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1.  Forward and backward wave morphology and central pressure augmentation in men and women in the Framingham Heart Study 
Hypertension  2014;64(2):259-265.
Central pressure augmentation is associated with greater backward wave amplitude and shorter transit time and is higher in women for reasons only partially elucidated. Augmentation also is affected by left ventricular function and shapes of the forward and backward waves. The goal of this study was to examine the relative contributions of forward and backward wave morphology to central pressure augmentation in men and women. From noninvasive measurements of central pressure and flow in 7437 participants (4036 women) from 19 to 90 years of age (mean age 51 years), we calculated several variables: augmentation index, backward wave arrival time, reflection factor, forward wave amplitude, forward wave peak width and slope of the backward wave upstroke. Linear regression models for augmentation index, adjusted for height and heart rate, demonstrated non-linear relations with age (age: βx00302; =4.6±0.1%, P<0.001; age2: βx00302;=−4.2±0.1%, P<0.001) and higher augmentation in women (βx00302; =4.5±0.4%, P<0.001, model R2=0.35). Addition of reflection factor and backward wave arrival time improved model fit (R2=0.62) and reduced the age coefficients: age (βx00302; =2.3±0.1%, P<0.001) and age2 (βx00302; =−2.2±0.1%, P<0.001). Addition of width of forward wave peak, slope of backward wave upstroke and forward wave amplitude further improved model fit (R2=0.75) and attenuated the sex coefficient (βx00302;=1.9±0.2%, P<0.001). Thus, shape and amplitude of the forward wave may be important correlates of augmentation index, and part of the sex-difference in augmentation index may be explained by forward and backward wave morphology.
PMCID: PMC4184952  PMID: 24866142
augmentation index; wave reflection; pulse pressure; aortic stiffness; left ventricular contraction
2.  Assessing the incremental predictive performance of novel biomarkers over standard predictors 
Statistics in medicine  2014;33(15):2577-2584.
It is unclear to what extent the incremental predictive performance of a novel biomarker is impacted by the method used to control for standard predictors. We investigated whether adding a biomarker to a model with a published risk score overestimates its incremental performance as compared to adding it to a multivariable model with individual predictors (or a composite risk score estimated from the sample of interest), and to a null model. We used 1000 simulated datasets (with a range of risk factor distributions and event rates) to compare these methods, using the continuous Net Reclassification Index (NRI), the Integrated Discrimination Index (IDI), and change in the C-statistic as discrimination metrics. The new biomarker was added to a: null model; model including a published risk score; model including a composite risk score estimated from the sample of interest; and multivariable model with individual predictors. We observed a gradient in the incremental performance of the biomarker, with the null model resulting in the highest predictive performance of the biomarker and the model using individual predictors resulting in the lowest (mean increases in C-statistic between models without and with the biomarker: 0.261, 0.085, 0.030, and 0.031; NRI: 0.767, 0.621, 0.513, and 0.530; IDI: 0.153, 0.093, 0.053 and 0.057, respectively). These findings were supported by Framingham Study data predicting atrial fibrillation using novel biomarkers. We recommend that authors report the effect of a new biomarker after controlling for standard predictors modeled as individual variables.
PMCID: PMC4047140  PMID: 24719270
biomarkers; model discrimination; risk model; risk prediction
3.  Epidemiology of heart failure with preserved ejection fraction 
Heart failure clinics  2014;10(3):377-388.
Heart failure with preserved ejection fraction (HFPEF) is a common condition, especially among the elderly and in women, with the reported prevalence approaching 10% in women over the age of 80 years. With an increasing prevalence of hypertension, obesity, atrial fibrillation, and diabetes, and the growing elderly segment of the general population, the prevalence of HFPEF is projected to increase further. HFPEF presents a diagnostic challenge. As a consequence, studies differ widely in their reported incidence and mortality rates associated with this condition, although there is agreement that between a third and one half of heart failure patients in the community have HFPEF. Although several consensus statements and guidelines have been published during the last decade, some of the recent randomized clinical trials have reported low mortality rates, raising doubts whether all patients diagnosed with HFPEF do actually suffer from HFPEF (as opposed to misdiagnosis) or if the condition is heterogeneous by nature in terms of its etiology and prognosis. The overall reported prognosis of patients with HFPEF remains poor, with patients experiencing substantial comorbidity, high rates of repeated hospitalizations, and a high mortality. In both community-based and hospital-based cohorts, HFPEF was recently reported to be associated with approximately 159 (154–165) deaths per 1000 person-years.
