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.
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.
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).
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.
Adipose Tissue; Intra-Abdominal Fat; Tomography; Spiral Computed; Framingham Heart Study; Metabolic Risk Factors
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.
atherosclerosis; aorta; calcification; computed tomography; epidemiology
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  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.
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.
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.
Obesity is associated with pathological cardiac remodeling and risk of heart failure (HF). Adipocytokines (ADKs) may mediate the increased risk of cardiovascular disease associated with excess adiposity. Yet data relating ADKs to cardiac remodeling phenotypes are sparse. We related two circulating ADKs, resistin and adiponectin, to three important echocardiographic markers of cardiac remodeling, left ventricular mass (LVM), left atrial diameter (LAD), and LV fractional shortening (LVFS) in 2,615 participants (mean age 61 years, 55% women) in the Framingham Offspring Study. Adiponectin concentrations were inversely related to LVM in multivariable linear regression models adjusting for key clinical correlates including BMI (regression coefficient per s.d.-increment in ln-adiponectin = −3.37, P = 0.02; P for trend across quartiles = 0.02). Adiponectin was not associated with LAD or LVFS (P > 0.56). Resistin concentrations were inversely related to LVFS (regression coefficient per s.d.-increment in ln-resistin = −0.01, P = 0.03; P for trend across quartiles = 0.04). Resistin was not associated with LVM or LAD (P > 0.05). In our moderate-sized, community-based sample, higher circulating concentrations of adiponectin and resistin were associated with lower LVM and lower LVFS, respectively. In conclusion, these associations identify potential mechanisms by which excess adiposity may mediate adverse cardiac remodeling and HF risk.
The relations of lipid concentrations to heart failure (HF) risk have not been comprehensively elucidated.
Methods and Results
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 (MI) at baseline and updating these at follow-up examinations. We evaluated dyslipidemia-specific population burden of HF by calculating population attributable risks (PAR).
During follow-up (mean of 26 years), 680 participants (49% women) developed HF. Unadjusted HF incidence in the low (<160mg/dl) vs. high (≥190mg/dl) non-HDL-C groups was 7.9% and 13.8%, respectively, whereas incidence in the high (≥55 [men], ≥65 [women]mg/dl) vs. low (003C 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 interval-CI) of 1.19 (1.11–1.27) and 0.82 (0.75–0.90) respectively per standard deviation (SD) increment. In models updating lipid concentrations every 8 years, the corresponding hazards (CI) were 1.23 (1.16–1.31) and 0.77 (0.70–0.85). Participants with high baseline non-HDL-C and those with low HDL-C experienced a 29% and 40% higher HF risk respectively, compared to those in the desirable categories; the PARs 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 MI.
Dyslipidemia carries HF risk independent of its association with MI, suggesting that lipid modification may be a means for reducing HF risk.
Heart failure; dyslipidemia; total cholesterol; HDL-C; non-HDL-C
Stratification of individuals at risk for chronic kidney disease may allow optimization of preventive measures to reduce disease incidence and complications. We sought to develop a risk score that estimates an individual’s absolute risk of incident chronic kidney disease.
Framingham Heart Study participants free of baseline chronic kidney disease, who attended a baseline examination in 1995–1998 and follow-up in 2005–2008, were included in the analysis (n=2,490). Chronic kidney disease was defined as an estimated glomerular filtration rate <60 ml/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation. Participants were assessed for the development of chronic kidney disease at 10 years follow-up. Stepwise logistic regression was used to identify chronic kidney disease risk factors, and these were used to construct a risk score predicting 10-year chronic kidney disease risk. Performance characteristics were assessed using calibration and discrimination measures. The final model was externally validated in the bi-ethnic Atherosclerosis Risk in Communities (ARIC) Study (n=1,777).
There were 1,171 men and 1,319 women at baseline, and the mean age was 57.1 years. At follow-up, 9.2% (n=229) had developed chronic kidney disease. Age, diabetes, hypertension, baseline estimated glomerular filtration rate and albuminuria were independently associated with incident chronic kidney disease (p<0.05), and these covariates were incorporated into a risk function (c-statistic 0.813). In external validation in the ARIC study, the c-statistic was 0.79 in whites (n=1,353) and 0.75 in blacks (n=424).
