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1.  A Genome-Wide Association Study of the Human Metabolome in a Community-Based Cohort 
Cell metabolism  2013;18(1):130-143.
SUMMARY
Because metabolites are hypothesized to play key roles as markers and effectors of cardio-metabolic diseases, recent studies have sought to annotate the genetic determinants of circulating metabolite levels. We report a genome-wide association study (GWAS) of 217 plasma metabolites, including >100 not measured in prior GWAS, in 2,076 participants of the Framingham Heart Study. For the majority of analytes, we find that estimated heritability explains >20% of inter-individual variation, and that variation attributable to heritable factors is greater than that attributable to clinical factors. Further, we identify 31 genetic loci associated with plasma metabolites, including 23 that have not previously been reported. Importantly, we include GWAS results for all surveyed metabolites, and demonstrate how this information highlights a role for AGXT2 in cholesterol ester and triacylglycerol metabolism. Thus, our study outlines the relative contributions of inherited and clinical factors on the plasma metabolome and provides a resource for metabolism research.
doi:10.1016/j.cmet.2013.06.013
PMCID: PMC3973158  PMID: 23823483
2.  Aldosterone and the Risk of Hypertension 
Current hypertension reports  2013;15(2):102-107.
Aldosterone, the key hormone in the mineralocorticoid pathway, plays a fundamental role in salt and water homeostasis, blood pressure regulation, and cardiovascular remodeling. Both genomic and non-genomic mechanisms influence aldosterone-induced renal sodium reabsorption. Furthermore, the mineralocorticoid receptor in non-epithelial tissues, including the heart and vascular smooth muscle cells, have recently been discovered. Thus, aldosterone likely has pleiotropic effects that contribute to the modulation of blood pressure. Among patients with hypertension in general, and among those with more severe or resistant hypertension in particular, a higher than expected prevalence of primary hyperaldosteronism is noted. Among individuals with resistant hypertension, aldosterone antagonists have also been shown to be effective in lowering blood pressure. Most significantly, recent community-based studies among non-hypertensive individuals in the general population have demonstrated that both a higher serum aldosterone concentrations and a higher aldosterone to renin ratio portend a greater risk of developing hypertension. The combination of the aforementioned observations underscores the importance of the mineralocorticoid pathway in the pathogenesis of hypertension.
doi:10.1007/s11906-013-0330-y
PMCID: PMC3619380  PMID: 23378101
Aldosterone; Mineralocorticoid receptor; Aldosterone/renin ratio; ARR; Primary hyperaldosteronism; Natriuretic peptides; Salt sensitivity; Blood pressure; Hypertension; Cardiovascular disease; Risk
3.  Biomarkers Of Cardiovascular Stress And Incident Chronic Kidney Disease 
Clinical chemistry  2013;59(11):1613-1620.
BACKGROUND
Growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity troponin I (hsTnI) are emerging predictors of adverse clinical outcomes. We sought to examine whether circulating concentrations are related to the development of kidney disease in the community.
METHODS
Plasma GDF-15, sST2, and hsTnI concentrations were measured in 2,614 Framingham Offspring cohort participants (mean age 57 years, 54% women) at the sixth examination cycle (1995–1998). Associations of biomarkers with incident chronic kidney disease (CKD, eGFR<60 ml/min/1.73m2, n=276), microalbuminuria (urinary albumin to creatinine ratio ≥ 25 mg/g in women and 17 mg/g in men, n=191), and rapid decline in renal function (decline in eGFR ≥ 3 ml/min/1.73m2 per year, n=237), were evaluated using multivariable logistic regression; P<0.006 was considered statistically significant in primary analyses.
RESULTS
Participants were followed over a mean of 9.5 years. Higher plasma GDF-15 was associated with incident CKD (multivariable-adjusted OR 1.9 per 1-unit increase in log-GDF-15, 95% CI 1.6–2.3, P<0.0001) and rapid decline in renal function (OR 1.6, 95% CI 1.3–1.8, P<0.0001). GDF-15, sST2, and hsTnI had suggestive associations with incident microalbuminuria but did not meet the pre-specified P-value threshold after multivariable adjustment. Adding plasma GDF-15 to clinical covariates improved risk prediction of incident CKD: the c-statistic increased from 0.826 to 0.845 (P=0.0007), and categorical net reclassification was 6.3% (95% CI 2.7–9.9%).
CONCLUSION
Higher circulating GDF-15 is associated with incident renal outcomes, and improves risk prediction of incident CKD. These findings may provide insights into mechanisms of renal injury.
doi:10.1373/clinchem.2013.205716
PMCID: PMC3972213  PMID: 23873716
Kidney; Risk Factors; Epidemiology
4.  Predictors of New-Onset Heart Failure: Differences in Preserved Versus Reduced Ejection Fraction 
Circulation. Heart failure  2012;6(2):279-286.
