Publications by authors named "Kenneth J Mukamal"

396 Publications

Serum Nonesterified Fatty Acids and Incident Stroke: The CHS.

J Am Heart Assoc 2021 Nov 10;10(22):e022725. Epub 2021 Nov 10.

Cardiovascular Nutrition Laboratory Jean Mayer USDA Human Nutrition Research Center on AgingTufts University Boston MA.

Background Significant associations between total nonesterified fatty acid (NEFA) concentrations and incident stroke have been reported in some prospective cohort studies. We evaluated the associations between incident stroke and serum concentrations of nonesterified saturated, monounsaturated, polyunsaturated, and fatty acids. Methods and Results CHS (Cardiovascular Health Study) participants (N=2028) who were free of stroke at baseline (1996-1997) and had an archived fasting serum sample were included in this study. A total of 35 NEFAs were quantified using gas chromatography. Cox proportional hazards regression models were used to evaluate associations of 5 subclasses (nonesterified saturated, monounsaturated, omega (n)-6 polyunsaturated, n-3 polyunsaturated, and fatty acids) of NEFAs and individual NEFAs with incident stroke. Sensitivity analysis was conducted by excluding cases with hemorrhagic stroke (n=45). A total of 338 cases of incident stroke occurred during the median 10.5-year follow-up period. Total n-3 (hazard ratio [HR], 0.77 [95% CI, 0.61-0.97]) and n-6 (HR, 1.32 [95% CI, 1.01-1.73]) subclasses of NEFA were negatively and positively associated with incident stroke, respectively. Among individual NEFAs, dihomo-γ-linolenic acid (20:3n-6) was associated with higher risk (HR, 1.29 [95% CI, 1.02-1.63]), whereas -7-hexadecenoic acid (16:1n-9) and arachidonic acid (20:4n-6) were associated with a lower risk (HR, 0.67 [95% CI, 0.47-0.97]; HR, 0.81 [95% CI. 0.65-1.00], respectively) of incident stroke per standard deviation increment. After the exclusion of cases with hemorrhagic stroke, these associations did not remain significant. Conclusions A total of 2 NEFA subclasses and 3 individual NEFAs were associated with incident stroke. Of these, the NEFA n-3 subclass and dihomo-γ-linolenic acid are diet derived and may be potential biomarkers for total stroke risk.
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http://dx.doi.org/10.1161/JAHA.121.022725DOI Listing
November 2021

Cardiovascular autonomic nervous system function and hip fracture risk: the Cardiovascular Health Study.

Arch Osteoporos 2021 10 31;16(1):163. Epub 2021 Oct 31.

Division of Endocrinology, Kaiser Permanente of Georgia and Division of Endocrinology, Emory University School of Medicine, Atlanta, GA, USA.

Among 1299 older adults with 24-h Holter monitoring data at baseline, followed for approximately 15 years, 190 incident hip fractures occurred. Increased heart rate variability was independently associated with reduced risk of hip fracture among female participants.

Purpose: Autonomic nervous system function modulates bone remodeling in rodent osteoporosis models. We tested whether cardiovascular autonomic function is associated with hip fracture risk in humans.

Methods: Participants were 1299 subjects from the Cardiovascular Health Study (mean age 72.8 years). Eight heart rate variability (HRV) measures (time and frequency domains, detrended fluctuation analysis variables, and heart rate turbulence) were derived from 24-h Holter monitor scans in sinus rhythm. Median follow-up for incident hip fracture was 14.7 years [IQR 9.1, 20.2]. Cox proportional hazards models were used to calculate hazard ratios (95% confidence intervals, CI).

Results: There were 144 hip fractures among 714 women (1.31 [1.06, 1.61] per 100-person years) and 46 among 585 men (0.62 [0.43, 0.90] per 100 person-years). From among HRV variables examined, a one standard deviation (SD) higher variation between normal heart beats over 24 h (the SD of NN intervals [SDNN]) was associated with a multivariable-adjusted lower hip fracture risk (HR [Formula: see text] 0.80; 95% CI 0.65-0.99; p = 0.04) in women. The adjusted association between very low frequency power, and hip fracture was borderline statistically significant in women (HR [Formula: see text] 0.82; 95% CI, 0.66-1.00; p = 0.06). When the 8 HRV variables were considered conjointly and adjusted for each other's association with hip fracture risk, a 1 SD higher SDNN value was significantly associated with reduced hip fracture risk in women (HR 0.74; 95% CI, 0.50-0.99; p = 0.05). No HRV variables were associated with hip fracture in men.

Conclusions: In older women, increased heart rate variation is associated with hip fracture risk.
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http://dx.doi.org/10.1007/s11657-021-01028-yDOI Listing
October 2021

Effects of Antihypertensive De-prescribing Strategies on Blood Pressure, Adverse Events, and Orthostatic Symptoms in Older Adults: Results from TONE.

Am J Hypertens 2021 Oct 29. Epub 2021 Oct 29.

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston Massachusetts.

Background: The Trial of Nonpharmacologic Interventions in the Elderly (TONE) demonstrated the efficacy of weight loss and sodium reduction to reduce hypertension medication use in older adults. However, the longer-term effects of drug withdrawal (DW) on blood pressure (BP), adverse events, and orthostatic symptoms were not reported.

Methods: TONE enrolled adults, ages 60-80 yrs, receiving treatment with a single antihypertensive and systolic BP (SBP)/diastolic BP (DBP) <145/<85 mmHg. Participants were randomized to weight loss, sodium reduction, both, or neither (usual care) and followed up to 36 months; ~3 months post-randomization, the antihypertensive was withdrawn and only restored if needed for uncontrolled hypertension. BP and orthostatic symptoms (light-headedness, feeling faint, imbalance), were assessed at randomization and throughout the study. Two physicians independently adjudicated adverse events, masked to intervention, classifying symptomatic (lightheadedness, dizziness, vertigo) or clinical events (fall, fracture, syncope).

Results: Among the 975 participants (mean age 66 yrs, 48% women, 24% black), mean (±SD) BP was 128±9/71±7 mmHg. Independent of assignment, DW increased SBP by 4.59 mmHg (95% CI:3.89,5.28) compared to baseline. There were 113 adverse events (84 symptomatic, 29 clinical), primarily during DW. Compared to usual care, combined weight loss and sodium reduction mitigated the effects of DW on BP (β=-4.33 mmHg;95%CI:-6.48,-2.17) and reduced orthostatic symptoms long-term (OR=0.62;95%CI:0.41,0.92), without affecting adverse events (HR=1.81;95%CI:0.90,3.65). In contrast, sodium reduction alone increased risk of adverse events (HR=1.75;95%CI:1.04,2.95), mainly during DW.

