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1.  The Framingham Heart Study and the Epidemiology of Cardiovascular Diseases: A Historical Perspective 
Lancet  2013;383(9921):999-1008.
Summary
On October 11, 2013, the Framingham Heart Study will celebrate 65 years since the examination of its first participant in 1948. During this period, the study has provided substantial insight into the epidemiology of cardiovascular disease and its risk factors. The origin of the study is closely linked to the cardiovascular health of President Franklin D. Roosevelt and his premature death from hypertensive heart disease and stroke in 1945. The present article describes the events leading to the founding of the Framingham Heart Study, and provides a brief historical overview of selected contributions from the study.
doi:10.1016/S0140-6736(13)61752-3
PMCID: PMC4159698  PMID: 24084292
2.  Preload Dependency of Left Ventricular Torsion:The Impact of Normal Saline Infusion 
Background
Left ventricular (LV) rotation results from contraction of obliquely oriented myocardial fibers. The net difference between systolic apical counterclockwise rotation and basal clockwise rotation is left ventricular torsion (LVT). Although LVT is altered in various cardiac diseases, determinants of LVT are incompletely understood.
Methods and Results
LV end-diastolic volume (LVEDV), LV apical and basal rotation, peak systolic LVT, and peak early diastolic untwisting rate (UTR) were measured by speckle tracking echocardiography in healthy subjects (n=8) before and after infusion of a weight-based normal saline bolus (2.1±0.3 L). Saline infusion lead to a significant increase in end-diastolic LV internal diameter (45.9±3.7 versus 47.6±4.2 mm; p=0.002) and LVEDV (90.0±21.6 versus 98.3±19.6 mL; p=0.01). Stroke volume (51.3±10.9 versus 63.0±15.5 mL; p = 0.003) and cardiac output (3.4±0.8 versus 4.4±1.5 L/min; p = 0.007) increased while there was no change in heart rate and blood pressure. There was a significant increase in the magnitude of peak systolic apical rotation (7.5±2.4 versus 10.5±2.8 degrees; p < 0.001) but no change in basal rotation (-4.1±2.3 versus -4.8±3.1 degrees; p = 0.44). Accordingly, peak systolic LVT increased by 33% following saline infusion (11.2±1.3 versus 14.9±1.7 degrees; p < 0.001). This saline-induced increase in LVT was associated with a marked increase in peak early diastolic UTR (72.3±21.4 versus 136.8±30.0 degrees/s; p < 0.001).
Conclusions
Peak systolic LVT and peak early diastolic UTR are preload dependent. Changes in LV preload should be considered when interpreting results of future LVT studies.
doi:10.1161/CIRCIMAGING.109.932921
PMCID: PMC4310464  PMID: 20826594
Echocardiography; mechanics; cardiac volume; torsion
3.  Left Ventricular Hypertrophy Patterns and Incidence of Heart Failure with Preserved versus Reduced Ejection Fraction 
The American journal of cardiology  2013;113(1):10.1016/j.amjcard.2013.09.028.
Higher left ventricular (LV) mass, wall thickness and internal dimension are associated with increased heart failure (HF) risk. Whether different LV hypertrophy patterns vary with respect to rates and types of HF incidence is unclear. We classified 4768 Framingham Heart Study participants (mean age 50 years; 56% women) into 4 mutually exclusive LV hypertrophy pattern groups (normal, concentric remodeling, concentric hypertrophy, eccentric hypertrophy) using American Society of Echocardiography recommended thresholds of echocardiographic LV mass/body surface area and relative wall thickness, and related them to HF incidence. We evaluated if risk for HF types (HF with reduced [<45%; HFREF] versus preserved [≥45%; HFPEF] ejection fraction) varied by hypertrophy pattern. On follow-up (mean 21 years), 458 participants (9.6%; 250 women) developed new-onset HF. The age-and-sex-adjusted 20-year HF incidence rose from 6.96% in normal LV group to 8.67%, 13.38% and 15.27% in the concentric remodeling, concentric hypertrophy and eccentric hypertrophy groups, respectively. After adjustment for co-morbidities and incident myocardial infarction, LV hypertrophy patterns were associated with higher HF incidence relative to normal LV (p=0.0002); eccentric hypertrophy carried the greatest risk (hazards ratio [HR] 1.89, 95% confidence interval [CI] 1.41-2.54), followed by concentric hypertrophy (HR [CI] 1.40 [1.04-1.87]). Participants with eccentric hypertrophy had a higher propensity for HFREF (HR 2.23; CI 1.48-3.37, whereas those with concentric hypertrophy were more prone to HFPEF (HR 1.66; CI 1.09-2.51). In conclusion, in our large community-based sample, HF risk varied by LV hypertrophy pattern, with eccentric and concentric hypertrophy predisposing to HFREF and HFPEF, respectively.
