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1.  Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization 
Arking, Dan E. | Pulit, Sara L. | Crotti, Lia | van der Harst, Pim | Munroe, Patricia B. | Koopmann, Tamara T. | Sotoodehnia, Nona | Rossin, Elizabeth J. | Morley, Michael | Wang, Xinchen | Johnson, Andrew D. | Lundby, Alicia | Gudbjartsson, Daníel F. | Noseworthy, Peter A. | Eijgelsheim, Mark | Bradford, Yuki | Tarasov, Kirill V. | Dörr, Marcus | Müller-Nurasyid, Martina | Lahtinen, Annukka M. | Nolte, Ilja M. | Smith, Albert Vernon | Bis, Joshua C. | Isaacs, Aaron | Newhouse, Stephen J. | Evans, Daniel S. | Post, Wendy S. | Waggott, Daryl | Lyytikäinen, Leo-Pekka | Hicks, Andrew A. | Eisele, Lewin | Ellinghaus, David | Hayward, Caroline | Navarro, Pau | Ulivi, Sheila | Tanaka, Toshiko | Tester, David J. | Chatel, Stéphanie | Gustafsson, Stefan | Kumari, Meena | Morris, Richard W. | Naluai, Åsa T. | Padmanabhan, Sandosh | Kluttig, Alexander | Strohmer, Bernhard | Panayiotou, Andrie G. | Torres, Maria | Knoflach, Michael | Hubacek, Jaroslav A. | Slowikowski, Kamil | Raychaudhuri, Soumya | Kumar, Runjun D. | Harris, Tamara B. | Launer, Lenore J. | Shuldiner, Alan R. | Alonso, Alvaro | Bader, Joel S. | Ehret, Georg | Huang, Hailiang | Kao, W.H. Linda | Strait, James B. | Macfarlane, Peter W. | Brown, Morris | Caulfield, Mark J. | Samani, Nilesh J. | Kronenberg, Florian | Willeit, Johann | Smith, J. Gustav | Greiser, Karin H. | zu Schwabedissen, Henriette Meyer | Werdan, Karl | Carella, Massimo | Zelante, Leopoldo | Heckbert, Susan R. | Psaty, Bruce M. | Rotter, Jerome I. | Kolcic, Ivana | Polašek, Ozren | Wright, Alan F. | Griffin, Maura | Daly, Mark J. | Arnar, David O. | Hólm, Hilma | Thorsteinsdottir, Unnur | Denny, Joshua C. | Roden, Dan M. | Zuvich, Rebecca L. | Emilsson, Valur | Plump, Andrew S. | Larson, Martin G. | O'Donnell, Christopher J. | Yin, Xiaoyan | Bobbo, Marco | D'Adamo, Adamo P. | Iorio, Annamaria | Sinagra, Gianfranco | Carracedo, Angel | Cummings, Steven R. | Nalls, Michael A. | Jula, Antti | Kontula, Kimmo K. | Marjamaa, Annukka | Oikarinen, Lasse | Perola, Markus | Porthan, Kimmo | Erbel, Raimund | Hoffmann, Per | Jöckel, Karl-Heinz | Kälsch, Hagen | Nöthen, Markus M. | consortium, HRGEN | den Hoed, Marcel | Loos, Ruth J.F. | Thelle, Dag S. | Gieger, Christian | Meitinger, Thomas | Perz, Siegfried | Peters, Annette | Prucha, Hanna | Sinner, Moritz F. | Waldenberger, Melanie | de Boer, Rudolf A. | Franke, Lude | van der Vleuten, Pieter A. | Beckmann, Britt Maria | Martens, Eimo | Bardai, Abdennasser | Hofman, Nynke | Wilde, Arthur A.M. | Behr, Elijah R. | Dalageorgou, Chrysoula | Giudicessi, John R. | Medeiros-Domingo, Argelia | Barc, Julien | Kyndt, Florence | Probst, Vincent | Ghidoni, Alice | Insolia, Roberto | Hamilton, Robert M. | Scherer, Stephen W. | Brandimarto, Jeffrey | Margulies, Kenneth | Moravec, Christine E. | Fabiola Del, Greco M. | Fuchsberger, Christian | O'Connell, Jeffrey R. | Lee, Wai K. | Watt, Graham C.M. | Campbell, Harry | Wild, Sarah H. | El Mokhtari, Nour E. | Frey, Norbert | Asselbergs, Folkert W. | Leach, Irene Mateo | Navis, Gerjan | van den Berg, Maarten P. | van Veldhuisen, Dirk J. | Kellis, Manolis | Krijthe, Bouwe P. | Franco, Oscar H. | Hofman, Albert | Kors, Jan A. | Uitterlinden, André G. | Witteman, Jacqueline C.M. | Kedenko, Lyudmyla | Lamina, Claudia | Oostra, Ben A. | Abecasis, Gonçalo R. | Lakatta, Edward G. | Mulas, Antonella | Orrú, Marco | Schlessinger, David | Uda, Manuela | Markus, Marcello R.P. | Völker, Uwe | Snieder, Harold | Spector, Timothy D. | Ärnlöv, Johan | Lind, Lars | Sundström, Johan | Syvänen, Ann-Christine | Kivimaki, Mika | Kähönen, Mika | Mononen, Nina | Raitakari, Olli T. | Viikari, Jorma S. | Adamkova, Vera | Kiechl, Stefan | Brion, Maria | Nicolaides, Andrew N. | Paulweber, Bernhard | Haerting, Johannes | Dominiczak, Anna F. | Nyberg, Fredrik | Whincup, Peter H. | Hingorani, Aroon | Schott, Jean-Jacques | Bezzina, Connie R. | Ingelsson, Erik | Ferrucci, Luigi | Gasparini, Paolo | Wilson, James F. | Rudan, Igor | Franke, Andre | Mühleisen, Thomas W. | Pramstaller, Peter P. | Lehtimäki, Terho J. | Paterson, Andrew D. | Parsa, Afshin | Liu, Yongmei | van Duijn, Cornelia | Siscovick, David S. | Gudnason, Vilmundur | Jamshidi, Yalda | Salomaa, Veikko | Felix, Stephan B. | Sanna, Serena | Ritchie, Marylyn D. | Stricker, Bruno H. | Stefansson, Kari | Boyer, Laurie A. | Cappola, Thomas P. | Olsen, Jesper V. | Lage, Kasper | Schwartz, Peter J. | Kääb, Stefan | Chakravarti, Aravinda | Ackerman, Michael J. | Pfeufer, Arne | de Bakker, Paul I.W. | Newton-Cheh, Christopher
Nature genetics  2014;46(8):826-836.
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
doi:10.1038/ng.3014
PMCID: PMC4124521  PMID: 24952745
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias
2.  Relationship Among Circulating Inflammatory Proteins, Platelet Gene Expression, and Cardiovascular Risk 
Objective
Cardiovascular disease is a complex disorder influenced by interactions of genetic variants with environmental factors. However, there is no information from large community-based studies examining the relationship of circulating cell–specific RNA to inflammatory proteins. In light of the associations among inflammatory biomarkers, obesity, platelet function, and cardiovascular disease, we sought to examine the relationships of C-reactive protein (CRP) and interleukin-6 (IL-6) to the expression of key inflammatory transcripts in platelets.
Approach and Results
We quantified circulating levels of CRP and IL-6 in 1625 participants of the Framingham Heart Study (FHS) Offspring cohort examination 8 (mean age, 66.6±6.6 years; 46% men). We measured the expression of 15 relevant genes by high-throughput quantitative reverse transcriptase polymerase chain reaction from platelet-derived RNA and used multivariable regression to relate serum concentrations of CRP and IL-6 with gene expression. Levels of CRP and IL-6 were associated with 10 of the 15 platelet-derived inflammatory transcripts, ALOX5, CRP, IFIT1, IL6, PTGER2, S100A9, SELENBP1, TLR2, TLR4, and TNFRSF1B (P<0.001). Associations between platelet mRNA expression with CRP and IL-6 persisted after multivariable adjustment for potentially confounding factors. Six genes positively associated with CRP or IL-6 in the FHS sample were also upregulated in megakaryocytes in response to CRP or IL-6 exposure.