Background
About one half of patients with HF have preserved rather than reduced ejection fraction (HFPEF; HFREF). The differences in risk factors predisposing to the two subtypes of HF are poorly understood. We sought to identify clinical predictors of new-onset HF, and to explore differences in HFPEF versus HFREF.
Methods and Results
We studied new-onset HF cases between 1981 and 2008 in Framingham Heart Study participants, classified into HFPEF and HFREF (EF > 45% vs ≤ 45%). We used Cox multivariable regression to examine predictors of 8-year risk of incident HF, and competing-risks analysis to identify predictors that differed between HFPEF and HFREF. Among 6,340 participants (60 ± 12 years) with 97,808 person-years of follow up, 512 developed incident HF. Of 457 participants with LVEF evaluation at the time of HF diagnosis, 196 (43%) were classified as HFPEF and 261 (56%) as HFREF. Fourteen predictors of overall HF were identified. Older age, diabetes mellitus, and a history of valvular disease predicted both types of HF (p ≤ 0.0025 for all). Higher BMI, smoking, and atrial fibrillation predicted HFPEF only, whereas male sex, higher total cholesterol, higher heart rate, hypertension, cardiovascular disease, left ventricular hypertrophy, and left bundle branch block predicted risk of HFREF.
Conclusions
While multiple risk factors preceded overall HF, distinct clusters of risk factors determine risk for new-onset HFPEF versus HFREF. This knowledge may enable the design of clinical trials of targeted prevention and the introduction of therapeutic strategies for prevention of HF and its two major subtypes.
doi:10.1161/CIRCHEARTFAILURE.112.972828
PMCID: PMC3705220  PMID: 23271790
heart failure; epidemiology; risk factors; ejection fraction
5.  Genome-Wide Association Study of Cardiac Structure and Systolic Function in African Americans: The Candidate Gene Association Resource (CARe) Study 
Background
Using data from four community-based cohorts of African Americans (AA), we tested the association between genome-wide markers (SNPs) and cardiac phenotypes in the Candidate-gene Association REsource (CARe) study.
Methods and Results
Among 6,765 AA, we related age, sex, height and weight-adjusted residuals for nine cardiac phenotypes (assessed by echocardiogram or MRI) to 2.5 million SNPs genotyped using Genome-Wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within cohort genome-wide association analysis was conducted followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10−07). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested look-ups in one consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (p=1.43 × 10−07) for left ventricular mass (LVM); rs7213314 in WIPI1 (p=1.68 × 10−07) for LV internal diastolic diameter (LVIDD); rs1571099 in PPAPDC1A (p= 2.57 × 10−08) for interventricular septal wall thickness (IVST); and rs9530176 in KLF5 (p=4.02 × 10−07) for ejection fraction (EF). Associated variants were enriched in three signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry were confirmed in look-ups in EchoGEN.
Conclusions
In the largest GWAS of cardiac structure and function to date in AA, we identified 4 genetic loci related to LVM, IVST, LVIDD and EF that reached genome-wide significance. Replication results suggest that these loci may represent unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.
doi:10.1161/CIRCGENETICS.111.962365
PMCID: PMC3591479  PMID: 23275298
echocardiography; ethnic; genome-wide association studies; Left atrium genetics; left ventricular mass genetics
6.  Aortic Root Remodeling and Risk of Heart Failure in the Framingham Heart Study 
JACC. Heart failure  2012;1(1):79-83.
Objectives
The aim of this study was to investigate the association between aortic root remodeling and incident heart failure (HF).
Background
Age-associated increases in aortic root diameter (AoD) might be associated with arterial stiffening, afterload changes, cardiac remodeling, and the development of HF.
Methods
The study sample consisted of participants of the Framingham Heart Study Original and Offspring cohorts who underwent serial echocardiographic measurements of AoD and continuous surveillance for new-onset HF. The AoD was measured at baseline, and the change in AoD between 8-year examination cycles was calculated. Pooled repeated observations (total 13,605 person-observations) in multivariable Cox regression analyses were used to relate baseline AoD and change in AoD to the incidence of HF on follow-up. Models were adjusted for known HF risk factors (age, sex, body mass index, blood pressure, hypertension treatment, diabetes, smoking, prior myocardial infarction, and valve disease).
Results
With adjustment for clinical risk factors, the risk of incident HF increased with greater AoD at baseline (hazard ratio: 1.19/1 SD; 95% confidence interval: 1.07 to 1.33) as well as increases in AoD over 8 years (hazard ratio: 1.20/1 SD; 95% confidence interval: 1.04 to 1.38). The AoD correlated with left ventricular mass (r = 0.50; p < 0.001). After adjustment for left ventricular mass in addition to clinical risk factors, the association of AoD with incident HF was rendered nonsignificant.