doi:10.1016/j.amjcard.2013.09.028
PMCID: PMC3881171  PMID: 24210333
Concentric hypertrophy; eccentric hypertrophy; left ventricular hypertrophy; heart failure; risk
4.  Relation between soluble ST2, GDF-15 and hsTnI and Incident Atrial Fibrillation 
American heart journal  2013;167(1):10.1016/j.ahj.2013.10.003.
Background
We investigated whether circulating concentrations of soluble ST2, growth differentiation factor-15 (GDF-15), and high-sensitivity troponin I (hsTnI) are associated with incident atrial fibrillation (AF), and whether these biomarkers, improve current risk prediction models including AF risk factors, B-type natriuretic peptide (BNP) and C-reactive protein (CRP).
Methods
We studied the relation between soluble ST2, GDF-15, and hsTnI and development of AF in Framingham Heart Study participants without prevalent AF. We used Cox proportional hazard regression analysis to examine the relation of incident AF during a 10-year follow-up period with each biomarker. We adjusted for standard AF clinical risk factors, BNP, and CRP.
Results
The mean age of the 3,217 participants was 59±10 years and 54% were women. During 10 years of follow-up, 242 participants developed AF. In age- and sex-adjusted models, GDF-15 and hsTnI were associated with risk of incident AF; however, after including the AF risk factors and BNP and CRP, only hsTnI was significantly associated with AF (hazard ratio per 1 standard deviation of loge hsTnI, 1.12; 95%CI, 1.00-1.26; P=0.045). The C-statistic of the base model including AF risk factors, BNP and CRP was 0.803 (95% CI 0.777–0.830), and did not improve by adding individual or all 3 biomarkers. None of the discrimination and reclassification statistics was significant compared to the base model.
Conclusion
In a community-based cohort, circulating hsTnI concentrations were associated with incident AF. None of the novel biomarkers evaluated improved AF risk discrimination or reclassification beyond standard clinical AF risk factors and biomarkers.
doi:10.1016/j.ahj.2013.10.003
PMCID: PMC3884900  PMID: 24332149
atrial fibrillation; biomarker; risk factor
5.  Clinical and Genetic Correlates of Growth Differentiation Factor-15 in the Community 
Clinical chemistry  2012;58(11):1582-1591.
BACKGROUND
Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine produced in cardiovascular cells under conditions of inflammation and oxidative stress, and is emerging as an important prognostic marker in individuals with and without existing cardiovascular disease. Thus, we examined the clinical and genetic correlates of circulating GDF-15 levels, which have not been collectively investigated.
METHODS
A total of 2,991 participants of the Framingham Offspring Study free of clinically overt cardiovascular disease underwent measurement of plasma GDF-15 levels (mean age 59 years, 56% women). Clinical correlates of GDF-15 were examined in multivariable analyses. A genome-wide association study of GDF-15 levels was then conducted, including participants of the Framingham Offspring Study and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.
RESULTS
GDF-15 was positively associated with age, smoking, antihypertensive treatment, diabetes, worse kidney function, and non-steroidal anti-inflammatory drug use, but it was negatively associated with total and high-density lipoprotein cholesterol. Clinical correlates accounted for 38% of inter-individual variation in circulating GDF-15, whereas genetic factors account for up to 38% of residual variability (h2=0.38; P=2.5 × 10−11). We identified one genome-wide significant locus, which included the GDF15 gene, on chromosome 19p13.11 associated with GDF-15 concentrations (smallest P=2.74−32 for rs888663). Conditional analyses revealed two independent association signals at this locus (rs888663 and rs1054564), which were associated with altered cis-gene expression in blood cell lines.
