Objective

Earlier studies have suggested that a common genetic architecture underlies the clinically heterogeneous polygenic Fredrickson hyperlipoproteinemia (HLP) phenotypes defined by hypertriglyceridemia (HTG). Here, we comprehensively analyzed 504 HLP-HTG patients and 1213 normotriglyceridemic controls and confirmed that a spectrum of common and rare lipid-associated variants underlies this heterogeneity.

Methods and Results

First, we demonstrated that genetic determinants of plasma lipids and lipoproteins, including common variants associated with plasma triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from the Global Lipids Genetics Consortium were associated with multiple HLP-HTG phenotypes. Second, we demonstrated that weighted risk scores composed of common TG-associated variants were distinctly increased across all HLP-HTG phenotypes compared with controls; weighted HDL-C and LDL-C risk scores were also increased, although to a less pronounced degree with some HLP-HTG phenotypes. Interestingly, decomposition of HDL-C and LDL-C risk scores revealed that pleiotropic variants (those jointly associated with TG) accounted for the greatest difference in HDL-C and LDL-C risk scores. The APOE E2/E2 genotype was significantly overrepresented in HLP type 3 versus other phenotypes. Finally, rare variants in 4 genes accumulated equally across HLP-HTG phenotypes.

Conclusion

HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants.

Background

Main pulmonary artery diameter (mPA) and ratio of mPA to ascending aorta diameter (ratio PA) derived from chest CT are commonly reported in clinical practice. We determined the age and sex-specific distribution and normal reference values for mPA and ratio PA by CT in an asymptomatic community-based population.

Methods and Results

In 3171 men and women (mean age 51 ± 10 years, 51% men) from the Framingham Heart Study, a non-contrast ECG gated eight-slice cardiac multi-detector CT was performed. We measured the mPA and transverse axial diameter of the ascending aorta at the level of the bifurcation of the right pulmonary artery and calculated the ratio PA. We defined the healthy referent cohort (n=706) as those without obesity, hypertension, current and past smokers, chronic obstructive pulmonary disease, history of pulmonary embolism, diabetics, cardiovascular disease, and heart valvular surgery. The mean mPA diameter in the overall cohort was 25.1 ± 2.8mm and mean ratio PA was 0.77 ± 0.09. The sex-specific 90th percentile cutoff value for mPA diameter was 28.9 mm in men and 26.9 mm in women and was associated with increase risk for self-reported dyspnea (adjusted odds ratio 1.31, p=0.02). The 90th percentile cutoff value for ratio PA of the healthy referent group was 0.91, similar between gender, but decreased with increasing age (range 0.82 to 0.94), though not associated with dyspnea.

Conclusions

For simplicity, we established 29 mm in men and 27 mm in women as sex-specific normative reference values for mPA and 0.9 for ratio PA.

Background

Coronary artery calcification (CAC) detected by computed tomography is a non-invasive measure of coronary atherosclerosis, that underlies most cases of myocardial infarction (MI). We aimed to identify common genetic variants associated with CAC and further investigate their associations with MI.

Methods and Results

Computed tomography was used to assess quantity of CAC. A meta-analysis of genome-wide association studies for CAC was carried out in 9,961 men and women from five independent community-based cohorts, with replication in three additional independent cohorts (n=6,032). We examined the top single nucleotide polymorphisms (SNPs) associated with CAC quantity for association with MI in multiple large genome-wide association studies of MI. Genome-wide significant associations with CAC for SNPs on chromosome 9p21 near CDKN2A and CDKN2B (top SNP: rs1333049, P=7.58×10−19) and 6p24 (top SNP: rs9349379, within the PHACTR1 gene, P=2.65×10−11) replicated for CAC and for MI. Additionally, there is evidence for concordance of SNP associations with both CAC and with MI at a number of other loci, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene).

Conclusions

SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with CAC and MI, and there are suggestive associations with both CAC and MI of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events.

Background

After age, gender is the most important risk factor for coronary artery disease (CAD). The mechanism through which women are protected from CAD is still largely unknown, but the observed gender difference suggests the involvement of the reproductive steroid hormone signaling system. Genetic association studies of the gene encoding Estrogen Receptor alpha (ESR1) have shown conflicting results, although only a limited range of variation in the gene has been investigated.

