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1.  [No title available] 
PMCID: PMC3943940  PMID: 24361073
2.  Reduction in Dietary Trans Fat Intake is Associated with Decreased LDL Particle Number in a Primary Prevention Population 
Background and Aims
Increased trans fat intake has been associated with an increased risk of cardiovascular disease (CVD). While the affect of trans fat on traditional lipids is known, it’s association with LDL particle number (LDL-P), a novel marker of CVD risk, has not been established. The purpose of this study was to determine the association between trans fat intake and LDL-P over 1-year among individuals participating in a lifestyle intervention trial.
Methods and Results
Family members (n = 400, 33% male, mean age 48 ± 13) of patients hospitalized with CVD who participated in a 1-year randomized controlled primary prevention lifestyle intervention trial and had complete dietary data and LDL-P measures at baseline and 1-year. Change in trans fat as a percentage of total diet and mean absolute change in LDL-P at 1-year was assessed using multivariate adjusted linear regression models. At baseline, there was a significant positive correlation between dietary trans fat intake and LDL-P (Beta = 37, p = 0.04). For every 1 percent change in trans fat intake there was a 27 nmol/L change in LDL-P (Beta = 27, p = 0.04) over 1-year which was independent of baseline predictors and confounders (age, sex, smoking, statin use, waist size and physical activity; Beta = 30, p = 0.03).
Conclusion
A reduction in trans fat intake over 1-year was significantly associated with a reduction in LDL-P independent of potential confounders. Healthcare providers should reinforce the beneficial impact of a healthy diet, and in particular modifications in trans fat intake on improving lipid profiles.
doi:10.1016/j.numecd.2013.06.003
PMCID: PMC3943937  PMID: 24099723
Prevention; Cardiovascular Disease; Nutrition
3.  Assessment of Old and New Proteins 
Nutrition, metabolism, and cardiovascular diseases : NMCD  2012;23(0 1):10.1016/j.numecd.2012.05.006.
Protein modifications and the accumulation of those proteins are implicated in a host of diseases from Parkinson’s and Alzheimer’s to both insulin independent and insulin dependent diabetes mellitus. Accumulation of irreversibly modified proteins occurs when the degradation rate of proteins is reduced or the rate of modification increases. Although the synthesis rates of individual proteins in vivo have been extensively studied the methodology to measure degradation rates of individual proteins in vivo remains to be well developed. However, the ability to measure the relative age of a particular protein pool in relation to the quality of the pool (amount of damage) is a recent advance. This brief review describes a novel methodology to simultaneously measure the synthesis rate of individual proteins along with the accumulation of oxidative damage to those proteins in vivo. The results of a recent investigation on individuals with type 1 diabetes mellitus are described. Accelerated damage to de novo synthesized ApoA1 is shown during short-term insulin cessation, which has potential clinical implications. Future implications of the novel method in diabetes and aging are also discussed.
doi:10.1016/j.numecd.2012.05.006
PMCID: PMC3537901  PMID: 22784971
protein; synthesis; turnover; isotope tracer; individual proteins
4.  Endothelial Function and the Regulation of Muscle Protein Anabolism in Older Adults 
Nutrition, metabolism, and cardiovascular diseases : NMCD  2012;23(0 1):10.1016/j.numecd.2012.03.013.
Sarcopenia, the loss of skeletal muscle mass and function with aging, is a major contributor to frailty and morbidity in older adults. Recent evidence has emerged suggesting that endothelial dysfunction and insulin resistance of muscle protein metabolism may significantly contribute to the development of sarcopenia. In this article we review: 1) recent studies and theories on the regulation of skeletal muscle protein balance in older adults; 2) the link between insulin-resistance of muscle protein synthesis and endothelial dysfunction in aging; 3) mechanisms for impaired endothelial responsiveness in aging; and 4) potential treatments that may restore the endothelial responsiveness and muscle protein anabolic sensitivity in older adults.
doi:10.1016/j.numecd.2012.03.013
PMCID: PMC3597759  PMID: 22902187
Sarcopenia; endothelial dysfunction; insulin resistance; muscle protein metabolism
5.  The Relationship between Visceral Adiposity and Left Ventricular Diastolic Function: Results from the Baltimore Longitudinal Study of Aging 
Nutrition, metabolism, and cardiovascular diseases : NMCD  2013;23(12):10.1016/j.numecd.2013.04.003.
BACKGROUND AND AIMS
It is unclear whether subcutaneous and visceral fat are differentially correlated to the decline in left ventricular (LV) diastolic function with aging. This study sought to examine the hypothesis that age-related changes in the regional fat distribution account for changes in LV diastolic function and to explore potential mediators of this association.
METHODS AND RESULTS
In this cross-sectional study, we evaluated 843 participants of the Baltimore Longitudinal Study of Aging with echocardiogram, dual-energy x-ray absorptiometry (DEXA), abdominal computed tomography (CT) and blood tests performed at the same visit. LV diastolic function was assessed by parameters of LV relaxation (E/A ratio, Em and Em/Am ratio) and LV filling pressures (E/Em ratio). Total body fat was computed by DEXA, while visceral and subcutaneous fat were determined from abdominal CT. In multivariate models adjusted for demographics, cardiovascular risk factors, antihypertensive medications, physical activity and LV mass, both visceral and subcutaneous fat were associated with LV diastolic dysfunction. When both measures of adiposity were simultaneously included in the same model, only visceral fat was significantly associated with LV diastolic dysfunction. Triglycerides and sex-hormone binding globulin, but not adiponectin and leptin, were found to be significant mediators of the relationship between visceral fat and LV diastolic function, explaining 28 to 47% of the association. Bootstrapping analyses confirmed the significance of these findings.
