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.
Concentric hypertrophy; eccentric hypertrophy; left ventricular hypertrophy; heart failure; risk
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.
mitral valve prolapse; echocardiography
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.
atrial fibrillation; biomarker; risk factor
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.
multilevel modeling; cohort study; risk factors
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.
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.
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.
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.
Several pathomechanisms are implicated in the pathogenesis of metabolic syndrome (MetS), most of which have not been investigated in African Americans (AAs). We examined the contribution of a selected panel of biomarkers to the development of MetS in Jackson Heart Study (JHS) participants in this investigation.
RESEARCH DESIGN AND METHODS
We evaluated 3,019 JHS participants (mean age, 54 years; 64% women) with measurements for seven biomarkers representing inflammation (high-sensitivity C-reactive protein [CRP]), adiposity (leptin), natriuretic pathway (B-natriuretic peptide [BNP]), adrenal pathway (cortisol and aldosterone), and endothelial function (endothelin and homocysteine). We related the biomarker panel to the development of MetS on follow-up and to longitudinal changes in MetS components.
There were 278 (22.9%) of 1,215 participants without MetS at baseline who had development of new-onset MetS at follow-up. The incidence of MetS was significantly associated with serum aldosterone (P = 0.004), CRP (P = 0.03), and BNP (P for trend = 0.005). The multivariable-adjusted odds ratios (95% CI) per SD increment of log biomarker were as follows: 1.25 (1.07–1.45) for aldosterone, 1.20 (1.02–1.43) for CRP, and 1.54 (1.07–2.23) and 1.91 (1.31–2.80) for low and high BNP quartiles, respectively. Aldosterone was positively associated with change in all MetS risk components, except low HDL cholesterol and waist circumference. CRP concentration was significantly and directly associated with change in systolic blood pressure (SBP) and waist circumference but inversely associated with HDL cholesterol. For BNP, we observed a U-shape relation with SBP and triglycerides.
Our analysis confirms that, in AAs, higher circulating aldosterone and CRP concentrations predict incident MetS. The nonlinear U-shape relation of BNP with MetS and its components has not been reported before and thus warrants replication.
Background and Purpose
BDNF, a major neurotrophin and VEGF, an endothelial growth factor have a documented role in neurogenesis, angiogenesis and neuronal survival. In animal experiments they impact infarct size and functional motor recovery after an ischemic brain lesion. We sought to examine the association of serum BDNF and VEGF with the risk of clinical stroke or subclinical vascular brain injury in a community-based sample.
In 3440 stroke/TIA-free FHS participants (mean age 65±11yrs, 56%W), we related baseline BDNF and logVEGF to risk of incident stroke/TIA. In a subsample with brain MRI and with neuropsychological (NP) tests available (N=1863 and 2104, respectively; mean age 61±9yrs, 55%W, in each) we related baseline BDNF and logVEGF to log-white matter hyperintensity volume (lWMHV) on brain MRI, and to visuospatial memory and executive function tests.
During a median follow-up of 10 years, 193 participants experienced incident stroke/TIA. In multivariable analyses adjusted for age-, sex- and traditional stroke risk factors, lower BDNF and higher logVEGF levels were associated with an increased risk of incident stroke/TIA (HR comparing BDNF Q1 versus Q2–4:1.47, 95%CI:1.09–2.00, p=0.012; and HR/SD increase in logVEGF:1.21, 95%CI:1.04–1.40, p=0.012). Persons with higher BDNF levels had less lWMHV (β±SE=−0.05±0.02; p=0.025), and better visual memory (β±SE=0.18±0.07; p=0.005).
Lower serum BDNF and higher VEGF concentrations were associated with increased risk of incident stroke/TIA. Higher levels of BDNF were also associated with less white matter hyperintensity and better visual memory. Our findings suggest that circulating BDNF and VEGF levels modify risk of clinical and subclinical vascular brain injury.
BDNF; VEGF; Risk; Stroke; Brain MRI; Subclinical
Whereas greater physical activity (PA) is known to prevent cardiovascular disease (CVD), the relative importance of performing PA in sustained bouts of activity versus shorter bouts of activity on CVD risk is not known. The objective of this study was to investigate the relationship between moderate-to-vigorous physical activity (MVPA), measured in bouts ≥10 minutes and <10 minutes, and CVD risk factors in a well-characterized, community-based sample of white adults.
