S J Robins

Boston University, Boston, Massachusetts, United States

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Publications (111)786.05 Total impact

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    ABSTRACT: Polyunsaturated fatty acids have been associated with beneficial influences on cardiovascular health. However, the underlying mechanisms are not clear, and data on the relations of polyunsaturated fatty acids to subclinical disease measures such as vascular stiffness and cardiac function are sparse and inconclusive. In a large community-based cohort, we examined the relations of omega-3 and other fatty acids to a comprehensive panel of vascular function measures (assessing microvascular function and large artery stiffness), cardiac structure and left ventricular function. Red blood cell (RBC) membrane fatty acid composition, a measure of long-term fatty acid intake, was assessed in participants of the Framingham Offspring Study and Omni cohorts and related to tonometry-derived measures of vascular stiffness and to a panel of echocardiographic traits using partial correlations. Up to n=3055 individuals (56% women, mean age 66 years) were available for analyses. In age- and sex-adjusted models, higher RBC omega-3 content was moderately associated (p≤0.002) with several measures of vascular stiffness and function in a protective direction. However, after multivariable adjustment, only an association of higher RBC omega-3 content with lower carotid-femoral pulse wave velocity (a measure of aortic stiffness) remained significant (r = -0.06, p=0.002). In secondary analyses, higher linoleic acid, the major nutritional omega-6 fatty acid, was associated with smaller left atrial size, even after multivariable adjustment (r = -0.064, p<0.001). In conclusion, in our cross-sectional community-based study, we found several associations consistent with the notion of protective effects of omega-3 and linoleic acid. The clinical significance of these modest associations remains to be elucidated. © The Author(s) 2014.
    Vascular medicine (London, England). 12/2014;
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    ABSTRACT: Background Blood levels of high low-density lipoprotein cholesterol (LDL-C), high triglycerides (TG), and low high-density lipoprotein cholesterol (HDL-C) have been associated with increased risk of cardiovascular disease (CVD). The long-term comparative CVD risk associated with these three major lipid classes in various combinations is, however, unknown. Methods 3501 participants of the Framingham Offspring Study (mean age 51 ± 10 years, 56% women) without CVD at baseline were followed for incident CVD between 1987 and 2011. Participants were grouped according to baseline lipid-values into eight distinct categories to compare the prognostic significance of values within an optimal range to ATP-III defined high LDL-C (>130 mg/dL), high TG (>150 mg/dL), and/or low HDL-C (<40 mg/dL) in various combinations using multivariable-adjusted Cox regression models. Results On follow-up (median 20.2 years), 724 (21%) had new-onset CVD. Adjusted for confounders and compared with the group with optimal lipid-values, hazards ratios (HR) and population attributable risks (PAR) were: isolated low HDL-C, 1.93 (95% confidence interval [CI]: 1.37-2.71), PAR = 3.1%; isolated high LDL-C, 1.28 (1.03-1.59), PAR 6.4%; isolated high TG, 1.35 (0.91-1.98), PAR = 1.1% (not significant); low HDL-C and high LDL-C, 1.82 (1.33-2.49), PAR = 3.9%; low HDL-C and high TG, 1.74 (1.28-2.37), PAR = 3.9%; high LDL-C and high TG, 1.52 (1.12-2.07), PAR = 6.4%; and high LDL-C, high TG and low HDL-C 2.28 (1.73-3.02), PAR = 7.5%. Conclusions Aside from isolated hypertriglyceridemia, low levels of HDL-C, high levels of LDL-C, and high levels of TG in any combination were associated with increased risk of cardiovascular disease.
