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1.  Circulating CD31+ Leukocyte Frequency is Associated with Cardiovascular Risk Factors 
Atherosclerosis  2013;229(1):228-233.
Objectives
CD31 identifies a heterogeneous population of cells in the blood, consisting of mature leukocytes and platelets, as well as smaller numbers of endothelial and progenitor cells. Because unfractionated CD31+ blood cells have demonstrated angiogenic properties in vivo, we hypothesized that circulating CD31+ cells would be related to the presence of cardiovascular risk factors in humans.
Methods and Results
We studied 1,487 participants, free of cardiovascular disease, from the Framingham Offspring Study. Using anti-human CD31 and CD45 antibodies, distinct CD31+/CD45+ leukocyte populations were enumerated in blood samples by FACS analysis. We used linear regression analyses to investigate the relation of each cell phenotype with cardiovascular risk factors. We identified 3 distinct leukocyte populations: CD31-, CD31dim, and CD31bright cells. Using forward/side scatter analyses, CD31- and CD31dim cells mapped to lymphoid gates while CD31bright cells were monocytoid. In multivariable analyses, higher frequency of CD31bright cells was associated with older age, male sex, and CRP (all P<0.001). In contrast, CD31dim was inversely associated with age, male sex, CRP, and smoking (all P<0.01). Framingham Risk Score was positively associated with CD31bright frequency (P=0.002), and negatively associated with CD31dim frequency (P=0.020).
Conclusions
CD31+ staining identifies 2 major leukocyte populations, CD31bright and CD31dim, which demonstrated significant and opposite associations with cardiovascular risk in humans. Further research is needed to define the biological and potential therapeutic roles of CD31+ subpopulations in vascular disease.
doi:10.1016/j.atherosclerosis.2013.04.017
PMCID: PMC3984590  PMID: 23701996
epidemiology; CD31; leukocytes; endothelial cells; cardiovascular risk factors
2.  GRASP: analysis of genotype–phenotype results from 1390 genome-wide association studies and corresponding open access database 
Bioinformatics  2014;30(12):i185-i194.
Summary: We created a deeply extracted and annotated database of genome-wide association studies (GWAS) results. GRASP v1.0 contains >6.2 million SNP-phenotype association from among 1390 GWAS studies. We re-annotated GWAS results with 16 annotation sources including some rarely compared to GWAS results (e.g. RNAediting sites, lincRNAs, PTMs).
Motivation: To create a high-quality resource to facilitate further use and interpretation of human GWAS results in order to address important scientific questions.
Results: GWAS have grown exponentially, with increases in sample sizes and markers tested, and continuing bias toward European ancestry samples. GRASP contains >100 000 phenotypes, roughly: eQTLs (71.5%), metabolite QTLs (21.2%), methylation QTLs (4.4%) and diseases, biomarkers and other traits (2.8%). cis-eQTLs, meQTLs, mQTLs and MHC region SNPs are highly enriched among significant results. After removing these categories, GRASP still contains a greater proportion of studies and results than comparable GWAS catalogs. Cardiovascular disease and related risk factors pre-dominate remaining GWAS results, followed by immunological, neurological and cancer traits. Significant results in GWAS display a highly gene-centric tendency. Sex chromosome X (OR = 0.18[0.16-0.20]) and Y (OR = 0.003[0.001-0.01]) genes are depleted for GWAS results. Gene length is correlated with GWAS results at nominal significance (P ≤ 0.05) levels. We show this gene-length correlation decays at increasingly more stringent P-value thresholds. Potential pleotropic genes and SNPs enriched for multi-phenotype association in GWAS are identified. However, we note possible population stratification at some of these loci. Finally, via re-annotation we identify compelling functional hypotheses at GWAS loci, in some cases unrealized in studies to date.
Conclusion: Pooling summary-level GWAS results and re-annotating with bioinformatics predictions and molecular features provides a good platform for new insights.
Availability: The GRASP database is available at http://apps.nhlbi.nih.gov/grasp.
Contact: johnsonad2@nhlbi.nih.gov
doi:10.1093/bioinformatics/btu273
PMCID: PMC4072913  PMID: 24931982
3.  Gene Expression Signatures of Coronary Heart Disease 
Objective
To identify transcriptomic biomarkers of coronary heart disease (CHD) in 188 CHD cases and 188 age- and sex-matched controls who were participants in the Framingham Heart Study.