Conclusions
Aortic root remodeling is associated with future risk of HF among middle-aged and older adults in the community, potentially because it reflects parallel ventricular-vascular remodeling in those with an enlarged aortic root. Additional studies are warranted to confirm our findings.
doi:10.1016/j.jchf.2012.10.003
PMCID: PMC3755769  PMID: 23998002
aortic root; general community; heart failure; remodeling; risk
7.  Relation of Circulating Liver Transaminase Concentrations to Risk of New-onset Atrial Fibrillation 
The American journal of cardiology  2012;111(2):219-224.
Heart failure, a strong risk factor for atrial fibrillation (AF), often is accompanied by elevated liver transaminases. We hypothesized that elevated transaminases are associated with the risk of incident AF in the community. We studied 3,744 participants (mean age 65 ± 10 years, 56.8% women) of the Framingham Heart Study Original and Offspring cohorts, free of clinical heart failure. We examined Cox proportional hazards models adjusted for standard AF risk factors (age, sex, body mass index, systolic blood pressure, electrocardiographic PR interval, anti-hypertensive treatment, smoking, diabetes, valvular heart disease, alcohol consumption) to investigate associations between baseline serum transaminase levels [alanine transaminase (ALT), aspartate transaminase (AST)] and incidence of AF in up to 10 years (29,099 person years) follow-up. During follow-up, 383 individuals developed AF. Both transaminases were significantly associated with greater risk of incident AF (hazard ratio expressed per standard deviation of natural logarithmically transformed biomarker: ALT hazard ratio 1.19, 95% confidence interval 1.07 to1.32, p = 0.002; AST hazard ratio 1.12, 95% confidence interval 1.01 to1.24, p = 0.03). The associations between transaminases and AF remained consistent after exclusion of participants with moderate-to-severe alcohol consumption. However, when added to known risk factors for AF, ALT and AST only subtly improved the prediction of AF. In conclusion, elevated transaminase concentrations are associated with increased AF incidence. The mechanisms by which higher mean transaminase concentrations are associated with incident AF remain to be determined.
doi:10.1016/j.amjcard.2012.09.021
PMCID: PMC3538882  PMID: 23127690
atrial fibrillation; biomarker; risk factors; liver function tests
8.  Association of Plasma B-type Natriuretic Peptide Concentrations with Longitudinal Blood Pressure Tracking in African Americans: Findings from the Jackson Heart Study 
Hypertension  2012;61(1):48-54.
Water and sodium retention precedes the development of high blood pressure (BP) and explains a compensatory rise in B-type natriuretic peptide (BNP) concentrations. It is unclear if BNP concentrations antedate the BP progression. We hypothesized higher BNP concentrations in our African American cohort will be associated with longitudinal increases in BP, progression of BP stage and incident hypertension.
Our study sample consisted of 888 normotensive [based on BP at Examination 1(2000-04)] participants of the Jackson Heart Study (mean age 47±12 years, 61% women). We examined the relation of BNP concentrations at the baseline examination to change in systolic and diastolic BP, BP progression (an increase by one BP stage as defined by JNC VI) and incident hypertension by Examination 2 (2005-08) adjusting for baseline BP stages, systolic and diastolic BP, traditional risk factors and echocardiographic LV mass.
Over a median follow-up period of 5.0± 0.8 years, 36.9% progressed to a higher BP stage and 19.3% developed hypertension. In multivariable regression models, higher log-BNP concentrations at Examination 1 were significantly and positively associated with changes in systolic and diastolic BP (p <0.05 for both). Baseline log-BNP was significantly associated with BP progression (p = 0.046). Every SD increase in baseline log BNP was associated with a 12% increased risk of BP progression. Log-BNP was not significantly associated with incident hypertension (p=0.12).
In our community-based sample of African Americans, higher BNP concentrations predict longitudinal increase in systolic and diastolic BP and progression of BP stage.
doi:10.1161/HYPERTENSIONAHA.112.197657
PMCID: PMC3521855  PMID: 23184379
Blood Pressure; B-type Natriuretic Peptide; African Americans
10.  Low Serum Magnesium and the Development of Atrial Fibrillation in the Community: The Framingham Heart Study 
Circulation  2012;127(1):33-38.
Background
Low serum magnesium has been linked to increased risk of atrial fibrillation (AF) following cardiac surgery. It is unknown whether hypomagnesemia predisposes to AF in the community.