CONCLUSIONS
In ambulatory individuals, both cardiometabolic risk factors and genetic factors play an important role in determining circulating GDF-15 concentrations, and contribute similarly to overall variation.
doi:10.1373/clinchem.2012.190322
PMCID: PMC4150608  PMID: 22997280
Epidemiology; Genetics; Risk factors; Cardiovascular diseases
6.  Branched chain and aromatic amino acids change acutely following two medical therapies for type 2 diabetes mellitus 
Metabolism: clinical and experimental  2013;62(12):10.1016/j.metabol.2013.07.003.
Objective
Elevated circulating levels of branched chain and aromatic amino acids (BCAA/AAAs) are associated with insulin resistance and incident type 2 diabetes (T2D). BCAA/AAAs decrease acutely during an oral glucose tolerance test (OGTT), a diagnostic test for T2D. It is unknown whether changes in BCAA/AAAs also signal an early response to commonly used medical therapies for T2D.
Materials and Methods
A liquid chromatography-mass spectrometry approach was used to measure BCAA/AAAs in 30 insulin sensitive (IS) and 30 insulin resistant (IR) subjects before and after: 1) one dose of a sulfonylurea medication, glipizide, 5 mg orally; 2) two days of twice daily metformin 500 mg orally; and 3) a 75-gram OGTT. Percent change in BCAA/AAAs was determined after each intervention.
Results
Following glipizide, which increased insulin and decreased glucose in both subject groups, BCAA/AAAs decreased in the IS subjects only (all P<0.05). Following metformin, which decreased glucose and insulin in only the IR subjects, 4 BCAA/AAAs increased in the IR subjects at or below P=0.05, and none changed in the IS subjects. Following OGTT, which increased glucose and insulin in all subjects, BCAA/AAAs decreased in all subjects (P<0.05).
Conclusions
BCAA/AAAs changed acutely during glipizide and metformin administration, and the magnitude and direction of change differed by the insulin resistance status of the individual and the intervention. These results indicate that BCAA/AAAs may be useful biomarkers for monitoring the early response to therapeutic interventions for T2D.
doi:10.1016/j.metabol.2013.07.003
PMCID: PMC3833885  PMID: 23953891
branched chain amino acids; aromatic amino acids
7.  Metabolite Profiles During Oral Glucose Challenge 
Diabetes  2013;62(8):2689-2698.
To identify distinct biological pathways of glucose metabolism, we conducted a systematic evaluation of biochemical changes after an oral glucose tolerance test (OGTT) in a community-based population. Metabolic profiling was performed on 377 nondiabetic Framingham Offspring cohort participants (mean age 57 years, 42% women, BMI 30 kg/m2) before and after OGTT. Changes in metabolite levels were evaluated with paired Student t tests, cluster-based analyses, and multivariable linear regression to examine differences associated with insulin resistance. Of 110 metabolites tested, 91 significantly changed with OGTT (P ≤ 0.0005 for all). Amino acids, β-hydroxybutyrate, and tricarboxylic acid cycle intermediates decreased after OGTT, and glycolysis products increased, consistent with physiological insulin actions. Other pathways affected by OGTT included decreases in serotonin derivatives, urea cycle metabolites, and B vitamins. We also observed an increase in conjugated, and a decrease in unconjugated, bile acids. Changes in β-hydroxybutyrate, isoleucine, lactate, and pyridoxate were blunted in those with insulin resistance. Our findings demonstrate changes in 91 metabolites representing distinct biological pathways that are perturbed in response to an OGTT. We also identify metabolite responses that distinguish individuals with and without insulin resistance. These findings suggest that unique metabolic phenotypes can be unmasked by OGTT in the prediabetic state.
doi:10.2337/db12-0754
PMCID: PMC3717862  PMID: 23382451
8.  Biomarkers and Cardiovascular Risk Assessment for Primary Prevention: an Update 
Clinical chemistry  2011;58(1):72-82.
BACKGROUND
Interest in cardiovascular biomarkers in primary prevention has increased dramatically in the past decade. This has been fueled by an improved understanding of cardiovascular pathophysiology, as well as novel technologies for biomarker identification.