Risk stratification for chronic kidney disease is achievable using a risk score derived from clinical factors that are readily accessible in primary care. The utility of this score in identifying individuals in the community at high risk of chronic kidney disease warrants further investigation.
Claudication is a common and disabling symptom of peripheral artery disease that can be treated with medication, supervised exercise or stent revascularization.
We randomly assigned 111 patients with aortoiliac peripheral artery disease to receive one of three treatments: optimal medical care [OMC], OMC plus supervised exercise [(SE], or OMC plus stent revascularization [ST]. The primary endpoint was the change in peak walking time (PWT) on a graded treadmill test at 6 months as compared with baseline. Secondary endpoints included free-living step activity, quality of life (QOL) using the Walking Impairment Questionnaire (WIQ) and Peripheral Artery Questionnaire (PAQ), and cardiovascular risk factors.
At six month follow-up, change in PWT (the primary endpoint) was greatest for SE, intermediate for ST, and least with OMC (mean change vs. baseline 5.8±4.6, 3.7±4.9, and 1.2±2.6 minutes, respectively; p<0.001 for the comparison of SE vs. OMC; p=0.02 for ST vs. OMC; and p=0.04 for SE vs. ST). Although disease-specific quality of life as assessed by the WIQ and PAQ also improved with both SE and ST compared with OMC, for most scales the extent of improvement was greater with ST than SE. Free-living step activity increased more with ST than with either SE or OMC alone (114±274 vs. 73±139 vs. −6±109 steps/hour) but these differences were not statistically significant.
Supervised exercise treatment results in superior treadmill walking performance than stent placement, even for those with aortoiliac PAD. The contrast between better walking performance for SE and better patient-reported QOL for ST warrants further study.
Diabetes mellitus and obesity are increasing in prevalence and are associated with an elevated risk of atrial fibrillation (AF). Given the aging of the US population, AF is projected to concomitantly increase in prevalence in the upcoming decades. Both diabetes and obesity are associated with insulin resistance. Whether insulin resistance is an intermediate step for the development of AF is uncertain. We hypothesized that insulin resistance is associated with an increased risk of incident AF. We examined the association of insulin resistance with incident AF using multivariable Cox proportional hazards regression adjusting for established AF risk factors (age, sex, systolic blood pressure, hypertension treatment, PR interval, significant heart murmur, heart failure and body mass index). Of the 3,023 eligible participants (55% women; mean age 59 years) representing 4,583 persons-examinations (Framingham Offspring 5th and 7th examination cycles), 279 individuals developed AF (9.3%) up to 10 years of follow-up. With multivariable modeling, insulin resistance was not significantly associated with incident AF (hazard ratio comparing the top with the other three quartiles of homeostatic model assessment index (HOMA) 1.18, 95% confidence interval 0.84 to 1.65, p = 0.34). In a community-based cohort with up to 10 years follow-up, no significant association was observed between insulin resistance and incident AF.
Insulin resistance; atrial fibrillation; risk factors; epidemiology
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.
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.
pulmonary artery; Framingham Heart Study; computed tomography
Thoracic periaortic adipose tissue (TAT) is associated with atherosclerosis and cardiovascular disease (CVD) risk factors and may play a role in obesity‐mediated vascular disease. We sought to determine the prevalence, distribution, and risk factor correlates of high TAT.
Methods and Results
Participants from the Framingham Heart Study (n=3246, 48% women, mean age 51.1 years) underwent multidetector computed tomography; high TAT and visceral adipose tissue (VAT) were defined on the basis of sex‐specific 90th percentiles in a healthy referent sample. The prevalence of high TAT was 38.1% in women and 35.7% in men. Among individuals without high VAT, 10.1% had high TAT. After adjustment for age and VAT, both women and men with high TAT in the absence of high VAT were older and had a higher prevalence of CVD (P<0.0001) compared with those without high TAT. In addition, men in this group were more likely to be smokers (P=0.02), whereas women were more likely to have low high‐density lipoprotein cholesterol (P=0.005).