CONCLUSIONS
Increased visceral adiposity is associated with LV diastolic dysfunction, possibly through a metabolic pathway involving blood lipids and ectopic fat accumulation rather than adipokines.
doi:10.1016/j.numecd.2013.04.003
PMCID: PMC3835727  PMID: 23809149
adiposity; diastolic function; triglycerides; sex hormone-binding globulin; adipokines
6.  Is measurement of non-HDL cholesterol an effective way to identify the metabolic syndrome? 
Nutrition, metabolism, and cardiovascular diseases : NMCD  2013;23(11):10.1016/j.numecd.2012.12.001.
Background and Aims
The metabolic syndrome (MetS) has been shown to predict coronary heart disease (CHD). Non-high-density lipoprotein cholesterol (non-HDL-C) is also known to predict CHD, and recent evidence indicated non-HDL-C was able to predict MetS in adolescents. The study aim was to determine whether non-HDL-C serves as a useful metabolic marker for MetS in adults.
Methods and Results
Fasting non-HDL-C measurements were obtained in 366 non-diabetic adults not on lipid-lowering therapy. In addition to traditional non-HDL-C cut-points based on Adult Treatment Panel III guidelines, receiver-operating characteristic curve analysis was used to identify an optimal cut-point for predicting MetS. A secondary goal was to assess the relationship between non-HDL-C and insulin resistance, defined as the upper tertile of steady-state plasma glucose concentrations measured during the insulin suppression test. Prevalence of MetS was 40% among participants. Those with MetS had higher mean non-HDL-C (4.17±1.0 vs 3.70±0.85 mmol/L, p<0.001), and the upper vs lower tertile of non-HDL-C concentrations was associated with 1.8-fold increased odds of MetS (p<0.05). Traditional non-HDL-C cut-points ≥4.14 and ≥4.92 mmol/L demonstrated respective sensitivities 46% and 24% (specificities 72% and 89%) for identifying MetS. The optimal non-HDL-C cut-point ≥4.45 mmol/L had sensitivity 39% (specificity 82%). Comparable results were observed when non-HDL-C was used to identify insulin resistance.
Conclusion
While MetS was associated with increased non-HDL-C, an effective non-HDL-C threshold to predict MetS in adults was not identified. Dyslipidemic nuances may explain why non-HDL-C may be less useful as a metabolic marker for MetS and/or insulin resistance than for CHD.
doi:10.1016/j.numecd.2012.12.001
PMCID: PMC3640736  PMID: 23352957
non-high-density lipoprotein cholesterol; coronary heart disease risk; insulin resistance; metabolic syndrome; obesity
7.  The Association Between LRP-1 Variants and Chylomicron Uptake After a High Fat Meal 
Nutrition, metabolism, and cardiovascular diseases : NMCD  2013;23(11):10.1016/j.numecd.2012.12.007.
Background and aims
In vitro studies suggest that low density lipoprotein receptor-related protein 1 (LRP1) plays a role in the secondary uptake of chylomicrons. In addition, in vivo studies using LRP-1 knockout mice show these animals exhibit delayed chylomicron clearance. Whether this is true in humans is unknown. We aimed to determine whether genetic variants in LRP-1 are associated with postprandial chylomicron uptake in humans given an oral fat challenge.
Methods and Results
817 Men and women (mean age +/− standard deviation = 48.4 +/− 16.4 years) forming the study population for the Genetics of Lipid Lowering Drugs Network (GOLDN) study ingested an oral fat load of 700 kilocalories per m2 of body surface area at 83% fat, after an 8-hour fast. Chylomicrons were measured by nuclear resonance spectroscopy (NMR) at fasting, and 3.5 and 6 hours after the meal. 26 Single nucleotide polymorphisms (SNPs) in the LRP-1 gene were genotyped on the Affymetrix 6.0 array. Chylomicrons were, as expected, zero at fasting. Mixed linear models adjusted for age, sex, study site and pedigree tested for associations between LRP-1 SNPs and changes in chylomicron concentrations 3.5–6 hours. A gene-based test across all 26 SNPs was conducted which corrected for the linkage disequilibrium (LD) between SNPs. 11 LRP-1 SNPs were significantly associated with the change in chylomicron concentration correction for multiple testing (Q<.05). The subsequent gene-based test, was also significant (P= .01).
Conclusion
These results require replication but strongly indicate the role of LRP1 in postprandial lipoprotein uptake and/or clearance.
doi:10.1016/j.numecd.2012.12.007
PMCID: PMC3686991  PMID: 23484911
candidate gene; LRP-1; postprandial; uptake; clearance; GOLDN
8.  Preliminary evidence of genetic determinants of adiponectin response to fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network 
Nutrition, metabolism, and cardiovascular diseases : NMCD  2012;23(10):10.1016/j.numecd.2012.07.010.
Background and Aims
Adiponectin is an adipose-secreted protein that has been linked to changes in insulin sensitivity, high-density lipoprotein cholesterol levels, and inflammatory patterns. Although fenofibrate therapy can raise adiponectin levels, treatment response is heterogeneous and heritable, suggesting a role for genetic mediators. This is the first genome-wide association study of fenofibrate effects on circulating adiponectin.