Approach and results
A total of 35 genes were differentially expressed in CHD cases vs. controls at FDR<0.5 including GZMB, TMEM56 and GUK1. Cluster analysis revealed three gene clusters associated with CHD, two linked to increased erythrocyte production and a third to reduced natural killer (NK) and T cell activity in CHD cases. Exon-level results corroborated and extended the gene-level results. Alternative splicing analysis suggested that GUK1 and 38 other genes were differentially spliced in CHD cases vs. controls. Gene ontology analysis linked ubiquitination and T-cell-related pathways with CHD.
Conclusion
Two bioinformatically defined groups of genes show consistent associations with CHD. Our findings are consistent with the hypotheses that hematopoesis is up-regulated in CHD, possibly reflecting a compensatory mechanism, and that innate immune activity is disrupted in CHD or altered by its treatment. Transcriptomic signatures may be useful in identifying pathways associated with CHD and point toward novel therapeutic targets for its treatment and prevention.
doi:10.1161/ATVBAHA.112.301169
PMCID: PMC3684247  PMID: 23539218
Gene expression; coronary heart disease; myocardial infarction; coronary artery disease; transcriptomics; biomarkers
4.  Common variants in and near IRS1 and subclinical cardiovascular disease in the Framingham Heart Study 
Atherosclerosis  2013;229(1):149-154.
Objective
Common variants at the 2q36.3-IRS1 locus are associated with insulin resistance (IR), type 2 diabetes (T2D) and coronary artery disease (CAD) in large-scale association studies. We tested the hypothesis that variants at this locus are associated with subclinical atherosclerosis traits.
Methods
We studied 2740 Framingham Heart Study participants (54.9% women; mean age 57.8 years) with measures of coronary artery or abdominal aortic calcium, internal and common carotid intimamedia thickness, and ankle-brachial index (ABI). We tested 1) four SNPs previously shown to be associated with IR (rs2972146, rs2943650), T2D (rs2943641) or CAD (rs2943634) and 2) any SNP at 2q36.3-IRS1, for association with subclinical atherosclerosis traits, adjusting for atherosclerosis risk factors. We set type 1 error rate for test 1) as 0.05/5 traits = P < 0.01, and for test 2) as 0.05 divided by the effective number of independent tests, divided by 5 for the number of traits analyzed.
Results
We found no association between the four known SNPs and subclinical atherosclerosis, but identified one SNP (rs10167219, r2 with rs2943634 = 0.07) at 2q36.3 that was significantly associated with ABI (corrected P = 0.009). However, rs10167219 was not associated with ABI (P = 0.70) in 35,404 participants in a published ABI association study.
Conclusion
Common variants at the 2q36.3-IRS1 locus were not associated with subclinical atherosclerosis traits in this study which was adequately powered to find associations with moderate effect size. Although IR and T2D may be mechanistically linked to CAD via subclinical atherosclerosis, an alternate mechanism for the IR-T2D-CAD associations at 2q36.3-IRS1 must be postulated.
doi:10.1016/j.atherosclerosis.2013.03.037
PMCID: PMC4040123  PMID: 23659870
IRS1; 2q36.3; Genetic association; Subclinical atherosclerosis; Ankle-brachial index
5.  Whole Genome Sequence-Based Analysis of a Model Complex Trait, High Density Lipoprotein Cholesterol 
Nature genetics  2013;45(8):899-901.
We describe initial steps for interrogating whole genome sequence (WGS) data to characterize the genetic architecture of a complex trait, such as high density lipoprotein cholesterol (HDL-C). We estimate that common variation contributes more to HDL-C heritability than rare variation, and screening for Mendelian dyslipidemia variants identified individuals with extreme HDL-C. WGS analyses highlight the value of regulatory and non-protein coding regions of the genome in addition to protein coding regions.
doi:10.1038/ng.2671
PMCID: PMC4030301  PMID: 23770607
6.  Distribution, Determinants,and Normal Reference Values of Thoracic and Abdominal Aortic Diameters by Computed Tomography (From the Framingham Heart Study) 
The American journal of cardiology  2013;111(10):1510-1516.
