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1.  Usefulness of the Triglyceride:High Density Lipoprotein versus the Cholesterol:High Density Lipoprotein Ratio for Predicting Insulin Resistance and Cardiometabolic Risk: from the Framingham Offspring Cohort 
The American journal of cardiology  2008;101(4):497-501.
Elevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) are key metabolic abnormalities in insulin resistance (IR) states, including diabetes mellitus. The TG/HDL-C ratio has been advocated as a simple clinical indicator of IR, but studies have yielded inconsistent results. The total cholesterol/HDL-C ratio is widely used to assess lipid atherogenesis but its utility for assessing IR or its associated coronary heart disease (CHD) risk is unknown. We related the TG/HDL-C and total cholesterol/HDL-C ratios to IR (top quartile of the homeostasis model assessment of insulin resistance) in 3014 individuals (mean age 54 years; 55% women). Logistic regression was used to construct receiver-operating-characteristic curves for predicting IR, with lipid ratios as predictors. Multivariable Cox regression was used to evaluate if adjusting for lipid ratios attenuated the association of IR with CHD. Cross-sectionally, the age- and sex-adjusted correlations of IR were: 0.46 with TG/HDL-C, and 0.38 with total cholesterol/HDL-C. IR Prevalence increased across tertiles of lipid ratios (p<0.0001). The area under the receiver-operating-characteristic curves for predicting IR with TG/HDL-C ratio was 0.745, which was slightly higher than that for total cholesterol/HDL-C ratio (0.707; p<0.001 for comparison). On follow-up (mean 6.4 years), 112 individuals experienced initial CHD events. IR was associated with CHD risk (multivariable-adjusted hazards ratio 2.71, 95% CI 1.79–4.11), which remained significant even after adjustment for the lipid ratios. In conclusion, our observations suggest that the TG/HDL-C ratio is an imperfect surrogate for IR and its associated CHD risk, and it is only slightly better than the total cholesterol/HDL-C ratio for this purpose.
PMCID: PMC3753679  PMID: 18312765
insulin resistance; epidemiology; lipids; coronary risk
2.  Clinical and economic outcomes after surgical aortic valve replacement in Medicare patients 
Aortic valve replacement (AVR) is the standard of care for patients with severe, symptomatic aortic stenosis who are suitable surgical candidates, benefiting both non-high-risk and high-risk patients. The purpose of this study was to report long-term medical resource use and costs for patients following AVR and validate our assumption that high-risk patients have worse outcomes and are more costly than non-high-risk patients in this population.
Patients with aortic stenosis who underwent AVR were identified in the 2003 Medicare 5% Standard Analytic Files and tracked over 5 years to measure clinical outcomes, medical resource use, and costs. An approximation to the logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) based on administrative data was used to assess surgical risk, with a computed logistic EuroSCORE > 20% considered high-risk.
We identified 1474 patients with aortic stenosis who underwent AVR, of whom 1222 (82.9%) were non-high-risk and 252 (17.1%) were high-risk. Among those who were non-high-risk, the mean age was 73.3 years, 464 (38.2%) were women, and the mean logistic EuroSCORE was 7%, whereas in those who were high-risk, the mean age was 77.6 years, 134 (52.8%) were women, and the mean logistic EuroSCORE was 37%. All-cause mortality was 33.2% for non-high-risk and 66.7% for high-risk patients at 5 years. Over this time period, non-high-risk patients experienced an average of 3.9 inpatient hospitalizations and total costs of $106,277 per patient versus 4.7 hospitalizations and total costs of $144,183 for high-risk patients.
Among elderly patients undergoing AVR, long-term mortality and costs are substantially greater for high-risk than for non-high-risk individuals. These findings indicate that further research is needed to understand whether newer approaches to aortic valve replacement such as transcatheter AVR may be a lower cost, clinically valuable alternative.
