In animal studies, brain-derived neurotrophic factor (BDNF) has been shown to impact neuronal survival and function and improve synaptic plasticity and long-term memory. Circulating BDNF levels increase with physical activity and caloric restriction, thus BDNF may mediate some of the observed associations between lifestyle and the risk for dementia. Some prior studies showed lower circulating BDNF in persons with Alzheimer disease (AD) compared with control participants; however, it remains uncertain whether reduced levels precede dementia onset.
To examine whether higher serum BDNF levels in cognitively healthy adults protect against the future risk for dementia and AD and to identify potential modifiers of this association.
DESIGN, SETTING, AND PARTICIPANTS
Framingham Study original and offspring participants were followed up from 1992 and 1998, respectively, for up to 10 years. We used Cox models to relate BDNF levels to the risk for dementia and AD and adjusted for potential confounders. We also ran sensitivity analyses stratified by sex, age, and education, as well as related BDNF genetic variants to AD risk. This community-based, prospective cohort study involved 2131 dementia-free participants aged 60 years and older (mean [SD] age, 72  years; 56% women).
MAIN OUTCOMES AND MEASURES
Ten-year incidence of dementia and AD.
During follow-up, 140 participants developed dementia, 117 of whom had AD. Controlling for age and sex, each standard-deviation increment in BDNF was associated with a 33% lower risk for dementia and AD (P = .006 and P = .01, respectively) and these associations persisted after additional adjustments. Compared with the bottom quintile, BDNF levels in the top quintile were associated with less than half the risk for dementia and AD (hazard ratio, 0.49; 95%CI, 0.28–0.85; P = .01; and hazard ratio, 0.46; 95%CI, 0.24–0.86; P = .02, respectively). These associations were apparent only among women, persons aged 80 years and older, and those with college degrees (hazard ratios for AD: 0.65, [95%CI, 0.50–0.85], P = .001; 0.63 [95%CI, 0.47–0.85], P = .002; and 0.27 [95%CI, 0.11–0.65], P = .003, respectively). Brain-derived neurotrophic factor genetic variants were not associated with AD risk.
CONCLUSIONS AND RELEVANCE
Higher serum BDNF levels may protect against future occurrence of dementia and AD. Our findings suggest a role for BDNF in the biology and possibly in the prevention of dementia and AD, especially in select subgroups of women and older and more highly educated persons.
Genome-wide association studies (GWAS) offer an excellent opportunity to identify the genetic variants underlying complex human diseases. Successful utilization of this approach requires a large sample size to identify single nucleotide polymorphisms (SNPs) with subtle effects. Meta-analysis is a cost-efficient means to achieve large sample size by combining data from multiple independent GWAS; however, results from studies performed on different populations can be variable due to various reasons, including varied linkage equilibrium structures as well as gene-gene and gene-environment interactions. Nevertheless, one should expect effects of the SNP are more similar between similar populations than those between populations with quite different genetic and environmental backgrounds. Prior information on populations of GWAS is often not considered in current meta-analysis methods, rendering such analyses less optimal for the detecting association. This paper describes a test that improves meta-analysis to incorporate variable heterogeneity among populations. The proposed method is remarkably simple in computation and hence can be performed in a rapid fashion in the setting of GWAS. Simulation results demonstrate the validity and higher power of the proposed method over conventional methods in the presence of heterogeneity. As a demonstration, we applied the test to real GWAS data to identify SNPs associated with circulating Insulin-like growth factor I concentrations.
Genome-wide association study; Meta-analysis; Variance-component model; Insulin-like growth factor I
Age trends in estradiol and estrone levels in men and how lifestyle factors, comorbid conditions, testosterone, and sex hormone–binding globulin affect these age trends remain poorly understood, and were examined in men of the Framingham Heart Study.
Estrone and estradiol concentrations were measured in morning fasting samples using liquid chromatography tandem mass spectrometry in men of Framingham Offspring Generation. Free estradiol was calculated using a law of mass action equation.
