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1.  Relation of Hypothyroidism and Incident Atrial Fibrillation (from the Framingham Heart Study) 
American heart journal  2013;167(1):10.1016/j.ahj.2013.10.012.
Hyperthyroidism has a well-described association with atrial fibrillation (AF). However, the relation of hypothyroidism to AF has had limited investigation. Hypothyroidism is associated with cardiovascular risk factors, subclinical cardiovascular disease and overt cardiovascular disease, all of which predispose to AF. We investigated 10-year incidence of AF in a community-dwelling cohort.
Among 6,653 Framingham heart Study participants, 5,069 participants, 52% woman, mean age 57±12, were eligible after excluding those with missing thyroid stimulating hormone (TSH), TSH <0.45 μU/L (hyperthyroid), TSH >19.9 μU/L or prevalent AF. TSH was categorized by range (≥0.45 to <4.5, 4.5 to <10.0, 10.0 to ≤19.9 μU/L) and by quartiles. We examined the associations between TSH and 10-year risk of AF using multivariable-adjusted Cox proportional hazards analysis.
Over 10-year follow-up, we observed 277 cases of incident AF. A 1-standard deviation (SD) increase in TSH was not associated with increased risk of AF (hazard ratio 1.01, 95% confidence interval 0.90 to 1.14, p=0.83). In categorical analysis, employing TSH ≥0.45 to <4.5 μU/L as the referent (equivalent to euthyroid state), we found no significant association between hypothyroidism and 10-year AF risk. Comparing the highest (2.6
In conclusion, we did not identify a significant association between hypothyroidism and 10-year risk of incident AF in a community-based study.
PMCID: PMC3868014  PMID: 24332151
Atrial fibrillation; hypothyroidism; risk factors; cohort study
Academic radiology  2013;20(11):10.1016/j.acra.2013.08.008.
Rationale and Objectives
Abdominal aortic calcification (AAC) can be quantified using computed tomography (CT), but imaging planes are prescribed based on bony landmarks, so that individual variation between the landmark and the aortoiliac junction can result in variable aortic coverage. In the Framingham CT substudy, we scanned a 15-cm (Z-direction) abdominal segment cranial to the S1 vertebral body. We sought to determine the range and distribution of length of aorta scanned, the distribution of AAC within the abdominal aorta, and to compare burden of AAC measured from fixed-length segments versus AAC from all slices cranial to the aortoiliac bifurcation.
Materials and Methods
AAC was quantified by modified Agatston score (AS) in 100 Framingham Heart Study participants (60±13 years, 51 men). We compared AS measured from 5-cm and 8-cm segments to ASALL (total visualized aorta).
73/100 participants had AAC > 0. The total length of aorta imaged was ≥ 8 cm in 84% of participants. Qualitatively, 5-cm and 8-cm segments correctly identified 96% and 99%, respectively, of participants as having or not having AAC. Quantitatively, AS8cm was within 20% of ASALL in four-fifths and within 30% of ASALL in nine-tenths of participants. AS5cm more severely underestimated ASALL.
Using S1 as the caudal imaging landmark in a 15-cm slab yields ≥ 8 cm aortic coverage in most adults. Both 5-cm and 8-cm analysis strategies are comparable to analyzing the total visualized abdominal aorta for prevalent AAC, but only 8-cm segment analysis yields quantitatively similar measures of AAC.
PMCID: PMC3842029  PMID: 24119355
abdominal aorta; calcium; population study; segment length; computed tomography
Whereas greater physical activity (PA) is known to prevent cardiovascular disease (CVD), the relative importance of performing PA in sustained bouts of activity versus shorter bouts of activity on CVD risk is not known. The objective of this study was to investigate the relationship between moderate-to-vigorous physical activity (MVPA), measured in bouts ≥10 minutes and <10 minutes, and CVD risk factors in a well-characterized, community-based sample of white adults.
We conducted a cross-sectional analysis of 2109 Framingham Heart Study Third Generation participants (mean age 47 years, 55% women) who underwent objective assessment of PA by accelerometry over 5–7 days. Total MVPA, MVPA done in bouts ≥10 minutes (MVPA10+), and MVPA done in bouts <10 minutes (MVPA<10) were calculated. MVPA exposures were related to individual CVD risk factors, including measures of adiposity and blood lipid and glucose levels, using linear and logistic regression.
Total MVPA was significantly associated with higher high-density lipoprotein (HDL) levels, and with lower triglycerides, BMI, waist circumference and Framingham risk score (P <0.0001). MVPA<10 showed similar statistically significant associations with these CVD risk factors (P <0.001). Compliance with national guidelines (≥150 minutes of total MVPA) was significantly related to lower BMI, triglycerides, Framingham risk score, waist circumference, higher HDL, and a lower prevalence of obesity and impaired fasting glucose (P < 0.001 for all).
