Fruit and vegetable consumption and LDL cholesterol: the National Heart, Lung, and Blood Institute Family Heart Study

BACKGROUND: An elevated LDL-cholesterol concentration is associated with an increased risk of cardiovascular disease. The association between fruit and vegetable consumption and LDL has been inconsistent. OBJECTIVE: The objective was to determine whether a high intake of fruit and vegetables is inversely associated with LDL concentrations. DESIGN: We used data collected from 4466 subjects in the National Heart, Lung, and Blood Institute Family Heart Study to study the association between fruit and vegetable consumption and serum LDL. We used a food-frequency questionnaire to assess fruit and vegetable intakes and regression models to estimate adjusted mean LDL according to fruit and vegetable consumption. RESULTS: The mean (+/-SD) age of the men (n = 2047) was 51.5 +/- 14.0 y and that of the women (n = 2419) was 52.2 +/- 13.7 y. The average daily serving of fruit and vegetables was 3.2 +/- 1.7 for men and was 3.5 +/- 1.8 for women. Fruit and vegetable consumption was inversely related to LDL: in the categories 0-1.9, 2.0-2.9, 3.0-3.9, and > or = 4 servings/d, multivariate-adjusted mean (95% CI) LDL concentrations were 3.36 (3.28, 3.44), 3.35 (3.27, 3.43), 3.26 (3.17, 3.35), and 3.17 (3.09, 3.25) mmol/L, respectively, for men (P for trend < 0.0001) and 3.35 (3.26, 3.44), 3.22 (3.14, 3.30), 3.21 (3.13, 3.29), and 3.11 (3.04, 3.18), respectively, for women (P for trend < 0.0001). This association was observed across categories of age, education, smoking status, physical activity, and tertiles of Keys score. Exclusion of subjects with prevalent diabetes mellitus or coronary artery disease did not alter these results significantly. CONCLUSION: Consumption of fruit and vegetables is inversely related to LDL in men and women.     

Inheritance of the waist-to-hip ratio in the National Heart, Lung, and Blood Institute Family Heart Study

OBJECTIVE: Considering that waist-to-hip ratio (WHR) is a simple anthropometric measure of obesity and is a better predictor of coronary heart disease than body mass index (BMI), the genetic underpinnings of WHR are of interest. The inheritance pattern of WHR, before and after adjustment for BMI (WHR-BMI), was investigated in 2713 individuals from 1038 nuclear families in the National Heart, Lung, and Blood Institute Family Heart Study (NHLBI-FHS). RESEARCH METHODS AND PROCEDURES: Waist and hip measurements were taken twice, and the means of the measurements were used to calculate the WHR. Adjustments for age were carried out separately by sex, using stepwise multiple regression procedures for WHR and WHR-BMI phenotypes. Segregation analysis was applied using the unified model as implemented in the computer program POINTER. RESULTS: For age-adjusted WHR, the segregation results suggested an additive major gene that accounts for 35% of the phenotypic variance, and approximately 30% of the sample are homozygous for the "high" genotype. The results for age- and BMI-adjusted WHR were also compatible with a major gene; however, the multifactorial model provided the most parsimonious fit to the data. DISCUSSION: Although the genetic mechanisms for several obesity traits have been studied, tests of Mendelian segregation on this simple anthropometric measure (WHR) have not been reported previously. This study provides evidence for the presence of a major gene for age-adjusted WHR, suggesting that it is an appropriate trait for further genetic analysis, especially because it has strong predictive value and probably relates biologically to cardiovascular risk.     

Contribution of genetic and environmental influences to ankle-brachial blood pressure index in the NHLBI Twin Study. National Heart, Lung, and Blood Institute