CONTENT
The article provides a brief overview of recent concepts in the evaluation of screening biomarkers, because biomarkers may behave differently when used for screening as opposed to diagnosis or disease staging. The following specific biomarker examples are then discussed, with a focus on data from primary prevention studies: high-sensitivity C-reactive protein, B-type natriuretic peptide, lipoprotein-associated phospholipase A2, and high-sensitivity troponin T. The article concludes by addressing novel platforms for biomarker discovery, reviewing recent examples from the field of metabolomics.
SUMMARY
An ongoing challenge is to develop screening strategies that can identify individuals at risk for cardiovascular events well before symptoms appear. For this purpose, the measurement of soluble biomarkers could be an important adjunct to traditional risk cardiovascular assessment. Recent studies highlight both the strengths and limitations of “novel” circulating biomarkers, and suggest that substantial work is still needed to identify biomarkers that are sufficiently accurate and cost-effective for routine use in primary prevention.
doi:10.1373/clinchem.2011.165712
PMCID: PMC4105324  PMID: 22125305
9.  Effects of subacute dietary salt intake and acute volume expansion on diastolic function in young normotensive individuals 
Aims
Chronic excess salt intake may have blood pressure-independent adverse effects on the heart such as myocardial hypertrophy and fibrosis. Effects of subacute sodium loading with excess dietary salt on diastolic function in normotensive individuals have been conflicting and the mechanisms are poorly understood.
Methods and results
Thirteen healthy normotensive subjects (age 24 ± 4 years) entered a 2-week crossover study with 1 week of a low-salt diet <10 mEq/day and 1 week of a high-salt diet >200 mEq/day. At the end of each study week, left ventricular dimensions, systolic, and diastolic function were assessed with echocardiography before and after 2 L of normal saline infusion. One week of high-salt and low-salt diets did not lead to differences in echocardiographic parameters of systolic or diastolic function, even after rapid volume expansion with saline infusion. The peak early diastolic strain rate (SR) increased after volume loading both after completion of low-salt (1.62 ± 0.23/s vs. 1.82 ± 0.14/s, P < 0.05) and high-salt diets (1.67 ± 0.16/s vs. 1.86 ± 0.22/s, P < 0.05). There was a positive correlation between the peak early diastolic SR and the cardiac index (r = 0.52, P = 0.017).
Conclusion
In healthy normotensive individuals, subacute excess dietary sodium intake does not affect diastolic function. The peak early diastolic SR, similar to other mitral Doppler and tissue Doppler parameters of diastolic function, appears to be strongly dependent on pre-load.
doi:10.1093/ehjci/jet036
PMCID: PMC3806580  PMID: 23515219
Diastolic function; Diastolic strain rate; Sodium
10.  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
11.  Circulating CD31+ Leukocyte Frequency is Associated with Cardiovascular Risk Factors 
Atherosclerosis  2013;229(1):228-233.
Objectives
CD31 identifies a heterogeneous population of cells in the blood, consisting of mature leukocytes and platelets, as well as smaller numbers of endothelial and progenitor cells. Because unfractionated CD31+ blood cells have demonstrated angiogenic properties in vivo, we hypothesized that circulating CD31+ cells would be related to the presence of cardiovascular risk factors in humans.
Methods and Results
We studied 1,487 participants, free of cardiovascular disease, from the Framingham Offspring Study. Using anti-human CD31 and CD45 antibodies, distinct CD31+/CD45+ leukocyte populations were enumerated in blood samples by FACS analysis. We used linear regression analyses to investigate the relation of each cell phenotype with cardiovascular risk factors. We identified 3 distinct leukocyte populations: CD31-, CD31dim, and CD31bright cells. Using forward/side scatter analyses, CD31- and CD31dim cells mapped to lymphoid gates while CD31bright cells were monocytoid. In multivariable analyses, higher frequency of CD31bright cells was associated with older age, male sex, and CRP (all P<0.001). In contrast, CD31dim was inversely associated with age, male sex, CRP, and smoking (all P<0.01). Framingham Risk Score was positively associated with CD31bright frequency (P=0.002), and negatively associated with CD31dim frequency (P=0.020).