PMCID: PMC3496980  PMID: 23152716
aortic valve; replacement; health economics
3.  Segment-specific association between plasma homocysteine and carotid artery intima-media thickness in the Framingham Heart Study 
Higher plasma total homocysteine (tHcy) is an established risk factor for cardiovascular disease. The relation between tHcy and carotid artery intima-media thickness (IMT) at the internal carotid artery (ICA)/bulb-IMT and common carotid artery (CCA)-IMT has not been systematically examined. Since the ICA/bulb segment is more prone to plaque formation than the CCA segment, differential associations with tHcy at these sites might suggest mechanisms of tHcy action.
We examined the cross-sectional segment-specific relations of tHcy to ICA/bulb-IMT and CCA-IMT in 2,499 participants from the Framingham Offspring Study, free of cardiovascular disease.
In multivariable linear regression analysis, ICA/bulb-IMT was significantly higher in the fourth tHcy quartile category compared to the other quartile categories, in both the age- and sex-adjusted and in the multivariable-adjusted model (P for trend <0.0001 and <0.01, respectively). We observed a significant age by tHcy interaction for ICA/bulb-IMT (P=0.03) and therefore stratified the analyses by median age (58 years). There was a significant positive trend between tHcy and ICA/bulb-IMT in individuals 58 years of age or older (P-trend <0.01), but not in the younger individuals (P-trend=0.24). For CCA-IMT, no significant trends were observed in any of the analyses.
The segment-specific association between elevated tHcy levels and ICA/bulb-IMT suggests an association between tHcy and plaque formation.
PMCID: PMC3011043  PMID: 20580253
carotid artery; intima-media thickness; homocysteine; atherosclerosis; Framingham Offspring Study
4.  Relation of QRS Width in Healthy Persons to Risk of Future Permanent Pacemaker Implantation 
The American journal of cardiology  2010;106(5):668-672.
In the setting of acute myocardial infarction, prolongation of the QRS interval on an electrocardiogram identifies patients at risk of needing permanent pacemaker implantation. However, the implications of a prolonged QRS in healthy individuals are unclear, especially since the QRS prolongation encountered in this setting is typically mild. We studied the relation between QRS duration and incident pacemaker implantation in a community-based cohort of 8,311 individuals (mean age 54 years, 55% women) who attended 17,731 routine examinations with resting 12-lead electrocardiography. QRS duration was analyzed as both a continuous and categorical variable (<100 milliseconds [ms]; 100 to <120 ms; ≥120 ms). During up to 35 years of follow up, 157 participants (56 women) developed need for a permanent pacemaker. In multivariable Cox regression models adjusting for cardiovascular risk factors and prior or incident myocardial infarction or heart failure, mild QRS prolongation was associated with a 3-fold risk of pacemaker implantation (adjusted hazards ratio [HR] 2.90; 95% confidence interval [CI] 1.81–4.66; P<0.0001), and bundle-branch block was associated with a 4-fold risk of pacemaker implantation (HR 4.43; 95% CI 2.94–6.68; P<0.0001). Each standard deviation increment in QRS duration (11 ms) was associated with an adjusted hazards ratio of 1.14 (95% CI 1.11–1.18; P<0.0001) for pacemaker placement. This association remained significant after excluding individuals with QRS ≥120 ms. In conclusion, individuals with a prolonged QRS duration, even without bundle-branch block, are at increased risk for future pacemaker implantation. Such individuals may warrant monitoring for progressive conduction disease.
PMCID: PMC3012354  PMID: 20723643
epidemiology; risk factors; pacemaker; conduction disease
5.  Visceral and Subcutaneous Adiposity and Brachial Artery Vasodilator Function 
Obesity (Silver Spring, Md.)  2009;17(11):2054-2059.
Endothelial dysfunction may link obesity to cardiovascular disease (CVD). We tested the hypothesis that visceral abdominal tissue (VAT) as compared with subcutaneous abdominal tissue (SAT) is more related to endothelium-dependent vasodilation. Among Framingham Offspring and Third Generation cohorts (n=3020, mean age 50 years, 47% women) We used multivariable linear regression adjusted for CVD and its risk factors to relate computed tomography-assessed VAT and SAT, body mass index (BMI) and waist circumference (WC), with brachial artery measures. In multivariable-adjusted models, BMI, WC, VAT and SAT were positively related to baseline artery diameter and baseline mean flow velocity (all p<0.001), but not hyperemic mean flow velocity. In multivariable-adjusted models, BMI (p=0.002), WC (p=0.001) and VAT (p=0.01), but not SAT (p=0.24) were inversely associated with FMD%. However there was little incremental increase in the proportion of variability explained by VAT (R2=0.266) as compared to SAT (R2=0.265), above and beyond traditional risk factors. VAT, but not SAT was associated with FMD% after adjusting for clinical covariates. Nevertheless, the differential association with VAT as compared to SAT was minimal.