Conclusion: In older adults, antihypertensive DW may increase risk of symptomatic adverse events, highlighting the need for caution in withdrawing their antihypertensive medications.
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http://dx.doi.org/10.1093/ajh/hpab171DOI Listing
October 2021

Adenosine deaminase 2 produced by infiltrative monocytes promotes liver fibrosis in nonalcoholic fatty liver disease.

Cell Rep 2021 Oct;37(4):109897

Department of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address:

Elevated circulating activity of adenosine deaminase 2 (ADA2) is associated with liver fibrosis in nonalcoholic fatty liver disease (NAFLD). In the liver of NAFLD patients, ADA2-positive portal macrophages are significantly associated with the degree of liver fibrosis. These liver macrophages are CD14- and CD16-positive and co-express chemokine receptors CCR2, CCR5, and CXCR3, indicating infiltrative monocyte origin. Human circulatory monocytes release ADA2 upon macrophage differentiation in vitro. When stimulated by recombinant human ADA2 (rhADA2), human monocyte-derived macrophages demonstrate upregulation of pro-inflammatory and pro-fibrotic genes, including PDGF-B, a key pro-fibrotic cytokine. This PDGF-B upregulation is reproduced by inosine, the enzymatic product of ADA2, but not adenosine, and is abolished by E359N, a loss-of-function mutation in ADA2. Finally, rhADA2 also stimulates PDGF-B production from Kupffer cells in primary human liver spheroids. Together, these data suggest that infiltrative monocytes promote fibrogenesis in NAFLD via ADA2-mediated autocrine/paracrine signaling culminating in enhanced PDGF-B production.
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http://dx.doi.org/10.1016/j.celrep.2021.109897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606247PMC
October 2021

Prevalence of High Liver Stiffness and a Screening Strategy Using the SODA-2B Score Among US Adults.

Hepatol Commun 2021 Oct 25. Epub 2021 Oct 25.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Cirrhosis, a rising cause of death in the United States, has an extended preclinical phase characterized by progressive liver fibrosis. Despite the developments in noninvasive fibrosis measurement, there is no recommended screening, in part due to an incomplete understanding of the disease epidemiology on a national scale. Herein, we aim to define the prevalence of liver fibrosis and compare strategies to identify the at-risk population. We analyzed 4,510 US adults with complete liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) in the 2017-2018 National Health and Nutrition Examination Survey to estimate the disease burden of increased liver stiffness. An estimated 11.6 million (95% confidence interval [C.I.], 8.1-15.0 million) US adults had LSM ≥9.5 kPa, indicating advanced fibrosis and representing 1 in every 18 adults. Among them, 7.1 million (95% CI, 5.0-9.1 million) had LSM ≥12.5 kPa, which is concerning for cirrhosis. LSM ≥9.5 kPa is associated with male sex (S), history of other liver diseases (O), diabetes (D), advanced age (A), and an elevated BMI (B). A simple SODA-2B score had a sensitivity of 96.4% in identifying individuals at risk for advanced cirrhosis (LSM ≥9.5 kPa) and a negative predictive value of 99.3% in stratifying more than half of the adult population. When the liver function test (LFT) is available, the inclusion of abnormal LFT and elevated fibrosis-4 index can further increase screening efficiency. Conclusion: Elevated liver stiffness is prevalent among US adults. A SODA-2B score can risk stratify adults for VCTE-based fibrosis screening.
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http://dx.doi.org/10.1002/hep4.1837DOI Listing
October 2021

Lipoprotein Z, A novel hepatotoxic lipoprotein, predicts outcome in alcoholic hepatitis.

Hepatology 2021 Oct 18. Epub 2021 Oct 18.

Laboratory Corporation of America Holdings (Labcorp), Morrisville, NC, USA.

Background & Aims: Lipoprotein Z (LP-Z) is an abnormal free cholesterol (FC)-enriched low density lipoprotein (LDL)-like particle discovered from patients with cholestatic liver disease. This study aims to define the diagnostic value of LP-Z in alcoholic hepatitis (AH) and interrogate the biology behind its formation.

Approach & Results: We measured serum levels of LP-Z using nuclear magnetic resonance spectroscopy, a well-established clinical assay. Serum levels of LP-Z were significantly elevated in four AH cohorts compared to control groups, including heavy drinkers and cirrhosis. We defined a Z-index, calculated by the ratio of LP-Z to total apolipoprotein B-containing lipoproteins, representing the degree of deviation from normal very low density lipoprotein (VLDL) metabolism. A high Z-index was associated with 90-day mortality independent from the Model for End-Stage Liver Disease and provided added prognosticative value. Both a Z-index ≤0.6 and a decline of Z-index by ≥ 0.1 in two weeks predicted 90-day survival. RNAseq analyses of liver tissues demonstrated an inverse association in the expression of enzymes responsible for the extrahepatic conversion of VLDL to LDL and AH disease severity, which was further confirmed by the measurement of serum enzyme activity. To evaluate whether the FC in LP-Z could contribute to the pathogenesis of AH, we found significantly altered FC levels in liver explant of AH patients. Furthermore, FC in reconstituted LP-Z particles caused direct toxicity to human hepatocytes in a concentration-dependent manner, supporting a pathogenic role of FC in LP-Z.

Conclusions: Impaired lipoprotein metabolism in AH leads to the accumulation of LP-Z in the circulation, which is hepatotoxic from excessive FC. A Z-index ≤ 0.6 predicts 90-day survival independent from conventional biomarkers for disease prognostication.
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http://dx.doi.org/10.1002/hep.32203DOI Listing
October 2021

HDL (High-Density Lipoprotein) Subspecies, Prevalent Covert Brain Infarcts, and Incident Overt Ischemic Stroke: Cardiovascular Health Study.

Stroke 2021 Oct 14:STROKEAHA121034299. Epub 2021 Oct 14.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (M.K., S.A.A., J.D.F., K.J.M., M.K.J.).

Background And Purpose: Whether HDL (high-density lipoprotein) is associated with risk of vascular brain injury is unclear. HDL is comprised of many apo (apolipoprotein) species, creating distinct subtypes of HDL.

Methods: We utilized sandwich ELISA to determine HDL subspecies from plasma collected in 1998/1999 from 2001 CHS (Cardiovascular Health Study) participants (mean age, 80 years).

