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1.  Circulating natriuretic peptide concentrations reflect changes in insulin sensitivity over time in the Diabetes Prevention Program 
Diabetologia  2014;57(5):935-939.
We aimed to study the relationship between measures of adiposity, insulin sensitivity and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the Diabetes Prevention Program (DPP).
The DPP is a completed clinical trial. Using stored samples from this resource, we measured BMI, waist circumference (WC), an insulin sensitivity index (ISI; [1/HOMA-IR]) and NT-proBNP at baseline and at 2 years of follow-up in participants randomised to placebo (n=692), intensive lifestyle intervention (n=832) or metformin (n=887).
At baseline, log NT-proBNP did not differ between treatment arms and was correlated with baseline log ISI (p<0.0001) and WC (p=0.0003) but not with BMI (p=0.39). After 2 years of treatment, BMI decreased in the lifestyle and metformin groups (both p<0.0001); WC decreased in all three groups (p<0.05 for all); and log ISI increased in the lifestyle and metformin groups (both p<0.001). The change in log NT-proBNP did not differ in the lifestyle or metformin group vs the placebo group (p>0.05 for both). In regression models, the change in log NT-proBNP was positively associated with the change in log ISI (p<0.005) in all three study groups after adjusting for changes in BMI and WC, but was not associated with the change in BMI or WC after adjusting for changes in log ISI.
Circulating NT-proBNP was associated with a measure of insulin sensitivity before and during preventive interventions for type 2 diabetes in the DPP. This relationship persisted after adjustment for measures of adiposity and was consistent regardless of whether a participant was treated with placebo, intensive lifestyle intervention or metformin.
PMCID: PMC4158711  PMID: 24554005
Diabetes prevention; Insulin sensitivity; Natriuretic peptides; NT-proBNP; Obesity
2.  Weight Loss, Saline Loading, and the Natriuretic Peptide System 
In epidemiologic studies, obesity has been associated with reduced natriuretic peptide (NP) concentrations. Reduced NP production could impair the ability of obese individuals to respond to salt loads, increasing the risk of hypertension and other disorders. We hypothesized that weight loss enhances NP production before and after salt loading.
Methods and Results
We enrolled 15 obese individuals (mean BMI 45±5.4 kg/m2) undergoing gastric bypass surgery. Before and 6 months after surgery, subjects were admitted to the clinical research center and administered a large‐volume intravenous saline challenge. Echocardiography and serial blood sampling were performed. From the pre‐operative visit to 6 months after surgery, subjects had a mean BMI decrease of 27%. At the 6‐month visit, N‐terminal pro‐atrial NP (Nt‐proANP) levels were 40% higher before, during, and after the saline infusion, compared with levels measured at the same time points during the pre‐operative visit (P<0.001). The rise in Nt‐pro‐ANP induced by the saline infusion (≈50%) was similar both before and after surgery (saline, P<0.001; interaction, P=0.2). Similar results were obtained for BNP and Nt‐proBNP; resting concentrations increased by 50% and 31%, respectively, after gastric bypass surgery. The increase in NP concentrations after surgery was accompanied by significant decreases in mean arterial pressure (P=0.004) and heart rate (P<0.001), and an increase in mitral annular diastolic velocity (P=0.02).
In obese individuals, weight loss is associated with a substantial increase in the “setpoint” of circulating NP concentrations. Higher NP concentrations could contribute to an enhanced ability to handle salt loads after weight loss.
PMCID: PMC4330054  PMID: 25595796
natriuretic peptide; obesity; salt intake
3.  The Framingham Heart Study and the Epidemiology of Cardiovascular Diseases: A Historical Perspective 
Lancet  2013;383(9921):999-1008.
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.
PMCID: PMC4159698  PMID: 24084292
4.  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.
PMCID: PMC3784523  PMID: 24091325
5.  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.
PMCID: PMC3784527  PMID: 23999434
6.  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.
PMCID: PMC3726159  PMID: 23867623
7.  Clinical and Genetic Correlates of Growth Differentiation Factor-15 in the Community 
Clinical chemistry  2012;58(11):1582-1591.