Methods and Results

We exploited information made available by advanced new methods and resources in complex disease genetics to revisit the question of ESR1's role in risk of CAD. We performed a meta-analysis of 14 genome-wide association studies (CARDIoGRAM discovery analysis, N~87,000) to search for population-wide and gender-specific associations between CAD risk and common genetic variants throughout the coding, non-coding and flanking regions of ESR1. In additional samples from the MIGen (N~6,000), WTCCC (N~7,400) and Framingham (N~3,700) studies, we extended this search to a larger number of common and uncommon variants by imputation into a panel of haplotypes constructed using data from the 1000 Genomes project. Despite the widespread expression of ER alpha in vascular tissues, we find no evidence for involvement of common or low-frequency genetic variation throughout the ESR1 gene in modifying risk of CAD, either in the general population or as a function of gender.

Conclusions

We suggest that future research on the genetic basis of gender-related differences in CAD risk should initially prioritize other genes in the reproductive steroid hormone biosynthesis system.

Background

Periaortic fat, because of its contiguity with the aorta, may promote vascular remodeling and aortic dilatation. However, the relations between perioartic fat depots and aortic dimensions have not been previously described.

Methods and Results

A total of 3001 individuals (mean age 50±10 years, 49% women) from the Framingham Offspring and Third Generation cohorts underwent computed tomography for quantification of periaortic fat and aortic dimensions. We estimated the association between quantitative periaortic and visceral adipose tissue volumes (per standard deviation [SD] increment of volume) with aortic dimensions in both the thorax and abdomen. Thoracic periaortic fat was associated with higher thoracic aortic dimensions (β coefficient per SD of fat volume 0.67 mm, 95% confidence interval 0.58 to 0.76 mm; P<0.001). The association persisted after adjustment for age, sex, and cardiovascular risk factors including body mass index and visceral adipose tissue volume. Results for the association of periaortic fat and abdominal aortic dimensions were similar. Further adjustment for adipokines (resistin and adiponectin) had no significant impact on these associations.

Conclusions

Periaortic fat volume was associated with aortic dimensions in both the thorax and abdomen, supporting the notion that local fat depots may contribute to aortic remodeling. Further work to understand the mechanisms underlying this association is warranted.

Heart failure is a risk factor for Alzheimer’s disease (AD) and cerebrovascular disease. In the absence of heart failure, we hypothesized that left ventricular ejection fraction (LVEF), an indicator of cardiac dysfunction, would be associated with pre-clinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and AD in the community. Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1114 Framingham Heart Study Offspring Cohort participants free from clinical stroke or dementia (40–89 years, 67±9; 54% women). Neuropsychological and neuroimaging markers of brain aging were related to cardiac MRI-assessed LVEF. In multivariable-adjusted linear regressions, LVEF was not associated with any brain aging variable (p-values>0.15). However, LVEF quintile analyses yielded several U-shape associations. Compared to the referent (Q2–Q4), the lowest quintile (Q1) LVEF was associated with a lower mean cognitive performance, including Visual Reproduction Delayed Recall (β= −0.27, p<0.001) and Hooper Visual Organization Test (β= −0.27, p<0.001). Compared to the referent, the highest quintile (Q5) LVEF values also were associated with lower mean cognitive performances, including Logical Memory Delayed Recall (β= −0.18, p=0.03), Visual Reproduction Delayed Recall (β= −0.17, p=0.03), Trail Making Test Part B-Part A (β= −0.22, p=0.02) and Hooper Visual Organization Test (Q5 β= −0.20, p=0.02). Findings were similar when analyses were repeated excluding prevalent cardiovascular disease. In conclusion, although our observational cross-sectional data cannot establish causality, they suggest a non-linear association between LVEF and measures of accelerated cognitive aging.

Objectives

γ′ fibrinogen is a newly-emerging biomarker that is associated with cardiovascular disease (CVD). However, the genetic determinants of γ′ fibrinogen levels are unknown. We therefore conducted a genome-wide association study on 3,042 participants of the Framingham Heart Study Offspring Cohort.

Methods and Results

A genome-wide association study with 2.5 million single-nucleotide polymorphisms (SNPs) was carried out for γ′ fibrinogen levels from the cycle 7 exam. 54 SNPs in or near the fibrinogen gene locus demonstrated genome-wide significance (P<5.0×10−8) for association with γ′ fibrinogen levels. The top-signal SNP was rs7681423 (P=9.97×10−110) in the fibrinogen gene locus near FGG, which encodes the γ chain. Conditional on the top SNP, the only other SNP that remained genome-wide significant was rs1049636. Associations between SNPs, γ′ fibrinogen levels, and prevalent CVD events were examined using multiple logistic regression. γ′ fibrinogen levels were associated with prevalent CVD (P=0.02), although the top two SNPs associated with γ′ fibrinogen levels were not associated with CVD. These findings contrast those for total fibrinogen levels, which are associated with different genetic loci, particularly FGB, which encodes the Bβ chain.