Results: In cross-sectional analyses, participants with higher apoA1 in plasma and lower apoE in HDL were less likely to have prevalent covert magnetic resonance imaging-defined infarcts: odds ratio for apoA1 Q4 versus Q1, 0.68 (95% CI, 0.50-0.93), and odds ratio for apoE Q4 versus Q1, 1.36 (95% CI, 1.01-1.84). Similarly, apoA1 in the subspecies of HDL that lacked apoC3, apoJ, or apoE was inversely related to covert infarcts, and apoE in the subspecies of HDL that lacked apoC3 or apoJ was directly related to covert infarcts in prospective analyses. In contrast, the concentrations of apoA1 and apoE in the complementary subspecies of HDL that contained these apos were unrelated to covert infarcts. Patterns of associations between incident overt ischemic stroke and apoA1, apoE, and apoA1 and apoE in subspecies of HDL were similar to those observed for covert infarcts but less pronounced.

Conclusions: This study highlights HDL subspecies defined by apo content as relevant biomarkers of covert and overt vascular brain injury.
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http://dx.doi.org/10.1161/STROKEAHA.121.034299DOI Listing
October 2021

Influenza vaccination among adults with cardiovascular disease in the United States: Results from the Behavioral Risk Factor Surveillance System 2018-2019.

Am Heart J 2021 Sep 29;244:50-53. Epub 2021 Sep 29.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. Electronic address:

Influenza causes significant morbidity and mortality among adults with cardiovascular disease (CVD). In nationally representative surveys of 101,210 individuals with CVD conducted in 2018 and 2019, the self-reported rate of vaccination was only 50%, with significant disparities by race and education. We advocate that cardiologists not only routinely emphasize vaccination but capitalize on the opportunity to vaccinate patients at office visits to improve overall rates of vaccination and their associated racial disparities.
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http://dx.doi.org/10.1016/j.ahj.2021.09.004DOI Listing
September 2021

Serum Non-Esterified Fatty Acids, Carotid Artery Intima-Media Thickness and Flow-Mediated Dilation in Older Adults: The Cardiovascular Health Study (CHS).

Nutrients 2021 Aug 31;13(9). Epub 2021 Aug 31.

Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA.

Elevated common carotid artery intima-media thickness (carotid IMT) and diminished flow-mediated dilation (FMD) are early subclinical indicators of atherosclerosis. Serum total non-esterified fatty acid (NEFA) concentrations have been positively associated with subclinical atherosclerosis. The relations between individual NEFA, carotid IMT and FMD have as yet to be assessed. We investigated the associations between fasting serum individual NEFA, carotid IMT and FMD among Cardiovascular Health Study (CHS) participants with ( = 255 for carotid IMT, 301 for FMD) or without ( = 1314 for carotid IMT, 1462 for FMD) known atherosclerotic cardiovascular disease (ASCVD). Using archived samples (fasting) collected from 1996-1997 (baseline), 35 individual NEFAs were measured using gas chromatography. Carotid IMT and estimated plaque thickness (mean of maximum internal carotid IMT) were determined in 1998-1999. FMD was measured in 1997-1998. Linear regression adjusted by the Holm-Bonferroni method was used to assess relations between individual NEFA, carotid IMT and FMD. In multivariable adjusted linear regression models per SD increment, the non-esterified fatty acid conjugated linoleic acid (-18:2 CLA) was positively associated with carotid IMT [β (95% CI): 44.8 (19.2, 70.4), = 0.025] among participants with, but not without, ASCVD [2.16 (-6.74, 11.5), = 1.000]. Non-esterified -palmitoleic acid (16:1n-7) was positively associated with FMD [19.7 (8.34, 31.0), = 0.024] among participants without, but not with ASCVD. No significant associations between NEFAs and estimated plaque thickness were observed. In older adults, serum non-esterified CLA and palmitoleic acid were positively associated with carotid IMT and FMD, respectively, suggesting potential modifiable biomarkers for arteriopathy.
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http://dx.doi.org/10.3390/nu13093052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465602PMC
August 2021

Plasma antioxidants and risk of dementia in older adults.

Alzheimers Dement (N Y) 2021 5;7(1):e12208. Epub 2021 Sep 5.

Department of Nutrition Harvard T.H. Chan School of Public Health Boston Massachusetts USA.

Introduction: Plant-based diets rich in fruits and vegetables have been associated with lower risk of dementia, but the specific role of antioxidants, a key class of bioactive phytochemicals, has not been well ascertained.

Methods: We measured antioxidants in a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 996 randomly selected participants and 521 participants who developed dementia, of which 351 were diagnosed with Alzheimer's disease (AD) during a median of 5.9 years of follow-up. We measured baseline plasma levels of retinol, α-, and γ-tocopherol; zeaxanthin and lutein (combined); beta-cryptoxanthin; cis-lycopene; trans-lycopene; α-carotene; and trans-β-carotene by organic phase extraction followed by chromatographic analysis and related these to neurologist-adjudicated risks of all-cause dementia and AD.

Results: Plasma retinol, α-, and γ-tocopherol, and carotenoids were not significantly related to risk of dementia or AD. Associations were not significant upon Bonferroni correction for multiple testing and were consistent within strata of sex, age, apolipoprotein E ε4 genotype, mild cognitive impairment at baseline, and intake of multivitamin, vitamin A or β-carotene, or vitamin E supplements. Higher trans-β-carotene tended to be related to a higher risk of dementia (adjusted hazard ratio [HR] per 1 standard deviation [SD] higher trans-β-carotene: 1.10; 95% confidence interval [CI]: 1.00, 1.20) and α-carotene tended to be associated with higher risk of AD only (adjusted HR per 1 SD higher α-carotene: 1.15; 95% CI: 1.02, 1.29).

Discussion: Plasma antioxidants were not significantly associated with risk of dementia or AD among older adults. Similar studies in younger populations are required to better understand the association between plasma antioxidants and dementia risk.
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http://dx.doi.org/10.1002/trc2.12208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418668PMC
September 2021

Impact of 30- Versus 60-Second Time Intervals Between Automated Office Blood Pressure Measurements on Measured Blood Pressure.

Hypertension 2021 Nov 7;78(5):1502-1510. Epub 2021 Sep 7.

Department of Medicine, Division of General Medicine (S.P.J., K.J.M., J.M.W., T.S.A., M.L.C., J.X.L., J.L.C.), Beth Israel Deaconess Medical Center, Boston, MA.

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.17876DOI Listing
November 2021

Contributions of Preterm Delivery to Cardiovascular Disease Risk Prediction in Women.

