Diet soda consumption increases cardiometabolic risk. The aim of this investigation was to assess the relations between self-reported soda consumption and subclinical cardiac remodeling.
We assessed the relations between self-reported soda consumption and left ventricular mass (LVM) and left atrial dimension (LAD) (both standardized within sex) in a sample of middle-aged attendees from the Framingham Heart Offspring cohort examination 5 and 6.
The overall mean age was 55 years and 59% of the participants were women. Compared to non-consumers (n=1010), soda consumers (n=3192) had greater body weight (mean 86 vs. 82 kg among men, and 70 vs. 67 kg among women). Compared with non-consumers, age- and height-adjusted LAD was increased (standard deviation units) among soda consumers by 0.15 standard error 0.042, p<0.001) for those drinking >0–7 diet soda (n=1023), −0.010 (0.043, p=0.82) for people drinking >0–7 regular soda (n=907), 0.22 (0.057, p<0.0001) for individuals consuming >7 diet soda (n=372), and 0.20 (0.092, p=0.034) for participants drinking >7 regular soda (n=116) per week. LVM was increased among participants consuming diet soda (p<0.05), but not in regular soda consumers (p>0.05). Upon adjustment for weight, however, all aforementioned associations were attenuated.
The observed associations between soda consumption and LAD or LVM were likely related to the greater body weight of soda drinkers relative to non-drinkers.
Soda consumption; body weight; cardiac remodeling; cardiovascular disease
Heritability measures the proportion of phenotypic variation attributable to genetic factors. In addition to a shared nuclear genetic component, a number of additional variance components, such as spousal correlation, sibship, household and maternal effects, may have strong contributions to inter-individual phenotype variation. In humans, the confounding effects of these components on heritability have not been studied thoroughly. We sought to obtain unbiased heritability estimates for complex traits in the presence of multiple variance components and also to estimate the contributions of these variance components to complex traits. We compared regression and variance component methods to estimate heritability in simulations when additional variance components existed. We then revisited heritability for several traits in Framingham Heart Study (FHS) participants. Using simulations, we found that failure to account for or misclassification of necessary variance components yielded biased heritability estimates. The direction and magnitude of the bias varied depending on a variance structure and an estimation method. Using the best fitted models to account for necessary variance components, we found that heritability estimates for most FHS traits were overestimated, ranging from 4 to 47 %, when we compared models that considered necessary variance components to models that only considered familial relationships. Spousal correlation explained 14–36 % of phenotypic variation in several anthropometric and lifestyle traits. Maternal and sibling effects also contributed to phenotypic variation, ranging from 3 to 5 % and 4 to 7 %, respectively, in several anthropometric and metabolic traits. Our findings may explain, in part, the missing heritability for some traits.
Elevated blood pressure is the leading modifiable risk factor for cardiovascular disease (CVD) and premature death. The blood pressure waveform consists of discrete hemodynamic components, derived from measured central pressure and flow, which may contribute separately to risk for an adverse outcome. However, pressure-flow measures have not been studied in a large, community-based sample.
Methods and Results
We used proportional hazards models to examine association of incident CVD with forward pressure wave amplitude, mean arterial pressure, and global reflection coefficient derived from wave separation analysis and echocardiography in 2492 participants (mean age 66 ± 9 years, 56% women) in the Framingham Heart Study. During follow up (0.04 – 6.8 years), 149 participants (6%) had a CVD event. In multivariable models adjusting for age, sex, antihypertensive therapy, body mass index, heart rate, total and high density lipoprotein cholesterol concentrations, smoking, and presence of diabetes, forward pressure wave amplitude (HR=1.40; 95% CI: 1.16, 1.67; P=0.0003) was associated with incident CVD whereas mean arterial pressure (HR=1.10; 95% CI: 0.94, 1.29; P=0.25) and global wave reflection (HR=0.93; 95% CI: 0.78, 1.12; P=0.58) were not. After adding systolic blood pressure and carotid-femoral pulse wave velocity to the model, forward pressure wave amplitude persisted as a correlate of events (HR=1.33; 95% CI, 1.05, 1.68; P=0.02).