    American Heart Journal. 12/2014;
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    ABSTRACT: OBJECTIVE: Cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) are two genetically-related plasma proteins involved in the exchange of cholesteryl esters and phospholipids between high-density lipoproteins (HDL) and other lipoproteins. Although low CETP and high PLTP activity both result in higher concentrations of plasma HDL-cholesterol (HDL-C), there is no evidence that either of these changes is associated with a decrease in cardiovascular disease (CVD) in a general population. METHODS: Plasma CETP and PLTP activities, measured by homogenous fluorometric assays using synthetic donor particle substrates, were related to the incidence of a first CVD event in Framingham Heart Study Offspring participants without CVD (n = 2679, mean age 59 y, 56% women) attending the 6th examination cycle (1995-98). Because of an effect modification by sex for both CETP and PLTP, analyzes were stratified by sex. RESULTS: During follow-up (mean 10.4 years) 187 participants experienced a first CVD event. In sex-specific Cox models, both CETP and PLTP as continuous and as binary variables were associated with significantly increased CVD in men, but not women. In men compared to a referent group with CETP ≥ median and PLTP < median, the multivariable-adjusted hazard ratio (HR) for new CVD events was significantly greater with either the combination of high CETP and high PLTP (HR 2.27, 95% CI 1.23-4.20); low CETP and low PLTP (HR 2.23, 95% CI 1.19-4.17); or low CETP and high PLTP (HR 2.85, 95% CI 1.53-5.31). In contrast, in women the multivariable-adjusted HR for new CVD events was non-significant and virtually equal to "1.0" with all combinations of high and low CETP or PLTP values. CONCLUSIONS: Lower plasma CETP or higher PLTP activity was each associated with a significantly increased risk of CVD. Inexplicably, the increase in CVD associated with both lipid transfer proteins was confined to men.
    Atherosclerosis 02/2013; · 3.71 Impact Factor
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    ABSTRACT: OBJECTIVES: Red blood cell (RBC) levels of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA, the omega-3 index, expressed as a percent of total fatty acids) are inversely related to risk for cardiovascular disease (CVD). Although several mechanisms underlying this relationship have been proposed, understanding the associations between the omega-3 index and markers of CVD in the community can shed additional light on this question. The objectives of this study were to define the relations between the omega-3 index and clinical factors and to determine the heritability of the omega-3 index. METHODS: RBC samples (n = 3196) drawn between 2005 and 2008 from participants in the Framingham Study [Examination 8 of the Offspring cohort plus Examination 3 of the Omni (minorities) cohort] were analyzed for fatty acid composition by gas chromatography. RESULTS: The mean (SD) omega-3 index was 5.6% (1.7%). In multivariable regression models, the factors significantly and directly associated with the omega-3 index were age, female sex, higher education, fish oil supplementation, dietary intake of EPA + DHA, aspirin use, lipid pharmacotherapy, and LDL-cholesterol. Factors inversely associated were Offspring cohort, heart rate, waist girth, triglycerides and smoking. The total explained variability in the omega-3 index for the fully adjusted model was 73%, which included major components due to heritability (24%), EPA + DHA intake (25%), and fish oil supplementation (15%). CONCLUSION: The variability in the omega-3 index is determined primarily by dietary and genetic factors. An increased omega-3 index is associated with a generally cardioprotective risk factor milieu.
    Atherosclerosis 06/2012; · 3.71 Impact Factor
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    ABSTRACT: Over the last several years, national programs to lower the content of industrially produced (IP) C18:1 and C18:2 trans fatty acids in foods have been implemented, but whether this has resulted in lower blood trans fatty acid levels is unknown. Likewise, an increased perception of the health benefits of fish oils rich in EPA and DHA may have resulted in an increase in consumption and blood levels of these fatty acids. To explore these issues, we analyzed the changes in RBC fatty acid composition between the 7th (1998-2001) and 8th (2005-2007) examination cycles in a random sample of the Framingham Offspring cohort. This was a retrospective cohort study of 291 participants from whom blood was drawn at both examinations and for whom complete covariate data were available. Overall, the proportion of trans fatty acids in RBC changed by -23% (95% CI: -26 to -21%). RBC EPA+DHA proportions increased by 41% (95% CI: 31 to 52%) in 38 individuals who were taking fish oil supplements at examination 8, but in 253 participants not taking fish oil, the proportion of RBC EPA+DHA did not change. In conclusion, in a random subsample of Framingham Offspring participants with serial observations over 6.7 y, the proportion of trans fatty acids in RBC decreased. Those of EPA+DHA increased in people taking fish oil supplements. These changes could potentially translate into a lower risk for cardiovascular disease.