J Womens Health (Larchmt) 2021 10 12;30(10):1431-1439. Epub 2021 Aug 12.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Preterm delivery is associated with a 1.4- to 2-fold increased risk of cardiovascular disease (CVD), but inclusion of preterm delivery in CVD risk prediction algorithms has not been tested. We evaluated whether including preterm delivery and parity in CVD risk scores improved identification of women at high risk versus scores based on traditional risk factors. We predicted 10-year CVD risk using 119,587 observations contributed by 76,512 women ≥40 years of age and 20-year CVD risk with 72,533 women ≥40 years of age and 72,872 women ≥30 years of age from the Nurses' Health Study II. Cox proportional hazards models were fit with established CVD risk factors (Model 1) and established risk factors plus preterm delivery and parity (Model 2). We evaluated model fit, calibration, discrimination, and risk reclassification. Very preterm delivery (<32 weeks) was associated with CVD in all 10- and 20-year models that included the established CVD risk factors (, hazard ratio: 1.61, 95% confidence interval: 1.19 to 2.20 in 10-year risk model). Model 2 had improved fit relative to Model 1, but discrimination was not improved in Model 2 based on the C-difference or net reclassification index. Similar models for 20-year CVD risk prediction at age ≥30 years indicated improved discrimination when including preterm delivery and parity. Incorporating preterm delivery and parity into CVD risk scores appears most useful when women are young, before they develop established CVD risk factors. Observed improvements in risk prediction were small and warrant further investigation to confirm our findings and assess utility in a clinical setting.
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http://dx.doi.org/10.1089/jwh.2021.0166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590142PMC
October 2021

Urine creatinine concentration and clinical outcomes in older adults: The Cardiovascular Health Study.

J Am Geriatr Soc 2021 Aug 7. Epub 2021 Aug 7.

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

Purpose: Loss of muscle mass and strength are associated with long-term adverse health outcomes in older adults. Urine creatinine concentrations (Ucr; mg/dl) are a measure of muscle tissue mass and turnover. This study assessed the associations of a spot Ucr level with muscle mass and with risk of hospitalization, mortality, and diabetes mellitus in older adults.

Methods: We examined 3424 participants from the Cardiovascular Health Study who provided spot urine samples in 1996-1997 and who were followed through June 2015. All participants underwent baseline measurement of grip strength. In a sub-cohort, 1331 participants underwent dual energy X-ray absorptiometry (DEXA) scans, from which lean muscle mass was derived. Participants were followed for a median of 10 years for hospitalizations and mortality, and 9 years for diabetes mellitus.

Results: In linear regression analysis, a one standard deviation higher Ucr concentration (64.6 mg/dl) was associated with greater grip strength (kg force) β = 0.44 [0.16, 0.72]; p = 0.002) and higher lean muscle mass (kg) (β = 0.43 [0.08, 0.78]; p = 0.02). In Cox regression analyses, each standard deviation greater Ucr concentration was associated with lower rates of hospitalizations (0.94 [95% confidence interval, 0.90, 0.98]; p < 0.001) and lower mortality risk (0.92 [0.88, 0.97]; p < 0.001), while a one standard deviation increase in muscle mass derived from DEXA had no such significant association. Ucr levels were not associated with incident diabetes mellitus risk (0.97 [0.85, 1.11]; p = 0.65).

Conclusion: A higher spot Ucr concentration was favorably associated with muscle mass and strength and with health outcomes in older community-living adults. The ease of obtaining a spot Ucr makes it an attractive analyte to use for gauging the health of older adults.
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http://dx.doi.org/10.1111/jgs.17388DOI Listing
August 2021

Associations of body size and composition with subclinical cardiac dysfunction in older individuals: the cardiovascular health study.

Int J Obes (Lond) 2021 12 4;45(12):2539-2545. Epub 2021 Aug 4.

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Background: Focused studies in younger to middle-aged populations have demonstrated a relationship between obesity and adverse cardiac mechanics. We examined whether measures of overall and central adiposity are associated with cardiac mechanics, assessed by speckle-tracking echocardiography, in an older population without prevalent coronary heart disease or heart failure.

Methods: Body composition was measured by anthropometry, bioelectrical impedance, and dual-energy x-ray absorptiometry among participants in the Cardiovascular Health Study, a population-based cohort of adults aged 65 years or older. Systolic and diastolic cardiac mechanics were measured with speckle-tracking analysis of echocardiograms. Multi-variable adjusted linear regression models were used to investigate associations of body composition measures and cardiac mechanics.

Results: Mean age for the 3525 included participants was 72.6 years, 39% were male, and 10% were black. Mean body-mass index (BMI) was 26.3 ± 4.4 kg/m, waist circumference (WC) was 93.2 ± 12.9 cm, and waist-to-hip ratio was 0.92 ± 0.09. In fully adjusted analyses, all adiposity measures were associated with worse LV longitudinal strain, LV early diastolic strain rate, and left atrial reservoir strain; however, associations were strongest for WC and BMI (p < 0.001). When both BMI and WC were included in the same model, only WC remained associated with each cardiac strain measure.

Conclusion: In this cross-sectional study of older adults, central obesity was most robustly associated with impaired left ventricular systolic and diastolic strain as well as left atrial strain. The adverse effects of central obesity appear to extend even into older age.
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http://dx.doi.org/10.1038/s41366-021-00926-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8608718PMC
December 2021

Associations of Body Mass Index and Waist Circumference in Young Adulthood with Later Life Incident Diabetes.

J Clin Endocrinol Metab 2021 Nov;106(12):e5011-e5020

Division of General Medicine; Columbia University, New York, NY, USA.

Context: The independent contribution of young adult exposure to overweight and obesity to later-life incident diabetes is not well studied.

Objective: To assess the associations of exposures to elevated body mass index (BMI) and waist circumference (WC) in young adulthood (ages 18-39 years) with incident diabetes later in life (≥40 years).

Design: Pooled data from 6 US prospective cohorts (Atherosclerosis Risk in Communities Study, Cardiovascular Risk Development in Young Adults Study, Cardiovascular Health Study, (4) Framingham Heart Study Offspring Cohort, (5) Health, Aging and Body Composition Study, and (6) Multi-Ethnic Study of Atherosclerosis.

Setting: Population-based cohort studies.

Participants: 30 780 participants (56.1% female, 69.8% non-Hispanic white) without a diagnosis of diabetes by age 40.

Interventions: We imputed BMI and WC trajectories from age 18 for every participant and estimated time-weighted average exposures to BMI or WC during young adulthood and later life.

Main Outcome Measure(s): Incident diabetes defined as fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, or use of diabetes medications.

Results: During a 9-year median follow-up, 4323 participants developed incident diabetes. Young adult BMI and WC were associated with later-life incident diabetes after controlling for later-life exposures [hazard ratios (HR) 1.99 for BMI ≥ 30 kg/m2 and 2.13 for WC > 88cm (women)/>102cm (men) compared to normal ranges]. Young adult homeostatic model of insulin resistance mediated 49% and 44% of the association between BMI and WC with later-life incident diabetes. High-density lipoproteins and triglycerides mediated a smaller proportion of these associations.