Conclusions

γ′ fibrinogen is associated with prevalent CVD and with SNPs exclusively in and near the fibrinogen gene locus.

Natriuretic peptides have important roles in the regulation of vasomotor tone, salt homeostasis, and ventricular remodeling. Lower natriuretic peptide levels observed in obese individuals may underlie the greater cardiovascular risk associated with obesity. Thus, the aim of this study was to determine whether lower natriuretic peptide levels in obesity are attributable to differences in regional fat distribution. We investigated the relationship of plasma N-terminal pro-B-type natriuretic peptide (N-BNP) with regional adiposity in 1,873 community-based individuals (46% women; mean age 45 years). Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes were measured by multi-detector computed tomography. In sex-specific, multivariable analyses adjusting for age and blood pressure, log N-BNP was inversely associated with VAT in both men (β −0.11, P<0.001) and women (β −0.19, P<0.001). Log N-BNP was inversely associated with SAT in women only (β −0.14, P<0.001). In models containing both VAT and SAT, only VAT was significantly associated with log N-BNP (men, β −0.137, P<0.001; women, β −0.184, P<0.001). VAT remained associated with log N-BNP even after adjustment for body mass index and waist circumference (β −0.119, P<0.001), and in analyses restricted to non-obese individuals (β −0.114; P<0.001). Adjustment for insulin resistance attenuated the associations of N-BNP with both VAT and SAT. In conclusion, this study demonstrates that circulating N-BNP is related to variation in regional and particularly visceral adiposity. These findings suggest that excess visceral adiposity and concomitant hyperinsulinemia may contribute to the natriuretic peptide “deficiency” observed in obesity.

Polymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50 000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2 000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16 324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12–13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors.

Motivation: The concept of pleiotropy was proposed a century ago, though up to now there have been insufficient efforts to design robust statistics and software aimed at visualizing and evaluating pleiotropy at a regional level. The Pleiotropic Region Identification Method (PRIMe) was developed to evaluate potentially pleiotropic loci based upon data from multiple genome-wide association studies (GWAS).

Methods: We first provide a software tool to systematically identify and characterize genomic regions where low association P-values are observed with multiple traits. We use the term Pleiotropy Index to denote the number of traits with low association P-values at a particular genomic region. For GWAS assumed to be uncorrelated, we adopted the binomial distribution to approximate the statistical significance of the Pleiotropy Index. For GWAS conducted on traits with known correlation coefficients, simulations are performed to derive the statistical distribution of the Pleiotropy Index under the null hypothesis of no genotype–phenotype association. For six hematologic and three blood pressure traits where full GWAS results were available from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, we estimated the trait correlations and applied the simulation approach to examine genomic regions with statistical evidence of pleiotropy. We then applied the approximation approach to explore GWAS summarized in the National Human Genome Research Institute (NHGRI) GWAS Catalog.

Results: By simulation, we identified pleiotropic regions including SH2B3 and BRAP (12q24.12) for hematologic and blood pressure traits. By approximation, we confirmed the genome-wide significant pleiotropy of these two regions based on the GWAS Catalog data, together with an exploration on other regions which highlights the FTO, GCKR and ABO regions.

Availability and Implementation: The Perl and R scripts are available at http://www.framinghamheartstudy.org/research/gwas_pleiotropictool.html.

Contact: odonnellc@nhlbi.nih.gov

Supplementary information: Supplementary data are available at Bioinformatics online.

The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice.The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality.Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction.A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines.These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.

