Circulating sphingolipids and subclinical brain pathology: the cardiovascular health study.

Background: Sphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults. Methods: Brain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40% male; and 25% APOE ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP. Results: In the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [ß = 0.05, false-discovery rate corrected P (PFDR) = 0.004 and ß = 0.06, PFDR = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex (P for interaction = <0.001), such that ceramide d18:1/20:0 associated with higher odds for infarcts in women [OR = 1.26 (95%CI: 1.07, 1.49), PFDR = 0.03]. We did not observe any associations with GFAP blood levels, white matter grade, ventricular grade, mean bilateral hippocampal volume, or total brain volume. Conclusion: Overall, our comprehensive investigation supports the evidence that ceramides and sphingomyelins are associated with increased aging brain pathology and that the direction of association depends on the fatty acid attached to the sphingosine backbone.

Associations of Neurological Biomarkers in Serum With Gait Measures: The Cardiovascular Health Study.

BACKGROUND: Gait impairment leads to increased mobility decline and may have neurological contributions. This study explores how neurological biomarkers are related to gait in older adults. METHODS: We studied participants in the Cardiovascular Health Study, a population-based cohort of older Americans, who underwent a serum biomarker assessment from samples collected in 1996-1997 for neurofilament light chain (NfL), glial fibrillary acidic protein, ubiquitin carboxy-terminal hydrolase L1, and total tau (n = 1 959, mean age = 78.0 years, 60.8% female). In a subsample (n = 380), cross-sectional associations with quantitative gait measures were explored. This subsample was assessed on a mat for gait speed, step length, double support time, step time, step length variability, and step time variability. Gait speed was also measured over a 15-ft walkway annually from 1996-1997 to 1998-1999 for longitudinal analyses. Linear regression models assessed cross-sectional associations of biomarkers with gait measures, whereas mixed effects models assessed longitudinal gait speed change from baseline to 1998-1999. RESULTS: Neurofilament light chain was significantly associated with annual gait speed decline (standardized ß = -0.64 m/s, 95% CI: [-1.23, -0.06]) after adjustment for demographic and health factors. Among gait mat-assessed phenotypes, NfL was also cross-sectionally associated with gait speed (ß = 0.001 m/s [0.0003, 0.002]) but not with other gait measures. None of the remaining biomarkers were significantly related to gait in either longitudinal or cross-sectional analyses. CONCLUSIONS: Higher NfL levels were related to greater annual gait speed decline. Gait speed decline may be related to axonal degeneration. The clinical utility of NfL should be explored.

Red Meat Intake and the Risk of Cardiovascular Diseases: A Prospective Cohort Study in the Million Veteran Program.

BACKGROUND: Red meat consumption was associated with an increased risk of cardiovascular disease (CVD) in prospective cohort studies and a profile of biomarkers favoring high CVD risk in short-term controlled trials. However, several recent systematic reviews and meta-analyses concluded with no or weak evidence for limiting red meat intake. OBJECTIVES: To prospectively examine the associations between red meat intake and incident CVD in an ongoing cohort study with diverse socioeconomic and racial or ethnic backgrounds. METHODS: Our study included 148,506 participants [17,804 female (12.0%)] who were free of cancer, diabetes, and CVD at baseline from the Million Veteran Program. A food frequency questionnaire measured red meat intakes at baseline. Nonfatal myocardial infarction and acute ischemic stroke were identified through a high-throughput phenotyping algorithm, and fatal CVD events were identified by searching the National Death Index. RESULTS: Comparing the extreme categories of intake, the multivariate-adjusted relative risks of CVD was 1.18 (95% CI: 1.01, 1.38; P-trend < 0.0001) for total red meat, 1.14 (95% CI: 0.96, 1.36; P-trend = 0.01) for unprocessed red meat, and 1.29 (95% CI: 1.04, 1.60; P-trend = 0.003) for processed red meat. We observed a more pronounced positive association between red meat intake and CVD in African American participants than in White participants (P-interaction = 0.01). Replacing 0.5 servings/d of red meat with 0.5 servings/d of nuts, whole grains, and skimmed milk was associated with 14% (RR: 0.86; 95% CI: 0.83, 0.90), 7% (RR: 0.93; 95% CI: 0.89, 0.96), and 4% (RR: 0.96; 95% CI: 0.94, 0.99) lower risks of CVD, respectively. CONCLUSIONS: Red meat consumption is associated with an increased risk of CVD. Our findings support lowering red meat intake and replacing red meat with plant-based protein sources or low-fat dairy foods as a key dietary recommendation for the prevention of CVD.