Methods and Results
We studied 3,530 participants (mean age, 44 years; 52% women) from the Framingham Offspring Study who attended a routine examination, and were free of AF and cardiovascular disease. We used Cox proportional hazard regression analysis to examine the association between serum magnesium at baseline and risk of incident AF. Analyses were adjusted for conventional AF risk factors, use of antihypertensive medications, and serum potassium. During up to 20 years of follow-up, 228 participants developed AF. Mean serum magnesium was 1.88 mg/dl. The age- and sex-adjusted incidence rate of AF was 9.4 per 1,000 person-years (95% confidence interval, 6.7 to 11.9) in the lowest quartile of serum magnesium (≤1.77 mg/dl), compared with 6.3 per 1,000 person-years (95% confidence interval, 4.1 to 8.4) in the highest quartile (≥1.99 mg/dl). In multivariable-adjusted models, individuals in the lowest quartile of serum magnesium were approximately 50% more likely to develop AF (adjusted hazard ratio, 1.52, 1.00 to 2.31; P=0.05), compared with those in the upper quartiles. Results were similar after excluding individuals on diuretics.
Conclusion
Low serum magnesium is moderately associated with the development of AF in individuals without cardiovascular disease. Because hypomagnesemia is common in the general population, a link with AF may have potential clinical implications. Further studies are warranted to confirm our findings and elucidate the underlying mechanisms.
doi:10.1161/CIRCULATIONAHA.111.082511
PMCID: PMC3541701  PMID: 23172839
arrhythmia; epidemiology; atrial fibrillation; magnesium
11.  Aminotransferase Levels are Associated with Cardiometabolic Risk above and beyond Visceral Fat and Insulin Resistance: The Framingham Heart Study 
Objective
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.
Conclusions
Aminotransferase levels are correlated with multiple cardiometabolic risk factors above and beyond VAT and insulin resistance.
doi:10.1161/ATVBAHA.112.300075
PMCID: PMC3593729  PMID: 23162012
liver function tests; obesity; visceral fat; insulin resistance; cardiometabolic risk factors
12.  Thoracic Periaortic and Visceral Adipose Tissue and Their Cross-sectional Associations with Measures of Vascular Function 
Obesity (Silver Spring, Md.)  2013;21(7):1496-1503.
Objective
Perivascular fat may have a local adverse effect on the vasculature. We evaluated whether thoracic periaortic adipose tissue (TAT), a type of perivascular fat, and visceral adipose tissue (VAT) are associated with vascular function.
Design and Methods
TAT and VAT were quantified in Framingham Heart Study participants using multidetector computed tomography; vascular function was assessed using brachial artery vasodilator function, peripheral arterial tone and arterial tonometry (n= 2735, 48% women, mean age 50 years, mean BMI 27.7 kg/m2). Using multiple linear regression, we examined relations between TAT, VAT, and vascular measures while adjusting for cardiovascular risk factors.
Results
Mean TAT and VAT volumes were 13.2 and 1763 cm3. TAT and VAT were associated with multiple vascular function measures after multivariable adjustment. After BMI adjustment, TAT and VAT remained negatively associated with peripheral arterial tone and inverse carotid femoral pulse wave velocity (p<0.02); TAT was negatively associated with hyperemic mean flow velocity (p=0.03). Associations of TAT with vascular function were attenuated after VAT adjustment (all p>0.06).
Conclusion
Thoracic periaortic and visceral fat are associated with microvascular function and large artery stiffness after BMI adjustment. These findings support the growing recognition of associations between ectopic fat and vascular function.
doi:10.1002/oby.20166
PMCID: PMC3742564  PMID: 23754461
obesity; vascular function; arterial stiffness; perivascular adipose tissue; visceral adipose tissue
13.  Clinical correlates of sex steroids and gonadotropins in men over the late adulthood : the Framingham Heart Study 
Background
Low serum concentrations of sex steroids and gonadotropins in men have been associated with increased cardiometabolic risk and mortality, but the clinical correlates of these hormones in men over the late adulthood are less clearly understood.
Methods
We analyzed up to five serial measurements of total testosterone (TT), dehydroepiandrosterone sulfate (DHEAS), follicle stimulating hormone (FSH), luteinizing hormone (LH), and total estradiol (EST) in older men in the original cohort of the Framingham Heart Study to determine the short- (2-years; 1,165 person-observations in 528 individuals) and long-term (up to 10-years follow-up; 2,520 person-observations in 835 individuals with mean baseline age: 71.2 years) clinical correlates of these sex steroids and gonadotropins using multilevel modelling and Generalized Estimating Equations.
Results
Age, body mass index, and pre-existing type 2 diabetes were inversely related to long-term TT concentrations, whereas higher systolic blood pressure showed a positive association. Furthermore, age and pre-existing cardiovascular disease (CVD) were inversely and HDL cholesterol concentrations positively associated with long-term DHEAS concentrations. Analyses of short-term changes revealed age was inversely related to DHEAS, but positively related to FSH and LH concentrations.