The prevalence and clinical correlates of left ventricular (LV) wall motion abnormalities (WMAs), associated with morbidity and mortality, are not well-characterized in the population. Framingham Heart Study Offspring Cohort participants (n=1794, 844M, 65±9 years) underwent cine cardiovascular magnetic resonance (CMR) for evaluation of LV function, and a subset (n=1009, 460M) underwent cardiac multidetector computed tomography (MDCT) for analysis of coronary artery calcium (CAC). Presence of coronary heart disease and heart failure (CHD-HF) were assessed in relation to WMAs. WMAs were present in 117 participants (6.5%) and were associated with male sex, elevated hemoglobin A1c, LV mass, LV end-diastolic volume (LVEDV), and lower LV ejection fraction. Among 1637 participants without CHD-HF, 68 (4.2%) had WMAs. In this group, WMAs were associated with obesity, hypertension, and Framingham coronary heart disease risk score in age- and sex-adjusted analyses, and associated with male sex and hypertension in multivariable analysis. Most individuals with WMAs fell in the highest CAC groups. The presence of CAC >75th percentile and Agatston score >100 were associated with a >2-fold risk of WMAs in age- and sex-adjusted analysis, were no longer significant when additionally adjusted for CHD-HF. Past Q wave myocardial infarction was present in 29% of the 117 participants with WMAs. In conclusion, in this longitudinally followed free-living population, 4.2% of participants without CHD-HF had WMAs. WMAs were associated with clinical parameters associated with cardiovascular disease risk. Aggressive risk factor modification may be prudent in individuals with WMAs, particularly in those free of clinical CHD-HF.

Background. Inflammation and chronic kidney disease (CKD) are both associated with cardiovascular disease (CVD). Whether inflammatory biomarkers are associated with kidney function and albuminuria after accounting for traditional CVD risk factors is not completely understood.

Methods. The sample comprised Framingham Offspring cohort participants (n = 3294, mean age 61, 53% women) who attended the seventh examination cycle (1998–2001). Inflammatory biomarkers [C-reactive protein (CRP), tumour necrosis factor (TNF)-alpha, interleukin-6, TNF receptor 2 (TNFR2), intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), P-selectin, CD-40 ligand, osteoprotegerin, urinary isoprostanes, myeloperoxidase and fibrinogen] were measured on fasting blood samples. Serum creatinine-based estimated glomerular filtration rate (eGFR) and serum cystatin C concentration were used to assess kidney function. Urinary albumin-to-creatinine ratio (UACR) was used to assess albuminuria. Linear or logistic regression was used to test associations between biomarkers and kidney measures.

Results. Chronic kidney disease (CKD), defined as eGFR < 59/64 mL/min/1.73 m2 in women/men, was present in 8.8% (n = 291) of participants. TNF-alpha, interleukin-6, TNFR2, MCP-1, osteoprotegerin, myeloperoxidase and fibrinogen were higher among individuals with CKD; all biomarkers except for urinary isoprostanes were elevated in higher cystatin C quartiles; and TNF-alpha, interleukin-6, TNFR2, ICAM-1 and osteoprotegerin were elevated in higher UACR quartiles—all assessed after multivariable adjustment. Almost 6% and 17% of variability in TNFR2 were explained by CKD status and higher cystatin C quartiles, respectively.

Conclusions. Biomarkers of inflammation are associated with kidney function and albuminuria. In particular, substantial variability in soluble TNFR2 is explained by CKD and cystatin C.

BACKGROUND

Intima–media thickness of the walls of the common carotid artery and internal carotid artery may add to the Framingham risk score for predicting cardiovascular events.

METHODS

We measured the mean intima–media thickness of the common carotid artery and the maximum intima–media thickness of the internal carotid artery in 2965 members of the Framingham Offspring Study cohort. Cardiovascular-disease outcomes were evaluated for an average follow-up of 7.2 years. Multivariable Cox proportional-hazards models were generated for intima–media thickness and risk factors. We evaluated the reclassification of cardiovascular disease on the basis of the 8-year Framingham risk score category (low, intermediate, or high) after adding intima–media thickness values.

RESULTS

A total of 296 participants had a cardiovascular event. The risk factors of the Framingham risk score predicted these events, with a C statistic of 0.748 (95% confidence interval [CI], 0.719 to 0.776). The adjusted hazard ratio for cardiovascular disease with a 1-SD increase in the mean intima–media thickness of the common carotid artery was 1.13 (95% CI, 1.02 to 1.24), with a nonsignificant change in the C statistic of 0.003 (95% CI, 0.000 to 0.007); the corresponding hazard ratio for the maximum intima–media thickness of the internal carotid artery was 1.21 (95% CI, 1.13 to 1.29), with a modest increase in the C statistic of 0.009 (95% CI, 0.003 to 0.016). The net reclassification index increased significantly after addition of intima–media thickness of the internal carotid artery (7.6%, P<0.001) but not intima–media thickness of the common carotid artery (0.0%, P = 0.99). With the presence of plaque, defined as intima–media thickness of the internal carotid artery of more than 1.5 mm, the net reclassification index was 7.3% (P = 0.01), with an increase in the C statistic of 0.014 (95% CI, 0.003 to 0.025).