Impact of 8 lifestyle factors on mortality and life expectancy among United States veterans: The Million Veteran Program.

BACKGROUND: Lifestyle medicine has been proposed as a way to address the root causes of chronic disease and their associated health care costs. OBJECTIVE: This study aimed to estimate mortality risk and longevity associated with individual lifestyle factors and comprehensive lifestyle therapy. METHODS: Age- and sex-specific mortality rates were calculated on the basis of 719,147 veterans aged 40-99 y enrolled in the Veteran Affairs Million Veteran Program (2011-2019). Hazard ratios and estimated increase in life expectancy were examined among a subgroup of 276,132 veterans with complete data on 8 lifestyle factors at baseline. The 8 lifestyle factors included never smoking, physical activity, no excessive alcohol consumption, restorative sleep, nutrition, stress management, social connections, and no opioid use disorder. RESULTS: On the basis of 1.12 million person-years of follow-up, 34,247 deaths were recorded. Among veterans who adopted 1, 2, 3, 4, 5, 6, 7, and 8 lifestyle factors, the adjusted hazard ratios for mortality were 0.74 (0.60-0.90), 0.60 (95% CI: 0.49, 0.73), 0.50 (95% CI: 0.41, 0.61), 0.43 (95% CI: 0.35, 0.52), 0.35 (95% CI: 0.29, 0.43), 0.27 (95% CI: 0.22, 0.33), 0.21 (95% CI: 0.17, 0.26), and 0.13 (95% CI: 0.10, 0.16), respectively, as compared with veterans with no adopted lifestyle factors. The estimated life expectancy at age 40 y was 23.0, 26.5, 28.8, 30.8, 32.7, 35.1, 38.3, 41.3, and 47.0 y among males and 27.0, 28.8, 33.1, 38.0, 39.2, 41.4, 43.8, 46.3, and 47.5 y for females who adopted 0, 1, 2, 3, 4, 5, 6, 7, and 8 lifestyle factors, respectively. The difference in life expectancy at age 40 y was 24.0 y for male veterans and 20.5 y for female veterans when comparing adoption of 8-9 lifestyle factors. CONCLUSIONS: A combination of 8 lifestyle factors is associated with a significantly lower risk of premature mortality and an estimated prolonged life expectancy.

Validity and Reproducibility of a Semiquantitative Food Frequency Questionnaire for Measuring Intakes of Foods and Food Groups.

We evaluated the validity and reproducibility of a semiquantitative food frequency questionnaire (FFQ) for measuring intakes of 149 foods and 25 food groups among 736 participants of the Women's Lifestyle Validation Study (WLVS, 2010-2012) and 649 participants of the Men's Lifestyle Validation Study (MLVS, 2011-2013). Validity of the FFQ compared with two 7-day dietary records measured 6 months apart and the reproducibility between 2 FFQs administered 1 year apart (FFQ1 and FFQ2) were assessed using Spearman correlations and intraclass correlation coefficients. The average 1-year reproducibility of FFQ-measured foods was 0.64 in both the WLVS and MLVS. Reproducibility of the food groups (mean = 0.71 among women and 0.72 among men) was generally higher than that for individual foods. Among women, the average validity correlation for individual foods was 0.59 when comparing FFQ2 with the 7-day dietary records. Among men, the corresponding average validity correlation was 0.61. Compared with individual foods, food groups had slightly higher validity correlations in both women (range, 0.45-0.92; mean = 0.61) and men (range, 0.46-0.88; mean = 0.65). This study reaffirms that the FFQ performs well in measuring most foods and food groups and provides data to adjust for measurement errors in epidemiologic studies of foods and food groups.

New statin use, mortality, and first cardiovascular events in older US Veterans by frailty status.