There were 1,461 eligible men (mean age [±SD] 61.1±9.5 years and body mass index [BMI] 28.8±4.5kg/m2). Total estradiol and estrone were positively associated with age, but free estradiol was negatively associated with age. Age-related increase in total estrone was greater than that in total estradiol. Estrone was positively associated with smoking, BMI, and testosterone, and total and free estradiol with diabetes, BMI, testosterone, and comorbid conditions; additionally, free estradiol was associated negatively with smoking. Collectively, age, BMI, testosterone, and other health and behavioral factors explained only 18% of variance in estradiol, and 9% of variance in estrone levels. Men in the highest quintile of estrone levels had significantly higher age and BMI, and a higher prevalence of smoking, diabetes, and cardiovascular disease than others, whereas those in the highest quintile of estradiol had higher BMI than others.
Total estrone and estradiol levels in men, measured using liquid chromatography tandem mass spectrometry, revealed significant age-related increases that were only partially accounted for by cross-sectional differences in BMI, diabetes status, and other comorbidities and health behaviors. Longitudinal studies are needed to confirm these findings.
Age trends; Estrogen levels in men; LC-MS/MS; Age-related changes in estrone and estradiol; Determinants of estrogen levels in men.
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.
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.
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.
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.
Biological markers; Longitudinal studies; Inflammation
Cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) are two genetically-related plasma proteins involved in the exchange of cholesteryl esters and phospholipids between high-density lipoproteins (HDL) and other lipoproteins. Although low CETP and high PLTP activity both result in higher concentrations of plasma HDL-cholesterol (HDL-C), there is no evidence that either of these changes is associated with a decrease in cardiovascular disease (CVD) in a general population.
Plasma CETP and PLTP activities, measured by homogenous fluorometric assays using synthetic donor particle substrates, were related to the incidence of a first CVD event in Framingham Heart Study Offspring participants without CVD (n = 2679, mean age 59 y, 56% women) attending the 6th examination cycle (1995–98). Because of an effect modification by sex for both CETP and PLTP, analyzes were stratified by sex.
During follow-up (mean 10.4 years) 187 participants experienced a first CVD event. In sex-specific Cox models, both CETP and PLTP as continuous and as binary variables were associated with significantly increased CVD in men, but not women. In men compared to a referent group with CETP ≥ median and PLTP < median, the multivariable-adjusted hazard ratio (HR) for new CVD events was significantly greater with either the combination of high CETP and high PLTP (HR 2.27, 95% CI 1.23–4.20); low CETP and low PLTP (HR 2.23, 95% CI 1.19–4.17); or low CETP and high PLTP (HR 2.85, 95% CI 1.53–5.31). In contrast, in women the multivariable-adjusted HR for new CVD events was non-significant and virtually equal to “1.0” with all combinations of high and low CETP or PLTP values.
Lower plasma CETP or higher PLTP activity was each associated with a significantly increased risk of CVD. Inexplicably, the increase in CVD associated with both lipid transfer proteins was confined to men.
High density lipoproteins; Cholesteryl ester transfer protein; Phospholipid transfer protein
Hypertension is a risk factor for coronary artery disease. Recent genome-wide association studies have identified 30 genetic variants associated with higher blood pressure at genome-wide significance (p<5×10−8). If elevated blood pressure is a causative factor for coronary artery disease, these variants should also increase coronary artery disease risk. Analyzing genome-wide association data from 22,233 coronary artery disease cases and 64,762 controls, we observed in the Coronary artery disease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) consortium that 88% of these blood pressure-associated polymorphisms were likewise positively associated with coronary artery disease, i.e. they had an odds ratio >1 for coronary artery disease, a proportion much higher than expected by chance (p=4.10−5). The average relative coronary artery disease risk increase per each of the multiple blood pressure-raising alleles observed in the consortium was 3.0% for systolic blood pressure-associated polymorphisms (95% confidence interval, 1.8 to 4.3%) and 2.9% for diastolic blood pressure-associated polymorphisms (95% confidence interval, 1.7 to 4.1%). In sub-studies, individuals carrying most systolic blood pressure- and diastolic blood pressure-related risk alleles (top quintile of a genetic risk score distribution) had 70% (95% confidence interval, 50-94%) and 59% (95% confidence interval, 40-81%) higher odds of having coronary artery disease, respectively, as compared to individuals in the bottom quintile. In conclusion, most blood pressure-associated polymorphisms also confer an increased risk for coronary artery disease. These findings are consistent with a causal relationship of increasing blood pressure to coronary artery disease. Genetic variants primarily affecting blood pressure contribute to the genetic basis of coronary artery disease.
