heart disease across age- and energy-adjusted quintiles of linolenic acid. From the lowest to the highest quintile of linolenic acid, the prevalence odds ratios (95 % CI) of coronary heart disease were 1.00 (referent), 0.77 (0.49-1.21), 0.51 (0.32-0.81), 0.52 (0.33-0.84), and 0.48 (0.30-0.76), respectively, for men (p for trend 0.0009) and 1.00, 0.55 (0.29-1.04), 0.75 (0.41-1.38), 0.43 (0.21-0.88), and 0.40 (0.20-0.82), respectively, for women (p for trend 0.015), controlling for age, energy intake, anthropometric, lifestyle, and metabolic factors. This association was observed across all categories of fish consumption frequency. When stratified by tertiles of linoleic-to-linolenic ratio (ranges of 2.3-8.4, 8.5-11.1, and 11.2-64.0), a statistically significant inverse relation between linolenic acid and CHD was observed only in the lowest tertile of linoleic-to-linolenic ratio (p for trend 0.0001, 0.39, and 0.13, respectively, for the first, second, and third tertile of linoleic-to-linolenic ratio). In conclusion, these data suggest an inverse relation between dietary linolenic acid intake and prevalent coronary heart disease in both sexes, independent of fish consumption. A lower ratio of linoleic-to-linolenic fatty acid might be necessary to observe the benefits of linolenic acid on coronary heart disease.
Maternal age and newborn blood pressure
Authors: Gillman Matthew W , Link Carol L , Rich-Edwards Janet W , Lieberman Ellice S , Lipshultz Steven E
Published: March 2022

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Background. Blood pressure (bp) level after birth may reflect the fetal cardiovascular environment, but few data exist on newborn bp. Methods. We report findings from a new cohort of pregnant women and their offspring, Project Viva. Enrollment as of September, 2000, is 1338 pregnant women (of a target 6000), and 581 have delivered. Data collected include maternal dietary, sociodemographic, economic, psychological, lifestyle, and clinical variables; and infant bp, pulse rate, length, weight, and circumferences measured during the first 2 days of life. We averaged 5 systolic bp readings taken with a Dinamap automated bp recorder. This abstract is limited to the first 260 measured newborns (131 girls and 129 boys) and partial maternal data. Results. The highest newborn systolic bp was in children of the oldest mothers, and the lowest in the maternal age group 20-24 years (

Table). Multivariate adjustment for infant birth weight and sex and for maternal body mass index, pregnancy weight gain, 3

rd

trimester bp, and number of pregnancies did not attenuate the differences. For example, adjusted mean newborn systolic bp was 10.8 (95% CI 2.4, 19.2) mmHg higher among children of 40-44 y.o. than 20-24 y.o. mothers. Variables minimally or not related to newborn systolic bp included birth weight and length, pulse rate, head, chest, and abdominal circumferences, gestational age, and maternal body mass index, weight gain, and systolic bp. Conclusions. Higher maternal age was associated with higher newborn systolic bp. Whereas bp later in childhood predicts adult hypertension and its consequences, newborn bp may represent different phenomena, such as pre- and peri-natal influences on cardiac structure and function. Studies of newborn bp may shed new light on effects of the fetal environment on lifelong cardiovascular health.

Table 1.
Relationship of Obesity with C-Reactive Protein and Interleukin-6 in Women
Authors: Rexrode Kathryn M. , Buring Julie E. , Rifai Nadir , Manson JoAnn E. , Ridker Paul M.
Published: March 2022

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Background: C-reactive protein (CRP) and interleukin-6 (IL6) have been associated with increased risk of cardiovascular disease (CVD). Adipocytes produce IL6, the chief determinant of hepatic CRP production. The purpose of this study was to examine the relationship between obesity and CRP and IL6 levels. Methods: We analyzed the relationship between obesity, elevated high sensitivity CRP (HS-CRP) levels (75th percentile: >0.54 mg/dl) and elevated IL6 levels (75th percentile: >2.04 pg/ml) among a sample of 328 women in the Women’s Health Study. The women in our analyses were age 45-84 years, free from pre-existing CVD or cancer at baseline and had complete covariate information. Results: Overweight (body mass index [BMI] 25-<30 kg/m

2

) and obese (BMI ≥30 kg/m

2

) women were significantly more likely to have elevated HS-CRP and IL6 levels than women with a normal BMI (<25 kg/m

2

). After adjustment for age, smoking, parental history of myocardial infarction, current use of hormone replacement therapy (HRT), menopausal status, physical activity, history of diabetes, hypertension, and elevated cholesterol, the odds ratios (OR) for elevated HS-CRP were 2.97 (95%CI, 1.61-5.50) for overweight women and 6.18 (95%CI, 2.82-13.56) for obese women. In multivariate models, the OR’s for elevated IL6 were 1.72 (95%CI, 0.90-3.27) for overweight women and 4.78 (95%CI, 2.18-10.47) for obese women. Since IL6 levels are highly correlated with CRP levels, adjusting for IL6 attenuated the relationship between obesity and elevated HS-CRP, such that the multivariate IL6-adjusted OR’s for elevated HS-CRP were 2.46 (95%CI, 1.28-4.75) and 4.43 (95% CI, 1.89-10.35) for overweight and obese women, respectively. Because HRT use is associated with higher CRP levels and generally lower BMI, we also examined the effects among the subgroup of postmenopausal women not currently using HRT. Results remained highly significant in this subgroup of women. Conclusion: Overweight and obese women are at substantially increased risk of having elevated CRP and IL6 levels. CRP remained independently associated with obesity, even after controlling for IL6.