02744nas a2200397 4500008004100000022001400041245010400055210006900159260001300228300001200241490000700253520165200260653000901912653002201921653002501943653001501968653001701983653001102000653001802011653001102029653000902040653002402049653000902073653001402082100003002096700001602126700002502142700002002167700002102187700002102208700001502229700002402244700002002268700002202288856003602310 2011 eng d a1945-719700aMineral metabolism markers and the long-term risk of hip fracture: the cardiovascular health study.0 aMineral metabolism markers and the longterm risk of hip fracture c2011 Jul a2186-930 v963 a

CONTEXT: Disturbances in mineral metabolism are associated with lower bone mineral density and fracture; however, previous human studies have assessed individual mineral metabolism markers in isolation.

OBJECTIVE: We assessed serum concentrations of 25-hydroxyvitamin D (25-OHD), PTH, and bone-specific alkaline phosphatase (BAP) concentrations individually, and in combination, in association with the long-term risk of hip fracture among a general population of older adults.

DESIGN AND SETTING: We studied 2294 participants from the Cardiovascular Health Study (mean age 74 yr) who were ambulatory and free of hip fracture and known cardiovascular disease at baseline. We used proportional hazards models to evaluate associations of baseline serum 25-OHD, PTH, and BAP concentrations with the time to first hospitalized hip fracture.

RESULTS: During a median of 13 yr of follow-up, 242 participants (10.6%) developed an incident hip fracture. Serum 25-OHD concentrations less than 15 ng/ml were associated with a 61% greater adjusted risk of fracture (95% confidence interval 12-132% greater). In contrast, neither serum PTH nor BAP concentrations were significantly associated with fracture risk. The association of 25-OHD deficiency with hip fracture was not significantly altered by either PTH or BAP concentrations.

CONCLUSIONS: Serum concentrations of 25-OHD, but not PTH or BAP, are associated with long-term hip fracture risk among ambulatory older adults. These data suggest that 25-OHD is the most relevant mineral metabolism marker of fracture risk among older people.

10aAged10aAged, 80 and over10aAlkaline Phosphatase10aBiomarkers10aBone Density10aFemale10aHip Fractures10aHumans10aMale10aParathyroid Hormone10aRisk10aVitamin D1 aRobinson-Cohen, Cassianne1 aKatz, Ronit1 aHoofnagle, Andrew, N1 aCauley, Jane, A1 aFurberg, Curt, D1 aRobbins, John, A1 aChen, Zhao1 aSiscovick, David, S1 ade Boer, Ian, H1 aKestenbaum, Bryan uhttps://chs-nhlbi.org/node/128502559nas a2200349 4500008004100000022001400041245009700055210006900152260001600221300001200237490000800249520158900257653000901846653001501855653003401870653001301904653001101917653001101928653000901939653003001948653001201978653001601990653001402006100002302020700002202043700001902065700002502084700002002109700002402129700002002153856003602173 2011 eng d a1476-625600aSeasonal variation in 25-hydroxyvitamin D concentrations in the cardiovascular health study.0 aSeasonal variation in 25hydroxyvitamin D concentrations in the c c2011 Dec 15 a1363-720 v1743 a

Low circulating concentrations of 25-hydroxyvitamin D (25(OH)D) are associated with adverse health outcomes in diverse populations. However, 25(OH)D concentrations vary seasonally with varying exposure to sunlight, so single measurements may poorly reflect long-term 25(OH)D exposure. The authors investigated cyclical trends in average serum 25(OH)D concentrations among 2,298 individuals enrolled in the Cardiovascular Health Study of community-based older adults (1992-1993). A sinusoidal model closely approximated observed 25(OH)D concentrations and fit the data significantly better than did a mean model (P < 0.0001). The mean annual 25(OH)D concentration was 25.1 ng/mL (95% confidence interval: 24.7, 25.5), and the mean peak-trough difference was 9.6 ng/mL (95% confidence interval: 8.5, 10.7). Male sex, higher latitude of study site, and greater physical activity levels were associated with larger peak-trough difference in 25(OH)D concentration (each P < 0.05). Serum concentrations of intact parathyroid hormone and bone-specific alkaline phosphatase also varied in a sinusoidal fashion (P < 0.0001), inversely to 25(OH)D. In conclusion, serum 25(OH)D varies in a sinusoidal manner, with large seasonal differences relative to mean concentration and laboratory evidence of biologic sequelae. Single 25(OH)D measurements might not capture overall vitamin D status, and the extent of misclassification could vary by demographic and behavioral factors. Accounting for collection time may reduce bias in research studies and improve decision-making in clinical care.