Blood pressure; polymorphism; genetics; coronary artery disease
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.
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.
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).
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.
biological markers; blood pressure; epidemiology; hypertension; immune system; risk factors
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.
Aldosterone, the key hormone in the mineralocorticoid pathway, plays a fundamental role in salt and water homeostasis, blood pressure regulation, and cardiovascular remodeling. Both genomic and non-genomic mechanisms influence aldosterone-induced renal sodium reabsorption. Furthermore, the mineralocorticoid receptor in non-epithelial tissues, including the heart and vascular smooth muscle cells, have recently been discovered. Thus, aldosterone likely has pleiotropic effects that contribute to the modulation of blood pressure. Among patients with hypertension in general, and among those with more severe or resistant hypertension in particular, a higher than expected prevalence of primary hyperaldosteronism is noted. Among individuals with resistant hypertension, aldosterone antagonists have also been shown to be effective in lowering blood pressure. Most significantly, recent community-based studies among non-hypertensive individuals in the general population have demonstrated that both a higher serum aldosterone concentrations and a higher aldosterone to renin ratio portend a greater risk of developing hypertension. The combination of the aforementioned observations underscores the importance of the mineralocorticoid pathway in the pathogenesis of hypertension.
Aldosterone; Mineralocorticoid receptor; Aldosterone/renin ratio; ARR; Primary hyperaldosteronism; Natriuretic peptides; Salt sensitivity; Blood pressure; Hypertension; Cardiovascular disease; Risk
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.
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.
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%).
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.
Kidney; Risk Factors; Epidemiology
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.
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.
heart failure; epidemiology; risk factors; ejection fraction
Using data from four community-based cohorts of African Americans (AA), we tested the association between genome-wide markers (SNPs) and cardiac phenotypes in the Candidate-gene Association REsource (CARe) study.
Methods and Results
Among 6,765 AA, we related age, sex, height and weight-adjusted residuals for nine cardiac phenotypes (assessed by echocardiogram or MRI) to 2.5 million SNPs genotyped using Genome-Wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within cohort genome-wide association analysis was conducted followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10−07). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested look-ups in one consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (p=1.43 × 10−07) for left ventricular mass (LVM); rs7213314 in WIPI1 (p=1.68 × 10−07) for LV internal diastolic diameter (LVIDD); rs1571099 in PPAPDC1A (p= 2.57 × 10−08) for interventricular septal wall thickness (IVST); and rs9530176 in KLF5 (p=4.02 × 10−07) for ejection fraction (EF). Associated variants were enriched in three signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry were confirmed in look-ups in EchoGEN.
In the largest GWAS of cardiac structure and function to date in AA, we identified 4 genetic loci related to LVM, IVST, LVIDD and EF that reached genome-wide significance. Replication results suggest that these loci may represent unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.
echocardiography; ethnic; genome-wide association studies; Left atrium genetics; left ventricular mass genetics
The aim of this study was to investigate the association between aortic root remodeling and incident heart failure (HF).
Age-associated increases in aortic root diameter (AoD) might be associated with arterial stiffening, afterload changes, cardiac remodeling, and the development of HF.
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).
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.