Higher forward pressure wave amplitude (a measure of proximal aortic geometry and stiffness) was whereas mean arterial pressure and relative wave reflection (correlates of resistance vessel structure and function) were not associated with increased risk for incident CVD.
hemodynamic load; pulsatile hemodynamics; forward pressure wave amplitude; cardiovascular disease
Knowledge of mitral valve prolapse (MVP) inheritance is based on pedigree observation and M-mode echocardiography. The extent of familial clustering of MVP among unselected individuals in the community based on current, more specific echocardiographic criteria is unknown. In addition, the importance of non-diagnostic MVP morphologies (NDM; first described in large pedigrees) has not been investigated in the general population. We hypothesized that parental MVP and NDM increase the risk of offspring MVP.
Methods and Results
Study participants were 3679 Generation 3 individuals with available parental data in the Offspring or the New Offspring Spouse cohorts. MVP and NDM were distinguished by leaflet displacement > 2 mm versus ≤ 2 mm beyond the mitral annulus, respectively. We compared MVP prevalence in Generation 3 participants with at least one parent with MVP (n=186) with that in individuals without parental MVP (n=3493). Among 3679 participants (53% women; mean age 40±9 years), 49 (1%) had MVP. Parental MVP was associated with a higher prevalence of MVP in Generation 3 participants (10/186 [5.4%]) compared to no parental MVP (39/3493 [1.1%] - adjusted odds ratio [OR], 4.51, 95% confidence interval [CI], 2.13–9.54; p<0.0001). When parental NDM was examined alone, prevalence of Generation 3 MVP remained higher (12/484 [2.5%]) compared to those without parental MVP or NDM (27/3009 [0.9%] - adjusted OR 2.52, 95% CI, 1.25–5.10; p=0.01).
Parental MVP and NDM are associated with increased prevalence of offspring MVP, highlighting the genetic substrate of MVP and the potential clinical significance of NDM in the community.
mitral valve prolapse; echocardiography; epidemiology; genetics
Kidney injury molecule 1 (KIM-1), liver fatty acid-binding protein (L-FABP), N-acetyl-β-D-glucosaminidase (NAG) and neutrophil gelatinase-associated lipocalin (NGAL) are urinary biomarkers of renal tubular injury. We examined their association with incident end-stage renal disease (ESRD) and all-cause mortality in American Indians with type 2 diabetes.
Biomarker concentrations were measured in baseline urine samples in 260 Pima Indians who were followed for a median of 14 years. HRs were reported per SD of creatinine (Cr)-normalised log-transformed KIM-1, NAG and NGAL, and for three categories of L-FABP.
During follow-up, 74 participants developed ESRD and 101 died. Median concentrations of KIM-1/Cr, NAG/Cr and NGAL/Cr and the proportion of detectable L-FABP were highest in those with macroalbuminuria (p < 0.001 for KIM-1/Cr, NAG/Cr and L-FABP; p = 0.006 for NGAL/Cr). After multivariable adjustment, NGAL/Cr was positively associated with ESRD (HR 1.59, 95% CI 1.20, 2.11) and mortality (HR 1.39, 95% CI 1.06, 1.82); L-FABP/Cr was inversely associated with ESRD (HR [for highest vs lowest tertile] 0.40, 95% CI 0.19, 0.83). Addition of NGAL/Cr to models that included albuminuria and glomerular filtration rate increased the c-statistic for predicting ESRD from 0.828 to 0.833 (p = 0.001) and for death from 0.710 to 0.722 (p = 0.018). Addition of L-FABP/Cr increased the c-statistic for ESRD from 0.828 to 0.832 (p = 0.042).
In Pima Indians with type 2 diabetes, urinary concentrations of NGAL and L-FABP are associated with important health outcomes, but they are unlikely to add to risk prediction with standard markers in a clinically meaningful way given the small increase in the c-statistic.
Biomarkers; End-stage renal disease; Mortality; Type 2 diabetes
To examine the relation of endothelial microparticles (EMPs) with cardiometabolic risk in the community.
Circulating EMPs are small membrane vesicles released after endothelial cell injury. Endothelial microparticles are reportedly increased among individuals with a high burden of cardiovascular risk factors. However, prior investigations have been limited to small, highly selected samples.
We studied 844 individuals without a history of cardiovascular disease in the Framingham Offspring cohort (mean age 66 ± 9 years, 57% women). We used standardized flow cytometry methods to identify and quantify circulating CD144+ and CD31+/CD41− EMPs. We then used multivariable regression analyses to investigate the relations of EMP phenotypes with cardiovascular and metabolic risk factors.