Methods and Results
Plasma adiponectin was measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n=793) before and after a 3-week daily treatment with 160 mg of fenofibrate. Associations between variants on the Affymetrix Genome-Wide Human SNP Array 6.0 and adiponectin were assessed using mixed linear models, adjusted for age, sex, site, and family. We observed a statistically significant (P=5×10−8) association between rs2384207 in 12q24, a region previously linked to several metabolic traits, and the fenofibrate-induced change in circulating adiponectin. Additionally, our genome-wide analysis of baseline adiponectin levels replicated the previously reported association with CDH13 and suggested novel associations with markers near the PCK1, ZBP1, TMEM18, and SCUBE1 genes. The findings from the single marker tests were corroborated in gene-based analyses. Biological pathway analyses suggested a borderline significant association between the EGF receptor signaling pathway and baseline adiponectin levels.
Conclusions
We present preliminary evidence linking several biologically relevant genetic variants to adiponectin levels at baseline and in response to fenofibrate therapy. Our findings provide support for fine-mapping of the 12q24 region to investigate the shared biological mechanisms underlying levels of circulating adiponectin and susceptibility to metabolic disease.
doi:10.1016/j.numecd.2012.07.010
PMCID: PMC3578131  PMID: 23149075
9.  Relationships Among Changes in C-Reactive Protein and Cardiovascular Disease Risk Factors With Lifestyle Interventions 
Background and Aims
Inflammation plays a role in the development of cardiovascular disease (CVD). Elevated levels of the inflammatory marker, C-reactive protein (CRP), are cross-sectionally associated with traditional CVD risk factors and are being considered as an emerging CVD risk factor. In a secondary data analysis, we examined changes in CRP and several CVD risk factors after one-year diet and exercise interventions to assess whether CRP changed concurrently with other risk factors, or was independent of the traditional risk factors.
Methods and Results
Data were analyzed from 143 men and 133 women with dyslipidemia who were randomized to one-year interventions of low-fat diet only, physical activity only, diet plus physical activity, or control. Plasma high-sensitivity CRP, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides (TG), fasting and 2-hr blood glucose and insulin, blood pressure (BP), and waist circumference were obtained at baseline and follow-up. Multiple linear regression models were used to predict CRP change based on other risk factor changes, controlling for age, race, alcohol intake, and hormone replacement therapy. Treatment groups were combined for analysis. Baseline mean (SD) CRP levels were 1.3±1.3 (men) and 1.9±1.8 mg/L (women), with mean changes of -0.11±1.3 and -0.17±1.5 mg/L, respectively. Plasma CRP change was negatively associated with TG change in men (p=0.003) and women (p=0.05), positively associated with change in systolic BP in men (p=0.01), but was not associated with changes in the other risk factors.
Conclusion
Dietary and/or physical activity induced changes in CRP may be largely independent of traditional CVD risk factors in persons with dyslipidemia.
doi:10.1016/j.numecd.2012.05.003
PMCID: PMC3502629  PMID: 22831953
C-reactive protein; cardiovascular disease risk; physical activity; low-fat diet; interventions
10.  Fish consumption, insulin sensitivity and beta-cell function in the Insulin Resistance Atherosclerosis Study (IRAS) 
Background and aims
Previous research on the association between fish consumption and incident type 2 diabetes has been inconclusive. In addition, few studies have investigated how fish consumption may be related to the metabolic abnormalities underlying diabetes. Therefore, we examined the association of fish consumption with measures of insulin sensitivity and beta-cell function in a multi-ethnic population.
Methods and results
We examined the cross-sectional association between fish consumption and measures of insulin sensitivity and secretion in 951 non-diabetic participants in the Insulin Resistance Atherosclerosis Study (IRAS). Fish consumption, categorized as <2 vs. ≥2 portions/week, was measured using a validated food frequency questionnaire. Insulin sensitivity (SI) and acute insulin response (AIR) were determined from frequently sampled intravenous glucose tolerance tests.
Higher fish consumption was independently associated with lower SI-adjusted AIR (β=−0.13 [−0.25, −0.016], p=0.03, comparing ≥ 2 vs. <2 portions/week). Fish consumption was positively associated with intact and split proinsulin/C-peptide ratios, however, these associations were confounded by ethnicity (multivariable-adjusted β=0.073 [−0.014, 0.16] for intact proinsulin/C-peptide ratio, β=0.031 [−0.065, 0.13] for split proinsulin/C-peptide ratio). We also observed a significant positive association between fish consumption and fasting blood glucose (multivariable-adjusted β=2.27 [0.68, 3.86], p=0.005). We found no association between fish consumption and SI (multivariable-adjusted β= −0.015 [−0.083, 0.053]) or fasting insulin (multivariable-adjusted β=0.016 [−0.066, 0.10]).
Conclusions
Fish consumption was not associated with measures of insulin sensitivity in the multi-ethnic IRAS cohort. However, higher fish consumption may be associated with pancreatic beta-cell dysfunction.
doi:10.1016/j.numecd.2012.06.001
PMCID: PMC3485446  PMID: 22835984
Fish consumption; beta-cell function; insulin sensitivity
11.  Dietary total antioxidant capacity is related to glucose tolerance in older people: The Hertfordshire Cohort Study 
Background and Aims
Dietary antioxidants may play a protective role in the aetiology of type 2 diabetes. However, observational studies that examine the relationship between the antioxidant capacity of the diet and glucose metabolism are limited, particularly in older people. We aimed to examine the relationships between dietary total antioxidant capacity (TAC) and markers of glucose metabolism among 1441 men and 1253 women aged 59–73 years who participated in the Hertfordshire Cohort Study, UK.