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.
aortic root; general community; heart failure; remodeling; risk
Heart failure, a strong risk factor for atrial fibrillation (AF), often is accompanied by elevated liver transaminases. We hypothesized that elevated transaminases are associated with the risk of incident AF in the community. We studied 3,744 participants (mean age 65 ± 10 years, 56.8% women) of the Framingham Heart Study Original and Offspring cohorts, free of clinical heart failure. We examined Cox proportional hazards models adjusted for standard AF risk factors (age, sex, body mass index, systolic blood pressure, electrocardiographic PR interval, anti-hypertensive treatment, smoking, diabetes, valvular heart disease, alcohol consumption) to investigate associations between baseline serum transaminase levels [alanine transaminase (ALT), aspartate transaminase (AST)] and incidence of AF in up to 10 years (29,099 person years) follow-up. During follow-up, 383 individuals developed AF. Both transaminases were significantly associated with greater risk of incident AF (hazard ratio expressed per standard deviation of natural logarithmically transformed biomarker: ALT hazard ratio 1.19, 95% confidence interval 1.07 to1.32, p = 0.002; AST hazard ratio 1.12, 95% confidence interval 1.01 to1.24, p = 0.03). The associations between transaminases and AF remained consistent after exclusion of participants with moderate-to-severe alcohol consumption. However, when added to known risk factors for AF, ALT and AST only subtly improved the prediction of AF. In conclusion, elevated transaminase concentrations are associated with increased AF incidence. The mechanisms by which higher mean transaminase concentrations are associated with incident AF remain to be determined.
atrial fibrillation; biomarker; risk factors; liver function tests
Water and sodium retention precedes the development of high blood pressure (BP) and explains a compensatory rise in B-type natriuretic peptide (BNP) concentrations. It is unclear if BNP concentrations antedate the BP progression. We hypothesized higher BNP concentrations in our African American cohort will be associated with longitudinal increases in BP, progression of BP stage and incident hypertension.
Our study sample consisted of 888 normotensive [based on BP at Examination 1(2000-04)] participants of the Jackson Heart Study (mean age 47±12 years, 61% women). We examined the relation of BNP concentrations at the baseline examination to change in systolic and diastolic BP, BP progression (an increase by one BP stage as defined by JNC VI) and incident hypertension by Examination 2 (2005-08) adjusting for baseline BP stages, systolic and diastolic BP, traditional risk factors and echocardiographic LV mass.
Over a median follow-up period of 5.0± 0.8 years, 36.9% progressed to a higher BP stage and 19.3% developed hypertension. In multivariable regression models, higher log-BNP concentrations at Examination 1 were significantly and positively associated with changes in systolic and diastolic BP (p <0.05 for both). Baseline log-BNP was significantly associated with BP progression (p = 0.046). Every SD increase in baseline log BNP was associated with a 12% increased risk of BP progression. Log-BNP was not significantly associated with incident hypertension (p=0.12).
In our community-based sample of African Americans, higher BNP concentrations predict longitudinal increase in systolic and diastolic BP and progression of BP stage.
Blood Pressure; B-type Natriuretic Peptide; African Americans
Low serum magnesium has been linked to increased risk of atrial fibrillation (AF) following cardiac surgery. It is unknown whether hypomagnesemia predisposes to AF in the community.
Methods and Results
We studied 3,530 participants (mean age, 44 years; 52% women) from the Framingham Offspring Study who attended a routine examination, and were free of AF and cardiovascular disease. We used Cox proportional hazard regression analysis to examine the association between serum magnesium at baseline and risk of incident AF. Analyses were adjusted for conventional AF risk factors, use of antihypertensive medications, and serum potassium. During up to 20 years of follow-up, 228 participants developed AF. Mean serum magnesium was 1.88 mg/dl. The age- and sex-adjusted incidence rate of AF was 9.4 per 1,000 person-years (95% confidence interval, 6.7 to 11.9) in the lowest quartile of serum magnesium (≤1.77 mg/dl), compared with 6.3 per 1,000 person-years (95% confidence interval, 4.1 to 8.4) in the highest quartile (≥1.99 mg/dl). In multivariable-adjusted models, individuals in the lowest quartile of serum magnesium were approximately 50% more likely to develop AF (adjusted hazard ratio, 1.52, 1.00 to 2.31; P=0.05), compared with those in the upper quartiles. Results were similar after excluding individuals on diuretics.