PMCID: PMC4084609  PMID: 24975902
epidemiology; heart failure; preserved ejection fraction; mortality; prognosis
4.  Relation of Long-term Exposure to Air Pollution to Brachial Artery Flow-Mediated Dilation and Reactive Hyperemia 
The American journal of cardiology  2014;113(12):2057-2063.
Long-term exposure to ambient air pollution has been associated with cardiovascular morbidity and mortality. Impaired vascular responses may in part explain these findings, but the association of such long-term exposure with measures of both conduit artery and microvascular function have not been widely reported. We evaluated the association between residential proximity to a major roadway (primary or secondary highway) and spatially resolved average fine particulate matter (PM2.5) and baseline brachial artery diameter and mean flow velocity, flow mediated dilation % and hyperemic flow velocity, in the Framingham Offspring and Third Generation Cohorts. We examined 5,112 participants (2,731 (53%) women, mean age 49±14 years). Spatially resolved average PM2.5 was associated with lower flow mediated dilation% and hyperemic flow velocity. An interquartile range difference in PM2.5 (1.99 μg/m3) was associated with −0.16% (95%CI: −0.27%, −0.05%) lower FMD% and −0.72 (95%CI: −1.38, −0.06) cm/s lower hyperemic flow velocity %. Residential proximity to a major roadway was negatively associated with flow mediated dilation %. Compared to living ≥400 m away, living <50 m from a major roadway was associated with 0.32% lower flow mediated dilation (95% confidence interval (CI): −0.58%, −0.06%), but results for hyperemic flow velocity had wide confidence intervals −0.68 cm/s (95%CI: −2.29, 0.93). In conclusion, residential proximity to a major roadway and higher levels of spatially resolved estimates of PM2.5 at participant residences are associated with impaired conduit artery and microvascular function in this large community-based cohort of middle-aged and elderly adults.
PMCID: PMC4066389  PMID: 24793676
Air Pollution; Brachial Artery; Microvessels; Endothelium; Vascular
5.  Epidemiology and Pathophysiology of Mitral Valve Prolapse: New Insights into Disease Progression, Genetics, and Molecular Basis 
Circulation  2014;129(21):2158-2170.
PMCID: PMC4052751  PMID: 24867995
mitral valve; mitral valve regurgitation; mitral valve prolapse
6.  Insulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy 
Neurology  2014;82(18):1613-1619.
To relate serum insulin-like growth factor-1 (IGF-1) to risk of Alzheimer disease (AD) dementia and to brain volumes in a dementia-free community sample spanning middle and older ages.
Dementia-free Framingham participants from generation 1 (n = 789, age 79 ± 4 years, 64% women) and generation 2 (n = 2,793, age 61 ± 9 years, 55% women; total = 3,582, age 65 ± 11 years, 57% women) had serum IGF-1 measured in 1990–1994 and 1998–2001, respectively, and were followed prospectively for incident dementia and AD dementia. Brain MRI was obtained in stroke- and dementia-free survivors of both generations 1 (n = 186) and 2 (n = 1,867) during 1999–2005. Baseline IGF-1 was related to risk of incident dementia using Cox models and to total brain and hippocampal volumes using linear regression in multivariable models adjusted for age, sex, APOE ε4, plasma homocysteine, waist-hip ratio, and physical activity.
Mean IGF-1 levels were 144 ± 60 μg/L in generation 1 and 114 ± 37 μg/L in generation 2. We observed 279 cases of incident dementia (230 AD dementia) over a mean follow-up of 7.4 ± 3.1 years. Persons with IGF-1 in the lowest quartile had a 51% greater risk of AD dementia (hazard ratio = 1.51, 95% confidence interval: 1.14–2.00; p = 0.004). Among persons without dementia, higher IGF-1 levels were associated with greater total brain volumes (β/SD increment in IGF-1 was 0.55 ± 0.24, p = 0.025; and 0.26 ± 0.06, p < 0.001, for generations 1 and 2, respectively).