Conclusions: Elevated BMI and WC during young adulthood were independently associated with later-life incident diabetes. Insulin resistance may be a key mediator.
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http://dx.doi.org/10.1210/clinem/dgab551DOI Listing
November 2021

Associations between alcohol consumption and hepatic steatosis in the USA.

Liver Int 2021 09 5;41(9):2020-2023. Epub 2021 Aug 5.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Despite being widely recognized as a common cause of fatty liver, the exact impact of alcohol consumption on hepatic steatosis in the general population is elusive. The recent National Health and Nutrition Examination Survey (NHANES) allowed us to examine this relationship among US adults. Herein, we extracted data on detailed alcohol consumption and controlled attenuation parameter (CAP) by FibroScan from 4509 participants in NHANES 2017-2018. Compared to metabolic risk factors such as diabetes and obesity, the association between alcohol consumption and CAP was less significant. In multivariable analysis, only those drinking 5-7 times per week showed significant increases in CAP scores. Although both frequency and quantity of drinking were positively associated with CAP score, only frequency remained significant after adjustment for quantity and binge drinking. These epidemiological observations suggested that the impact of alcohol on hepatic steatosis was much smaller than metabolic factors and dependent upon the frequency of drinking.
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http://dx.doi.org/10.1111/liv.15020DOI Listing
September 2021

Smartphone-recorded physical activity for estimating cardiorespiratory fitness.

Sci Rep 2021 07 21;11(1):14851. Epub 2021 Jul 21.

Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA.

While cardiorespiratory fitness is strongly associated with mortality and diverse outcomes, routine measurement is limited. We used smartphone-derived physical activity data to estimate fitness among 50 older adults. We recruited iPhone owners undergoing cardiac stress testing and collected recent iPhone physical activity data. Cardiorespiratory fitness was measured as peak metabolic equivalents of task (METs) achieved on cardiac stress test. We then estimated peak METs using multivariable regression models incorporating iPhone physical activity data, and validated with bootstrapping. Individual smartphone variables most significantly correlated with peak METs (p-values both < 0.001) included daily peak gait speed averaged over the preceding 30 days (r = 0.63) and root mean square of the successive differences of daily distance averaged over 365 days (r = 0.57). The best-performing multivariable regression model included the latter variable, as well as age and body mass index. This model explained 68% of variability in observed METs (95% CI 46%, 81%), and estimated peak METs with a bootstrapped mean absolute error of 1.28 METs (95% CI 0.98, 1.60). Our model using smartphone physical activity estimated cardiorespiratory fitness with high performance. Our results suggest larger, independent samples might yield estimates accurate and precise for risk stratification and disease prognostication.
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http://dx.doi.org/10.1038/s41598-021-94164-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295266PMC
July 2021

Associations of Community Water Lead Concentrations with Hemoglobin Concentrations and Erythropoietin-Stimulating Agent Use among Patients with Advanced CKD.

J Am Soc Nephrol 2021 10 15;32(10):2425-2434. Epub 2021 Jul 15.

Chronic Disease Research Group, Hennepin Healthcare Research Institute, Minneapolis, Minnesota.

Background: Although patients with kidney disease may be particularly susceptible to the adverse health effects associated with lead exposure, whether levels of lead found commonly in drinking water are associated with adverse outcomes in patients with ESKD is not known.

Methods: To investigate associations of lead in community water systems with hemoglobin concentrations and erythropoietin stimulating agent (ESA) use among incident patients with ESKD, we merged data from the Environmental Protection Agency (EPA) Safe Drinking Water Information System (documenting average 90 percentile lead concentrations in community water systems during 5 years before dialysis initiation, according to city of residence) with patient-level data from the United States Renal Data System.

Results: Among 597,968 patients initiating dialysis in the United States in 2005 through 2017, those in cities with detectable lead levels in community water had significantly lower pre-ESKD hemoglobin concentrations and more ESA use per 0.01 mg/L increase in 90 percentile water lead. Findings were similar for the 208,912 patients with data from the first month of ESKD therapy, with lower hemoglobin and higher ESA use per 0.01 mg/L higher lead concentration. These associations were observed at lead levels below the EPA threshold (0.015 mg/L) that mandates regulatory action. We also observed environmental inequities, finding significantly higher water lead levels and slower declines over time among Black versus White patients.

Conclusions: This first nationwide analysis linking EPA water supply records to patient data shows that even low levels of lead that are commonly encountered in community water systems throughout the United States are associated with lower hemoglobin levels and higher ESA use among patients with advanced kidney disease.
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http://dx.doi.org/10.1681/ASN.2020091281DOI Listing
October 2021

Effects of Diet and Sodium Reduction on Cardiac Injury, Strain, and Inflammation: The DASH-Sodium Trial.

J Am Coll Cardiol 2021 06;77(21):2625-2634

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Background: The DASH (Dietary Approaches to Stop Hypertension) diet has been determined to have beneficial effects on cardiac biomarkers. The effects of sodium reduction on cardiac biomarkers, alone or combined with the DASH diet, are unknown.

Objectives: The purpose of this study was to determine the effects of sodium reduction and the DASH diet, alone or combined, on biomarkers of cardiac injury, strain, and inflammation.

Methods: DASH-Sodium was a controlled feeding study in adults with systolic blood pressure (BP) 120 to 159 mm Hg and diastolic BP 80 to 95 mm Hg, randomly assigned to the DASH diet or a control diet. On their assigned diet, participants consumed each of three sodium levels for 4 weeks. Body weight was kept constant. At the 2,100 kcal level, the 3 sodium levels were low (50 mmol/day), medium (100 mmol/day), and high (150 mmol/day). Outcomes were 3 cardiac biomarkers: high-sensitivity cardiac troponin I (hs-cTnI) (measure of cardiac injury), N-terminal pro-B-type natriuretic peptide (NT-proBNP) (measure of strain), and high-sensitivity C-reactive protein (hs-CRP) (measure of inflammation), collected at baseline and at the end of each feeding period.

Results: Of the original 412 participants, the mean age was 48 years; 56% were women, and 56% were Black. Mean baseline systolic/diastolic BP was 135/86 mm Hg. DASH (vs. control) reduced hs-cTnI by 18% (95% confidence interval [CI]: -27% to -7%) and hs-CRP by 13% (95% CI: -24% to -1%), but not NT-proBNP. In contrast, lowering sodium from high to low levels reduced NT-proBNP independently of diet (19%; 95% CI: -24% to -14%), but did not alter hs-cTnI and mildly increased hs-CRP (9%; 95% CI: 0.4% to 18%). Combining DASH with sodium reduction lowered hs-cTnI by 20% (95% CI: -31% to -7%) and NT-proBNP by 23% (95% CI: -32% to -12%), whereas hs-CRP was not significantly changed (-7%; 95% CI: -22% to 9%) compared with the high sodium-control diet.