Current screening and detection of asymptomatic aortic aneurysms is largely based on uniform cut-point diameters. Our objective was to define normal aortic diameters in asymptomatic men and women in a community-based cohort and to determine the association between aortic diameters and traditional risk factors for cardiovascular disease (CVD).Measurements of the diameter of the ascending aorta(AA), descending thoracic aorta (DTA), infrarenal abdominal (IRA) and lower abdominal aorta (LAA) were acquired from 3,431 Framingham Heart Study participants. Mean diameters were stratified by sex, age, and body surface area (BSA). Univariate associations with risk factor levels were examined and multivariable linear regression analysis was used to assess the significance of covariate-adjusted relations with aortic diameters. For men, the average diameter was 34.1 mm for AA, 25.8 mm for DTA, 19.3 mm for IRA and 18.7 mm for LAA.For women, the average diameter was 31.9 mm for AA, 23.1 mm for DTA, 16.7 mm for IRA, and 16.0 mm for LAA. The mean aorticdiameters were strongly correlated (p<0.0001) with age and BSA in age-adjusted analyses, and these relations remained significant in multivariable regression analyses. Positive associations of diastolic BP with AA and DTA in both sexes and pack years of cigarette smoking with DTA in women and with IRA in men and women were observed. In conclusion, average diameters of the thoracic and abdominal aorta by CT are larger in men compared with women, vary significantly with age and BSA, and are associated with modifiable CVD risk factors including diastolic blood pressure and cigarette smoking.
doi:10.1016/j.amjcard.2013.01.306
PMCID: PMC3644324  PMID: 23497775
Aortic diameter; computed tomography; sex; age; body surface area
7.  A Genome-Wide Association Study of the Human Metabolome in a Community-Based Cohort 
Cell metabolism  2013;18(1):130-143.
SUMMARY
Because metabolites are hypothesized to play key roles as markers and effectors of cardio-metabolic diseases, recent studies have sought to annotate the genetic determinants of circulating metabolite levels. We report a genome-wide association study (GWAS) of 217 plasma metabolites, including >100 not measured in prior GWAS, in 2,076 participants of the Framingham Heart Study. For the majority of analytes, we find that estimated heritability explains >20% of inter-individual variation, and that variation attributable to heritable factors is greater than that attributable to clinical factors. Further, we identify 31 genetic loci associated with plasma metabolites, including 23 that have not previously been reported. Importantly, we include GWAS results for all surveyed metabolites, and demonstrate how this information highlights a role for AGXT2 in cholesterol ester and triacylglycerol metabolism. Thus, our study outlines the relative contributions of inherited and clinical factors on the plasma metabolome and provides a resource for metabolism research.
doi:10.1016/j.cmet.2013.06.013
PMCID: PMC3973158  PMID: 23823483
9.  Relations of Long-Term and Contemporary Lipid Levels and Lipid Genetic Risk Scores with Coronary Artery Calcium in the Framingham Heart Study 
Objectives
This study evaluated the association of timing of lipid levels and lipid genetic risk score (GRS) with subclinical atherosclerosis.
Background
Atherosclerosis is a slowly progressive disorder influenced by suboptimal lipid levels. Long-term versus contemporary lipid levels may more strongly impact the development of coronary artery calcium (CAC).
Methods
Framingham Heart Study (FHS) Offspring Cohort participants (n=1156, 44%M, 63±9 years) underwent serial fasting lipids [low-density lipoprotein (LDL-C), high-density lipoprotein, and triglycerides], Exam 1 (1971–1975) – Exam 7 (1998–2001). FHS Third Generation Cohort participants (n=1954, 55%M, 45±6 years) had fasting lipid profiles assessed, 2002–2005. Computed tomography (2002–2005) measured CAC. Lipid GRSs were computed from significantly associated single nucleotide polymorphisms. The association between early, long-term average, and contemporary lipids, and lipid GRS, with elevated CAC was assessed using logistic regression.
Results
In FHS Offspring, Exam 1 and long-term average versus Exam 7 lipid measurements, including untreated lipid levels, were strongly associated with elevated CAC. In the FHS Third Generation, contemporary lipids were associated with CAC. The LDL-C GRS was associated with CAC (age/sex-adjusted OR 1.14, 95%CI 1.00–1.29, p=0.04). However, addition of the GRS to the lipid models did not result in a significant increase in the OR or C-statistic for any lipid measure.