Low serum magnesium is moderately associated with the development of AF in individuals without cardiovascular disease. Because hypomagnesemia is common in the general population, a link with AF may have potential clinical implications. Further studies are warranted to confirm our findings and elucidate the underlying mechanisms.
arrhythmia; epidemiology; atrial fibrillation; magnesium
We sought to characterize associations between aminotransferase levels and cardiometabolic risk after accounting for visceral adipose tissue (VAT) and insulin resistance.
Methods and Results
Participants (n=2621) from the Framingham Heart Study (mean age 51, 49.8% women) were included. Sex-specific linear and logistic regressions were used to evaluate associations between aminotransferase levels and cardiometabolic risk factors. In multivariable models, increased ALT levels were associated with elevated blood pressure, fasting plasma glucose, and triglycerides and lower HDL levels (all p ≤ 0.007). Further, each 1 standard deviation (SD) increase in ALT corresponded to an increased odds of hypertension, diabetes, the metabolic syndrome, impaired fasting glucose, and insulin resistance estimated by HOMA-IR (OR 1.29–1.85, all p ≤ 0.002). Associations with ALT persisted after additional adjustment for VAT, insulin resistance, and BMI with the exception of HDL cholesterol in both sexes and blood pressure in women. Results were materially unchanged when moderate drinkers were excluded, when the sample was restricted to those with ALT<40 U/L, and when the sample was restricted to those without diabetes. Similar trends were observed for AST levels, but associations were more modest.
Aminotransferase levels are correlated with multiple cardiometabolic risk factors above and beyond VAT and insulin resistance.
liver function tests; obesity; visceral fat; insulin resistance; cardiometabolic risk factors
Perivascular fat may have a local adverse effect on the vasculature. We evaluated whether thoracic periaortic adipose tissue (TAT), a type of perivascular fat, and visceral adipose tissue (VAT) are associated with vascular function.
Design and Methods
TAT and VAT were quantified in Framingham Heart Study participants using multidetector computed tomography; vascular function was assessed using brachial artery vasodilator function, peripheral arterial tone and arterial tonometry (n= 2735, 48% women, mean age 50 years, mean BMI 27.7 kg/m2). Using multiple linear regression, we examined relations between TAT, VAT, and vascular measures while adjusting for cardiovascular risk factors.
Mean TAT and VAT volumes were 13.2 and 1763 cm3. TAT and VAT were associated with multiple vascular function measures after multivariable adjustment. After BMI adjustment, TAT and VAT remained negatively associated with peripheral arterial tone and inverse carotid femoral pulse wave velocity (p<0.02); TAT was negatively associated with hyperemic mean flow velocity (p=0.03). Associations of TAT with vascular function were attenuated after VAT adjustment (all p>0.06).
Thoracic periaortic and visceral fat are associated with microvascular function and large artery stiffness after BMI adjustment. These findings support the growing recognition of associations between ectopic fat and vascular function.
obesity; vascular function; arterial stiffness; perivascular adipose tissue; visceral adipose tissue
Low serum concentrations of sex steroids and gonadotropins in men have been associated with increased cardiometabolic risk and mortality, but the clinical correlates of these hormones in men over the late adulthood are less clearly understood.
We analyzed up to five serial measurements of total testosterone (TT), dehydroepiandrosterone sulfate (DHEAS), follicle stimulating hormone (FSH), luteinizing hormone (LH), and total estradiol (EST) in older men in the original cohort of the Framingham Heart Study to determine the short- (2-years; 1,165 person-observations in 528 individuals) and long-term (up to 10-years follow-up; 2,520 person-observations in 835 individuals with mean baseline age: 71.2 years) clinical correlates of these sex steroids and gonadotropins using multilevel modelling and Generalized Estimating Equations.