Methods and Results
Diet was assessed by food frequency questionnaire. Dietary TAC was estimated using published databases of TAC measured by four different assays: oxygen radical absorbance capacity (ORAC), ferric-reducing ability of plasma (FRAP), total radical-trapping antioxidant parameter (TRAP) and trolox equivalent antioxidant capacity (TEAC). Fasting and 120-min plasma glucose and insulin concentrations were measured during a standard 75-g oral glucose tolerance test. In men, dietary TAC estimated by all four assays was inversely associated with fasting insulin concentration and homeostasis model assessment of insulin resistance (HOMA-IR); with the exception of ORAC, dietary TAC was also inversely related to 120-min glucose concentration. There were no associations with fasting glucose or 120-min insulin concentrations. In women, with the exception of the association between ORAC and 120-min insulin concentration, dietary TAC estimated by all assays showed consistent inverse associations with fasting and 120-min glucose and insulin concentrations and HOMA-IR. These associations were more marked among women with BMI≥30kg/m2.
Conclusion
These findings suggest dietary TAC may have important protective effects on glucose tolerance, especially in older obese women.
doi:10.1016/j.numecd.2013.08.001
PMCID: PMC4112602  PMID: 24370447
Total antioxidant capacity; Diet; Glucose tolerance; Epidemiology
12.  Sedentary time and markers of inflammation in people with newly diagnosed type 2 diabetes 
Background and aims
We investigated whether objectively measured sedentary time was associated with markers of inflammation in adults with newly diagnosed type 2 diabetes.
Methods and results
We studied 285 adults (184 men, 101 women, mean age 59.0 ± 9.7) who had been recruited to the Early ACTivity in Diabetes (Early ACTID) randomised controlled trial. C-reactive protein (CRP), adiponectin, soluble intracellular adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6), and accelerometer-determined sedentary time and moderate-vigorous physical activity (MVPA) were measured at baseline and after six-months. Linear regression analysis was used to investigate the independent cross-sectional and longitudinal associations of sedentary time with markers of inflammation.
At baseline, associations between sedentary time and IL-6 were observed in men and women, an association that was attenuated following adjustment for waist circumference. After 6 months of follow-up, sedentary time was reduced by 0.4 ± 1.2 h per day in women, with the change in sedentary time predicting CRP at follow-up. Every hour decrease in sedentary time between baseline and six-months was associated with 24% (1, 48) lower CRP. No changes in sedentary time between baseline and 6 months were seen in men.
Conclusions
Higher sedentary time is associated with IL-6 in men and women with type 2 diabetes, and reducing sedentary time is associated with improved levels of CRP in women. Interventions to reduce sedentary time may help to reduce inflammation in women with type 2 diabetes.
Highlights
•Sedentary time is associated with inflammation in adults with type 2 diabetes.•Reducing sedentary time in women improved C-reactive protein.•Interventions to reduce sedentary time may reduce cardiovascular risk in women.
doi:10.1016/j.numecd.2014.03.009
PMCID: PMC4154448  PMID: 24925122
Sedentary time; Type 2 diabetes; Breaks in sedentary time; Inflammation
13.  Time course of histomorphological changes in adipose tissue upon acute lipoatrophy 
SUMMARY
Background and Aims
Crown-like structures (CLS) are characteristic histopathology features of inflamed adipose tissues in obese mice and humans. In previous work, we suggested that these cells derived from macrophages primarily involved in the reabsorption of dead adipocytes. Here, we used a well-characterized transgenic mouse model in which the death of adipocytes in adult mice is inducible and highly synchronized. In this “FAT-ATTAC” model, apoptosis is induced through forced dimerization of a caspase-8 fusion protein.
Methods and Results
0, 0.5, 1, 2, 3 and 10 days post induction of adipocyte cell death, we analyzed mesenteric and epididymal adipose depots by histology, immunohistochemistry and electron microscopy. Upon induction of caspase-8 dimerization, numerous adipocytes lost immunoreactivity for perilipin, a marker for live adipocytes. In the same areas, we found adipocytes with hypertrophic mitochondria and signs of organelle degeneration. Neutrophils and lymphocytes were the main inflammatory cells present in the tissue, and the macrophages were predominantly Mac-2 negative. Over the course of ablation, Mac-2 positive macrophages substituted for Mac-2 negative macrophages, followed by CLS formation. All perilipin-negative, dead adipocytes were surrounded by CLS structures. The time course of histopathology was similar in both fat pads studied, but occurred at earlier stages and was more gradual in mesenteric fat.
Conclusion
Our data demonstrate that CLS formation results as a direct consequence of adipocyte death, and that infiltrating macrophages actively uptake remnant lipids of dead adipocytes. Upon induction of adipocyte apoptosis, inflammatory cells infiltrate adipose tissue initially consisting of neutrophils followed by macrophages that are involved in CLS formation.
doi:10.1016/j.numecd.2012.03.005
PMCID: PMC3465635  PMID: 22682975
CLS; inflammation; fat; apoptosis; FAT-ATTAC; adipocytes
14.  Low 25-Hydroxyvitamin D Level is Independently Associated with Non-Alcoholic Fatty Liver Disease 
Background and Aims
We sought to explore associations between serum 25-hydroxyvitamin D [25(OH)D] levels and non-alcoholic fatty liver disease [NAFLD] in an integrated healthcare delivery system in the U.S.
