Objectives The aim of this study was to determine whether ectopic fat depots are prospectively associated with cardiovascular disease, cancer, and all-cause mortality. Background The morbidity ...associated with excess body weight varies among individuals of similar body mass index. Ectopic fat depots may underlie this risk differential. However, prospective studies of directly measured fat are limited. Methods Participants from the Framingham Heart Study (n = 3,086; 49% women; mean age of 50.2 years) underwent assessment of fat depots (visceral adipose tissue, pericardial adipose tissue, and periaortic adipose tissue) using multidetector computed tomography and were followed up longitudinally for a median of 5.0 years. Cox proportional hazards regression models were used to examine the association of each fat depot (per 1 SD increment) with the risk of incident cardiovascular disease, cancer, and all-cause mortality after adjustment for standard risk factors, including body mass index. Results Overall, there were 90 cardiovascular events, 141 cancer events, and 71 deaths. After multivariable adjustment, visceral adipose tissue was associated with cardiovascular disease (hazard ratio: 1.44; 95% confidence interval: 1.08 to 1.92; p = 0.01) and cancer (hazard ratio: 1.43; 95% confidence interval: 1.12 to 1.84; p = 0.005). Addition of visceral adipose tissue to a multivariable model that included body mass index modestly improved cardiovascular risk prediction (net reclassification improvement of 16.3%). None of the fat depots were associated with all-cause mortality. Conclusions Visceral adiposity is associated with incident cardiovascular disease and cancer after adjustment for clinical risk factors and generalized adiposity. These findings support the growing appreciation of a pathogenic role of ectopic fat.
Objectives The aim of this study was to evaluate whether computed tomography (CT) attenuation, as a measure of fat quality, is associated with cardiometabolic risk factors above and beyond fat ...quantity. Background Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) are pathogenic fat depots associated with cardiometabolic risk. Adipose tissue attenuation in CT images is variable, similar to adipose tissue volume. However, whether the quality of abdominal fat attenuation is associated with cardiometabolic risk independent of the quantity is uncertain. Methods Participants were drawn from the Framingham Heart Study CT substudy. The VAT and SAT volumes were acquired by semiquantitative assessment. Fat quality was measured by CT attenuation and recorded as mean Hounsfield unit (HU) within each fat depot. Sex-specific linear and logistic multivariable regression models were used to assess the association between standard deviation (SD) decrease in HU and each risk factor. Results Lower CT attenuation of VAT and SAT was correlated with higher body mass index levels in both sexes. Risk factors were generally more adverse with decreasing HU values. For example, in women, per 1 SD decrease in VAT HU, the odds ratio (OR) was increased for hypertension (OR: 1.80), impaired fasting glucose (OR: 2.10), metabolic syndrome (OR: 3.65), and insulin resistance (OR: 3.36; all p < 0.0001). In models that further adjusted for VAT volume, impaired fasting glucose, metabolic syndrome, and insulin resistance remained significant. Trends were similar but less pronounced for SAT and for men. There was evidence of an interaction between HU and fat volume among both women and men. Conclusions Lower CT attenuation of VAT and SAT is associated with adverse cardiometabolic risk above and beyond total adipose tissue volume. Qualitative indices of abdominal fat depots may provide insight regarding cardiometabolic risk independent of fat quantity.
