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Background: Low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the low physiologic range, surrogate markers for reduced liver metabolic function, are associated with cerebral hypometabolism, impairment in neurotransmitter production and synaptic maintenance, and a higher prevalence of dementia. It is unknown whether a prospective association exists between low liver enzyme levels and incident dementia. Objective: To determine whether low levels of ALT and AST are associated with higher risk of incident dementia. Methods: Plasma ALT and AST were measured on 10,100 study participants (mean age 63.2 years, 55% female, 22% black) in 1996–1998. Dementia was ascertained from comprehensive neuropsychological assessments, annual contact, and medical record surveillance. Cox proportional hazards regression was used to estimate the association. Results: During a median follow-up of 18.3 years (maximum 21.9 years), 1,857 individuals developed dementia. Adjusted for demographic factors, incidence rates of dementia were higher at the lower levels of ALT and AST. Compared to the second quintile, ALT values

Introduction Laboratory studies suggest an involvement of growth differentiation factor 15 (GDF-15) in metabolic dysregulation. However, the utility of GDF-15 for assessing risk of cardiometabolic outcomes has not been rigorously examined among older adults. Methods We conducted a cross-sectional analysis of older adults who attended visit 6 (2016–2017) of the Atherosclerosis Risk in Communities (ARIC) Study. We used multivariable logistic regression to quantify cross-sectional associations of GDF-15 (in quartiles) with prevalent diabetes, obesity, atherosclerotic cardiovascular disease (ASCVD), subclinical myocardial stress/injury (assessed by NT-proB-type Natriuretic Peptide [NT-proBNP] and high-sensitivity cardiac troponin T [hs-cTnT]), and heart failure (HF). Results Among 3792 ARIC study participants (mean age 80 years, 59% women, 23% Blacks and 77% Whites, mean GDF-15: 2094.9 pg/mL [SD: 1395.6]), higher GDF-15 concentrations (highest vs. lowest quartile) were positively associated with diabetes (adjusted odds ratio [aOR]:] : 2.48, 95% CI : 1.89, 3.26), ASCVD (aOR: 1.57, 95% CI: 1.16, 2.11), increased hscTnT (aOR: 2.27, 95%CI: 1.54, 3.34), increased NT-proBNP (aOR: 1.98, 95%CI: 1.46, 2.70), and HF (aOR: 3.22, 95%CI : 2.13, 4.85), in models adjusted for demographics and traditional cardiovascular risk factors. Conclusions In this sample of older US black and whites, increased GDF-15 was positively associated with diabetes, ASCVD, HF, and markers of subclinical myocardial stress or injury. These results illustrate the diverse aspects of the link between GDF-15 and diseases states, and its potential utility as robust biomarker of adverse cardiometabolic outcomes.

Background Lipoprotein(a) (Lp(a)) is a potent causal risk factor for cardiovascular events and mortality. However, its relationship with subclinical atherosclerosis, as defined by arterial calcification, remains unclear. This study uses the ARIC (Atherosclerosis Risk in Communities Study) to evaluate the relationship between Lp(a) in middle age and measures of vascular and valvular calcification in older age. Methods and Results Lp(a) was measured at ARIC visit 4 (1996–1998), and coronary artery calcium (CAC), together with extracoronary calcification (including aortic valve calcium, aortic valve ring calcium, mitral valve calcification, and thoracic aortic calcification), was measured at visit 7 (2018–2019). Lp(a) was defined as elevated if >50 mg/dL and CAC/extracoronary calcification were defined as elevated if >100. Logistic and linear regression models were used to evaluate the association between Lp(a) and CAC/extracoronary calcification, with further stratification by race. The mean age of participants at visit 4 was 59.2 (SD 4.3) years, with 62.2% women. In multivariable adjusted analyses, elevated Lp(a) was associated with higher odds of elevated aortic valve calcium (adjusted odds ratio [aOR], 1.82; 95% CI, 1.34–2.47), CAC (aOR, 1.40; 95% CI, 1.08–1.81), aortic valve ring calcium (aOR, 1.36; 95% CI, 1.07–1.73), mitral valve calcification (aOR, 1.37; 95% CI, 1.06–1.78), and thoracic aortic calcification (aOR, 1.36; 95% CI, 1.05–1.77). Similar results were obtained when Lp(a) and CAC/extracoronary calcification were examined on continuous logarithmic scales. There was no significant difference in the association between Lp(a) and each measure of calcification by race or sex. Conclusions Elevated Lp(a) at middle age is significantly associated with vascular and valvular calcification in older age, represented by elevated CAC, aortic valve calcium, aortic valve ring calcium, mitral valve calcification, thoracic aortic calcification. Our findings encourage assessing Lp(a) levels in individuals with increased cardiovascular disease risk, with subsequent comprehensive vascular and valvular assessment where elevated.

It remains unclear whether elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) can serve as a "risk equivalent" for cardiovascular disease to adults at high cardiovascular risk.We included 9789 participants (mean age 63.2 years, 55% women, 19.4% Black, 13% with a history of cardiovascular disease) who attended Atherosclerosis Risk in Communities Study Visit 4 (1996-1998). We classified participants as having a history of cardiovascular disease at baseline and, among those without cardiovascular disease, we defined categories of NT-proBNP (125, 125-449, ≥450 pg/mL). We used Cox regression to estimate associations of NT-proBNP with incident cardiovascular disease and mortality.Over a median 20.5 years of follow-up, there were 4562 deaths (917 cardiovascular deaths). There were 2817 first events and 806 recurrent events (in those with a history of cardiovascular disease at baseline). Among individuals without a history of cardiovascular disease, those adults with NT-proBNP ≥450 pg/mL had significantly higher risks of all-cause death (hazard ratio [HR] 2.12; 95% confidence interval [CI], 1.78-2.53), cardiovascular mortality (HR 2.92; 95% CI, 2.15-3.97), incident total cardiovascular disease (HR 2.59; 95% CI, 2.13-3.16), atherosclerotic cardiovascular disease (HR 2.20; 95% CI, 1.72-2.80), and heart failure (HR 3.81; 95% CI, 3.01-4.81), compared with individuals with NT-proBNP125 pg/mL. The elevated cardiovascular risk in persons with high NT-proBNP and no history of cardiovascular disease was similar to, or higher than, the risk conferred by a history of cardiovascular disease.Our findings suggest that it might be appropriate to manage adults with NT-proBNP ≥450 pg/mL as if they had a history of clinical cardiovascular disease.

Background Laboratory data suggest obesity is linked to myocardial inflammation and fibrosis, but clinical data are limited. We aimed to examine the association of obesity with galectin‐3, a biomarker of cardiac inflammation and fibrosis, and the related implications for heart failure (HF) risk. Methods and Results We evaluated 8687 participants (mean age 63 years; 21% Black) at ARIC (Atherosclerosis Risk in Communities) Visit 4 (1996–1998) who were free of heart disease. We used adjusted logistic regression to estimate the association of body mass index (BMI) categories with elevated galectin‐3 (≥75th sex‐specific percentile) overall and across demographic subgroups, with tests for interaction. We used Cox proportional hazards models to assess the combined associations of galectin‐3 and BMI with incident HF (through December 31, 2019). Higher BMI was associated with higher odds of elevated galectin‐3 (odds ratio [OR], 2.32; 95% CI, 1.88–2.86) for severe obesity ([BMI ≥35 kg/m 2 ] versus normal weight [BMI 18.5‐2 ]). There were stronger associations of BMI with elevated galectin‐3 among women versus men and White versus Black participants (both P ‐for‐interaction 4‐fold higher risk of HF (HR, 4.19; 95% CI, 2.98–5.88) than those with normal weight and galectin‐3 Conclusions Obesity is strongly associated with elevated galectin‐3. Additionally, the combination of obesity and elevated galectin‐3 is associated with marked HF risk, underscoring the importance of elucidating pathways linking obesity with cardiac inflammation and fibrosis.

Background Cardiac markers such as high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B natriuretic peptide (NTproBNP) are predictors of developing acute kidney injury (AKI) during hospitalization for surgery or revascularization. However, their associations with the long-term risk of AKI in the general population are uncharacterized. Methods We conducted a prospective cohort study in 10 669 participants of the Atherosclerosis Risk in Communities Study (visit 4, 1996–1998, mean age, 63 years, 56% female, 22% black race) to examine the association of plasma concentrations of hs-cTnT and NTproBNP with the incident hospitalization with AKI. We used multivariable Cox regression analysis to estimate hazard ratios (HRs). Results During follow-up, 1907 participants had an incident hospitalization with AKI. Participants with higher concentrations of hs-cTnT had a higher risk of hospitalization with AKI in a graded fashion (adjusted HR, 1.88 [95%CI , 1.59–2.21] for ≥14 ng/L, 1.36 [1.18–1.57] for 9–13 ng/L, and 1.16 [1.03–1.30] for 5-8 ng/L compared to Conclusions In middle-aged to older black and white adults in the community, higher concentrations of hs-cTnT and NTproBNP were robustly associated with an increased risk of hospitalization with AKI. These results suggest the usefulness of hs-cTnT and NT-proBNP to identify people at risk of AKI in the general population.

