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1.
PLoS One ; 14(10): e0222886, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31613888

RESUMO

BACKGROUND: Heart failure (HF) is a heterogeneous clinical syndrome with varying prognosis. Subphenotyping of HF is a research priority to advance our understanding of the syndrome. We formulated a subphenotyping schema and compared long-term mortality risk among the HF subphenotypes in the community-based Framingham Study. METHODS AND RESULTS: In hierarchical order, we grouped participants with new-onset HF (stratified by HF with reduced [HFrEF] vs. preserved ejection fraction [HFpEF]) according to the presence of: (1) coronary heart disease (CHD), (2) metabolic syndrome (MetS), (3) hypertension, and (4) 'other' causes. Age at HF onset was lowest in people with the MetS (mean 76 vs. 77 years for HFrEF and HFpEF, respectively) and highest in those with hypertension only (mean 82 and 85 years for HFrEF and HFpEF, respectively). For HFrEF, 10-year cumulative mortality and hazards ratios [HR] were 87% for CHD (n = 219; referent group), 88% for MetS (n = 105; HR 0.95 [95% CI 0.73-1.23]), 82% for hypertension (n = 104; HR 0.71 [0.55-0.91]), and 78% for other (n = 37; HR 0.81 [0.55-1.19]). Corresponding 10-year cumulative mortality and HR data for HFpEF were: 85% for CHD (n = 84; referent), 83% for MetS (n = 118; HR 0.98 [0.72-1.33]), 81% for hypertension (n = 127; HR 0.71 [0.52-0.95]), and 76% for other (n = 43; HR 0.76 [0.50-1.14]). In a sample without overt heart failure (n = 5536), several echocardiographic and vascular indices showed graded worsening of age- and sex adjusted-values among those having CHD, MetS, hypertension, or obesity, compared with individuals not having these risk factors. CONCLUSIONS: HF subphenotypes characterized by the presence of CHD or metabolic syndrome present at a younger age and are marked by greater mortality risk. The clinical utility of the proposed subphenotyping schema warrants further research.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31624026

RESUMO

BACKGROUND: In recent decades, novel echocardiographic measures have constantly emerged. It is still unclear which echocardiographic measures have the most significant prognostic value in the general population. Accordingly, the aim of this study was to compare the prognostic value of a large panel of echocardiographic measures to identify the most promising measures. METHODS: A total of 1,497 Framingham study participants (mean age, 65 years; 55.4% women) who underwent echocardiographic measurements of left ventricular ejection fraction, left ventricular mass index, global longitudinal strain, global circumferential strain, mitral annular plane systolic excursion, mitral E/e' ratio, maximum and minimum left atrial (LA) volume index, LA emptying fraction, and left ventricular longitudinal synchrony were evaluated. These measures were related to the incidence of two composite outcomes: cardiovascular disease (CVD) or death and atrial fibrillation (AF) or congestive heart failure (CHF). RESULTS: On follow-up (mean, 8.3 years), there were 241 CVD events or deaths and 139 AF or CHF events. In multivariate-adjusted Cox models, higher LA emptying fraction was associated with a lower risk (hazard ratios per SD, 0.80 and 0.70 for CVD or death and AF or CHF, respectively; P ≤ .001 for both) while higher minimum LA volume index (hazard ratios per SD, 1.32 and 1.70 for CVD or death and AF or CHF, respectively; P ≤ .001 for both) and maximum LA volume index (hazard ratios per SD, 1.26 and 1.54 for CVD or death and AF or CHF, respectively; P ≤ .002 for both) were associated with a higher risk for both composite outcomes. CONCLUSIONS: In this community-based sample, LA volumes and function were the best echocardiographic predictors of clinical outcomes. Therefore, these values should be considered for inclusion in standard echocardiographic assessments for the purpose of risk stratification.