PMCID: PMC3086764  PMID: 19282819
Adiposity; obesity; endothelial dysfunction; visceral fat; subcutaneous fat; flow-mediated dilation; epidemiology; computed tomography
6.  Adiposity, Cardiometabolic Risk, and Vitamin D Status: The Framingham Heart Study 
Diabetes  2009;59(1):242-248.
Because vitamin D deficiency is associated with a variety of chronic diseases, understanding the characteristics that promote vitamin D deficiency in otherwise healthy adults could have important clinical implications. Few studies relating vitamin D deficiency to obesity have included direct measures of adiposity. Furthermore, the degree to which vitamin D is associated with metabolic traits after adjusting for adiposity measures is unclear.
We investigated the relations of serum 25-hydroxyvitamin D (25[OH]D) concentrations with indexes of cardiometabolic risk in 3,890 nondiabetic individuals; 1,882 had subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes measured by multidetector computed tomography (CT).
In multivariable-adjusted regression models, 25(OH)D was inversely associated with winter season, waist circumference, and serum insulin (P < 0.005 for all). In models further adjusted for CT measures, 25(OH)D was inversely related to SAT (−1.1 ng/ml per SD increment in SAT, P = 0.016) and VAT (−2.3 ng/ml per SD, P < 0.0001). The association of 25(OH)D with insulin resistance measures became nonsignificant after adjustment for VAT. Higher adiposity volumes were correlated with lower 25(OH)D across different categories of BMI, including in lean individuals (BMI <25 kg/m2). The prevalence of vitamin D deficiency (25[OH]D <20 ng/ml) was threefold higher in those with high SAT and high VAT than in those with low SAT and low VAT (P < 0.0001).
Vitamin D status is strongly associated with variation in subcutaneous and especially visceral adiposity. The mechanisms by which adiposity promotes vitamin D deficiency warrant further study.
PMCID: PMC2797928  PMID: 19833894
7.  Brachial Artery Diameter, Blood Flow and Flow-mediated Dilation in Sleep-Disordered Breathing 
Clinic-based case-control studies linked sleep-disordered breathing (SDB) to markers of endothelial dysfunction. We attempted to validate this association in a large community-based sample, and evaluate the relation of SDB to arterial diameter and peripheral blood flow. This community-based cross-sectional observational study included 327 men and 355 women, age 42 to 83 years, from the Framingham Heart Study site of the Sleep Heart Health Study. Polysomnographically derived apnea-hypopnea index and hypoxemia index (percent sleep time with oxyhemoglobin saturation below 90%) were used to quantify the severity of SDB. Brachial artery ultrasound measurements included baseline diameter, percent flow-mediated dilation, and baseline and hyperemic flow velocity and volume. Baseline brachial artery diameter was significantly associated with both apnea-hypopnea index and hypoxemia index. The association was diminished by adjustment for body mass index, but remained significant for apnea-hypopnea index. Age-, sex-, race-and body mass index-adjusted mean diameters were 4.32, 4.33, 4.33, 4.56, 4.53 mm, respectively, for those with apnea-hypopnea index <1.5, 1.5–4.9, 5–14.9, 15–29.9, ≥30; p=0.03. Baseline flow measures were associated with apnea-hypopnea index but this association was non-significant after adjusting for body mass index. No significant association was observed between measures of SDB and percent flow-mediated dilation or hyperemic flow in any model. In conclusion, this study supports a moderate association of SDB and larger baseline brachial artery diameter, which may reflect SDB-induced vascular remodeling. This study does not support a link between SDB and endothelial dysfunction as measured by brachial artery flow-mediated dilation.