Context Lower dehydroepiandrosterone-sulfate (DHEA-S) levels have been inconsistently associated with coronary heart disease (CHD) and mortality. Data are limited for heart failure (HF) and association between DHEA-S change and events. Objective Assess associations between low DHEA-S/DHEA-S change and incident HF hospitalization, CHD, and mortality in older adults. Design DHEA-S was measured in stored plasma from visits 4 (1996-1998) and 5 (2011-2013) of the Atherosclerosis Risk in Communities study. Follow-up for incident events: 18 years for DHEA-S level; 5.5 years for DHEA-S change. Setting General community. Participants Individuals without prevalent cardiovascular disease (n = 8143, mean age 63 years). Main Outcome Measure Associations between DHEA-S and incident HF hospitalization, CHD, or mortality; associations between 15-year change in DHEA-S (n = 3706) and cardiovascular events. Results DHEA-S below the 15th sex-specific percentile of the study population (men: 55.4 µg/dL; women: 27.4 µg/dL) was associated with increased HF hospitalization (men: hazard ratio [HR] 1.30, 95% confidence interval [CI], 1.07-1.58; women: HR 1.42, 95% CI, 1.13-1.79); DHEA-S below the 25th sex-specific percentile (men: 70.0 µg/dL; women: 37.1 µg/dL) was associated with increased death (men: HR 1.12, 95% CI, 1.01-1.25; women: HR 1.19, 95% CI, 1.03-1.37). In men, but not women, greater percentage decrease in DHEA-S was associated with increased HF hospitalization (HR 1.94, 95% CI, 1.11-3.39). Low DHEA-S and change in DHEA-S were not associated with incident CHD. Conclusions Low DHEA-S is associated with increased risk for HF and mortality but not CHD. Further investigation is warranted to evaluate mechanisms underlying these associations.

Context Sex differences exist in heart failure (HF) phenotypes, but there is limited research on the role of sex hormones in HF and its subtypes. Objective To examine the associations of total testosterone, dehydroepiandrosterone sulfate (DHEA-S), and sex hormone-binding globulin (SHBG) with incident HF, HF with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF). Design Atherosclerosis Risk in Communities (ARIC) study (prospective cohort study). Median follow-up is 19.2 years. Setting General community. Participants 4107 men and 4839 postmenopausal women, with mean age of 63.2 (standard deviation [SD] 5.7) and 62.8 (5.5) years, respectively. Exposure Plasma sex hormone levels were measured at visit 4 (1996-1998). Main Outcome Measures Incident HF events were identified through hospital discharge codes and death certificates. Results The Hazard Ratios for HF associated with 1 SD decrease in log-transformed total testosterone, DHEA-S, and SHBG were 1.10 (95% confidence interval 1.03, 1.17), 1.07 (1.00, 1.15), and 1.04 (0.96, 1.11) in men, and 1.05 (0.99, 1.13), 1.17 (1.09, 1.24), and 0.93 (0.85, 1.01) in women, respectively. The associations between sex hormones with subtypes of HF had similar patterns but were attenuated and became statistically insignificant. Conclusion In this prospective cohort, lower levels of endogenous testosterone and DHEA-S in men and DHEA-S in postmenopausal women were associated with the development of HF. Similar directions of association in both sexes and both HF subtypes suggest that sex hormones play a role in the development of HF through common pathways regardless of sex.

AIMS/HYPOTHESIS: Elevated circulating growth differentiation factor-15 (GDF-15), a marker of cellular stress, is associated with both heart failure (HF) and diabetes. However, it is unclear to what extent GDF-15 is associated with HF among individuals with and without diabetes. METHODS: We evaluated 10,570 participants free of HF at Visit 3 (1993–1995) of the Atherosclerosis Risk in Communities study. We used Cox regression to evaluate the joint associations of GDF-15 and diabetes with incident HF. Models were adjusted for traditional cardiovascular risk factors. RESULTS: Among a total of 10,570 individuals (mean age of 60.5 years, 58% women, 27% black adults), elevated GDF-15 (≥75th percentile) was more common in people with diabetes compared with those without diabetes (32.8% vs 23.6%, p

New therapeutics for cardiovascular disease (CVD) prevention in diabetes are costly, highlighting the need for better risk stratification so that interventions may be targeted to those at the highest risk. High-sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) are measures of subclinical cardiac damage associated with cardiovascular risk in the general population (1,2). The troponins appear differentially associated with diabetes (3). We assessed whether hs-cTnI or hs-cTnT could improve cardiovascular and mortality risk stratification in adults with diabetes and whether elevated concentrations of either troponin (≥90th percentile) were associated with mortality risk similar to those having a history of clinical CVD. We included 1,704 adults (ages 54–75 years) with diabetes (47.5% of whom were male, 33.8% Black, and 24.4% with CVD) in the Atherosclerosis Risk in Communities (ARIC) study who attended visit 4 (1996–1998). Diabetes status was defined based on self-reported physician diagnosis, medication use, or blood glucose (fasting ≥126 mg/dL; nonfasting ≥200 mg/dL). hs-cTnI was measured in stored plasma using the ARCHITECT STAT High Sensitive Troponin-I assay (Abbott Diagnostics, Chicago, IL). hs-cTnT was measured in stored plasma using the Elecsys Troponin T assay (Roche Diagnostics, Indianapolis, IN). To compare hs-cTnI and hs-cTnT, we used percentile categories among those without CVD

Objective: A Mediterranean diet supplemented with olive oil and nuts prevents cardiovascular disease in clinical studies, but the underlying mechanisms are incompletely understood. We investigated whether the preventive effect of the diet could be due to inhibition of atherosclerosis and foamy monocyte formation in Ldlr –/– mice fed with a diet in which milkfat in a Western diet (WD) was replaced with extra-virgin olive oil and nuts (EVOND). Approach and Results: Ldlr –/– mice were fed EVOND or a Western diet for 3 (or 6) months. Compared with the Western diet, EVOND decreased triglyceride and cholesterol levels but increased unsaturated fatty acid concentrations in plasma. EVOND also lowered intracellular lipid accumulation in circulating monocytes, indicating less formation of foamy monocytes, compared with the Western diet. In addition, compared with the Western diet, EVOND reduced monocyte expression of inflammatory cytokines, CD36, and CD11c, with decreased monocyte uptake of oxLDL (oxidized LDL [low-density lipoprotein]) ex vivo and reduced CD11c + foamy monocyte firm arrest on vascular cell adhesion molecule-1 and E-selectin–coated slides in an ex vivo shear flow assay. Along with these changes, EVOND compared with the Western diet reduced the number of CD11c + macrophages in atherosclerotic lesions and lowered atherosclerotic lesion area of the whole aorta and aortic sinus. Conclusions: A diet enriched in extra-virgin olive oil and nuts, compared with a Western diet high in saturated fat, lowered plasma cholesterol and triglyceride levels, inhibited foamy monocyte formation, inflammation, and adhesion, and reduced atherosclerosis in Ldlr –/– mice.

OBJECTIVES Cardiac troponin T, measured using a high-sensitive assay (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are associated with increased stroke risk and perhaps with cognitive decline. However, few well-designed prospective studies with extended follow-up have been conducted. We aimed to estimate the association of hs-cTnT and NT-proBNP with 15-year cognitive change in the Atherosclerosis Risk in Communities (ARIC) study. DESIGN Prospective cohort study. SETTING Four US communities. PARTICIPANTS A total of 9114 and 9108 participants from the Atherosclerosis Risk in Communities study for analyses of hs-cTnT and NT-proBNP, respectively. MEASUREMENTS We examined association of hs-cTnT and NT-proBNP with 15-year change (1996-1998 to 2011-2013) in three cognitive tests of executive function (Digit Symbol Substitution Test), verbal learning memory (Delayed Word Recall Test), and semantic fluency (Word Fluency Test), and an overall score combining the three tests using multivariable linear mixed effect models. We conducted several sensitivity analyses including multiple imputations to address bias due to missing data and attrition, and we compared associations within groups combining hs-cTnT and NT-proBNP into a three-level categorical variable. RESULTS At baseline (1996-1998), mean age was 63.4 (standard deviation [SD] = 5.7) years; 56.4% were women, and 17.5% were black. The hs-cTnT at baseline was not associated with cognitive change in any measure. Some evidence indicated accelerated decline in verbal learning and memory when comparing those in the highest with the lowest NT-proBNP quintiles; however, this association was not replicated when considering clinically relevant cutoffs or deciles of exposure in survivors. Sensitivity analyses were consistent with our primary analyses. There was little evidence to support effect modification by any considered factors. People with highest levels of both biomarkers had excessive decline in global z scores vs people with lowest levels (-.34; 95% confidence interval = -.63 to -.04). CONCLUSION Markers of myocardial injury and stretch were not associated with cognitive decline following 15 years among survivors, but when combined together they were suggestive in post hoc analysis. Whether this represents targets of intervention should be examined in the future. J Am Geriatr Soc 67:2353-2361, 2019.

Background There is growing interest in the use of multiplexed aptamer-based assays for large-scale proteomic studies. However, the analytic, short- and long-term variation of the measured proteins is largely uncharacterized. Methods We quantified 4001 plasma protein analytes from 42 participants in the Atherosclerosis Risk in Communities (ARIC) Study in split samples and at multiple visits using a multiplexed modified aptamer assay. We calculated the CV, Spearman correlation, and intraclass correlation (ICC) between split samples and evaluated the short-term (4–9 weeks) and long-term (approximately 20 years) variability using paired t-tests with log-transformed protein concentrations and Bonferroni-corrected significance thresholds. We performed principal component (PC) analysis of protein analyte concentrations and evaluated their associations with age, sex, race, and estimated glomerular filtration rate (eGFR). Results The mean baseline age was 57 years at the first visit, 43% of participants were male and 57% were white. Among 3693 protein analytes that passed quality control, half (n = 1846) had CVs < 5.0%, Spearman correlations > 0.89, and ICCs > 0.96 among the split samples. Over the short term, only 1 analyte had a statistically significant difference between the 2 time points, whereas, over approximately 20 years, 866 analytes (23.4%) had statistically significant differences (P < 1.4 × 10−5, 681 increased, 185 decreased). PC1 had high correlations with age (−0.73) and eGFR (0.60). PC2 had moderate correlation with male sex (0.18) and white race (0.31). Conclusions Multiplexed modified aptamer technology can assay thousands of proteins with excellent precision. Our results support the potential for large-scale studies of the plasma proteome over the lifespan.