Abstract Background An increased interarm systolic blood pressure difference is an easily determined physical examination finding. The relationship between interarm systolic blood pressure difference ...and risk of future cardiovascular disease is uncertain. We described the prevalence and risk factor correlates of interarm systolic blood pressure difference in the Framingham Heart Study (FHS) original and offspring cohorts and examined the association between interarm systolic blood pressure difference and incident cardiovascular disease and all-cause mortality. Methods An increased interarm systolic blood pressure difference was defined as ≥10 mm Hg using the average of initial and repeat blood pressure measurements obtained in both arms. Participants were followed through 2010 for incident cardiovascular disease events. Multivariable Cox proportional hazards regression analyses were performed to investigate the effect of interarm systolic blood pressure difference on incident cardiovascular disease. Results We examined 3390 (56.3% female) participants aged 40 years and older, free of cardiovascular disease at baseline, mean age of 61.1 years, who attended a FHS examination between 1991 and 1994 (original cohort) and from 1995 to 1998 (offspring cohort). The mean absolute interarm systolic blood pressure difference was 4.6 mm Hg (range 0-78). Increased interarm systolic blood pressure difference was present in 317 (9.4%) participants. The median follow-up time was 13.3 years, during which time 598 participants (17.6%) experienced a first cardiovascular event, including 83 (26.2%) participants with interarm systolic blood pressure difference ≥10 mm Hg. Compared with those with normal interarm systolic blood pressure difference, participants with an elevated interarm systolic blood pressure difference were older (63.0 years vs 60.9 years), had a greater prevalence of diabetes mellitus (13.3% vs 7.5%,), higher systolic blood pressure (136.3 mm Hg vs 129.3 mm Hg), and a higher total cholesterol level (212.1 mg/dL vs 206.5 mg/dL). Interarm systolic blood pressure difference was associated with a significantly increased hazard of incident cardiovascular events in the multivariable adjusted model (hazard ratio 1.38; 95% CI, 1.09-1.75). For each 1-SD-unit increase in absolute interarm systolic blood pressure difference, the hazard ratio for incident cardiovascular events was 1.07 (95% CI, 1.00-1.14) in the fully adjusted model. There was no such association with mortality (hazard ratio 1.02; 95% CI 0.76-1.38). Conclusions In this community-based cohort, an interarm systolic blood pressure difference is common and associated with a significant increased risk for future cardiovascular events, even when the absolute difference in arm systolic blood pressure is modest. These findings support research to expand clinical use of this simple measurement.
Inflammatory cytokines and chemokines related to the innate and adaptive immune system have been linked to neuroinflammation in Alzheimer's Disease, dementia, and cognitive disorders. We examined the ...association of 11 plasma proteins (CD14, CD163, CD5L, CD56, CD40L, CXCL16, SDF1, DPP4, SGP130, sRAGE, and MPO) related to immune and inflammatory responses with measures of cognitive function, brain MRI and dementia risk. We identified Framingham Heart Study Offspring participants who underwent neuropsychological testing (n = 2358) or brain MRI (n = 2100) within five years of the seventh examination where a blood sample for quantifying the protein biomarkers was obtained; and who were followed for 10 years for incident all-cause dementia (n = 1616). We investigated the association of inflammatory biomarkers with neuropsychological test performance and brain MRI volumes using linear mixed effect models accounting for family relationships. We further used Cox proportional hazards models to examine the association with incident dementia. False discovery rate p-values were used to account for multiple testing. Participants included in the neuropsychological test and MRI samples were on average 61 years old and 54% female. Participants from the incident dementia sample (average 68 years old at baseline) included 124 participants with incident dementia. In addition to CD14, which has an established association, we found significant associations between higher levels of CD40L and myeloperoxidase (MPO) with executive dysfunction. Higher CD5L levels were significantly associated with smaller total brain volumes (TCBV), whereas higher levels of sRAGE were associated with larger TCBV. Associations persisted after adjustment for APOE ε4 carrier status and additional cardiovascular risk factors. None of the studied inflammatory biomarkers were significantly associated with risk of incident all-cause dementia. Higher circulating levels of soluble CD40L and MPO, markers of immune cell activation, were associated with poorer performance on neuropsychological tests, while higher CD5L, a key regulator of inflammation, was associated with smaller total brain volumes. Higher circulating soluble RAGE, a decoy receptor for the proinflammatory RAGE/AGE pathway, was associated with larger total brain volume. If confirmed in other studies, this data indicates the involvement of an activated immune system in abnormal brain aging.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
► GWAS identified novel loci for age at menarche and age at natural menopause. ► The loci identified so far account for only a small fraction of heritability. ► Future research efforts need to focus ...on the search for missing heritability. ► Functional characterization of novel loci is needed to advance our knowledge.