10aAged10aBiomarkers10aContinental Population Groups10aExercise10aFemale10aHumans10aMale10aResidence Characteristics10aSeasons10aSex Factors10aVitamin D1 aShoben, Abigail, B1 aKestenbaum, Bryan1 aLevin, Gregory1 aHoofnagle, Andrew, N1 aPsaty, Bruce, M1 aSiscovick, David, S1 ade Boer, Ian, H uhttps://chs-nhlbi.org/node/135304205nas a2200529 4500008004100000022001400041245014500055210006900200260001300269300001100282490000700293520262400300653003102924653001002955653000902965653002202974653001502996653001903011653002803030653002203058653001103080653003103091653001103122653002803133653000903161653001603170653003503186653004203221653001603263100002003279700002203299700002103321700002503342700002503367700001903392700002403411700001903435700002203454700003003476700002403506700002403530700002403554700002203578700001703600700002203617856003603639 2014 eng d a1523-683800aEstimated GFR and circulating 24,25-dihydroxyvitamin D3 concentration: a participant-level analysis of 5 cohort studies and clinical trials.0 aEstimated GFR and circulating 2425dihydroxyvitamin D3 concentrat c2014 Aug a187-970 v643 a

BACKGROUND: Decreased glomerular filtration rate (GFR) leads to reduced production of 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 (25[OH]D3). Effects of low GFR on vitamin D catabolism are less well understood. We tested associations of estimated GFR (eGFR) with the circulating concentration of 24,25-dihydroxyvitamin D3 (24,25[OH]2D3), the most abundant product of 25(OH)D3 catabolism, across populations with a wide range of GFRs.

STUDY DESIGN: Cross-sectional study.

SETTING & PARTICIPANTS: 9,596 participants in 5 cohort studies and clinical trials: the Diabetes Control and Complications Trial (N=1,193), Multi-Ethnic Study of Atherosclerosis (N=6,470), Cardiovascular Health Study (N=932), Seattle Kidney Study (N=289), and Hemodialysis Study (N=712).

PREDICTOR: eGFR.

OUTCOME: Circulating 24,25(OH)2D3 concentration.

MEASUREMENTS: GFR was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation. Vitamin D metabolites were measured by mass spectrometry.

RESULTS: Circulating 24,25(OH)2D3 concentration was correlated with circulating 25(OH)D3 concentration (Pearson r range, 0.64-0.88). This correlation was weaker with lower eGFRs. Moreover, the increment in 24,25(OH)2D3 concentration associated with higher 25(OH)D3 concentration (slope) was lower with lower eGFRs: 2.06 (95% CI, 2.01-2.10), 1.77 (95% CI, 1.74-1.81), 1.55 (95% CI, 1.48-1.62), 1.17 (95% CI, 1.05-1.29), 0.92 (95% CI, 0.74-1.10), 0.61 (95% CI, 0.22-1.00), and 0.37 (95% CI, 0.35-0.39) ng/mL of 24,25(OH)2D3 per 10 ng/mL of 25(OH)D3 for eGFRs≥90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m2 and end-stage renal disease treated with hemodialysis, respectively. As a result, at a 25(OH)D3 concentration of 20 ng/mL, mean 24,25(OH)2D3 concentrations were 2.92 (95% CI, 2.87-2.96), 2.68 (95% CI, 2.64-2.72), 2.35 (95% CI, 2.26-2.45), 1.92 (95% CI, 1.74-2.10), 1.69 (95% CI, 1.43-1.95), 1.14 (95% CI, 0.62-1.66), and 1.04 (95% CI,1.02-1.07) ng/mL for each category, respectively. This interaction was independent of other relevant clinical characteristics. Race, diabetes, urine albumin excretion, and circulating parathyroid hormone and fibroblast growth factor 23 concentrations more modestly modified the association of 24,25(OH)2D3 with 25(OH)D3.

LIMITATIONS: Lack of direct pharmacokinetic measurements of vitamin D catabolism.

CONCLUSIONS: Lower eGFR is associated strongly with reduced vitamin D catabolism, as measured by circulating 24,25(OH)2D3 concentration.

10a24,25-Dihydroxyvitamin D 310aAdult10aAged10aAged, 80 and over10aBiomarkers10aCohort Studies10aCross-Sectional Studies10aDiabetes Mellitus10aFemale10aGlomerular Filtration Rate10aHumans10aKidney Failure, Chronic10aMale10aMiddle Aged10aObservational Studies as Topic10aRandomized Controlled Trials as Topic10aYoung Adult1 ade Boer, Ian, H1 aSachs, Michael, C1 aChonchol, Michel1 aHimmelfarb, Jonathan1 aHoofnagle, Andrew, N1 aIx, Joachim, H1 aKremsdorf, Robin, A1 aLin, Yvonne, S1 aMehrotra, Rajnish1 aRobinson-Cohen, Cassianne1 aSiscovick, David, S1 aSteffes, Michael, W1 aThummel, Kenneth, E1 aTracy, Russell, P1 aWang, Zhican1 aKestenbaum, Bryan uhttps://chs-nhlbi.org/node/634003407nas a2200553 4500008004100000022001400041245015800055210006900213260001600282300001200298490000800310520176800318653000902086653002202095653002402117653001602141653001802157653001102175653003102186653002202217653003102239653001802270653001102288653003402299653000902333653001602342653001502358653003202373653003302405653001702438653001802455653003402473653002702507653001402534100002002548700002202568700001602590700002302606700002302629700002502652700001902677700002102696700001502717700001902732700002402751700002202775700002002797856003602817 2014 eng d a1524-453900aFibroblast growth factor-23 and incident atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS).0 aFibroblast growth factor23 and incident atrial fibrillation the  c2014 Jul 22 a298-3070 v1303 a

BACKGROUND: Fibroblast growth factor-23 (FGF-23) is a hormone that promotes urinary phosphate excretion and regulates vitamin D metabolism. Circulating FGF-23 concentrations increase markedly in chronic kidney disease and are associated with increased risk of clinical cardiovascular events. FGF-23 may promote atrial fibrillation (AF) by inducing left ventricular hypertrophy and diastolic and left atrial dysfunction.