CONCLUSIONS

The maximum internal and mean common carotid-artery intima–media thicknesses both predict cardiovascular outcomes, but only the maximum intima–media thickness of (and presence of plaque in) the internal carotid artery significantly (albeit modestly) improves the classification of risk of cardiovascular disease in the Framingham Offspring Study cohort. (Funded by the National Heart, Lung, and Blood Institute.)

We aimed to determine the relationships between resting left ventricular (LV) wall motion abnormalities (WMAs), aortic plaque, and PAD in a community cohort. 1726 Framingham Heart Study Offspring Cohort participants (806 males, 65±9 years) underwent cardiovascular magnetic resonance with quantification of aortic plaque volume and assessment of regional LV systolic function. Claudication, lower extremity revascularization, and ankle-brachial index (ABI) were recorded at Examination 7. WMAs were associated with greater aortic plaque burden, decreased ABI, and claudication in age- and sex-adjusted analyses (all p<0.001), which were not significant after adjustment for cardiovascular risk factors. In age- and sex-adjusted analyses, both the presence (p<0.001) and volume of aortic plaque were associated with decreased ABI (p<0.001). After multivariable adjustment, ABI≤0.9 or prior revascularization was associated with a three-fold odds of aortic plaque (p=0.0083). Plaque volume significantly increased with decreasing ABI in multivariable-adjusted analyses (p<0.0001). In this free-living population, associations of WMAs with aortic plaque burden and clinical measures of PAD were attenuated after adjustment for coronary heart disease risk factors. Aortic plaque volume and ABI remained strongly negatively correlated after multivariable adjustment. Our findings suggest that the association between coronary heart disease and non-coronary atherosclerosis is explained by cardiovascular risk factors. Aortic atherosclerosis and PAD remain strongly associated after multivariable adjustment suggesting shared mechanisms beyond those captured by traditional risk factors.

Objectives

To describe the clinical correlates and heritability of the early repolarization pattern (ERP) in two large population-based cohorts.

Background

There is growing recognition that ERP is associated with adverse outcomes.

Methods

Participants of the Framingham Heart Study (FHS, n = 3,995) and the Health 2000 Survey (H2K, n = 5,489) were included. ERP was defined as J-point elevation ≥0.1 mV in ≥2 leads in either the inferior (II, III, aVF) or lateral (I, aVL, V4–6) territory or both. We tested the association between clinical characteristics and ERP and estimated sibling recurrence risk.

Results

ERP was present in 243/3,955 (6.1%) of FHS and 180/5,489 (3.3%) of H2K subjects. Male sex, younger age, lower systolic blood pressure, higher Sokolow-Lyon index, and lower Cornell voltage were independently associated with the presence of ERP. In the FHS sample, siblings of individuals with ERP had an ERP prevalence of 11.6% (recurrence risk ratio of 1.89). Siblings of individuals with ERP had an increased unadjusted odds of ERP (OR 2.22, 95% CI 1.01–4.85, p = 0.047).

Conclusion

ERP shows strong association with clinical factors and has evidence for a heritable basis in general population. Further assessment of the genetic determinants of ERP is warranted.

Background

Central obesity is associated with peripheral arterial disease (PAD), suggesting that ectopic fat depots may be associated with localized diseases of the aorta and lower extremity arteries. We hypothesized that individuals with greater amounts of peri-aortic fat are more likely to have clinical peripheral arterial disease (PAD) and a low ankle-brachial index (ABI).

Methods and Results

We quantified peri-aortic fat surrounding the thoracic aorta using a novel volumetric quantitative approach in 1205 individuals from the Framingham Heart Study Offspring cohort (mean age 65.9 years, 54% women); visceral abdominal fat (VAT) was also measured. Clinical PAD was defined as a history of intermittent claudication and ABI was dichotomized as low ABI≤0.9 or lower extremity revascularization vs normal ABI >0.9 to < 1.4. Regression models were created to examine the association between peri-aortic fat and intermittent claudication or low ABI (n=66 participants). In multivariable logistic regression, per 1 standard deviation increase in peri-aortic fat, the odds ratio (OR) for the combined end-point was 1.52 (p-value=0.004); these results were strengthened with additional adjustment for BMI (OR 1.69, p=0.002) or visceral abdominal fat (OR 1.67, p=0.009) whereas no association was observed for VAT (p=0.16). Similarly, per standard deviation increase in BMI or waist circumference, no association was observed after accounting for VAT (p=0.35 [BMI]; p=0.49 [waist circumference]).