Genome-wide association studies (GWAS) have been successful in uncovering genetic determinants of age at menarche and age at natural menopause. To date, more than 30 novel genetic loci have been identified in GWAS for age at menarche and 17 for age at natural menopause. These findings have stimulated a plethora of follow-up studies particularly with respect to the functional characterization of these novel loci and how these results can be translated into risk prediction. However, the genetic loci identified so far account for only a small fraction of the overall heritability. This review provides an overview of the current state of our knowledge of the genetic basis of menarche and menopause timing. It emphasizes recent GWAS results and outlines strategies for discovering the missing heritability and strategies to further our understanding of the underlying molecular mechanisms of the observed genetic associations.
Abstract
Aims
While greater physical activity (PA) is associated with improved health outcomes, the direct links between distinct components of PA, their changes over time, and cardiorespiratory ...fitness are incompletely understood.
Methods and results
Maximum effort cardiopulmonary exercise testing (CPET) and objective PA measures sedentary time (SED), steps/day, and moderate-vigorous PA (MVPA) via accelerometers worn for 1 week concurrent with CPET and 7.8 years prior were obtained in 2070 Framingham Heart Study participants age 54 ± 9 years, 51% women, SED 810 ± 83 min/day, steps/day 7737 ± 3520, MVPA 22.3 ± 20.3 min/day, peak oxygen uptake (VO2) 23.6 ± 6.9 mL/kg/min. Adjusted for clinical risk factors, increases in steps/day and MVPA and reduced SED between the two assessments were associated with distinct aspects of cardiorespiratory fitness (measured by VO2) during initiation, early-moderate level, peak exercise, and recovery, with the highest effect estimates for MVPA (false discovery rate <5% for all). Findings were largely consistent across categories of age, sex, obesity, and cardiovascular risk. Increases of 17 min of MVPA/day 95% confidence interval (CI) 14–21 or 4312 steps/day (95% CI 3439–5781; ≈54 min at 80 steps/min), or reductions of 249 min of SED per day (95% CI 149–777) between the two exam cycles corresponded to a 5% (1.2 mL/kg/min) higher peak VO2. Individuals with high (above-mean) steps or MVPA demonstrated above average peak VO2 values regardless of whether they had high or low SED.
Conclusions
Our findings provide a detailed assessment of relations of different types of PA with multidimensional cardiorespiratory fitness measures and suggest favourable longitudinal changes in PA (and MVPA in particular) are associated with greater objective fitness.
Graphical Abstract
An overview of the study design is displayed. Cardiopulmonary fitness measures were associated with omnidirectional accelerometry data concurrent with exercise testing and from ≈8 years prior to evaluate the relations of physical activity and fitness.
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 PA (MVPA), measured in bouts ≥10 and <10 min, and CVD risk factors in a well-characterized community-based sample of white adults.
We conducted a cross-sectional analysis of 2109 participants in the Third Generation Cohort of the Framingham Heart Study (mean age = 47 yr, 55% women) who underwent objective assessment of PA by accelerometry over 5-7 d. Total MVPA, MVPA done in bouts ≥10 min (MVPA(10+)), and MVPA done in bouts <10 min (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 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 min 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-age community-based sample confirm a positive association of MVPA with a healthier CVD risk factor profile and indicate that accruing PA in bouts <10 min may favorably influence cardiometabolic risk. Additional investigations are warranted to confirm our findings.