BACKGROUND: Statins are part of long-term medical regimens for many older adults. Whether frailty modifies the protective relationship between statins, mortality, and major adverse cardiovascular events (MACE) is unknown. METHODS: This was a retrospective study of US Veterans ≥65, without CVD or prior statin use seen in 2002-2012, followed through 2017. A 31-item frailty index was used. The co-primary endpoint was all-cause mortality or MACE (MI, stroke/TIA, revascularization, or cardiovascular death). Cox proportional hazards models were developed to evaluate the association of statin use with outcomes; propensity score overlap weighting accounted for confounding by indication. RESULTS: We identified 710,313 Veterans (mean age (SD) 75.3(6.5), 98% male, 89% white); 86,327 (12.1%) were frail. Over mean follow-up of 8 (5) years, there were 48.6 and 72.6 deaths per 1000 person-years (PY) among non-frail statin-users vs nonusers (weighted Incidence Rate Difference (wIRD)/1000 person years (PY), -24.0[95% CI, -24.5 to -23.6]), and 90.4 and 130.4 deaths per 1000PY among frail statin-users vs nonusers (wIRD/1000PY, -40.0[95% CI, -41.8 to -38.2]). There were 51.7 and 60.8 MACE per 1000PY among non-frail statin-users vs nonusers (wIRD/1000PY, -9.1[95% CI, -9.7 to -8.5]), and 88.2 and 102.0 MACE per 1000PY among frail statin-users vs nonusers (wIRD/1000PY, -13.8[95% CI, -16.2 to -11.4]). There were no significant interactions by frailty for statin users vs non-users by either mortality or MACE outcomes, p-interaction 0.770 and 0.319, respectively. Statin use was associated with lower risk of all-cause mortality (HR, 0.61 (0.60-0.61)) and MACE (HR 0.86 (0.85-0.87)). CONCLUSIONS: New statin use is associated with a lower risk of mortality and MACE, independent of frailty. These findings should be confirmed in a randomized clinical trial.

Clinical predictors of right ventricular dysfunction and association with adverse outcomes in peripartum cardiomyopathy.

AIMS: We sought to identify factors associated with right ventricular (RV) dysfunction and elevated pulmonary artery systolic pressure (PASP) and association with adverse outcomes in peripartum cardiomyopathy (PPCM). METHODS AND RESULTS: We conducted a multi-centre cohort study to identify subjects with PPCM with the following criteria: left ventricular ejection fraction (LVEF) < 40%, development of heart failure within the last month of pregnancy or 5 months of delivery, and no other identifiable cause of heart failure with reduced ejection fraction. Outcomes included a composite of (i) major adverse events (need for extracorporeal membrane oxygenation, ventricular assist device, orthotopic heart transplantation, or death) or (ii) recurrent heart failure hospitalization. RV function was obtained from echocardiogram reports. In total, 229 women (1993-2017) met criteria for PPCM. Mean age was 32.4 ± 6.8 years, 28% were of African descent, 50 (22%) had RV dysfunction, and 38 (17%) had PASP ≥ 30 mmHg. After a median follow-up of 3.4 years (interquartile range 1.0-8.8), 58 (25%) experienced the composite outcome of adverse events. African descent, family history of cardiomyopathy, LVEF, and PASP were significant predictors of RV dysfunction. Using Cox proportional hazards models, we found that women with RV dysfunction were three times more likely to experience the adverse composite outcome: hazard ratio 3.21 (95% confidence interval: 1.11-9.28), P = 0.03, in a multivariable model adjusting for age, race, body mass index, preeclampsia, hypertension, diabetes, kidney disease, and LVEF. Women with PASP ≥ 30 mmHg had a lower probability of survival free from adverse events (log-rank P = 0.04). CONCLUSIONS: African descent and family history of cardiomyopathy were significant predictors of RV dysfunction. RV dysfunction and elevated PASP were significantly associated with a composite of major adverse cardiac events. This at-risk group may prompt closer monitoring or early referral for advanced therapies.

Moderate alcohol consumption on the risk of stroke in the Million Veteran Program.