Lower serum levels of IGF-1 are associated with an increased risk of developing AD dementia and higher levels with greater brain volumes even among middle-aged community-dwelling participants free of stroke and dementia. Higher levels of IGF-1 may protect against subclinical and clinical neurodegeneration.
PMCID: PMC4013812  PMID: 24706014
7.  Galectin 3 and incident atrial fibrillation in the community 
American heart journal  2014;167(5):729-734.e1.
Galectin 3 (Gal-3) is a potential mediator of cardiac fibrosis, and Gal-3 concentrations predict incident heart failure. The same mechanisms that lead to cardiac fibrosis in heart failure may influence development of atrial fibrosis and atrial fibrillation (AF). We examined the association of Gal-3 and incident AF in the community.
Plasma Gal-3 concentrations were measured in 3,306 participants of the Framingham Offspring cohort who attended the sixth examination cycle (1995–1998, mean age 58 years, 54% women). Cox proportional hazards regression models were used to assess the association of baseline Gal-3 concentrations and incident AF.
Over a median follow-up period of 10 years, 250 participants developed incident AF. Crude incidence rates of AF by increasing sex-specific Gal-3 quartiles were 3.7%, 5.9%, 9.1%, and 11.5% (log-rank test P < .0001). In age- and sex-adjusted analyses, each 1-SD increase in loge-Gal-3 was associated with a 19% increased hazard of incident AF (hazard ratio 1.19, 95% CI 1.05–1.36, P = .009). This association was not significant after adjustment for traditional clinical AF risk factors (hazard ratio 1.12, 95% CI 0.98–1.28, P = .10).
Higher circulating Gal-3 concentrations were associated with increased risk of developing AF over the subsequent 10 years in age- and sex-adjusted analyses but not after accounting for other traditional clinical AF risk factors. Our results do not support a role for Gal-3 in AF risk prediction. Further studies are needed to evaluate whether Gal-3 plays a role in the development of AF substrate similar to HF.
PMCID: PMC4007212  PMID: 24766984
8.  Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects 
To determine whether aortic pulse wave velocity (aPWV) improves prediction of cardiovascular (CVD) events beyond conventional risk factors.
Several studies have shown that aPWV may be a useful risk factor for predicting CVD but have been underpowered to examine whether this is true for different sub-groups.
We undertook a systematic review and obtained individual participant data from 16 studies. Study-specific associations of aPWV with cardiovascular outcomes were determined using Cox proportional hazard models and random effect models to estimate pooled effects.
Of 17,635 participants, 1,785 (10%) had a cardiovascular (CVD) event. The pooled age- and sex-adjusted hazard ratio [95% CI] per SD change in loge aPWV was 1.35 [1.22, 1.50, p<0.001] for coronary heart disease (CHD), 1.54 [1.34, 1.78, p<0.001] for stroke, and 1.45 [1.30, 1.61, p<0.001) for CVD. Associations stratified by sex, diabetes and hypertension were similar, but decreased with age (1.89, 1.77, 1.36 and 1.23 for ≤50, 51–60, 61–70 and >70 years respectively, pinteraction <0.001). After adjusting for conventional risk factors, aPWV remained a predictor: CHD 1.23, [1.11, 1.35 p<0.001]; stroke 1.28, [1.16, 1.42 p<0.001]; cardiovascular events 1.30 [1.18, 1.43, p<0.001]. Reclassification indices showed the addition of aPWV improved risk prediction (13% for 10 year CVD risk for intermediate risk) for some sub-groups.
Consideration of aPWV improves model fit and reclassifies risk for future cardiovascular events in models that include standard risk factors. aPWV may enable better identification of high-risk populations who may benefit from more aggressive cardiovascular risk factor management.
PMCID: PMC4401072  PMID: 24239664
pulse wave velocity; meta-analysis; cardiovascular disease; prognostic factor
9.  Integrative network analysis reveals molecular mechanisms of blood pressure regulation 
Molecular Systems Biology  2015;11(4):799.