METHODS AND RESULTS: We tested the associations of circulating FGF-23 concentration with incident AF among 6398 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and 1350 participants in the Cardiovascular Health Study (CHS), all free of clinical cardiovascular disease at baseline. Over a median of 7.7 and 8.0 years of follow-up, we observed 291 and 229 incident AF events in MESA and CHS, respectively. In multivariable Cox proportional hazards models, each 2-fold-higher FGF-23 concentration was associated with a 41% higher risk of incident AF in MESA (hazard ratio, 1.41; 95% confidence interval, 1.13-1.76; P=0.003) and a 30% higher risk of incident AF in CHS (hazard ratio, 1.30; 95% confidence interval, 1.05-1.61; P=0.016) after adjustment for potential confounding characteristics, including kidney disease. Serum phosphate concentration was significantly associated with incident AF in MESA (hazard ratio, 1.15 per 0.5 mg/dL; 95% confidence interval, 1.02-1.31; P=0.023) but not CHS. In MESA, an association of low estimated glomerular filtration rate with incident AF was partially attenuated by adjustment for FGF-23.

CONCLUSION: Higher circulating FGF-23 concentration is associated with incident AF and may, in part, explain the link between chronic kidney disease and AF.

10aAged10aAged, 80 and over10aAtrial Fibrillation10aComorbidity10aEthnic Groups10aFemale10aFibroblast Growth Factor 310aFollow-Up Studies10aGlomerular Filtration Rate10aHeart Failure10aHumans10aHypertrophy, Left Ventricular10aMale10aMiddle Aged10aPhosphates10aProportional Hazards Models10aRenal Insufficiency, Chronic10aRisk Factors10aUnited States10aVentricular Dysfunction, Left10aVentricular Remodeling10aVitamin D1 aMathew, Jehu, S1 aSachs, Michael, C1 aKatz, Ronit1 aPatton, Kristen, K1 aHeckbert, Susan, R1 aHoofnagle, Andrew, N1 aAlonso, Alvaro1 aChonchol, Michel1 aDeo, Rajat1 aIx, Joachim, H1 aSiscovick, David, S1 aKestenbaum, Bryan1 ade Boer, Ian, H uhttps://chs-nhlbi.org/node/639903388nas a2200457 4500008004100000022001400041245012000055210006900175260001300244300001000257490000700267520205200274653000902326653001802335653001502353653002802368653002802396653003802424653001102462653003002473653001802503653003102521653001102552653002302563653002502586653000902611653001402620653001702634653003102651100001802682700001902700700002402719700002002743700002002763700002502783700002102808700002502829700002002854700002002874856003602894 2016 eng d a1532-541500aFibroblast Growth Factor-23 and Frailty in Elderly Community-Dwelling Individuals: The Cardiovascular Health Study.0 aFibroblast Growth Factor23 and Frailty in Elderly CommunityDwell c2016 Feb a270-60 v643 a

OBJECTIVES: To evaluate whether fibroblast growth factor 23 (FGF-23) is related to frailty and to characterize the nature of their joint association with mortality.

DESIGN: Cross-sectional analysis for frailty and longitudinal cohort analysis for mortality.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Community-dwelling individuals (N = 2,977; mean age 77.9 ± 4.7, 40% male, 83% white).

MEASUREMENTS: The predictor was serum FGF-23 concentration (C-terminal enzyme-linked immunosorbent assay), and the outcomes were frailty status (determined according to frailty phenotype criteria of weight loss, weakness, exhaustion, slowness, and low physical activity) and mortality. Multinomial logistic regression was used to assess the cross-sectional association between FGF-23 and frailty and prefrailty, adjusting for demographic characteristics, cardiovascular disease and risk factors, and kidney markers. Proportional hazards Cox proportional hazards regression was used to assess the association between FGF-23, frailty, and all-cause mortality.

RESULTS: Mean estimated glomerular filtration rate (eGFR) was 64 ± 17 mL/min per 1.73 m(2) . Median FGF-23 was 70.3 RU/mL (interquartile range 53.4-99.2); 52% were prefrail, and 13% were frail. After multivariate adjustment, each doubling in FGF-23 concentration was associated with 38% (95% confidence interval (CI) = 17-62%) higher odds of frailty than of nonfrailty and 16% (95% CI = 3-30%) higher odds of prefrailty. FGF-23 (hazard ratio (HR) = 1.16, 95% CI = 1.10-1.23) and frailty (HR = 1.82, 95% CI = 1.57-2.12) were independently associated with mortality, but neither association was meaningfully attenuated when adjusted for the other.