Conclusions
Early and long-term average lipid levels, as compared with contemporary measures, are more strongly associated with elevated CAC. Lipid GRS was associated with lipid levels but did not predict elevated CAC. Adult early and long-term average lipid levels provide important information when assessing subclinical atherosclerosis and cardiovascular risk.
doi:10.1016/j.jacc.2012.09.007
PMCID: PMC3702262  PMID: 23141485
Lipids; Genetic risk score; Coronary artery calcium
10.  Atherosclerotic Biomarkers and Aortic Atherosclerosis by Cardiovascular Magnetic Resonance Imaging in the Framingham Heart Study 
Background
The relations between subclinical atherosclerosis and inflammatory biomarkers have generated intense interest but their significance remains unclear. We sought to determine the association between a panel of biomarkers and subclinical aortic atherosclerosis in a community‐based cohort.
Methods and Results
We evaluated 1547 participants of the Framingham Heart Study Offspring cohort who attended the 7th examination cycle and underwent both cardiovascular magnetic resonance imaging (CMR) and assays for 10 biomarkers associated with atherosclerosis: high‐sensitivity C‐reactive protein, fibrinogen, intercellular adhesion molecule‐1, interleukin‐6, interleukin‐18, lipoprotein‐associated phospholipase‐A2 activity and mass, monocyte chemoattractant protein‐1, P‐selectin, and tumor necrosis factor receptor‐2. In logistic regression analysis, we found no significant association between the biomarker panel and the presence of aortic plaque (global P=0.53). Using Tobit regression with aortic plaque as a continuous variable, we noted a modest association between biomarker panel and aortic plaque volume in age‐ and sex‐adjusted analyses (P=0.003). However, this association was attenuated after further adjustment for clinical covariates (P=0.09).
Conclusions
In our community‐based cohort, we found no significant association between our multibiomarker panel and aortic plaque. Our results underscore the strengths and limitations of the use of biomarkers for the identification of subclinical atherosclerosis and the importance of traditional risk factors.
doi:10.1161/JAHA.113.000307
PMCID: PMC3886740  PMID: 24242683
aorta; atherosclerosis; biomarkers; cardiovascular magnetic resonance imaging
12.  Development and Application of a Longitudinal ECG Repository: the Framingham Heart Study 
Journal of electrocardiology  2012;45(6):673-676.
The electrocardiogram (ECG) has wide-spread use in clinical care and research. Despite its extensive use and study, important gaps remain in examining prospective, repeated longitudinal ECG measures and their association with cardiovascular outcomes. The Framingham Heart Study (FHS) is a community-based study designed to examine risk factors and outcomes associated with cardiovascular disease. Here we describe a novel effort in the FHS to develop a unique resource: serial ECGs conducted on three generations of study participants spanning multiple decades (1986 to the present). We describe the FHS and the role the ECG has had in conducting cardiovascular epidemiology in the FHS. We then describe potential applications for a longitudinal ECG repository. We expect the Framingham ECG repository to enhance cardiovascular research and epidemiologic study. Such a resource will complement the FHS’ phenotypic and genotypic characterization, facilitating novel investigations of cardiovascular epidemiology.
doi:10.1016/j.jelectrocard.2012.06.016
PMCID: PMC3483375  PMID: 22832152
electrocardiography; epidemiology; repository; Framingham
13.  Left Ventricular Trabeculae and Papillary Muscles: Correlation With Clinical and Cardiac Characteristics and Impact on Cardiovascular Magnetic Resonance Measures of Left Ventricular Anatomy and Function 
JACC. Cardiovascular imaging  2012;5(11):1115-1123.
Objective
We sought to assess the relationship of left ventricular (LV) trabeculae and papillary muscles (TPM) with clinical characteristics in a community-based, free living adult cohort and to determine the effect of TPM on quantitative measures of LV volume, mass and ejection fraction (EF).
Background
Hypertrabeculation has been associated with adverse cardiovascular events, but the distribution and clinical correlates of the volume and mass of the TPM in a normal left ventricle have not been well characterized.
Methods
Short-axis cine cardiovascular magnetic resonance (CMR) images, obtained using a steady-state free precession sequence, from 1494 members of the Framingham Offspring cohort were analyzed using software that automatically segments TPM. Absolute TPM volume, TPM as a fraction of end-diastolic volume (TPM/EDV), and TPM mass as a fraction of LV mass (TPMm/LVM) were determined on all Offspring and in a referent group of Offspring free of clinical cardiovascular disease and hypertension.