Conclusions: Combining a DASH dietary pattern with sodium reduction can lower 2 distinct mechanisms of subclinical cardiac damage: injury and strain, whereas DASH alone reduced inflammation. (Dietary Patterns, Sodium Intake and Blood Pressure [DASH - Sodium]; NCT00000608).
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http://dx.doi.org/10.1016/j.jacc.2021.03.320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256779PMC
June 2021

Estimating the effect of nutritional interventions using observational data: the American Heart Association's 2020 Dietary Goals and mortality.

Am J Clin Nutr 2021 08;114(2):690-703

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Because randomized trials of sustained dietary changes are sometimes impractical for long-term outcomes, the explicit emulation of a (hypothetical) target trial using observational data may be an important tool for nutritional epidemiology.

Objectives: We describe a methodological approach that aims to emulate a target trial of dietary interventions sustained over many years using data from observational cohort studies.

Methods: We estimated the 20-y risk of all-cause mortality under the sustained implementation of the food-based goals of the American Heart Association (AHA) 2020 using data from 3 prospective observational studies of US men [Health Professionals Follow-up Study (HPFS)] and women [Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II)]. We applied the parametric g-formula to estimate the 20-y mortality risk under a dietary intervention and under no dietary intervention.

Results: There were 165,411 participants who met the eligibility criteria. The mean age at baseline was 57.4 y (range, 43-82 y) in the HPFS, 52.4 y (range, 39-66 y) in the NHS, and 40.2 y (range, 30-50 y) in the NHS II. During 20 y of follow-up, 13,241 participants died. The estimated 20-y mortality risks under a dietary intervention versus no intervention were 21.9% compared with 25.8%, respectively, in the HPFS (risk difference, -3.9%; 95% CI: -4.9% to -3.2%); 10.0% compared with 12.6%, respectively, in the NHS (risk difference, -2.6%; 95% CI: -3.1% to -1.8%); and 2.1% compared with 2.5%, respectively, in the NHS II (risk difference, -0.35%; 95% CI: -0.56% to -0.09%). The corresponding risk ratios were 0.85 (95% CI: 0.81-0.88) in the HPFS, 0.79 (95% CI: 0.75-0.85) in the NHS, and 0.86 (95% CI: 0.78-0.96) in the NHS II.

Conclusions: We estimated that adherence to the food-based AHA 2020 Dietary Goals starting in midlife may reduce the 20-y risk of mortality.
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http://dx.doi.org/10.1093/ajcn/nqab100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326054PMC
August 2021

A novel protocol to assess the impact of prescription stimulants on blood pressure in adults using ambulatory blood pressure monitoring.

J Clin Hypertens (Greenwich) 2021 06 3;23(6):1264-1268. Epub 2021 May 3.

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Prescription stimulants are an important cause of secondary hypertension and their use is increasing in adult patients who are also at risk for essential hypertension. Although stimulants increase blood pressure, a systematic approach for assessing their impact in individual patients is lacking. We developed a protocol using ambulatory blood pressure monitoring for up to 36 h to compare blood pressure over two sequential days. Average blood pressure on the first day (without stimulant medication) was compared to average blood pressure on the second day (after re-starting stimulant medication). We describe the outcomes of this protocol for a case series of eleven adults. Patients demonstrated one of three outcomes: normal blood pressure on both days, hypertension on both days, or hypertension only on the day patients received their stimulant medications. This novel protocol provides valuable information on the blood pressure effects of stimulant medications and allows clinicians to make personalized decisions regarding treatment.
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http://dx.doi.org/10.1111/jch.14250DOI Listing
June 2021

Case-cohort study of plasma phospholipid fatty acid profiles, cognitive function, and risk of dementia: a secondary analysis in the Ginkgo Evaluation of Memory Study.

Am J Clin Nutr 2021 07;114(1):154-162

Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA.

Background: Phospholipids are biomarkers of dietary fat intake and metabolism, linked to several cardiometabolic disorders. Few prospective studies have assessed plasma phospholipids in relation to dementia risk and cognitive function.

Objectives: We aimed to evaluate the association between a decrease in linoleic acid accompanied with an increase in other fatty acids and cognitive function and dementia risk.

Methods: We conducted a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 1252 participants, 498 of whom who developed dementia during a mean of 5 y of follow-up. We measured 45 individual plasma phospholipids (as a percentage of total plasma phospholipid fatty acids) by GC and related these to Modified Mini-Mental State Examination (3MSE) scores at baseline and neurologist-adjudicated incidence of all-cause dementia and Alzheimer disease (AD), adjusting for sociodemographic and clinical characteristics.

Results: Substitution of 1% of SFAs for 1% of linoleic acid, the predominant polyunsaturated n-6 (ɷ-6) fatty acid, was associated with higher risk of dementia (HR per 1% of SFAs instead of linoleic acid = 1.03; 95% CI: 1.00, 1.07) and a 0.08 point lower 3MSE score at baseline (95% CI: -0.12, -0.03), signifying worse cognitive function. When compared with linoleic acid, we found no associations of total monounsaturated, n-3 polyunsaturated, or trans fatty acids with risk of dementia or AD. However, the substitution of 1% of the marine n-3 PUFA DHA for linoleic acid was associated with lower risk of dementia (HR = 0.86 per 1% of DHA instead of linoleic acid; 95% CI: 0.76, 0.96). These associations were not modified by apolipoprotein E genotype, mild cognitive impairment at baseline, age, or sex.

Conclusions: Specific elements of diet may be associated with late-life dementia, a hypothesis that requires formal testing in randomized controlled trials and that represents a possible preventive intervention.
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http://dx.doi.org/10.1093/ajcn/nqab087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277434PMC
July 2021

Reply to: Comment on: Non-esterified fatty acids and risks of frailty, disability, and mobility limitation in older adults: The cardiovascular health study.

J Am Geriatr Soc 2021 05 15;69(5):1408-1409. Epub 2021 Apr 15.

Division of General Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1111/jgs.17130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372672PMC
May 2021

Gut microbiota-derived metabolites and risk of coronary artery disease: a prospective study among US men and women.

Am J Clin Nutr 2021 07;114(1):238-247

Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA.

Background: Accumulating evidence has suggested that human gut microbiota metabolize certain dietary compounds and subsequently produce bioactive metabolites that may exert beneficial or harmful effects on coronary artery disease (CAD) risk.