Methods and Results
607 NAFLD cases were randomly matched 1:1 with controls for age, sex, race and season of measurement. Conditional logistic regression was used to evaluate if serum 25(OH)D levels were associated with increased odds of NAFLD (diagnosed by ultrasound) after adjusting for body mass index and history of diabetes, renal, peripheral vascular and liver diseases (model 1) and also for hypertension (model 2). Mean (SD) serum 25(OH)D level was significantly lower in the group with NAFLD as compared with that in the matched control group (75±17 vs. 85±20 nmol/L [30±7 vs. 34±8 ng/mL], P<0.001). Inadequate 25(OH)D status progressively increased the odds of NAFLD when classified categorically as sufficient (25(OH)D 75 nmol/L [>30 ng/mL], reference group), insufficient (37–75 nmol/L [15–30 ng/mL]; adjusted odds ratio [OR]: 2.40, 95% confidence interval [CI]: 0.90–6.34) or deficient (<37 nmol/L [<15 ng/mL]; adjusted OR: 2.56, 95% CI: 1.27–5.19). When modeled as a continuous variable, increased log10 25(OH)D was inversely associated with the risk of prevalent NAFLD (adjusted OR: 0.25, 95% CI: 0.064–0.96, P=0.02).
Conclusion
Compared with matched controls, patients with NAFLD have significantly decreased serum 25(OH)D levels, suggesting that low 25(OH)D status might play a role in the development and progression of NAFLD.
doi:10.1016/j.numecd.2012.12.006
PMCID: PMC3659172  PMID: 23415456
inflammation; fatty liver; NAFLD; risk factors; vitamin D; 25(OH)D
15.  Increased density of inhibitory noradrenergic parenchymal nerve fibers in hypertrophic islets of Langerhans of obese mice 
Background and aim
We sought to identify mechanisms of beta cell failure in genetically obese mice. Little is known about the role of pancreatic innervation in the progression of beta cell failure. In this work we studied adrenergic innervation, in view of its potent inhibitory effect on insulin secretion. We analyzed genetically obese ob/ob and db/db mice at different ages (6- and 15-week-old), corresponding to different compensatory stages in the course of beta cell dysfunction. 15 week-old HFD mice were also studied.
Methods and results
All mice were characterized by measures of plasma glucose, insulin, and HOMA. After perfusion, pancreata were dissected and studied by light microscopy, electron microscopy, and morphometry. Insulin, Tyrosine Hydroxylase-positive fibers and cells and Neuropeptide Y-positive cells were scored by immunohistochemistry.
Islets of obese mice showed increased noradrenergic fiber innervation, with significant increases of synaptoid structures contacting beta cells compared to controls. Noradrenergic innervation of the endocrine area in obese db/db mice tended to increase with age, as diabetes progressed. In ob/ob mice, we also detected an age-dependent trend toward increased noradrenergic innervation that, unlike in db/db mice, was unrelated to glucose levels. We also observed a progressive increase in Neuropeptide Y-immunoreactive elements localized to the islet core.
Conclusions
Our data show increased numbers of sympathetic nerve fibers with a potential to convey inhibitory signals on insulin secretion in pancreatic islets of genetically obese animals, regardless of their diabetic state. The findings suggest an alternative interpretation of the pathogenesis of beta cell failure, as well as novel strategies to reverse abnormalities in insulin secretion.
doi:10.1016/j.numecd.2013.09.006
PMCID: PMC4082304  PMID: 24462047
Islets; Noradrenergic fibers; Obesity
16.  Dietary Patterns and Their Association with Cardiovascular Risk Factors in a Population Undergoing Lifestyle Changes: The Strong Heart Study 
Background and Aims
Rates of cardiovascular disease (CVD) are disproportionately high in American Indians (AI), and changes in lifestyle may be responsible. It is not known whether diverse dietary patterns exist in this population and whether the patterns are associated with CVD risk factors. This article describes the relationships between dietary patterns and CVD risk factors in this high-risk population.
Methods and Results
Nutrition data were collected via food frequency questionnaire from 3438 Strong Heart Study (SHS) participants, ≥ age 15 y. All participants were members of 94 extended families. The final sample consisted of 3172 men and women. Diet patterns were ascertained using factor analysis with the principal component factoring method. We derived four predominant dietary patterns: Western, traditional AI/Mexican, healthy, and unhealthy. Participants following the Western pattern had higher LDL cholesterol (LDL-C) (p<0.001), slightly higher systolic blood pressure (BP) (p<0.001), lower HDL cholesterol (HDL-C) (p<0.001), and slightly lower homeostasis model assessment estimates of insulin resistance (HOMA-IR) in the lowest vs. highest deciles of adherence to this pattern (p<0.001). The traditional diet was associated with higher HDL-C (p<0.001), but higher body mass index (BMI) (p<0.001) and HOMA-IR (p<0.001). Followers of the healthy pattern had lower systolic BP, LDL-C, BMI, and HOMA-IR in increasing deciles (p<0.001). The unhealthy pattern was associated with higher LDL-C.