Our cross-sectional observations on a large middle-aged community-based sample confirm a positive association of MVPA with a healthier CVD risk factor profile, and indicate that accruing physical activity in bouts <10 minutes may favorably influence cardiometabolic risk. Additional investigations are warranted to confirm our findings.
PMCID: PMC4166425  PMID: 22895372
accelerometer; heart disease; exercise; guidelines
JAMA  2012;307(18):1925-1933.
Laboratory studies suggest that in the setting of cardiac ischemia, immediate intravenous glucose-insulin-potassium (GIK) reduces ischemia-related arrhythmias and myocardial injury. Clinical trials have not consistently shown these benefits, possibly due to delayed administration.
To test out-of hospital emergency medical service (EMS) administration of GIK in the first hours of suspected acute coronary syndromes (ACS).
Design, Setting, and Participants
Randomized, placebo-controlled, double-blind effectiveness trial in 13 US cities (36 EMS agencies), from December 2006 through July 31, 2011, in which paramedics, aided by electrocardiograph (ECG)-based decision support, randomized 911 (871 enrolled) patients (mean age, 63.6 years; 71.0% men) with high probability of ACS.
Intravenous GIK solution (n=411) or identical-appearing 5% glucose placebo (n=460) administered by paramedics in the out-of-hospital setting and continued for 12 hours.
Main Outcome Measures
The prespecified primary end point was progression of ACS to myocardial infarction (MI) within 24 hours, as assessed by biomarkers and ECG evidence. Prespecified secondary end points included survival at 30 days and a composite of prehospital or in-hospital cardiac arrest or in-hospital mortality, analyzed by intent-to-treat and by presentation with ST-segment elevation.
There was no significant difference in the rate of progression to MI among patients who received GIK (n=200; 48.7%) vs those who received placebo (n=242; 52.6%) (odds ratio [OR], 0.88; 95% CI, 0.66–1.13; P=.28). Thirty-day mortality was 4.4% with GIK vs 6.1% with placebo (hazard ratio [HR], 0.72; 95% CI, 0.40–1.29; P=.27). The composite of cardiac arrest or in-hospital mortality occurred in 4.4% with GIK vs 8.7% with placebo (OR, 0.48; 95% CI, 0.27–0.85; P=.01). Among patients with ST-segment elevation (163 with GIK and 194 with placebo), progression to MI was 85.3% with GIK vs 88.7% with placebo (OR, 0.74; 95% CI, 0.40–1.38; P=.34); 30-day mortality was 4.9% with GIK vs 7.7% with placebo (HR, 0.63; 95% CI, 0.27–1.49; P=.29). The composite outcome of cardiac arrest or in-hospital mortality was 6.1% with GIK vs 14.4% with placebo (OR, 0.39; 95% CI, 0.18–0.82; P=.01). Serious adverse events occurred in 6.8% (n=28) with GIK vs 8.9% (n=41) with placebo (P=.26).
Among patients with suspected ACS, out-of-hospital administration of intravenous GIK, compared with glucose placebo, did not reduce progression to MI. Compared with placebo, GIK administration was not associated with improvement in 30-day survival but was associated with lower rates of the composite outcome of cardiac arrest or in-hospital mortality.
Trial Registration Identifier: NCT00091507
PMCID: PMC4167391  PMID: 22452807
To determine whether ectopic fat depots are prospectively associated with cardiovascular disease, cancer and all-cause mortality.
The morbidity associated with excess body weight varies among individuals of similar body mass index. Ectopic fat depots may underlie this risk differential. However, prospective studies of directly measured fat are limited.
Participants from the Framingham Heart Study (n=3086, 49% women, mean age 50.2 years) underwent assessment of fat depots (visceral adipose tissue, pericardial adipose tissue, and periaortic adipose tissue) using multidetector computed tomography, and were followed longitudinally for a median of 5.0 years. Cox proportional hazards regression models were used to examine the association of each fat depot (per 1 standard deviation increment) with the risk of incident cardiovascular disease, cancer, and all-cause mortality after adjustment for standard risk factors, including body mass index.
Overall, there were 90 cardiovascular events, 141 cancer events, and 71 deaths. After multivariable adjustment, visceral adipose tissue was associated with cardiovascular disease (HR 1.44, 95% CI 1.08–1.92, p=0.01) and cancer (HR 1.43, 95% CI 1.12–1.84, p=0.005). Addition of visceral adipose tissue to a multivariable model that included body mass index modestly improved cardiovascular risk prediction (net reclassification improvement of 16.3%). None of the fat depots were associated with all-cause mortality.