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.
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.
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.
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.
PMCID: PMC4150608  PMID: 22997280
Epidemiology; Genetics; Risk factors; Cardiovascular diseases
8.  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.
PMCID: PMC3717862  PMID: 23382451
9.  Biomarkers and Cardiovascular Risk Assessment for Primary Prevention: an Update 
Clinical chemistry  2011;58(1):72-82.
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.
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.
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.
PMCID: PMC4105324  PMID: 22125305
10.  Circulating CD31+ Leukocyte Frequency is Associated with Cardiovascular Risk Factors 
Atherosclerosis  2013;229(1):228-233.
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).
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.
PMCID: PMC3984590  PMID: 23701996
epidemiology; CD31; leukocytes; endothelial cells; cardiovascular risk factors
11.  Growth Differentiation Factor-15: A Canary in a Coal Mine? 
Clinical chemistry  2011;58(1):3-5.
PMCID: PMC4002288  PMID: 22065154
12.  A Genome-Wide Association Study of the Human Metabolome in a Community-Based Cohort 
Cell metabolism  2013;18(1):130-143.
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.
PMCID: PMC3973158  PMID: 23823483
13.  Elevated circulating branched chain amino acids are an early event in pancreatic adenocarcinoma development 
Nature medicine  2014;20(10):1193-1198.
Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months1. PDAC has been linked with obesity and glucose intolerance2-4, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from pancreatic cancer cases and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched chain amino acids (BCAAs) are associated with a greater than 2–fold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years prior to diagnosis when occult disease is likely present. We show that plasma BCAAs are also elevated in mice with early stage pancreatic cancers driven by mutant Kras expression, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early stage disease. Together, these findings suggest that increased whole–body protein breakdown is an early event in development of PDAC.
PMCID: PMC4191991  PMID: 25261994
14.  Biomarkers of Cardiovascular Stress and Subclinical Atherosclerosis in the Community 
Clinical chemistry  2014;60(11):1402-1408.
Biomarkers of cardiovascular stress have been associated with incident cardiovascular outcomes. Their relations with measures of subclinical atherosclerosis, as assessed by carotid intima-media thickness, have not been well described.
Plasma growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity troponin I (hsTnI) were measured in 3111 Framingham Offspring participants who also underwent carotid ultrasonography during the sixth examination (1995 – 1998, mean age 58 years, 54% women). Carotid measurements included maximal internal carotid artery (ICA) intima-media thickness (IMT), plaque presence (defined as ICA IMT > 1.5 mm), and mean common carotid artery IMT. Multivariable regressions for carotid measurements versus biomarkers were carried out using linear and logistic models; P < 0.0056 was deemed statistically significant.
Maximal ICA IMT was significantly associated with plasma GDF-15 (β-estimate 0.04 per 1 unit increase in log-GDF-15 SE 0.01, P < 0.0001). Similarly, the odds of having carotid plaque increased 33% (OR 1.33 per 1-unit increase in log-GDF-15, 95% CI 1.20-1.48, P < 0.0001). In contrast, there was no significant association of maximal ICA IMT or plaque presence with sST2 or hsTnI, and none of the three biomarkers was significantly associated with mean CCA IMT. GDF-15 was a stronger predictor of maximal ICA thickness and plaque presence compared with BNP and CRP when these conventional biomarkers were tested together.
Higher GDF-15 concentrations are associated with subclinical atherosclerosis, including maximal ICA IMT and carotid plaque presence. Future studies investigating the role of GDF-15 for screening and management of patients with subclinical atherosclerosis are warranted.
PMCID: PMC4376479  PMID: 25237063
carotid intima-media thickness; atherosclerosis; biomarkers
15.  The epidemiology of congestive heart failure: the Framingham Heart Study perspective 
Global heart  2013;8(1):77-82.
PMCID: PMC3756692  PMID: 23998000
16.  Preload Dependency of Left Ventricular Torsion:The Impact of Normal Saline Infusion 
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).
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.