The ankle-brachial index (ABI) is widely used in the clinical diagnosis of peripheral arterial disease. The contributions of genetic and environmental influences to normal and abnormal ABI values are unknown. In this study, the authors used available data on 94 monozygotic pairs and 90 dizygotic pairs of elderly, White, male twins examined in 1995-1997 to investigate the contributions of genetic and environmental influences to normative ABI values. Within-twin-pair correlations for normative ABI values were statistically significant, and the correlation in monozygotic twin pairs was significantly greater than that in dizygotic pairs. Structural equation modeling of the variance-covariance matrices of monozygotic and dizygotic twins indicated that 48% of the observed variability in ABI values could be attributed to additive genetic effects. In contrast, concordance rates for low ABI values (ABI< or =0.9) for both monozygotic and dizygotic twins were significantly greater than would be expected by chance alone, but within-pair monozygotic similarity was not significantly greater than dizygotic similarity. A matched-cotwin analysis in 21 pairs that were discordant for low ABI values found that twins with low ABI values were physically less active and more likely to be persistent smokers than their normal-control brothers. These findings reinforce the role of individual health practices (e.g., physical activity, smoking) in the manifestation of peripheral arterial disease among subjects matched for age, genetics, and early shared environment.     

Dietary linolenic acid and carotid atherosclerosis: the National Heart,Lung, and Blood Institute Family Heart Study

BACKGROUND: Dietary intake of linolenic acid is associated with a lower risk of cardiovascular disease mortality. However, it is unknown whether linolenic acid is associated with a lower risk of carotid atherosclerosis. OBJECTIVE: The objective was to examine the association between dietary linolenic acid and the presence of atherosclerotic plaques and the intima-media thickness of the carotid arteries. DESIGN: In a cross-sectional design, we studied 1575 white participants of the National Heart, Lung, and Blood Institute Family Heart Study who were free of coronary artery disease, stroke, hypertension, and diabetes mellitus. High-resolution ultrasound was used to assess intima-media thickness and the presence of carotid plaques beginning 1 cm below to 1 cm above the carotid bulb. We used logistic regression and a generalized linear model for the analyses. RESULTS: From the lowest to the highest quartile of linolenic acid intake, the prevalence odds ratio (95% CI) of a carotid plaque was 1.0 (reference), 0.47 (0.30, 0.73), 0.38 (0.22, 0.66), and 0.49 (0.26, 0.94), respectively, in a model that adjusted for age, sex, energy intake, waist-to-hip ratio, education, field center, smoking, and the consumption of linoleic acid, saturated fat, fish, and vegetables. Linoleic acid, fish long-chain fatty acids, and fish consumption were not significantly related to carotid artery disease. Linolenic acid was inversely related to thickness of the internal and bifurcation segments of the carotid arteries but not to the common carotid artery. CONCLUSION: Higher consumption of total linolenic acid is associated with a lower prevalence odds of carotid plaques and with lesser thickness of segment-specific carotid intima-media thickness.     

Effects of selective return on estimates of heritability for body mass index in the National Heart, Lung, and Blood Institute Twin Study.

In the National Heart, Lung, and Blood Institute Twin Study, body mass index (BMI) was studied at military induction and at three subsequent examinations spanning five decades in a cohort of white, male World War II veterans. At military induction (1940s) and again at the first clinical examination of this study (1969-1973), there was close agreement of three commonly used estimates of heritability (range 0.72 to 0.80), and no evidence of a difference in total variance of BMI between the zygosities. However, at the last two examinations (1980s), the total variance in dizygotic (DZ) twins was significantly greater than that of monozygotic (MZ) twins (P less than 0.01) and these same heritability estimates varied widely. The among-pair estimate of heritability fell to unrealistic negative values, the within-pair estimate rose to values of 1.0 or greater, and the intraclass correlation coefficient estimate was slightly lower than in the entire cohort at baseline. The cause of the unequal zygosity total variance appears to have been nonparticipation at later examinations of MZ twins with extreme values of BMI, with no evidence of a similar selection process influencing DZ twins. This selection process biased the three estimates of heritability, making it difficult to determine which estimate is the most appropriate. Despite these biases, it remains clear that genetic factors contribute substantially to BMI in this population.     