Visceral adiposity is associated with incident cardiovascular disease and cancer after adjustment for clinical risk factors and generalized adiposity. These findings support the growing appreciation of a pathogenic role of ectopic fat.
PMCID: PMC4142485  PMID: 23850922
obesity; visceral fat; body fat distribution; cardiovascular disease; cancer
The British journal of nutrition  2013;110(3):545-551.
Evidence for cardioprotective effects of lycopene is inconsistent. Studies of circulating lycopene generally report inverse associations with cardiovascular disease (CVD) risk, but studies based on lycopene intake do not. The failure of the dietary studies to support the findings based on biomarkers may be due in part to misclassification of lycopene intakes. To address this potential misclassification, we used repeated measures of intake obtained over 10 years to characterize the relation between lycopene intake and incidence of CVD (n=314), coronary heart disease (CHD, n=171) and stroke (n=99) in the Framingham Offspring Study. Hazards ratios (HR) for incident outcomes were derived from Cox proportional hazards regression models using logarithmically transformed lycopene intake adjusted for CVD risk factors and correlates of lycopene intake. HRs were interpreted as the increased risk for a 2.7-fold difference in lycopene intake, a difference approximately equal to its inter-quartile range. Using an average of three intake measures with a 9 year follow-up, lycopene intake was inversely associated with CVD incidence (hazards ratio (HR): 0.83, 95% confidence interval (CI): 0.70-0.98). Using an average of two intake measures and 11 years of follow-up, lycopene intake was inversely associated with CHD incidence (HR: 0.74, 95% CI: 0.58-0.94). Lycopene intake was unrelated to stroke incidence. Our study of lycopene intake and CVD provides supporting evidence for an inverse association between lycopene and CVD risk but additional research is needed to determine if lycopene or other components of tomatoes, the major dietary source of lycopene, are responsible for the observed association.
PMCID: PMC3710301  PMID: 23317928
lycopene; cardiovascular disease; coronary heart disease; stroke
Ectopic fat density is associated with cardiovascular disease (CVD) risk factors above and beyond fat volume. Volumetric measures of ectopic fat have been associated with CVD risk factors and subclinical atherosclerosis. The aim of this study was to investigate the association between fat density and subclinical atherosclerosis.
Methods and Results
Participants were drawn from the Multi‐Detector Computed Tomography (MDCT) substudy of the Framingham Heart Study (n=3079; mean age, 50.1 years; 49.2% women). Fat density was indirectly estimated by computed tomography attenuation (Hounsfield Units [HU]) on abdominal scan slices. Visceral fat (VAT), subcutaneous fat (SAT), and pericardial fat HU and volumes were quantified using standard protocols; coronary and abdominal aortic calcium (CAC and AAC, respectively) were measured radiographically. Multivariable‐adjusted logistic regression models were used to evaluate the association between adipose tissue HU and the presence of CAC and AAC. Overall, 17.1% of the participants had elevated CAC (Agatston score [AS]>100), and 23.3% had elevated AAC (AS>age‐/sex‐specific cutoffs). Per 5‐unit decrement in VAT HU, the odds ratio (OR) for elevated CAC was 0.76 (95% confidence interval [CI], 0.65 to 0.89; P=0.0005), even after adjustment for body mass index or VAT volume. Results were similar for SAT HU. With decreasing VAT HU, we also observed an OR of 0.79 (95% CI, 0.67 to 0.92; P=0.004) for elevated AAC after multivariable adjustment. We found no significant associations between SAT HU and AAC. There was no significant association between pericardial fat HU and either CAC or AAC.
Lower VAT and SAT HU, indirect estimates of fat quality, are associated with a lower risk of subclinical atherosclerosis.
PMCID: PMC4310364  PMID: 25169793
atherosclerosis; epidemiology; fat density; obesity
Achallenge for emergency medical service (EMS) is accurate identification of acute coronary syndromes (ACS) and ST elevation myocardial infarction (STEMI) for immediate treatment and transport. The electrocardiograph-based acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI) and the thrombolytic predictive instrument (TPI) have been shown to improve diagnosis and treatment in emergency departments (EDs), but their use by paramedics in the community has been less studied.