Conclusions
CD31+ staining identifies 2 major leukocyte populations, CD31bright and CD31dim, which demonstrated significant and opposite associations with cardiovascular risk in humans. Further research is needed to define the biological and potential therapeutic roles of CD31+ subpopulations in vascular disease.
doi:10.1016/j.atherosclerosis.2013.04.017
PMCID: PMC3984590  PMID: 23701996
epidemiology; CD31; leukocytes; endothelial cells; cardiovascular risk factors
12.  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
13.  Atrial natriuretic peptide is negatively regulated by microRNA-425 
The Journal of Clinical Investigation  2013;123(8):3378-3382.
Numerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that the variant rs5068 (A/G) in the 3′ untranslated region of NPPA, the gene encoding atrial natriuretic peptide (ANP), is associated with blood pressure. We selected individuals on the basis of rs5068 genotype (AG vs. AA) and fed them a low- or high-salt diet for 1 week, after which they were challenged with an intravenous saline infusion. On both diets, before and after saline administration, ANP levels were up to 50% higher in AG individuals than in AA individuals, a difference comparable to the changes induced by high-salt diet or saline infusion. In contrast, B-type natriuretic peptide levels did not differ by rs5068 genotype. We identified a microRNA, miR-425, that is expressed in human atria and ventricles and is predicted to bind the sequence spanning rs5068 for the A, but not the G, allele. miR-425 silenced NPPA mRNA in an allele-specific manner, with the G allele conferring resistance to miR-425. This study identifies miR-425 as a regulator of ANP production, raising the possibility that miR-425 antagonists could be used to treat disorders of salt overload, including hypertension and heart failure.
doi:10.1172/JCI67383
PMCID: PMC3726159  PMID: 23867623
14.  Growth Differentiation Factor-15: A Canary in a Coal Mine? 
Clinical chemistry  2011;58(1):3-5.
doi:10.1373/clinchem.2011.175406
PMCID: PMC4002288  PMID: 22065154
15.  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
16.  The epidemiology of congestive heart failure: the Framingham Heart Study perspective 
Global heart  2013;8(1):77-82.
doi:10.1016/j.gheart.2012.12.006
PMCID: PMC3756692  PMID: 23998000
17.  Risk assessment for incident heart failure in individuals with atrial fibrillation 
European Journal of Heart Failure  2013;15(8):843-849.
Background
Atrial fibrillation (AF) is a strong risk factor for heart failure (HF); HF onset in patients with AF is associated with increased morbidity and mortality. Risk factors that predict HF in individuals with AF in the community are not well established.
Methods and results
We examined clinical variables related to the 10-year incidence of HF in 725 individuals (mean 73.3 years, 45% women) with documented AF in the Framingham Heart Study. Event rates for incident HF (n = 161, 48% in women) were comparable in women (4.30 per 100 person-years) and men (3.34 per 100 person-years). Age, body mass index, ECG LV hypertrophy, diabetes, significant murmur, and history of myocardial infarction were positively associated with incident HF in multivariable models (C-statistic 0.71; 95% confidence interval 0.67–0.75). We developed a risk algorithm for estimating absolute risk of HF in AF patients with good model fit and calibration (adjusted calibration χ2 statistic 7.29; Pχ2 = 0.61). Applying the algorithm, 47.6% of HF events occurred in the top tertile in men compared with 13.1% in the bottom tertile, and 58.4% in women in the upper tertile compared with 18.2% in the lowest category. For HF type, women had a non-significantly higher incidence of HF with preserved EF compared with men.
Conclusions
We describe advancing age, LV hypertrophy, body mass index, diabetes, significant heart murmur, and history of myocardial infarction as clinical predictors of incident HF in individuals with AF. A risk algorithm may help identify individuals with AF at high risk of developing HF.
doi:10.1093/eurjhf/hft041
PMCID: PMC3858114  PMID: 23594831
Atrial fibrillation; Risk score; Epidemiology; Heart failure
18.  A diabetes-predictive amino acid score and future cardiovascular disease 
European Heart Journal  2012;34(26):1982-1989.