PMCID: PMC2956304  PMID: 19808720
Sleep Apnea; Obstructive; Endothelium; Vascular; Remodeling; Vascular; Epidemiology
8.  Cross-sectional Relations of Multiple Inflammatory Biomarkers to Peripheral Arterial Disease: The Framingham Offspring Study 
Atherosclerosis  2008;203(2):509-514.
Emerging evidence suggests that different inflammatory biomarkers operate through distinct biologic mechanisms. We hypothesized that the relation to peripheral arterial disease (PAD) varies for individual markers.
In a community-based sample we measured 12 biomarkers including plasma CD40 ligand, fibrinogen, lipoprotein-associated phospholipase-A2 mass and activity, osteoprotegerin, P-selectin, and tumor necrosis factor receptor 2 (TNFR2); and serum C-reactive protein, intracellular adhesion molecule-1, interleukin-6, monocyte chemoattractant protein-1, and myeloperoxidase in Framingham Offspring Study participants (n=2800, 53% women, mean age 61 years). We examined the cross-sectional relation of the biomarker panel to PAD using 1) a global test of significance to determine whether at least one of 12 biomarkers was related to PAD using the TEST statement in the LOGISTIC procedure in SAS and 2) stepwise multivariable logistic regression with forward selection of markers with separate models for 1) ankle-brachial index (ABI) category (<0.9, 0.9 to 1.0, >1.0) and 2) presence of clinical PAD (intermittent claudication or lower extremity revascularization).
The group of inflammatory biomarkers were significantly related to both ABI and clinical PAD (p= 0.01 and p= 0.02, respectively, multi-marker adjusted global significance test). Multivariable forward elimination regression retained interleukin-6 and TNFR2 as significantly associated with PAD. For one standard deviation change in interleukin-6 and TNFR2 concentrations, there was a 1.21 (p=0.005) and 1.19 (p=0.009) increased odds of a change in ABI level respectively. Similar results were observed for clinical PAD.
Interleukin-6 and TNFR2 were significantly associated with PAD independent of established risk factors and each other, suggesting that each marker represents a distinct biologic pathway.
PMCID: PMC2690511  PMID: 18701106
peripheral arterial disease; ankle-brachial index; interleukin-6; tumor necrosis factor receptor 2
9.  Relation of Corneal Arcus to Cardiovascular Disease (From the Framingham Heart Study Data Set) 
Corneal arcus is a lipid-rich deposit at the corneoscleral limbus that shares some similarities with the lipid deposition of atherosclerosis. Epidemiologic studies examining the association between corneal arcus and coronary heart disease (CHD) have yielded mixed results. This study was conducted to determine if corneal arcus is an independent risk factor for cardiovascular disease (CVD) and coronary heart disease (CHD). We performed a prospective analysis using Cox-proportional hazards regression models in the Framingham Heart Study Original Cohort and Offspring database. This cohort included 23,376 person-exams, 3,890 (17%) of whom were identified as having corneal arcus during their physical exam. Corneal arcus was a predictor of both CVD and CHD at 4 years [hazard ratio (HR) = 2.28 and 1.99, respectively] and 8 years of follow-up (HR = 2.52 and 2.35, p<0.0001 for all). Corneal arcus was no longer predictive of either CVD or CHD, however, after adjustment for age and sex at 4 years [hazard ratio (HR) = 1.07 and 1.01, respectively] and 8 years of follow-up (HR = 1.18 and 1.17, p>0.05 for all). In conclusion, corneal arcus predicts CVD and CHD in the community-based Framingham Heart Study cohort due to the strong association of corneal arcus with increasing age. To date, this is the largest and lengthiest population-based cohort study examining the direct association between corneal arcus and CVD and CHD.
PMCID: PMC2636700  PMID: 19101231
Corneal arcus; atherosclerosis; coronary heart disease; hypercholesterolemia
10.  Relations of Measures of Endothelial Function and Kidney Disease: The Framingham Heart Study 
Endothelial dysfunction is prevalent among individuals with end-stage renal disease. Whether endothelial dysfunction is present in moderate chronic kidney disease (CKD) is uncertain.
Study Design
Cross-sectional study.