Age, body mass index, and pre-existing type 2 diabetes were inversely related to long-term TT concentrations, whereas higher systolic blood pressure showed a positive association. Furthermore, age and pre-existing cardiovascular disease (CVD) were inversely and HDL cholesterol concentrations positively associated with long-term DHEAS concentrations. Analyses of short-term changes revealed age was inversely related to DHEAS, but positively related to FSH and LH concentrations.
Our community-based study identified modifiable correlates of decreasing TT and DHEAS concentrations in elderly men, suggesting that maintenance of a low CVD risk factor burden may mitigate the age-related decline of these hormones over the late adulthood.
sex steroids; gonadotropins; testosterone; aging male; Framingham Heart Study
The extent to which select vascular risk factors differentially influence blood pressure (BP) is incompletely understood. Thus, we used multilevel modeling to analyze serial BP measurements using 21,732 person-observations obtained on Framingham Heart Study participants (mean age 38 years, 52% women; 4,993 unique individuals) over a 28-year period. We related longitudinal tracking of each BP measure (systolic BP [SBP], diastolic BP [DBP], mean arterial pressure [MAP], and pulse pressure [PP]) to age, sex, body mass index (BMI), smoking, diabetes, total/high-density lipoprotein (HDL) cholesterol ratio, and heart rate. In multivariable-adjusted analyses, we observed that older age, male sex, greater BMI, and higher heart rate were positively associated with increase in all BP measures (p<0.0001). Notably, higher total/HDL cholesterol ratio was associated with greater MAP (p<0.01). Conversely, diabetes and smoking were associated with higher PP (p<0.01). We also observed effect modification by sex: the increase in PP with age and BMI was more pronounced in women compared to men (p<0.0001). All BP measures tracked at higher levels in both men and women with multiple vascular risk factors. Taken together, our longitudinal observations of a large community-based sample demonstrate a greater pulsatile load in women than men with increasing age. We also observed a differential impact of select vascular risk factors on the individual components of BP, underscoring distinct regulation of these measures over the life course.
aging; blood pressure; epidemiology; hypertension; risk factors
Currently available screening tools for left ventricular (LV) hypertrophy (LVH) and systolic dysfunction (LVSD) are either expensive (echocardiography) or perform suboptimally (B‐type natriuretic peptide [BNP]). It is unknown whether newer biomarkers are associated with LVH and LVSD and can serve as screening tools.
Methods and Results
We studied 2460 Framingham Study participants (mean age 58 years, 57% women) with measurements of biomarkers mirroring cardiac biomechanical stress (soluble ST‐2 [ST2], growth differentiation factor‐15 [GDF‐15] and high‐sensitivity troponin I [hsTnI]) and BNP. We defined LVH as LV mass/height2 ≥the sex‐specific 80th percentile and LVSD as mild/greater impairment of LV ejection fraction (LVEF) or a fractional shortening <0.29. Adjusting for standard risk factors in logistic models, BNP, GDF‐15, and hsTnI were associated with the composite echocardiographic outcome (LVH or LVSD), odds ratios (OR) per SD increment in log‐biomarker 1.29, 1.14, and 1.18 (95% CI: 1.15 to 1.44, 1.004 to 1.28, and 1.06 to 1.31), respectively. The C‐statistic for the composite outcome increased from 0.765 with risk factors to 0.770 adding BNP, to 0.774 adding novel biomarkers. The continuous Net Reclassification Improvement was 0.212 (95% CI: 0.119 to 0.305, P<0.0001) after adding the novel biomarkers to risk factors plus BNP. BNP was associated with LVH and LVSD in multivariable models, whereas GDF‐15 was associated with LVSD (OR 1.41, 95% CI: 1.16 to 1.70), and hsTnI with LVH (OR 1.22, 95% CI: 1.09 to 1.36). ST2 was not significantly associated with any outcome.