PMCID: PMC4310464  PMID: 20826594
Echocardiography; mechanics; cardiac volume; torsion
17.  Prognostic Utility of Novel Biomarkers of Cardiovascular Stress: The Framingham Heart Study 
Circulation  2012;126(13):10.1161/CIRCULATIONAHA.112.129437.
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).
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.
PMCID: PMC3656719  PMID: 22907935
biomarkers; risk assessment; risk prediction
18.  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.
PMCID: PMC3881171  PMID: 24210333
Concentric hypertrophy; eccentric hypertrophy; left ventricular hypertrophy; heart failure; risk
19.  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.
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).
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.
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.
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.
PMCID: PMC3884900  PMID: 24332149
atrial fibrillation; biomarker; risk factor
20.  Lipid profiling identifies a triacylglycerol signature of insulin resistance and improves diabetes prediction in humans 
The Journal of Clinical Investigation  2011;121(4):1402-1411.
Dyslipidemia is an independent risk factor for type 2 diabetes, although exactly which of the many plasma lipids contribute to this remains unclear. We therefore investigated whether lipid profiling can inform diabetes prediction by performing liquid chromatography/mass spectrometry–based lipid profiling in 189 individuals who developed type 2 diabetes and 189 matched disease-free individuals, with over 12 years of follow up in the Framingham Heart Study. We found that lipids of lower carbon number and double bond content were associated with an increased risk of diabetes, whereas lipids of higher carbon number and double bond content were associated with decreased risk. This pattern was strongest for triacylglycerols (TAGs) and persisted after multivariable adjustment for age, sex, BMI, fasting glucose, fasting insulin, total triglycerides, and HDL cholesterol. A combination of 2 TAGs further improved diabetes prediction. To explore potential mechanisms that modulate the distribution of plasma lipids, we performed lipid profiling during oral glucose tolerance testing, pharmacologic interventions, and acute exercise testing. Levels of TAGs associated with increased risk for diabetes decreased in response to insulin action and were elevated in the setting of insulin resistance. Conversely, levels of TAGs associated with decreased diabetes risk rose in response to insulin and were poorly correlated with insulin resistance. These studies identify a relationship between lipid acyl chain content and diabetes risk and demonstrate how lipid profiling could aid in clinical risk assessment.
PMCID: PMC3069773  PMID: 21403394
21.  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.
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.
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).
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.
PMCID: PMC3833885  PMID: 23953891
branched chain amino acids; aromatic amino acids
22.  Effects of subacute dietary salt intake and acute volume expansion on diastolic function in young normotensive individuals 
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).
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.
PMCID: PMC3806580  PMID: 23515219
Diastolic function; Diastolic strain rate; Sodium
23.  Effect of Phosphodiesterase Inhibition on Insulin Resistance in Obese Individuals 
Obesity is associated with cardiometabolic disease, including insulin resistance (IR) and diabetes. Cyclic guanosine monophosphate (cGMP) signaling affects energy balance, IR, and glucose metabolism in experimental models. We sought to examine effects of phosphodiesterase‐5 inhibition with tadalafil on IR in a pilot study of obese nondiabetic individuals.
Methods and Results
We conducted a randomized, double‐blinded, placebo‐controlled trial of adults age 18 to 50 years with obesity and elevated fasting insulin levels (≥10 μU/mL). Participants were randomized to tadalafil 20 mg daily or placebo for 3 months. Oral glucose tolerance tests were performed, and the effect of tadalafil on IR was examined. A total of 53 participants (mean age, 33 years; body mass index [BMI], 38 kg/m2) were analyzed, 25 randomized to tadalafil and 28 to placebo. In the overall sample, measures of IR did not differ between tadalafil and placebo groups at 3 months. However, in individuals with severe obesity (BMI ≥36.2 kg/m2), tadalafil use was associated with improved IR (homeostatic model assessment for IR), compared to placebo (P=0.02, respectively). Furthermore, one measure of β‐cell compensation for IR (oral disposition index) improved with tadalafil in the overall sample (P=0.009) and in the subgroup with severe obesity (P=0.01).