    Journal of Nutrition 05/2012; 142(7):1297-303. · 4.20 Impact Factor
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    ABSTRACT: The natriuretic peptides play an important role in salt homeostasis and blood pressure regulation. It has been suggested that obesity promotes a relative natriuretic peptide deficiency, but this has been a variable finding in prior studies and the cause is unknown. The aim of this study was to examine the association between obesity and natriuretic peptide levels and evaluate the role of hyperinsulinemia and testosterone as mediators of this interaction. We studied 7770 individuals from the Framingham Heart Study (n = 3833, 54% women) and the Malmö Diet and Cancer study (n = 3918, 60% women). We examined the relation of plasma N-terminal pro-B-type natriuretic peptide levels (N-BNP) with obesity, insulin resistance, and various metabolic subtypes. Obesity was associated with 6-20% lower levels of N-BNP (P < 0.001 in Framingham, P = 0.001 in Malmö), whereas insulin resistance was associated with 10-30% lower levels of N-BNP (P < 0.001 in both cohorts). Individuals with obesity who were insulin sensitive had only modest reductions in N-BNP compared with nonobese, insulin-sensitive individuals. On the other hand, individuals who were nonobese but insulin resistant had 26% lower N-BNP in Framingham (P < 0.001) and 10% lower N-BNP in Malmö (P < 0.001), compared with nonobese and insulin-sensitive individuals. Adjustment for serum-free testosterone did not alter these associations. In both nonobese and obese individuals, insulin resistance is associated with lower natriuretic peptide levels. The relative natriuretic peptide deficiency seen in obesity could be partly attributable to insulin resistance, and could be one mechanism by which insulin resistance promotes hypertension.
    The Journal of Clinical Endocrinology and Metabolism 08/2011; 96(10):3242-9. · 6.31 Impact Factor
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    ABSTRACT: The goal of this study was to examine the effect of insulin resistance (IR) in subjects without diabetes on the relationship of a dyslipidemia with high triglycerides and low high-density lipoprotein cholesterol (HDL-C) to the development of coronary heart disease (CHD). Lower and higher fasting plasma HDL-C and triglyceride concentrations (defined at the study population median) and presence or absence of IR (defined by upper quartile Homeostatic Model Assessment values) were related to the development of myocardial infarction or CHD death in Framingham Heart Study participants without diabetes or a history of CHD (n=2910) attending the 1991 to 1995 examination. During follow-up (mean, 14 years), 128 participants experienced an incident CHD event. With Kaplan-Meier plots, the incidence of CHD was significantly greater with than without IR at either the lowest HDL-C or the highest triglycerides (P<0.001). In multivariable Cox models adjusted for major CHD risk factors, including waist circumference, only subgroups with IR had a significantly higher incidence of CHD. Compared with a reference group without IR and with higher-than-median HDL-C or lower-than-median triglycerides, the hazard ratio (HR) for incident events was significant with only IR and a lower HDL-C (HR 2.83, P<0.001) or higher triglycerides (HR 2.50, P<0.001). These findings were similar in men and women. In this community-based sample exclusive of diabetes, incident CHD risk associated with plasma HDL-C or triglycerides was significantly increased only in the presence of IR.
    Arteriosclerosis Thrombosis and Vascular Biology 02/2011; 31(5):1208-14. · 6.34 Impact Factor
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    ABSTRACT: Microalbuminuria is a common condition associated with increased incidence of cardiovascular events and mortality. Abdominal obesity is associated with microalbuminuria, but studies linking visceral adipose tissue (VAT) and microalbuminuria are limited. Our objective was to determine the associations of albuminuria with VAT and subcutaneous adipose tissue (SAT). We performed a cross-sectional study in the Framingham Multi-Detector Computed Tomography (MDCT) cohort (n = 3099, 48.2% women, mean age 53 years). VAT and SAT volumes were measured using computed tomography. Urinary albumin-to-creatinine ratio (UACR) was calculated from spot urine samples. Microalbuminuria was defined as a UACR >25 mg/g in women or >17 mg/g in men. Overall, 7.9% (n = 244) of the sample had microalbuminuria. Among men, VAT (odds ratio (OR) 1.48 per s.d., P < 0.0001) and SAT (OR 1.37 per s.d., P = 0.0002) were associated with microalbuminuria in minimally adjusted models, which remained significant after multivariable adjustment (VAT OR 1.34 per s.d., P = 0.001; SAT OR 1.28 per s.d., P = 0.005). Additionally, when considered jointly, VAT (P = 0.002) but not SAT (P = 0.2) was associated with microalbuminuria. In women, VAT was associated with microalbuminuria after minimal adjustment (OR 1.28, P = 0.01), but not after multivariable adjustment (OR 1.03, P = 0.8). In multivariable models in women, SAT was associated with a decreased odds of having microalbuminuria (OR 0.75 per s.d., P = 0.03). In conclusion, VAT is associated with microalbuminuria in men but not women. Albuminuria may be a manifestation of visceral adiposity.
