%0 Journal Article %J J Clin Endocrinol Metab %D 2011 %T Mineral metabolism markers and the long-term risk of hip fracture: the cardiovascular health study. %A Robinson-Cohen, Cassianne %A Katz, Ronit %A Hoofnagle, Andrew N %A Cauley, Jane A %A Furberg, Curt D %A Robbins, John A %A Chen, Zhao %A Siscovick, David S %A de Boer, Ian H %A Kestenbaum, Bryan %K Aged %K Aged, 80 and over %K Alkaline Phosphatase %K Biomarkers %K Bone Density %K Female %K Hip Fractures %K Humans %K Male %K Parathyroid Hormone %K Risk %K Vitamin D %X

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.

%B J Clin Endocrinol Metab %V 96 %P 2186-93 %8 2011 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/21508146?dopt=Abstract %R 10.1210/jc.2010-2878 %0 Journal Article %J Am J Epidemiol %D 2011 %T Seasonal variation in 25-hydroxyvitamin D concentrations in the cardiovascular health study. %A Shoben, Abigail B %A Kestenbaum, Bryan %A Levin, Gregory %A Hoofnagle, Andrew N %A Psaty, Bruce M %A Siscovick, David S %A de Boer, Ian H %K Aged %K Biomarkers %K Continental Population Groups %K Exercise %K Female %K Humans %K Male %K Residence Characteristics %K Seasons %K Sex Factors %K Vitamin D %X

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.

%B Am J Epidemiol %V 174 %P 1363-72 %8 2011 Dec 15 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/22112344?dopt=Abstract %R 10.1093/aje/kwr258 %0 Journal Article %J Am J Kidney Dis %D 2014 %T Estimated GFR and circulating 24,25-dihydroxyvitamin D3 concentration: a participant-level analysis of 5 cohort studies and clinical trials. %A de Boer, Ian H %A Sachs, Michael C %A Chonchol, Michel %A Himmelfarb, Jonathan %A Hoofnagle, Andrew N %A Ix, Joachim H %A Kremsdorf, Robin A %A Lin, Yvonne S %A Mehrotra, Rajnish %A Robinson-Cohen, Cassianne %A Siscovick, David S %A Steffes, Michael W %A Thummel, Kenneth E %A Tracy, Russell P %A Wang, Zhican %A Kestenbaum, Bryan %K 24,25-Dihydroxyvitamin D 3 %K Adult %K Aged %K Aged, 80 and over %K Biomarkers %K Cohort Studies %K Cross-Sectional Studies %K Diabetes Mellitus %K Female %K Glomerular Filtration Rate %K Humans %K Kidney Failure, Chronic %K Male %K Middle Aged %K Observational Studies as Topic %K Randomized Controlled Trials as Topic %K Young Adult %X

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.

%B Am J Kidney Dis %V 64 %P 187-97 %8 2014 Aug %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24703961?dopt=Abstract %R 10.1053/j.ajkd.2014.02.015 %0 Journal Article %J Circulation %D 2014 %T Fibroblast growth factor-23 and incident atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS). %A Mathew, Jehu S %A Sachs, Michael C %A Katz, Ronit %A Patton, Kristen K %A Heckbert, Susan R %A Hoofnagle, Andrew N %A Alonso, Alvaro %A Chonchol, Michel %A Deo, Rajat %A Ix, Joachim H %A Siscovick, David S %A Kestenbaum, Bryan %A de Boer, Ian H %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Comorbidity %K Ethnic Groups %K Female %K Fibroblast Growth Factor 3 %K Follow-Up Studies %K Glomerular Filtration Rate %K Heart Failure %K Humans %K Hypertrophy, Left Ventricular %K Male %K Middle Aged %K Phosphates %K Proportional Hazards Models %K Renal Insufficiency, Chronic %K Risk Factors %K United States %K Ventricular Dysfunction, Left %K Ventricular Remodeling %K Vitamin D %X

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.

%B Circulation %V 130 %P 298-307 %8 2014 Jul 22 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24920722?dopt=Abstract %R 10.1161/CIRCULATIONAHA.113.005499 %0 Journal Article %J J Am Geriatr Soc %D 2016 %T Fibroblast Growth Factor-23 and Frailty in Elderly Community-Dwelling Individuals: The Cardiovascular Health Study. %A Beben, Tomasz %A Ix, Joachim H %A Shlipak, Michael G %A Sarnak, Mark J %A Fried, Linda F %A Hoofnagle, Andrew N %A Chonchol, Michel %A Kestenbaum, Bryan R %A de Boer, Ian H %A Rifkin, Dena E %K Aged %K Anthropometry %K Biomarkers %K Cardiovascular Diseases %K Cross-Sectional Studies %K Enzyme-Linked Immunosorbent Assay %K Female %K Fibroblast Growth Factors %K Frail Elderly %K Glomerular Filtration Rate %K Humans %K Independent Living %K Longitudinal Studies %K Male %K Phenotype %K Risk Factors %K Surveys and Questionnaires %X

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.

%B J Am Geriatr Soc %V 64 %P 270-6 %8 2016 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26889836?dopt=Abstract %R 10.1111/jgs.13951 %0 Journal Article %J Clin J Am Soc Nephrol %D 2017 %T The Relation of Serum Potassium Concentration with Cardiovascular Events and Mortality in Community-Living Individuals. %A Hughes-Austin, Jan M %A Rifkin, Dena E %A Beben, Tomasz %A Katz, Ronit %A Sarnak, Mark J %A Deo, Rajat %A Hoofnagle, Andrew N %A Homma, Shunichi %A Siscovick, David S %A Sotoodehnia, Nona %A Psaty, Bruce M %A de Boer, Ian H %A Kestenbaum, Bryan %A Shlipak, Michael G %A Ix, Joachim H %X

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.