Apolipoprotein E polymorphism modifies the alcohol-HDL association observed in the National Heart, Lung, and Blood Institute Family Heart Study

BACKGROUND: The apolipoprotein E gene (APOE) allele epsilon4 is associated with an increased risk of cardiovascular disease. The presence of the epsilon4 allele has been associated with lower concentrations of HDL cholesterol, but it is not known whether the epsilon4 allele modifies the association between alcohol consumption and HDL-cholesterol concentrations. OBJECTIVE: The objective of the study was to assess whether the epsilon4 allele modifies the association between alcohol consumption and HDL-cholesterol concentrations. DESIGN: In a cross-sectional design, we studied 670 men and women aged 26-78 y who participated in the National Heart, Lung, and Blood Institute Family Heart Study to assess whether the epsilon4 allele of the gene APOE modifies the association between alcohol consumption and HDL-cholesterol concentrations. Alcohol data were self-reported, and we used multivariate, generalized estimating equations to assess interactions. RESULTS: In a model with adjustment for age, sex, body mass index, smoking, exercise, waist-hip ratio, TV viewing, and study site, there was a significant effect of the interaction between the epsilon4 allele and alcohol consumption on HDL cholesterol (P=0.0001). In the absence of the epsilon4 allele, multivariate adjusted means of HDL were 1.24, 1.36, and 1.54 mmol/L among subjects who never drank and those who currently drink 0.1-12 and >12 g alcohol/d, respectively; in the presence of the epsilon4 allele, the corresponding values were 1.19, 1.27, and 1.25 mmol/L. CONCLUSION: Our data show a significant effect of the interaction between the epsilon4 allele and alcohol consumption on HDL. The increase in HDL associated with alcohol appears to be stronger in subjects without the epsilon4 allele than in those with the epsilon4 allele.     

Family history of ischemic heart disease with respect to mean twin-pair cholesterol and subsequent ischemic heart disease in the NHLBI twin study

This study examines the independent and interactive effects of family history scores (FHxS) for the prevalence of ischemic heart disease with plasma lipids and subsequent morbidity and mortality from ischemic heart disease. FHxS were calculated for 514 sets of middle aged male twins who participated in the entry examination of the NHLBI Veteran twin study in 1969-1973. Comparison of the FHxS with the level of plasma total cholesterol and HDL cholesterol (HDLc) paralleled earlier reported findings in young adults; individuals with high total cholesterol in two exams 8-12 years apart had significantly (P less than .01) higher FHxS. The same relationship was noted when using the mean twin-pair cholesterol level at the initial exam when the twins were in their 40s. Using the pair means over two exams as the cotwins aged into their 50s, the association of FHxS with total cholesterol declined and pairs with HDLc persistently in the highest quintile at both exams had significantly (P less than .01) lower FHxS. The changes in the pattern of association of lipid fractions with FHxS with age parallel the reported age decline of total cholesterol as a risk factor for heart disease. Assessment of ischemic heart disease events up to January 1988 revealed a highly significant association (P less than .0001) of later ischemic heart disease events with FHxS. At each level of lipid categorization pairs who later had events had higher FHxS than those without any subsequent heart disease; these differences were significant in all but the low risk lipid groups (low total cholesterol, high HDLc, and low total cholesterol/HDLc ratio). We conclude that FHxS is related to total cholesterol and HDLc but also is an independent predictor of subsequent ischemic heart disease after 14-18 years of follow-up.     

Shared random parameter models: A legacy of the biostatistics program at the National Heart,Lung, and Blood Institute

Shared random parameter models (SRPMs) were first introduced by researchers at the National Heart Lung and Blood Institute (NHLBI) Biostatistics Branch for analyzing longitudinal data with informative dropout (Wu and Carroll, 1987; Wu and Bailey, 1988; Follmann and Wu, 1995; Albert and Follmann, 2000; Albert et al, 2002). This work was all focused on characterizing the longitudinal data process in the presence of an informative missing data mechanism that is treated as a nuisance. Shared random parameter modeling approaches have also been developed from the perspective of characterizing the relationship between longitudinal data and a subsequent outcome that may be an event time, a dichotomous measurement, or another longitudinal outcome. This article will review the early contributions of the NHLBI biostatisticians on SRPMs for analyzing longitudinal data with dropout and demonstrate how these ideas have, more recently, been applied in these other areas of biostatistics. Rather than focus on technical details or specific analyses, this article presents a conceptual framework for SRPMs within a historical context.     

Relation between dietary linolenic acid and coronary artery disease in the National Heart, Lung, and Blood Institute Family Heart Study.