Ambulances in study municipalities were outfitted with electrocardiographs with ACI-TIPI and TPI software. Using a before-after quasi-experimental design, in Phase 1, for seven months, paramedics were provided with the ACI-TIPI/TPI continuous 0–100% predictions automatically printed on electrocardiogram (ECG) text headers to supplement their identification of ACS; in Phase 2, for 11 months, paramedics were told to identify ACS based on an ACI-TIPI cutoff probability of ACS ≥ 75% and/or TPI detection of STEMI. In Phase 3, this cutoff approach was used in seven additional municipalities. Confirmed diagnoses of ACS, acute myocardial infarction (AMI), and STEMI were made by blinded physician review for 100% of patients.
In Phase 1, paramedics identified 107 patients as having ACS; in Phase 2, 104. In Phase 1, 45.8% (49) of patients so-identified had ACS confirmed, which increased to 76.0% (79) in Phase 2 (p < 0.001). Of those with ACS, in Phase 1 59.2% (29) had AMI versus 84.8% (67) with AMI in Phase 2 (p <0.01), and, STEMI was confirmed, respectively, in 40.8% (20), versus 68.4% (54) (p <0.01). In Phase 3, of 226 patients identified by paramedics as having ACS, 74.3% (168) had ACS confirmed, of whom 81.0% (136) had AMI and 65.5% (110) had STEMI.
In a wide range of EMS systems, use of electrocardiographs with ACI-TIPI and TPI decision support using a 75% ACI-TIPI cutoff improves paramedic diagnostic performance for ACS, AMI, and STEMI.
PMCID: PMC4104416  PMID: 21366431
acute coronary syndromes; acute myocardial infarction; electrocardiology; emergency medical service; clinical decision support
American heart journal  2013;166(1):171-178.e3.
Atrial fibrillation (AF)-related symptoms and physical performance are relied upon to guide therapeutic management of patients with AF. We sought to understand whether AF predisposes to or is a result of physical disability and poor subjective health in the community.
We studied relations between physical disability (Rosow-Breslau Functional Health Scale), subjective health (self-report) and incident AF, and the converse, in the Framingham Heart Study.
In 3609 participants (age 73±8 years, 59% women), a subset of 861 participants (24%) had prevalent physical disability at baseline. During 5.8±1.8 years follow-up, 555 participants (10-year age- and sex-adjusted incidence rate 13%) developed incident AF. Prevalent physical disability was related to incident AF (multivariable-adjusted hazard ratio [HR], 1.25; 95% CI, 1.02–1.54; P=0.03). In 3525 participants, prevalent poor subjective health (n=333) also was related to incident AF (n=552; multivariable-adjusted HR, 1.31; 95% CI, 1.00–1.70; P=0.048). Conversely, in 2080 participants (age 69±6 years, 55% women), interim AF (n=106) was associated with newly reported physical disability (n=573) at a follow-up examination (multivariable-adjusted odds ratio [OR], 1.58; 95% CI, 1.08–2.31; P=0.01). In 1954 participants, interim AF (n=96) likewise was related to newly reported poor subjective health (n=224; multivariable-adjusted OR, 1.83; 95% CI, 1.10–3.02; P=0.02).
Physical disability and poor subjective health were related to incident AF in a community-based cohort. Conversely, interim AF was related to newly reported physical disability and poor subjective health. Since AF guidelines incorporate symptoms, it is essential to clarify the temporality and mechanisms linking physical disability, subjective health and AF.
PMCID: PMC3701157  PMID: 23816037
Atrial fibrillation; functional status; disability; epidemiology; risk factor
JACC. Cardiovascular imaging  2013;6(7):762-771.
The aim of this study was to evaluate whether computed tomography (CT) attenuation, as a measure of fat quality, is associated with cardiometabolic risk factors above and beyond fat quantity.
Visceral (VAT) and subcutaneous adipose tissue (SAT) are pathogenic fat depots associated with cardiometabolic risk. Adipose tissue attenuation in CT images is variable, similar to adipose tissue volume. However, whether the quality of abdominal fat attenuation is associated to cardiometabolic risk independent of the quantity is uncertain.
Participants were drawn from the Framingham Heart Study CT sub-study. VAT and SAT volumes were acquired by semi-quantitative assessment. Fat quality was measured by CT attenuation and recorded as mean Hounsfield Units (HU) within each fat depot. Sex-specific linear and logistic multivariable regression models were used to assess the association between standard deviation (SD) decrease in HU and each risk factor.
Lower CT attenuation of VAT and SAT was correlated with higher BMI levels in both sexes. Risk factors were generally more adverse with decreasing HU values. For example, in women, per 1-SD decrease in VAT HU, the odds ratio (OR) was increased for hypertension (OR 1.80), impaired fasting glucose (OR 2.10), metabolic syndrome (OR 3.65) and insulin resistance (OR 3.36) (all p<0.0001). In models that further adjusted for VAT volume, impaired fasting glucose, metabolic syndrome and insulin resistance remained significant. Trends were similar but less pronounced in SAT and in men. There was evidence of an interaction between HU and fat volume among both women and men.