Isolated systolic hypertension (ISH) and elevated pulse pressure (PP) are common blood pressure (BP) abnormalities in older adults, reflect poor vascular compliance, and can signify risk for cardiovascular outcomes. We sought to characterize the associations of ISH and widened PP with high-sensitivity Troponin-T (hs-cTnT; a marker of myocardial damage) and N-terminal pro-B-type natriuretic peptide (NT-proBNP; a marker of hemodynamic stress) levels in older adults. We performed a cross-sectional analysis of 5,251 Atherosclerosis Risk in Communities (ARIC) study participants without heart failure who attended visit 5 (2011 to 2013). We used logistic regression to evaluate the association of ISH (systolic BP ≥140 mm Hg and diastolic BP < 90 mm Hg) and quartiles of PP with detectable (≥5 ng/L) and elevated hs-cTnT (≥14 ng/L); as well as elevated NT-proBNP (≥100 pg/mL). The mean age was 75 years, 58% were women, and 78% were white. ISH was present in 24.7% and PP ≥ 70 mm Hg in 30.3% of this cohort. Compared to participants with nonhypertensive BP (

Background: We assessed whether plasma troponin I measured by a high-sensitivity assay (hs-TnI) is associated with incident cardiovascular disease (CVD) and mortality in a community-based sample without prior CVD. Methods: ARIC study (Atherosclerosis Risk in Communities) participants aged 54 to 74 years without baseline CVD were included in this study (n=8121). Cox proportional hazards models were constructed to determine associations between hs-TnI and incident coronary heart disease (CHD; myocardial infarction and fatal CHD), ischemic stroke, atherosclerotic CVD (CHD and stroke), heart failure hospitalization, global CVD (atherosclerotic CVD and heart failure), and all-cause mortality. The comparative association of hs-TnI and high-sensitivity troponin T with incident CVD events was also evaluated. Risk prediction models were constructed to assess prediction improvement when hs-TnI was added to traditional risk factors used in the Pooled Cohort Equation. Results: The median follow-up period was ≈15 years. Detectable hs-TnI levels were observed in 85% of the study population. In adjusted models, in comparison to low hs-TnI (lowest quintile, hs-TnI ≤1.3 ng/L), elevated hs-TnI (highest quintile, hs-TnI ≥3.8 ng/L) was associated with greater incident CHD (hazard ratio [HR], 2.20; 95% CI, 1.64–2.95), ischemic stroke (HR, 2.99; 95% CI, 2.01–4.46), atherosclerotic CVD (HR, 2.36; 95% CI, 1.86–3.00), heart failure hospitalization (HR, 4.20; 95% CI, 3.28–5.37), global CVD (HR, 3.01; 95% CI, 2.50–3.63), and all-cause mortality (HR, 1.83; 95% CI, 1.56–2.14). hs-TnI was observed to have a stronger association with incident global CVD events in white than in black individuals and a stronger association with incident CHD in women than in men. hs-TnI and high-sensitivity troponin T were only modestly correlated ( r =0.47) and were complementary in prediction of incident CVD events, with elevation of both troponins conferring the highest risk in comparison with elevation in either one alone. The addition of hs-TnI to the Pooled Cohort Equation model improved risk prediction for atherosclerotic CVD, heart failure, and global CVD. Conclusions: Elevated hs-TnI is strongly associated with increased global CVD incidence in the general population independent of traditional risk factors. hs-TnI and high-sensitivity troponin T provide complementary rather than redundant information.

Whether persons without prevalent cardiovascular disease (CVD) but elevated levels of high-sensitivity cardiac troponin T (hs-cTnT) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) are at high risk of infection is unknown. Using 1996–2013 data from the Atherosclerosis Risk in Communities Study, we estimated hazard ratios for incident hospitalization with infection in relation to plasma hs-cTnT and NT-proBNP concentrations among participants without prevalent CVD and contrasted them with hazard ratios for persons with prevalent CVD (coronary heart disease, heart failure, or stroke). In a multivariable Cox model, prevalent CVD was significantly associated with risk of hospitalization with infection (hazard ratio (HR) = 1.31, 95% confidence interval (CI): 1.19, 1.45). Among participants without prevalent CVD, hs-cTnT and NT-proBNP were independently associated with infection risk in a graded fashion (e.g., HR = 1.44 (95% CI: 1.24, 1.69) for hs-cTnT ≥14 ng/L and HR = 1.28 (95% CI: 1.14, 1.44) for hs-cTnT 9–13 ng/L vs.

Cancer survivors might have an excess risk of cardiovascular disease (CVD) resulting from toxicities of cancer therapies and a high burden of CVD risk factors. We sought to evaluate the association of cancer survivorship with subclinical myocardial damage, as assessed by elevated high-sensitivity cardiac troponin T (hs-cTnT) test results. We included 3,512 participants of the Atherosclerosis Risk in Communities Study who attended visit 5 (2011–2013) and were free of CVD (coronary heart disease, heart failure, or stroke). We used multivariate logistic regression to evaluate the cross-sectional associations of survivorship from any, non-sex-related, and sex-related cancers (e.g., breast, prostate) with elevated hs-cTnT (≥14 ng/L). Of 3,512 participants (mean age, 76 years; 62% women; 21% black), 19% were cancer survivors. Cancer survivors had significantly higher odds of elevated hs-cTnT (OR = 1.26, 95% CI: 1.03, 1.53). Results were similar for survivors of non-sex-related and colorectal cancers, but there was no association between survivorship from breast and prostate cancers and elevated hs-cTnT. Results were similar after additional adjustments for CVD risk factors. Survivors of some cancers might be more likely to have elevated hs-cTnT than persons without prior cancer. The excess burden of subclinical myocardial damage in this population might not be fully explained by traditional CVD risk factors.

Purpose: Cyclic guanosine monophosphate (cGMP) is a second messenger for natriuretic peptide (NP) and nitric oxide pathways; its enhancement a target for heart failure and cardiovascular disease (CVD). We evaluated whether plasma cGMP was associated with change in left ventricular mass (LVM) among individuals free of CVD and if this differed by sex. Methods and Results: In 611 men and 612 women aged 45–84 years with plasma cGMP measured at baseline and cardiac MRI performed at baseline and 10 years later, we tested associations of cGMP [log-transformed, per 1 SD increment] with LVM, adjusting for CVD risk factors and N-terminal pro-B-type-NP (NT-proBNP). Participants had mean (SD) age of 63.1(8.5) years and cGMP 4.8(2.6) pmol/mL. Cross-sectionally, higher cGMP was associated with lesser LVM, non-lin- early. In contrast, longitudinally, higher cGMP was associated with increase in LVM [1.70g (0.61, 2.78)] over 10 years. Higher cGMP was associated with greater LVM change in men [2.68g (1.57, 3.79)] but not women [0.24g ((−0.92, 1.39); p-interaction < 0.001]. Conclusion: In conclusion, in a community-based cohort, higher cGMP levels were associated with increase in LVM over 10 years independent of CVD risk factors and NT-proBNP in men, perhaps reflecting compensatory changes. Further studies are needed to understand mechanistic roles of cGMP in LV remodelling and associated sex differences.

Objective: The aim of this study was to comprehensively assess the association of multiple lipid measures with incident peripheral artery disease (PAD). Approach and Results: We used Cox proportional hazards models to characterize the associations of each of the fasting lipid measures (total cholesterol, LDL-C [low-density lipoprotein cholesterol], HDL-C [high-density lipoprotein cholesterol], triglycerides, RLP-C [remnant lipoprotein cholesterol], LDL-TG [LDL-triglycerides], sdLDL-C [small dense LDL-C], and Apo-E-HDL [Apo-E-containing HDL-C]) with incident PAD identified by pertinent International Classification of Diseases, Ninth Revision, Clinical Modification ( ICD-9-CM ) hospital discharge codes (eg, 440.2) among 8330 Black and White ARIC (Atherosclerosis Risk in Communities) participants (mean age 62.8 [SD 5.6] years) free of PAD at baseline (1996–1998) through 2015. Since lipid traits are biologically correlated to each other, we also conducted principal component analysis to identify underlying components for PAD risk. There were 246 incident PAD cases with a median follow-up of 17 years. After accounting for potential confounders, the following lipid measures were significantly associated with PAD (hazard ratio per 1-SD increment [decrement for HDL-C and Apo-E-HDL]): triglycerides, 1.21 (95% CI, 1.08–1.36); RLP-C, 1.18 (1.08–1.29); LDL-TG, 1.18 (1.05–1.33); HDL-C, 1.39 (1.16–1.67); and Apo-E-HDL, 1.27 (1.07–1.51). The principal component analysis identified 3 components (1: mainly loaded by triglycerides, RLP-C, LDL-TG, and sdLDL-C; 2: by HDL-C and Apo-E-HDL; and 3: by LDL-C and RLP-C). Components 1 and 2 showed independent associations with incident PAD. Conclusions: Triglyceride-related and HDL-related lipids were independently associated with incident PAD, which has implications on preventive strategies for PAD. However, none of the novel lipid measures outperformed conventional ones. Graphic Abstract: A graphic abstract is available for this article.