Settings and Participants
Brachial reactivity measurements were obtained during the seventh examination cycle in 2818 (diameter measurements) and 2256 (flow measurements) Framingham Heart Study Offspring cohort participants (53% women, mean age 61±9 years).
Estimated glomerular filtration rate [eGFR] <60 mL/min/1.73m2, derived from creatinine- and cystatin-C based estimating equations; microalbuminuria status.
Brachial reactivity measurements (baseline brachial diameter, flow-mediated dilation, baseline and hyperemic mean flow).
Linear regression models were used to model brachial measures as a function of CKD status and microalbuminuria status.
Overall, 7.3% (n=206) of participants had CKD, and of 2301 with urinary measurements, 10.0% (n=230) had microalbuminuria. Brachial reactivity measures did not differ significantly by CKD status in either creatinine- or cystatin-C based equations, in either age- and sex-, or multivariable-adjusted models. In age- and sex-adjusted models, microalbuminuria was associated with decreased hyperemic mean flow (47.2±1.4 versus 51.4±0.5 mg/g, p=0.005), but the association was not significant after multivariable adjustment (p=0.09).
Predominantly white, ambulatory cohort; results may not be generalizable to other ethnic groups or to individuals with severe CKD.
Endothelial dysfunction was not a major correlate of CKD in our sample.
PMCID: PMC2665728  PMID: 18617305
chronic kidney disease; brachial reactivity; cystatin C; Framingham Heart Study
11.  Long-term Outcomes in Individuals with a Prolonged PR Interval or First-Degree Atrioventricular Block 
Prolongation of the electrocardiographic PR interval, known as first-degree atrioventricular block when the PR exceeds 200 milliseconds, is frequently encountered in clinical practice.
To determine the clinical significance of PR prolongation in ambulatory individuals.
Design, Setting, and Participants
Prospective, community-based cohort in Framingham, MA. We studied 7,575 individuals (mean age 46 years, 54% women) who underwent routine 12-lead electrocardiography. The study cohort was followed prospectively from baseline examinations in 1968–1974 through 2007. We used multivariable-adjusted Cox proportional hazards models to examine the relations of PR interval with the incidence of arrhythmic events and death.
Main Outcome Measures
Incident atrial fibrillation (AF), pacemaker implantation, and all-cause mortality.
During follow up, 481 participants developed AF, 124 required pacemaker implantation, and 1,739 died. At the baseline examination, 124 individuals had PR >200 milliseconds. Incidence rates per 10,000 person-years for those with PR >200 milliseconds compared to those with PR ≤200 milliseconds were 140 (95% confidence interval [CI], 95–208) versus 36 (95% CI, 32–39) for AF, 59 (95% CI, 40–87) versus 6 (95% CI, 5–7) for pacemaker implantation, and 333 (95%, CI 260–428) versus 129 (95% CI, 123–135) for death. Corresponding absolute risk increases were 1.04% (AF), 0.53% (pacemaker), and 2.05% (death) per year. In multivariable analyses, each 20-millisecond increment in PR was associated with an adjusted hazards ratio (HR) of 1.12 (95% CI, 1.02–1.22; p=0.018) for AF, 1.22 (95% CI, 1.14–1.30; p<0.001) for pacemaker implantation, and 1.08 (95% CI, 1.02–1.13; p=0.005) for death. Individuals with first-degree atrioventricular block had a two-fold adjusted risk of AF (HR 2.06; 95% CI, 1.36–3.12; p<0.001), three-fold adjusted risk of pacemaker implantation (HR 2.89; 95% CI, 1.83–4.57; p<0.001), and 1.4-fold adjusted risk of death (HR 1.44, 95% C,I 1.09–1.91; p=0.01).
PR prolongation is associated with increased risks of AF, pacemaker implantation, and death.
PMCID: PMC2765917  PMID: 19549974
12.  Cross-sectional relations of digital vascular function to cardiovascular risk factors in The Framingham Heart Study 
Circulation  2008;117(19):2467-2474.