Individuals in our community‐based sample with high TAT in the absence of high VAT were characterized by an adverse cardiometabolic profile. This adipose tissue phenotype may identify a subset of individuals with distinct metabolic characteristics.
body fat distribution; obesity; perivascular adipose tissue; risk factors; visceral adipose tissue
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.
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.
adipose tissue; aneurysm; aorta; peripheral vascular disease
Ectopic fat depots may mediate local and systemic disease. Animal models of diet-induced obesity demonstrate increased fat accumulation in the renal sinus. The association of renal sinus fat with hypertension, chronic kidney disease (CKD), and other metabolic disorders has not been studied in a large, community-based sample. Participants from the Framingham Heart Study (n=2923, mean age 54 years, 51% women) underwent quantification of renal sinus fat area using computed tomography. High renal sinus fat (“fatty kidney”) was defined using sex-specific 90th percentiles in a healthy referent sub-sample. Multivariable linear and logistic regression was used to model metabolic risk factors as a function of fatty kidney and log-transformed renal sinus fat. Multivariable models were adjusted for age, sex, outcome-specific covariates, and then additionally adjusted for body mass index (BMI) or abdominal visceral adipose tissue (VAT). The prevalence of fatty kidney was 30.1% (n=879). Individuals with fatty kidney had a higher odds ratio (OR) of hypertension (OR 2.12, p<0.0001), which persisted after adjustment for BMI (OR 1.49, p<0.0001) and VAT (OR 1.24, p=0.049). Fatty kidney was also associated with an increased odds ratio for CKD (OR 2.30, p=0.005), even after additionally adjusting for BMI (OR 1.86, p=0.04) or VAT (OR 1.86, p=0.05). We observed no association between fatty kidney and diabetes after adjusting for VAT. In conclusion, fatty kidney is a common condition that is associated with an increased risk of hypertension and chronic kidney disease. Renal sinus fat may play a role in blood pressure regulation and CKD.
renal sinus fat; hypertension; chronic kidney disease; blood pressure; computed tomography; epidemiology
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.
γ′ fibrinogen is associated with prevalent CVD and with SNPs exclusively in and near the fibrinogen gene locus.
cardiovascular disease; gamma′ fibrinogen; genetics; polymorphisms; risk factors
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.
adiposity; natriuretic peptides; cardiovascular risk
We hypothesized that inflammatory markers are cross-sectionally and longitudinally associated with neuropsychological indicators of early ischemia and Alzheimer's disease.
Framingham Offspring Study participants, free of clinical stroke or dementia (n = 1,878; 60 ± 9 years; 54% women), underwent neuropsychological assessment and ascertainment of 11 inflammatory markers. Follow-up neuropsychological assessments (6.3 ± 1.0 years) were conducted on 1,352 of the original 1,878 participants.
Multivariable linear regression related the inflammatory markers to cross-sectional performance and longitudinal change in neuropsychological performances. Secondary models included a twelfth factor, tumor necrosis factor-α (TNF-α), available on a subset of the sample (n = 1,393 cross-sectional; n = 1,213 longitudinal). Results suggest a few modest cross-sectional inflammatory and neuropsychological associations, particularly for tests assessing visual organization (C-reactive protein, p = 0.007), and a few modest relations between inflammatory markers and neuropsychological change, particularly for executive functioning (TNF-α, p = 0.004). Secondary analyses suggested that inflammatory markers were cross-sectionally (TNF-α, p = 0.004) related to reading performance.
Our findings are largely negative, but suggest that specific inflammatory markers may have limited associations with poorer cognition and reading performance among community-dwelling adults. Because of multiple testing concerns, our limited positive findings are offered as hypothesis generating and require replication in other studies.
Memory; Executive functioning; Inflammation; Cognition; WRAT-3 reading
Heart failure (HF) is a clinical syndrome characterized by signs and symptoms involving multiple organ systems. Longitudinal data demonstrating that asymptomatic cardiac dysfunction precedes overt HF are scarce, and the contribution of non-cardiac dysfunction to HF progression is unclear. We hypothesized that subclinical cardiac and non-cardiac organ dysfunction would accelerate the manifestation of HF.