Conclusions
Dietary patterns reflect the changing lifestyle of AI and several of the patterns are associated with CVD risk factors. Evolving methods of food preparation have made the traditional pattern less healthy.
doi:10.1016/j.numecd.2011.12.005
PMCID: PMC3674116  PMID: 22534653
cardiovascular risk; dietary patterns; lifestyle; Strong Heart Study
17.  Cardiovascular Diseases in American Women 
Aims
Cardiovascular disease (CVD) is one of the major public health issues in women among diverse populations across the world. This article reports current information about the occurrence and risk factors of atherosclerotic CVD in American women.
Data Synthesis
The most recent scientific publications from the American Heart Association, the Centers for Disease Control and Prevention, and the National Heart, Lung, and Blood Institute and elsewhere were reviewed in regard to CVD in the US population. We focused on the atherosclerotic CVD in women, which includes coronary heart disease, stroke, and heart failure. Prevalence, incidence, and mortality of these diseases in women were described. The statistics about CVD on women were compared to men’s. Special physiological changes in women and their relationships to CVD were discussed. The major modifiable risk factors were discussed.
Conclusion
About 35% women in the United States have some form of CVD and for men, this number is 37.6%. The CVD incidence for women was close to that of men 10 years younger. The gap narrows with advancing age. Since 1984, the number of CVD deaths for women has exceeded those for men. Women represent 52.6% of CVD deaths, and CVD is the leading cause of death in US women. In both men and women risk factors such as hypertension, high blood cholesterol level, smoking, lack of physical activity, and obesity increase the probability of developing CVD. Menopause, oral contraceptive use, and bilateral oophorectomy in premenopausal women also affect the risk of CVD in women.
doi:10.1016/j.numecd.2010.02.001
PMCID: PMC4039306  PMID: 20554179
18.  The effects of ABCG5/G8 polymorphisms on HDL cholesterol concentrations depend on ABCA1 genetic variants in the Boston Puerto Rican Health Study 
Background and aims
ATP-binding cassette transporters G5/G8 (ABCG5/G8) are associated with HDL-C concentrations. To assess whether the effect of ABCG5/G8 genetic variants on HDL-C concentrations is dependent on ATP-binding cassette transporters A1 (ABCA1), we studied potential interactions between single nucleotide polymorphisms (SNPs) at ABCG5/G8 (i7892T>C, 5U145A>C, T54CA>G, T400KC>A) and ABCA1 (i27943G>A, i48168G>A, K219RG>A, i125970G>C, 3U8995A>G) genes with HDL-C concentrations.
Methods and Results
ABCG5/G8 and ABCA1 SNPs were genotyped in 788 subjects (228 men and 560 women) who participated in the Boston Puerto Rican Health Study. Biochemical measurements were determined by standard procedures. Genotyping was performed using TaqMan® assays according to routine laboratory protocols. Significant gene-gene interactions for HDL-C were found between ABCG8 (5U145A>C, T54CA>G, T400KC>A) SNPs and ABCA1_ i48168G>A genetic variant (P=0.009, P=0.042 and P=0.036, respectively), in which carriers of the 5U145C and 54C alleles, and homozygotes for the T400 allele at ABCG8 genetic variants displayed lower HDL-C concentrations than homozygotes for the 5U145A and T54 alleles, and heterozygotes for the 400K allele at ABCG8 SNPs, only if they were also homozygous for the minor allele (A) at the aforementioned ABCA1 SNP.
Conclusions
The gene-gene interactions reported in the present study support the hypothesis that the effect of ABCG5/G8 genetic variants on HDL-C concentrations is dependent on ABCA1 expression. Replication of these analyses to further populations, particularly with low HDL-C, is clearly warranted.
doi:10.1016/j.numecd.2009.05.005
PMCID: PMC4038034  PMID: 19692220
ATP binding cassette transporters; HDL-cholesterol; gene-gene interaction; pathway; reverse cholesterol transport
19.  A COMPOSITE SCORING OF GENOTYPES DISCRIMINATES CORONARY HEART DISEASE RISK BEYOND CONVENTIONAL RISK FACTORS IN THE BOSTON PUERTO RICAN HEALTH STUDY 
Background and aims
Using a genetic predisposition score (GPS), integrating the additive associations of a set of single nucleotide polymorphisms (SNPs) with CHD, we examined the consequences of the joint presence of a high GPS and conventional risk factors (CRFs).
Methods and Results
We studied eleven SNPs at eight loci in 197 participants with prior CHD and 524 CHD-free subjects from the Boston Puerto Rican Health Study. Each polymorphism contributed 1 unit (high-risk allele homozygous), 0.5 units (heterozygous) and 0 units (low-risk allele homozygous) to the GPS. Odds ratio (OR) of CHD for those at high-risk because of GPS (>5) and simultaneous presence of CRFs were estimated, compared with subjects at low-risk, for both measurements. The mean score was higher in participants with prior CHD than those CHD-free (P=0.015), and the OR for CHD with a GPS>5 was 2.90 (P<0.001).The joint presence of a high GPS and each CRF was associated with higher risk of CHD. Compared to participants with high GPS, those with low GPS (≤5) were protected against CHD even if they were smokers (OR=0.44), heavy drinkers (OR=0.43), displayed low physical activity (OR=0.35), had hypertension (OR=0.52) or hyperlipidemia (OR=0.34) (P values ranging from 0.004 to 0.023).