In multivariable analyses, the following cardiovascular risk factors were associated with one or more of the circulating EMP populations: hypertension (P = 0.025 for CD144+,), elevated triglycerides (P = 0.002 for CD144+, P < 0.0001 for CD31+/CD41−), and metabolic syndrome (P < 0.0001 for CD144+,). Overall, each tertile increase in the Framingham risk score corresponded to a 9% increase in log-CD31+/CD41− EMPs (P = 0.022). Furthermore, the presence of hypertriglyceridaemic waist status was associated with 38% higher levels of CD144+ EMPs (P < 0.0001) and 46% higher levels of CD31+/CD41− EMPs (P < 0.0001).
In a large community-based sample, circulating EMP levels were associated with the presence of cardiometabolic risk factors, particularly dyslipidaemia. These data underscore the potential influence of high-risk metabolic profiles on endothelial integrity.
Microparticles; Cardiovascular risk factors; Endothelium
Whereas endogenous carbon monoxide (CO) is cytoprotective at physiologic levels, excess CO concentrations are associated with cardiometabolic risk and may represent an important marker of progression from subclinical to clinical cardiovascular disease (CVD).
Methods and results
In 1926 participants of the Framingham Offspring Study (aged 57 ± 10 years, 46% women), we investigated the relationship of exhaled CO, a surrogate of blood CO concentration, with both prevalent subclinical CVD and incident clinical CVD events. Presence of subclinical CVD was determined using a comprehensive panel of diagnostic tests used to assess cardiac and vascular structure and function. Individuals with the highest (>5 p.p.m.) compared with lowest (≤4 p.p.m.) CO exposure were more likely to have subclinical CVD [odds ratios (OR): 1.67, 95% CI: 1.32–2.12; P < 0.001]. During the follow-up period (mean 5 ± 3 years), 193 individuals developed overt CVD. Individuals with both high CO levels and any baseline subclinical CVD developed overt CVD at an almost four-fold higher rate compared with those with low CO levels and no subclinical disease (22.1 vs. 6.3%). Notably, elevated CO was associated with incident CVD in the presence [hazards ration (HR): 1.83, 95% CI: 1.08–3.11; P = 0.026] but not in the absence (HR: 0.80, 95% CI: 0.42–1.53; P = 0.51) of subclinical CVD (Pinteraction = 0.019). Similarly, subclinical CVD was associated with incident CVD in the presence of high but not low CO exposure.
Our findings in a community-based sample suggest that elevated CO is a marker of greater subclinical CVD burden and, furthermore, a potential key component in the progression from subclinical to clinical CVD.
Carbon monoxide; Subclinical vascular disease; Cardiovascular outcomes
Arterial hemodynamics and vascular calcification are associated with increased risk for CVD, but their inter-relations remain unclear. We sought to examine the associations of arterial stiffness, pressure pulsatility, and wave reflection with arterial calcification in individuals free of prevalent cardiovascular disease (CVD).
Approach and Results
Framingham Heart Study Third Generation and Offspring Cohort participants free of CVD underwent applanation tonometry to measure arterial stiffness, pressure pulsatility, and wave reflection, including carotid-femoral pulse wave velocity (CFPWV), central pulse pressure (CPP), forward wave amplitude, and augmentation index (AI). Participants in each cohort (n=1905, 45±6 years and n=1015, 65±9 years, respectively) underwent multi-detector computed tomography to assess presence and quantity of thoracic (TAC) and abdominal (AAC) aortic calcification and coronary artery calcification (CAC). In multivariable-adjusted models, both higher CFPWV and CPP were associated with greater TAC and AAC, whereas higher AI was associated with AAC. Among the tonometry measures, CFPWV was the strongest correlate of all calcification measures in multivariable-adjusted models (odds ratio [OR] per SD for TAC 2.69 (95%CI 2.17-3.35), AAC 1.47 (95%CI 1.26-1.73), and CAC 1.48 (95%CI 1.28-1.72), all p<0.001, respectively). We observed stronger relations of CFPWV, CPP, and forward wave amplitude with nearly all continuous calcification measures in the younger Third Generation Cohort as compared with the Offspring Cohort.