Conclusions
Our data highlight the strong connection between the circulating inflammatory biomarkers CRP and IL-6 and platelet gene expression, adjusting for cardiovascular disease risk factors. Our results also suggest that body weight may directly influence these associations.
doi:10.1161/ATVBAHA.112.301112
PMCID: PMC4289138  PMID: 23968978
cardiovascular disease; inflammation; mRNA platelets
3.  Early Expression of Mitral Valve Prolapse in the Framingham Offspring: Phenotypic Spectrum 
Background
Mitral valve prolapse (MVP) is a common disorder associated with mitral regurgitation (MR), endocarditis, heart failure and sudden death. In the familial context, prior studies have described non-diagnostic mitral valve morphologies (‘prodromal forms’ and ‘minimal superior displacement’ [MSD]) that may represent early expression of MVP in those genetically predisposed. Our objective was to explore the spectrum of MVP abnormalities in the community and compare their clinical and echocardiographic features.
Methods
Phenotypic heterogeneity of MVP was assessed by measuring annular diameter (D), leaflet displacement (Dis), thickness (T), anterior/posterior leaflet projections (A, P) onto the annulus, coaptation height (C or P/D), and MR jet height (JH) in a sample of 296 individuals of the Framingham Offspring Study who were identified as having MVP (n=77) or its prodromal form (N=11) or MSD (N=57), with 151 controls with no feature of MVP or its non-diagnostic forms.
Results
The prodromal form did not meet diagnostic criteria but resembled fully diagnostic MVP with regards to D, T and JH (all p > 0.05); they were similar to individuals with posterior MVP with regard to leaflet asymmetry and coaptation height (p = 0.91). Compared to MSDs and controls, prodromals had greater C, T, D and JH (all p < 0.05). MSDs shared the posterior leaflet asymmetry with classic MVP, but their coaptation point was more posterior (C = 31% versus 42%, p<0.0001).
Conclusion
Non-diagnostic morphologies of MVP are observed in the community and share the common feature of posterior leaflet asymmetry with fully affected individuals. Prodromal morphology and MSD may represent early expressions of MVP and additional studies are warranted to elucidate the natural history of these phenotypes.
doi:10.1016/j.echo.2013.09.015
PMCID: PMC4239996  PMID: 24206636
mitral valve prolapse; echocardiography
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.  Reproducibility of Speckle-Tracking Based Strain Measures of Left Ventricular Function in a Community-Based Study 
Background
The reproducibility of echocardiographic measurements of myocardial strain, performed in a community-based setting, has not been reported previously.
Methods
We examined the reproducibility of left ventricular (LV) strain measurements in two samples of 20 participants each from the Offspring cohort of the Framingham Heart Study (mean age 63±9 years, 59% women). Two-dimensional speckle tracking-based measurements of global peak LV strain in systole were performed in the apical 4-chamber, apical 2-chamber, and mid-ventricular parasternal short-axis views.
Results
Inter-observer intra-class correlation coefficients (ICC) were ≥0.84 for all global strain measurements, with average coefficients of variation (CV) of ≤4% for global longitudinal and circumferential strain, and <8% for global transverse and radial strain. For LV strain measurements performed in each of the 3 views, intra-observer ICCs were ≥0.91 among time points spanning a total 8-month period. The average CVs were <6% for global longitudinal and circumferential strain, and <9% for global transverse and radial strain. Inter- and intra-observer reproducibility findings were similar in analyses adjusting for frame rate.
Conclusions
We observed excellent reproducibility of global longitudinal and circumferential strain measurements and very good reproducibility of global transverse and radial strain measurements. Taken together, our findings demonstrate the reproducibility of performing echocardiographic strain measurements in a large, epidemiologic community-based setting.
doi:10.1016/j.echo.2013.07.002
PMCID: PMC3812381  PMID: 23953701
6.  Protein Biomarkers of New-Onset Cardiovascular Disease: A Prospective Study from the Systems Approach to Biomarker Research in Cardiovascular Disease (SABRe CVD) Initiative 
Objective
Incorporation of novel plasma protein biomarkers may improve current models for prediction of atherosclerotic cardiovascular disease (ASCVD) risk.