Methods and Results
We studied 1038 participants of the Framingham Heart Study original cohort (mean age 76±5 years; 39% men) with routine assessment of left ventricular (LV) systolic and diastolic function. Major non-cardiac organ systems were assessed using serum creatinine (renal), serum albumin (hepatic), ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) (pulmonary), hemoglobin concentration (hematologic/oxygen carrying capacity) and white blood cell count (systemic inflammation). On follow-up (mean 11 years), there were 248 incident HF events (146 in women). Adjusting for established HF risk factors, antecedent LV systolic (hazards ratio 2.33; 95%CI, 1.43–3.78) and diastolic (hazards ratio 1.32; 95%CI, 1.01-1.71) dysfunction were associated with increased HF risk. Adjusting for cardiac dysfunction, higher serum creatinine, lower FEV1:FVC ratios and lower hemoglobin concentrations were associated with increased HF risk (all P<0.05); serum albumin and white blood cell count were not. Subclinical dysfunction in each non-cardiac organ system was associated with a 30% increased risk of HF (P=0.013).
Antecedent cardiac and non-cardiac organ dysfunction are associated with increased incidence of HF, supporting the notion that HF is a progressive syndrome and underscoring the importance of non-cardiac factors in its occurrence.
Heart failure; Epidemiology; Echocardiography; Risk factors
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).
METHODS and RESULTS
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 1991–95 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 lowest HDL-C or 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 to a referent group without IR and 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.
insulin; lipids; coronary disease; risk factors; epidemiology
Endogenous carbon monoxide (CO) at physiologic concentrations is cytoprotective, whereas excess levels reflect underlying oxidative stress, inflammation, and vascular pathology and portend adverse clinical sequelae. However, the relation of exhaled CO to metabolic/vascular risk in the community is unknown.
Methods and Results
We related exhaled CO, a surrogate measure of blood CO concentration, to the risk of developing new-onset metabolic syndrome and incident cardiovascular disease (CVD) following 14,943 routine examinations (4,139 unique participants; mean age 46 years, 53% women) in the Framingham Heart Study. Baseline exhaled CO was associated with the presence of cardiometabolic risk factors (including smoking) and prevalent metabolic syndrome (odds ratio [OR] 1.08 per log-CO; 95% confidence interval [CI] 1.02–1.16; P=0.01). During up to 4 years of follow up, 1,458 participants developed new-onset metabolic syndrome, and 416 experienced a first CVD event. Compared to individuals in the lowest quartile of exhaled CO, those in the highest quartile were more likely to develop metabolic syndrome (OR 1.48, 95% CI 1.25–1.76; P<0.0001) and CVD events (hazards ratio 1.66, 95% CI 1.14–2.40; P=0.008) in multivariable analyses that included adjustment for smoking status.
In our community-based sample, higher exhaled CO levels predicted the development of metabolic syndrome and future CVD events, underscoring the importance of this endogenous second messenger in the pathogenesis of metabolic and vascular risk.
carbon monoxide; risk factors; metabolic syndrome; cardiovascular disease
Renal sinus fat may mediate obesity-related vascular disease, although this fat depot has not been assessed in a community-based sample. We sought to develop a protocol to quantify renal sinus fat accumulation using multi-detector computed tomography (MDCT).
Protocol development was performed in participants in the Framingham Offspring cohort who underwent MDCT. Volumetric renal sinus fat was measured separately within the right and left kidneys, and renal sinus fat area within a single MDCT scan slice was measured in the right kidney. Due to the high correlation of volumetric and single-slice renal sinus fat in the right kidney (Pearson correlation [r] = 0.85, p < 0.0001), we optimized a single-slice protocol to capture renal sinus fat in the right kidney alone. Pearson correlation coefficients were used to compare to assess the correlation of volumetric and single-slice renal sinus fat in the right kidney with other measures of adiposity. Inter- and intra-reader reproducibility was assessed using intra-class correlation coefficients.