Conclusion
Our community-based study identified modifiable correlates of decreasing TT and DHEAS concentrations in elderly men, suggesting that maintenance of a low CVD risk factor burden may mitigate the age-related decline of these hormones over the late adulthood.
doi:10.1111/j.1365-2605.2012.01285.x
PMCID: PMC3434249  PMID: 22640232
sex steroids; gonadotropins; testosterone; aging male; Framingham Heart Study
14.  Blood Pressure Tracking Over the Adult Life Course: Patterns and Correlates in the Framingham Heart Study 
Hypertension  2012;60(6):1393-1399.
The extent to which select vascular risk factors differentially influence blood pressure (BP) is incompletely understood. Thus, we used multilevel modeling to analyze serial BP measurements using 21,732 person-observations obtained on Framingham Heart Study participants (mean age 38 years, 52% women; 4,993 unique individuals) over a 28-year period. We related longitudinal tracking of each BP measure (systolic BP [SBP], diastolic BP [DBP], mean arterial pressure [MAP], and pulse pressure [PP]) to age, sex, body mass index (BMI), smoking, diabetes, total/high-density lipoprotein (HDL) cholesterol ratio, and heart rate. In multivariable-adjusted analyses, we observed that older age, male sex, greater BMI, and higher heart rate were positively associated with increase in all BP measures (p<0.0001). Notably, higher total/HDL cholesterol ratio was associated with greater MAP (p<0.01). Conversely, diabetes and smoking were associated with higher PP (p<0.01). We also observed effect modification by sex: the increase in PP with age and BMI was more pronounced in women compared to men (p<0.0001). All BP measures tracked at higher levels in both men and women with multiple vascular risk factors. Taken together, our longitudinal observations of a large community-based sample demonstrate a greater pulsatile load in women than men with increasing age. We also observed a differential impact of select vascular risk factors on the individual components of BP, underscoring distinct regulation of these measures over the life course.
doi:10.1161/HYPERTENSIONAHA.112.201780
PMCID: PMC3499677  PMID: 23108660
aging; blood pressure; epidemiology; hypertension; risk factors
15.  Association of Novel Biomarkers of Cardiovascular Stress With Left Ventricular Hypertrophy and Dysfunction: Implications for Screening 
Background
Currently available screening tools for left ventricular (LV) hypertrophy (LVH) and systolic dysfunction (LVSD) are either expensive (echocardiography) or perform suboptimally (B‐type natriuretic peptide [BNP]). It is unknown whether newer biomarkers are associated with LVH and LVSD and can serve as screening tools.
Methods and Results
We studied 2460 Framingham Study participants (mean age 58 years, 57% women) with measurements of biomarkers mirroring cardiac biomechanical stress (soluble ST‐2 [ST2], growth differentiation factor‐15 [GDF‐15] and high‐sensitivity troponin I [hsTnI]) and BNP. We defined LVH as LV mass/height2 ≥the sex‐specific 80th percentile and LVSD as mild/greater impairment of LV ejection fraction (LVEF) or a fractional shortening <0.29. Adjusting for standard risk factors in logistic models, BNP, GDF‐15, and hsTnI were associated with the composite echocardiographic outcome (LVH or LVSD), odds ratios (OR) per SD increment in log‐biomarker 1.29, 1.14, and 1.18 (95% CI: 1.15 to 1.44, 1.004 to 1.28, and 1.06 to 1.31), respectively. The C‐statistic for the composite outcome increased from 0.765 with risk factors to 0.770 adding BNP, to 0.774 adding novel biomarkers. The continuous Net Reclassification Improvement was 0.212 (95% CI: 0.119 to 0.305, P<0.0001) after adding the novel biomarkers to risk factors plus BNP. BNP was associated with LVH and LVSD in multivariable models, whereas GDF‐15 was associated with LVSD (OR 1.41, 95% CI: 1.16 to 1.70), and hsTnI with LVH (OR 1.22, 95% CI: 1.09 to 1.36). ST2 was not significantly associated with any outcome.
Conclusions
Our community‐based investigation suggests that cardiac stress biomarkers are associated with LVH and LVSD but may have limited clinical utility as screening tools.
doi:10.1161/JAHA.113.000399
PMCID: PMC3886765  PMID: 24200688
biomarkers; echocardiography; heart failure; hypertrophy; screening
16.  Asymmetric Dimethylarginine Reference Intervals Determined with Liquid Chromatography–Tandem Mass Spectrometry: Results from the Framingham Offspring Cohort 
Clinical chemistry  2009;55(8):1539-1545.
BACKGROUND
Accumulating evidence links higher circulating asymmetric dimethylarginine (ADMA) to greater risk of cardiovascular disease (CVD). Relatively small differences in ADMA concentrations between healthy individuals and those with disease underscore the need to formulate reference intervals that may aid risk stratification of individuals.