In community-dwelling individuals without prevalent CVD, abnormal central arterial hemodynamics were positively associated with vascular calcification, and were observed at younger ages than previously recognized. The mechanisms of these associations may be bidirectional and deserve further study.
Aortic stiffness; pressure pulsatility; wave reflection; hemodynamics; vascular calcification
Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.
Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).
Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10−8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.
Alterations in metabolism influence lifespan in experimental models, but data in humans are lacking. Here we use liquid chromatography/mass spectrometry to quantify 217 plasma metabolites and examine their relation to longevity in a large cohort of men and women. In 647 individuals followed for up to 20 years, higher concentrations of the citric acid cycle intermediate, isocitrate, and the bile acid, taurocholate, are associated with lower odds of longevity, defined as attaining 80 years of age. In a larger cohort of 2,327 individuals with metabolite data available, higher concentrations of isocitrate but not taurocholate are also associated with worse cardiovascular health at baseline, as well as risk of future cardiovascular disease and death. None of the metabolites identified are associated with cancer risk. Our findings suggest that some, but not all, metabolic pathways to human longevity are dependent on modifying risk for the two most common causes of death.
B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.
Methods and results
We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56–1.76], P < 0.0001 and 1.18 (95% CI, 1.11–1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ2 = 17.0; CRP, χ2 = 10.5; BNP and CRP, χ2 = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022–0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322–0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.
B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.
Atrial fibrillation; Risk prediction; Epidemiology; Biomarker; B-type natriuretic peptide; C-reactive protein
We investigated associations between ambient air pollution and microvessel function measured by peripheral arterial tonometry between 2003 and 2008 in the Framingham Heart Study Offspring and Third Generation Cohorts. We measured particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5), black carbon, sulfates, particle number, nitrogen oxides, and ozone by using fixed monitors, and we determined moving averages for 1–7 days preceding vascular testing. We examined associations between these exposures and hyperemic response to ischemia and baseline pulse amplitude, a measure of arterial tone (n = 2,369). Higher short-term exposure to air pollutants, including PM2.5, black carbon, and particle number was associated with higher baseline pulse amplitude. For example, higher 3-day average PM2.5 exposure was associated with 6.3% higher baseline pulse amplitude (95% confidence interval: 2.0, 10.9). However, there were no consistent associations between the air pollution exposures assessed and hyperemic response. Our findings in a community-based sample exposed to relatively low pollution levels suggest that short-term exposure to ambient particulate pollution is not associated with vasodilator response, but that particulate air pollution is associated with baseline pulse amplitude, suggesting potentially adverse alterations in baseline vascular tone or compliance.
air pollutants; endothelium, vascular; particulate matter; vascular diseases
Background: Multiple abnormal metabolic traits are found together or “cluster” within individuals more often than is predicted by chance. The individual and combined role of adiposity and insulin resistance (IR) on metabolic trait clustering is uncertain. We tested the hypothesis that change in trait clustering is a function of both baseline level and change in these measures.
Methods: In 2616 nondiabetic Framingham Offspring Study participants, body mass index (BMI) and fasting insulin were related to a within-person 7-year change in a trait score of 0–4 Adult Treatment Panel III metabolic syndrome traits (hypertension, high triglycerides, low high-density lipoprotein cholesterol, hyperglycemia).
Results: At baseline assessment, mean trait score was 1.4 traits, and 7-year mean (SEM) change in trait score was +0.25 (0.02) traits, P<0.0001. In models with BMI predictors only, for every quintile difference in baseline BMI, the 7-year trait score increase was 0.14 traits, and for every quintile increase in BMI during 7-year follow-up, the trait score increased by 0.3 traits. Baseline level and change in fasting insulin were similarly related to trait score change. In models adjusted for age–sex–baseline cluster score, 7-year change in trait score was significantly related to both a 1-quintile difference in baseline BMI (0.07 traits) and fasting insulin (0.18 traits), and to both a 1-quintile 7-year increase in BMI (0.21 traits) and fasting insulin (0.18 traits).
Conclusions: Change in metabolic trait clustering was significantly associated with baseline levels and changes in both BMI and fasting insulin, highlighting the importance of both obesity and IR in the clustering of metabolic traits.
We evaluated pattern and clinical correlates of change in left ventricular (LV) geometry over a 4-year period in the community; we also assessed whether the pattern of change in LV geometry over 4 years predicts incident cardiovascular disease (CVD), including myocardial infarction, heart failure and cardiovascular death during an additional subsequent follow-up period.