%B Clin J Am Soc Nephrol %V 12 %P 245-252 %8 2017 Feb 07 %G eng %N 2 %R 10.2215/CJN.06290616 %0 Journal Article %J Bone %D 2018 %T The 24,25 to 25-hydroxyvitamin D ratio and fracture risk in older adults: The cardiovascular health study. %A Ginsberg, Charles %A Katz, Ronit %A de Boer, Ian H %A Kestenbaum, Bryan R %A Chonchol, Michel %A Shlipak, Michael G %A Sarnak, Mark J %A Hoofnagle, Andrew N %A Rifkin, Dena E %A Garimella, Pranav S %A Ix, Joachim H %X

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.

%B Bone %V 107 %P 124-130 %8 2018 Feb %G eng %R 10.1016/j.bone.2017.11.011 %0 Journal Article %J J Am Heart Assoc %D 2020 %T Plasma Ceramides and Sphingomyelins in Relation to Atrial Fibrillation Risk: The Cardiovascular Health Study. %A Jensen, Paul N %A Fretts, Amanda M %A Hoofnagle, Andrew N %A Sitlani, Colleen M %A McKnight, Barbara %A King, Irena B %A Siscovick, David S %A Psaty, Bruce M %A Heckbert, Susan R %A Mozaffarian, Dariush %A Sotoodehnia, Nona %A Lemaitre, Rozenn N %X

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.

%B J Am Heart Assoc %V 9 %P e012853 %8 2020 Feb 18 %G eng %N 4 %R 10.1161/JAHA.119.012853 %0 Journal Article %J Clin Chem %D 2021 %T Circulating Ceramides and Sphingomyelins and Risk of Mortality: The Cardiovascular Health Study. %A Fretts, Amanda M %A Jensen, Paul N %A Hoofnagle, Andrew N %A McKnight, Barbara %A Sitlani, Colleen M %A Siscovick, David S %A King, Irena B %A Psaty, Bruce M %A Sotoodehnia, Nona %A Lemaitre, Rozenn N %X

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.

%B Clin Chem %V 67 %P 1650-1659 %8 2021 Nov 26 %G eng %N 12 %R 10.1093/clinchem/hvab182 %0 Journal Article %J J Lipid Res %D 2021 %T Plasma Ceramides containing Saturated Fatty Acids are Associated with Risk of Type 2 Diabetes. %A Fretts, Amanda M %A Jensen, Paul N %A Hoofnagle, Andrew N %A McKnight, Barbara %A Howard, Barbara V %A Umans, Jason %A Sitlani, Colleen M %A Siscovick, David S %A King, Irena B %A Djoussé, Luc %A Sotoodehnia, Nona %A Lemaitre, Rozenn N %X

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.

%B J Lipid Res %P 100119 %8 2021 Sep 20 %G eng %R 10.1016/j.jlr.2021.100119 %0 Journal Article %J EBioMedicine %D 2023 %T Evaluation of plasma sphingolipids as mediators of the relationship between kidney disease and cardiovascular events. %A Lidgard, Benjamin %A Bansal, Nisha %A Zelnick, Leila R %A Hoofnagle, Andrew N %A Fretts, Amanda M %A Longstreth, William T %A Shlipak, Michael G %A Siscovick, David S %A Umans, Jason G %A Lemaitre, Rozenn N %X

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).

%B EBioMedicine %V 95 %P 104765 %8 2023 Aug 24 %G eng %R 10.1016/j.ebiom.2023.104765 %0 Journal Article %J JAMA Netw Open %D 2023 %T Plasma Ceramides and Sphingomyelins and Sudden Cardiac Death in the Cardiovascular Health Study. %A Bockus, Lee B %A Jensen, Paul N %A Fretts, Amanda M %A Hoofnagle, Andrew N %A McKnight, Barbara %A Sitlani, Colleen M %A Siscovick, David S %A King, Irena B %A Psaty, Bruce M %A Sotoodehnia, Nona %A Lemaitre, Rozenn N %K Aged %K Ceramides %K Cohort Studies %K Death, Sudden, Cardiac %K Eicosanoic Acids %K Fatty Acids %K Female %K Humans %K Male %K Sphingolipids %K Sphingomyelins %X

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.

%B JAMA Netw Open %V 6 %P e2343854 %8 2023 Nov 01 %G eng %N 11 %R 10.1001/jamanetworkopen.2023.43854 %0 Journal Article %J ERJ Open Res %D 2023 %T Plasma sphingolipids, lung function and COPD: the Cardiovascular Health Study. %A Gharib, Arya R %A Jensen, Paul N %A Psaty, Bruce M %A Hoofnagle, Andrew N %A Siscovick, David %A Gharib, Sina A %A Sitlani, Colleen M %A Sotoodehnia, Nona %A Lemaitre, Rozenn N %X

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.

%B ERJ Open Res %V 9 %8 2023 Mar %G eng %N 2 %R 10.1183/23120541.00346-2022 %0 Journal Article %J ESC Heart Fail %D 2024 %T Iron Deficiency and Incident Heart Failure in Older Community-Dwelling Individuals. %A Sharma, Shilpa %A Katz, Ronit %A Chaves, Paulo H M %A Hoofnagle, Andrew N %A Kizer, Jorge R %A Bansal, Nisha %A Ganz, Tomas %A Ix, Joachim H %X

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.

%B ESC Heart Fail %8 2024 Feb 26 %G eng %R 10.1002/ehf2.14724