BACKGROUND: Limited information exists regarding the association between midlife lipid levels and late-life total and regional brain volumes. METHODS: We studied 1,872 participants in the longitudinal community-based Atherosclerosis Risk in Communities Neurocognitive Study. Serum lipid levels were measured in 1987–1989 (mean age, 53 ± 5 years). Participants underwent 3T brain MRI scans in 2011–2013. Brain volumes were measured using FreeSurfer image analysis software. Linear regression models were used to assess the associations between serum lipids and brain volumes modeled in standard deviation (SD) units, adjusting for potential confounders. RESULTS: In adjusted analyses, one SD higher low-density lipoprotein cholesterol (LDL) levels were associated with larger total brain volumes (β 0.033, 95% CI 0.006–0.060) as well as larger volumes of the temporal (β 0.038, 95% CI 0.003–0.074) and parietal lobes (β 0.044, 95% CI 0.009–0.07) and Alzheimer disease-related region (β 0.048, 95% CI 0.048–0.085). Higher triglyceride levels were associated with smaller total brain volumes (β −0.033, 95% CI −0.060, −0.007). The associations between LDL levels and brain volumes were modified by age (P for interaction 53 years at baseline, and were attenuated after application of weights to account for informative attrition, although associations with the parietal and Alzheimer’s disease-related region remained significant. High-density lipoprotein cholesterol was not associated with brain volumes. CONCLUSION: Higher LDL levels in late midlife were associated with larger brain volumes later in life, while higher triglyceride levels were associated with smaller brain volumes. These associations were driven by adults >53 years at baseline.

Membrane-bound angiotensin-converting enzyme 2 is important in regulation of the renin–angiotensin–aldosterone system, but the association of cleaved soluble ACE2 (sACE2) with cardiovascular disease (CVD) is unclear. We evaluated the association of sACE2 with cardiac biomarkers, structure, and function and cardiovascular events in the Atherosclerosis Risk in Communities Study. sACE2 was measured in a subset of 497 participants (mean age 78±5.4 years, 53% men, 27% black); Cox regression analyses assessed prospective associations of sACE2 with time to first CVD event at median 6.1-year follow-up. sACE2 was higher in men, blacks, and participants with prevalent CVD, diabetes, or hypertension. Higher sACE2 levels were associated with significantly higher biomarkers of cardiac injury (high-sensitivity cardiac troponin I and T, N-terminal pro–B-type natriuretic peptide), greater left ventricular mass index, and impaired diastolic function in linear regression analyses, and with increased risk for heart failure hospitalization (adjusted hazard ratio per natural log unit increase [HR] 1.32, 95% confidence interval [CI] 1.10 to 1.58), CVD events (HR 1.34, 95% CI 1.13 to 1.60), and all-cause death (HR 1.26, 95% CI 1.01 to 1.57). In an elderly biracial cohort, sACE2 was positively associated with biomarkers reflecting myocardial injury and neurohormonal activation, left ventricular mass index, impaired diastolic function, CVD, events and all-cause death.

BACKGROUND/OBJECTIVES: Traditional cardiovascular risk factors are less predictive in older age. High-sensitivity cardiac troponin I (hs-cTnI) is a marker of subclinical cardiomyocyte damage associated with cardiovascular risk in middle-aged adults. We hypothesized hs-cTnI would be indicative of mortality and cardiovascular risk beyond traditional cardiovascular risk factors in older adults and may be more discriminatory compared to hs-troponin T (hs-cTnT). DESIGN: Prospective cohort study. SETTING: Population-based Atherosclerosis Risk in Communities (ARIC) Study. PARTICIPANTS: We included 5,876 ARIC participants at Visit 5 (2011–2013). OUTCOMES AND MEASURES: We used Cox regression for the association of hs-cTnI categories (women

Although intensive blood pressure reduction has cardiovascular benefits, the absolute benefit is greater in those at higher cardiovascular disease (CVD) risk.This study examined whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) helps identify subjects at higher risk for CVD events across systolic blood pressure (SBP), diastolic blood pressure (DBP), or pulse pressure (PP) categories.Participants from the ARIC (Atherosclerosis Risk In Communities) study visit 4 (1996 to 98) were grouped according to SBP, DBP, or PP categories and further stratified by NT-proBNP categories. Cox regression models were used to estimate hazard ratios for incident CVD (coronary heart disease, ischemic stroke, or heart failure hospitalization) and mortality across combined NT-proBNP and/or BP categories, adjusting for CVD risk factors.There were 9,309 participants (age: 62.6 ± 5.6 years; 58.3% women) with 2,416 CVD events over a median follow-up of 16.7 years. Within each SBP, DBP, or PP category, a higher category of NT-proBNP (100 to 300 or 300 pg/ml, compared with NT-proBNP 100 pg/ml) was associated with a graded increased risk for CVD events and mortality. Participants with SBP 130 to 139 mm Hg but NT-proBNP ≥300 pg/ml had a hazards ratio of 3.4 for CVD (95% confidence interval: 2.44 to 4.77) compared with a NT-proBNP of 100 pg/ml and SBP of 140 to 149 mm Hg.Elevated NT-proBNP is independently associated with CVD and mortality across SBP, DBP, and PP categories and helps identify subjects at the highest risk. Participants with stage 1 hypertension but elevated NT-proBNP had greater cardiovascular risk compared with those with stage 2 SBP but lower NT-proBNP. Future studies are needed to evaluate use of biomarker-based strategies for CVD risk assessment to assist with initiation or intensification of BP treatment.

Objective: Inflammatory markers, such as hs-CRP (high-sensitivity C-reactive protein), have been reported to be related to peripheral artery disease (PAD). Galectin-3, a biomarker of fibrosis, has been linked to vascular remodeling and atherogenesis. However, its prospective association with incident PAD is unknown; as is the influence of inflammation on the association between galectin-3 and PAD. Approach and Results: In 9851 Atherosclerosis Risk in Communities Study participants free of PAD at baseline (1996–1998), we quantified the association of galactin-3 and hs-CRP with incident PAD (hospitalizations with PAD diagnosis [ International Classification of Diseases - Ninth Revision : 440.2–440.4] or leg revascularization [eg, International Classification of Diseases - Ninth Revision : 38.18]) as well as its severe form, critical limb ischemia (PAD cases with resting pain, ulcer, gangrene, or leg amputation) using Cox models. Over a median follow-up of 17.4 years, there were 316 cases of PAD including 119 critical limb ischemia cases. Log-transformed galectin-3 was associated with incident PAD (adjusted hazard ratio, 1.17 [1.05–1.31] per 1 SD increment) and critical limb ischemia (1.25 [1.05–1.49] per 1 SD increment). The association was slightly attenuated after further adjusting for hs-CRP (1.14 [1.02–1.27] and 1.22 [1.02–1.45], respectively). Log-transformed hs-CRP demonstrated robust associations with PAD and critical limb ischemia even after adjusting for galectin-3 (adjusted hazard ratio per 1 SD increment 1.34 [1.18–1.52] and 1.34 [1.09–1.65], respectively). The addition of galectin-3 and hs-CRP to traditional atherosclerotic predictors (C statistic of the base model 0.843 [0.815–0.871]) improved the risk prediction of PAD (ΔC statistics, 0.011 [0.002–0.020]). Conclusions: Galectin-3 and hs-CRP were independently associated with incident PAD in the general population, supporting the involvement of fibrosis and inflammation in the pathophysiology of PAD.

Background Circulating galectin‐3 levels provide prognostic information in patients with established heart failure (HF), but the associations between galectin‐3 levels and other incident cardiovascular events in asymptomatic individuals at midlife and when remeasured ≈15 years later are largely uncharacterized. Methods and Results Using multivariable Cox proportional hazards models, we identified associations between plasma galectin‐3 levels (hazard ratio [HR] per 1 SD increase in natural log galectin‐3) and incident coronary heart disease, ischemic stroke, HF hospitalization, and total mortality in ARIC (Atherosclerosis Risk in Communities) participants free of cardiovascular disease at ARIC visit 4 (1996–1998; n=9247) and at ARIC visit 5 (2011–2013; n=4829). Higher galectin‐3 level at visit 4 (median age 62) was independently associated with incident coronary heart disease (adjusted HR, 1.30; 95% CI, 1.06–1.60), ischemic stroke (HR, 1.42; 95% CI, 1.01–2.00), HF (HR, 1.44; 95% CI, 1.17–1.76), and mortality (HR, 1.56; 95% CI, 1.35–1.80). At visit 5 (median age, 74), higher galectin‐3 level was associated with incident HF (HR, 1.93; 95% CI, 1.15–3.24) and total mortality (HR, 1.70; 95% CI, 1.15–2.52), but not coronary heart disease or stoke. Individuals with the greatest increase in galectin‐3 levels from visit 4 to visit 5 were also at increased risk of incident HF and total mortality. Conclusions In a large, biracial community‐based cohort, galectin‐3 measured at midlife and older age was associated with increased risk of cardiovascular events. An increase in galectin‐3 levels over this period was also associated with increased risk.