It is unclear how LV geometric patterns change over time and whether changes in LV geometry have prognostic significance.
We evaluated 4492 observations (2604 unique Framingham Study participants attending consecutive examinations) to categorize LV geometry at baseline and after 4 years. Four groups were defined based on the sex-specific distributions of LV mass (LVM) and relative wall thickness (RWT) (normal: LVM and RWT<80th percentile; concentric remodeling: LVM< but RWT≥80th percentile; eccentric hypertrophy: LVM≥ but RWT<80th percentile; and concentric hypertrophy: LVM and RWT≥80th percentile).
At baseline, 2874/4492 observations (64%) had normal LVM and RWT. Individuals with normal geometry or concentric remodeling progressed infrequently (4–8%) to eccentric or concentric hypertrophy. Change from eccentric to concentric hypertrophy was uncommon (8%). Among participants with concentric hypertrophy, 19% developed eccentric hypertrophy within the 4-years period. Among individuals with abnormal LV geometry at baseline, a significant proportion (29–53%) reverted to normal geometry within 4-years. Higher blood pressure, greater body mass index (BMI), advancing age and male sex were key correlates of developing an abnormal geometry. Development of an abnormal LV geometric pattern over 4 years was associated with increased CVD risk (140 events) during a subsequent median follow-up of 12.0 years (adjusted-hazards ratio, 1.59; 95%CI, 1.04–2.43).
Our longitudinal observations in the community suggest that dynamic changes in LV geometric pattern over time are common. Higher blood pressure and greater BMI are modifiable factors associated with the development of abnormal LV geometry, and such progression portends an adverse prognosis.
LV geometry; change over time; remodeling; echocardiography; cardiovascular disease; heart failure; epidemiology
Central pressure augmentation is associated with greater backward wave amplitude and shorter transit time and is higher in women for reasons only partially elucidated. Augmentation also is affected by left ventricular function and shapes of the forward and backward waves. The goal of this study was to examine the relative contributions of forward and backward wave morphology to central pressure augmentation in men and women. From noninvasive measurements of central pressure and flow in 7437 participants (4036 women) from 19 to 90 years of age (mean age 51 years), we calculated several variables: augmentation index, backward wave arrival time, reflection factor, forward wave amplitude, forward wave peak width and slope of the backward wave upstroke. Linear regression models for augmentation index, adjusted for height and heart rate, demonstrated non-linear relations with age (age: βx00302; =4.6±0.1%, P<0.001; age2: βx00302;=−4.2±0.1%, P<0.001) and higher augmentation in women (βx00302; =4.5±0.4%, P<0.001, model R2=0.35). Addition of reflection factor and backward wave arrival time improved model fit (R2=0.62) and reduced the age coefficients: age (βx00302; =2.3±0.1%, P<0.001) and age2 (βx00302; =−2.2±0.1%, P<0.001). Addition of width of forward wave peak, slope of backward wave upstroke and forward wave amplitude further improved model fit (R2=0.75) and attenuated the sex coefficient (βx00302;=1.9±0.2%, P<0.001). Thus, shape and amplitude of the forward wave may be important correlates of augmentation index, and part of the sex-difference in augmentation index may be explained by forward and backward wave morphology.
augmentation index; wave reflection; pulse pressure; aortic stiffness; left ventricular contraction
It is unclear to what extent the incremental predictive performance of a novel biomarker is impacted by the method used to control for standard predictors. We investigated whether adding a biomarker to a model with a published risk score overestimates its incremental performance as compared to adding it to a multivariable model with individual predictors (or a composite risk score estimated from the sample of interest), and to a null model. We used 1000 simulated datasets (with a range of risk factor distributions and event rates) to compare these methods, using the continuous Net Reclassification Index (NRI), the Integrated Discrimination Index (IDI), and change in the C-statistic as discrimination metrics. The new biomarker was added to a: null model; model including a published risk score; model including a composite risk score estimated from the sample of interest; and multivariable model with individual predictors. We observed a gradient in the incremental performance of the biomarker, with the null model resulting in the highest predictive performance of the biomarker and the model using individual predictors resulting in the lowest (mean increases in C-statistic between models without and with the biomarker: 0.261, 0.085, 0.030, and 0.031; NRI: 0.767, 0.621, 0.513, and 0.530; IDI: 0.153, 0.093, 0.053 and 0.057, respectively). These findings were supported by Framingham Study data predicting atrial fibrillation using novel biomarkers. We recommend that authors report the effect of a new biomarker after controlling for standard predictors modeled as individual variables.