3.
J Am Coll Cardiol ; 74(12): 1543-1553, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31537263

RESUMO

BACKGROUND: Differences in proteomic profiles between men and women may provide insights into the biological pathways that contribute to known sex differences in cardiovascular disease (CVD). OBJECTIVES: This study sought to investigate sex differences in circulating biomarkers representative of biological pathways implicated in the development of CVD among Framingham Heart Study participants. METHODS: The authors measured 71 circulating CVD protein biomarkers in 7,184 participants (54% women, mean age 49 years). Multivariable models were used to evaluate the associations of sex, menopause, and hormone status with biomarkers. Cox models were used to examine whether sex modified the association of biomarkers with incident CVD. RESULTS: Of 71 biomarkers examined, 61 (86%) differed significantly between men and women, of which 37 were higher in women (including adipokines and inflammatory markers such as leptin and C-reactive protein), and 24 were higher in men (including fibrosis and platelet markers such as MMP-8 (matrix metalloproteinase-8) and TIMP-1 (tissue inhibitor of metalloproteinases 1); false discovery rate q < 0.05 for all). Sex differences in biomarker profiles were most pronounced between pre-menopausal women versus men, with attenuated sex differences among post-menopausal women not taking hormone replacement therapy. Sex modified the association of specific biomarkers with incident CVD, including CD14 and apolipoprotein B (pinteraction <0.05 for all). CONCLUSIONS: In a predominantly Caucasian population, the authors identified widespread sex differences in circulating biomarkers that reflect distinct pathways implicated in CVD, including inflammation, adiposity, fibrosis, and platelet homeostasis. Menopause and hormone status accounted for some, but not all, of the observed sex differences. Further investigation into factors underlying sex-based differences may provide mechanistic insight into CVD development.

4.
BMJ ; 366: l4570, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434697

RESUMO

OBJECTIVE: To examine the dose-response associations between accelerometer assessed total physical activity, different intensities of physical activity, and sedentary time and all cause mortality. DESIGN: Systematic review and harmonised meta-analysis. DATA SOURCES: PubMed, PsycINFO, Embase, Web of Science, Sport Discus from inception to 31 July 2018. ELIGIBILITY CRITERIA: Prospective cohort studies assessing physical activity and sedentary time by accelerometry and associations with all cause mortality and reported effect estimates as hazard ratios, odds ratios, or relative risks with 95% confidence intervals. DATA EXTRACTION AND ANALYSIS: Guidelines for meta-analyses and systematic reviews for observational studies and PRISMA guidelines were followed. Two authors independently screened the titles and abstracts. One author performed a full text review and another extracted the data. Two authors independently assessed the risk of bias. Individual level participant data were harmonised and analysed at study level. Data on physical activity were categorised by quarters at study level, and study specific associations with all cause mortality were analysed using Cox proportional hazards regression analyses. Study specific results were summarised using random effects meta-analysis. MAIN OUTCOME MEASURE: All cause mortality. RESULTS: 39 studies were retrieved for full text review; 10 were eligible for inclusion, three were excluded owing to harmonisation challenges (eg, wrist placement of the accelerometer), and one study did not participate. Two additional studies with unpublished mortality data were also included. Thus, individual level data from eight studies (n=36 383; mean age 62.6 years; 72.8% women), with median follow-up of 5.8 years (range 3.0-14.5 years) and 2149 (5.9%) deaths were analysed. Any physical activity, regardless of intensity, was associated with lower risk of mortality, with a non-linear dose-response. Hazards ratios for mortality were 1.00 (referent) in the first quarter (least active), 0.48 (95% confidence interval 0.43 to 0.54) in the second quarter, 0.34 (0.26 to 0.45) in the third quarter, and 0.27 (0.23 to 0.32) in the fourth quarter (most active). Corresponding hazards ratios for light physical activity were 1.00, 0.60 (0.54 to 0.68), 0.44 (0.38 to 0.51), and 0.38 (0.28 to 0.51), and for moderate-to-vigorous physical activity were 1.00, 0.64 (0.55 to 0.74), 0.55 (0.40 to 0.74), and 0.52 (0.43 to 0.61). For sedentary time, hazards ratios were 1.00 (referent; least sedentary), 1.28 (1.09 to 1.51), 1.71 (1.36 to 2.15), and 2.63 (1.94 to 3.56). CONCLUSION: Higher levels of total physical activity, at any intensity, and less time spent sedentary, are associated with substantially reduced risk for premature mortality, with evidence of a non-linear dose-response pattern in middle aged and older adults. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018091808.