Lower CT attenuation of VAT and SAT is associated with adverse cardiometabolic risk above and beyond total adipose tissue volume. Qualitative indices of abdominal fat depots may provide insight regarding cardiometabolic risk independent of fat quantity.
PMCID: PMC3745280  PMID: 23664720
Obesity; Epidemiology; CT Imaging; Risk Factors
European Journal of Heart Failure  2013;15(7):742-746.
Reduced physical activity is associated with increased risk of heart failure (HF) in middle-aged individuals. We hypothesized that physical inactivity is also associated with greater HF risk in older individuals, and examined if the association was consistent for HF with preserved ejection fraction (HFPEF) vs. HF with a reduced ejection fraction (HFREF).
Methods and results
We evaluated 1142 elderly participants (mean age 76 years) from the Framingham Study without prior myocardial infarction and who attended a routine examination when daily physical activity was assessed systematically with a questionnaire. A composite score, the physical activity index (PAI), was calculated and modelled as tertiles, and related to incidence of HF, HFPEF, and HFREF on follow-up using proportional hazards regression models adjusting for age and sex, and then additionally for standard HF risk factors. Participants with HF and EF <45% vs. ≥45% were categorized as HFREF and HFPEF, respectively. On follow-up (mean 10 years), 250 participants developed HF (108 with HFPEF, 106 with HFREF, 36 with unavailable EF). In age- and sex-adjusted models, the middle and highest PAI tertiles were associated with a 15–56% lower risk of any HF, of HFREF, and of HFPEF, with a graded response across tertiles. In multivariable models, the association of higher PAI with lower risk of any HF and with HFPEF was maintained, whereas the association with HFREF was attenuated.
Our study of an older community-based sample extends to the elderly and to HFPEF previous findings of a protective effect of physical activity on HF risk.
PMCID: PMC3857918  PMID: 23435761
Physical activity; Heart failure; Elderly
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.
PMCID: PMC3644324  PMID: 23497775
Aortic diameter; computed tomography; sex; age; body surface area
American heart journal  2012;163(3):315-322.
Experimental studies suggest that metabolic myocardial support by intravenous (IV) glucose, insulin, and potassium (GIK) reduces ischemia-induced arrhythmias, cardiac arrest, mortality, progression from unstable angina pectoris (UAP) to acute myocardial infarction (AMI), and MI size. However, trials of hospital administration of IV GIK to patients with ST elevation MI (STEMI) have generally not shown favorable effects, possibly due to the GIK intervention taking place many hours after ischemic symptom onset. A trial of GIK used in the very first hours of ischemia has been needed, consistent with the timing of benefit seen in experimental studies.
The Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care (IMMEDIATE) Trial tested whether, if given very early, GIK could have the impact seen in experimental studies. Accordingly, distinct from prior trials, IMMEDIATE tested the impact of GIK 1) in patients with acute coronary syndromes (ACS), rather than only AMI or STEMI, and 2) administered in prehospital emergency medical service (EMS) settings, rather than later, in hospitals, following emergency department evaluation.
IMMEDIATE was an EMS-based randomized placebo-controlled clinical effectiveness trial conducted in 13 cities across the US which enrolled 911 participants. Eligible were patients age 30 or older for whom a paramedic performed a 12-lead electrocardiogram (ECG)to evaluate chest pain or other symptoms suggestive of ACS for whom electrocardiograph-based ACI-TIPI (acute cardiac ischemia time-insensitive predictive instrument) indicated a > 75% probability of ACS, and/or the TPI (thrombolytic predictive instrument) indicated presence of a STEMI, or if local criteria for STEMI notification of receiving hospitals were met. Prehospital IV GIK or placebo was started immediately.
Pre-specified were the primary endpoint of progression of ACS to infarction, and as major secondary endpoints, the composite of cardiac arrest or in-hospital mortality; 30-day mortality; and the composite of cardiac arrest, 30-day mortality or hospitalization for heart failure (HF). Analyses were planned on an intent-to-treat basis, on a modified intent-to-treat group who were confirmed in emergency departments to have ACS, and for participants presenting with STEMI.
The IMMEDIATE Trial tested whether GIK, when administered as early as possible in the course of ACS by paramedics using ACI-TIPI and TPI decision support, would reduce progression to AMI, mortality, cardiac arrest, and HF. It also tested whether it would provide clinical and pathophysiological information on GIK’s biological mechanisms.