Digital pulse amplitude augmentation in response to hyperemia is a novel measure of peripheral vasodilator function that partially depends on endothelium-derived nitric oxide. Baseline digital pulse amplitude reflects local peripheral arterial tone. The relation of digital pulse amplitude and digital hyperemic response to cardiovascular risk factors in the community is unknown.
Methods and Results
Using a fingertip peripheral arterial tonometry (PAT) device, we measured digital pulse amplitude in Framingham Third Generation Cohort participants (n=1957, mean age 40±9 years, 49% women) at baseline and in 30 second intervals for 4-minutes during reactive hyperemia induced by 5-minute forearm cuff occlusion. To evaluate the vascular response in relation to baseline, adjusting for systemic effects and skewed data, we expressed the hyperemic response (termed PAT ratio) as the natural logarithm of the post-deflation to baseline pulse amplitude ratio in the hyperemic finger divided by the same ratio in the contralateral finger that served as control. The relation of PAT ratio to cardiovascular risk factors was strongest in the 90-120 second post-deflation interval (overall model R2=0.159). In stepwise multivariable linear regression models, male sex, body mass index, total/HDL cholesterol, diabetes, smoking and lipid-lowering treatment were inversely related to PAT ratio; whereas increasing age was positively related to PAT ratio (all P<0.01).
Reactive hyperemia produced a time-dependent increase in fingertip pulse amplitude. Digital vasodilator function is related to multiple traditional and metabolic cardiovascular risk factors. Our findings support further investigations to define the clinical utility and predictive value of digital pulse amplitude.
PMCID: PMC2734141  PMID: 18458169
vascular; epidemiology; risk factors; cohort study
13.  LDL Particle Number and Risk of Future Cardiovascular Disease in the Framingham Offspring Study – Implications for LDL Management 
Journal of clinical lipidology  2007;1(6):583-592.
The cholesterol content of LDL particles is variable, causing frequent discrepancies between concentrations of LDL cholesterol and LDL particle number. In managing patients at risk for cardiovascular disease (CVD) to LDL target levels, it is unclear whether LDL cholesterol provides the optimum measure of residual risk and adequacy of LDL lowering treatment.
To compare the ability of alternative measures of LDL to provide CVD risk discrimination at relatively low levels consistent with current therapeutic targets.
Concentrations of LDL cholesterol (LDL-C) and non-HDL cholesterol (non-HDL-C) were measured chemically and LDL particle number (LDL-P) and VLDL particle number (VLDL-P) were measured by nuclear magnetic resonance (NMR) in 3066 middle-aged white participants (53% women) without CVD in the Framingham Offspring cohort. The main outcome measure was incidence of first CVD event.
At baseline, the cholesterol content per LDL particle was negatively associated with triglycerides and positively associated with LDL-C. On follow-up (median 14.8 yrs), 265 men and 266 women experienced a CVD event. In multivariable models adjusting for non-lipid CVD risk factors, LDL-P was related more strongly to future CVD in both sexes than LDL-C or non-HDL-C. Subjects with a low level of LDL-P (<25th percentile) had a lower CVD event rate (59 events per 1000 person-years) than those with an equivalently low level of LDL-C or non-HDL-C (81 and 74 events per 1000 person-years, respectively).
In a large community-based sample, LDL-P was a more sensitive indicator of low CVD risk than either LDL-C or non-HDL-C, suggesting a potential clinical role for LDL-P as a goal of LDL management.
PMCID: PMC2720529  PMID: 19657464
14.  Metabolic Syndrome, Insulin Resistance and Brachial Artery Vasodilator Function in Framingham Offspring Participants without Clinical Evidence of Cardiovascular Disease 
The metabolic syndrome (MS), a clustering of metabolic disturbances, is associated with increased cardiovascular risk. Limited information is available about the relations between MS, insulin resistance and vascular function. We measured brachial artery flow-mediated dilation (n=2123), and reactive hyperemia (n=1521) in Framingham Offspring participants without diabetes or clinical cardiovascular disease (mean age 59±9 years, 57% women). MS, determined by National Cholesterol Education Program criteria, was present in 36% of participants. Insulin resistance was determined using Homeostatic Model Assessment (HOMA-IR). In age- and sex-adjusted models, MS was associated with lower flow-mediated dilation and reactive hyperemia. There was progressively lower vasodilator function with increasing number of MS components (p for trend <0.0001). In multivariable models adjusting for the 5 MS components as continuous variables, MS (presence vs. absence) remained associated with lower flow-mediated dilation (2.84±0.12% vs. 3.17±0.08%, p=0.0496) and reactive hyperemia (50.8±1.0 cm/sec vs. 54.4±0.7cm/sec, p=0.009). Insulin resistance was inversely associated with flow-mediated dilation and reactive hyperemia in age- and sex-adjusted models, but these relations were no longer significant in models adjusting for the MS components. In conclusion, our observations are consistent with the hypothesis that MS and insulin resistance impair vascular function predominantly through the influence of the component metabolic abnormalities that comprise MS.