Assuntos
Acelerometria/estatística & dados numéricos , Exercício , Mortalidade/tendências , Comportamento Sedentário , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco
5.
PLoS One ; 14(8): e0219261, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31393881

RESUMO

Emerging evidence suggests microRNAs (miRNAs) may play an important role in explaining variation in stroke risk and recovery in humans, yet there are still few longitudinal studies examining the association between whole blood miRNAs and stroke. Accounting for multiple testing and adjusting for potentially confounding technical and clinical variables, here we show that whole blood miR-574-3p expression was significantly lower in participants with chronic stroke compared to non-cases. To explore the functional relevance of our findings, we analyzed miRNA-mRNA whole blood co-expression, pathway enrichment, and brain tissue gene expression. Results suggest miR-574-3p is involved in neurometabolic and chronic neuronal injury response pathways, including brain gene expression of DBNDD2 and ELOVL1. These results suggest miR-574-3p plays a role in regulating chronic brain and systemic cellular response to stroke and thus may implicate miR-574-3p as a partial mediator of long-term stroke outcomes.

6.
J Am Heart Assoc ; 8(14): e012300, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31266389

RESUMO

Background Waveform parameters derived from pressure-only Windkessel models are related to cardiovascular disease risk and could be useful for understanding arterial system function. However, prior reports varied in their adjustment for potential confounders. Methods and Results Carotid tonometry waveform data from 2539 participants (mean age 63±11 years, 58% women) of the Framingham Heart Study were used to derive Windkessel measures using pressure and assuming a linear model with fixed diastolic time constant (τdias) and variable asymptotic pressure (Pinf, median 54.5; 25th, 75th percentiles: 38.4, 64.9 mm Hg) or nonlinear model with inverse pressure-dependent τdias and fixed Pinf (20 mm Hg). During follow-up (median 15.1 years), 459 (18%) participants had a first cardiovascular disease event. In proportional hazards models adjusted for age, sex, total cholesterol, high-density lipoprotein cholesterol, smoking, antihypertensive medication use, diabetes mellitus, and physician-acquired systolic blood pressure, only the systolic time constant (τsys) derived from the nonlinear model was related to risk for cardiovascular disease events (hazard ratio=0.91 per 1 SD, 95% CI=0.84-0.99, P=0.04). When heart rate was added to the model, τsys (hazard ratio=0.92, CI=0.84-1.00, P=0.04) and reservoir pressure amplitude (hazard ratio=1.14, CI=1.01-1.28, P=0.04) were related to events. In contrast, measures derived from the linear model were not related to events in models that adjusted for risk factors including systolic blood pressure ( P>0.31) and heart rate ( P>0.19). Conclusions Our results suggest that pressure-only Windkessel measures derived by using a nonlinear model may provide incremental risk stratification, although associations were modest and further validation is required.