PMCID: PMC4009621  PMID: 22424000
Atherosclerosis  2013;228(1):230-236.
Cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) are two genetically-related plasma proteins involved in the exchange of cholesteryl esters and phospholipids between high-density lipoproteins (HDL) and other lipoproteins. Although low CETP and high PLTP activity both result in higher concentrations of plasma HDL-cholesterol (HDL-C), there is no evidence that either of these changes is associated with a decrease in cardiovascular disease (CVD) in a general population.
Plasma CETP and PLTP activities, measured by homogenous fluorometric assays using synthetic donor particle substrates, were related to the incidence of a first CVD event in Framingham Heart Study Offspring participants without CVD (n = 2679, mean age 59 y, 56% women) attending the 6th examination cycle (1995–98). Because of an effect modification by sex for both CETP and PLTP, analyzes were stratified by sex.
During follow-up (mean 10.4 years) 187 participants experienced a first CVD event. In sex-specific Cox models, both CETP and PLTP as continuous and as binary variables were associated with significantly increased CVD in men, but not women. In men compared to a referent group with CETP ≥ median and PLTP < median, the multivariable-adjusted hazard ratio (HR) for new CVD events was significantly greater with either the combination of high CETP and high PLTP (HR 2.27, 95% CI 1.23–4.20); low CETP and low PLTP (HR 2.23, 95% CI 1.19–4.17); or low CETP and high PLTP (HR 2.85, 95% CI 1.53–5.31). In contrast, in women the multivariable-adjusted HR for new CVD events was non-significant and virtually equal to “1.0” with all combinations of high and low CETP or PLTP values.
Lower plasma CETP or higher PLTP activity was each associated with a significantly increased risk of CVD. Inexplicably, the increase in CVD associated with both lipid transfer proteins was confined to men.
PMCID: PMC3692011  PMID: 23477743
High density lipoproteins; Cholesteryl ester transfer protein; Phospholipid transfer protein
Lifetime data analysis  2012;19(2):10.1007/s10985-012-9238-0.
The area under the receiver operating characteristic curve (AUC) is the most commonly reported measure of discrimination for prediction models with binary outcomes. However, recently it has been criticized for its inability to increase when important risk factors are added to a baseline model with good discrimination. This has led to the claim that the reliance on the AUC as a measure of discrimination may miss important improvements in clinical performance of risk prediction rules derived from a baseline model. In this paper we investigate this claim by relating the AUC to measures of clinical performance based on sensitivity and specificity under the assumption of multivariate normality. The behavior of the AUC is contrasted with that of discrimination slope. We show that unless rules with very good specificity are desired, the change in the AUC does an adequate job as a predictor of the change in measures of clinical performance. However, stronger or more numerous predictors are needed to achieve the same increment in the AUC for baseline models with good versus poor discrimination. When excellent specificity is desired, our results suggest that the discrimination slope might be a better measure of model improvement than AUC. The theoretical results are illustrated using a Framingham Heart Study example of a model for predicting the 10-year incidence of atrial fibrillation.
PMCID: PMC3656609  PMID: 23242535
risk prediction; discrimination; AUC; IDI; Youden index; relative utility
Intramuscular fat accumulates between muscle fibers or within muscle cells. We investigated the association of intramuscular fat with other ectopic fat deposits and metabolic risk factors.
Approach and Results
Participants (n = 2945; 50.2% women; mean age 50.8 years) from the Framingham Heart Study underwent multidetector computed tomography scanning of the abdomen. Regions of interest were placed on the left and right paraspinous muscle and the muscle attenuation (MA) in Hounsfield units were averaged. We examined the association between MA and metabolic risk factors in multivariable models and additionally adjusted for BMI and visceral fat (VAT) in separate models. MA was associated with dysglycemia, dyslipidemia, and hypertension in both sexes. In women, per standard deviation decrease in MA, there was a 1.34 (95% CI 1.10–1.64) increase in the odds of diabetes, a 1.40 (95% CI 1.22 – 1.61) increase in the odds of high triglycerides, and a 1.29 (95% CI 1.12 – 1.48) increase in the odds of hypertension. However, none of these associations persisted after adjustment for BMI or VAT. In men, we observed similar patterns for most risk factors. The exception was metabolic syndrome, which retained association in women even after adjustment for BMI and VAT, and low HDL and high triglycerides in men, whose associations also persisted after adjustment for BMI and VAT.
MA was associated with metabolic risk factors, but most of these associations were lost after adjustment for BMI or VAT. However, a unique association remained for metabolic syndrome in women and lipids in men.