    Obesity 12/2010; 19(6):1284-9. · 3.92 Impact Factor
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    ABSTRACT: A low level of HDL-C is the most common plasma lipid abnormality observed in men with established coronary heart disease (CHD). To identify allelic variants associated with susceptibility to low HDL-C and CHD, we examined 60 candidate genes with key roles in HDL metabolism, insulin resistance, and inflammation using samples from the Veterans Affairs HDL Intervention Trial (VA-HIT; cases, n = 699) and the Framingham Offspring Study (FOS; controls, n = 705). VA-HIT was designed to examine the benefits of HDL-raising with gemfibrozil in men with low HDL-C (≤40 mg/dl) and established CHD. After adjustment for multiple testing within each gene, single-nucleotide polymorphisms (SNP) significantly associated with case status were identified in the genes encoding LIPC (rs4775065, P < 0.0001); CETP (rs5882, P = 0.0002); RXRA (rs11185660, P = 0.0021); ABCA1 (rs2249891, P = 0.0126); ABCC6 (rs150468, P = 0.0206; rs212077, P = 0.0443); CUBN (rs7893395, P = 0.0246); APOA2 (rs3813627, P = 0.0324); SELP (rs732314, P = 0.0376); and APOC4 (rs10413089, P = 0.0425). Included among the novel findings of this study are the identification of susceptibility alleles for low HDL-C/CHD risk in the genes encoding CUBN and RXRA, and the observation that genetic variation in SELP may influence CHD risk through its effects on HDL.
    The Journal of Lipid Research 12/2010; 51(12):3524-32. · 4.39 Impact Factor
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    ABSTRACT: Insulin resistance is associated with central obesity and an increased risk of cardiovascular disease. Our objective is to examine the association between abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) and insulin resistance, to determine which fat depot is a stronger correlate of insulin resistance, and to assess whether there was an interaction between SAT, VAT, and age, sex, or BMI. Participants without diabetes from the Framingham Heart Study (FHS), who underwent multidetector computed tomography to assess SAT and VAT (n = 3,093; 48% women; mean age 50.4 years; mean BMI 27.6 kg/m(2)), were evaluated. Insulin resistance was measured using the homeostasis model and defined as HOMA(IR) ≥75th percentile. Logistic regression models, adjusted for age, sex, smoking, alcohol, menopausal status, and hormone replacement therapy use, were used to assess the association between fat measures and insulin resistance. The odds ratio (OR) for insulin resistance per standard deviation increase in SAT was 2.5 (95% confidence interval (CI): 2.2-2.7; P < 0.0001), whereas the OR for insulin resistance per standard deviation increase in VAT was 3.5 (95% CI: 3.1-3.9; P < 0.0001). Overall, VAT was a stronger correlate of insulin resistance than SAT (P < 0.0001 for SAT vs. VAT comparison). After adjustment for BMI, the OR of insulin resistance for VAT was 2.2 (95% CI: 1.9-2.5; P < 0.0001). We observed an interaction between VAT and BMI for insulin (P interaction = 0.0004), proinsulin (P interaction = 0.003), and HOMA(IR) (P interaction = 0.003), where VAT had a stronger association in obese individuals. In conclusion, SAT and VAT are both correlates of insulin resistance; however, VAT is a stronger correlate of insulin resistance than SAT.