7.
Epigenetics ; : 1-16, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31282290

RESUMO

DNA methylation (DNAm) and microRNAs (miRNAs) have been implicated in a wide-range of human diseases. While often studied in isolation, DNAm and miRNAs are not independent. We analyzed associations of expression of 283 miRNAs with DNAm at >400K CpG sites in whole blood obtained from 3565 individuals and identified 227 CpGs at which differential methylation was associated with the expression of 40 nearby miRNAs (cis-miR-eQTMs) at FDR<0.01, including 91 independent CpG sites at r2 < 0.2. cis-miR-eQTMs were enriched for CpGs in promoter and polycomb-repressed state regions, and 60% were inversely associated with miRNA expression. Bidirectional Mendelian randomization (MR) analysis further identified 58 cis-miR-eQTMCpG-miRNA pairs where DNAm changes appeared to drive miRNA expression changes and opposite directional effects were unlikely. Integration of genetic variants in joint analyses revealed an average partial between cis-miR-eQTM CpGs and miRNAs of 2% after conditioning on site-specific genetic variation, suggesting that DNAm is an important epigenetic regulator of miRNA expression. Finally, two-step MR analysis was performed to identify putatively causal CpGs driving miRNA expression in relation to human complex traits. We found that an imprinted region on 14q32 that was previously identified in relation to age at menarche is enriched with cis-miR-eQTMs. Nine CpGs and three miRNAs at this locus tested causal for age at menarche, reflecting novel epigenetic-driven molecular pathways underlying this complex trait. Our study sheds light on the joint genetic and epigenetic regulation of miRNA expression and provides insights into the relations of miRNAs to their targets and to complex phenotypes.

8.
Circ Arrhythm Electrophysiol ; 12(7): e007150, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31216886

RESUMO

BACKGROUND: The etiopathogenesis of electrocardiographic bundle branch and atrioventricular blocks is not fully understood. We investigated familial clustering of cardiac conduction defects and pacemaker insertion in the FHS (Framingham Heart Study). Additionally, we assessed familial clustering of pacemaker insertion in the Danish general population. METHODS: In FHS, we used multivariable-adjusted logistic regression models to investigate the association of parental atrioventricular block (PR interval, ≥0.2 s), complete bundle branch block (QRS, ≥0.12 s), or pacemaker insertion with the occurrence of cardiac conduction abnormalities in their offspring. The Danish nationwide administrative registries were interrogated to assess the relations of parental pacemaker insertion with offspring pacemaker insertion. RESULTS: In FHS (n=371 cases with first-degree atrioventricular block, complete bundle branch block, or pacemaker insertion, and 1471 age- and sex-matched controls), individuals with at least 1 affected parent with a conduction defect had a 1.65-fold odds (odds ratio, 95% CI, 1.32-2.07) for manifesting an atrioventricular block and a 1.62-fold odds (95% CI, 1.08-2.42) for developing a complete bundle branch block. If at least 1 parent had any electrocardiographic conduction defect or pacemaker insertion, the offspring had a 1.62-fold odds (95% CI, 1.31-2.00) for experiencing any of these conditions. In Denmark (n=2 824 199 individuals; 5397 incident pacemaker implantations), individuals with at least 1 first-degree relative with history of pacemaker insertion had a multivariable-adjusted 1.68-fold (incidence rate ratio, 95% CI, 1.49-1.89) risk of undergoing a pacemaker insertion. If the affected relative was ≤45 years of age, the incidence rate ratio was markedly increased to 51.0 (95% CI, 32.7-79.9). CONCLUSIONS: Cardiac conduction blocks and risk for pacemaker insertion cluster within families. A family history of conduction system disturbance or pacemaker insertion should trigger increased awareness of a similar propensity in other family members, especially so when the conduction system disease occurs at a younger age.