biomarkers; model discrimination; risk model; risk prediction
Heart failure with preserved ejection fraction (HFPEF) is a common condition, especially among the elderly and in women, with the reported prevalence approaching 10% in women over the age of 80 years. With an increasing prevalence of hypertension, obesity, atrial fibrillation, and diabetes, and the growing elderly segment of the general population, the prevalence of HFPEF is projected to increase further. HFPEF presents a diagnostic challenge. As a consequence, studies differ widely in their reported incidence and mortality rates associated with this condition, although there is agreement that between a third and one half of heart failure patients in the community have HFPEF. Although several consensus statements and guidelines have been published during the last decade, some of the recent randomized clinical trials have reported low mortality rates, raising doubts whether all patients diagnosed with HFPEF do actually suffer from HFPEF (as opposed to misdiagnosis) or if the condition is heterogeneous by nature in terms of its etiology and prognosis. The overall reported prognosis of patients with HFPEF remains poor, with patients experiencing substantial comorbidity, high rates of repeated hospitalizations, and a high mortality. In both community-based and hospital-based cohorts, HFPEF was recently reported to be associated with approximately 159 (154–165) deaths per 1000 person-years.
epidemiology; heart failure; preserved ejection fraction; mortality; prognosis
Long-term exposure to ambient air pollution has been associated with cardiovascular morbidity and mortality. Impaired vascular responses may in part explain these findings, but the association of such long-term exposure with measures of both conduit artery and microvascular function have not been widely reported. We evaluated the association between residential proximity to a major roadway (primary or secondary highway) and spatially resolved average fine particulate matter (PM2.5) and baseline brachial artery diameter and mean flow velocity, flow mediated dilation % and hyperemic flow velocity, in the Framingham Offspring and Third Generation Cohorts. We examined 5,112 participants (2,731 (53%) women, mean age 49±14 years). Spatially resolved average PM2.5 was associated with lower flow mediated dilation% and hyperemic flow velocity. An interquartile range difference in PM2.5 (1.99 μg/m3) was associated with −0.16% (95%CI: −0.27%, −0.05%) lower FMD% and −0.72 (95%CI: −1.38, −0.06) cm/s lower hyperemic flow velocity %. Residential proximity to a major roadway was negatively associated with flow mediated dilation %. Compared to living ≥400 m away, living <50 m from a major roadway was associated with 0.32% lower flow mediated dilation (95% confidence interval (CI): −0.58%, −0.06%), but results for hyperemic flow velocity had wide confidence intervals −0.68 cm/s (95%CI: −2.29, 0.93). In conclusion, residential proximity to a major roadway and higher levels of spatially resolved estimates of PM2.5 at participant residences are associated with impaired conduit artery and microvascular function in this large community-based cohort of middle-aged and elderly adults.
Air Pollution; Brachial Artery; Microvessels; Endothelium; Vascular
mitral valve; mitral valve regurgitation; mitral valve prolapse
To relate serum insulin-like growth factor-1 (IGF-1) to risk of Alzheimer disease (AD) dementia and to brain volumes in a dementia-free community sample spanning middle and older ages.
Dementia-free Framingham participants from generation 1 (n = 789, age 79 ± 4 years, 64% women) and generation 2 (n = 2,793, age 61 ± 9 years, 55% women; total = 3,582, age 65 ± 11 years, 57% women) had serum IGF-1 measured in 1990–1994 and 1998–2001, respectively, and were followed prospectively for incident dementia and AD dementia. Brain MRI was obtained in stroke- and dementia-free survivors of both generations 1 (n = 186) and 2 (n = 1,867) during 1999–2005. Baseline IGF-1 was related to risk of incident dementia using Cox models and to total brain and hippocampal volumes using linear regression in multivariable models adjusted for age, sex, APOE ε4, plasma homocysteine, waist-hip ratio, and physical activity.