Results
In the referent group (aged 61±9 years, with 262 men and 423 women) TPM was 23±3 % of LV EDV in both sexes (p=0.9). TPM/EDV decreased with age (p<0.02) but was not associated with body mass index (BMI). TPMm/LVM was inversely correlated with age (p<0.0001), BMI (p<0.018) and systolic blood pressure (p<0.0001). Among all 1494 participants (699 men) LV volumes decreased 23%, LV mass increased 28% and EF increased by 7.5 EF units (p<0.0001) when TPM were considered myocardial mass rather than part of the LV blood pool.
Conclusions
Global CMR LV parameters are significantly affected by whether TPM are considered as part of the LV blood pool or as part of LV mass. Our cross-sectional data from a healthy referent group of adults free of clinical cardiovascular disease demonstrate that TPM/EDV decreases with increasing age in both sexes, but is not related to hypertension or obesity.
doi:10.1016/j.jcmg.2012.05.015
PMCID: PMC3502069  PMID: 23153911
magnetic resonance imaging; population study; trabeculae; papillary muscle; left ventricular ejection fraction
14.  QT interval and long-term mortality risk in the Framingham Heart Study 
Background
The association between QT interval and mortality has been demonstrated in large, prospective population-based studies, but the strength of the association varies considerably based on the method of heart rate correction. We examined the QT-mortality relationship in the Framingham Heart Study (FHS).
Methods
Participants in the first (original cohort, n = 2,365) and second generation (offspring cohort, n = 4,530) cohorts were included in this study with a mean follow up of 27.5 years. QT interval measurements were obtained manually using a highly reproducible digital caliper technique.
Results
Using Cox proportional hazards regression adjusting for age and sex, a 20 msec increase in QTC (using Bazett’s correction; QT/RR1/2 interval) was associated with a modest increase in risk of all-cause mortality (HR 1.14, 95% CI 1.10–1.18, p<0.0001), coronary heart disease (CHD) mortality (HR 1.15, 95% CI 1.05–1.26, p = 0.003), and sudden cardiac death (SCD, HR 1.19, 95% CI 1.03–1.37, p = 0.02). However, adjustment for heart rate using RR interval in linear regression attenuated this association. The association of QT interval with all-cause mortality persisted after adjustment for cardiovascular risk factors, but associations with CHD mortality and SCD were no longer significant.
Conclusion
In FHS, there is evidence of a graded relation between QTC and all-cause mortality, CHD death, and SCD; however, this association is attenuated by adjustment for RR interval. These data confirm that using Bazett’s heart rate correction, QTC, overestimates the association with mortality. An association with all-cause mortality persists despite a more complete adjustment for heart rate and known cardiovascular risk factors.
doi:10.1111/j.1542-474X.2012.00535.x
PMCID: PMC3481183  PMID: 23094880
Heart rate; Mortality; QT interval; Sudden cardiac death
16.  Novel measurements of periaortic adipose tissue in comparison to anthropometric measures of obesity, and abdominal adipose tissue 
Background
Perivascular adipose tissue may be associated with the amount of local atherosclerosis. We developed a novel and reproducible method to standardize volumetric quantification of periaortic adipose tissue by computed tomography (CT) and determined the association with anthropometric measures of obesity, and abdominal adipose tissue.
Methods
Measurements of adipose tissue were performed in a random subset of participants from the Framingham Heart Study (n=100) who underwent multidetector CT of the thorax (ECG triggering, 2.5 mm slice thickness) and the abdomen (helical CT acquisition, 2.5 mm slice thickness). Abdominal periaortic adipose tissue (AAT) was defined by a 5 mm cylindrical region of interest around the aortic wall; thoracic periaortic adipose tissue (TAT) was defined by anatomic landmarks. TAT and AAT were defined as any voxel between −195 HU to −45HU and volumes were measured using dedicated semiautomatic software. Measurement reproducibility and association with anthropometric measures of obesity, and abdominal adipose tissue were determined.
Results
The intra- and inter-observer reproducibility for both AAT and TAT was excellent (ICC: 0.97, 0.97; 0.99, and 0.98, respectively). Similarly, the relative intra-and inter-observer difference was small for both AAT (−1.85±1.28% and 7.85±6.08%; respectively) and TAT (3.56±0.83% and −4.56±0.85%, respectively). Both AAT and TAT were highly correlated with visceral abdominal fat (r=0.65 and 0.77, p<0.0001 for both) and moderately correlated with subcutaneous abdominal fat (r=0.39 and 0.42, p<0.0001 and p=0.009), waist circumference (r=0.49 and 0.57, p<0.0001 for both), and body mass index (r=0.47 and 0.58, p<0.0001 for both).