9.
J Am Heart Assoc ; 8(6): e010976, 2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30841775

RESUMO

Background Prior studies relating proteomics markers to incident AF screened for limited numbers of proteins. Methods and Results We performed proteomics assays among participants from the Framingham Heart Study Offspring attending their fifth examination. Plasma protein levels (n=1373) were measured by the SOMAscan proteomic profiling platform. We used robust inference for the Cox proportional hazards model to relate each protein level with incident AF. In addition, we examined the association between AF-related genetic loci and levels of proteins associated with AF. Our study included 1885 participants (mean age 55±10 years, 54% women) who had proteomic profiles measured. A total of 349 participants developed AF during follow-up (mean follow-up 18.3 years). We observed that 8 proteins were significantly associated with incident AF after adjusting for age, sex, technical covariates, and correction for multiple testing ( P<0.05/1373=3.6×10-5). After additional adjustments for clinical factors associated with AF, ADAMTS13 and N-terminal pro-B-type natriuretic peptide remained significantly associated with the risk of incident AF (hazard ratio, 0.78; 95% CI, 0.70-0.88; and 1.44; 95% CI, 1.22-1.70, respectively; P<3.6×10-5 for both). None of the 8 proteins were encoded by genes at AF-related genetic loci previously identified by genome-wide association studies. Conclusions We identified 8 proteins associated with risk of incident AF after adjustment for age and sex; 2 proteins were associated with AF after adjustment for AF risk factors. Future studies are needed to replicate our findings, identify whether the markers are mechanistically related to AF development, and whether they are clinically useful for identification of future AF risk.

11.
Exp Gerontol ; 119: 203-211, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30771463

RESUMO

BACKGROUND: Older adults may have difficulty meeting the Physical Activity (PA) Guidelines. A favorable balance between PA and sedentary time (SED) is an important determinant of physical performance in older adults. Our objective was to explore associations of PA/SED with physical performance across mid-older age in adults without overt mobility disability. METHODS: Framingham Offspring Study participants free of mobility disability with accelerometry and physical performance data (gait speed, chair stand time, and handgrip strength), were studied in cross-sectional analysis (n = 1352). We regressed physical performance on PA level, measured using steps, moderate to vigorous (MV)PA and SED. We stratified by age groups, adjusted for covariates, and modelled MVPA and SED separately and together as predictors. RESULTS: Only 38% of adults 50-64 years and 15% of adults ≥75 years met the PA Guidelines (i.e., 150 min MVPA per week). Individuals achieving at least 5 min/day of MVPA had 0.062 ±â€¯0.013 m/s greater gait speed and better chair stands and handgrip strength (in women) than those with <5 min/day of MVPA (p < 0.01) across mid-older age. SED was associated with poorer performance on gait speed and chair stand tests, but results were not significant after adjusting for MVPA (p > 0.05). For adults ≥75 years, every 5000 more steps/day related to ~0.045 m/s greater gait speed (p = 0.006). CONCLUSION: Our cross-sectional study demonstrated that, across mid-older adulthood, MVPA related to better physical performance, but in adults ≥75 years, total steps walked associated with better gait speed. These data warrant future research on the impact of PA on physical performance and health outcomes in older age.

12.
Cell Chem Biol ; 26(3): 433-442.e4, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30661990

RESUMO

Eicosanoids and related oxylipins are critical, small bioactive mediators of human physiology and inflammation. While ∼1,100 distinct species have been predicted to exist, to date, less than 150 of these molecules have been measured in humans, limiting our understanding of their role in human biology. Using a directed non-targeted mass spectrometry approach in conjunction with chemical networking of spectral fragmentation patterns, we find over 500 discrete chemical signals highly consistent with known and putative eicosanoids and related oxylipins in human plasma including 46 putative molecules not previously described. In plasma samples from 1,500 individuals, we find members of this expanded oxylipin library hold close association with markers of inflammation, as well as clinical characteristics linked with inflammation, including advancing age and obesity. These experimental and computational approaches enable discovery of new chemical entities and will shed important insight into the role of bioactive molecules in human health and disease.