Objectives: This study examined the joint association of 2 gut microbiota metabolites, enterolactone and trimethylamine N-oxide (TMAO), that originate from intake of plant-based foods and animal products, respectively, in relation to CAD risk.

Methods: A prospective nested case-control study of CAD was conducted among participants who were free of diabetes, cardiovascular disease, and cancer in the Nurses' Health Study II and the Health Professionals Follow-up Study. Plasma concentrations of enterolactone and TMAO, as well as choline and L-carnitine, were assayed among 608 CAD case-control pairs.

Results: A high enterolactone and low TMAO profile was associated with better diet quality, especially higher intake of whole grains and fiber and lower intake of red meats, as well as lower concentrations of plasma triglycerides and C-reactive protein. Participants with a high enterolactone/low TMAO profile had a significantly lower risk of CAD: the multivariate-adjusted OR was 0.58 (95% CI: 0.38, 0.90), compared with participants with a low enterolactone/high TMAO profile. No significant interaction between enterolactone and TMAO on CAD risk was observed. Neither TMAO nor enterolactone alone were associated with CAD risk in pooled analyses. In women, a higher enterolactone concentration was significantly associated with a 54% lower CAD risk (P trend = 0.03), although the interaction by sex was not significant.

Conclusions: Our results show that a profile characterized by high enterolactone and low TMAO concentrations in plasma is linked to a healthful dietary pattern and significantly associated with a lower risk of CAD. Overall, these data suggest that, compared with individual markers, multiple microbiota-derived metabolites may facilitate better differentiation of CAD risk and characterization of the relations between diet, microbiota, and CAD risk.
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http://dx.doi.org/10.1093/ajcn/nqab053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277432PMC
July 2021

The Effects of a Low Sodium Meal Plan on Blood Pressure in Older Adults: The SOTRUE Randomized Feasibility Trial.

Nutrients 2021 Mar 16;13(3). Epub 2021 Mar 16.

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

Reduced sodium meal plans are recommended by the Centers of Disease Control to lower blood pressure in older adults; however, this strategy has not been tested in a clinical trial. The Satter House Trial of Reduced Sodium Meals (SOTRUE) was an individual-level, double-blind, randomized controlled pilot study of adults living in a congregate living facility subsidized by the Federal Department of Housing and Urban Development (HUD). Adults over age 60 years ate 3 isocaloric meals with two snacks daily for 14 days. The meal plans differed in sodium density (<0.95 vs. >2 mg/kcal), but were equivalent in potassium and macronutrients. Seated systolic BP (SBP) was the primary outcome, while urine sodium-creatinine ratio was used to measure compliance. Twenty participants were randomized (95% women; 95% white; mean age 78 ± 8 years), beginning in 7 October 2019. Retention was 100% with the last participant ending 4 November 2019. Mean baseline SBP changed from 121 to 116 mmHg with the typical sodium diet (-5 mmHg; 95% CI: -18, 8) and from 123 to 112 mmHg with the low sodium diet (-11 mmHg; 95% CI: -15.2, -7.7). Compared to the typical sodium meal plan, the low sodium meal plan lowered SBP by 4.8 mmHg (95% CI: -14.4, 4.9; = 0.31) and urine sodium-creatinine ratio by 36% (-36.0; 95% CI: -60.3, 3.4; = 0.07), both non-significant. SOTRUE demonstrates the feasibility of sodium reduction in federally mandated meal plans. A longer and larger study is needed to establish the efficacy and safety of low sodium meals in older adults.
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http://dx.doi.org/10.3390/nu13030964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002543PMC
March 2021

Brachial Flow-Mediated Dilation and Risk of Atrial Fibrillation in Older Adults: The Cardiovascular Health Study.

Vasc Health Risk Manag 2021 11;17:95-102. Epub 2021 Mar 11.

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Background: Endothelial dysfunction is associated with common risk factors for AF and has been implicated in the pathophysiology of atrial fibrillation (AF) through a variety of mechanisms. We determined the prospective association of brachial flow-mediated dilation (FMD) with incident AF among older adults.

Methods: We included 2027 Cardiovascular Health Study participants (mean age=78.3 years, male=39%, Black=17%) who underwent brachial FMD measurement at the 1997 to 1998 clinic visit. Incident AF was ascertained by study electrocardiograms, hospital discharge diagnosis coding and Medicare claims data. Cox regression models were used to examine the association between FMD and incident AF.

Results: We identified 754 incident of AF cases (37%) over a median follow-up of 11.0 years. After adjusting for age, sex, race, height, weight, cardiovascular disease, cigarette smoking, hypertension, diabetes, kidney function, c-reactive protein, physical activity, alcohol consumption, and statins, the risk of AF did not differ according to brachial FMD response (4th vs 1st quartile hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.81, 1.26; per FMD unit increment HR=1.01, 95% CI: 0.97, 1.05).

Conclusion: We found no relationship between brachial FMD and the risk of developing AF in this elderly cohort. Our findings suggest that the utility of brachial FMD as a risk marker for AF in older individuals is minimal.
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http://dx.doi.org/10.2147/VHRM.S297720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961139PMC
March 2021

Hemostatic factor levels and cognitive decline in older adults: The Cardiovascular Health Study.

J Thromb Haemost 2021 05 29;19(5):1219-1227. Epub 2021 Mar 29.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Hemostasis is a key factor in cerebrovascular disease, but the association of hemostatic factors with cognitive decline is unclear.

Objective: To prospectively evaluate associations of 20 hemostatic factor levels with changes in cognition during ≥8 years of follow-up in the Cardiovascular Health Study (CHS) of older adults.

Methods: We included participants of an existing CHS cross-sectional substudy (n = 400) with hemostatic factors measured in 1989-1990. Between 1989-1990 and 1998-1999, cognitive function was measured using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Tests. Mixed-effects linear regression models estimated change in cognitive function over time, adjusting for sociodemographic and clinical factors and APOE genotype, using Bonferroni adjustment. We also derived principal components to account for the interrelationship among factors.

Results: Of 20 factors evaluated individually, only higher levels of plasmin-α -antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), and lower factor X (FXc) levels were associated with faster cognitive decline, estimated by annual change in 3MSE points (1 standard deviation PAP β = -0.65, 95% confidence interval [CI]: -1.08 to -0.21; TFPI β = -0.55, 95% CI: -0.90 to -0.19; FXc β = 0.52, 95% CI: 0.21-0.84). One of four principal components, loading positively on D-dimer, prothrombin fragment 1.2 (F1.2), and PAP was significantly associated with change in 3MSE.