BACKGROUND: There is inconsistent evidence on the association of moderate alcohol consumption and stroke risk in the general population and is not well studied among U.S. Veterans. Furthermore, it is unclear whether primarily drinking beer, wine, or liquor is associated with a difference in stroke risk. METHODS: The study included 185,323 Million Veteran Program participants who self-reported alcohol consumption on the Lifestyle Survey. Moderate consumption was defined as 1-2 drinks/day and beverage preference of beer, wine or liquor was defined if ≥ 50% of total drinks consumed were from a single type of beverage. Strokes were defined using ICD-9 and ICD-10 codes from the participants' electronic health record. RESULTS: The mean (sd) age of the sample was 64 (13) years and 11% were women. We observed 4,339 (94% ischemic; 6% hemorrhagic) strokes over a median follow-up of 5.2 years. In Cox models adjusted for age, sex, race, education, income, body mass index, smoking, exercise, diet, cholesterol, prevalent diabetes, prevalent hypertension, lipid-lowering medication, antihypertensive medication, and diabetes medication, moderate alcohol consumption (1-2 drinks/day) was associated with a 22% lower risk of total stroke compared with never drinking [Hazards ratio (HR) 95% confidence interval (CI): 0.78 (0.67, 0.92)]. When stratifying by stroke type, we observed a similar protective association with moderate consumption and ischemic stroke [HR (95% CI): 0.76 (0.65, 0.90)], but a non-statistically significant higher risk of hemorrhagic stroke [HR (95% CI): 1.29 (0.64, 2.61)]. We did not observe a difference in ischemic or hemorrhagic stroke risk among those who preferred beer, liquor or wine vs. no beverage preference. When stratifying by prior number of hospital visits (≤ 15, 16-33, 34-64, ≥ 65) as a proxy for health status, we observed attenuation of the protective association with greater number of visits [HR (95% CI): 0.87 (0.63, 1.19) for ≥ 65 visits vs. 0.80 (0.59, 1.08) for ≤ 15 visits]. CONCLUSIONS: We observed a lower risk of ischemic stroke, but not hemorrhagic stroke with moderate alcohol consumption and did not observe substantial differences in risk by beverage preference among a sample of U.S. Veterans. Healthy user bias of moderate alcohol consumption may be driving some of the observed protective association.

Statins, Mortality, and Major Adverse Cardiovascular Events Among US Veterans With Chronic Kidney Disease.

Importance: There are limited data for the utility of statins for primary prevention of atherosclerotic cardiovascular disease (ASCVD) and death in adults with chronic kidney disease (CKD). Objective: To evaluate the association of statin use with all-cause mortality and major adverse cardiovascular events (MACE) among US veterans older than 65 years with CKD stages 3 to 4. Design, Setting, and Participants: This cohort study used a target trial emulation design for statin initiation among veterans with moderate CKD (stages 3 or 4) using nested trials with a propensity weighting approach. Linked Veterans Affairs (VA) Healthcare System, Medicare, and Medicaid data were used. This study considered veterans newly diagnosed with moderate CKD between 2005 and 2015 in the VA, with follow-up through December 31, 2017. Veterans were older than 65 years, within 5 years of CKD diagnosis, had no prior ASCVD or statin use, and had at least 1 clinical visit in the year prior to trial baseline. Eligibility criteria were assessed for each nested trial, and Cox proportional hazards models with bootstrapping were run. Analysis was conducted from July 2021 to October 2023. Exposure: Statin initiation vs none. Main Outcomes and Measures: Primary outcome was all-cause mortality; secondary outcome was time to first MACE (myocardial infarction, transient ischemic attack, stroke, revascularization, or mortality). Results: Included in the analysis were 14 828 veterans. Mean (SD) age at CKD diagnosis was 76.9 (8.2) years, 14 616 (99%) were men, 10 539 (72%) White, and 2568 (17%) Black. After expanding to person-trials and assessing eligibility at each baseline, there were 151 243 person-trials (14 685 individuals) of nonstatin initiators and 2924 person-trials (2924 individuals) of statin initiators included. Propensity score adjustment via overlap weighting with nonparametric bootstrapping resulted in covariate balance, with mean (SD) follow-up of 3.6 (2.7) years. The hazard ratio for all-cause mortality was 0.91 (95% CI, 0.85-0.97) comparing statin initiators to noninitiators. The hazard ratio for MACE was 0.96 (95% CI, 0.91-1.02). Results remained consistent in prespecified subgroup analyses. Conclusions and Relevance: In this target trial emulation of statin initiation in US veterans older than 65 years with CKD stages 3 to 4 and no prior ASCVD, statin initiation was significantly associated with a lower risk of all-cause mortality but not MACE. Results should be confirmed in a randomized clinical trial.