Genome-wide association studies (GWAS) have identified numerous loci associated with blood pressure (BP). The molecular mechanisms underlying BP regulation, however, remain unclear. We investigated BP-associated molecular mechanisms by integrating BP GWAS with whole blood mRNA expression profiles in 3,679 individuals, using network approaches. BP transcriptomic signatures at the single-gene and the coexpression network module levels were identified. Four coexpression modules were identified as potentially causal based on genetic inference because expression-related SNPs for their corresponding genes demonstrated enrichment for BP GWAS signals. Genes from the four modules were further projected onto predefined molecular interaction networks, revealing key drivers. Gene subnetworks entailing molecular interactions between key drivers and BP-related genes were uncovered. As proof-of-concept, we validated SH2B3, one of the top key drivers, using Sh2b3−/− mice. We found that a significant number of genes predicted to be regulated by SH2B3 in gene networks are perturbed in Sh2b3−/− mice, which demonstrate an exaggerated pressor response to angiotensin II infusion. Our findings may help to identify novel targets for the prevention or treatment of hypertension.
PMCID: PMC4422556  PMID: 25882670
blood pressure; coexpression network; gene expression; hypertension; systems biology
10.  Association of Sex Hormones, Aging and Atrial Fibrillation in Men: The Framingham Heart Study 
Endogenous sex hormones have been related to cardiovascular outcomes and mortality. We hypothesized that sex hormones are related to atrial fibrillation (AF) in a community-based cohort of middle-aged to older men.
Methods and Results
We examined testosterone, estradiol, and dehydroepiandrosterone sulfate [DHEA-S]) in relation to incident AF in men participating in the Framingham Heart Study. We assessed the 10-year risk of AF in multivariable-adjusted hazard models. The cohort consisted of 1251 men (age 68.0±8.2), of whom 275 developed incident AF. We identified a significant interaction between age and testosterone, and therefore stratified men into age 55–69 (n=786), 70–79 (n=351), and ≥80 (n=114). In men 55–69 each 1-standard deviation (SD) decrease in testosterone was associated with hazard ratio (HR) 1.30 (95% confidence interval [CI], 1.07 to 1.59) for incident AF. The association between testosterone and 10-year incident AF in men 70–79 did not reach statistical significance. In men ≥80 years a 1-SD decrease in testosterone was associated with HR 3.53 (95% CI, 1.96 to 6.37) for AF risk. Estradiol was associated with incident AF (HR, 1.12; 95% CI, 1.01 to 1.26). DHEA-S had a borderline association with risk of AF that was not statistically significant (HR, 1.12; 95% CI, 0.99 to 1.28).
Testosterone and estradiol are associated with incident AF in a cohort of older men. Testosterone deficiency in men ≥80 is strongly associated with AF risk. The clinical and electrophysiologic mechanisms underlying the associations between sex hormones and AF in older men merit continued investigation.
PMCID: PMC4035016  PMID: 24610804
atrial fibrillation; sex hormones; men; aging; epidemiology
11.  A Meta-analysis of Gene Expression Signatures of Blood Pressure and Hypertension 
PLoS Genetics  2015;11(3):e1005035.
Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%–9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension.
Author Summary
The focus of blood pressure (BP) GWAS has been the identification of common DNA sequence variants associated with the phenotype; this approach provides only one dimension of molecular information about BP. While it is a critical dimension, analyzing DNA variation alone is not sufficient for achieving an understanding of the multidimensional complexity of BP physiology. The top loci identified by GWAS explain only about 1 percent of inter-individual BP variability. In this study, we performed a meta-analysis of gene expression profiles in relation to BP and hypertension in 7017 individuals from six studies. We identified 34 differentially expressed genes for BP, and discovered that the top BP signature genes explain 5%–9% of BP variability. We further linked BP gene expression signature genes with BP GWAS results by integrating expression associated SNPs (eSNPs) and discovered that one of the top BP loci from GWAS, rs3184504 in SH2B3, is a trans regulator of expression of 6 of the top 34 BP signature genes. Our study, in conjunction with prior GWAS, provides a deeper understanding of the molecular and genetic basis of BP regulation, and identifies several potential targets and pathways for the treatment and prevention of hypertension and its sequelae.