Aims
We recently identified a metabolic signature of three amino acids (tyrosine, phenylalanine, and isoleucine) that strongly predicts diabetes development. As novel modifiable targets for intervention are needed to meet the expected increase of cardiovascular disease (CVD) caused by the diabetes epidemic, we investigated whether this diabetes-predictive amino acid score (DM-AA score) predicts development of CVD and its functional consequences.
Methods and results
We performed a matched case–control study derived from the population-based Malmö Diet and Cancer Cardiovascular Cohort (MDC-CC), all free of CVD. During 12 years of follow-up, 253 individuals developed CVD and were matched for age, sex, and Framingham risk score with 253 controls. Amino acids were profiled in baseline plasma samples, using liquid chromatography-tandem mass spectrometry, and relationship to incident CVD was assessed using conditional logistic regression. We further examined whether the amino acid score also correlated with anatomical [intima-media thickness (IMT) and plaque formation] and functional (exercise-induced myocardial ischaemia) abnormalities. Compared with the lowest quartile of the DM-AA score, the odds ratio (95% confidence interval) for incident CVD in subjects belonging to quartiles 2, 3, and 4 was 1.27 (0.72–2.22), 1.96 (1.07–3.60), and 2.20 (1.12–4.31) (Ptrend = 0.010), respectively, after multivariate adjustment. Increasing quartile of the DM-AA score was cross-sectionally related to carotid IMT (Ptrend = 0.037) and with the presence of at least one plaque larger than 10 mm2 (Ptrend = 0.001). Compared with the lowest quartile of the DM-AA score, the odds ratio (95% confidence interval) for inducible ischaemia in subjects belonging to quartiles 2, 3, and 4 was 3.31 (1.05–10.4), 4.24 (1.36–13.3), and 4.86 (1.47–16.1) (Ptrend = 0.011), respectively.
Conclusion
This study identifies branched-chain and aromatic amino acids as novel markers of CVD development and as an early link between diabetes and CVD susceptibility.
doi:10.1093/eurheartj/ehs424
PMCID: PMC3703309  PMID: 23242195
Metabolomics; Amino acids; Diabetes; Cardiovascular disease
19.  Multiple Inflammatory Biomarkers in Relation to Cardiovascular Events and Mortality in the Community 
Objective
Evidence suggests that chronic low-grade inflammation and oxidative stress are related to cardiovascular disease (CVD) and mortality.
Approach and Results
We examined 11 established and novel biomarkers representing inflammation and oxidative stress (C-reactive protein [CRP], fibrinogen, interleukin-6, intercellular adhesion molecule-1 [ICAM-1], lipoprotein-associated phospholipase A2 (mass and activity), monocyte chemoattractant protein-1, myeloperoxidase, CD40 ligand, P-selectin, tumor necrosis factor receptor II [TNFRII]) in relation to incident major CVD and mortality in the community. We studied 3035 participants (mean age 61±9 years, 53% women). During follow-up (median 8.9 years), 253 participants experienced a CVD event and 343 died. CRP (hazard ratios [HR] reported per standard deviation ln-transformed biomarker, 1.18, 95% confidence interval [CI] 1.02-1.35; nominal P=0.02) and TNFRII (HR 1.15, 95% CI; 1.01-1.32; nominal P=0.04) were retained in multivariable-adjusted models for major CVD, but were not significant after adjustment for multiple testing. The biomarkers related to mortality were TNFRII (HR 1.33, 95% CI: 1.19-1.49; P<0.0001); ICAM-1 (HR 1.24, 95% CI: 1.12-1.37; P<0.0001), and interleukin-6 (HR 1.25, 95% CI: 1.12-1.39; P<0.0001). The addition of these markers to the model including traditional risk factors increased discrimination and reclassification for risk of death (P<0.0001), but not for CVD.
Conclusions
Of 11 biomarkers, TNFRII was associated nominally with incident major CVD, and significantly with all-cause mortality, which renders it an interesting target for future research. The combination of TNFRII with CRP in relation to CVD and with interleukin-6 to mortality increased the predictive ability in addition to CVD risk factors for total mortality but not for incident CVD.
doi:10.1161/ATVBAHA.112.301174
PMCID: PMC3753537  PMID: 23640499
mortality; cardiovascular disease; inflammation; epidemiology; cohort
20.  Mild Renal Dysfunction and Metabolites Tied to Low HDL Cholesterol Are Associated With Monocytosis and Atherosclerosis 
Circulation  2013;127(9):988-996.