The determinants of fasting and post-load non-esterified fatty acids in older adults: The cardiovascular health study.

Aim: Non-esterified fatty acids (NEFA) are potential targets for prevention of key cardiometabolic diseases of aging, but their population-level correlates remain uncertain. We sought to identify modifiable factors associated with fasting and post-load NEFA levels in older adults. Methods: We used linear regression to determine the cross-sectional associations of demographic, anthropometric, and lifestyle characteristics and medication use with serum fasting and post-load NEFA concentrations amongst community-dwelling older adults enrolled in the Cardiovascular Health Study (n = 1924). Results: Fasting NEFA levels generally demonstrated a broader set of determinants, while post-load NEFA were more consistently associated with metabolic factors. Waist circumference and weight were associated with higher fasting and post-load NEFA. Cigarette smoking and caffeine intake were associated with lower levels of both species, and moderate alcohol intake was associated with higher fasting levels whereas greater consumption was associated with lower post-load levels. Unique factors associated with higher fasting NEFA included female sex, higher age, loop and thiazide diuretic use and calcium intake, while factors associated with lower fasting levels included higher educational attainment, beta-blocker use, and protein intake. Hours spent sleeping during the daytime were associated with higher post-load NEFA, while DASH score was associated with lower levels. Conclusion: Fasting and post-load NEFA have both common and unique modifiable risk factors, including sociodemographics, anthropometric, medications, and diet. Post-load NEFA were particularly sensitive to metabolic factors, while a broader range of determinants were associated with fasting levels. These factors warrant study as targets for lowering levels of NEFA in older adults.

Association of potato consumption with calcified atherosclerotic plaques in the coronary arteries: The NHLBI Family Heart Study.

BACKGROUND AND AIMS: While the association of potato consumption with risk factors for coronary artery disease has been inconsistent, no data are available in the literature on the influence of potato consumption on subclinical disease. Thus, we sought to examine whether baked/mashed potato consumption is associated with calcified atherosclerotic plaques in the coronary arteries. METHODS AND RESULTS: In a cross-sectional design, we studied 2208 participants of the NHLBI Family Heart Study. These subjects were selected based on their elevated cardiovascular disease risk compared to the general population. Potato consumption was assessed by a semi-quantitative food frequency questionnaire. We defined prevalent CAC using an Agatston score of at least 100 and fitted generalized estimating equations to calculate prevalence odds ratios of CAC. Mean age at initial clinic visit was 58.2 years and 55% were female. Median consumption of potatoes was 2-4/week. There was no statistically significant association between frequency of potato consumption and prevalent CAC: odds ratios (95% CI) for CAC were 1.0 (reference), 0.85 (0.56-1.30), 0.85 (0.58-1.26), and 0.95 (0.60-1.53) among subjects reporting potato consumption of <1/week, 1/week, 2-4/week, and 5+/week, respectively (p for linear trend 0.83), adjusting for age, sex, BMI, smoking, exercise, diabetes, hypertension, total calories, prevalent coronary heart disease, income, education, and daily red meat intake. CONCLUSIONS: We found no significant association between baked/mashed potato consumption and CAC in older adults. STUDY REGISTRATION NUMBER: NCT00005136. Study registration date: 5/25/2000.

Serum NfL and GFAP are associated with incident dementia and dementia mortality in older adults: The cardiovascular health study.

INTRODUCTION: Circulating neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have been independently associated with dementia risk. Their additive association, and their associations with dementia-specific mortality, have not been investigated. METHODS: We associated serum NfL, GFAP, total tau ,and ubiquitin carboxyl-terminal hydrolase-L1, measured in 1712 dementia-free adults, with 19-year incident dementia and dementia-specific mortality risk, and with 3-year cognitive decline. RESULTS: In adjusted models, being in the highest versus lowest tertile of NfL or GFAP associated with a hazard ratio (HR) of 1.49 (1.20-1.84) and 1.38 (1.15-1.66) for incident dementia, and 2.87 (1.79-4.61) and 2.76 (1.73-4.40) for dementia-specific mortality. Joint third versus first tertile exposure further increased risk; HR = 2.06 (1.60-2.67) and 9.22 (4.48-18.9). NfL was independently associated with accelerated cognitive decline. DISCUSSION: Circulating NfL and GFAP may, independently and jointly, provide useful clinical insight regarding dementia risk and prognosis.