Background Elevated lipoprotein(a) (Lp[a]) and family history (FHx) of coronary heart disease (CHD) are individually associated with cardiovascular risk, and Lp(a) is commonly measured in those with FHx. Objectives The aim of this study was to determine independent and joint associations of Lp(a) and FHx with atherosclerotic cardiovascular disease (ASCVD) and CHD among asymptomatic subjects. Methods Plasma Lp(a) was measured and FHx was ascertained in 2 cohorts. Elevated Lp(a) was defined as the highest race-specific quintile. Independent and joint associations of Lp(a) and FHx with cardiovascular risk were determined using Cox regression models adjusted for cardiovascular risk factors. Results Among 12,149 ARIC (Atherosclerosis Risk In Communities) participants (54 years, 56% women, 23% black, 44% with FHx), 3,114 ASCVD events were observed during 21 years of follow-up. FHx and elevated Lp(a) were independently associated with ASCVD (hazard ratio [HR]: 1.17; 95% confidence interval [CI]: 1.09 to 1.26, and HR: 1.25; 95% CI: 1.12 to 1.40, respectively), and no Lp(a)-by-FHx interaction was noted (p = 0.75). Compared with subjects without FHx and nonelevated Lp(a), those with either elevated Lp(a) or FHx were at a higher ASCVD risk, while those with both had the highest risk (HR: 1.43; 95% CI: 1.27 to 1.62). Similar findings were observed for CHD risk in ARIC, in analyses stratified by premature FHx, and in an independent cohort, the DHS (Dallas Heart Study). Presence of both elevated Lp(a) and FHx resulted in greater improvement in ASCVD and CHD risk reclassification and discrimination indexes than either marker alone. Conclusions Elevated plasma Lp(a) and FHx have independent and additive joint associations with cardiovascular risk and may be useful concurrently for guiding primary prevention therapy decisions.

Rationale: Proinflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of MCP-1 (monocyte chemoattractant protein-1) in atherosclerosis and stroke. However, data from large-scale observational studies are lacking. Objective: To determine whether circulating levels of MCP-1 are associated with risk of incident stroke in the general population. Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke during a mean follow-up interval of 16.3 years (280 522 person-years at risk; 1435 incident stroke events). We applied Cox proportional-hazards models and pooled hazard ratios (HRs) using random-effects meta-analyses. After adjustments for age, sex, race, and vascular risk factors, higher MCP-1 levels were associated with increased risk of any stroke (HR per 1-SD increment in ln-transformed MCP-1, 1.07; 95% CI, 1.01–1.14). Focusing on stroke subtypes, we found a significant association between baseline MCP-1 levels and higher risk of ischemic stroke (HR, 1.11 [1.02–1.21]) but not hemorrhagic stroke (HR, 1.02 [0.82–1.29]). The results followed a dose-response pattern with a higher risk of ischemic stroke among individuals in the upper quartiles of MCP-1 levels as compared with the first quartile (HRs, second quartile: 1.19 [1.00–1.42]; third quartile: 1.35 [1.14–1.59]; fourth quartile: 1.38 [1.07–1.77]). There was no indication for heterogeneity across studies, and in a subsample of 4 studies (12 516 individuals), the risk estimates were stable after additional adjustments for circulating levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein). Conclusions: Higher circulating levels of MCP-1 are associated with increased long-term risk of stroke. Our findings along with genetic and experimental evidence suggest that MCP-1 signaling might represent a therapeutic target to lower stroke risk.Visual Overview: An online visual overview is available for this article.

Background hs‐ cTnT (high‐sensitivity cardiac troponin T), but not NT ‐pro BNP (N‐terminal pro–B natriuretic peptide), has been shown to predict bleeding in patients with atrial fibrillation. Whether these biomarkers are independently associated with bleeding in the general population is unknown. Methods and Results We used Cox proportional hazards models to examine the association of hs‐ cTnT and NT ‐pro BNP with incident bleeding (defined by International Classification of Diseases, Ninth Revision [ ICD‐9 ] codes) among 9550 middle‐aged men and women without a history of cardiovascular disease or bleeding. There were 847 hospitalizations with bleeding (92% from gastrointestinal bleeding) during a median follow‐up of 9.0 years. Serum levels of hs‐ cTnT were associated with bleeding in a graded fashion, with a hazard ratio of 1.28 (95% CI , 1.06–1.59) for 6 to NT ‐pro BNP , the highest category (≥264 versus mL ) showed a hazard ratio of 2.00 (1.59–2.61), and the remaining 3 categories had hazard ratios ranging from 1.2 to 1.3. Individuals in the highest category of both hs‐ cTnT and NT ‐pro BNP had a hazard ratio of 3.03 (1.97–4.68) compared with those in the lowest categories. Conclusions In a community‐based population, elevated hs‐ cTnT and NT ‐pro BNP were associated with bleeding‐related hospitalizations. These biomarkers may have a high utility in identifying people at high risk for bleeding. There is a need for research on the underlying mechanisms linking subclinical cardiac abnormalities and bleeding.

Exogenous hormone treatments in women (oral contraceptives and hormone replacement therapy [HRT]) are established risk factors for venous thromboembolism (VTE), but less is known about associations between plasma levels of endogenous hormones and VTE risk. We examined the association of baseline dehydroepiandrosterone sulphate (DHEAS), testosterone and sex hormone-binding globulin (SHBG) with risk of future VTE in men and post-menopausal women in the Atherosclerosis Risk in Communities Study. Testosterone, DHEAS and SHBG were measured in plasma samples collected in 1996 to 1998. Cox proportional hazards models were used to estimate hazard ratios for incident VTE adjusting for age, race/ethnicity, body mass index, height, smoking, estimated glomerular filtration rate and C-reactive protein. All analyses were stratified by sex and by current HRT use in women. Among 3,051 non-HRT-using women, 1,414 HRT-using women and 3,925 men at risk at baseline, 184, 62 and 206 experienced incident VTE after a median follow-up of 17.6 years. Plasma hormones were not associated with incidence of VTE among men and non-HRT-using women, although lower plasma DHEAS, when modelled using quartiles or restricted cubic splines, was associated with higher risk of VTE among HRT-using women. This study does not support the existence of an important association between plasma concentrations of endogenous testosterone, DHEAS or SHBG with risk of VTE in middle-aged to older men or post-menopausal women not using HRT.

Background Circulating N-terminal pro B-type natriuretic peptide (NT-proBNP) predicts incidence of atrial fibrillation (AF), but the association of longitudinal changes in NT-proBNP concentrations with incident AF has not been explored. Methods We studied 9705 individuals without prevalent AF in 1996–1998 and with available NT-proBNP measurements obtained in samples collected during two visits in 1990–1992 (visit 2) and 1996–1998 (visit 4) in the Atherosclerosis Risk in Communities (ARIC) Study. Participants were followed through the end of 2013. AF was ascertained from electrocardiograms, hospital discharge codes, and death certificates. Multivariable Cox regression was used to evaluate the association of absolute change in log-transformed NT-proBNP [ln(NT-proBNP)] with incident AF. We also assessed the impact of adding ln(NT-proBNP) change as a predictor of AF by difference in the C-statistic and net reclassification improvement (NRI). Results Over a median follow up of 16 years, there were 1503 incident cases of AF. The means (SD) ln(NT-proBNP) at visit 2 and visit 4 were 3.83 (1.01) and 4.35 (0.94), respectively. There was a 0.52 (0.79) increase in ln(NT-proBNP) over the 6-year period. Greater increases in ln(NT-proBNP) were associated with higher risk of AF [hazard ratio, 2.82 (95% confidence interval 2.34, 3.39), comparing top to bottom quintiles, and 1.74 (1.61, 1.87) per 1-unit increase in ln(NT-proBNP)]. Adding ln(NT-proBNP) change to a model with multiple predictors including baseline NT-proBNP had relatively limited impact in the C-statistic (increase from 0.748, 95%CI 0.736–0.761, to 0.762, 95%CI 0.750, 0.774). Adding ln(NT-proBNP) change to initial predictive models resulted in a categorical NRI of 0.062 (95% CI 0.033, 0.092) and a continuous NRI of 0.092 (95%CI, 0.017, 0.182). Conclusion Positive NT-proBNP change is associated with an increased incidence rate of AF. Adding NT-proBNP change into the prediction model modestly improved incident AF prediction. Future studies should assess the value of monitoring NT-proBNP concentration among individuals at high risk of developing AF.

Essentials Inflammatory and cardiac diseases are associated with increased venous thromboembolism (VTE) risk. Our prospective study assessed rise in inflammatory or cardiac biomarkers and VTE risk. A greater 6-year rise in N-terminal natriuretic peptide is associated with increased VTE incidence. Volume overload or impending cardiac disease may contribute to VTE occurrence. SUMMARY Background We previously showed that participants in the population-based Atherosclerosis Risk in Communities (ARIC) cohort with elevated levels of blood biomarkers of inflammation or cardiac disease were at increased risk of venous thromboembolism (VTE). Objective We hypothesized that ARIC participants with larger 6-year increases in the levels of three biomarkers - C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin T - would also have an increased subsequent risk of VTE. Methods We measured changes in the levels of these biomarkers in 9844 participants from 1990-1992 to 1996-1998, and then identified VTEs through 2015. Results A greater 6-year rise in the level of NT-proBNP, but not in that of CRP or troponin T, was significantly associated with increased VTE incidence over a median of 17.6 years of follow-up. After adjustment for other VTE risk factors, those whose NT-proBNP level rose from < 100 pg mL-1 to ≥ 100 pg mL-1 had a hazard ratio for VTE of 1.44 (95% confidence interval [CI] 1.15-1.80), as compared with the reference group with an NT-proBNP level of < 100 pg mL-1 at both times. This hazard ratio was slightly higher (1.66, 95% CI 1.19-2.31) during the first 10 years of follow-up, but was attenuated (1.24, 95% CI 0.99-1.56) after adjustment for prevalent and incident coronary heart disease, heart failure, and atrial fibrillation. Conclusions The two most likely explanations for our results are that: (i) an increasing NT-proBNP level reflects increasing subclinical volume overload and potentially increased venous stasis or subclinical PE that had gone unrecognized over time; or (ii) an increasing NT-proBNP level is a risk marker for impending cardiac disease that places patients at risk of VTE.