METHODS
We formulated reference intervals for plasma ADMA concentrations using a community-based reference sample from the Framingham Offspring Study consisting of 1126 nonsmoking individuals [mean (SD) age 56 (9) years; 60% women] who were free of clinical CVD, hypertension, diabetes, and obesity and who attended a routine examination at which ADMA was assayed. ADMA concentrations were determined using a validated tandem mass spectrometry–liquid chromatography assay.
RESULTS
In the study sample, the mean ADMA concentration was 0.52 (0.11) μmol/L, and the reference limits were 0.311 and 0.732 (2.5th and 97.5th percentile). The sex-specific reference limits were 0.310 and 0.745 in men and 0.313 and 0.721 μmol/L in women. In multivariable regression analysis, ADMA plasma concentrations were positively correlated with age and total plasma homocysteine (both P < 0.001).
CONCLUSIONS
Reference limits calculated for circulating ADMA in our large community-based healthy reference sample confirm the previous observation of a relatively narrow distribution of concentrations. This suggests a tight physiological control of ADMA plasma concentrations, presumably by dimethylarginine dimethylaminohydrolase (DDAH) metabolism of ADMA.
doi:10.1373/clinchem.2009.124263
PMCID: PMC3794429  PMID: 19541865
17.  Galectin-3, a Marker of Cardiac Fibrosis, Predicts Incident Heart Failure in the Community 
Objectives
We sought to examine the relation of galectin-3 (Gal-3), a marker of cardiac fibrosis, with incident heart failure (HF) in the community.
Background
Gal-3 is an emerging prognostic biomarker in HF, and experimental studies suggest that Gal-3 is an important mediator of cardiac fibrosis. Whether elevated Gal-3 concentrations precede the development of HF is unknown.
Methods
Gal-3 concentrations were measured in 3,353 participants in the Framingham Offspring Cohort (mean age 59 years, 53% women). The relation of Gal-3 to incident HF was assessed using proportional hazards regression.
Results
Gal-3 was associated with increased left ventricular mass in age- and sex-adjusted analyses (P=0.001); this association was attenuated in multivariable analyses (P=0.06). A total of 166 participants developed incident HF and 468 died during a mean follow-up of 8.1 years. Gal-3 was associated with risk of incident HF (HR 1.28 per 1 standard deviation increase in log-Gal-3, 95% CI 1.14–1.43, P<0.0001), and remained significant after adjustment for clinical variables and B-type natriuretic peptide (HR 1.23, 95% CI 1.04–1.47, P=0.02). Gal-3 was also associated with risk of all-cause mortality (multivariable-adjusted HR 1.15, 95% CI 1.04–1.28, P=0.01). The addition of Gal-3 to clinical factors resulted in negligible changes to the c-statistic and minor improvements in the net reclassification index.
Conclusions
Higher concentration of Gal-3, a marker of cardiac fibrosis, is associated with increased risk of incident HF and mortality. Future studies evaluating the role of Gal-3 in cardiac remodeling may provide further insights into the role of Gal-3 in the pathophysiology of HF.
doi:10.1016/j.jacc.2012.04.053
PMCID: PMC3512095  PMID: 22939561
heart failure; epidemiology; biomarker; prognosis
18.  Association of Genetic Variation in the Mitochondrial Genome with Blood Pressure and Metabolic Traits 
Hypertension  2012;60(4):949-956.
Elevated blood pressure (BP) is a major risk factor for cardiovascular disease. Several studies have noted a consistent maternal effect on BP; consequently, mitochondrial DNA (mtDNA) variation has become an additional target of investigation of the missing BP heritability. Analyses of common mtDNA polymorphisms, however, have not found evidence of association with hypertension. To explore associations of relatively rare (frequency < 5%) mtDNA variants with BP, we identified uncommon/rare variants through sequencing the entire mitochondrial genome in 32 unrelated individuals with extreme-high BP in the Framingham Heart Study (FHS) and genotyped 40 mtSNPs in 7,219 FHS participants. The nonsynonymous mtSNP 5913G>A (Asp4Asn) in the cytochrome c oxidase subunit 1 of Complex IV demonstrated significant associations with BP and fasting blood glucose (FBG) levels. Individuals with the rare 5913A allele had, on average, 7 mm Hg higher systolic BP at baseline (Pempirical = 0.05) and 17 mg/dL higher mean FBG over 25 years of follow up (Pempirical = 0.009). Significant associations with FBG levels were also detected for nonsynonymous mtSNP 3316G>A (Ala4Thr) in the NADH dehydrogenase subunit 1 of Complex I. On average, individuals with rare allele 3316A had 17 and 25 mg/dL higher FBG at baseline (Pempirical = 0.01) and over 25 years of follow up (Pempirical = 0.007). Our findings provide the first evidence of putative association of variants in the mitochondrial genome with SBP and FBG in the general population. Replication in independent samples, however, is needed to confirm these putative associations.
doi:10.1161/HYPERTENSIONAHA.112.196519
PMCID: PMC3753106  PMID: 22949535
Mitochondrial genome; Association study; Genetics; Hypertension; Diabetes
19.  Cross-sectional association of dietary patterns with insulin resistance phenotypes among adults without diabetes in the Framingham Offspring Study 
The British journal of nutrition  2009;102(4):576-583.