    Obesity 11/2010; 18(11):2191-8. · 3.92 Impact Factor
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    ABSTRACT: Neck circumference, a proxy for upper-body sc fat, may be a unique fat depot that confers additional cardiovascular risk above and beyond central body fat. Participants with neck circumference measures who underwent multidetector computed tomography to assess visceral adipose tissue (VAT) were included [n=3307, 48% women; mean age=51 yr; mean body mass index (BMI)=27.8 kg/m2; mean neck circumference=40.5 cm (men) and 34.2 cm (women)]. Sex-specific linear regression models were used to assess the association between sd increase in neck circumference and cardiovascular disease (CVD) risk factors (systolic and diastolic blood pressure; total, low-density lipoprotein, and high-density lipoprotein cholesterol and triglycerides; and fasting plasma glucose, insulin, proinsulin, and homeostasis model assessment of insulin resistance). Neck circumference was correlated with VAT [r=0.63 (men); r=0.74 (women); P<0.001] and BMI [r=0.79 (men); r=0.80 (women); P<0.001]. After further adjustment for VAT, neck circumference was positively associated with systolic blood pressure, diastolic blood pressure in men only, triglycerides, fasting plasma glucose in women only, insulin, proinsulin, and homeostasis model assessment of insulin resistance and was inversely associated with high-density lipoprotein (all P values<0.01). Similar results were observed in models that adjusted for both VAT and BMI. In a secondary analysis of incident CVD as an outcome, there was no statistically significant association observed for neck circumference in multivariable-adjusted models. Neck circumference is associated with CVD risk factors even after adjustment for VAT and BMI. These findings suggest that upper-body sc fat may be a unique, pathogenic fat depot.
    The Journal of Clinical Endocrinology and Metabolism 08/2010; 95(8):3701-10. · 6.31 Impact Factor
  • Circulation 01/2010; 122(6). · 15.20 Impact Factor
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    ABSTRACT: The relations of lipid concentrations to heart failure (HF) risk have not been elucidated comprehensively. In 6860 Framingham Heart Study participants (mean age, 44 years; 54% women) free of baseline coronary heart disease, we related high-density lipoprotein cholesterol (HDL-C) and non-HDL-C to HF incidence during long-term follow-up, adjusting for clinical covariates and myocardial infarction at baseline and updating these at follow-up examinations. We evaluated dyslipidemia-specific population burden of HF by calculating population attributable risks. During follow-up (mean of 26 years), 680 participants (49% women) developed HF. Unadjusted HF incidence in the low (<160 mg/dL) versus high (> or =190 mg/dL) non-HDL-C groups was 7.9% and 13.8%, respectively, whereas incidence in the high (> or =55 [men], > or =65 [women] mg/dL) versus low (<40 [men], <50 [women] mg/dL) HDL-C groups was 6.1% and 12.8%, respectively. In multivariable models, baseline non-HDL-C and HDL-C, modeled as continuous measures, carried HF hazards (confidence intervals) of 1.19 (1.11 to 1.27) and 0.82 (0.75 to 0.90), respectively, per SD increment. In models updating lipid concentrations every 8 years, the corresponding hazards (confidence intervals) were 1.23 (1.16 to 1.31) and 0.77 (0.70 to 0.85). Participants with high baseline non-HDL-C and those with low HDL-C experienced a 29% and 40% higher HF risk, respectively, compared with those in the desirable categories; the population attributable risks for high non-HDL-C and low HDL-C were 7.5% and 15%, respectively. Hazards associated with non-HDL-C and HDL-C remained statistically significant after additional adjustment for interim myocardial infarction. Dyslipidemia carries HF risk independent of its association with myocardial infarction, suggesting that lipid modification may be a means for reducing HF risk.