Conclusion
A simple genetic score of eleven polymorphisms may identify those subjects at increased risk of CHD beyond conventional risk factors.
doi:10.1016/j.numecd.2009.03.016
PMCID: PMC4031647  PMID: 19501493
genes; coronary heart disease; conventional risk factors; genetic predisposition score; single nucleotide polymorphism
20.  Stroke in women 
Aims
The aim of this article is to provide an overview of stroke in women and describe modifiable and non-modifiable risk factors for stroke.
Data synthesis
Data supporting this article come from the National Center for Health Statistics, from American Heart Association publications, and from some of the large, multicenter trials and observational studies that inform guidelines for prevention of stroke. These data indicate that stroke is the third leading cause of death in women, that risk for stroke rises rapidly with age, and that the strongest risk factors for stroke are high blood pressure and atrial fibrillation, as well as diabetes and smoking. Risk rises rapidly when two or more risk factors are present. Hormone therapy in postmenopausal women increases risk of ischemic, but not hemorrhagic stroke, by 40–50%. Biomarkers of inflammation are associated with stroke risk. Other risk factors include certain lipids, physical inactivity, and low potassium diets. Although there has been improvement in the past decade, control of hypertension is inadequate in older women and many strokes could be prevented by better treatment of hypertension.
Conclusion
Death and disability from stroke can be reduced with modification, treatment, and better control of risk factors like hypertension, diabetes and atrial fibrillation.
doi:10.1016/j.numecd.2010.02.017
PMCID: PMC3993990  PMID: 20605084
Stroke in women; Ischemic stroke; Hemorrhagic stroke; Hormone therapy; Risk factors for stroke
21.  Does cardiovascular phenotype explain the association between diabetes and incident heart failure? The Strong Heart Study 
Background and Aims
Diabetes remains a predictor of incident heart failure (HF), independent of intercurrent myocardial infarction (MI) and concomitant risk factors. Initial cardiovascular (CV) characteristics, associated with incident heart failure (HF) might explain the association of diabetes with incident HF.
Methods and Results
Participants to the 2nd Strong Heart Study exam, without prevalent HF or coronary heart disease, or glomerular filtration rate <30 mL/min/1.73m2, were analyzed (n=2,757, 1,777 women, 1,278 diabetic). Cox regression of incident HF (follow-up 8.91±2.76 years) included incident MI censored as a competing risk event. Acute MI occurred in 96 diabetic (7%) and 84 non-diabetic participants (6%, p=ns). HF occurred in 156 diabetic (12%) and in 68 non-diabetic participants (5%; OR=2.89, p<0.001). After accounting for competing MI and controlling for age, gender, BMI, systolic blood pressure, smoking habit, plasma cholesterol, antihypertensive treatment, heart rate, fibrinogen and C-reactive protein, incident HF was predicted by greater LV mass index, larger left atrium, lower systolic function, greater left atrial systolic force and urinary albumin/creatinine excretion. Risk of HF was reduced with more rapid LV relaxation and anti-hypertensive therapy. Diabetes increases hazard of HF by 66% (0.02
Conclusions
Incident HF occurs more frequently in diabetes, independent of intercurrent MI, abnormal LV geometry, subclinical systolic dysfunction and indicators of less rapid LV relaxation, and is influenced by poor metabolic control. Identification of CV phenotype at high-risk for HF in diabetes should be advised.
doi:10.1016/j.numecd.2011.06.007
PMCID: PMC3246029  PMID: 21940153
coronary disease; risk factors; diastolic function; systolic function; hypertrophy; obesity
Aim
To evaluate the relationship of diet to incident diabetes among non-Black and Black participants in the Adventist Health Study-2.
Methods and Results
Participants were 15,200 men and 26,187 women (17.3% Blacks) across the U.S. and Canada who were free of diabetes and who provided demographic, anthropometric, lifestyle and dietary data. Participants were grouped as vegan, lacto ovo vegetarian, pesco vegetarian, semi-vegetarian or non-vegetarian (reference group). A follow-up questionnaire after two years elicited information on the development of diabetes. Cases of diabetes developed in 0.54% of vegans, 1.08% of lacto ovo vegetarians, 1.29% of pesco vegetarians, 0.92% of semi-vegetarians and 2.12% of non-vegetarians. Blacks had an increased risk compared to non-Blacks (odds ratio [OR] 1.364; 95% confidence interval [CI], 1.093–1.702). In multiple logistic regression analysis controlling for age, gender, education, income, television watching, physical activity, sleep, alcohol use, smoking and BMI, vegans (OR 0.381; 95% CI 0.236–0.617), lacto ovo vegetarians (OR 0.618; 95% CI 0.503–0.760) and semi-vegetarians (OR 0.486, 95% CI 0.312–0.755) had a lower risk of diabetes than non-vegetarians. In non-Blacks vegan, lacto ovo and semi-vegetarian diets were protective against diabetes (OR 0.429, 95% CI 0.249–0.740; OR 0.684, 95% CI 0.542–0.862; OR 0.501, 95% CI 0.303–0.827); among Blacks vegan and lacto ovo vegetarian diets were protective (OR 0.304, 95% CI 0.110–0.842; OR 0.472, 95% CI 0.270–0.825). These associations were strengthened when BMI was removed from the analyses.