Cluster analysis is a valuable tool for exploring the health consequences of consuming different dietary patterns. We used this approach to examine the cross-sectional relationship between dietary patterns and insulin resistance phenotypes, including waist circumference, body mass index (BMI), fasting insulin, 2-h post-challenge insulin, insulin sensitivity index (ISI0,120), HDL cholesterol, triacylglycerol and blood pressure, using data from the fifth examination cycle of the Framingham Offspring Study. Among 2,875 participants without diabetes, we identified four dietary patterns based on the predominant sources of energy: “Fruits, Reduced Fat Dairy and Whole Grains”, “Refined Grains and Sweets”, “Beer”, and “Soda”. After adjusting for multiple comparisons and potential confounders, compared with the “Fruits, Reduced Fat Dairy and Whole Grains” pattern, the “Refined Grains and Sweets” pattern had significantly higher mean waist circumference (92.4 versus 90.5 cm, P=0.008) and BMI (27.3 versus 26.6 kg/m2, P=0.02); the “Soda” pattern had significantly higher mean fasting insulin concentration (31.3 versus 28.0 μU/ml, P≤0.001); the “Beer” pattern had significantly higher mean HDL cholesterol concentration (1.46 versus 1.31 mmol/l, P<0.001). No associations were observed between dietary patterns and ISI0,120, triacylglycerol, and systolic or diastolic blood pressure. Our findings suggest that consumption of a diet rich in fruits, vegetables, whole grains and reduced fat dairy protects against insulin resistance phenotypes and displacing these healthy choices with refined grains, high fat dairy, sweet baked foods, candy and sugar sweetened soda promotes insulin resistant phenotypes.
doi:10.1017/S0007114509220836
PMCID: PMC3785063  PMID: 19216828
Dietary patterns; cluster analysis; insulin resistance phenotypes; Framingham Offspring Study
20.  Familial Aggregation of Left Ventricular Geometry and Association with Parental Heart Failure: The Framingham Heart Study 
Background
Data regarding the familial aggregation of left ventricular (LV) geometry and its relations to parental heart failure (HF) are limited.
Methods and Results
We evaluated concordance of LV geometry within 1093 nuclear families in 5758 participants of the Original (parents; N=2351) and Offspring (N=3407) cohorts of the Framingham Heart Study undergoing routine echocardiography in mid-to-late adulthood. LV geometry was categorized based on cohort- and sex-specific 80th percentile cutoffs of LV mass and relative wall thickness (RWT) into normal (both <80th percentile), concentric remodeling (LV mass<80th percentile, RWT>80th percentile), concentric hypertrophy (both >80th percentile) and eccentric hypertrophy (LV mass>80th percentile, RWT<80th percentile). Within nuclear families, LV geometry was concordant among related pairs (parent-child, sibling-sibling) (P=0.0015), but not among unrelated spousal pairs (P=0.60), a finding that remained unchanged after adjusting for clinical covariates known to influence LV remodeling (age, systolic blood pressure, body mass index), excluding individuals with prevalent HF and myocardial infarction, and varying the thresholds for defining LV geometry. The prevalence of abnormal LV geometry was higher in family members of affected individuals, with recurrence risks of 1.4 for concentric remodeling (95%CI, 1.2–1.7) and eccentric hypertrophy (95%CI, 1.1–1.8), and 3.9 (95%CI, 3.2–4.6) for concentric hypertrophy. In a subset of 1497 offspring, we observed an association between parental HF (N=458) and eccentric hypertrophy in offspring (P<0.0001).
Conclusions
Our investigation of a two-generational community-based sample demonstrates familial aggregation of LV geometry, with the greatest recurrence risk for concentric LV geometry, and establishes an association of eccentric LV geometry with parental HF.
doi:10.1161/CIRCGENETICS.110.941088
PMCID: PMC3785074  PMID: 20884845
echocardiography; remodeling; risk factors
21.  Prognostic Utility of Novel Biomarkers of Cardiovascular Stress: The Framingham Heart Study 
Circulation  2012;126(13):10.1161/CIRCULATIONAHA.112.129437.
Background
Biomarkers for predicting cardiovascular events in community-based populations have not consistently added information to standard risk factors. A limitation of many previously studied biomarkers is their lack of cardiovascular specificity.