Background
The number of circulating blood monocytes impacts atherosclerotic lesion size, and in mouse models, elevated levels of high-density lipoprotein cholesterol suppress blood monocyte counts and atherosclerosis. We hypothesized that individuals with mild renal dysfunction at increased cardiovascular risk would have reduced high-density lipoprotein levels, high blood monocyte counts, and accelerated atherosclerosis.
Methods and Results
To test whether mild renal dysfunction is associated with an increase in a leukocyte subpopulation rich in monocytes that has a known association with future coronary events, we divided individuals from the Malmö Diet and Cancer study (MDC) into baseline cystatin C quintiles (n=4757). Lower levels of renal function were accompanied by higher monocyte counts, and monocytes were independently associated with carotid bulb intima-media thickness cross-sectionally (P=0.02). Cystatin C levels were positively and plasma high-density lipoprotein cholesterol levels negatively associated with monocyte counts at baseline, after adjustment for traditional risk factors. Several amino acid metabolites tied to low levels of high-density lipoprotein cholesterol and insulin resistance measured in a subset of individuals (n=752) by use of liquid chromatography–mass spectrometry were independently associated with a 22% to 34% increased risk of being in the top quartile of monocytes (P<0.05).
Conclusions
A low high-density lipoprotein cholesterol, insulin resistance phenotype occurs in subjects with mild renal dysfunction and is associated with elevated monocytes and atherosclerosis. High blood monocyte counts may represent a previously unrecognized mechanism underlying the strong relationship between cystatin C and cardiovascular risk.
doi:10.1161/CIRCULATIONAHA.112.000682
PMCID: PMC4074592  PMID: 23378299
atherosclerosis; immunology; kidney; metabolomics; risk factors
21.  Long‐term Cardiovascular Risks Associated With an Elevated Heart Rate: The Framingham Heart Study 
Background
Higher heart rate has been associated with an adverse prognosis, but most prior studies focused on individuals with known cardiovascular disease or examined a limited number of outcomes. We sought to examine the association of baseline heart rate with both fatal and nonfatal outcomes during 2 decades of follow‐up.
Methods and Results
Our study included 4058 Framingham Heart Study participants (mean age 55 years, 56% women). Cox models were performed with multivariable adjustment for clinical risk factors and physical activity. A total of 708 participants developed incident cardiovascular disease (303 heart failure, 343 coronary heart disease, and 216 stroke events), 48 received a permanent pacemaker, and 1186 died. Baseline heart rate was associated with incident cardiovascular disease (hazard ratio [HR] 1.15 per 1 SD [11 bpm] increase in heart rate, 95% CI 1.07 to 1.24, P=0.0002), particularly heart failure (HR 1.32, 95% CI 1.18 to 1.48, P<0.0001). Higher heart rate was also associated with higher all‐cause (HR 1.17, 95% CI 1.11 to 1.24, P<0.0001) and cardiovascular mortality (HR 1.18, 95% CI 1.04 to 1.33, P=0.01). Spline analyses did not suggest a lower threshold beyond which the benefit of a lower heart rate abated or increased. In contrast, individuals with a higher heart rate had a lower risk of requiring permanent pacemaker placement (HR 0.55, 95% CI 0.38 to 0.79, P=0.001).
Conclusions
Individuals with a higher heart rate are at elevated long‐term risk for cardiovascular events, in particular, heart failure, and all‐cause death. On the other hand, a higher heart rate is associated with a lower risk of future permanent pacemaker implantation.
doi:10.1161/JAHA.113.000668
PMCID: PMC4309047  PMID: 24811610
cardiovascular disease; epidemiology; heart failure; risk factor
22.  Racial Differences in the Prevalence of Severe Aortic Stenosis 
Background
In an era of expanded treatment options for severe aortic stenosis, it is important to understand risk factors for the condition. It has been suggested that severe aortic stenosis is less common in African Americans, but there are limited data from large studies.
