Addition of Inflammatory Biomarkers Did Not Improve Diabetes Prediction in the Community: The Framingham Heart Study

Background: Prior studies have reported conflicting findings with regard to the association of biomarkers in the prediction of incident type 2 diabetes. We evaluated 12 biomarkers as possible diabetes predictors in the Framingham Heart Study. Methods and results: Biomarkers representing inflammation (C-reactive protein, interleukin-6, monocyte chemoattractant protein-1, tumor necrosis factor receptor 2, osteoprotegerin, and fibrinogen), endothelial dysfunction (intercellular adhesion molecule-1), vascular damage (CD40-ligand, P-selectin, and lipoprotein-associated phospholipase A2 mass and activity), and oxidative stress (urinary isoprostanes) were measured in participants without diabetes attending the Offspring seventh (n=2499) or multiethnic Omni second (n=189) examination (1998–2001). Biomarkers were loge transformed and standardized. Multivariable logistic regression tested each biomarker in association with incident diabetes at a follow-up examination (the Offspring eighth and Omni third examination; mean 6.6 years later), with adjustment for age, sex, cohort, body mass index, fasting glucose, systolic blood pressure, high-density lipoprotein cholesterol, triglycerides, and smoking. C statistics were evaluated with and without inflammatory markers. In 2638 participants (56% women, mean age 59 years), 162 (6.1%) developed type 2 diabetes. All biomarkers, excluding osteoprotegerin, were associated with the outcome with adjustment for age, sex, and cohort; however, none remained significant after multivariable adjustment (all P>0.05). The c statistic from the model including only clinical covariates (0.89) did not statistically significantly improve after addition of biomarkers (all P>0.10). Conclusions: Biomarkers representing different inflammatory pathways are associated with incident diabetes but do not remain statistically significant after adjustment for established clinical covariates. Inflammatory biomarkers might not be an effective resource to predict type 2 diabetes in community-based samples

Plasma Leptin Levels and Incidence of Heart Failure, Cardiovascular Disease, and Total Mortality in Elderly Individuals

OBJECTIVE: Obesity predisposes individuals to congestive heart failure (CHF) and cardiovascular disease (CVD). Leptin regulates energy homeostasis, is elevated in obesity, and influences ventricular and vascular remodeling. We tested the hypothesis that leptin levels are associated with greater risk of CHF, CVD, and mortality in elderly individuals. RESEARCH DESIGN AND METHODS: We evaluated 818 elderly (mean age 79 years, 62% women) Framingham Study participants attending a routine examination at which plasma leptin was assayed. RESULTS: Leptin levels were higher in women and strongly correlated with BMI (P < 0.0001). On follow-up (mean 8.0 years), 129 (of 775 free of CHF) participants developed CHF, 187 (of 532 free of CVD) experienced a first CVD event, and 391 individuals died. In multivariable Cox regression models adjusting for established risk factors, log-leptin was positively associated with incidence of CHF and CVD (hazard ratio [HR] per SD increment 1.26 [95% CI 1.03–1.55] and 1.28 [1.09–1.50], respectively). Additional adjustment for BMI nullified the association with CHF (0.97 [0.75–1.24]) but only modestly attenuated the relation to CVD incidence (1.23 [1.00–1.51], P = 0.052). We observed a nonlinear, U-shaped relation between log-leptin and mortality (P = 0.005 for quadratic term) with greater risk of death evident at both low and high leptin levels. CONCLUSIONS: In our moderate-sized community-based elderly sample, higher circulating leptin levels were associated with a greater risk of CHF and CVD, but leptin did not provide incremental prognostic information beyond BMI. Additional investigations are warranted to elucidate the U-shaped relation of leptin to mortality.National Institutes of Health's National Heart, Lung, and Blood Institute (N01-HC25195, N01-HV28178, K24-HL04334, R01-DK080739

Newly diagnosed atrial fibrillation and hospital utilization in heart failure:a nationwide cohort study

AIMS: Atrial fibrillation (AF) constitutes a major burden to health services, but the importance of incident AF in patients with heart failure (HF) is unclear. We examined the associations between incident AF and hospital utilization in patients with HF. METHODS AND RESULTS: In a nationwide matched‐cohort study of HF patients, we identified patients diagnosed with incident AF between 2008 and 2018 in the Danish Heart Failure Registry (N = 4463), and we compared them to matched referents without AF (N = 17 802). Incident AF was associated with a multivariable‐adjusted 4.8‐fold increase (95% CI 4.1–5.6) and 4.3‐fold increase (95% CI 3.9–4.8) in the cumulative incidence of inpatient and outpatient contacts within 30 days, respectively. At 1 year, the cumulative incidence ratios were 1.8 (95% CI 1.7–1.9) and 1.4 (95% CI 1.4–1.5). Incident AF was also associated with increases in the total numbers of inpatient and outpatient hospital contacts within 30 days (multivariable‐adjusted rate ratio 1.4, 95% CI 1.4–1.5, and 1.6, 95% CI 1.6–1.7, respectively). At 1 year, the ratios were 2.2 (95% CI 2.1–2.3) and 2.0 (95% CI 1.9–2.1). The multivariable‐adjusted proportion of bed‐day use among HF patients with incident AF was 10.9‐fold (95% CI 9.3–12.9) higher at 30 days and 5.3‐fold (95% CI 4.3–6.4) higher at 1 year compared with AF‐free referents. CONCLUSIONS: Incident AF in HF is associated with earlier hospital contact, more hospital contacts, and more hospital bed‐days. More evidence on interventions that may prevent the risk and subsequent burden of AF in HF is urgently needed

Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study

BACKGROUND: Family studies and heritability estimates provide evidence for a genetic contribution to variation in the human life span. METHODS:We conducted a genome wide association study (Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on 5 longevity and aging traits in up to 1345 Framingham Study participants from 330 families. Multivariable-adjusted residuals were computed using appropriate models (Cox proportional hazards, logistic, or linear regression) and the residuals from these models were used to test for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate [greater than or equal to]80%, minor allele frequency [greater than or equal to]10%, Hardy-Weinberg test p [greater than or equal to] 0.001).RESULTS:In family-based association test (FBAT) models, 8 SNPs in two regions approximately 500 kb apart on chromosome 1 (physical positions 73,091,610 and 73, 527,652) were associated with age at death (p-value < 10-5). The two sets of SNPs were in high linkage disequilibrium (minimum r2 = 0.58). The top 30 SNPs for generalized estimating equation (GEE) tests of association with age at death included rs10507486 (p = 0.0001) and rs4943794 (p = 0.0002), SNPs intronic to FOXO1A, a gene implicated in lifespan extension in animal models. FBAT models identified 7 SNPs and GEE models identified 9 SNPs associated with both age at death and morbidity-free survival at age 65 including rs2374983 near PON1. In the analysis of selected candidate genes, SNP associations (FBAT or GEE p-value < 0.01) were identified for age at death in or near the following genes: FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN. Top ranked SNP associations in the GEE model for age at natural menopause included rs6910534 (p = 0.00003) near FOXO3a and rs3751591 (p = 0.00006) in CYP19A1. Results of all longevity phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. CONCLUSION: Longevity and aging traits are associated with SNPs on the Affymetrix 100K GeneChip. None of the associations achieved genome-wide significance. These data generate hypotheses and serve as a resource for replication as more genes and biologic pathways are proposed as contributing to longevity and healthy aging

Incremental value of rare genetic variants for the prediction of multifactorial diseases

Background: It is often assumed that rare genetic variants will improve available risk prediction scores. We aimed to estimate the added predictive ability of rare variants for risk prediction of common diseases in hypothetical scenarios.Methods: In simulated data, we constructed risk models with an area under the ROC curve (AUC) ranging between 0.50 and 0.95, to which we added a single variant representing the cumulative frequency and effect (odds ratio, OR) of multiple rare variants. The frequency of the rare variant ranged between 0.0001 and 0.01 and the OR between 2 and 10. We assessed the resulting AUC, increment in AUC, integrated discrimination improvement (IDI), net reclassification improvement (NRI(>0.01)) and categorical NRI. The analyses were illustrated by a simulation of atrial fibrillation risk prediction based on a published clinical risk model.Results: We observed minimal improvement in AUC with the addition of rare variants. All measures increased with the frequency and OR of the variant, but maximum increment in AUC remained below 0.05. Increment in AUC and NRI(>0.01) decreased with higher AUC of the baseline model, w

The Natural History of Left Ventricular Geometry in the Community Clinical Correlates and Prognostic Significance of Change in LV Geometric Pattern

AbstractObjectivesThis study sought to evaluate pattern and clinical correlates of change in left ventricular (LV) geometry over a 4-year period in the community; it 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.BackgroundIt is unclear how LV geometric patterns change over time and whether changes in LV geometry have prognostic significance.MethodsThis study evaluated 4,492 observations (2,604 unique Framingham Heart Study participants attending consecutive examinations) to categorize LV geometry at baseline and after 4 years. Four groups were defined on the basis of the sex-specific distributions of left ventricular mass (LVM) and relative wall thickness (RWT) (normal: LVM and RWT <80th percentile; concentric remodeling: LVM <80th percentile but RWT ≥80th percentile; eccentric hypertrophy: LVM ≥80th percentile but RWT <80th percentile; and concentric hypertrophy: LVM and RWT ≥80th percentile).ResultsAt baseline, 2,874 of 4,492 observations (64%) had normal LVM and RWT. Participants with normal geometry or concentric remodeling progressed infrequently (4% to 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-year period. Among participants with abnormal LV geometry at baseline, a significant proportion (29% to 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 years (adjusted-hazards ratio: 1.59; 95% confidence interval: 1.04 to 2.43).ConclusionsThe 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

Alcohol Consumption, Left Atrial Diameter, and Atrial Fibrillation

BACKGROUND: Alcohol consumption has been associated with atrial fibrillation (AF) in several epidemiologic studies, but the underlying mechanisms remain unknown. We sought to test the hypothesis that an atrial myopathy, manifested by echocardiographic left atrial enlargement, explains the association between chronic alcohol use and AF. METHODS AND RESULTS: We evaluated the relationship between cumulative alcohol consumption and risk of incident AF in 5220 Offspring and Original Framingham Heart Study participants (mean age 56.3 years, 54% women) with echocardiographic left atrial size measurements. The incidence of AF was 8.4 per 1000 person-years, with 1088 incident AF cases occurring over a median 6.0 years (25th-75th percentiles 4.0-8.7 years) of follow-up. After multivariable adjustment for potential confounders, every additional 10 g of alcohol per day (just under 1 drink per day) was associated with a 0.16 mm (95% CI, 0.10-0.21 mm) larger left atrial dimension. Also in multivariable adjusted analysis, every 10 g per day of alcohol consumed was associated with a 5% higher risk of developing new-onset AF (hazard ratio, 1.05; 95% CI, 1.01-1.09). An estimated 24% (95% CI, 8-75) of the association between alcohol and AF risk was explained by left atrial enlargement. CONCLUSIONS: Our study of a large, community-based sample identified alcohol consumption as a predictor of left atrial enlargement and subsequent incident AF. Left atrial enlargement may be an intermediate phenotype along the causal pathway linking long-term alcohol consumption to AF