Methods and Results
To determine the prognostic value of 3 novel biomarkers induced by cardiovascular stress, we measured soluble ST2, growth differentiation factor-15, and high-sensitivity troponin I in 3,428 participants (mean age 59, 53% women) in the Framingham Heart Study. We performed multivariable-adjusted proportional hazards models to assess the individual and combined ability of the biomarkers to predict adverse outcomes. We also constructed a “multimarker” score composed of the 3 biomarkers, in addition to B-type natriuretic peptide and high-sensitivity C-reactive protein. During a mean follow-up of 11.3 years, there were 488 deaths, 336 major cardiovascular events, 162 heart failure events, and 142 coronary events. In multivariable-adjusted models, the 3 new biomarkers were associated with each endpoint (p<0.001) except for coronary events. Individuals with multimarker scores in the highest quartile had a 3-fold risk of death (adjusted hazard ratio, 3.2, 95% CI, 2.2–4.7; p<0.001), 6-fold risk of heart failure (6.2, 95% CI, 2.6–14.8; p<0.001), and 2-fold risk of cardiovascular events (1.9, 95% CI, 1.3–2.7; p=0.001). Addition of the multimarker score to clinical variables led to significant increases in the c-statistic (p=0.007 or lower) and net reclassification improvement (p=0.001 or lower).
Conclusions
Multiple biomarkers of cardiovascular stress are detectable in ambulatory individuals, and add prognostic value to standard risk factors for predicting death, overall cardiovascular events, and heart failure.
doi:10.1161/CIRCULATIONAHA.112.129437
PMCID: PMC3656719  PMID: 22907935
biomarkers; risk assessment; risk prediction
22.  2-Aminoadipic acid is a biomarker for diabetes risk 
The Journal of Clinical Investigation  2013;123(10):4309-4317.
Improvements in metabolite-profiling techniques are providing increased breadth of coverage of the human metabolome and may highlight biomarkers and pathways in common diseases such as diabetes. Using a metabolomics platform that analyzes intermediary organic acids, purines, pyrimidines, and other compounds, we performed a nested case-control study of 188 individuals who developed diabetes and 188 propensity-matched controls from 2,422 normoglycemic participants followed for 12 years in the Framingham Heart Study. The metabolite 2-aminoadipic acid (2-AAA) was most strongly associated with the risk of developing diabetes. Individuals with 2-AAA concentrations in the top quartile had greater than a 4-fold risk of developing diabetes. Levels of 2-AAA were not well correlated with other metabolite biomarkers of diabetes, such as branched chain amino acids and aromatic amino acids, suggesting they report on a distinct pathophysiological pathway. In experimental studies, administration of 2-AAA lowered fasting plasma glucose levels in mice fed both standard chow and high-fat diets. Further, 2-AAA treatment enhanced insulin secretion from a pancreatic β cell line as well as murine and human islets. These data highlight a metabolite not previously associated with diabetes risk that is increased up to 12 years before the onset of overt disease. Our findings suggest that 2-AAA is a marker of diabetes risk and a potential modulator of glucose homeostasis in humans.
doi:10.1172/JCI64801
PMCID: PMC3784523  PMID: 24091325
23.  Is Age Really a Non-modifiable Cardiovascular Risk Factor? 
The American journal of cardiology  2009;104(9):1307-1310.
doi:10.1016/j.amjcard.2009.06.051
PMCID: PMC3760670  PMID: 19840582
24.  Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling  
The Journal of Clinical Investigation  2013;123(10):4208-4218.
The suppression of tumorigenicity 2/IL-33 (ST2/IL-33) pathway has been implicated in several immune and inflammatory diseases. ST2 is produced as 2 isoforms. The membrane-bound isoform (ST2L) induces an immune response when bound to its ligand, IL-33. The other isoform is a soluble protein (sST2) that is thought to be a decoy receptor for IL-33 signaling. Elevated sST2 levels in serum are associated with an increased risk for cardiovascular disease. We investigated the determinants of sST2 plasma concentrations in 2,991 Framingham Offspring Cohort participants. While clinical and environmental factors explained some variation in sST2 levels, much of the variation in sST2 production was driven by genetic factors. In a genome-wide association study (GWAS), multiple SNPs within IL1RL1 (the gene encoding ST2) demonstrated associations with sST2 concentrations. Five missense variants of IL1RL1 correlated with higher sST2 levels in the GWAS and mapped to the intracellular domain of ST2, which is absent in sST2. In a cell culture model, IL1RL1 missense variants increased sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness (via ST2L). Our data suggest that genetic variation in IL1RL1 can result in increased levels of sST2 and alter immune and inflammatory signaling through the ST2/IL-33 pathway.
doi:10.1172/JCI67119
PMCID: PMC3784527  PMID: 23999434
25.  Relations of Circulating Resistin and Adiponectin and Cardiac structure and Function: the Framingham Offspring study 
Obesity (Silver Spring, Md.)  2011;20(9):1882-1886.
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.
doi:10.1038/oby.2011.32
PMCID: PMC3716016  PMID: 21350435

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