Conclusion
Standardized semiautomatic CT-based volumetric quantification of periaortic adipose tissue is feasible and highly reproducible. Further investigation is warranted regarding associations of periaortic adipose tissue with other body fat deposits, cardiovascular risk factors, and clinical outcomes.
doi:10.1038/ijo.2008.267
PMCID: PMC3779879  PMID: 19139753
Adipose Tissue; Intra-Abdominal Fat; Tomography; Spiral Computed; Framingham Heart Study; Metabolic Risk Factors
17.  2-Aminoadipic acid is a biomarker for diabetes risk 
The Journal of Clinical Investigation  2013;123(10):4309-4317.
Improvements in metabolite-profiling techniques are providing increased breadth of coverage of the human metabolome and may highlight biomarkers and pathways in common diseases such as diabetes. Using a metabolomics platform that analyzes intermediary organic acids, purines, pyrimidines, and other compounds, we performed a nested case-control study of 188 individuals who developed diabetes and 188 propensity-matched controls from 2,422 normoglycemic participants followed for 12 years in the Framingham Heart Study. The metabolite 2-aminoadipic acid (2-AAA) was most strongly associated with the risk of developing diabetes. Individuals with 2-AAA concentrations in the top quartile had greater than a 4-fold risk of developing diabetes. Levels of 2-AAA were not well correlated with other metabolite biomarkers of diabetes, such as branched chain amino acids and aromatic amino acids, suggesting they report on a distinct pathophysiological pathway. In experimental studies, administration of 2-AAA lowered fasting plasma glucose levels in mice fed both standard chow and high-fat diets. Further, 2-AAA treatment enhanced insulin secretion from a pancreatic β cell line as well as murine and human islets. These data highlight a metabolite not previously associated with diabetes risk that is increased up to 12 years before the onset of overt disease. Our findings suggest that 2-AAA is a marker of diabetes risk and a potential modulator of glucose homeostasis in humans.
doi:10.1172/JCI64801
PMCID: PMC3784523  PMID: 24091325
18.  Prevalence and Distribution of Abdominal Aortic Calcium by Sex and Age-Group in a Community-based Cohort (From The Framingham Heart Study) 
The American journal of cardiology  2012;110(6):891-896.
Abdominal aortic calcium (AAC) is associated with incident cardiovascular disease but the age and sex-related distribution of AAC in a community-dwelling population free of standard cardiovascular disease risk factors has not been described. A total of 3285 participants (aged 50.2±9.9 years) in the Framingham Heart Study Offspring and Third Generation cohorts underwent abdominal multidetector computed tomography (MDCT) scanning during 1998-2005. The presence and amount of AAC was quantified (Agatston score) by an experienced reader using standardized criteria. A healthy referent subsample (N=1656, 803 men) free of hypertension, hyperlipidemia, diabetes, obesity and smoking was identified, and participants were stratified by sex and age group (<45, 45-54, 55-64, 65-74, ≥75 years). The prevalence and burden of AAC increased monotonically and supralinearly with age in both sexes but was greater in men than women in each age group. Below age 45 <16% of referent-subsample participants had any quantifiable AAC, while above age 65 nearly 90% of referent participants had >0 AAC. Across the entire study sample, AAC prevalence and burden similarly increased with greater age. Defining the 90th percentile of referent group AAC as “high,” the prevalence of high AAC was 19% for each sex in the overall study sample. AAC also increased across categories of 10-year coronary heart disease risk, as calculated using the Framingham Risk Score, in the entire study sample. We found AAC to be widely prevalent, with the burden of AAC associated with 10-year coronary risk, in a white, free-living adult cohort.
doi:10.1016/j.amjcard.2012.05.020
PMCID: PMC3432173  PMID: 22727181
atherosclerosis; aorta; calcification; computed tomography; epidemiology
19.  Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling  
The Journal of Clinical Investigation  2013;123(10):4208-4218.