PMCID: PMC4365001  PMID: 25785607
13.  Moderate‐to‐Vigorous Physical Activity With Accelerometry is Associated With Visceral Adipose Tissue in Adults 
We examined the relation between objectively measured physical activity with accelerometry and subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in a community‐based sample.
Methods and Results
We evaluated 1249 participants of the Framingham Third Generation and Omni II cohorts (mean age 51.7 years, 47% women) who underwent assessment of moderate‐to‐vigorous physical activity (MVPA) with accelerometry over 5 to 7 days, and multi‐detector computed tomography for measurement of SAT and VAT volume; fat attenuation was estimated by SAT and VAT hounsfield units (HU). In women, higher levels of MVPA were associated with decreased SAT (P<0.0001) and VAT volume (P<0.0001). The average decrement in VAT per 30 minute/day increase in MVPA was −453 cm3 (95% CI −574, −331). The association was attenuated but persisted upon adjustment for BMI (−122 cm3, P=0.002). Higher levels of MVPA were associated with higher SAT HU (all P≤0.01), a marker of fat quality, even after adjustment for SAT volume. Similar findings were observed in men but the magnitude of the association was less. Sedentary time was not associated with SAT or VAT volume or quality in men or women.
MVPA was associated with less VAT and SAT and better fat quality.
PMCID: PMC4392428  PMID: 25736442
accelerometry; physical activity; visceral adipose tissue
14.  Physical Activity Measured by Accelerometry and its Associations With Cardiac Structure and Vascular Function in Young and Middle‐Aged Adults 
Physical activity is associated with several health benefits, including lower cardiovascular disease risk. The independent influence of physical activity on cardiac and vascular function in the community, however, has been sparsely investigated.
Measures and Results
We related objective measures of moderate‐ to vigorous‐intensity physical activity (MVPA, assessed by accelerometry) to cardiac and vascular indices in 2376 participants of the Framingham Heart Study third generation cohort (54% women, mean age 47 years). Using multivariable regression models, we related MVPA to the following echocardiographic and vascular measures: left ventricular mass, left atrial and aortic root sizes, carotid–femoral pulse wave velocity, augmentation index, and forward pressure wave. Men and women engaged in MVPA 29.9±21.4 and 25.5±19.4 min/day, respectively. Higher values of MVPA (per 10‐minute increment) were associated with lower carotid–femoral pulse wave velocity (estimate −0.53 ms/m; P=0.006) and lower forward pressure wave (estimate −0.23 mm Hg; P=0.03) but were not associated with augmentation index (estimate 0.13%; P=0.25). MVPA was associated positively with loge left ventricular mass (estimate 0.006 loge [g/m2]; P=0.0003), left ventricular wall thickness (estimate 0.07 mm; P=0.0001), and left atrial dimension (estimate 0.10 mm; P=0.01). MVPA also tended to be positively associated with aortic root dimension (estimate 0.05 mm; P=0.052). Associations of MVPA with cardiovascular measures were similar, in general, for bouts lasting <10 versus ≥10 minutes.
In our community‐based sample, greater physical activity was associated with lower vascular stiffness but with higher echocardiographic left ventricular mass and left atrial size. These findings suggest complex relations of usual levels of physical activity and cardiovascular remodeling.
PMCID: PMC4392434  PMID: 25792127
echocardiography; epidemiology; physical activity; vascular measures
15.  Circulating Brain‐Derived Neurotrophic Factor Concentrations and the Risk of Cardiovascular Disease in the Community 
Brain‐derived neurotrophic factor (BDNF) is a pleiotropic peptide involved in maintaining endothelial integrity. It is unknown if circulating BDNF levels are associated with risk of cardiovascular disease (CVD).