PMCID: PMC2214853  PMID: 18157970
Metabolic Syndrome X; endothelium; epidemiology; risk factors
15.  Relation of Season and Temperature to Endothelium-Dependent Flow-Mediated Vasodilation in Subjects Without Clinical Evidence of Cardiovascular Disease (From The Framingham Heart Study) 
The American journal of cardiology  2007;100(3):518-523.
Multiple studies have documented an increased incidence of cardiovascular events in the winter, but the pathophysiological mechanisms remain incompletely understood. We hypothesized that brachial flow and flow-mediated dilation (FMD) would vary by season and temperature. We related season and temperature to ultrasonic brachial artery endothelium-dependent FMD% (n=2587), baseline flow velocity and maximal reactive hyperemia (n=1973) in the Framingham Offspring cohort (mean age 61±10 years; 53% women). We obtained outdoor temperature from National Climate Data Center records for Bedford, Massachusetts (about 14 miles from testing site) and we measured the examination room temperature. In multivariable models, FMD% was highest in summer and lowest in winter (3.01±0.09 vs. 2.56±0.10%, respectively; P=0.02 for differences across all 4 seasons). FMD% was highest in the warmest and lowest in the coldest outdoor temperature quartiles. In stepwise models adjusting for risk factors, and selecting among season, outdoor temperature, and room temperature, FMD% was associated with season (P=0.02); temperature did not enter the model. In contrast, hyperemic flow velocity was significantly lower for cooler, and higher for warmer room temperatures (P=0.02 overall); season did not enter the model. Season, outdoor and room temperature were each retained in a stepwise model of baseline flow velocity (P<0.0001, P=0.02, P<0.0001, respectively). In conclusion, we observed a significant association between season and FMD. Microvascular vasodilator function, as reflected by hyperemic flow, was more strongly related to temperature than season. In conclusion, we speculate that endothelial dysfunction may be 1 of the mechanisms influencing seasonal variation in cardiovascular events.
PMCID: PMC1994775  PMID: 17659939
endothelium; epidemiology; temperature; season
16.  Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study 
BMC Medical Genetics  2007;8(Suppl 1):S2.
Echocardiographic left ventricular (LV) measurements, exercise responses to standardized treadmill test (ETT) and brachial artery (BA) vascular function are heritable traits that are associated with cardiovascular disease risk. We conducted a genome-wide association study (GWAS) in the community-based Framingham Heart Study.
We estimated multivariable-adjusted residuals for quantitative echocardiography, ETT and BA function traits. Echocardiography residuals were averaged across 4 examinations and included LV mass, diastolic and systolic dimensions, wall thickness, fractional shortening, left atrial and aortic root size. ETT measures (single exam) included systolic blood pressure and heart rate responses during exercise stage 2, and at 3 minutes post-exercise. BA measures (single exam) included vessel diameter, flow-mediated dilation (FMD), and baseline and hyperemic flow responses. Generalized estimating equations (GEE), family-based association tests (FBAT) and variance-components linkage were used to relate multivariable-adjusted trait residuals to 70,987 SNPs (Human 100K GeneChip, Affymetrix) restricted to autosomal SNPs with minor allele frequency ≥0.10, genotype call rate ≥0.80, and Hardy-Weinberg equilibrium p ≥ 0.001.