13.
J Am Coll Cardiol ; 72(25): 3246-3254, 2018 12 25.
Artigo em Inglês | MEDLINE | ID: mdl-30573026

RESUMO

BACKGROUND: Galectin-3 (Gal-3) has been associated with heart failure (HF) and poor cardiovascular outcomes. However, the effect of longitudinal changes in Gal-3 on clinical outcomes remains unclear. OBJECTIVES: The authors sought to study clinical determinants of change in Gal-3 among community-dwelling individuals. Further, they sought to examine the role of serial Gal-3 measurements in predicting risk of future HF, cardiovascular disease (CVD), and mortality. METHODS: A total of 2,477 participants in the Framingham Heart Study Offspring cohort underwent measurement of plasma Gal-3 levels at 2 examinations (1995 to 1998 and 2005 to 2008). Linear regression models were used to examine clinical correlates of change in Gal-3. Proportional hazards models were used to relate future clinical outcomes with change in Gal-3. RESULTS: The following clinical correlates were associated with greater longitudinal increases in Gal-3 levels: age, female sex, hypertension, diabetes, body mass index, interim development of chronic kidney disease, and HF (p < 0.0001 for all in multivariable model). Change in Gal-3 was associated with future HF (hazard ratio [HR]: 1.39 per 1-SD increase; 95% confidence interval [CI]: 1.13 to 1.71), CVD (HR: 1.29; 95% CI: 1.11 to 1.51), and all-cause mortality (HR: 1.30; 95% CI: 1.17 to 1.46). Change in Gal-3 was associated with both HF with preserved as well as reduced ejection fraction (p < 0.05 for both). CONCLUSIONS: Longitudinal changes in Gal-3 are associated with traditional cardiovascular risk factors and renal disease. In turn, change in Gal-3 predicts future HF, CVD, and mortality in the community. Future studies are needed to determine whether serial Gal-3 measures may be useful in disease prevention.


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Galectina 3/sangue , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Estudos de Coortes , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Estudos Prospectivos
14.
Artigo em Inglês | MEDLINE | ID: mdl-30358808

RESUMO

Background: Comprehensive conjoint characterization of long-term trajectories representing several biological systems are lacking. Methods: We measured serially indicators representing 14 distinct biological systems in up to 3453 participants attending four Framingham Study examinations: bone mineral density, body mass index (BMI), C-reactive protein, glomerular filtration rate, forced vital capacity (FVC), one-second forced expiratory volume/FVC ratio (FEV1/FVC), gait speed, grip strength, glycosylated hemoglobin (HbA1c), heart rate, left ventricular mass, Mini-Mental State Examination (MMSE), pulse pressure, and total/high-density lipoprotein cholesterol ratio (TC/HDL). Results: We observed that correlations among the 14 sex-specific trajectories were modest (r<0.30 for 169 of 182 sex-specific correlations). During follow-up (median 8 years), 232 individuals experienced a CVD event and 393 participants died. In multivariable regression models, CVD incidence was positively related to trajectories of BMI, HbA1c, TC/HDL, gait time, and pulse pressure (P<0.06); mortality risk was related directly to trajectories of gait time, C-reactive protein, heart rate, and pulse pressure but inversely to MMSE, and FEV1/FVC (P<0.006). A unit increase in the trajectory risk score was associated a 2.80-fold risk of CVD (95% confidence interval [CI], 2.04-3.84, P<0.001), and a 2.71-fold risk of death (95% CI, 2.30-3.20, P<0.001). Trajectory risk scores were suggestive of a greater increase in model c-statistic compared to single occasion measures (delta-c compared to age- and sex-adjusted models: 0.032 vs. 0.026 for CVD; 0.042 vs. 0.030 for mortality). Conclusion: Biological systems age differentially over the life course. Longitudinal data on a parsimonious set of biomarkers reflecting key biological systems may facilitate identification of high-risk individuals.