Methods and Results
We prospectively investigated the association of circulating BDNF levels with cardiovascular events and mortality in 3687 participants (mean age 65 years, 2068 women) from the Framingham Heart Study (FHS). Using a common nonsynonomous single nucleotide polymorphism (SNP) in the BDNF gene (rs6265), we then performed a Mendelian randomization experiment in the CARDIoGRAM (Coronary ARtery DIsease Genome‐Wide Replication And Meta‐Analysis) consortium (>22 000 coronary artery disease [CAD] cases, >60 000 controls) to investigate whether SNP rs6265 was associated with CAD in CARDIoGRAM and, if so, whether the effect estimate differed from that predicted based on FHS data. On follow‐up (median 8.9 years), 467 individuals (261 women) in FHS experienced a CVD event, and 835 (430 women) died. In multivariable‐adjusted Cox regression, serum BDNF was associated inversely with CVD risk (hazard ratio [HR] per 1‐SD increase 0.88, 95% CI 0.80 to 0.97, P=0.01) and with mortality (HR 0.87, 95% CI 0.80 to 0.93, P=0.0002). SNP rs6265 was associated with BDNF concentrations (0.772 ng/mL increase per minor allele copy) in FHS. In CARDIoGRAM, SNP rs6265 was associated with CAD (odds ratio 0.957, 95% CI 0.923 to 0.992), a magnitude consistent with the predicted effect (HR per minor allele copy 0.99, 95% CI 0.98 to 1.0; P=0.06 for difference between predicted and observed effect).
Higher serum BDNF is associated with a decreased risk of CVD and mortality. Mendelian randomization suggests a causal protective role of BDNF in the pathogenesis of CVD.
PMCID: PMC4392437  PMID: 25762803
cardiovascular disease; growth factors; Mendelian randomization; mortality; risk factors
16.  Clinical Correlates and Prognostic Significance of Change in Standardized Left Ventricular Mass in a Community‐Based Cohort of African Americans 
Though left ventricular mass (LVM) predicts cardiovascular events (CVD) and mortality in African Americans, limited data exists on factors contributing to change in LVM and its prognostic significance. We hypothesized that baseline blood pressure (BP) and body mass index (BMI) and change in these variables over time are associated with longitudinal increases in LVM and that such increase is associated with greater incidence of CVD.
Methods and Results
We investigated the clinical correlates of change in standardized logarithmically transformed‐LVM indexed to height2.7 (log‐LVMI) and its association with incident CVD in 606 African Americans (mean age 58±6 years, 66% women) who attended serial examinations 8 years apart. Log‐LVMI and clinical covariates were standardized within sex to obtain z scores for both visits. Standardized log‐LVMI was modeled using linear regression (correlates of change in standardized log‐LVMI) and Cox proportional hazards regression (incidence of CVD [defined as coronary heart disease, stroke, heart failure and intermittent claudication]). Baseline clinical correlates (standardized log‐LVM, BMI, systolic BP) and change in systolic BP over time were significantly associated with 8‐year change in standardized log‐LVMI. In prospective analysis, change in standardized LVM was significantly (P=0.0011) associated with incident CVD (hazards ratio per unit standard deviation change log‐LVMI 1.51, 95% CI 1.18 to 1.93).
In our community‐based sample of African Americans, baseline BMI and BP, and change in BP on follow‐up were key determinants of increase in standardized log‐LVMI, which in turn carried an adverse prognosis, underscoring the need for greater control of BP and weight in this group.
PMCID: PMC4345860  PMID: 25655570
African Americans; blood pressure; cardiovascular disease; cardiovascular events; left ventricular mass risk factors
17.  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
18.  Early Expression of Mitral Valve Prolapse in the Framingham Offspring: Phenotypic Spectrum 
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.
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.
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).
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.
PMCID: PMC4239996  PMID: 24206636
mitral valve prolapse; echocardiography
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.  Multilevel modeling versus cross-sectional analysis for assessing the longitudinal tracking of cardiovascular risk factors over time 
Statistics in medicine  2013;32(28):5028-5038.