CONCLUSION: In a large cohort of older adults, higher FGF-23 was independently associated with prevalent frailty and prefrailty. FGF-23 and frailty were independent and additive risk factors for mortality. FGF-23 may be a marker for functional outcomes.

10aAged10aAnthropometry10aBiomarkers10aCardiovascular Diseases10aCross-Sectional Studies10aEnzyme-Linked Immunosorbent Assay10aFemale10aFibroblast Growth Factors10aFrail Elderly10aGlomerular Filtration Rate10aHumans10aIndependent Living10aLongitudinal Studies10aMale10aPhenotype10aRisk Factors10aSurveys and Questionnaires1 aBeben, Tomasz1 aIx, Joachim, H1 aShlipak, Michael, G1 aSarnak, Mark, J1 aFried, Linda, F1 aHoofnagle, Andrew, N1 aChonchol, Michel1 aKestenbaum, Bryan, R1 ade Boer, Ian, H1 aRifkin, Dena, E uhttps://chs-nhlbi.org/node/699003136nas a2200313 4500008004100000022001400041245012400055210006900179260001600248300001200264490000700276520219200283100002602475700002002501700001802521700001602539700002002555700001502575700002502590700002002615700002402635700002202659700002002681700002002701700002202721700002402743700001902767856003602786 2017 eng d a1555-905X00aThe Relation of Serum Potassium Concentration with Cardiovascular Events and Mortality in Community-Living Individuals.0 aRelation of Serum Potassium Concentration with Cardiovascular Ev c2017 Feb 07 a245-2520 v123 a

BACKGROUND AND OBJECTIVES: Hyperkalemia is associated with adverse outcomes in patients with CKD and in hospitalized patients with acute medical conditions. Little is known regarding hyperkalemia, cardiovascular disease (CVD), and mortality in community-living populations. In a pooled analysis of two large observational cohorts, we investigated associations between serum potassium concentrations and CVD events and mortality, and whether potassium-altering medications and eGFR<60 ml/min per 1.73 m(2) modified these associations.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 9651 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS), who were free of CVD at baseline (2000-2002 in the MESA and 1989-1993 in the CHS), we investigated associations between serum potassium categories (<3.5, 3.5-3.9, 4.0-4.4, 4.5-4.9, and ≥5.0 mEq/L) and CVD events, mortality, and mortality subtypes (CVD versus non-CVD) using Cox proportional hazards models, adjusting for demographics, time-varying eGFR, traditional CVD risk factors, and use of potassium-altering medications.

RESULTS: Compared with serum potassium concentrations between 4.0 and 4.4 mEq/L, those with concentrations ≥5.0 mEq/L were at higher risk for all-cause mortality (hazard ratio, 1.41; 95% confidence interval, 1.12 to 1.76), CVD death (hazard ratio, 1.50; 95% confidence interval, 1.00 to 2.26), and non-CVD death (hazard ratio, 1.40; 95% confidence interval, 1.07 to 1.83) in fully adjusted models. Associations of serum potassium with these end points differed among diuretic users (Pinteraction<0.02 for all), such that participants who had serum potassium ≥5.0 mEq/L and were concurrently using diuretics were at higher risk of each end point compared with those not using diuretics.

CONCLUSIONS: Serum potassium concentration ≥5.0 mEq/L was associated with all-cause mortality, CVD death, and non-CVD death in community-living individuals; associations were stronger in diuretic users. Whether maintenance of potassium within the normal range may improve clinical outcomes requires future study.

1 aHughes-Austin, Jan, M1 aRifkin, Dena, E1 aBeben, Tomasz1 aKatz, Ronit1 aSarnak, Mark, J1 aDeo, Rajat1 aHoofnagle, Andrew, N1 aHomma, Shunichi1 aSiscovick, David, S1 aSotoodehnia, Nona1 aPsaty, Bruce, M1 ade Boer, Ian, H1 aKestenbaum, Bryan1 aShlipak, Michael, G1 aIx, Joachim, H uhttps://chs-nhlbi.org/node/734702495nas a2200265 4500008004100000022001400041245011100055210006900166260001300235300001200248490000800260520168800268100002201956700001601978700002001994700002502014700002102039700002402060700002002084700002502104700002002129700002502149700001902174856003602193 2018 eng d a1873-276300aThe 24,25 to 25-hydroxyvitamin D ratio and fracture risk in older adults: The cardiovascular health study.0 a2425 to 25hydroxyvitamin D ratio and fracture risk in older adul c2018 Feb a124-1300 v1073 a