BACKGROUND: Epidemiologic studies suggest that a higher consumption of eicosapentaenoic acid and docosahexaenoic acid is associated with a reduced risk of cardiovascular disease. Studies in humans and animals also reported an inverse association between alpha-linolenic acid and cardiovascular disease morbidity and mortality. OBJECTIVE: We examined the relation between dietary linolenic acid and prevalent coronary artery disease (CAD). DESIGN: We studied 4584 participants with a mean (+/-SD) age of 52.1 +/- 13.7 y in the National Heart, Lung, and Blood Institute Family Heart Study in a cross-sectional design. Participants' diets were assessed with a semiquantitative food-frequency questionnaire. For each sex, we created age- and energy-adjusted quintiles of linolenic acid, and we used logistic regression to estimate prevalent odds ratios for CAD. RESULTS: From the lowest to the highest quintile of linolenic acid, the prevalence odds ratios of CAD were 1.0, 0.77, 0.61, 0.58, and 0.60 for the men (P for trend = 0.012) and 1.0, 0.57, 0.52, 0.30, and 0.42 for the women (P for trend = 0.014) after adjustment for age, linoleic acid, and anthropometric, lifestyle, and metabolic factors. Linoleic acid was also inversely related to the prevalence odds ratios of CAD in the multivariate model (0.60 and 0.61 in the second and third tertiles, respectively) after adjustment for linolenic acid. The combined effect of linoleic and linolenic acids was stronger than the individual effects of either fatty acid. CONCLUSIONS: A higher intake of either linolenic or linoleic acid was inversely related to the prevalence odds ratio of CAD. The 2 fatty acids had synergistic effects on the prevalence odds ratio of CAD.     

Early methodological developments for clinical trials at the National Heart, Lung and Blood Institute

The National Heart Institute, now known as the National Heart, Lung and Blood Institute (NHLBI), initiated its first multicentre randomized clinical trials of rheumatic fever and rheumatic heart disease in 1951. The modern era of multicentre trials began, however, when the Coronary Drug Project was initiated in the 1960s. This trial and subsequent NHLBI trials stimulated a wide variety of research on clinical trial methodology. This paper reviews early methodologic developments in four areas. First, an organizational structure for multicentre clinical trials was developed and codified in the 'Greenberg Report' in 1967. Second, design considerations related to patient risk, non-compliance, a lag in treatment effect, and changing risk were explored. The 'intention-to-treat' principle was implicit in these investigations. Thirdly, the concept of periodic review of accumulating data, recommended in the Greenberg report, stimulated research on methods for sequential analysis. Three statistical approaches were developed and investigation of their statistical properties continues today. These approaches are usually described as group sequential, stochastic curtailment, and Bayesian methods. Finally, comparison of treatments in longitudinal studies has been an increasing part of NHLBI research and methods have been developed for design and analysis of longitudinal studies.     

Dietary linolenic acid is inversely associated with plasma triacylglycerol: the National Heart, Lung, and Blood Institute Family Heart Study

BACKGROUND: Dietary intake of linolenic acid is associated with a decreased risk of cardiovascular disease mortality. However, the mechanisms by which dietary linolenic acid affects cardiovascular disease risk are not clearly understood. OBJECTIVE: We examined the association between dietary linolenic acid and plasma triacylglycerol concentrations. DESIGN: In a cross-sectional design, we studied 4440 white subjects (2036 men and 2404 women) aged 25-93 y who participated in the National Heart, Lung, and Blood Institute Family Heart Study. We used generalized linear models to estimate adjusted mean triacylglycerol concentrations according to categories of total dietary linolenic acid (alpha- and gamma-linolenic acid) intake. RESULTS: The mean dietary linolenic acid intakes were 0.81 and 0.69 g/d for the men and the women, respectively. High consumption of dietary linolenic acid was associated with young age; high intakes of energy, fat, carbohydrates, fruit, vegetables, and fish; low HDL cholesterol; current smoking; and frequent consumption of creamy salad dressing. High consumption of dietary linolenic acid was also associated with low plasma triacylglycerol concentrations. From the lowest to the highest quintile of linolenic acid intake, the multivariate-adjusted mean triacylglycerol concentrations were 1.75 (95% CI: 1.65, 1.85), 1.74 (1.66, 1.82), 1.69 (1.61, 1.77), 1.66 (1.58, 1.74), and 1.54 (1.44, 1.64) mmol/L, respectively (P for linear trend = 0.007). When linolenic acid was used as a continuous variable, the corresponding regression coefficient was -0.2811 (-0.4922, -0.07001). CONCLUSIONS: Consumption of total linolenic acid is inversely related to plasma triacylglycerol concentrations in both white men and white women. This suggests a pathway by which dietary linolenic acid might reduce cardiovascular disease risk.     