We conducted a cross-sectional analysis of 2109 Framingham Heart Study Third Generation participants (mean age 47 years, 55% women) who underwent objective assessment of PA by accelerometry over 5–7 days. Total MVPA, MVPA done in bouts ≥10 minutes (MVPA10+), and MVPA done in bouts <10 minutes (MVPA<10) were calculated. MVPA exposures were related to individual CVD risk factors, including measures of adiposity and blood lipid and glucose levels, using linear and logistic regression.
Total MVPA was significantly associated with higher high-density lipoprotein (HDL) levels, and with lower triglycerides, BMI, waist circumference and Framingham risk score (P <0.0001). MVPA<10 showed similar statistically significant associations with these CVD risk factors (P <0.001). Compliance with national guidelines (≥150 minutes of total MVPA) was significantly related to lower BMI, triglycerides, Framingham risk score, waist circumference, higher HDL, and a lower prevalence of obesity and impaired fasting glucose (P < 0.001 for all).
Our cross-sectional observations on a large middle-aged community-based sample confirm a positive association of MVPA with a healthier CVD risk factor profile, and indicate that accruing physical activity in bouts <10 minutes may favorably influence cardiometabolic risk. Additional investigations are warranted to confirm our findings.
accelerometer; heart disease; exercise; guidelines
Emerging data from longitudinal studies suggests that low sex steroid concentrations in men are associated with increased cardiovascular risk and mortality. The impact of longitudinal trajectory patterns from serial sex steroid and gonadotropin measurements on the observed associations is unknown to date.
We prospectively evaluated 254 elderly men (mean age: 75.5 years) of the Framingham Heart Study with up to four serial measurements of serum total testosterone (TT), dehydroepiandrosterone sulfate (DHEAS), follicle stimulating hormone (FSH), luteinizing hormone (LH), and total estradiol (EST); and constructed age- and multivariable-adjusted Cox proportional hazard regression models relating baseline hormone concentrations and their mean, slope, and variation over time (modelled as continuous and categorized into quartiles) to the incidence of clinical cardiovascular disease (CVD) and all-cause mortality at 5-years and 10-years of follow-up.
We observed no association between baseline concentrations of sex steroids, gonadotropins, and their trajectories with incident clinical CVD over 5-years and 10-years follow-up, respectively. Although higher baseline TT concentrations were associated with lower mortality risk at 5-years (hazard ratio per quartile increment, 0.74; 95% confidence interval, 0.56 – 0.98), correction for multiple statistical testing (p <0.005) rendered this association statistically non-significant. Repeat analyses at the 10-year follow-up time point also demonstrated no significant association between sex steroids, gonadotropins, or their trajectories and mortality.
Investigating longitudinal trajectory patterns of serial sex steroid and gonadotropin measurements, the present study found no consistent associations with incident clinical CVD and all-cause mortality risk in elderly men in the community.
sex steroids; gonadotropins; testosterone; men; cardiovascular disease; trajectories; longitudinal; Framingham Heart Study
To determine the association of arterial stiffness and pressure pulsatility, which can damage small vessels in the brain, with vascular and Alzheimer-type brain aging.
Stroke- and dementia-free Framingham Offspring Study participants (n = 1,587, 61 ± 9 years, 45% male) underwent study of tonometric arterial stiffness and endothelial function (1998–2001) and brain MRI and cognition (1999–2002). We related carotid-femoral pulse wave velocity (CFPWV), mean arterial and central pulse pressure, and endothelial function to vascular brain aging by MRI (total cerebral brain volume [TCBV], white matter hyperintensity volume, silent cerebral infarcts) and vascular and Alzheimer-type cognitive aging (Trails B minus Trails A and logical memory-delayed recall, respectively).
Higher CFPWV was associated with lower TCBV, greater white matter hyperintensity volume, and greater prevalence of silent cerebral infarcts (all p < 0.05). Each SD greater CFPWV was associated with lower TCBV equivalent to 1.2 years of brain aging. Mean arterial and central pulse pressure were associated with greater white matter hyperintensity volume (p = 0.005) and lower TCBV (p = 0.02), respectively, and worse verbal memory (both p < 0.05). Associations of tonometry variables with TCBV and white matter hyperintensity volume were stronger among those aged 65 years and older vs those younger than 65 years (p < 0.10 for interaction). Brachial artery endothelial function was unrelated to MRI measures (all p > 0.05).