We summarize results from 17 traits in up to 1238 related middle-aged to elderly men and women. Results of all association and linkage analyses are web-posted at . We confirmed modest-to-strong heritabilities (estimates 0.30–0.52) for several Echo, ETT and BA function traits. Overall, p < 10-5 in either GEE or FBAT models were observed for 21 SNPs (nine for echocardiography, eleven for ETT and one for BA function). The top SNPs associated were (GEE results): LV diastolic dimension, rs1379659 (SLIT2, p = 1.17*10-7); LV systolic dimension, rs10504543 (KCNB2, p = 5.18*10-6); LV mass, rs10498091 (p = 5.68*10-6); Left atrial size, rs1935881 (FAM5C, p = 6.56*10-6); exercise heart rate, rs6847149 (NOLA1, p = 2.74*10-6); exercise systolic blood pressure, rs2553268 (WRN, p = 6.3*10-6); BA baseline flow, rs3814219 (OBFC1, 9.48*10-7), and FMD, rs4148686 (CFTR, p = 1.13*10-5). Several SNPs are reasonable biological candidates, with some being related to multiple traits suggesting pleiotropy. The peak LOD score was for LV mass (4.38; chromosome 5); the 1.5 LOD support interval included NRG2.
In hypothesis-generating GWAS of echocardiography, ETT and BA vascular function in a moderate-sized community-based sample, we identified several SNPs that are candidates for replication attempts and we provide a web-based GWAS resource for the research community.
PMCID: PMC1995617  PMID: 17903301
17.  Genome-wide association with select biomarker traits in the Framingham Heart Study 
BMC Medical Genetics  2007;8(Suppl 1):S11.
Systemic biomarkers provide insights into disease pathogenesis, diagnosis, and risk stratification. Many systemic biomarker concentrations are heritable phenotypes. Genome-wide association studies (GWAS) provide mechanisms to investigate the genetic contributions to biomarker variability unconstrained by current knowledge of physiological relations.
We examined the association of Affymetrix 100K GeneChip single nucleotide polymorphisms (SNPs) to 22 systemic biomarker concentrations in 4 biological domains: inflammation/oxidative stress; natriuretic peptides; liver function; and vitamins. Related members of the Framingham Offspring cohort (n = 1012; mean age 59 ± 10 years, 51% women) had both phenotype and genotype data (minimum-maximum per phenotype n = 507–1008). We used Generalized Estimating Equations (GEE), Family Based Association Tests (FBAT) and variance components linkage to relate SNPs to multivariable-adjusted biomarker residuals. Autosomal SNPs (n = 70,987) meeting the following criteria were studied: minor allele frequency ≥ 10%, call rate ≥ 80% and Hardy-Weinberg equilibrium p ≥ 0.001.
With GEE, 58 SNPs had p < 10-6: the top SNPs were rs2494250 (p = 1.00*10-14) and rs4128725 (p = 3.68*10-12) for monocyte chemoattractant protein-1 (MCP1), and rs2794520 (p = 2.83*10-8) and rs2808629 (p = 3.19*10-8) for C-reactive protein (CRP) averaged from 3 examinations (over about 20 years). With FBAT, 11 SNPs had p < 10-6: the top SNPs were the same for MCP1 (rs4128725, p = 3.28*10-8, and rs2494250, p = 3.55*10-8), and also included B-type natriuretic peptide (rs437021, p = 1.01*10-6) and Vitamin K percent undercarboxylated osteocalcin (rs2052028, p = 1.07*10-6). The peak LOD (logarithm of the odds) scores were for MCP1 (4.38, chromosome 1) and CRP (3.28, chromosome 1; previously described) concentrations; of note the 1.5 support interval included the MCP1 and CRP SNPs reported above (GEE model). Previous candidate SNP associations with circulating CRP concentrations were replicated at p < 0.05; the SNPs rs2794520 and rs2808629 are in linkage disequilibrium with previously reported SNPs. GEE, FBAT and linkage results are posted at .
The Framingham GWAS represents a resource to describe potentially novel genetic influences on systemic biomarker variability. The newly described associations will need to be replicated in other studies.
PMCID: PMC1995615  PMID: 17903293

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