Our community‐based investigation suggests that cardiac stress biomarkers are associated with LVH and LVSD but may have limited clinical utility as screening tools.
biomarkers; echocardiography; heart failure; hypertrophy; screening
Accumulating evidence links higher circulating asymmetric dimethylarginine (ADMA) to greater risk of cardiovascular disease (CVD). Relatively small differences in ADMA concentrations between healthy individuals and those with disease underscore the need to formulate reference intervals that may aid risk stratification of individuals.
We formulated reference intervals for plasma ADMA concentrations using a community-based reference sample from the Framingham Offspring Study consisting of 1126 nonsmoking individuals [mean (SD) age 56 (9) years; 60% women] who were free of clinical CVD, hypertension, diabetes, and obesity and who attended a routine examination at which ADMA was assayed. ADMA concentrations were determined using a validated tandem mass spectrometry–liquid chromatography assay.
In the study sample, the mean ADMA concentration was 0.52 (0.11) μmol/L, and the reference limits were 0.311 and 0.732 (2.5th and 97.5th percentile). The sex-specific reference limits were 0.310 and 0.745 in men and 0.313 and 0.721 μmol/L in women. In multivariable regression analysis, ADMA plasma concentrations were positively correlated with age and total plasma homocysteine (both P < 0.001).
Reference limits calculated for circulating ADMA in our large community-based healthy reference sample confirm the previous observation of a relatively narrow distribution of concentrations. This suggests a tight physiological control of ADMA plasma concentrations, presumably by dimethylarginine dimethylaminohydrolase (DDAH) metabolism of ADMA.
We sought to examine the relation of galectin-3 (Gal-3), a marker of cardiac fibrosis, with incident heart failure (HF) in the community.
Gal-3 is an emerging prognostic biomarker in HF, and experimental studies suggest that Gal-3 is an important mediator of cardiac fibrosis. Whether elevated Gal-3 concentrations precede the development of HF is unknown.
Gal-3 concentrations were measured in 3,353 participants in the Framingham Offspring Cohort (mean age 59 years, 53% women). The relation of Gal-3 to incident HF was assessed using proportional hazards regression.
Gal-3 was associated with increased left ventricular mass in age- and sex-adjusted analyses (P=0.001); this association was attenuated in multivariable analyses (P=0.06). A total of 166 participants developed incident HF and 468 died during a mean follow-up of 8.1 years. Gal-3 was associated with risk of incident HF (HR 1.28 per 1 standard deviation increase in log-Gal-3, 95% CI 1.14–1.43, P<0.0001), and remained significant after adjustment for clinical variables and B-type natriuretic peptide (HR 1.23, 95% CI 1.04–1.47, P=0.02). Gal-3 was also associated with risk of all-cause mortality (multivariable-adjusted HR 1.15, 95% CI 1.04–1.28, P=0.01). The addition of Gal-3 to clinical factors resulted in negligible changes to the c-statistic and minor improvements in the net reclassification index.
Higher concentration of Gal-3, a marker of cardiac fibrosis, is associated with increased risk of incident HF and mortality. Future studies evaluating the role of Gal-3 in cardiac remodeling may provide further insights into the role of Gal-3 in the pathophysiology of HF.
heart failure; epidemiology; biomarker; prognosis
Background The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.
Methods We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual–participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.
Results For people born between 1900 and 1960, mean adult height increased 0.5–1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96–0.99) for death from any cause, 0.94 (0.93–0.96) for death from vascular causes, 1.04 (1.03–1.06) for death from cancer and 0.92 (0.90–0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12–1.42) for risk of melanoma death to 0.84 (0.80–0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.
Conclusion Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
Height; cardiovascular disease; cancer; cause-specific mortality; epidemiological study; meta-analysis