Correlated data are obtained in longitudinal epidemiological studies, where repeated measurements are taken on individuals or groups over time. Such longitudinal data are ideally analyzed using multilevel modeling approaches, which appropriately account for the correlations in repeated responses in the same individual. Commonly used regression models are inappropriate as they assume that measurements are independent. In this tutorial, we use multilevel modeling to demonstrate its use for analysis of correlated data obtained from serial examinations on individuals. We focus on cardiovascular epidemiological research where investigators are often interested in quantifying the relations between clinical risk factors and outcome measures (X and Y, respectively), where X and Y are measured repeatedly over time, e.g., using serial observations on participants attending multiple examinations in a longitudinal cohort study. For instance, it may be of interest to evaluate the relations between serial measures of left ventricular mass (outcome) and of its potential determinants (i.e., body mass index, blood pressure etc.), both of which are measured over time. In this tutorial, we describe the application of multilevel modeling to cardiovascular risk factors and outcome data (using serial echocardiographic data as an example of an outcome). We suggest an analytical approach that can be implemented to evaluate relations between any potential outcome of interest and risk factors, including assessment of random effects and non-linear relations. We illustrate these steps using echocardiographic data from the Framingham Heart Study with SAS PROC MIXED.
PMCID: PMC4068405  PMID: 23784950
multilevel modeling; cohort study; risk factors
21.  Prioritizing causal disease genes using unbiased genomic features 
Genome Biology  2014;15(12):3274.
Cardiovascular disease (CVD) is the leading cause of death in the developed world. Human genetic studies, including genome-wide sequencing and SNP-array approaches, promise to reveal disease genes and mechanisms representing new therapeutic targets. In practice, however, identification of the actual genes contributing to disease pathogenesis has lagged behind identification of associated loci, thus limiting the clinical benefits.
To aid in localizing causal genes, we develop a machine learning approach, Objective Prioritization for Enhanced Novelty (OPEN), which quantitatively prioritizes gene-disease associations based on a diverse group of genomic features. This approach uses only unbiased predictive features and thus is not hampered by a preference towards previously well-characterized genes. We demonstrate success in identifying genetic determinants for CVD-related traits, including cholesterol levels, blood pressure, and conduction system and cardiomyopathy phenotypes. Using OPEN, we prioritize genes, including FLNC, for association with increased left ventricular diameter, which is a defining feature of a prevalent cardiovascular disorder, dilated cardiomyopathy or DCM. Using a zebrafish model, we experimentally validate FLNC and identify a novel FLNC splice-site mutation in a patient with severe DCM.
Our approach stands to assist interpretation of large-scale genetic studies without compromising their fundamentally unbiased nature.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0534-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4279789  PMID: 25633252
22.  Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins 
Postmus, Iris | Trompet, Stella | Deshmukh, Harshal A. | Barnes, Michael R. | Li, Xiaohui | Warren, Helen R. | Chasman, Daniel I. | Zhou, Kaixin | Arsenault, Benoit J. | Donnelly, Louise A. | Wiggins, Kerri L. | Avery, Christy L. | Griffin, Paula | Feng, QiPing | Taylor, Kent D. | Li, Guo | Evans, Daniel S. | Smith, Albert V. | de Keyser, Catherine E. | Johnson, Andrew D. | de Craen, Anton J. M. | Stott, David J. | Buckley, Brendan M. | Ford, Ian | Westendorp, Rudi G. J. | Eline Slagboom, P. | Sattar, Naveed | Munroe, Patricia B. | Sever, Peter | Poulter, Neil | Stanton, Alice | Shields, Denis C. | O’Brien, Eoin | Shaw-Hawkins, Sue | Ida Chen, Y.-D. | Nickerson, Deborah A. | Smith, Joshua D. | Pierre Dubé, Marie | Matthijs Boekholdt, S. | Kees Hovingh, G. | Kastelein, John J. P. | McKeigue, Paul M. | Betteridge, John | Neil, Andrew | Durrington, Paul N. | Doney, Alex | Carr, Fiona | Morris, Andrew | McCarthy, Mark I. | Groop, Leif | Ahlqvist, Emma | Bis, Joshua C. | Rice, Kenneth | Smith, Nicholas L. | Lumley, Thomas | Whitsel, Eric A. | Stürmer, Til | Boerwinkle, Eric | Ngwa, Julius S. | O’Donnell, Christopher J. | Vasan, Ramachandran S. | Wei, Wei-Qi | Wilke, Russell A. | Liu, Ching-Ti | Sun, Fangui | Guo, Xiuqing | Heckbert, Susan R | Post, Wendy | Sotoodehnia, Nona | Arnold, Alice M. | Stafford, Jeanette M. | Ding, Jingzhong | Herrington, David M. | Kritchevsky, Stephen B. | Eiriksdottir, Gudny | Launer, Leonore J. | Harris, Tamara B. | Chu, Audrey Y. | Giulianini, Franco | MacFadyen, Jean G. | Barratt, Bryan J. | Nyberg, Fredrik | Stricker, Bruno H. | Uitterlinden, André G. | Hofman, Albert | Rivadeneira, Fernando | Emilsson, Valur | Franco, Oscar H. | Ridker, Paul M. | Gudnason, Vilmundur | Liu, Yongmei | Denny, Joshua C. | Ballantyne, Christie M. | Rotter, Jerome I. | Adrienne Cupples, L. | Psaty, Bruce M. | Palmer, Colin N. A. | Tardif, Jean-Claude | Colhoun, Helen M. | Hitman, Graham | Krauss, Ronald M. | Wouter Jukema, J | Caulfield, Mark J.