The suppression of tumorigenicity 2/IL-33 (ST2/IL-33) pathway has been implicated in several immune and inflammatory diseases. ST2 is produced as 2 isoforms. The membrane-bound isoform (ST2L) induces an immune response when bound to its ligand, IL-33. The other isoform is a soluble protein (sST2) that is thought to be a decoy receptor for IL-33 signaling. Elevated sST2 levels in serum are associated with an increased risk for cardiovascular disease. We investigated the determinants of sST2 plasma concentrations in 2,991 Framingham Offspring Cohort participants. While clinical and environmental factors explained some variation in sST2 levels, much of the variation in sST2 production was driven by genetic factors. In a genome-wide association study (GWAS), multiple SNPs within IL1RL1 (the gene encoding ST2) demonstrated associations with sST2 concentrations. Five missense variants of IL1RL1 correlated with higher sST2 levels in the GWAS and mapped to the intracellular domain of ST2, which is absent in sST2. In a cell culture model, IL1RL1 missense variants increased sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness (via ST2L). Our data suggest that genetic variation in IL1RL1 can result in increased levels of sST2 and alter immune and inflammatory signaling through the ST2/IL-33 pathway.
doi:10.1172/JCI67119
PMCID: PMC3784527  PMID: 23999434
20.  Fasting Glucose, Obesity, and Coronary Artery Calcification in Community-Based People Without Diabetes 
Diabetes Care  2012;35(9):1944-1950.
OBJECTIVE
Our objective was to assess whether impaired fasting glucose (IFG) and obesity are independently related to coronary artery calcification (CAC) in a community-based population.
RESEARCH DESIGN AND METHODS
We assessed CAC using multidetector computed tomography in 3,054 Framingham Heart Study participants (mean [SD] age was 50 [10] years, 49% were women, 29% had IFG, and 25% were obese) free from known vascular disease or diabetes. We tested the hypothesis that IFG (5.6–6.9 mmol/L) and obesity (BMI ≥30 kg/m2) were independently associated with high CAC (>90th percentile for age and sex) after adjusting for hypertension, lipids, smoking, and medication.
RESULTS
High CAC was significantly related to IFG in an age- and sex-adjusted model (odds ratio 1.4 [95% CI 1.1–1.7], P = 0.002; referent: normal fasting glucose) and after further adjustment for obesity (1.3 [1.0–1.6], P = 0.045). However, IFG was not associated with high CAC in multivariable-adjusted models before (1.2 [0.9–1.4], P = 0.20) or after adjustment for obesity. Obesity was associated with high CAC in age- and sex-adjusted models (1.6 [1.3–2.0], P < 0.001) and in multivariable models that included IFG (1.4 [1.1–1.7], P = 0.005). Multivariable-adjusted spline regression models suggested nonlinear relationships linking high CAC with BMI (J-shaped), waist circumference (J-shaped), and fasting glucose.
CONCLUSIONS
In this community-based cohort, CAC was associated with obesity, but not IFG, after adjusting for important confounders. With the increasing worldwide prevalence of obesity and nondiabetic hyperglycemia, these data underscore the importance of obesity in the pathogenesis of CAC.
doi:10.2337/dc11-1950
PMCID: PMC3425010  PMID: 22773705
21.  Usefulness of the Left Ventricular Myocardial Contraction Fraction in Healthy Men and Women to Predict Cardiovascular Morbidity and Mortality 
The American journal of cardiology  2012;109(10):1454-1458.
We sought to determine whether depressed myocardial contraction fraction (MCF, the ratio of left ventricular (LV) stroke volume to myocardial volume) predicts cardiovascular disease (CVD) events in initially healthy adults. A subset (N=318, 60±9 yrs, 158 men) of the Framingham Heart Study Offspring cohort free of clinical CVD underwent volumetric cardiovascular magnetic resonance (CMR) imaging in 1998–1999. LV ejection fraction (EF), mass and MCF were determined. “Hard” CVD events comprised cardiovascular death, myocardial infarction, stroke or new heart failure. A Cox proportional hazards model adjusting for Framingham Coronary Risk Score (FCRS) was used to estimate hazard ratios for incident hard CVD events for sex-specific quartiles of MCF, LV mass and LVEF. The lowest quartile of LV mass and highest quartiles of MCF and EF served as referent. Kaplan-Meier survival plots and the log rank test were used to compare event-free survival. MCF was greater in women (0.58±0.13) than men (0.52±0.11), p<0.01. Nearly all (99%) participants had EF ≥ 0.55. Over up to 9-year (median 5.2) follow-up, 31 participants (10%) experienced an incident hard CVD event. Lowest-quartile MCF was 7 times more likely to develop hard CVD (hazard ratio 7.11, p=0.010) compared to the lowest quartile, and the elevated hazards persisted even after adjustment for LV mass (hazard ratio=6.09, p=0.020). The highest-quartile LV mass/height2.7 had nearly five-fold risk (hazard ratio 4.68, p=0.016). Event-free survival was shorter in lowest-quartile MCF, p = 0.0006, but not in lowest-quartile LVEF. Conclusion: In a cohort of adults initially without clinical CVD, lowest-quartile MCF conferred an increased hazard for hard CVD events after adjustment for traditional CVD risk factors and LV mass.