PMCID: PMC3696991  PMID: 23349188
Metabolism; obesity; intramuscular fat; epidemiology
Hek, Karin | Demirkan, Ayse | Lahti, Jari | Terracciano, Antonio | Teumer, Alexander | Cornelis, Marilyn C. | Amin, Najaf | Bakshis, Erin | Baumert, Jens | Ding, Jingzhong | Liu, Yongmei | Marciante, Kristin | Meirelles, Osorio | Nalls, Michael A. | Sun, Yan V. | Vogelzangs, Nicole | Yu, Lei | Bandinelli, Stefania | Benjamin, Emelia J. | Bennett, David A. | Boomsma, Dorret | Cannas, Alessandra | Coker, Laura H. | de Geus, Eco | De Jager, Philip L. | Diez-Roux, Ana V. | Purcell, Shaun | Hu, Frank B. | Rimma, Eric B. | Hunter, David J. | Jensen, Majken K. | Curhan, Gary | Rice, Kenneth | Penman, Alan D. | Rotter, Jerome I. | Sotoodehnia, Nona | Emeny, Rebecca | Eriksson, Johan G. | Evans, Denis A. | Ferrucci, Luigi | Fornage, Myriam | Gudnason, Vilmundur | Hofman, Albert | Illig, Thomas | Kardia, Sharon | Kelly-Hayes, Margaret | Koenen, Karestan | Kraft, Peter | Kuningas, Maris | Massaro, Joseph M. | Melzer, David | Mulas, Antonella | Mulder, Cornelis L. | Murray, Anna | Oostra, Ben A. | Palotie, Aarno | Penninx, Brenda | Petersmann, Astrid | Pilling, Luke C. | Psaty, Bruce | Rawal, Rajesh | Reiman, Eric M. | Schulz, Andrea | Shulman, Joshua M. | Singleton, Andrew B. | Smith, Albert V. | Sutin, Angelina R. | Uitterlinden, André G. | Völzke, Henry | Widen, Elisabeth | Yaffe, Kristine | Zonderman, Alan B. | Cucca, Francesco | Harris, Tamara | Ladwig, Karl-Heinz | Llewellyn, David J. | Räikkönen, Katri | Tanaka, Toshiko | van Duijn, Cornelia M. | Grabe, Hans J. | Launer, Lenore J. | Lunetta, Kathryn L. | Mosley, Thomas H. | Newman, Anne B. | Tiemeier, Henning | Murabito, Joanne
Biological psychiatry  2013;73(7):10.1016/j.biopsych.2012.09.033.
Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.
In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p < 1 × 10−5) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.
The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05 × 10−7). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19 × 10−3). This 5q21 region reached genome-wide significance (p = 4.78 × 10−8) in the overall meta-analysis combining discovery and replication studies (n = 51,258).
The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.
PMCID: PMC3845085  PMID: 23290196
Center for Epidemiologic Studies Depression Scale; CHARGE consortium; depression; depressive symptoms; genetics; genome-wide association study; meta-analysis
Obesity is associated with altered atrial electrophysiology and a prominent risk factor for atrial fibrillation. Body mass index, the most widely used adiposity measure, has been related to atrial electrical remodeling. We tested the hypothesis that pericardial fat is independently associated with electrocardiographic measures of atrial conduction.
Methods and Results
We performed a cross‐sectional analysis of 1946 Framingham Heart Study participants (45% women) to determine the relation between pericardial fat and atrial conduction as measured by P wave indices (PWI): PR interval, P wave duration (P‐duration), P wave amplitude (P‐amplitude), P wave area (P‐area), and P wave terminal force (P‐terminal). We performed sex‐stratified linear regression analyses adjusted for relevant clinical variables and ectopic fat depots. Each 1‐SD increase in pericardial fat was significantly associated with PR interval (β=1.7 ms, P=0.049), P‐duration (β=2.3 ms, P<0.001), and P‐terminal (β=297 μV·ms, P<0.001) among women; and P‐duration (β=1.2 ms, P=0.002), P‐amplitude (β=−2.5 μV, P<0. 001), and P‐terminal (β=160 μV·ms, P=0.002) among men. Among both sexes, pericardial fat was significantly associated with P‐duration in analyses additionally adjusting for visceral fat or intrathoracic fat; a similar but non‐significant trend existed with P‐terminal. Among women, pericardial fat was significantly associated with P wave area after adjustment for visceral and intrathoracic fat.