25-hydroxyvitamin D [25(OH)D] may not optimally indicate vitamin D receptor activity. Higher concentrations of its catabolic product 24,25-dihydroxyvitmin D [24,25(OH)2D] and a higher ratio of 24,25(OH)2D to 25(OH)D (the vitamin D metabolite ratio [VMR]) may provide additional information on receptor activity. We compared the strength of associations of these markers with serum PTH concentrations, hip bone mineral density (BMD), and risk of incident hip fracture in community-living older participants in the Cardiovascular Health Study. Among 890 participants, the mean age was 78years, 60% were women, and the mean 25(OH)D was 28±11ng/ml. In cross-sectional analysis, the strength of association of each vitamin D measure with PTH was similar; a 1% higher 25(OH)D, 24,25(OH)2D, and VMR were associated with 0.32%, 0.25%, and 0.26% lower PTH, respectively (p<0.05 for all). Among 358 participants with available BMD data, we found no associations of 25(OH)D or VMR with BMD, whereas higher 24,25(OH)2D was modestly associated with greater hip BMD (1% higher 24,25(OH)2D associated with 0.04% [95% CI 0.01-0.08%] higher BMD). Risk of incident hip fracture risk was evaluated using a case-cohort design. There were 289 hip fractures during a mean follow up time of 8.4years. Both higher 24,25(OH)2D and VMR were associated with lower risk of hip fracture (HR per SD higher, 0.73 [0.61, 0.87] and 0.74 [0.61, 0.88], respectively) whereas 25(OH)D was not associated with hip fracture (HR 0.93 [0.79, 1.10]). We conclude that evaluating vitamin D status by incorporating assessment of 24,25(OH)D and the VMR provides information on bone health above and beyond 25(OH)D alone.

1 aGinsberg, Charles1 aKatz, Ronit1 ade Boer, Ian, H1 aKestenbaum, Bryan, R1 aChonchol, Michel1 aShlipak, Michael, G1 aSarnak, Mark, J1 aHoofnagle, Andrew, N1 aRifkin, Dena, E1 aGarimella, Pranav, S1 aIx, Joachim, H uhttps://chs-nhlbi.org/node/756102717nas a2200277 4500008004100000022001400041245011400055210006900169260001600238300001200254490000600266520186100272100002002133700002202153700002502175700002402200700002202224700001902246700002402265700002002289700002302309700002502332700002202357700002402379856003602403 2020 eng d a2047-998000aPlasma Ceramides and Sphingomyelins in Relation to Atrial Fibrillation Risk: The Cardiovascular Health Study.0 aPlasma Ceramides and Sphingomyelins in Relation to Atrial Fibril c2020 Feb 18 ae0128530 v93 a

Background Ceramides exhibit multiple biological activities that may influence the pathophysiological characteristics of atrial fibrillation (AF). Whether the length of the saturated fatty acid carried by the ceramide or their sphingomyelin precursors are associated with AF risk is not known. Methods and Results Among 4206 CHS (Cardiovascular Health Study) participants (mean age, 76 years; 40% men) who were free of prevalent AF at baseline, we identified 1198 incident AF cases over a median 8.7 years of follow-up. We examined 8 sphingolipid species: ceramide and sphingomyelin species with palmitic acid and species with very-long-chain saturated fatty acids: arachidic; behenic; and lignoceric. In adjusted Cox regression analyses, ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk (ie, per 2-fold higher ceramide with behenic acid hazard ratio, 0.71; 95% CI, 0.59-0.86; sphingomyelin with behenic acid hazard ratio, 0.60; 95% CI, 0.46-0.77). In contrast, ceramides and sphingomyelins with palmitic acid were associated with increased AF risk (ceramide with palmitic acid hazard ratio, 1.31; 95% CI, 1.03-1.66; sphingomyelin with palmitic acid hazard ratio, 1.73; 95% CI, 1.18-2.55). Associations were attenuated with adjustment for NT-proBNP (N-terminal pro-B-type natriuretic peptide), but did not differ significantly by age, sex, race, body mass index, or history of coronary heart disease. Conclusions Our findings suggest that several ceramide and sphingomyelin species are associated with incident AF, and that these associations differ on the basis of the fatty acid. Ceramides and sphingomyelins with palmitic acid were associated with increased AF risk, whereas ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk.

1 aJensen, Paul, N1 aFretts, Amanda, M1 aHoofnagle, Andrew, N1 aSitlani, Colleen, M1 aMcKnight, Barbara1 aKing, Irena, B1 aSiscovick, David, S1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aMozaffarian, Dariush1 aSotoodehnia, Nona1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/828402485nas a2200253 4500008004100000022001400041245010100055210006900156260001600225300001400241490000700255520171100262100002201973700002001995700002502015700002202040700002402062700002402086700001902110700002002129700002202149700002402171856003602195 2021 eng d a1530-856100aCirculating Ceramides and Sphingomyelins and Risk of Mortality: The Cardiovascular Health Study.0 aCirculating Ceramides and Sphingomyelins and Risk of Mortality T c2021 Nov 26 a1650-16590 v673 a

BACKGROUND: Recent studies suggest that associations of ceramides (Cer) and sphingomyelins (SM) with health outcomes differ according to the fatty acid acylated to the sphingoid backbone. The purpose of this study was to assess associations of Cer and SM species with mortality.

METHODS: The study population included participants from the Cardiovascular Health Study (CHS), a community-based cohort of adults aged ≥65 years who were followed from 1992-2015 (n = 4612). Associations of plasma Cer and SM species carrying long-chain (i.e., 16:0) and very-long-chain (i.e., 20:0, 22:0, 24:0) saturated fatty acids with mortality were assessed using Cox proportional hazards models.