Methods and Results
The Synthetic Derivative at Vanderbilt University Medical Center, a database of over 2.1 million de‐identified patient records, was used to identify individuals who had undergone echocardiography. The association of race with severe aortic stenosis was examined using multivariable logistic regression analyses adjusting for conventional risk factors. Of the 272 429 eligible patients (mean age 45 years, 44% male) with echocardiography, 14% were African American and 82% were Caucasian. Severe aortic stenosis was identified in 106 (0.29%) African‐American patients and 2030 (0.91%) Caucasian patients (crude OR 0.32, 95% CI [0.26, 0.38]). This difference persisted in multivariable‐adjusted analyses (OR 0.41 [0.33, 0.50], P<0.0001). African‐American individuals were also less likely to have severe aortic stenosis due to degenerative calcific disease (adjusted OR 0.47 [0.36, 0.61]) or congenitally bicuspid valve (crude OR 0.13 [0.02, 0.80], adjusted OR dependent on age). Referral bias against those with severe valvular disease was assessed by comparing the prevalence of severe mitral regurgitation in Caucasians and African Americans and no difference was found.
Conclusions
These findings suggest that African Americans are at significantly lower risk of developing severe aortic stenosis than Caucasians.
doi:10.1161/JAHA.114.000879
PMCID: PMC4309086  PMID: 24870936
aortic valve stenosis; database; epidemiology; race and ethnicity; risk factor
23.  β-Aminoisobutyric Acid Induces Browning of White Fat and Hepatic β-oxidation and is Inversely Correlated with Cardiometabolic Risk Factors 
Cell metabolism  2014;19(1):96-108.
Summary
The transcriptional co-activator peroxisome proliferator-activated receptor-gamma co-activator-1 α (PGC-1α) regulates metabolic genes in skeletal muscle, and contributes substantially to the response of muscle to exercise. Muscle specific PGC-1α transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1α mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined. We employed a metabolic profiling approach to examine metabolites secreted from myocytes with forced expression of PGC-1α, and identified β-aminoisobutyric acid (BAIBA) as a novel small molecule myokine. BAIBA increases the expression of brown adipocyte-specific genes in white adipose tissue and fatty acid β-oxidation in hepatocytes both in vitro and in vivo through a PPARα mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases.
doi:10.1016/j.cmet.2013.12.003
PMCID: PMC4017355  PMID: 24411942
24.  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
25.  Soluble ST2 predicts elevated SBP in the community 
Journal of hypertension  2013;31(7):1431-1436.
Background
Soluble ST2 (sST2) is an emerging prognostic biomarker in patients with existing cardiovascular disease. ST2 and its ligand, interleukin-33 (IL-33), are expressed in endothelial cells, and may play an important role in the development of early atherosclerosis and vascular biology. We sought to investigate the association of sST2 and progression of blood pressure (BP), as well as the development of hypertension.
Methods
Circulating sST2 concentrations were measured in 1834 participants (mean age 56 years, 57% women) of the community-based Framingham Offspring study. Participants were free of hypertension at baseline. Multivariable linear and logistic regression models were used to evaluate the association of sST2 concentrations and subsequent BP outcomes.
Results
Higher sST2 concentrations were associated with incident hypertension over 3 years of follow-up [multivariable-adjusted odds ratio per 1 standard deviation increase in sST2 1.22, 95% confidence interval 1.05–1.42, P =0.01]. Individuals in the upper sST2 quartile had a 2.6 mmHg greater increase in SBP compared with those in the lowest quartile (P for trend across quartiles 0.002) and a 1.8 mmHg greater increase in pulse pressure (P for trend 0.005). In contrast, sST2 concentrations were not associated with changes in DBP (P =0.27).
Conclusion
These findings suggest that sST2 concentrations predict changes in BP physiology typically seen with aging and progressive arterial stiffness. Further studies are needed to elucidate underlying mechanisms by which the ST2/IL-33 pathway may contribute to BP physiology.
doi:10.1097/HJH.0b013e3283611bdf
PMCID: PMC3986262  PMID: 23615326
biological markers; blood pressure; epidemiology; hypertension; immune system; risk factors

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