Mean IGF-1 levels were 144 ± 60 μg/L in generation 1 and 114 ± 37 μg/L in generation 2. We observed 279 cases of incident dementia (230 AD dementia) over a mean follow-up of 7.4 ± 3.1 years. Persons with IGF-1 in the lowest quartile had a 51% greater risk of AD dementia (hazard ratio = 1.51, 95% confidence interval: 1.14–2.00; p = 0.004). Among persons without dementia, higher IGF-1 levels were associated with greater total brain volumes (β/SD increment in IGF-1 was 0.55 ± 0.24, p = 0.025; and 0.26 ± 0.06, p < 0.001, for generations 1 and 2, respectively).
Lower serum levels of IGF-1 are associated with an increased risk of developing AD dementia and higher levels with greater brain volumes even among middle-aged community-dwelling participants free of stroke and dementia. Higher levels of IGF-1 may protect against subclinical and clinical neurodegeneration.
Galectin 3 (Gal-3) is a potential mediator of cardiac fibrosis, and Gal-3 concentrations predict incident heart failure. The same mechanisms that lead to cardiac fibrosis in heart failure may influence development of atrial fibrosis and atrial fibrillation (AF). We examined the association of Gal-3 and incident AF in the community.
Plasma Gal-3 concentrations were measured in 3,306 participants of the Framingham Offspring cohort who attended the sixth examination cycle (1995–1998, mean age 58 years, 54% women). Cox proportional hazards regression models were used to assess the association of baseline Gal-3 concentrations and incident AF.
Over a median follow-up period of 10 years, 250 participants developed incident AF. Crude incidence rates of AF by increasing sex-specific Gal-3 quartiles were 3.7%, 5.9%, 9.1%, and 11.5% (log-rank test P < .0001). In age- and sex-adjusted analyses, each 1-SD increase in loge-Gal-3 was associated with a 19% increased hazard of incident AF (hazard ratio 1.19, 95% CI 1.05–1.36, P = .009). This association was not significant after adjustment for traditional clinical AF risk factors (hazard ratio 1.12, 95% CI 0.98–1.28, P = .10).
Higher circulating Gal-3 concentrations were associated with increased risk of developing AF over the subsequent 10 years in age- and sex-adjusted analyses but not after accounting for other traditional clinical AF risk factors. Our results do not support a role for Gal-3 in AF risk prediction. Further studies are needed to evaluate whether Gal-3 plays a role in the development of AF substrate similar to HF.
To determine whether aortic pulse wave velocity (aPWV) improves prediction of cardiovascular (CVD) events beyond conventional risk factors.
Several studies have shown that aPWV may be a useful risk factor for predicting CVD but have been underpowered to examine whether this is true for different sub-groups.
We undertook a systematic review and obtained individual participant data from 16 studies. Study-specific associations of aPWV with cardiovascular outcomes were determined using Cox proportional hazard models and random effect models to estimate pooled effects.
Of 17,635 participants, 1,785 (10%) had a cardiovascular (CVD) event. The pooled age- and sex-adjusted hazard ratio [95% CI] per SD change in loge aPWV was 1.35 [1.22, 1.50, p<0.001] for coronary heart disease (CHD), 1.54 [1.34, 1.78, p<0.001] for stroke, and 1.45 [1.30, 1.61, p<0.001) for CVD. Associations stratified by sex, diabetes and hypertension were similar, but decreased with age (1.89, 1.77, 1.36 and 1.23 for ≤50, 51–60, 61–70 and >70 years respectively, pinteraction <0.001). After adjusting for conventional risk factors, aPWV remained a predictor: CHD 1.23, [1.11, 1.35 p<0.001]; stroke 1.28, [1.16, 1.42 p<0.001]; cardiovascular events 1.30 [1.18, 1.43, p<0.001]. Reclassification indices showed the addition of aPWV improved risk prediction (13% for 10 year CVD risk for intermediate risk) for some sub-groups.