Approach and Results
We utilized discovery mass spectrometry (MS) to determine plasma concentrations of 861 proteins in 135 myocardial infarction (MI) cases and 135 matched controls. We then measured 59markers by targeted MS in 336 ASCVD case-control pairs. Associations with MI or ASCVD were tested in single marker and multimarker analyses adjusted for established ASCVD risk factors.
Twelve single markers from discovery MS were associated with MI incidence (at p<0.01) adjusting for clinical risk factors. Seven proteins in aggregate (cyclophilin A, CD5 antigen-like, cell surface glycoprotein MUC18, collagen-alpha 1 [XVIII] chain, salivary alpha-amylase 1, C-reactive protein, and multimerin-2) were highly associated with MI (p<0.0001) and significantly improved its prediction compared to a model with clinical risk factors alone (C-statistic of 0.71 vs. 0.84). Through targeted MS, twelve single proteins were predictors of ASCVD (at p<0.05) after adjusting for established risk factors. In multimarker analyses, four proteins in combination (alpha-1-acid glycoprotein 1, paraoxonase 1, tetranectin, and CD5 antigen-like, predicted incident ASCVD (p<0.0001) and moderately improved the C-statistic from the model with clinical covariates alone (C-statistic of 0.69 vs. 0.73).
Conclusions
Proteomics profiling identified single and multimarker protein panels that are associated with new onset ASCVD and may lead to a better understanding of underlying disease mechanisms. Our findings include many novel protein biomarkers that, if externally validated, may improve risk assessment for MI and ASCVD.
doi:10.1161/ATVBAHA.113.302918
PMCID: PMC4061732  PMID: 24526693
Biomarker; cardiovascular disease; epidemiology; myocardial infarction; proteomics
7.  Association Testing of the Mitochondrial Genome Using Pedigree Data 
Genetic epidemiology  2013;37(3):239-247.
In humans, mitochondria contain their own DNA (mtDNA) that is inherited exclusively from the mother. The mitochondrial genome encodes thirteen polypeptides that are components of oxidative phosphorylation to produce energy. Any disruption in these genes might interfere with energy production and thus contribute to metabolic derangement. Mitochondria also regulate several important cellular activities including cell death and calcium homeostasis. Aided by sharply declining costs of high-density genotyping, hundreds of mitochondrial variants will soon be available in several cohorts with pedigree structures. Association testing of mitochondrial variants with disease traits using pedigree data raises unique challenges because of the difficulty in separating the effects of nuclear and mitochondrial genomes, which display different modes of inheritance. Failing to correctly account for these effects might decrease power or inflate type I error in association tests. In this report, we sought to identify the best strategy for association testing of mitochondrial variants when genotype and phenotype data are available in pedigrees. We proposed several strategies to account for polygenic effects of the nuclear and mitochondrial genomes and we performed extensive simulation studies to evaluate type I error and power of these strategies. In addition, we proposed two permutation tests to obtain empirical p-values for these strategies. Furthermore, we applied two of the analytical strategies to association analysis of 196 mitochondrial variants with blood pressure and fasting blood glucose in the pedigree rich, Framingham Heart Study. Finally, we discussed strategies for study design, genotyping, and data cleaning in association testing of mtDNA in pedigrees.
doi:10.1002/gepi.21706
PMCID: PMC4171957  PMID: 23319385
mitochondrial DNA; association test; polygenic effect; maternal lineage; permutation test
8.  Correlates and reference limits of plasma gamma-glutamyltransferase fractions from the Framingham Heart Study 
Background
We assessed GGT fractions correlates and their reference values in the Offspring Cohort of the Framingham Heart Study.