15.
Artigo em Inglês | MEDLINE | ID: mdl-30339231

RESUMO

Context: The natural histories of obesity sub-phenotypes are incompletely delineated. Objectives: To investigate dynamic changes in obesity sub-phenotypes and associations with outcomes. Design, setting, participants and measurements: Framingham Offspring Cohort participants (n= 4,291) who attended the examination cycles 2 (1979-1983) to 7 (1998-2001) - 26,508 participant-observations. Obesity sub-phenotypes (metabolically healthy non-obese [MHNO], metabolically healthy obese [MHO], metabolically unhealthy non-obese [MUNO], metabolically unhealthy obese [MUO]) were ascertained based on metabolic health (<2 Adult Treatment Panel-III criteria). The outcomes were subclinical cardiovascular disease (CVD), and incident diseases (diabetes, hypertension, chronic kidney disease [CKD], CVD) and all-cause mortality. Results: At baseline, 4% and 31% of participants exhibited the MHO and MUNO sub-phenotypes, respectively. Four-year probability of MHO participants becoming MUO was 43% in women and 46% in men. Compared to MHNO, MHO participants had a 1.28-fold (95% confidence interval [CI]: 0.85-1.93) and a 1.9-fold (95% CI 1.38-2.68) higher odds of subclinical CVD and coronary artery calcification, respectively; corresponding values for MUNO were 1.95 (1.54-2.47) and 1.92 (1.38-2.68). During follow-up (median 14 years), 231 participants developed diabetes, 784 hypertension, 423 CKD, 639 CVD, and 1296 died. Compared to MHNO, MHO conferred higher risks of diabetes (hazard ratio [HR]: 4.69 [95% CI: 2.21-9.96]), and hypertension (HR 2.21 [1.66-2.94]). Compared to MUO, MHO conferred lower risks of diabetes (0.21 [0.12-0.39]), CVD (0.64 [0.43-0.95]) and CKD (0.44 [0.27-0.73]), but similar hypertension, cardiovascular mortality and overall-mortality risks. Conclusion: Over time, most MHO participants developed metabolic abnormalities and clinical disease. The MHO sub-phenotype is a harbinger of future risk.

16.
Nat Commun ; 9(1): 3853, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30228274

RESUMO

In the originally published version of this Article, financial support was not fully acknowledged. The sentence "KS was supported by the 'Biomedical Research Program' funds at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation" has been added to the acknowledgement section in both the PDF and HTML versions of the Article.

17.
JAMA Cardiol ; 3(9): 871-876, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30090932

RESUMO

Importance: Mortality is high among patients heart failure (HF) who are receiving treatment, and therefore identifying new pathways rooted in preclinical cardiac remodeling phenotypes may afford novel biomarkers and therapeutic avenues. Circulating extracellular RNAs (ex-RNAs) are an emerging class of biomarkers with target-organ epigenetic effects relevant to myocardial biology, although large human investigations remain limited. Objective: To measure the association of highly expressed circulating ex-RNAs with left ventricular remodeling and incident HF in a community-based cohort. Design, Setting, and Participants: This is a prospective observational cohort study of individuals who were included in the eighth examination of the Framingham Offspring Cohort (2005-2008). Collected data include measurements of the left ventricle via electrocardiography, determination of circulating ex-RNAs in plasma, and incidence of heart failure. Data analysis was completed from December 2016 to June 2018. Exposures: A total of 398 circulating ex-RNA molecules in plasma were measured by reverse transcription polymerase chain reaction; disease ontology analysis was also performed. Main Outcomes and Measures: Echocardiographic indices of left ventricular (LV) remodeling and incident heart failure. Results: A total of 2763 participants of the Framingham Heart Study with measured ex-RNAs (mean [SD] age, 66.3 [9.0] years; 1499 [54.3%] female) were included in this study. Of this sample, 2429 to 2432 individuals had echocardiographic measures recorded (depending on the measurement). A total of 2681 individuals had HF status determined, of whom 116 (4.3%) experienced HF (median [interquartile range] follow-up, 7.7 [6.6-8.6] years). We identified 12 ex-RNAs associated with LV mass and at least 1 other echocardiographic phenotype (LV end-diastolic volume or left atrial dimension). Of these 12 ex-RNAs, 3 micro RNAs (miR-17, miR-20a, and miR-106b) were associated with a 15% reduction in long-term incident HF per 2-fold increase in circulating level during the follow-up period, after adjustments for age, sex, established HF risk factors, and prevalent or interim myocardial infarction. These 3 RNAs shared sequence homology and targeted a shared group of messenger RNAs that specified pathways relevant to HF (eg, transforming growth factor-ß signaling, growth/cell cycle, and apoptosis), and shared a disease association with hypertension in disease ontology analysis. Conclusions and Relevance: This study identifies a group of circulating, noncoding RNAs associated with echocardiographic phenotypes, long-term incident HF, and pathways relevant to myocardial remodeling in a large community-based sample. Further investigations into the functional biology of these ex-RNAs are warranted for surveillance for HF prevention.