BACKGROUND AND AIMS: Traditional glycemic markers, fasting glucose and hemoglobin A1c (HbA1c), predict incident peripheral artery disease (PAD). However, it is unknown whether nontraditional glycemic markers, fructosamine, glycated albumin, and 1,5-anhydroglucitol, are associated with PAD and whether these glycemic markers demonstrate particularly strong associations with severe PAD, critical limb ischemia (CLI). METHODS: We quantified the associations of these five glycemic markers with incident PAD (hospitalizations with PAD diagnosis or leg revascularization) in 11,634 ARIC participants using Cox regression models. Participants were categorized according to diabetes diagnosis and clinical cut-points of glycemic markers (nontraditional glycemic markers were categorized according to percentiles corresponding to the HbA1c cut-points). RESULTS: Over a median follow-up of 20.7 years, there were 392 cases of PAD (133 were CLI with tissue loss). HbA1c was more strongly associated with incident PAD than fasting glucose, with adjusted hazard ratios (HR) 6.00 (95% CI, 3.73–9.66) for diagnosed diabetes with HbA1c ≥ 7% and 3.53 (2.39–5.22) for no diagnosed diabetes with HbA1c ≥ 6.5% compared to no diagnosed diabetes with HbA1c

Hypertriglyceridemia is associated with increased remnant-like particle cholesterol (RLP-C) and triglycerides in low-density lipoprotein (LDL-TG). Recent studies have focused on atherogenicity of RLP-C, with few data on LDL-TG.The aim of this study was to examine associations of RLP-C and LDL-TG with incident cardiovascular disease (CVD) events and genetic variants in the ARIC (Atherosclerosis Risk In Communities) study.Fasting plasma RLP-C and LDL-TG levels were measured in 9,334 men and women without prevalent CVD. Participants were followed for incident CVD events (coronary heart disease and ischemic stroke) for up to 16 years. Associations between LDL-TG and RLP-C levels and genetic variants were assessed by whole-exome sequencing using single-variant analysis for common variants and gene-based burden tests for rare variants; both an unbiased and a candidate gene approach were explored.RLP-C and LDL-TG levels were correlated with triglyceride levels (r = 0.85 and r = 0.64, p 0.0001). In minimally adjusted analyses, RLP-C and LDL-TG were associated with CVD risk, but in models adjusted for traditional risk factors including lipids, only LDL-TG was associated with incident CHD (hazard ratio: 1.28; 95% confidence interval: 1.10 to 1.50) and stroke (hazard ratio: 1.47; 95% confidence interval: 1.13 to 1.92). A common APOE variant, rs7412, had the strongest association with LDL-TG and RLP-C (p 5 × 10RLP-C and LDL-TG levels were predictive of CVD and associated with APOE variants. LDL-TG may represent a marker of dysfunctional remnant lipoprotein metabolism associated with increased CVD risk. Further research is needed to determine whether LDL-TG plays a causal role in CVD and may be a target for therapy.

Animal and human laboratory studies suggest that the pathogenesis of abdominal aortic aneurysms (AAAs) involves inflammation and degradation and remodeling of the extracellular matrix. This study prospectively assessed the association between biomarkers for these mechanisms and the presence of AAA during 24 years of follow-up in the Atherosclerosis Risk in Communities (ARIC) study. The ARIC prospectively identified clinically diagnosed AAAs in 15 792 men and women from baseline in 1987 to 1989 to 2011 using hospital discharge codes and death records. Additional asymptomatic AAAs were detected by an abdominal ultrasound scan in 2011 to 2013. Matrix metalloproteinase (MMP)-3, MMP-9, interleukin 6 (IL-6), N-terminal propeptide of Type III procollagen (PIIINP), and osteopontin were measured in blood samples collected between 1987 and 1992 in participants with AAA (544 clinically diagnosed AAAs and 72 ultrasound-detected AAAs) and a random sample of 723 participants selected from baseline and matched with AAAs by age, race and sex. Higher concentrations of MMP-9 and IL-6 were associated with future risk of clinically diagnosed AAA (hazard ratios [95% confidence intervals]: 1.55 [1.22-1.97] and 1.87 [1.48-2.35], respectively, comparing highest versus lowest tertiles) after multivariable adjustment ( P for trend < .001). Matrix metalloproteinase-9 was also associated with ultrasound-detected AAA. In conclusion, blood concentrations of MMP-9 and IL-6 measured in middle age predicted the risk of AAA during 24 years of follow-up.

The impact of lifestyle-related factors on temporal decreases in high-sensitivity cardiac troponin T (hs-cTnT), possibly reflecting reversal of subclinical myocardial damage, has not been evaluated in a community-based setting. We measured hs-cTnT twice, 6 years apart, in 9,256 participants from the Atherosclerosis Risk in Communities (ARIC) Study who were free of baseline cardiovascular disease. We used Poisson and multinomial regression to evaluate the associations of cigarette smoking, alcohol consumption, body mass index (BMI), healthy diet score, physical activity, and Life’s Simple 7 (LS7) score (a composite measure of lifestyle-related health factors) with 6-year decreases in hs-cTnT. Of the 3,017 persons with detectable baseline hs-cTnT (≥5ng/L), 2,418 (80%) remained detectable while 599 (20%) had undetectable levels (

Background and aims Results from prospective studies evaluating the relationship between elevated lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and incident peripheral arterial disease (PAD) have been mixed. We investigated whether higher Lp-PLA2 levels are associated with increased risk of incident PAD and whether PLA2G7 gene variants, which result in lower Lp-PLA2 levels, are associated with reduced risk of incident PAD. Methods Our analysis included 9922 participants (56% female; 21% African-American; mean age 63 years) without baseline PAD at ARIC Visit 4 (1996–1998), who had Lp-PLA2 activity measured and were subsequently followed for the development of PAD, defined by occurrence of a PAD-related hospitalization, through 2012. Cox proportional hazard models were performed to determine the association of Lp-PLA2 levels and PLA2G7 gene variants with incident PAD. Results During a median follow-up of 14.9 years, we identified 756 incident cases of PAD. In analyses adjusting for age, race, and sex, each standard deviation increment in Lp-PLA2 activity (62 nmol/ml/min) was associated with a higher risk of developing PAD (hazard ratio (HR) 1.17; 95% confidence interval (CI) 1.09, 1.26). This association remained significant after additional adjustment for risk factors, other cardiovascular disease, and medication use, but was strongly attenuated (HR: 1.09; 95% CI 1.00, 1.20). PLA2G7 variants were not associated with a lower risk of PAD in both white carriers (HR: 1.21; 95% CI: 0.17–8.56) and African-American carriers (HR: 0.83; 95% CI: 0.41–1.67), although statistical power was quite limited for this analysis, particularly in whites. Conclusions While higher Lp-PLA2 activity was associated with an increased risk for incident PAD, it is likely a risk marker largely represented by traditional risk factors.

Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL)-like particle that associates with major adverse cardiovascular events (MACE). We examined relationships between Lp(a) measurements and changes in coronary atheroma volume following long-term maximally-intensive statin therapy in coronary artery disease patients.Study of coronary atheroma by intravascular ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) used serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. Baseline and follow-up Lp(a) levels were measured in 915 of the 1039 SATURN participants, and were correlated with changes in percent atheroma volume (ΔPAV).Mean age was 57.7 ± 8.6 years, 74% were men, 96% were Caucasian, with statin use prior to study enrolment occurring in 59.3% of participants. Baseline [median (IQR)] LDL-cholesterol (LDL-C) and measured Lp(a) levels (mg/dL) were 114 (99, 137) and 17.4 (7.6, 52.9) respectively; follow-up measures were 60 (47, 77), and 16.5 (6.7, 57.7) (change from baseline: p 0.001, p = 0.31 respectively). At baseline, there were 676 patients with Lp(a) levels50 mg/dL [median Lp(a) of 10.9 mg/dL], and 239 patients with Lp(a) levels ≥ 50 mg/dL [median Lp(a) of 83.2 mg/dL]. Quartiles of baseline and follow-up Lp(a) did not associate with ΔPAV. Irrespective of the achieved LDL-C (vs. ≥70 mg/dL), neither baseline nor on-treatment (vs. ≥median) Lp(a) levels significantly associated with ΔPAV. No significant differences were observed in ΔPAV in Lp(a) risers versus non-risers, nor in those patients with baseline or on-treatment Lp(a) levelsvs.50 mg/dL.In coronary artery disease patients prescribed long-term maximally intensive statin therapy with low on-treatment LDL-C levels, measured Lp(a) levels (predominantly below the 50 mg/dL threshold) do not associate with coronary atheroma progression. Alternative biomarkers may thus associate with residual cardiovascular risk in such patients.