Methods
Correlates of GGT fractions were assessed by multivariable regression analysis in 3203 individuals [47% men, mean age (SD): 59 (10) yrs.]. GGT fractions reference values were established by empirical quantile analysis in a reference group of 432 healthy subjects [45% men, 57 (10) years].
Results
Fractional GGT levels were higher in men than in women (P < 0.0001). In both sexes, fractions were associated with: triglycerides were associated with b-GGT, alcohol consumption with m-, s- and f-GGT. C-reactive protein with m- and s-GGT, while plasminogen activator inhibitor-1 with b- and f-GGT. Body mass index, blood pressure, glucose and triglycerides correlated with b- and f-GGT. In comparison with the reference group [b-GGT/s-GGT median (Q1-Q3): 0.51 (0.35-0.79) U/L], subjects affected by cardiovascular disease or diabetes showed no change of b/s ratio [0.52 (0.34-0.79) U/L, 0.57 (0.40-0.83) U/L, respectively]. The b/s ratio was higher in presence of metabolic syndrome [0.61 (0.42-0.87) U/L, P<0.0001], while lower in heavy alcohol consumers [0.41 (0.28-0.64) U/L, P<0.0001].
Conclusions
Metabolic and cardiovascular risk markers are important correlates of GGT fractions, in particular of b-GGT.
doi:10.1016/j.cca.2012.12.002
PMCID: PMC4154585  PMID: 23247050
gamma-glutamyltransferase activity; gamma-glutamyltransferase fractions; gel-filtration chromatography; reference values; markers
9.  Age- and Sex-based Reference Limits and Clinical Correlates of Myocardial Strain and Synchrony: The Framingham Heart Study 
Circulation. Cardiovascular imaging  2013;6(5):10.1161/CIRCIMAGING.112.000627.
Background
There is rapidly growing interest in applying measures of myocardial strain and segmental synchrony in clinical investigations and in practice, but data are limited regarding their reference ranges in healthy individuals.
Methods and Results
We performed speckle-tracking-based echocardiographic measures of left ventricular (LV) myocardial strain and segmental synchrony in healthy Framingham Heart Study participants (n=738, mean age 63 years, 64% women) who were free of cardiovascular disease. Reference values (2.5th, 50th, 97.5th quantiles) were estimated using quantile regression. Age- and sex-based upper (97.5th quantile) limits were as follows: −15.5% to −16.9% (women) and −14.5 to −15.4% (men) for longitudinal strain; −21.9% to −24.3% (women) and −18.9% to −25.0% (men) for circumferential strain; 114-158 msec (women) and 133-206 msec (men) for longitudinal segmental synchrony (SD of regional time-to-peak strains); and, 204-224 msec (women) and 201-288 msec (men) for transverse segmental synchrony. In multivariable analyses, women compared to men had ~1.7% greater longitudinal strain, ~2.2% greater transverse strain, and ~3.2% greater circumferential strain (P<0.0001 for all). Older age and higher diastolic blood pressure, even within the normal range, was associated with worse transverse segmental synchrony (P<0.001). Overall, clinical covariates contributed ≤12% of the variation in myocardial strain or synchrony in this healthy sample.
Conclusions
We estimated age- and sex-specific reference limits for echocardiographic measures of LV strain and synchrony in a healthy community-based sample, wherein clinical covariates contributed only a modest proportion of the variation. These data may facilitate interpretation of LV strain-based measures obtained in future clinical research and practice.
doi:10.1161/CIRCIMAGING.112.000627
PMCID: PMC3856433  PMID: 23917618
reference limits; myocardial deformation; echocardiography
10.  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
11.  Secular trends in echocardiographic left ventricular mass in the community: The Framingham Heart Study 
Heart (British Cardiac Society)  2013;99(22):1693-1698.
Objective
To investigate secular trends in echocardiographically-determined left ventricular mass (LVM).
Design, Setting and participants
Longitudinal community-based cohort study in Framingham, Massachussetts. LVM was calculated from routine echocardiography in 4,320 participants (52% women) of the Framingham Offspring cohort at examination cycles 4 (1987-91), 5 (1991-95), 6 (1995-98) and 8 (2005-08), totalling 13,971 person-observations.