Single-slice measurements were obtained in 92 participants (mean age 60 years, 49% women, median renal sinus fat 0.43 cm2). Intra- and inter-reader intra-class correlation coefficients were 0.93 and 0.86, respectively. Single-slice renal sinus fat was correlated with body mass index (r = 0.35, p = 0.0006), waist circumference (r = 0.31, p = 0.003), and abdominal visceral fat (r = 0.48, p < 0.0001). Similar correlations were observed for volumetric renal sinus fat in the right kidney.
Measuring renal sinus fat is feasible and reproducible using MDCT scans in a community-based sample.
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]).
Peri-aortic fat is associated with low ABI and intermittent claudication.
obesity; atherosclerosis; peripheral arterial disease
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).
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.
pericardial fat; obesity; epidemiology
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).
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.
brain; cardiac output; epidemiology; imaging; neuropsychology
The heart progressively remodels over the life course, yet longitudinal data characterizing such remodeling in the community are limited.
Methods and Results
Using multilevel modeling, we analyzed up to 4 serial echocardiographic observations obtained over a 16-year period in 4,062 Framingham Study participants (mean age 45 years, 54% women; 11,485 person-observations). We related LV wall thickness (LVWT), LV systolic (LVDS) and diastolic (LVDD) dimensions and fractional shortening (FS) to age, sex, body mass index (BMI), blood pressure (BP, including antihypertensive medication use), smoking, and diabetes (separate analyses for each echocardiographic measure). With advancing age, LV dimensions decreased, whereas FS and LVWT increased concomitantly. Male sex, BMI, and BP indices/hypertension treatment were significantly related to both greater LV dimensions and LVWT. The effect of age on cardiac remodeling was influenced by key covariates (P>0.05 for all interactions): women and individuals with diabetes experienced greater age-associated increases in LVWT; presence of diabetes or a higher BP was associated with a lesser decrease in LV diastolic dimensions with increasing age; antihypertensive medication use was a marker of an attenuated increase in FS with aging.
Cardiac remodeling over the adult life course is characterized by a distinct pattern of increasing LVWT, decreasing LV dimensions and increasing FS with advancing age. Overall, female sex, greater BP load, and presence of diabetes serve to attenuate this remodeling pattern. These observations suggest a mechanism for the preponderance of women with hypertension and individuals with diabetes among patients with diastolic heart failure.
aging; cardiac remodeling; heart failure
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.
inflammation; vitamin K; vitamin D; epidemiology
Midlife obesity has been associated with an increased risk of dementia. The underlying mechanisms are poorly understood. Our aim was to examine the cross-sectional association of body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR) and CT-based measures of subcutaneous (SAT) and visceral (VAT) adipose tissue with various MRI-markers of brain aging in middle-aged community adults.
Participants from the Framingham Offspring cohort were eligible if in addition to having measures of BMI, WC, WHR, SAT and VAT, they had undergone a volumetric brain MRI scan with measures of total brain volume (TCBV), temporal horn volume (THV), white matter hyperintensity volume (WMHV) and MRI-defined brain infarcts (BI). All analyses were adjusted for age, sex and time interval between abdominal CT and brain MRI.
In a sample of 733 community participants (mean age 60 years, 53% women), we observed an inverse association of BMI (estimate by standard deviation unit ± standard error =−0.27±0.12,p=0.02), WC (−0.30±0.12,p=0.01), WHR (−0.37±0.12,p=0.02), SAT (−0.23±0.11,p=0.04) and VAT (−0.36±0.12,p=0.002) with TCBV, independent of vascular risk factors. The association between VAT and TCBV was the strongest and most robust, and was also independent of BMI (−0.35±0.15,p=0.02) and insulin resistance (−0.32±0.13,p=0.01). When adjusting for C-reactive protein levels the associations were attenuated (−0.17±0.13,p=0.17 for VAT). No consistently significant association was observed between the anthropometric or CT-based abdominal fat measures and THV, WMHV or BI.
In middle-aged community participants we observed a significant inverse association of anthropometric and CT-based measures of abdominal, especially visceral, fat with total brain volume.