Pericardial fat is associated with atrial conduction as quantified by PWI, even with adjustment for extracardiac fat depots. Further studies are warranted to identify the mechanisms through which pericardial fat may modify atrial electrophysiology and promote subsequent risk for arrhythmogenesis.
PMCID: PMC4187474  PMID: 24595189
atrium; conduction; electrocardiography; epidemiology; obesity
Global heart  2013;8(1):11-23.
Cardiovascular disease (CVD) is among the leading causes of death and disability worldwide. Since its beginning, the Framingham study has been a leader in identifying CVD risk factors. Clinical trials have demonstrated that when the modifiable risk factors are treated and corrected, the chances of CVD occurring can be reduced. The Framingham study also recognized that CVD risk factors are multifactorial and interact over time to produce CVD. In response, Framingham investigators developed the Framingham Risk Functions (also called Framingham Risk Scores) to evaluate the chance or likelihood of developing CVD in individuals. These functions are multivariate functions (algorithms) that combine the information in CVD risk factors such as sex, age, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking behavior, and diabetes status to produce an estimate (or risk) of developing CVD or a component of CVD (such as coronary heart disease, stroke, peripheral vascular disease, or heart failure) over a fixed time, for example, the next 10 years. These estimates of CVD risk are often major inputs in recommending drug treatments such as cholesterol-lowering drugs.
PMCID: PMC3673738  PMID: 23750335
Obesity (Silver Spring, Md.)  2013;21(8):1713-1719.
To examine the relation between measures of adiposity and depressive symptoms in a large well characterized community-based sample, we examined the relations of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) to depressive symptoms in 1581 women (mean age 52.2 years) and 1718 men (mean age 49.8 years) in the Framingham Heart Study. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression (CES-D) scale. Regression models were created to examine the association between each fat depot (exposure) and depressive symptoms (outcome). Sex specific models were adjusted for age, body mass index, smoking, alcohol consumption, diabetes, hypertension, total and HDL cholesterol, lipid lowering treatment, CVD, menopause, C-reactive protein, and physical activity. Mean CES-D scores were 6.8 and 5.6 in women and men. High levels of depressive symptoms were present in 22.5% of women and 12.3% of men. In women, one standard deviation increase in VAT was associated with a 1.3 point higher CES-D score after adjusting for age and BMI (p<0.01) and remained significant in the fully adjusted model (p=0.03). The odds ratio of depressive symptoms per 1 standard deviation increase in VAT in women was 1.33 (p=0.015); results were attenuated in fully adjusted models (OR 1.29, p=0.055). In men, the association between VAT and CES-D score and depressive symptoms was not significant. SAT was not associated with CES-D score or depressive symptoms. This study supports an association between VAT and depressive symptoms in women. Further work is needed to uncover the complex biologic mechanisms mediating the association.
PMCID: PMC3748158  PMID: 23666906
We sought to characterize associations between aminotransferase levels and cardiometabolic risk after accounting for visceral adipose tissue (VAT) and insulin resistance.
Methods and Results
Participants (n=2621) from the Framingham Heart Study (mean age 51, 49.8% women) were included. Sex-specific linear and logistic regressions were used to evaluate associations between aminotransferase levels and cardiometabolic risk factors. In multivariable models, increased ALT levels were associated with elevated blood pressure, fasting plasma glucose, and triglycerides and lower HDL levels (all p ≤ 0.007). Further, each 1 standard deviation (SD) increase in ALT corresponded to an increased odds of hypertension, diabetes, the metabolic syndrome, impaired fasting glucose, and insulin resistance estimated by HOMA-IR (OR 1.29–1.85, all p ≤ 0.002). Associations with ALT persisted after additional adjustment for VAT, insulin resistance, and BMI with the exception of HDL cholesterol in both sexes and blood pressure in women. Results were materially unchanged when moderate drinkers were excluded, when the sample was restricted to those with ALT<40 U/L, and when the sample was restricted to those without diabetes. Similar trends were observed for AST levels, but associations were more modest.
Aminotransferase levels are correlated with multiple cardiometabolic risk factors above and beyond VAT and insulin resistance.
PMCID: PMC3593729  PMID: 23162012
liver function tests; obesity; visceral fat; insulin resistance; cardiometabolic risk factors
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.
PMCID: PMC3779879  PMID: 19139753
Adipose Tissue; Intra-Abdominal Fat; Tomography; Spiral Computed; Framingham Heart Study; Metabolic Risk Factors
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.
PMCID: PMC3432173  PMID: 22727181
atherosclerosis; aorta; calcification; computed tomography; epidemiology
Diabetes Care  2012;35(9):1944-1950.
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.
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.
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.
PMCID: PMC3425010  PMID: 22773705

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