Plasma fetuin-A is associated with type 2 diabetes, and AHSG, the gene encoding fetuin-A, has been identified as a susceptibility locus for diabetes and metabolic syndrome. Thus far, unbiased investigations of the genetic determinants of plasma fetuin-A concentrations have not been conducted. We searched for single nucleotide polymorphisms (SNPs) related to fetuin-A concentrations by a genome-wide association study in six population-based studies. We examined the association of fetuin-A levels with ∼ 2.5 million genotyped and imputed SNPs in 9,055 participants of European descent and 2,119 African Americans. In both ethnicities, the strongest associations were centered in a region with a high degree of LD near the AHSG locus. Among 136 genome-wide significant (P

Background Cyclic guanosine monophosphate ( cGMP ) is a second messenger regulated through natriuretic peptide and nitric oxide pathways. Stimulation of cGMP signaling is a potential therapeutic strategy for heart failure with preserved ejection fraction ( HF p EF ) and atherosclerotic cardiovascular disease ( ASCVD ). We hypothesized that plasma cGMP levels would be associated with lower risk for incident HF p EF , any HF , ASCVD , and coronary heart disease (CHD). Methods and Results We conducted a case–cohort analysis nested in the ARIC (Atherosclerosis Risk in Communities) study. Plasma cGMP was measured in 875 participants at visit 4 (1996–1998), with oversampling of incident HF p EF cases. We used Cox proportional hazard models to assess associations of cGMP with incident HF p EF , HF , ASCVD ( CHD +stroke), and CHD . The mean ( SD ) age was 62.4 (5.6) years and median (interquartile interval) cGMP was 3.4 pmol/ mL (2.4–4.6). During a median follow‐up of 9.9 years, there were 283 incident cases of HF p EF , 329 any HF , 151 ASCVD , and 125 CHD . In models adjusted for CVD risk factors, the hazard ratios (95% CI ) associated with the highest cGMP tertile compared with lowest for HF p EF , HF , ASCVD , and CHD were 1.88 (1.17–3.02), 2.18 (1.18–4.06), 2.84 (1.44–5.60), and 2.43 (1.19–5.00), respectively. In models further adjusted for N‐terminal‐proB‐type natriuretic peptide, associations were attenuated for HF p EF and HF but remained statistically significant for ASCVD (2.56 [1.26–5.20]) and CHD (2.25 [1.07–4.71]). Conclusions Contrary to our hypothesis, higher cGMP levels were associated with incident CVD in a community‐based cohort. The associations of cGMP with HF or HF p EF may be explained by N‐terminal‐proB‐type natriuretic peptide, but not for ASCVD and CHD.

Background High-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at the time of myocardial infarction (MI) are strong predictors of prognosis. However, whether their premorbid (before MI occurrence) levels are associated with prognosis after incident MI is unknown. Methods In 1,054 participants from the Atherosclerosis Risk in Communities Study with incident MI, we evaluated premorbid levels of hs-cTnT and NT-proBNP measured on median 5.8 (interquartile interval 3.0-11.5 [mean 5.5]) years prior to incident MI and their associations with subsequent composite and individual outcomes of all-cause mortality, cardiovascular mortality, recurrent MI, heart failure, and stroke. Results During a median follow-up of 3.0 years after MI, 801 participants developed the composite outcome. Both hs-cTnT and NT-proBNP were independently associated with the composite outcome after incident MI. Among individual outcomes, all-cause mortality, cardiovascular mortality, and heart failure showed significant associations with both cardiac markers. Overall, NT-proBNP demonstrated a more evident relationship than hs-cTnT. Indeed, the addition of premorbid NT-proBNP alone, but not hs-cTnT alone, to conventional predictors at incident MI significantly improved risk prediction of the composite outcome after incident MI (Δc-statistic 0.013 [95% CI 0.005-0.022] from 0.691 with conventional predictors). Conclusions Premorbid levels of hs-cTnT and NT-proBNP assessed on average 6 years prior to incident MI were associated with adverse outcomes after incident MI. These results further highlight the importance of cardiac health at an earlier stage of life.

Measures of serum cardiac troponins and natriuretic peptides have become established as prognostic heart failure risk markers. In addition to detecting myocardial fibrosis through late gadolinium enhancement (LGE), extracellular volume fraction (ECV) measures by cardiac magnetic resonance (CMR) have emerged as a phenotypic imaging risk marker for incident heart failure outcomes. We sought to examine the relationship between cardiac troponins, natriuretic peptides, ECV and their associations with incident heart failure events in a CMR referral base. Mid short axis T1 maps were divided into 6 cardiac segments, each classified as LGE absent or present. Global ECV was derived from T1 maps using the area-weighted average of only LGE-absent segments. ECV was considered elevated if measured >30%, the upper 95% bounds of a reference healthy group without known cardiac disease (n = 28). Patients were dichotomized by presence of elevated ECV. High-sensitivity cardiac troponin T (hs-cTnT) and N-terminal B-type natriuretic peptide (NT-proBNP) were measured using serum samples acquired and stored at time of CMR scan, and patients were categorized into 3 groups for each blood marker based on recommended cutoff values. Subsequent heart failure admission and any death were ascertained. Relationships with ECV, hs-cTnT, and NT-proBNP were examined separately and as a composite with Cox proportional hazard models. Of 1,604 serial patients referred for a clinical CMR with myocardial T1 maps, 331 were eligible after exclusions and had blood available and were followed over a median 25.0 [interquartile range 21.8, 31.7] months. After adjustments for age (mean 57.3 [standard deviation (SD) 15.1 years), gender (61% male), and ethnicity (12.7% black), elevated ECV remained a predictor of a first composite heart failure outcome for patients with high levels of hs-cTnT (≥14 ng/L; hazard ratio [HR] 2.42 [95% confidence interval (CI) 1.17, 5.03]; p = 0.02) and NT-proBNP (≥300 pg/mL; HR 2.28 [95% CI 1.24, 4.29]; p = 0.01). Similar trends were seen for lower category levels of blood markers, but did not persist with minimal covariate adjustments. Elevated measures of ECV by CMR are associated with incident heart failure outcomes in patients with high hs-cTnT and NT-proBNP levels. This imaging marker may have a role for additional heart failure risk stratification.

Background Blacks harbor more cardiovascular risk factors than whites, but experience less atrial fibrillation ( AF ). Conversely, whites may have a lower risk of heart failure ( CHF ). N‐terminal pro‐B‐type natriuretic peptide ( NT ‐pro BNP) levels are higher in whites, predict incident AF , and have diuretic effects in the setting of increased ventricular diastolic pressures, potentially providing a unifying explanation for these racial differences. Methods and Results We used data from the CHS (Cardiovascular Health Study) to determine the degree to which baseline NT ‐pro BNP levels mediate the relationships between race and incident AF and CHF by comparing beta estimates between models with and without NT ‐pro BNP . The ARIC (Atherosclerosis Risk in Communities) study was used to assess reproducibility. Among 4731 CHS (770 black) and 12 418 ARIC (3091 black) participants, there were 1277 and 1253 incident AF events, respectively. Whites had higher baseline NT ‐pro BNP ( CHS : 40% higher than blacks; 95% CI , 29–53; ARIC : 39% higher; 95% CI , 33–46) and had a greater risk of incident AF compared with blacks ( CHS : adjusted hazard ratio, 1.60; 95% CI , 1.31–1.93; ARIC : hazard ratio, 1.93; 95% CI , 1.57–2.27). NT ‐pro BNP levels explained a significant proportion of the racial difference in AF risk ( CHS : 36.2%; 95% CI , 23.2–69.2%; ARIC : 24.6%; 95% CI , 14.8–39.6%). Contrary to our hypothesis, given an increased risk of CHF among whites in CHS (adjusted hazard ratio, 1.20; 95% CI , 1.05–1.47) and the absence of a significant association between race and CHF in ARIC (adjusted hazard ratio, 1.07; 95% CI , 0.94–1.23), CHF ‐related mediation analyses were not performed. Conclusions A substantial portion of the relationship between race and AF was statistically explained by baseline NT ‐pro BNP levels. No consistent relationship between race and CHF was observed.

Context: Postprandial hyperlipidemia has been suggested to contribute to atherogenesis by inducing proinflammatory changes in monocytes. Individuals with metabolic syndrome (MS), shown to have higher blood triglyceride concentration and delayed triglyceride clearance, may thus have increased risk for development of atherosclerosis. Objective: Our objective was to examine fasting levels and effects of a high-fat meal on phenotypes of monocyte subsets in individuals with obesity and MS and in healthy controls. Design, Setting, Participants, Intervention: Individuals with obesity and MS and gender- and age-matched healthy controls were recruited. Blood was collected from participants after an overnight fast (baseline) and at 3 and 5 hours after ingestion of a high-fat meal. At each time point, monocyte phenotypes were examined by multiparameter flow cytometry. Main Outcome Measures: Baseline levels of activation markers and postprandial inflammatory response in each of the three monocyte subsets were measured. Results: At baseline, individuals with obesity and MS had higher proportions of circulating lipid-laden foamy monocytes than controls, which were positively correlated with fasting triglyceride levels. Additionally, the MS group had increased counts of nonclassical monocytes, higher CD11c, CX3CR1, and human leukocyte antigen-DR levels on intermediate monocytes, and higher CCR5 and tumor necrosis factor-α levels on classical monocytes in the circulation. Postprandial triglyceride increases in both groups were paralleled by upregulation of lipid-laden foamy monocytes. MS, but not control, subjects had significant postprandial increases of CD11c and percentages of IL-1β+ and tumor necrosis factor-α+ cells in nonclassical monocytes. Conclusions: Compared to controls, individuals with obesity and MS had increased fasting and postprandial monocyte lipid accumulation and activation.