Association of dietary fatty acids with the risk of atherosclerotic cardiovascular disease in a prospective cohort of United States veterans.

BACKGROUND: Atherosclerotic cardiovascular diseases (ASCVDs) are the leading cause of worldwide adult mortality. Although broad classes of dietary fats have been shown to alter ASCVD risk, the roles that individual dietary fatty acids play in influencing ASCVD risk are unclear. OBJECTIVES: The aim of this prospective cohort study was to examine the relationships of the total fat classes and individual fatty acids with the risk of ASCVD. METHODS: The Million Veteran Program is a prospective cohort whereby dietary intake of fatty acids was assessed in 158,198 participants that had enrolled between January 2011 and November 2018 and were free of ASCVD at baseline. Incident ASCVD was ascertained from the Veterans Affairs electronic health records and the National Death Index. Multivariable-adjusted hazard ratios (HRs) for the relationship between fat intake and ASCVD risk were computed using Cox regression models. RESULTS: The mean age was 61 years, 88% were males. A total of 11,771 ASCVD events were identified during the follow-up. When compared with the lowest quintile, participants in the highest quintile of dietary trans-monounsaturated fats and conjugated linoleic acids had an increased risk (HR [95% CI]) of ASCVD events: 1.10 (1.04, 1.17) and 1.11 (1.05, 1.18), respectively. When compared with low consumers, participants in the highest quintile of total cis-polyunsaturated fatty acid intake had a lower risk of experiencing an ASCVD event 0.93 (0.87, 0.99). CONCLUSION: Although higher intakes of specific trans-fatty acids and conjugated linoleic were associated with an increased risk of ASCVD, the same cannot be said for all other fat classes. This work suggests that care must be taken when drawing general conclusions regarding the health effects of dietary individual fatty acids.

Dietary ω-3 fatty acids and the incidence of atrial fibrillation in the Million Veteran Program.

BACKGROUND: Although recent large randomized clinical trials have reported an increased risk of atrial fibrillation (AF) with marine ω-3 fatty acid supplements, it is unclear whether dietary marine ω-3 fatty acids assessed through food frequency questionnaires are associated with AF risk. OBJECTIVES: We sought to test the hypothesis that dietary eicosapentaenoic acid/docosahexaenoic acid/docosapentaecnoic acid (EPA/DHA/DPA) is associated with a higher risk of AF in a large prospective cohort of US Veterans. METHODS: We analyzed data from Million Veteran Program participants who completed self-reported food frequency questionnaires. We used multivariable Cox regression to estimate the HRs of AF across quintiles of ω-3 fatty acid consumption and a cubic spline analysis to assess the dose-response relations between ω-3 fatty acids and AF. RESULTS: Of the 301,294 veterans studied, the median intake of ω-3 fatty acids (EPA/DHA/DPA) was 219 mg/d (IQR: 144-575), and the mean age was 64.9 y (SD: 12.0); 91% were men, and 84% were White. Consumption of EPA/DHA/DPA exhibited a nonlinear inverse relation with incident AF characterized by an initial decline to 11% at 750 mg/d of marine ω-3 fatty acid intake followed by a plateau. CONCLUSIONS: Contrary to our hypothesis, dietary EPA/DHA/DPA was not associated with a higher risk of AF but was inversely related to AF risk in a nonlinear manner.

Non-esterified fatty acids and risk of peripheral artery disease in older adults: The cardiovascular health study.