RESULTS: During a median follow-up of 10.2 years, 4099 deaths occurred. High concentrations of Cer and SM carrying fatty acid 16:0 were each associated with an increased risk of mortality. Conversely, high concentrations of several ceramide and sphingomyelin species carrying longer fatty acids were each associated with a decreased risk of mortality. The hazard ratios for total mortality per 2-fold difference in each Cer and SM species were: 1.89 (95% CI), 1.65-2.17 for Cer-16, 0.79 (95% CI, 0.70-0.88) for Cer-22, 0.74 (95% CI, 0.65-0.84) for Cer-24, 2.51 (95% CI, 2.01-3.14) for SM-16, 0.68 (95% CI, 0.58-0.79) for SM-20, 0.57 (95% CI, 0.49-0.67) for SM-22, and 0.66 (0.57-0.75) for SM-24. We found no association of Cer-20 with risk of death.

CONCLUSIONS: Associations of Cer and SM with the risk of death differ according to the length of their acylated saturated fatty acid. Future studies are needed to explore mechanisms underlying these relationships.

1 aFretts, Amanda, M1 aJensen, Paul, N1 aHoofnagle, Andrew, N1 aMcKnight, Barbara1 aSitlani, Colleen, M1 aSiscovick, David, S1 aKing, Irena, B1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/891002453nas a2200265 4500008004100000022001400041245009900055210006900154260001600223300001100239520164100250100002201891700002001913700002501933700002201958700002301980700001702003700002402020700002402044700001902068700001802087700002202105700002402127856003602151 2021 eng d a1539-726200aPlasma Ceramides containing Saturated Fatty Acids are Associated with Risk of Type 2 Diabetes.0 aPlasma Ceramides containing Saturated Fatty Acids are Associated c2021 Sep 20 a1001193 a

Recent studies suggest that the type of saturated fatty acid bound to sphingolipids influences the biological activity of those sphingolipids. However, it is unknown whether associations of sphingolipids with diabetes may differ by the identity of bound lipid species. Here we investigated associations of 15 ceramide and sphingomyelin species (i.e., all sphingolipids, measured with coefficient of variation less than 20%) with incident type 2 diabetes in the Cardiovascular Health Study (n = 3,645), a large cohort study of cardiovascular disease (CVD) among elderly adults who were followed from 1989-2015. Diabetes incidence was defined as fasting glucose ≥126 mg/dL or non-fasting glucose ≥200 mg/dL; reported use of insulin or oral hypoglycemic medication; or documentation of diabetes diagnosis through the Centers for Medicare and Medicaid Services records. Associations of each sphingolipid with incident diabetes were assessed using a Cox proportional hazards regression model. We found that higher circulating levels of ceramide with acylated palmitic acid (Cer-16), stearic acid containing ceramide (Cer-18), arachidic acid containing ceramide (Cer-20), and behenic acid containing ceramide (Cer-22) were each associated with a higher risk of diabetes. The hazard ratios for incident diabetes per 1 SD higher log levels of each ceramide species were: 1.21 (95% CI 1.09-1.34) for Cer-16, 1.23 (95% CI 1.10-1.37) for Cer-18, 1.14 (95% CI 1.02-1.26) for Cer-20, and 1.18 (95% CI 1.06-1.32) for Cer-22. In conclusion, higher levels of Cer-16, Cer-18, Cer-20, and Cer-22 were associated with a higher risk of diabetes.

1 aFretts, Amanda, M1 aJensen, Paul, N1 aHoofnagle, Andrew, N1 aMcKnight, Barbara1 aHoward, Barbara, V1 aUmans, Jason1 aSitlani, Colleen, M1 aSiscovick, David, S1 aKing, Irena, B1 aDjoussé, Luc1 aSotoodehnia, Nona1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/890903115nas a2200253 4500008004100000022001400041245012200055210006900177260001600246300001100262490000700273520231700280100002202597700001802619700002202637700002502659700002202684700002702706700002402733700002402757700002002781700002402801856003602825 2023 eng d a2352-396400aEvaluation of plasma sphingolipids as mediators of the relationship between kidney disease and cardiovascular events.0 aEvaluation of plasma sphingolipids as mediators of the relations c2023 Aug 24 a1047650 v953 a

BACKGROUND: Sphingolipids are a family of circulating lipids with regulatory and signaling roles that are strongly associated with both eGFR and cardiovascular disease. Patients with chronic kidney disease (CKD) are at high risk for cardiovascular events, and have different plasma concentrations of certain plasma sphingolipids compared to patients with normal kidney function. We hypothesize that circulating sphingolipids partially mediate the associations between eGFR and cardiovascular events.