doi:10.1016/j.amjcard.2012.01.357
PMCID: PMC3742100  PMID: 22381161
magnetic resonance imaging; myocardial contraction fraction; risk factors; left ventricular function
23.  Relations of Exercise Blood Pressure Response to Cardiovascular Risk Factors and Vascular Function in the Framingham Heart Study 
Circulation  2012;125(23):2836-2843.
Background
Exercise blood pressure (BP) is an important marker of left ventricular hypertrophy, incident hypertension and future cardiovascular events. Although impaired vascular function is hypothesized to influence the BP response during exercise, limited data exist on the association of vascular function with exercise BP in the community.
Methods and Results
Framingham Offspring cohort participants (n=2115, 53% women, mean age 59 years) underwent a submaximal exercise test (first 2 stages of the Bruce protocol), applanation tonometry and brachial artery flow-mediated dilation (FMD) testing. We related exercise systolic and diastolic BP at second stage of the Bruce protocol to standard cardiovascular risk factors and to vascular function measures. In multivariable linear regression models, exercise systolic BP was positively related to age, standing BP, standing heart rate, smoking, body mass index, and the total cholesterol-to-high-density cholesterol (HDL) ratio (p≤0.01 for all). Similar associations were observed for exercise diastolic BP. Carotid-femoral pulse wave velocity (p=0.02), central pulse pressure (p<0.0001), mean arterial pressure (p=0.04) and baseline brachial flow (p=0.002) were positively associated with exercise systolic BP, whereas FMD was negatively associated (P<0.001). For exercise diastolic BP, forward pressure wave amplitude was negatively related (p<0.0001) whereas mean arterial pressure was positively related (p<0.0001).
Conclusions
Increased arterial stiffness and impaired endothelial function are significant correlates of a higher exercise systolic BP response. Our findings suggest that impaired vascular function may contribute to exaggerated BP responses during daily living, resulting in repetitive increments in load on the heart and vessels and increased cardiovascular disease risk.
doi:10.1161/CIRCULATIONAHA.111.063933
PMCID: PMC3636551  PMID: 22572915
blood pressure; endothelial function; exercise; vascular function; vascular stiffness
24.  Population Health, Outcomes Research and Prevention Policy: Example of the American Heart Association 2020 Goals 
doi:10.1161/CIRCOUTCOMES.111.964734
PMCID: PMC3676931  PMID: 22253367
Prevention; Healthcare delivery; Outcomes
25.  Accurate Computer-Aided Quantification of Left Ventricular Parameters: Experience in 1555 CMR Studies from the Framingham Heart Study 
Magnetic Resonance in Medicine  2011;67(5):1478-1486.
Quantitative analysis of short-axis functional cardiac magnetic resonance (CMR) images can be performed using automatic contour detection methods. The resulting myocardial contours must be reviewed and possibly corrected, which can be time-consuming, particularly when performed across all cardiac phases. We quantified the impact of manual contour corrections on both analysis time and quantitative measurements obtained from left ventricular (LV) short-axis cine images acquired from 1555 participants of the Framingham Heart Study Offspring cohort using computer aided contour detection methods. The total analysis time for a single case was 7.6±1.7 minutes for an average of 221±36 myocardial contours per participant. This included 4.8±1.6 minutes for manual contour correction of 2% of all automatically-detected endocardial contours and 8% of all automatically-detected epicardial contours. However, the impact of these corrections on global LV parameters was limited, introducing differences of 0.4±4.1ml for end-diastolic volume, −0.3±2.9ml for end-systolic volume, 0.7±3.1 ml for stroke volume and 0.3±1.8% for ejection fraction. We conclude that LV functional parameters can be obtained under 5 minutes from short-axis functional CMR images using automatic contour detection methods. Manual correction more than doubles analysis time, with minimal impact on LV volumes and ejection fraction.
doi:10.1002/mrm.23127
PMCID: PMC3267005  PMID: 22021128

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