Consideration of aPWV improves model fit and reclassifies risk for future cardiovascular events in models that include standard risk factors. aPWV may enable better identification of high-risk populations who may benefit from more aggressive cardiovascular risk factor management.
pulse wave velocity; meta-analysis; cardiovascular disease; prognostic factor
Genome-wide association studies (GWAS) have identified numerous loci associated with blood pressure (BP). The molecular mechanisms underlying BP regulation, however, remain unclear. We investigated BP-associated molecular mechanisms by integrating BP GWAS with whole blood mRNA expression profiles in 3,679 individuals, using network approaches. BP transcriptomic signatures at the single-gene and the coexpression network module levels were identified. Four coexpression modules were identified as potentially causal based on genetic inference because expression-related SNPs for their corresponding genes demonstrated enrichment for BP GWAS signals. Genes from the four modules were further projected onto predefined molecular interaction networks, revealing key drivers. Gene subnetworks entailing molecular interactions between key drivers and BP-related genes were uncovered. As proof-of-concept, we validated SH2B3, one of the top key drivers, using Sh2b3−/− mice. We found that a significant number of genes predicted to be regulated by SH2B3 in gene networks are perturbed in Sh2b3−/− mice, which demonstrate an exaggerated pressor response to angiotensin II infusion. Our findings may help to identify novel targets for the prevention or treatment of hypertension.
blood pressure; coexpression network; gene expression; hypertension; systems biology
Endogenous sex hormones have been related to cardiovascular outcomes and mortality. We hypothesized that sex hormones are related to atrial fibrillation (AF) in a community-based cohort of middle-aged to older men.
Methods and Results
We examined testosterone, estradiol, and dehydroepiandrosterone sulfate [DHEA-S]) in relation to incident AF in men participating in the Framingham Heart Study. We assessed the 10-year risk of AF in multivariable-adjusted hazard models. The cohort consisted of 1251 men (age 68.0±8.2), of whom 275 developed incident AF. We identified a significant interaction between age and testosterone, and therefore stratified men into age 55–69 (n=786), 70–79 (n=351), and ≥80 (n=114). In men 55–69 each 1-standard deviation (SD) decrease in testosterone was associated with hazard ratio (HR) 1.30 (95% confidence interval [CI], 1.07 to 1.59) for incident AF. The association between testosterone and 10-year incident AF in men 70–79 did not reach statistical significance. In men ≥80 years a 1-SD decrease in testosterone was associated with HR 3.53 (95% CI, 1.96 to 6.37) for AF risk. Estradiol was associated with incident AF (HR, 1.12; 95% CI, 1.01 to 1.26). DHEA-S had a borderline association with risk of AF that was not statistically significant (HR, 1.12; 95% CI, 0.99 to 1.28).
Testosterone and estradiol are associated with incident AF in a cohort of older men. Testosterone deficiency in men ≥80 is strongly associated with AF risk. The clinical and electrophysiologic mechanisms underlying the associations between sex hormones and AF in older men merit continued investigation.
atrial fibrillation; sex hormones; men; aging; epidemiology
Concerns have been raised that the 2013 atherosclerotic cardiovascular disease (ASCVD) risk estimator overpredicts risk in contemporary cohorts. Whether suboptimal calibration will lead to overtreatment with statins is unknown. We investigated the numbers of people eligible for statin treatment in the Framingham Heart Study Offspring Cohort, based on the 2013 cholesterol guidelines, and estimated the proportion that may be overtreated as a result of potential miscalibration of the ASCVD estimator.
Methods and Results
During a median follow‐up of 10 years, we observed 285 ASCVD events (8.4%; comprising ischemic stroke, myocardial infarction, and coronary artery disease death) among 3396 men and 112 events (2.9%) among 3838 women. Hosmer–Lemeshow chi‐square statistics were 16.3 in men (340 predicted versus 285 observed events) and 29.1 in women (166 predicted versus 112 observed events). Overprediction predominantly occurred among women in the highest risk decile and among men in the ≥7th risk deciles, for which observed ASCVD event rates were ≥7.5%. In total, 2615 participants (36%; 867 women) were eligible for statins based on the new guidelines. Of these, 171 women (20%) and 154 men (9%) were reclassified downward (as not eligible for statin therapy) using a recalibrated ASCVD estimator. In the latter group, 18 women (10.5%; 95% CI 5.9% to 15.2%) and 11 men (7.1%; 95% CI 3.0% to 11.3%) experienced ASCVD.
The risk estimator overpredicted ASCVD risk but did so mainly among high‐risk participants who would be considered eligible for statin use anyway. Our findings may mitigate concerns regarding the potential impact of miscalibration of the ASCVD estimator in contemporary cohorts.
primary prevention; risk prediction; statin