METHODS: We measured the circulating concentrations of 8 sphingolipids, including 4 ceramides and 4 sphingomyelins with the fatty acids 16:0, 20:0, 22:0, and 24:0, in plasma from 3,463 participants in a population-based cohort (Cardiovascular Health Study) without prevalent cardiovascular disease. We tested the adjusted mediation effects by these sphingolipids of the associations between eGFR and incident cardiovascular disease via quasi-Bayesian Monte Carlo method with 2,000 simulations, using a Bonferroni correction for significance.

FINDINGS: The mean (±SD) eGFR was 70 (±16) mL/min/1.73 m; 62% of participants were women. Lower eGFR was associated with higher plasma ceramide-16:0 and sphingomyelin-16:0, and lower ceramides and sphingomyelins-20:0 and -22:0. Lower eGFR was associated with risk of incident heart failure and ischemic stroke, but not myocardial infarction. Five of eight sphingolipids partially mediated the association between eGFR and heart failure. The sphingolipids associated with the greatest proportion mediated were ceramide-16:0 (proportion mediated 13%, 95% CI 8-22%) and sphingomyelin-16:0 (proportion mediated 10%, 95% CI 5-17%). No sphingolipids mediated the association between eGFR and ischemic stroke.

INTERPRETATION: Plasma sphingolipids partially mediated the association between lower eGFR and incident heart failure. Altered sphingolipids metabolism may be a novel mechanism for heart failure in patients with CKD.

FUNDING: This study was supported by T32 DK007467 and a KidneyCure Ben J. Lipps Research Fellowship (Dr. Lidgard). Sphingolipid measurements were supported by R01 HL128575 (Dr. Lemaitre) and R01 HL111375 (Dr. Hoofnagle) from the National Heart, Lung, and Blood Institute (NHLBI).

1 aLidgard, Benjamin1 aBansal, Nisha1 aZelnick, Leila, R1 aHoofnagle, Andrew, N1 aFretts, Amanda, M1 aLongstreth, William, T1 aShlipak, Michael, G1 aSiscovick, David, S1 aUmans, Jason, G1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/948203876nas a2200397 4500008004100000022001400041245010100055210006900156260001600225300001300241490000600254520276700260653000903027653001403036653001903050653002703069653002103096653001603117653001103133653001103144653000903155653001803164653001903182100001903201700002003220700002203240700002503262700002203287700002403309700002403333700001903357700002003376700002203396700002403418856003603442 2023 eng d a2574-380500aPlasma Ceramides and Sphingomyelins and Sudden Cardiac Death in the Cardiovascular Health Study.0 aPlasma Ceramides and Sphingomyelins and Sudden Cardiac Death in  c2023 Nov 01 ae23438540 v63 a

IMPORTANCE: Sphingolipids, including ceramides and sphingomyelins, may influence the pathophysiology and risk of sudden cardiac death (SCD) through multiple biological activities. Whether the length of the fatty acid acylated to plasma sphingolipid species is associated with SCD risk is not known.

OBJECTIVE: To determine whether the saturated fatty acid length of plasma ceramides and sphingomyelins influences the association with SCD risk.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, multivariable Cox proportional hazards regression models were used to examine the association of sphingolipid species with SCD risk. The study population included 4612 participants in the Cardiovascular Health Study followed up prospectively for a median of 10.2 (IQR, 5.5-11.6) years. Baseline data were collected from January 1992 to December 1995 during annual examinations. Data were analyzed from February 11, 2020, to September 9, 2023.

EXPOSURES: Eight plasma sphingolipid species (4 ceramides and 4 sphingomyelins) with saturated fatty acids of 16, 20, 22, and 24 carbons.

MAIN OUTCOME AND MEASURE: Association of plasma ceramides and sphingomyelins with saturated fatty acids of different lengths with SCD risk.

RESULTS: Among the 4612 CHS participants included in the analysis (mean [SD] age, 77 [5] years; 2724 [59.1%] women; 6 [0.1%] American Indian; 4 [0.1%] Asian; 718 [15.6%] Black; 3869 [83.9%] White, and 15 [0.3%] Other), 215 SCD cases were identified. In adjusted Cox proportional hazards regression analyses, plasma ceramides and sphingomyelins with palmitic acid (Cer-16 and SM-16) were associated with higher SCD risk per higher SD of log sphingolipid levels (hazard ratio [HR] for Cer-16, 1.34 [95% CI, 1.12-1.59]; HR for SM-16, 1.37 [95% CI, 1.12-1.67]). Associations did not differ by baseline age, sex, race, or body mass index. No significant association of SCD with sphingolipids with very-long-chain saturated fatty acids was observed after correction for multiple testing (HR for ceramide with arachidic acid, 1.06 [95% CI, 0.90-1.24]; HR for ceramide with behenic acid, 0.92 [95% CI, 0.77-1.10]; HR for ceramide with lignoceric acid, 0.92 [95% CI, 0.77-1.09]; HR for sphingomyelin with arachidic acid, 0.83 [95% CI, 0.71-0.98]; HR for sphingomyelin with behenic acid, 0.84 [95% CI, 0.70-1.00]; HR for sphingomyelin with lignoceric acid, 0.86 [95% CI, 0.72-1.03]).