Conclusions

Peri-aortic fat is associated with low ABI and intermittent claudication.

Background

Pericardial and intra-thoracic fat depots may represent novel risk factors for obesity-related cardiovascular disease. We sought to determine the prevalence, distribution and risk factor correlates of high pericardial and intra-thoracic fat deposits.

Methods and Results

Participants from the Framingham Heart Study (n=3312; mean age 52 years, 48% women) underwent multi-detector CT imaging in 2002–2005; high pericardial and high intra-thoracic fat were defined based on the sex-specific 90th percentile for these fat depots in a healthy reference sample. For men and women, the prevalence of high pericardial fat was 29.3% and 26.3%, respectively, and high intra-thoracic fat was 31.4% and 35.3%, respectively. Overall, 22.1% of the sample was discordant for pericardial and intra-thoracic fat depots: 8.3% had high pericardial but normal intra-thoracic fat, and 13.8% had high intra-thoracic but normal pericardial fat. Higher body mass index, higher waist circumference (WC) and increased prevalence of metabolic syndrome were more likely in participants with high intra-thoracic fat depots than with high pericardial fat (p<0.05 for all comparisons). High abdominal visceral adipose tissue was more frequent in participants with high intra-thoracic adipose tissue compared to those with high pericardial fat (p<0.001). Intra-thoracic fat, but not WC, was more highly correlated with VAT (r=0.76 and 0.78 in men and women, respectively; p<0.0001) than with SAT (r=0.46 and 0.54 in men and women, respectively; p<0.0001).

Conclusions

Although prevalence of pericardial fat and intra-thoracic fat were comparable at 30%, intra-thoracic fat correlated more closely with metabolic risk and visceral fat. Intra-thoracic fat may be a potential marker of metabolic risk and visceral fat on thoracic imaging.

Background

Cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults with prevalent cardiovascular disease (CVD), theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to subclinical brain injury. We hypothesized that cardiac function, as measured by cardiac index, would be associated with pre-clinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer’s disease in the community.

Methods and Results

Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1504 Framingham Offspring Cohort participants free from clinical stroke, transient ischemic attack, or dementia (61±9 years; 54% women). Neuropsychological and brain MRI variables were related to cardiac MRI-assessed cardiac index (cardiac output/body surface area). In multivariable-adjusted models, cardiac index was positively related to total brain volume (P=0.03) and information processing speed (P=0.02) and inversely related to lateral ventricular volume (P=0.048). When participants with clinically prevalent CVD were excluded, the relation between cardiac index and total brain volume remained (P=0.02). Post-hoc comparisons revealed that participants in the bottom cardiac index tertile (values<2.54) and middle cardiac index tertile (values between 2.54 and 2.92) had significantly lower brain volumes (P=0.04) than participants in the top cardiac index tertile (values>2.92).

Conclusions

Although observational data cannot establish causality, our findings are consistent with the hypothesis that decreasing cardiac function, even at normal cardiac index levels, is associated with accelerated brain aging.

In vitro data suggest protective roles for vitamins K and D in inflammation. To examine associations between vitamins K and D and inflammation in vivo, we used multiple linear regression analyses, adjusted for age, sex, body mass index, triglyceride concentrations, use of aspirin, lipid lowering and hormone replacement medications, season, and menopausal status. Participants were from the Framingham Offspring Study (n=1381; mean age 59 years; 52% women). Vitamin K status, measured by plasma phylloquinone and phylloquinone intake, was inversely associated with circulating inflammatory markers as a group, and with several individual inflammatory biomarkers (p< 0.01). Percent undercarboxylated osteocalcin, a functional measure of vitamin K status, was not associated with overall inflammation, but was associated with C-reactive protein (p<0.01). Although plasma 25-hydroxyvitamin D was inversely associated with urinary isoprostanes, an oxidative stress indicator (p<0.01), overall associations between vitamin D status and inflammation were inconsistent. The observation that high vitamin K status was associated with lower concentrations of inflammatory markers suggests that a protective role for vitamin K in inflammation merits further investigation.