Cardiovascular epidemiology in a changing world--challenges to investigators and the National Heart, Lung, and Blood Institute

Over the past 60 years, revolutionary discoveries made by epidemiologists have contributed to marked declines in cardiovascular disease morbidity and mortality. Now, in an era of increasingly constrained resources, researchers in cardiovascular epidemiology face a number of challenges that call for novel, paradigm-shifting approaches. In this paper, the authors pose to the community 4 critical questions: 1) How can we avoid wasting resources on studies that provide little incremental knowledge? 2) How can we assure that we direct our resources as economically as possible towards innovative science? 3) How can we be nimble, responding quickly to new opportunities? 4) How can we identify prospectively the most meritorious research questions? Senior program staff at the National Heart, Lung, and Blood Institute invite the epidemiology community to join them in an ongoing Web-based blog conversation so that together we might develop novel approaches that will facilitate the next generation of high-impact discoveries.     

Unscrambling the research: Eggs, serum cholesterol and coronary heart disease

The role of dietary cholesterol in raising plasma cholesterol levels has been debated over the past 25 years. Consequently, eggs, as a food high in dietary cholesterol, have been targeted as a food to limit when advising patients on a diet to lower serum cholesterol levels. The aim of the present review was to evaluate the literature to address the effects of dietary cholesterol from eggs on serum cholesterol levels and risk of coronary heart disease. An increase in dietary cholesterol from eggs by 100 mg daily, equivalent to half a medium egg or three to four eggs a week, results in an increase of approximately 0.05 mmol/L in LDL cholesterol. Adding 100 mg of cholesterol per day (equivalent to three to four eggs a week) to a high saturated fat diet caused an increase in LDL cholesterol of 0.061 ± 0.006 mmol/L, whereas adding the same quantity of cholesterol to a low saturated fat diet caused an increase in LDL cholesterol of only 0.036 ± 0.004 mmol/L (P = 0.03). Despite the small increase in LDL‐cholesterol levels with increasing egg intake, most epidemiological studies have shown little or no association between egg intake and risk of coronary heart disease. However, the impact of dietary cholesterol for people with type 2 diabetes has been poorly studied. In conclusion, in a healthy Western population, there is insufficient evidence to excessively restrict egg intake as part of a healthy diet. Eggs should be considered in a similar way as other protein‐rich foods and selected as part of a varied diet that is low in saturated fat and contains a variety of cardio‐protective foods such as fish, wholegrains, fruits, vegetables, legumes and nuts.     

冠心病心力衰竭患者血浆纤维蛋白原（Fib）与血清尿酸（uA）浓度的相关性研究

目的探讨冠心病心力衰竭患者血浆纤维蛋白原（Fib）与血清尿酸（uA）浓度之间的相互关系。方法选取82例冠心病并心力衰竭患者与118例健康人进行研究,以82例冠心病并心力衰竭患者为观察组,以118例健康人为对照组。检测观察组和对照组所有研究对象的血浆纤维蛋白原（Fib）与血清尿酸（uA）水平,并统计分析对比两组研究对象Fib和uA两个研究指标的差异,探索冠心病并心力衰竭患者血浆纤维蛋白原与血清尿酸浓度之间关联。结果对两组研究对象的性别比例、体重质量指数、平均年龄进行对比分析,组间差异均不具有统计学意义（P〉0．05）;观察组Fib和UA水平高于对照组,差异具有统计学意义（P〈0．05）;分别以340μmol／L,3．1g／L为UA和Fib的临界值,观察组研究对象60％在临界值之上,而对照组对象40％在临界值之下。结论冠心病并心力衰竭患者的血浆纤维蛋白原含量和血清尿酸的浓度都显著高于健康对照组水平．两指标间呈正相关关系,均与该疾病存在着密切关联,有理由假设过高的Fib水平与UA水平都是心功能恶化的预测因子。