Genetic factors clearly contribute to exceptional longevity and healthy aging in humans, yet the identification of the underlying genes remains a challenge. Longevity is a complex phenotype with ...modest heritability. Age-related phenotypes with higher heritability may have greater success in gene discovery. Candidate gene and genome-wide association studies (GWAS) for longevity have had only limited success to date. The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium conducted a meta-analysis of GWAS data for longevity, defined as survival to age 90 years or older, that identified several interesting associations but none achieved genome-wide significance. A recent GWAS of longevity conducted in the Leiden Longevity Study identified the ApoE E4 isoform as deleterious to longevity that was confirmed in an independent GWAS of long-lived individuals of German descent. Notably, no other genetic loci for longevity have been identified in these GWAS. To examine the conserved genetic mechanisms between the mouse and humans for life span, we mapped the top Cohorts for Heart and Aging Research in Genomic Epidemiology GWAS associations for longevity to the mouse chromosomal map and noted that eight of the ten top human associations were located within a previously reported mouse life-span quantitative trait loci. This work suggests that the mouse and human may share mechanisms leading to aging and that the mouse model may help speed the understanding of how genes identified in humans affect the biology of aging. We expect these ongoing collaborations and the translational work with basic scientists to accelerate the identification of genes that delay aging and promote a healthy life span.
Abstract
Background
Frailty is a risk factor for cardiovascular disease (CVD). Underlying mechanisms to explain the connection between frailty and CVD are unclear. We sought to examine the ...association between frailty and arterial stiffness, a precursor of hypertension and CVD.
Methods
We conducted a cross-sectional analysis of community-dwelling Framingham Heart Study Offspring and Omni participants ≥60 years of age examined in 2005–2008. Frailty was defined primarily according to the Fried physical phenotype definition, which identifies nonfrail, prefrail, and frail individuals. Arterial stiffness was assessed using carotid–femoral pulse wave velocity (CFPWV). Generalized linear regression was used to examine the association between frailty level and CFPWV (modeled as −1000/CFPWV in msec/m, then transformed back to the original scale, m/s), adjusted for age, sex, cohort, mean arterial pressure, heart rate, height, and smoking.
Results
Of 2,171 participants (55% women, 91% white), 45% were prefrail and 7% were frail. Mean ages were 67, 70, and 73 years, and adjusted CFPWV least squares means were 10.0 (95% CI, 9.9–10.1), 10.3 (10.2–10.5), and 10.5 m/s (10.1–11.0); p = .0002 for nonfrail, prefrail, and frail groups, respectively. Results were similar using the Rockwood cumulative deficit model of frailty, and in a sensitivity analysis adjusting for prevalent coronary heart disease and diabetes.
Conclusions
Prefrailty and frailty were associated with higher arterial stiffness in a cohort of community-dwelling older adults. Arterial stiffness may help explain the relationship between frailty and CVD.
Objectives The aim of this study was to assess the relationship between sex hormones and natriuretic peptide levels in community-based adults. Background Women have higher circulating natriuretic ...peptide concentrations than men, but the mechanisms for these sex-related differences and the impact of hormone therapy are unclear. Experimental studies suggest that androgens may suppress natriuretic peptide secretion. Methods We measured N-terminal pro–B-type natriuretic peptide (NT-proBNP), total testosterone, and sex hormone–binding globulin plasma levels in 4,056 men and women (mean age 40 ± 9 years) from the Framingham Heart Study Third-Generation cohort. Sex/hormone status was grouped as: 1) men; 2) post-menopausal women not receiving hormone replacement therapy; 3) pre-menopausal women not receiving hormonal contraceptives; 4) post-menopausal women receiving hormone replacement therapy; and 5) pre-menopausal women receiving hormonal contraceptives. Results Circulating NT-proBNP levels were associated with sex/hormone status (overall p < 0.0001). Men had lower NT-proBNP levels than women of all menopause or hormone groups, and women receiving hormonal contraceptives had higher NT-proBNP levels than women who were not receiving hormone therapy (all p < 0.0001). These relationships remained significant after adjusting for age, body mass index, and cardiovascular risk factors. Across sex/hormone status groups, free testosterone (FT) levels decreased and sex hormone–binding globulin levels increased in tandem with increasing NT-proBNP levels. In sex-specific analyses, NT-proBNP levels decreased across increasing quartiles of FT in men (p for trend <0.01) and women (p for trend <0.0001). Adjustment for FT markedly attenuated the association between sex/hormone status and NT-proBNP concentrations. Conclusions These findings suggest that lower levels of circulating androgens and the potentiating effect of exogenous female hormone therapy contribute to the higher circulating NT-proBNP concentrations in women.
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