18.
Nat Commun ; 9(1): 3268, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111768

RESUMO

Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome's causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment.

19.
Artigo em Inglês | MEDLINE | ID: mdl-30010802

RESUMO

Background: Biologic age may better reflect an individual's rate of aging than chronologic age. Methods: We conducted a transcriptome-wide association study with biologic age estimated with clinical biomarkers, which included: systolic blood pressure, forced expiratory volume at one second (FEV1), total cholesterol, fasting glucose, C-reactive protein, and serum creatinine. We assessed the association between the difference between biologic age and chronologic age (∆age) and gene expression in whole blood measured using the Affymetrix Human Exon 1.0st Array. Results: Our discovery sample included 2163 participants from the Framingham Offspring cohort (mean age 67±9 years, 55% women). A total of 481 genes were significantly associated with ∆age (P<2.8x10-6). Among them, 415 genes were validated (P<0.05/481=1.0x10-4) in 2946 participants from the Framingham Third Generation cohort (mean age 46± 9 years, 53% women). Many of significant genes were involved in the ubiquitin mediated proteolysis pathway. The replication in 414 Rotterdam Study participants (mean age 59±8, 52% women) found 104 of 415 validated genes reached nominal significance (P <0.05). Conclusion: We identified and validated 415 genes associated with ∆age in a community-based cohort. Future functional characterization of the biologic age-related gene network may identify targets to test for interventions to delay aging in older adults.

20.
J Am Heart Assoc ; 7(14)2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30006491

RESUMO

BACKGROUND: The discovery of novel and highly predictive biomarkers of cardiovascular disease (CVD) has the potential to improve risk-stratification methods and may be informative regarding biological pathways contributing to disease. METHODS AND RESULTS: We used a discovery proteomic platform that targeted high-value proteins for CVD to ascertain 85 circulating protein biomarkers in 3523 Framingham Heart Study participants (mean age, 62 years; 53% women). Using multivariable-adjusted Cox models to account for clinical variables, we found 8 biomarkers associated with incident atherosclerotic CVD, 18 with incident heart failure, 38 with all-cause mortality, and 35 with CVD death (false discovery rate, q<0.05 for all; P-value ranges, 9.8×10-34 to 3.6×10-2). Notably, a number of regulators of metabolic and adipocyte homeostasis were associated with cardiovascular events, including insulin-like growth factor 1 (IGF1), insulin-like growth factor binding protein 1 (IGFBP1), insulin-like growth factor binding protein 2 (IGFBP2), leptin, and adipsin. In a multimarker approach that accounted for clinical factors, growth differentiation factor 15 (GDF15) was associated with all outcomes. In addition, N-terminal pro-b-type natriuretic peptide, C-reactive protein, and leptin were associated with incident heart failure, and C-type lectin domain family 3 member B (CLEC3B; tetranectin), N-terminal pro-b-type natriuretic peptide, arabinogalactan protein 1 (AGP1), soluble receptor for advanced glycation end products (sRAGE), peripheral myelin protein 2 (PMP2), uncarboxylated matrix Gla protein (UCMGP), kallikrein B1 (KLKB1), IGFBP2, IGF1, leptin receptor, and cystatin-C were associated with all-cause mortality in a multimarker model. CONCLUSIONS: We identified numerous protein biomarkers that predicted cardiovascular outcomes and all-cause mortality, including biomarkers representing regulators of metabolic homeostasis and inflammatory pathways. Further studies are needed to validate our findings and define clinical utility, with the ultimate goal of improving strategies for CVD prevention.

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