CONCLUSIONS AND RELEVANCE: The findings of this large, population-based cohort study of SCD identified that higher plasma levels of Cer-16 and SM-16 were associated with higher risk of SCD. Future studies are needed to examine the underlying mechanism of these associations.

10aAged10aCeramides10aCohort Studies10aDeath, Sudden, Cardiac10aEicosanoic Acids10aFatty Acids10aFemale10aHumans10aMale10aSphingolipids10aSphingomyelins1 aBockus, Lee, B1 aJensen, Paul, N1 aFretts, Amanda, M1 aHoofnagle, Andrew, N1 aMcKnight, Barbara1 aSitlani, Colleen, M1 aSiscovick, David, S1 aKing, Irena, B1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/953302360nas a2200229 4500008004100000022001400041245008300055210006900138260001300207490000600220520167200226100002001898700002001918700002001938700002501958700002101983700002002004700002402024700002202048700002402070856003602094 2023 eng d a2312-054100aPlasma sphingolipids, lung function and COPD: the Cardiovascular Health Study.0 aPlasma sphingolipids lung function and COPD the Cardiovascular H c2023 Mar0 v93 a

RATIONALE: COPD is the third leading cause of death in the United States. Sphingolipids, structural membrane constituents that play a role in cellular stress and apoptosis signalling, may be involved in lung function.

METHODS: In the Cardiovascular Health Study, a prospective cohort of older adults, we cross-sectionally examined the association of plasma levels of 17 sphingolipid species with lung function and COPD. Multivariable linear regression and logistic regression were used to evaluate associations of sphingolipid concentrations with forced expiratory volume in 1 s (FEV) and odds of COPD, respectively.

RESULTS: Of the 17 sphingolipids evaluated, ceramide-18 (Cer-18) and sphingomyelin-18 (SM-18) were associated with lower FEV values (-0.061 L per two-fold higher Cer-18, p=0.001; -0.092 L per two-fold higher SM-18, p=0.002) after correction for multiple testing. Several other associations were significant at a 0.05 level, but did not reach statistical significance after correction for multiple testing. Specifically, Cer-18 and SM-18 were associated with higher odds of COPD (odds ratio per two-fold higher Cer-18 1.29, p=0.03 and SM-18 1.73, p=0.008). Additionally, Cer-16 and SM-16 were associated with lower FEV values, and Cer-14, SM-14 and SM-16 with a higher odds of COPD.

CONCLUSION: In this large cross-sectional study, specific ceramides and sphingomyelins were associated with reduced lung function in a population-based study. Future studies are needed to examine whether these biomarkers are associated with longitudinal change in FEV within individuals or with incident COPD.

1 aGharib, Arya, R1 aJensen, Paul, N1 aPsaty, Bruce, M1 aHoofnagle, Andrew, N1 aSiscovick, David1 aGharib, Sina, A1 aSitlani, Colleen, M1 aSotoodehnia, Nona1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/933002440nas a2200205 4500008004100000022001400041245008800055210006900143260001600212520181400228100001902042700001602061700002302077700002502100700002002125700001802145700001602163700001902179856003602198 2024 eng d a2055-582200aIron Deficiency and Incident Heart Failure in Older Community-Dwelling Individuals.0 aIron Deficiency and Incident Heart Failure in Older CommunityDwe c2024 Feb 263 a

AIMS: Among persons with prevalent heart failure (HF), iron deficiency has been linked to HF admissions, and intravenous iron replacement improves HF outcomes. Recent studies in persons with chronic kidney disease (CKD) demonstrate that iron deficiency is associated with incident HF. This study aimed to determine the relationship of iron status with incident HF in community-dwelling older adults irrespective of their kidney function.

METHODS: In this case-cohort study, 1,006 Cardiovascular Health Study participants (785 from the random sub-cohort [including 193 HF cases] and 221 additional HF cases [N = 414 total HF cases]) aged ≥ 65 years without HF (41% with CKD), we used weighted Cox models to evaluate associations of iron status with incident HF. Participants were categorized based on quartiles of transferrin saturation and ferritin as "iron replete" (27.3%), "functional iron deficiency" (7.7%), "iron deficiency" (11.8%), "mixed iron deficiency" (5.6%), "high iron" (9.3%) and "non-classified" (38.1%), consistent with prior studies.

RESULTS: Compared to older persons who were iron replete, those with iron deficiency were at higher risk of incident HF (HR 1.47; 1.02-2.11) in models adjusting for demographics, HF risk factors, and estimated glomerular filtration rate. Other iron categories did not associate with incident HF. The relationship of iron deficiency with incident HF did not differ by CKD status (interaction P value 0.2).

CONCLUSIONS: Among community-dwelling elders, iron deficiency is independently associated with incident HF, an association that was similar irrespective of CKD status. Our findings support conduct of clinical trials of iron replacement for prevention of HF in older adults with iron deficiency.

1 aSharma, Shilpa1 aKatz, Ronit1 aChaves, Paulo, H M1 aHoofnagle, Andrew, N1 aKizer, Jorge, R1 aBansal, Nisha1 aGanz, Tomas1 aIx, Joachim, H uhttps://chs-nhlbi.org/node/9615