Main outcome measures
Sex-specific trends in mean LVM (and its components, LV diastolic diameter [LVDD] and LV wall thickness [LVWT]), and LVM indexed to body surface area (BSA).
Results
In men, age-adjusted LVM modestly increased from examination 4 to 8 (192 g to 198 g, P-trend=0.0005), whereas in women it decreased from 147 g at examination 4 to 140 g at examination 8 (P-trend<0.0001). The trend for increasing LVM in men tracked with an increasing LVDD (P-trend=0.0002), whereas the decline in LVM in women was accompanied by a decrease in LVWT (P-trend<0.0001). Indexing LVM to BSA abolished the increasing trend in men (P-trend=0.49), whereas the decreasing trend in women was maintained.
Conclusions
In our longitudinal analysis of a large community-based sample spanning two decades, we observed sex-related differences in trends in LVM, with a modest increase of LVM in men (likely attributable to increasing body size), but a decrease in women. Additional studies are warranted to elucidate the basis for these sex-related differences.
doi:10.1136/heartjnl-2013-304600
PMCID: PMC4139052  PMID: 24041649
12.  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
13.  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
14.  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
15.  Interleukin 1 Receptor 1 and Interleukin 1β Regulate Megakaryocyte Maturation, Platelet Activation, and Transcript Profile During Inflammation in Mice and Humans 
Objective
Interleukin 1 Receptor 1 (IL1R1) and its ligand, IL1β, are upregulated in cardiovascular disease, obesity, and infection. Previously, we reported a higher level of IL1R1 transcripts in platelets from obese individuals of the Framingham Heart Study (FHS), but its functional effect in platelets has never been described. Additionally, IL1β levels are increased in atherosclerotic plaques and in bacterial infections. The aim of this work is to determine whether IL1β, through IL1R1, can activate platelets and megakaryocytes to promote atherothrombosis.
Approach and Results
We found that IL1β-related genes from platelets, as measured in 1819 FHS participants, were associated with increased body mass index, and a direct relationship was shown in wild-type mice fed a high-fat diet. Mechanistically, IL1β activated nuclear factor-κB and mitogen-activated protein kinase signaling pathways in megakaryocytes. IL1β, through IL1R1, increased ploidy of megakaryocytes to 64+ N by 2-fold over control. IL1β increased agonist-induced platelet aggregation by 1.2-fold with thrombin and 4.2-fold with collagen. IL1β increased adhesion to both collagen and fibrinogen, and heterotypic aggregation by 1.9-fold over resting. High fat diet-enhanced platelet adhesion was absent in IL1R1−/− mice. Wild-type mice infected with Porphyromonas gingivalis had circulating heterotypic aggregates (1.5-fold more than control at 24 hours and 6.2-fold more at 6 weeks) that were absent in infected IL1R1−/− and IL1β−/− mice.
Conclusions
In summary, IL1R1- and IL1β-related transcripts are elevated in the setting of obesity. IL1R1/IL1β augment both megakaryocyte and platelet functions, thereby promoting a prothrombotic environment during infection and obesity; potentially contributing to the development of atherothrombotic disease.
doi:10.1161/ATVBAHA.113.302700
PMCID: PMC4070375  PMID: 24458711
blood platelets; diet; high-fat; IL1R1 protein; human; infection; megakaryocytes
16.  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
17.  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
18.  Whole Blood Gene Expression and Atrial Fibrillation: The Framingham Heart Study 
PLoS ONE  2014;9(5):e96794.
Background
Atrial fibrillation (AF) involves substantial electrophysiological, structural and contractile remodeling. We hypothesize that characterizing gene expression might uncover important pathways related to AF.
Methods and Results
We performed genome-wide whole blood transcriptomic profiling (Affymetrix Human Exon 1.0 ST Array) of 2446 participants (mean age 66±9 years, 55% women) from the Offspring cohort of Framingham Heart Study. The study included 177 participants with prevalent AF, 143 with incident AF during up to 7 years follow up, and 2126 participants with no AF. We identified seven genes statistically significantly up-regulated with prevalent AF. The most significant gene, PBX1 (P = 2.8×10−7), plays an important role in cardiovascular development. We integrated differential gene expression with gene-gene interaction information to identify several signaling pathways possibly involved in AF-related transcriptional regulation. We did not detect any statistically significant transcriptomic associations with incident AF.