Greater arterial stiffness and pressure pulsatility are associated with brain aging, MRI vascular insults, and memory deficits typically seen in Alzheimer dementia. Future investigations are warranted to evaluate the potential impact of prevention and treatment of unfavorable arterial hemodynamics on neurocognitive outcomes.
On October 11, 2013, the Framingham Heart Study will celebrate 65 years since the examination of its first participant in 1948. During this period, the study has provided substantial insight into the epidemiology of cardiovascular disease and its risk factors. The origin of the study is closely linked to the cardiovascular health of President Franklin D. Roosevelt and his premature death from hypertensive heart disease and stroke in 1945. The present article describes the events leading to the founding of the Framingham Heart Study, and provides a brief historical overview of selected contributions from the study.
We assessed GGT fractions correlates and their reference values in the Offspring Cohort of the Framingham Heart Study.
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].
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].
Metabolic and cardiovascular risk markers are important correlates of GGT fractions, in particular of b-GGT.
gamma-glutamyltransferase activity; gamma-glutamyltransferase fractions; gel-filtration chromatography; reference values; markers
In low-renin hypertension (LRH), serum aldosterone levels are higher in those subjects with primary aldosteronism and may be lower in those with non-aldosterone mineralocorticoid excess or primary renal sodium retention. We investigated the hypothesis that the frequency distribution of aldosterone in LRH is bimodal.
Of the 3,532 attendees at the sixth examination cycle of the Framingham Offspring Study, 1,831 were included in this cross-sectional analysis after we excluded those with conditions or taking medications such as antihypertensive drugs that might affect renin or aldosterone.
Three hundred three subjects (17%) had untreated hypertension (SBP ≥140mm Hg or DBP ≥90mm Hg). LRH, defined as plasma renin ≤5 mU/L, was present in 93 of those 303 hypertensive subjects (31%). Aldosterone values were adjusted statistically for age, sex, and the urinary sodium/creatinine ratio. In the subjects with LRH, the adjusted aldosterone distribution was bimodal (dip test for unimodality, P = 0.008). The adjusted aldosterone distribution was unimodal in the normal subjects (P = 0.98) and in the hypertensive subjects with normal plasma renin (P = 0.94).
In this community-based sample of white subjects, those with low-renin hypertension had a bimodal adjusted aldosterone distribution. Subjects with normal-renin hypertension and subjects with normal blood pressure had unimodal adjusted aldosterone distributions. These findings suggest 2 pathophysiological variants of LRH, one that is aldosterone-dependent and one that is non-aldosterone-dependent.
aldosterone; blood pressure; hypertension; low-renin hypertension; renin.
In postmenopausal women and preclinical murine models, estrogen administration reduces diabetes risk; however, the relationship of estradiol and estrone to diabetes in men is poorly understood. We determined the relationship between circulating estradiol and estrone levels and diabetes risk in community-dwelling men of the Framingham Heart Study (FHS).
RESEARCH DESIGN AND METHODS
Cross-sectional relationships of estradiol and estrone levels with diabetes were assessed at examination 7 (1998–2001) in FHS generation 2 men (n = 1,458); prospective associations between hormone levels at examination 7 and incident diabetes were assessed 6.8 years later at examination 8. Type 2 diabetes mellitus was defined as fasting glucose >125 mg/dL, medication use, or both. Estradiol, estrone, and testosterone levels were measured with liquid chromatography–tandem mass spectrometry, and free estradiol and estrone were calculated.
In cross-sectional models, men with elevated estrone and estradiol had 40% and 62% increased likelihoods of existing diabetes per cross-sectional doubling of estrone and estradiol levels, respectively. Free estrone (cross-sectional odds ratio 1.28 [95% CI 1.02–1.62], P = 0.04) was associated with impaired fasting glucose at examination 7. There was an increase in risk of existing diabetes with increasing quartiles of total and free estrone and estradiol and an increase in risk of incident diabetes with increasing quartiles of estrone levels. In multivariate longitudinal analyses, a twofold increase in total or free estrone levels at examination 7 was associated with 77 and 93% increases, respectively, in odds of incident diabetes at examination 8.
Although both estradiol and estrone exhibit cross-sectional associations with diabetes in men, in longitudinal analyses estrone is a more sensitive marker of diabetes risk than is estradiol.