Conclusion
Vegetarian diets (vegan, lacto ovo, semi-) were associated with a substantial and independent reduction in diabetes incidence. In Blacks the dimension of the protection associated with vegetarian diets was as great as the excess risk associated with Black ethnicity.
doi:10.1016/j.numecd.2011.07.004
PMCID: PMC3638849  PMID: 21983060
Vegetarianism; Black; African American; Diabetes; Ethnicity; Diet
Background and Aims
Few studies have evaluated the effects of food-based eating patterns on adolescent lipid levels. This study examines whether usual adolescent eating patterns (ages 9–17 years) predict lipid levels at 18–20 years of age.
Methods and Results
This study uses previously collected data from the longitudinal NHLBI Growth and Health Study in which 2,379 girls were enrolled at ages 9–10 years and followed for ten years. Food-based eating patterns were derived from multiple 3-day diet records. After adjusting for age, race, socioeconomic status, height, physical activity, and television viewing, girls with higher intakes of dairy, fruit and non-starchy vegetables had about a 40–50% reduced risk an LDL-C ≥170 mg/dL and non-HDL-C ≥145 mg/dL. Diets characterized by higher intakes of dairy and whole grains had similar benefits on TC and LDL-C. Girls consuming more fruits and non-starchy vegetables as well as more whole grains were much less likely to have high-risk lipid levels. Lean meat, poultry and fish when consumed in the context of other healthy eating patterns had no adverse effects on lipid levels in late adolescence. In fact when consumed with higher amounts of fruit and non-starchy vegetables, lean meat, poultry and fish had beneficial effects on HDL. Finally, dietary patterns that included more whole grains tended to be associated with lower TG levels.
Conclusion
Healthy childhood eating patterns characterized by higher intakes of a variety of fruits, vegetables, whole grains, dairy, lean meat, poultry and fish are important modifiable predictors of lipid levels in late adolescence.
doi:10.1016/j.numecd.2011.10.010
PMCID: PMC3399938  PMID: 22417625
Diet; lipids; adolescence
Background and Aims
Metabolic syndrome (MetS) is a complex condition characterized by different phenotypes, according to combinations of risk factors and is associated with cardiovascular abnormalities. Whether control of MetS components by treatment produces improvement in the associated cardiovascular abnormalities is unknown. We investigated whether partial control of components of MetS was associated with less echocardiographic abnormalities than the complete presentation of MetS based on measured components.
Methods and Results
We evaluated markers of echocardiographic preclinical cardiovascular disease in MetS (ATPIII) defined by measured components or by history of treatment, in 1,421 African- American and 1,195 Caucasian non-diabetic HyperGEN participants, without prevalent cardiovascular disease or serum creatinine>2 mg/dL. Of 2,616 subjects, 512 subjects had MetS by measured components and 328 by history. Hypertension was found in 16% of participants without MetS, 6% of those with MetS by history and 42% of those with MetS by measured components. Obesity and central fat distribution had similar prevalence in both MetS groups (both p<0.0001 vs No-MetS). Blood pressure was similar in MetS by history and No-MetS, and lower than in MetS by measured components (p<0.0001). LV mass and midwall shortening, left atrial (LA) dimension and LA systolic force were similarly abnormal in both MetS groups (all p<0.0001 vs. No-MetS) without difference between them.
Conclusions
There is little impact of control by treatment of single components of MetS (namely hypertension) on echocardiographic abnormalities. Lower blood pressure in participants with MetS by history was not associated with substantially reduced alterations in cardiac geometry and function.
doi:10.1016/j.numecd.2011.02.004
PMCID: PMC3158296  PMID: 21570269
Background and aims
While clinical trials have reported beneficial effects of diet, exercise, and weight loss on incident diabetes in subjects with obesity or impaired glucose tolerance, little is known about the incremental benefit of not smoking and moderate drinking on diabetes risk. We sought to examine the association between modifiable lifestyle factors and residual lifetime risk of diabetes.
Methods and Results
Prospective cohorts involving 20,915 men (1982–2008) and 36,594 women (1992–2008). Modifiable lifestyle factors and adiposity were ascertained at baseline in each cohort and incident diabetes was ascertained during follow up. The mean age at baseline was 53.5 y in men and 54.6 y in women. During an average follow up of 22.6 y in men and 13.0 y in women, 2,096 men and 2,390 women developed diabetes. At age 45 y, the residual lifetime risk of diabetes (95% CI) for men with 0, 1, 2, 3, and 4+ healthy lifestyle factors was 30.5 (27.3–33.7); 21.5 (19.9–23.0); 15.1 (13.9–16.3); 10.3 (9.1–11.5); and 7.3 (5.7–8.9) percent; respectively. Corresponding values for women were 31.4 (28.3–34.5); 24.1 (21.8–26.5); 14.2 (12.7–15.7); 11.6 (9.7–13.5); and 6.4 (4.2–8.6) percent, respectively.
Conclusions
These data show an inverse and graded relation between desirable lifestyle factors and residual lifetime risk of diabetes in men and women. Not smoking and moderate drinking may have additional benefits when added to exercise, weight control, and diet.
doi:10.1016/j.numecd.2011.08.002
PMCID: PMC3274624  PMID: 21982361
Smoking; exercise; weight loss; diabetes; diet; risk factors; epidemiology; obesity; Physicians' Health Study; Women's Health Study

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