Results of this pilot study did not show improvements in IR with tadalafil, compared to placebo. However, tadalafil may have favorable effects on β‐cell compensation, particularly in individuals with severe obesity. Future studies evaluating the potential metabolic benefits of cGMP modulation in obesity are warranted.
Clinical Trial Registration
URL: Unique Identifier: NCT01444651.
PMCID: PMC4323801  PMID: 25213566
cGMP; insulin resistance; obesity; phosphodiesterase type 5 inhibition
24.  Reference Limits for N-terminal-pro-B-type Natriuretic Peptide in Healthy Individuals (From the Framingham Heart Study) 
The American journal of cardiology  2011;108(9):1341-1345.
N-terminal-pro-B-type natriuretic peptide (NT-proBNP) is a commonly measured cardiovascular biomarker in both ambulatory and hospital settings. Nonetheless, there are limited data regarding “normal” ranges for NT-proBNP in healthy individuals, despite the importance of such information for interpreting natriuretic peptide measurements. We examined a healthy reference sample free of cardiovascular disease from the Framingham Heart Study Generation 3 cohort; there were 2,285 subjects (mean age 38 years, 56% women). Plasma NT-proBNP levels were measured using the Roche Diagnostics Elecsys 2010 assay, and reference values (2.5, 50, 97.5 quantiles) were determined using empiric and quantile regression methods. Gender, age, and body mass index accounted for approximately 33% of the inter-individual variability in NT-proBNP in the reference sample. NT-proBNP values were substantially higher in women compared with men at every age, and levels increased with increasing age for both sexes. Using quantile regression, the upper reference values (97.5 quantile) for NT-proBNP were 42.5 pg/ml to 106.4 pg/ml in men (depending on age), and 111.0 pg/ml to 215.9 pg/ml in women. Intra-individual variability was assessed in an additional 12 healthy individuals, who had serial NT-proBNP measurements over a month. Intra-class correlation was 0.85, indicating that most of the variability in NT-proBNP concentrations was among-persons rather than within-persons. However, the reference change value was 100%, suggesting that small proportional differences in NT-proBNP could be attributable to analytic variability. In conclusion, the reference limits obtained from this large, healthy community-based sample may aid in the evaluation of NT-proBNP concentrations measured for both clinical and research purposes.
PMCID: PMC3209520  PMID: 21864812
Natriuretic peptides; Cardiac Biomarkers; Heart Failure
25.  Relation of Visceral Adiposity to Circulating Natriuretic Peptides in Ambulatory Individuals 
The American journal of cardiology  2011;108(7):979-984.
Natriuretic peptides have important roles in the regulation of vasomotor tone, salt homeostasis, and ventricular remodeling. Lower natriuretic peptide levels observed in obese individuals may underlie the greater cardiovascular risk associated with obesity. Thus, the aim of this study was to determine whether lower natriuretic peptide levels in obesity are attributable to differences in regional fat distribution. We investigated the relationship of plasma N-terminal pro-B-type natriuretic peptide (N-BNP) with regional adiposity in 1,873 community-based individuals (46% women; mean age 45 years). Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes were measured by multi-detector computed tomography. In sex-specific, multivariable analyses adjusting for age and blood pressure, log N-BNP was inversely associated with VAT in both men (β −0.11, P<0.001) and women (β −0.19, P<0.001). Log N-BNP was inversely associated with SAT in women only (β −0.14, P<0.001). In models containing both VAT and SAT, only VAT was significantly associated with log N-BNP (men, β −0.137, P<0.001; women, β −0.184, P<0.001). VAT remained associated with log N-BNP even after adjustment for body mass index and waist circumference (β −0.119, P<0.001), and in analyses restricted to non-obese individuals (β −0.114; P<0.001). Adjustment for insulin resistance attenuated the associations of N-BNP with both VAT and SAT. In conclusion, this study demonstrates that circulating N-BNP is related to variation in regional and particularly visceral adiposity. These findings suggest that excess visceral adiposity and concomitant hyperinsulinemia may contribute to the natriuretic peptide “deficiency” observed in obesity.
PMCID: PMC3175269  PMID: 21813106
adiposity; natriuretic peptides; cardiovascular risk

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