    Circulation 11/2009; 120(23):2345-51. · 15.20 Impact Factor
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    ABSTRACT: Plasma high-density lipoprotein cholesterol concentration is related inversely to the risk of cardiovascular disease (CVD). Inhibiting cholesteryl ester transfer protein (CETP) activity raises high-density lipoprotein cholesterol and may be cardioprotective, but an initial clinical trial with a CETP inhibitor was stopped prematurely because of increased CVD in treated patients, raising concerns about this approach. Data relating circulating CETP concentrations to CVD incidence in the community are conflicting. Plasma CETP activity was measured in 1978 Framingham Heart Study participants (mean age, 51 years; 54% women) who attended a routine examination in 1987-1990 and were free of CVD. On follow-up (mean, 15.1 years), 320 participants experienced a first CVD event (fatal or nonfatal coronary heart disease, cerebrovascular disease, peripheral vascular disease, or heart failure). In multivariable analyses adjusted for standard risk factors including high-density lipoprotein cholesterol, plasma CETP activity was related inversely to the incidence of CVD events (hazard ratio for activity, at or above the median of 0.72; 95% confidence interval, 0.57 to 0.90; P=0.004 [compared with below median]; hazard ratio per SD increment, 0.86; 95% confidence interval, 0.76 to 0.97; P=0.01). The inverse association of CETP activity with CVD incidence remained robust in time-dependent models updating standard risk factors every 4 years and was maintained in analyses of incident "hard" CVD events (myocardial infarction, stroke, or heart failure). In our prospective investigation of a community-based sample, lower plasma CETP activity was associated with greater CVD risk. These observations, if confirmed, challenge the concept that CETP inhibition may lower CVD risk.
    Circulation 11/2009; 120(24):2414-20. · 15.20 Impact Factor
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    ABSTRACT: Because vitamin D deficiency is associated with a variety of chronic diseases, understanding the characteristics that promote vitamin D deficiency in otherwise healthy adults could have important clinical implications. Few studies relating vitamin D deficiency to obesity have included direct measures of adiposity. Furthermore, the degree to which vitamin D is associated with metabolic traits after adjusting for adiposity measures is unclear. We investigated the relations of serum 25-hydroxyvitamin D (25[OH]D) concentrations with indexes of cardiometabolic risk in 3,890 nondiabetic individuals; 1,882 had subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes measured by multidetector computed tomography (CT). In multivariable-adjusted regression models, 25(OH)D was inversely associated with winter season, waist circumference, and serum insulin (P < 0.005 for all). In models further adjusted for CT measures, 25(OH)D was inversely related to SAT (-1.1 ng/ml per SD increment in SAT, P = 0.016) and VAT (-2.3 ng/ml per SD, P < 0.0001). The association of 25(OH)D with insulin resistance measures became nonsignificant after adjustment for VAT. Higher adiposity volumes were correlated with lower 25(OH)D across different categories of BMI, including in lean individuals (BMI <25 kg/m(2)). The prevalence of vitamin D deficiency (25[OH]D <20 ng/ml) was threefold higher in those with high SAT and high VAT than in those with low SAT and low VAT (P < 0.0001). Vitamin D status is strongly associated with variation in subcutaneous and especially visceral adiposity. The mechanisms by which adiposity promotes vitamin D deficiency warrant further study.
    Diabetes 10/2009; 59(1):242-8. · 7.90 Impact Factor
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    ABSTRACT: Recent cross-sectional population studies in the United States have shown an increase in obesity, a decrease in cholesterol values, but no changes in levels of high-density lipoprotein cholesterol (HDL-C) or triglycerides (TG). Plasma total cholesterol, HDL-C, and TG levels, measured by the same methods at the 3 most recently completed examinations of Framingham Offspring Study participants (1991-2001), were compared in 1666 participants without prevalent cardiovascular disease, lipid therapy, or hormone replacement therapy (56% were men; mean ages of participants at the first and last examinations, 53 and 60 years, respectively). Changes in age- and multivariate-adjusted mean lipid levels were related to changes in body mass index (BMI). Over the 3 examinations, comparing the findings of the earliest examination with those of the most recent examination, the mean HDL-C level was significantly increased (multivariate-adjusted means, 44.4 and 46.6 mg/dL in men; 56.9 and 60.1 mg/dL in women; P value for trend, P <.001 in both sexes), whereas levels of TG were decreased (144.5 and 134.1 mg/dL in men; 122.3 and 112.3 mg/dL in women; P value for trend, P = .004 in men and <.001 in women). Over the same time interval, BMI (calculated as weight in kilograms divided by height in meters squared) increased (27.8 and 28.5 in men; 27.0 and 27.6 in women; P value for trend, P < .001 in men and P = .001 in women). There was an inverse relationship between changes in BMI and magnitude of dyslipidemia (ie, individuals with the least increase in BMI had the most favorable changes in levels of HDL-C and TG). During a 10-year period of recent examinations in the Framingham Heart Study there was a decrease in dyslipidemia with an increase in HDL-C levels and a decrease in levels of TG despite an overall increase in BMI.