The association of familial as compared to genetic factors in the current obesogenic environment, compared to earlier, leaner time periods, is uncertain.
Design and Methods
Participants from the Framingham Heart Study were classified according to parental obesity status in the Original, Offspring, and Third Generation cohorts; mean BMI levels were estimated and we compared the association of parental history across generations. Finally, a genetic risk score comprised of 32 well-replicated single nucleotide polymorphisms for BMI was examined in association with BMI levels in 1948, 1971, and 2002.
BMI was 1.49 kg/m2 higher per each affected parent among the Offspring, and increased to 2.09 kg/m2 higher among the Third Generation participants (p-value for the cohort comparison=0.007). Parental history of obesity was associated with increased weight gain (p<0.0001) and incident obesity (p=0.009). Despite a stronger association of parental obesity with offspring BMI in more contemporary time periods, we observed no change in the effect size of a BMI genetic risk score from 1948 to 2002 (p=0.11 for test of trend across the time periods).
The association of parental obesity has become stronger in more contemporary time period, whereas the association of a BMI genetic risk score has not changed.
obesity; epidemiology; weight change; family history; Framingham Heart Study
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.
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.
reference limits; myocardial deformation; echocardiography
Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine produced in cardiovascular cells under conditions of inflammation and oxidative stress, and is emerging as an important prognostic marker in individuals with and without existing cardiovascular disease. Thus, we examined the clinical and genetic correlates of circulating GDF-15 levels, which have not been collectively investigated.
A total of 2,991 participants of the Framingham Offspring Study free of clinically overt cardiovascular disease underwent measurement of plasma GDF-15 levels (mean age 59 years, 56% women). Clinical correlates of GDF-15 were examined in multivariable analyses. A genome-wide association study of GDF-15 levels was then conducted, including participants of the Framingham Offspring Study and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.
GDF-15 was positively associated with age, smoking, antihypertensive treatment, diabetes, worse kidney function, and non-steroidal anti-inflammatory drug use, but it was negatively associated with total and high-density lipoprotein cholesterol. Clinical correlates accounted for 38% of inter-individual variation in circulating GDF-15, whereas genetic factors account for up to 38% of residual variability (h2=0.38; P=2.5 × 10−11). We identified one genome-wide significant locus, which included the GDF15 gene, on chromosome 19p13.11 associated with GDF-15 concentrations (smallest P=2.74−32 for rs888663). Conditional analyses revealed two independent association signals at this locus (rs888663 and rs1054564), which were associated with altered cis-gene expression in blood cell lines.
In ambulatory individuals, both cardiometabolic risk factors and genetic factors play an important role in determining circulating GDF-15 concentrations, and contribute similarly to overall variation.
Epidemiology; Genetics; Risk factors; Cardiovascular diseases
Evidence for cardioprotective effects of lycopene is inconsistent. Studies of circulating lycopene generally report inverse associations with cardiovascular disease (CVD) risk, but studies based on lycopene intake do not. The failure of the dietary studies to support the findings based on biomarkers may be due in part to misclassification of lycopene intakes. To address this potential misclassification, we used repeated measures of intake obtained over 10 years to characterize the relation between lycopene intake and incidence of CVD (n=314), coronary heart disease (CHD, n=171) and stroke (n=99) in the Framingham Offspring Study. Hazards ratios (HR) for incident outcomes were derived from Cox proportional hazards regression models using logarithmically transformed lycopene intake adjusted for CVD risk factors and correlates of lycopene intake. HRs were interpreted as the increased risk for a 2.7-fold difference in lycopene intake, a difference approximately equal to its inter-quartile range. Using an average of three intake measures with a 9 year follow-up, lycopene intake was inversely associated with CVD incidence (hazards ratio (HR): 0.83, 95% confidence interval (CI): 0.70-0.98). Using an average of two intake measures and 11 years of follow-up, lycopene intake was inversely associated with CHD incidence (HR: 0.74, 95% CI: 0.58-0.94). Lycopene intake was unrelated to stroke incidence. Our study of lycopene intake and CVD provides supporting evidence for an inverse association between lycopene and CVD risk but additional research is needed to determine if lycopene or other components of tomatoes, the major dietary source of lycopene, are responsible for the observed association.
lycopene; cardiovascular disease; coronary heart disease; stroke
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).
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.
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.
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.