Conclusion
We examined associations of gene expression with AF in a large community-based cohort. Our study revealed several genes and signaling pathways that are potentially involved in AF-related transcriptional regulation.
doi:10.1371/journal.pone.0096794
PMCID: PMC4013062  PMID: 24805109
19.  Clinical correlates of change in inflammatory biomarkers: The Framingham Heart Study 
Atherosclerosis  2013;228(1):217-223.
Objectives
Traditional clinical risk factors are associated with inflammation cross-sectionally, but associations of longitudinal variation in inflammatory biomarkers with corresponding changes in clinical risk factors are incompletely described. We sought to analyze clinical factors associated with change in inflammation in the community.
Methods
We studied 3013 Framingham Offspring (n = 2735) and Omni Cohort (n = 278) participants (mean age 59 years, 55% women, 9% ethnic/racial minority) who attended two consecutive examination cycles (mean 6.7 years apart). We selected ten inflammatory biomarkers representing distinctive biological functions: C-reactive protein (CRP), intercellular adhesion molecule-1, interleukin-6, isoprostanes, lipoprotein-associated phospholipase-2 (Lp-PLA2) activity, Lp-PLA2-mass, monocyte chemoattractant protein-1, osteoprotegerin, P-selectin, and tumor necrosis factor receptor II (TNFRII). We constructed multivariable-adjusted regression models to assess the relations of baseline, follow-up and change in clinical risk factors with change in biomarker concentrations over time.
Results
Baseline, follow-up and change in clinical risk factors explain a moderate amount of the variation in biomarker concentrations across 2 consecutive examinations (ranging from r2 = 0.28 [TNFRII] up to 0.52 [Lp-PLA2-mass]). In multivariable models, increasing body-mass index, smoking initiation, worsening lipid profile, and increasing waist size were associated with increasing concentrations of several biomarkers. Conversely, hypercholesterolemia therapy and hormone replacement cessation were associated with decreasing concentrations of biomarkers such as CRP, Lp-PLA2-mass and activity.
Conclusion
Cardiovascular risk factors have different patterns of association with longitudinal change in inflammatory biomarkers and explain modest amounts of variability in biomarker concentrations. Nevertheless, a substantial proportion of longitudinal change in inflammatory markers is not explained by traditional risk factors.
doi:10.1016/j.atherosclerosis.2013.01.019
PMCID: PMC3650714  PMID: 23489346
Biological markers; Longitudinal studies; Inflammation
20.  Structural Equation Modeling for Analyzing Erythrocyte Fatty Acids in Framingham 
Research has shown that several types of erythrocyte fatty acids (i.e., omega-3, omega-6, and trans) are associated with risk for cardiovascular diseases. However, there are complex metabolic and dietary relations among fatty acids, which induce correlations that are typically ignored when using them as risk predictors. A latent variable approach could summarize these complex relations into a few latent variable scores for use in statistical models. Twenty-two red blood cell (RBC) fatty acids were measured in Framingham (N = 3196). The correlation matrix of the fatty acids was modeled using structural equation modeling; the model was tested for goodness-of-fit and gender invariance. Thirteen fatty acids were summarized by three latent variables, and gender invariance was rejected so separate models were developed for men and women. A score was developed for the polyunsaturated fatty acid (PUFA) latent variable, which explained about 30% of the variance in the data. The PUFA score included loadings in opposing directions among three omega-3 and three omega-6 fatty acids, and incorporated the biosynthetic and dietary relations among them. Whether the PUFA factor score can improve the performance of risk prediction in cardiovascular diseases remains to be tested.
doi:10.1155/2014/160520
PMCID: PMC4052884  PMID: 24959197
21.  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
22.  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
23.  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
24.  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
25.  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

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