    Archives of internal medicine 03/2009; 169(3):279-86. · 11.46 Impact Factor
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    ABSTRACT: This analysis was undertaken to determine the long-term intraindividual variability, determinants of change, and capacity of the inflammatory marker C-reactive protein (CRP) to predict metabolic traits and diabetes in a large community-based population. Intraindividual CRP variability, predictors of CRP change, and metabolic events were evaluated in the Framingham Heart Study Offspring cohort using data from the same 2409 participants with CRP measured by the same methodology at each of 3 examination cycles, spanning 20 years. Between the first and second examinations (averaging 16 years apart), 23% to 47% of men and 27% to 49% of women remained within the same quintile of CRP values. An additional 24% to 51% of men and 24% to 50% of women occupied an adjacent quintile. Intermediate-term CRP variability (over 4 years) was similar to long-term variability. Both long- and intermediate-term variability of CRP were significantly less than that of plasma cholesterol measured in these same groups. Linear regression models for CRP at the intermediate examination demonstrated that CRP at the initial examination contributed the largest proportion of the variability (partial R-square = 0.27) seen in the overall model after adjustment for other covariates known to affect CRP concentrations. Although logistic regression models demonstrated that CRP over the intermediate term did not predict new-onset metabolic syndrome at the final examination, CRP did predict an increase in glucose and new-onset diabetes. The results of this longitudinal analysis suggest the intraindividual, long-term variability of CRP concentrations is relatively small and predictive of new diabetes over an intermediate-term of 4 years.
    The American journal of medicine 02/2009; 122(1):53-61. · 5.30 Impact Factor
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    ABSTRACT: To conduct an investigation of clinical and genetic correlates of lipoprotein-associated phospholipase (Lp-PLA(2)) activity and mass in a large community-based cohort. Higher circulating Lp-PLA(2) predicts cardiovascular disease risk, but sources of inter-individual variability are incompletely understood. We conducted stepwise regression of clinical correlates of Lp-PLA(2) in four Framingham Heart Study cohorts (n=8185; mean age 50+/-14 years, 53.8% women, 9.8% ethnic/racial minority cohort). We also conducted heritability and linkage analyses in Offspring and Generation 3 cohorts (n=6945). In Offspring cohort participants we performed association analyses (n=1535 unrelated) with 1943 common tagging SNPs in 233 inflammatory candidate genes. Sixteen clinical variables explained 57% of the variability in Lp-PLA(2) activity; covariates associated with Lp-PLA(2) mass were similar but only explained 27% of the variability. Multivariable-adjusted heritability estimates for Lp-PLA(2) activity and mass were 41% and 25%, respectively. A linkage peak was observed for Lp-PLA(2) activity (chromosome 6, LOD score 2.4). None of the SNPs achieved experiment-wide statistical significance, though 12 had q values <0.50, and hence we expect at least 50% of these associations to be true positives. The strongest multivariable-association with Lp-PLA(2) activity was found for MEF2A (rs2033547; nominal p=3.20 x 10(-4)); SNP rs1051931 in PLA2G7 was nominally associated (p=1.26 x 10(-3)). The most significant association to Lp-PLA(2) mass was in VEGFC (rs10520358, p=9.14 x 10(-4)). Cardiovascular risk factors and genetic variation contribute to variability in Lp-PLA(2) activity and mass. Our genetic association analyses need replication, which will be facilitated by web posting of our genetic association results.