Nature Communications  2014;5:5068.
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
Statins are effectively used to prevent and manage cardiovascular disease, but patient response to these drugs is highly variable. Here, the authors identify two new genes associated with the response of LDL cholesterol to statins and advance our understanding of the genetic basis of drug response.
PMCID: PMC4220464  PMID: 25350695
23.  Reproducibility of Speckle-Tracking Based Strain Measures of Left Ventricular Function in a Community-Based Study 
The reproducibility of echocardiographic measurements of myocardial strain, performed in a community-based setting, has not been reported previously.
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.
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.
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.
PMCID: PMC3812381  PMID: 23953701
24.  Clinically Relevant Functional Annotation of Genotype 
PMCID: PMC4188549  PMID: 24550428
25.  Mendelian Randomization Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes 
Yaghootkar, Hanieh | Lamina, Claudia | Scott, Robert A. | Dastani, Zari | Hivert, Marie-France | Warren, Liling L. | Stancáková, Alena | Buxbaum, Sarah G. | Lyytikäinen, Leo-Pekka | Henneman, Peter | Wu, Ying | Cheung, Chloe Y.Y. | Pankow, James S. | Jackson, Anne U. | Gustafsson, Stefan | Zhao, Jing Hua | Ballantyne, Christie M. | Xie, Weijia | Bergman, Richard N. | Boehnke, Michael | el Bouazzaoui, Fatiha | Collins, Francis S. | Dunn, Sandra H. | Dupuis, Josee | Forouhi, Nita G. | Gillson, Christopher | Hattersley, Andrew T. | Hong, Jaeyoung | Kähönen, Mika | Kuusisto, Johanna | Kedenko, Lyudmyla | Kronenberg, Florian | Doria, Alessandro | Assimes, Themistocles L. | Ferrannini, Ele | Hansen, Torben | Hao, Ke | Häring, Hans | Knowles, Joshua W. | Lindgren, Cecilia M. | Nolan, John J. | Paananen, Jussi | Pedersen, Oluf | Quertermous, Thomas | Smith, Ulf | Lehtimäki, Terho | Liu, Ching-Ti | Loos, Ruth J.F. | McCarthy, Mark I. | Morris, Andrew D. | Vasan, Ramachandran S. | Spector, Tim D. | Teslovich, Tanya M. | Tuomilehto, Jaakko | van Dijk, Ko Willems | Viikari, Jorma S. | Zhu, Na | Langenberg, Claudia | Ingelsson, Erik | Semple, Robert K. | Sinaiko, Alan R. | Palmer, Colin N.A. | Walker, Mark | Lam, Karen S.L. | Paulweber, Bernhard | Mohlke, Karen L. | van Duijn, Cornelia | Raitakari, Olli T. | Bidulescu, Aurelian | Wareham, Nick J. | Laakso, Markku | Waterworth, Dawn M. | Lawlor, Debbie A. | Meigs, James B. | Richards, J. Brent | Frayling, Timothy M.
Diabetes  2013;62(10):3589-3598.
Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics–based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26–0.35) increase in fasting insulin, a 0.34-SD (0.30–0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47–2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI −0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (−0.20 SD; 95% CI −0.38 to −0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75–1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: −0.03 SD; 95% CI −0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95–1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.
PMCID: PMC3781444  PMID: 23835345

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