BACKGROUND AND AIMS: Non-esterified fatty acids have been implicated in the pathogenesis of diabetes and cardiovascular disease. No longitudinal study has assessed their effects on peripheral artery disease (PAD). We determined the relationships between NEFAs and incident clinical PAD and abnormal ankle-brachial index (ABI) in a population-based cohort of older persons. METHODS: We evaluated 4575 community living participants aged >65 years who underwent measurement of circulating NEFAs in fasting specimens and ABI in 1992-1993. Participants were assessed annually for clinical PAD until 2015 and underwent repeat ABI in 1998-1999. We used Cox proportional hazards regression to model the associations between NEFAs and risk of clinical PAD and logistic regression to model the associations of NEFAs with incident abnormal ABI. RESULTS: Mean age was 74.8 years, 59% were female, and 17% were Black. NEFAs were associated with higher risk of clinical PAD in unadjusted and adjusted models. The adjusted hazard ratios for incident clinical PAD were 1.51 (95%CI = 1.06-2.13, p = 0.02) across extreme tertiles, and 1.14 (95%CI = 0.99-1.31, p = 0.08) per standard deviation higher NEFA. The corresponding odds ratios for abnormal ABI were 0.95 (95%CI = 0.69-1.32, p = 0.76) across extreme tertiles, and 1.03 (95%CI = 0.89-1.20, p = 0.68) per standard deviation higher NEFA. Relationships appeared similar irrespective of sex, race, or pre-existing cardiovascular disease, but were stronger later than earlier in follow-up. CONCLUSIONS: Higher serum levels of NEFAs are significantly associated with increased likelihood of clinical PAD over long-term follow-up but not with 6-year decline in ABI. NEFAs may offer a potential target for intervention against clinical PAD.

Plasma Proteomic Risk Markers of Incident Type 2 Diabetes Reflect Physiologically Distinct Components of Glucose-Insulin Homeostasis.

High-throughput proteomics allows researchers to simultaneously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physiologic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose homeostasis and diabetes risk. We tested 4,776 SomaScan proteins measured in relation to 18-year incident diabetes risk in participants from the Cardiovascular Health Study (N = 2,631) and IVGTT-derived measures in participants from the HERITAGE Family Study (N = 752). We characterize 51 proteins that were associated with longitudinal diabetes risk, using their respective 39, 9, and 8 concurrent associations with insulin sensitivity index (SI), acute insulin response to glucose (AIRG), and glucose effectiveness (SG). Twelve of the 51 diabetes associations appear to be novel, including ß-glucuronidase, which was associated with increased diabetes risk and lower SG, suggesting an alternative pathway to insulin for glucose disposal; and plexin-B2, which also was associated with increased diabetes risk, but with lower AIRG, and not with SI, indicating a mechanism related instead to pancreatic dysfunction. Other novel protein associations included alcohol dehydrogenase-1C, fructose-bisphosphate aldolase-B, sorbitol dehydrogenase with elevated type 2 diabetes risk, and a leucine-rich repeat containing protein-15 and myocilin with decreased risk. ARTICLE HIGHLIGHTS: Plasma proteins are associated with the risk of incident diabetes in older adults independent of various demographic, lifestyle, and biochemical risk factors. These same proteins are associated with subtle differences in measures of glucose homeostasis earlier in life. Proteins that are associated with lower insulin sensitivity in individuals without diabetes tend to be associated with appropriate compensatory mechanisms, such as a stronger acute insulin response or higher glucose effectiveness. Proteins that are associated with future diabetes risk, but not with insulin insensitivity, tend to be associated with lower glucose effectiveness and/or impaired acute insulin response.

Dysregulated carbohydrate and lipid metabolism and risk of atrial fibrillation in advanced old age.

OBJECTIVE: Obesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Fasting and postload levels of glucose and non-esterified fatty acids (NEFAs) reflect different facets of metabolic regulation. We sought to study their respective contributions to AF risk concurrently. METHODS: We assessed levels of fasting and postload glucose and NEFA in the Cardiovascular Health Study to identify associations with AF incidence and, secondarily, with ECG parameters of AF risk available at baseline. Linear and Cox regressions were performed. RESULTS: The study included 1876 participants (age 77.7±4.4). During the median follow-up of 11.4 years, 717 cases of incident AF occurred. After adjustment for potential confounders, postload glucose showed an association with incident AF (HR per SD increment of postload glucose=1.11, 95% CI 1.02 to 1.21, p=0.017). Both glucose measures, but not NEFA, were positively associated with higher P wave terminal force in V1 (PTFV1); the association remained significant only for postload glucose when the two measures were entered together (ß per SD increment=138 µV·ms, 95% CI 15 to 260, p=0.028). Exploratory analyses showed significant interaction by sex for fasting NEFA (pinteraction=0.044) and postload glucose (pinteraction=0.015) relative to AF, with relationships stronger in women. For postload glucose, the association with incident AF was observed among women but not among men. CONCLUSIONS: Among older adults, postload glucose was positively associated with incident AF, with consistent findings for PTFV1. In exploratory analyses, the relationship with AF appeared specific to women. These findings require further study but suggest that interventions to address postprandial dysglycaemia late in life might reduce AF.