    Atherosclerosis 12/2008; 204(2):601-7. · 3.71 Impact Factor
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    ABSTRACT: Cystatin C (CysC) is associated with cardiovascular disease (CVD) and chronic kidney disease (CKD). We examined the clinical correlates and heritability of CysC and determined if associations between CVD risk factors and CysC differed by CKD status. Among Framingham Heart Study offspring (examined from 1998-2001, n = 3,241, mean age 61 years, 54% women), the 95(th) percentile cut-point was developed for CysC in a healthy subset (n = 779) after excluding participants with diabetes, hypertension, low high-density lipoproteins, obesity, smoking, high triglycerides, prevalent CVD, and CKD (as defined by glomerular filtration rate <60 mL/min per 1.73 m(2)). Multivariable logistic regression was used to evaluate the association between CVD risk factors and high CysC (CysC > or =95(th) percentile cut-point). In a family-based subset (n = 1,188), we estimated CysC heritability using the variance-components method. The cut-point for high CysC was 1.07 mg/L. Age, hypertension treatment, low diastolic blood pressure, body mass index, low high-density lipoprotein cholesterol, and smoking were associated with high CysC in multivariable models. These factors and estimated glomerular filtration rate (egFR) explained 39.2% of CysC variability (R(2)). Excluding CKD did not materially change associations. Multivariable-adjusted heritability for CysC was 0.35 (p <0.001). In conclusion, high CysC is associated with CVD risk factors even in the absence of CKD. The strong associations between CysC and CVD risk factors may partially explain why CysC is a strong predictor of incident CVD.
    The American journal of cardiology 11/2008; 102(9):1194-8. · 3.58 Impact Factor
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    ABSTRACT: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), a proinflammatory enzyme that predominantly circulates with low-density lipoprotein (LDL), has been shown in general populations to predict cardiovascular (CV) events. We sought to determine whether increased Lp-PLA(2) would also predict CV events in the absence of high LDL-cholesterol (LDL-C), in a population with low high-density lipoprotein-cholesterol (HDL-C). Plasma Lp-PLA(2) activity was measured at baseline and after 6 months on-trial in 1451 men with low HDL-C (mean, 32 mg/dL) and low LDL-C (mean 110 mg/dL), randomized to either placebo or gemfibrozil therapy in the Veterans Affairs HDL Intervention Trial (VA-HIT). Over a quartile range of increasing Lp-PLA(2) there was a significant increase in LDL-C and decrease in HDL-C (P < 0.0001), and an increased percentage of myocardial infarction (MI), stroke, or CHD death (P=0.03 for trend). In Cox models, adjusted for major CV risk factors, a 1-SD increase in Lp-PLA(2) was associated with a significant increase in CV events (hazard ratio [HR] 1.17 95% CI 1.04 to 1.32). Although gemfibrozil reduced Lp-PLA(2) only modestly (6.6%), at higher levels of Lp-PLA(2) gemfibrozil produced a significant reduction in CV events. In VA-HIT, a population with low HDL-C and LDL-C, high Lp-PLA(2) independently predicted CV events that were reduced by gemfibrozil.
    Arteriosclerosis Thrombosis and Vascular Biology 06/2008; 28(6):1172-8. · 6.34 Impact Factor

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7k Citations
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Institutions

  • 1999–2013
    • Boston University
      • • Framingham Heart Study
      • • Department of Medicine
      • • Endocrinology, Diabetes, and Nutrition
      Boston, Massachusetts, United States
  • 2012
    • University of Sioux Falls
      Sioux Falls, South Dakota, United States
  • 2008–2011
    • Karl Jaspers Society of North America
      United States
  • 1988–2011
    • Beverly Hospital, Boston MA
      Beverly, Massachusetts, United States
  • 2006–2010
    • National Heart, Lung, and Blood Institute
      • Division of Cardiovascular Sciences (DCVS)
      Maryland, United States
    • LIPOSCIENCE
      New York City, New York, United States
  • 2002–2008
    • Tufts University
      • • Lipid Metabolism Research Laboratory
      • • Department of Medicine
      Boston, GA, United States
  • 2007
    • University of Toronto
      • Division of Cardiology
      Toronto, Ontario, Canada
  • 2006–2007
    • Partners HealthCare
      Boston, Massachusetts, United States
  • 2004
    • Laval University
      Québec, Quebec, Canada
  • 2000–2004
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 1998
    • Washington DC VA Medical Center
      Washington, Washington, D.C., United States
  • 1989–1998
    • Boston Medical Center
      Boston, Massachusetts, United States