Conclusions: Levels of PAP, TPFI, and FXc and a combination of factors driven by PAP, D-dimer, and F1.2 were associated with cognitive decline. Whether these findings can be used to improve dementia prevention or prediction requires further study.
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http://dx.doi.org/10.1111/jth.15300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136364PMC
May 2021

Associations of Serum Nonesterified Fatty Acids With Coronary Heart Disease Mortality and Nonfatal Myocardial Infarction: The CHS (Cardiovascular Health Study) Cohort.

J Am Heart Assoc 2021 03 8;10(6):e019135. Epub 2021 Mar 8.

Cardiovascular Nutrition Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging Tufts University Boston MA.

Background Significant associations have been reported between serum total nonesterified fatty acid (NEFA) concentrations and coronary heart disease (CHD) mortality and incident nonfatal myocardial infarction (MI) in some prospective cohort studies. Little is known about whether individual or subclasses (saturated, polyunsaturated [n-6 and n-3], and fatty acids) of serum NEFAs relate to CHD mortality and nonfatal MI. Methods and Results CHS (Cardiovascular Health Study) participants (N=1681) who had no history of MI, angina, or revascularization or were free of MI at baseline (1996-1997) were included. NEFAs were quantified using gas chromatography. Cox regression analysis was used to evaluate associations of 5 subclasses and individual NEFAs with CHD composite (CHD mortality and nonfatal MI), CHD mortality, and incident nonfatal MI. During a median follow-up of 11.7 years, 266 cases of CHD death and 271 cases of nonfatal MI occurred. In the fully adjusted model, no significant associations were identified between individual NEFA and CHD composite. Exploratory analyses indicated that lauric acid (12:0) was negatively associated (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; =0.0328) and dihomo-γ-linolenic acid (20:3n-6) was positively associated with CHD mortality (HR, 1.34; 95% CI, 1.02-1.76; =0.0351). Elaidic acid (18:1n-7) was positively associated with incident nonfatal MI (HR, 1.46; 95% CI, 1.01-2.12; =0.0445). No significant associations were observed for NEFA subclass and any outcomes. Conclusions In CHS participants, 2 NEFAs, dihomo-γ-linolenic and elaidic acids, were positively associated with CHD mortality and nonfatal MI, respectively, suggesting potential susceptibility biomarkers for risks of CHD mortality and nonfatal MI.
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http://dx.doi.org/10.1161/JAHA.120.019135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174223PMC
March 2021

Effects of dietary macronutrients on serum urate: results from the OmniHeart trial.

Am J Clin Nutr 2021 06;113(6):1593-1599

Division of General Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA.

Background: Dietary recommendations to prevent gout emphasize a low-purine diet. Recent evidence suggests that the Dietary Approaches to Stop Hypertension (DASH) diet reduces serum urate while also improving blood pressure and lipids.

Objective: To compare the effects of DASH-style diets emphasizing different macronutrient proportions on serum urate reduction.

Methods: We conducted a secondary analysis of the Optimal Macronutrient Intake Trial to Prevent Heart Disease feeding study, a 3-period, crossover design, randomized trial of adults with prehypertension or hypertension. Participants were provided with 3 DASH-style diets in random order, each for 6 wk. Each DASH-style diet emphasized different macronutrient proportions: a carbohydrate-rich (CARB) diet, a protein-rich (PROT) diet, and an unsaturated fat-rich (UNSAT) diet. In the PROT diet, approximately half of the protein came from plant sources. We compared the effects of these diets on serum urate at weeks 4 and 6 of each feeding period.

Results: Of the 163 individuals included in the final analysis, the mean serum urate at baseline was 5.1 mg/dL. Only the PROT diet reduced serum urate from baseline at the end of the 6-wk feeding period (-0.16 mg/dL; 95% CI: -0.28, -0.04; P = 0.007). Neither the CARB diet (-0.03 mg/dL; 95% CI: -0.14, 0.09; P = 0.66) nor the UNSAT diet (-0.01 mg/dL; 95% CI: -0.12, 0.09; P = 0.78) reduced serum urate from baseline. The PROT diet lowered serum urate by 0.12 mg/dL (95% CI: -0.20, -0.03; P = 0.006) compared with CARB and by 0.12 mg/dL (95% CI: -0.20, -0.05; P = 0.002) compared with UNSAT.

Conclusions: A DASH-style diet emphasizing plant-based protein lowered serum urate compared with those emphasizing carbohydrates or unsaturated fat. Future trials should test the ability of a DASH-style diet emphasizing plant-based protein to lower serum urate and prevent gout flares in patients with gout. This trial was registered at clinicaltrials.gov as NCT00051350.
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http://dx.doi.org/10.1093/ajcn/nqaa424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168362PMC
June 2021

Serum Individual Nonesterified Fatty Acids and Risk of Heart Failure in Older Adults.

Cardiology 2021;146(3):351-358. Epub 2021 Feb 25.

New York Academy of Medicine, New York, New York, USA.

Background: Heart failure (HF) is highly prevalent among older adults and is associated with high costs. Although serum total nonesterified fatty acids (NEFAs) have been positively associated with HF risk, the contribution of each individual NEFA to HF risk has not been examined.

Objective: The aim of this study was to examine the association of individual fasting NEFAs with HF risk in older adults.

Methods: In this prospective cohort study of older adults, we measured 35 individual NEFAs in 2,140 participants of the Cardiovascular Health Study using gas chromatography. HF was ascertained using review of medical records by an endpoint committee.

Results: The mean age was 77.7 ± 4.4 years, and 38.8% were male. During a median follow-up of 9.7 (maximum 19.0) years, 655 new cases of HF occurred. In a multivariable Cox regression model controlling for demographic and anthropometric variables, field center, education, serum albumin, glomerular filtration rate, physical activity, alcohol consumption, smoking, hormone replacement therapy, unintentional weight loss, and all other measured NEFAs, we observed inverse associations (HR [95% CI] per standard deviation) of nonesterified pentadecanoic (15:0) (0.73 [0.57-0.94]), γ-linolenic acid (GLA) (0.87 [0.75-1.00]), and docosahexaenoic acid (DHA) (0.73 [0.61-0.88]) acids with HF, and positive associations of nonesterified stearic (18:0) (1.30 [1.04-1.63]) and nervonic (24:1n-9) (1.17 [1.06-1.29]) acids with HF.

Conclusion: Our data are consistent with a higher risk of HF with nonesterified stearic and nervonic acids and a lower risk with nonesterified 15:0, GLA, and DHA in older adults. If confirmed in other studies, specific NEFAs may provide new targets for HF prevention.
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http://dx.doi.org/10.1159/000513917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547188PMC
August 2021
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