Objectives To study the relationship between cardiovascular risk factors and detectable cardiac troponin-T using a highly sensitive assay (hs-cTnT) among persons without a history of cardiovascular disease. Design and methods We examined the cross-sectional associations between cardiovascular risk factors and hs-cTnT in 9593 participants (mean age 65.6 (SD, 5.6), 41% female, 22% black) free of cardiovascular disease in a community-based cohort, through the Atherosclerosis Risk in Communities (ARIC) Study. We used multivariable logistic regression to characterize the association between cardiovascular risk factors and detectable (≥ 3.0 to 13.9 ng/L) and elevated (≥ 14.0 ng/L) hs-cTnT. Results hs-cTnT was detectable in 59% and elevated in 7% of the study population. Among persons with ideal cardiovascular health, hs-cTnT was detectable in 44%. In models adjusting for significant determinants of hs-cTnT concentration, detectable hs-cTnT was more frequent among males, blacks and persons with diabetes and hypertension and less frequent among statin users, current smokers and drinkers. Other risk factors associated with detectable hs-cTnT were older age, lower kidney function and higher body mass index. These risk factors were associated with elevated hs-cTnT in a similar pattern. Conclusion In a community-based sample without cardiovascular disease hs-cTnT is detectable in most adults, even among those with ideal cardiovascular health. Although most traditional cardiovascular risk factors were significant determinants of detectable and elevated hs-cTnT, the associations were particularly robust for sex, age, race, hypertension and diabetes.

The association between socioeconomic status (SES) and subclinical cardiovascular disease is not well understood. Using data from the Atherosclerosis Risk in Communities Study, we sought to evaluate the cross-sectional and prospective associations of SES, measured by annual income and educational level, with elevated high-sensitivity cardiac troponin T (hs-cTnT) concentrations (≥14 ng/L) using Poisson and multinomial logistic regressions, respectively. We used Cox proportional hazard models to compare the risks of coronary heart disease, heart failure, and mortality according to SES, stratified by baseline hs-cTnT concentration. Our study baseline was 1990-1992, with follow-up through 2011. We found an independent association between SES and hs-cTnT. When comparing participants in the lowest educational level group to those in the highest, the adjusted prevalence ratios for elevated hs-cTnT were 1.36 (95% confidence interval: 1.05, 1.75) overall, 1.83 (95% confidence interval: 1.23, 2.71) in blacks, and 1.05 (95% confidence interval: 0.73, 1.52) in whites (P for interaction = 0.08). Among participants with nonelevated hs-cTnT concentrations, when comparing those in the lowest income groups to those in the highest, the adjusted hazard ratios were strongest for heart failure and death. Having elevated baseline hs-cTnT doubled the risk of heart failure and death. Persons with low SES and elevated hs-cTnT concentrations have the greatest risk of cardiovascular events, which suggests that this group should be aggressively targeted for cardiovascular risk reduction.

Background Arterial stiffness independently predicts cardiovascular disease. However, few studies have evaluated the associations of central and peripheral pulse wave velocity (PWV) with biomarkers of both myocardial stress (natriuretic peptide [NT-proBNP]) and damage (high-sensitivity cardiac troponin-T [hs-cTnT]) among persons without cardiac disease. Methods We examined 3,348 participants (67–90 years) without prevalent cardiac disease in the Atherosclerosis Risk in Communities (ARIC) Study (2011–13). The cross-sectional associations of PWV quartiles for central arterial segments (carotid-femoral, heart-carotid, heart-femoral) and peripheral artery (femoral-ankle) with NT-proBNP and hs-cTnT were evaluated accounting for potential confounders. Results Most PWV measures demonstrated J- or U-shaped associations with the two cardiac biomarkers. The highest (Q4) vs. second lowest (Q2) quartile of central PWV measures (carotid-femoral, heart-carotid, heart-femoral PWV) were associated with higher levels of NT-proBNP independently of demographic characteristics. The associations were less evident for hs-cTnT. These associations were attenuated after adjusting for traditional cardiovascular risk factors, but the heart-carotid PWV-NT-proBNP relationship remained borderline significant (difference in log-NT-proBNP = 0.08 [-0.01, 0.17] in Q4 vs. Q2, p = 0.07). Peripheral PWV demonstrated inverse associations. Higher values of NT-proBNP were seen in the lowest vs. second lowest quartile of all PWV measures. Conclusions Central stiffness measures showed stronger associations with cardiac biomarkers (particularly NT-proBNP) than peripheral measures among older adults without cardiac disease. Our findings are consistent with the concept of ventricular-vascular coupling and suggest that central rather than peripheral arterial hemodynamics are more closely related to myocardial stress rather than damage.

BACKGROUND AND AIMS: Diabetes increases risk for atherosclerotic cardiovascular disease (ASCVD). Current guidelines do not recommend measuring lipoprotein(a), another ASCVD risk factor, in these individuals. We examined the association of lipoprotein(a) levels with incident ASCVD events in persons with and without diabetes or prediabetes. METHODS: Lipoprotein(a) and other ASCVD risk factors were measured at baseline (1996–1998) in the biracial Atherosclerosis Risk in Communities study; participants without prevalent ASCVD (coronary heart disease or stroke) were monitored ~15 years for incident ASCVD events. RESULTS: Of 9871 eligible participants (mean age 63 years; 5816 women; 2155 African Americans), 1543 had diabetes and 3615 had prediabetes. Cumulative ASCVD incidence rates (event/1,000-person years) were higher in participants with diabetes (26%) or prediabetes (13%) than in nondiabetic individuals (10%, p

To the Editor: Glucose measured 2 h after a 75-g carbohydrate challenge is considered gold standard for diabetes diagnosis but is a burdensome test. 1,5-anhydroglucitol (1,5-AG) is a biomarker of glucose excursions that is of growing interest and is sometimes used in diabetes care. Blood concentrations of 1,5-AG are decreased when blood glucose exceeds the renal threshold (approximately 160–180 mg/dL); thus, low plasma 1,5-AG reflects recent (1–2 weeks) glucose excursions. Some preliminary reports have suggested that 1,5-AG may be useful as a screening test for diabetes (1, 2). We evaluated the diagnostic performance of 1,5-AG compared to 2-h and fasting glucose in a community-based population. We conducted a cross-sectional analysis of 7813 participants without diagnosed diabetes at the fourth study visit (1996–1998) of the Atherosclerosis Risk in Communities study. Plasma glucose was analyzed with an enzymatic method on the Roche Hitachi 911 machine. 1,5-AG (GlycoMark®) was measured in 2015–2016 in stored plasma samples (collected at the same study visit in 1996–1998) with the Beckman AU480 Chemistry Analyzer (interassay coefficient of variation, 4.54%). We examined the performance of low 1,5-AG (

Background Current prevention guidelines recommend using the Pooled Cohort Equation (PCE) for 10-year atherosclerotic cardiovascular disease (CVD) risk assessment. However, the PCE has serious limitations in older adults: it excludes heart failure (HF) hospitalization, estimates 10-year risk, which may not be the most relevant time frame, and is not indicated for individuals age >79 years. Objectives This study sought to determine whether adding biomarkers to PCE variables improves global CVD (coronary heart disease, stroke, and HF) risk prediction in older adults over a shorter time period. Methods Atherosclerosis Risk in Communities study participants without prevalent CVD including HF (n = 4,760; age 75.4 ± 5.1 years) were followed for incident global CVD events. Adding N-terminal pro–B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein to the PCE and a “lab model” with the biomarkers, age, race, and gender were assessed for prediction improvement. Area under the receiver operating characteristic curve (AUC) and net reclassification index (NRI) were calculated. Results Over median follow-up of ∼4 years, incident HF was the leading CVD event (n = 193 vs. 118 coronary heart disease and 81 stroke events). Compared to the PCE, each biomarker improved risk prediction. The largest improvement in risk prediction metrics was with the addition of all 3 biomarkers (ΔAUC 0.103; continuous NRI 0.484). The lab model also performed better than the PCE model (ΔAUC 0.091, continuous NRI 0.355). Conclusions Adding biomarkers to the PCE or a simpler “lab model” improves short-term global CVD risk prediction and may be useful to inform short-term preventive strategies in older adults.

Aim To investigate the genetic influence of circulating lactate level, a marker of oxidative capacity associated with diabetes. Methods We conducted a genome-wide association study of log-transformed plasma lactate levels in 6901 European-American participants in the Atherosclerosis Risk in Communities study. For regions that achieved genome-wide significance in European-American participants, we conducted candidate region analysis in African-American subjects and tested for interaction between metformin use and the index single nucleotide polymorphisms for plasma lactate in European-American subjects. Results The genome-wide association study in European-American subjects identified two genome-wide significant loci, GCKR (rs1260326, T allele β=0.08; P=1.8×10-47) and PPP1R3B/LOC157273 (rs9987289, A allele β=0.06; P=1.6×10-9). The index single nucleotide polymorphisms in these two loci explain 3.3% of the variance in log-transformed plasma lactate levels among the European-American subjects. In the African-American subjects, based on a region-significant threshold, the index single nucleotide polymorphism at GCKR was associated with plasma lactate but that at PPP1R3B/LOC157273 was not. Metformin use appeared to strengthen the association between the index single nucleotide polymorphism at PPP1R3B/LOC157273 and plasma lactate in European-American subjects (P for interaction=0.01). Conclusions We identified GCKR and PPP1R3B/LOC157273 as two genome-wide significant loci of plasma lactate. Both loci are associated with other diabetes-related phenotypes. These findings increase our understanding of the genetic control of lactate metabolism.