Fasting and Post-Load Glucose and Non-Esterified Fatty Acids and Risk of Heart Failure and Its Subtypes in Older Adults.

BACKGROUND: Glucose and non-esterified fatty acids (NEFA) are myocardial fuels whose fasting and post-prandial levels are under different homeostatic regulation. The relationships of fasting and post-load glucose and NEFA with incident heart failure (HF) remain incompletely defined. METHODS: Serum glucose and NEFA were measured during fasting and 2 hours post-oral glucose tolerance test, performed in Cardiovascular Health Study participants not receiving hypoglycemic medication. Participants with prevalent HF or lacking relevant data were excluded. Outcomes were incident HF (primary), and HF with preserved (HFpEF) and reduced (HFrEF) ejection fraction (secondary). RESULTS: Among 2 238 participants (age 78 ± 4) with a median follow-up of 9.9 years, there were 737 HF events. After adjustment for demographic and lifestyle factors, both fasting (hazard ratio [HR] = 1.11 per SD [95% confidence interval {CI} = 1.01-1.23], p = .040) and post-load (HR = 1.14 per SD [1.05-1.24], p = 0.002) glucose were significantly associated with incident HF. No association was seen for fasting or post-load NEFA. Upon mutual adjustment, only post-load glucose (HR = 1.11 [1.003-1.22], p = .044), but not fasting glucose (HR = 1.06 [0.94-1.20], p = .340), remained associated with HF. Further adjustment for cardiovascular disease and other risk factors in the causal pathway did not affect the association for post-load glucose, but eliminated that for fasting glucose. Associations for fasting and post-load glucose appeared stronger with higher adiposity and were observed specifically for HFrEF but not HFpEF. CONCLUSIONS: Fasting and post-load glucose, but not NEFA, were associated with incident HF. The association was especially robust for post-load glucose, suggesting that pathways involved in post-prandial dysglycemia could offer new targets for HF prevention late in life.

The Associations of Individual and Subclasses of Nonesterified Fatty Acids With Disability, and Mobility Limitation in Older Adults: The Cardiovascular Health Study.

BACKGROUND: We sought to determine the associations between individual nonesterified fatty acids (NEFAs) and disability and mobility limitation. METHODS: We studied 1 734 participants in the Cardiovascular Health Study (CHS), an ongoing population-based cohort study of community-living older American adults. We measured 35 individual NEFA species in fasting serum samples obtained at the 1996-1997 clinic visit. Using yearly assessments of activities of daily living and self-reported mobility, we identified participants with incident disability or mobility limitation during 15 years of follow-up. Cox proportional hazards regression models were used to determine the associations between per SD increment in the individual NEFAs and incident disability and mobility limitations with adjustment for potential confounding factors. RESULTS: Higher concentrations of total and a broad range of individual NEFA species were associated with risk of disability and mobility limitation (disability: HR per SD of total NEFA [SD = 174.70] = 1.11, 95% CI = 1.04-1.18, p = .001; mobility limitation: HR per SD of total NEFA = 1.09, 95% CI = 1.02-1.16, p = .01). Among individual saturated NEFAs (SFAs), myristic (14:0) and palmitic (16:0) acids were significantly associated with higher risk of both disability and mobility limitations, but longer-chain FAs were not. Most individual monounsaturated (MUFA), n-6 polyunsaturated fatty acids (PUFAs), and trans FAs were positively significantly associated with higher risks of both disability and mobility limitation. In contrast, most n-3 PUFA species were not associated with disability or mobility limitation. CONCLUSIONS: Higher risks of disability and mobility limitation were observed for proinflammatory intermediate-chain SFAs, MUFAs, n-6 PUFAs, and trans FAs. Our findings indicated no significant association for anti-inflammatory n-3 PUFAs.