@article {5852, title = {Racial differences in the incidence of and risk factors for atrial fibrillation in older adults: the cardiovascular health study.}, journal = {J Am Geriatr Soc}, volume = {61}, year = {2013}, month = {2013 Feb}, pages = {276-80}, abstract = {

This study examined whether different associations between risk factors and atrial fibrillation (AF) according to race could explain the lower incidence of AF in blacks. Baseline risk factor information was obtained from interviews, clinical examinations, and echocardiography in 4,774 white and 911 black Cardiovascular Health Study participants aged 65 and older without a history of AF at baseline in 1989/90 or 1992/93. Incident AF was determined according to hospital discharge diagnosis or annual study electrocardiogram. Cox regression was used to assess associations between risk factors and race and incident AF. During a mean 11.2 years of follow-up, 1,403 whites and 182 blacks had incident AF. Associations between all examined risk factors were similar in both races, except left ventricular posterior wall thickness, which was more strongly associated with AF in blacks (per 0.2 cm, blacks: hazard ratio (HR) = 1.72, 95\% confidence interval (CI) = 1.44-2.06; whites: HR = 1.30, 95\% CI = 1.18-1.43). Overall, the relative risk of AF was 25\% lower in blacks than whites after adjustment for age and sex (HR = 0.75, 95\% CI = 0.64-0.87) and 45\% lower after adjustment for all considered risk factors (HR = 0.55, 95\% CI = 0.35-0.88). Different associations of the considered risk factors and incident AF by race do not explain the lower incidence of AF in blacks.

}, keywords = {Aged, Atrial Fibrillation, Continental Population Groups, Female, Follow-Up Studies, Humans, Incidence, Male, Prevalence, Risk Assessment, Risk Factors, Stroke, United States}, issn = {1532-5415}, doi = {10.1111/jgs.12085}, author = {Jensen, Paul N and Thacker, Evan L and Dublin, Sascha and Psaty, Bruce M and Heckbert, Susan R} } @article {6543, title = {Association of sick sinus syndrome with incident cardiovascular disease and mortality: the Atherosclerosis Risk in Communities study and Cardiovascular Health Study.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e109662}, abstract = {

BACKGROUND: Sick sinus syndrome (SSS) is a common indication for pacemaker implantation. Limited information exists on the association of sick sinus syndrome (SSS) with mortality and cardiovascular disease (CVD) in the general population.

METHODS: We studied 19,893 men and women age 45 and older in the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS), two community-based cohorts, who were without a pacemaker or atrial fibrillation (AF) at baseline. Incident SSS cases were validated by review of medical charts. Incident CVD and mortality were ascertained using standardized protocols. Multivariable Cox models were used to estimate the association of incident SSS with selected outcomes.

RESULTS: During a mean follow-up of 17 years, 213 incident SSS events were identified and validated (incidence, 0.6 events per 1,000 person-years). After adjustment for confounders, SSS incidence was associated with increased mortality (hazard ratio [HR] 1.39, 95\% confidence interval [CI] 1.14-1.70), coronary heart disease (HR 1.72, 95\%CI 1.11-2.66), heart failure (HR 2.87, 95\%CI 2.17-3.80), stroke (HR 1.56, 95\%CI 0.99-2.46), AF (HR 5.75, 95\%CI 4.43-7.46), and pacemaker implantation (HR 53.7, 95\%CI 42.9-67.2). After additional adjustment for other incident CVD during follow-up, SSS was no longer associated with increased mortality, coronary heart disease, or stroke, but remained associated with higher risk of heart failure (HR 2.00, 95\%CI 1.51-2.66), AF (HR 4.25, 95\%CI 3.28-5.51), and pacemaker implantation (HR 25.2, 95\%CI 19.8-32.1).

CONCLUSION: Individuals who develop SSS are at increased risk of death and CVD. The mechanisms underlying these associations warrant further investigation.

}, keywords = {Age Distribution, Atherosclerosis, Cohort Studies, Continental Population Groups, Female, Humans, Incidence, Male, Middle Aged, Residence Characteristics, Risk, Sex Distribution, Sick Sinus Syndrome}, issn = {1932-6203}, doi = {10.1371/journal.pone.0109662}, author = {Alonso, Alvaro and Jensen, Paul N and Lopez, Faye L and Chen, Lin Y and Psaty, Bruce M and Folsom, Aaron R and Heckbert, Susan R} } @article {6572, title = {Incidence of and risk factors for sick sinus~syndrome in the general population.}, journal = {J Am Coll Cardiol}, volume = {64}, year = {2014}, month = {2014 Aug 12}, pages = {531-8}, abstract = {

BACKGROUND: Little is known about the incidence of and risk factors for sick sinus syndrome (SSS), a common indication for pacemaker implantation.

OBJECTIVES: This study sought to describe the epidemiology of SSS.

METHODS: This analysis included 20,572 participants (mean baseline age 59 years, 43\% male) in the ARIC (Atherosclerosis Risk In Communities) study and the CHS (Cardiovascular Health Study), who at baseline were free of prevalent atrial fibrillation and pacemaker therapy, had a heart rate of >= 50 beats/min unless using beta blockers, and were identified as of white or black race. Incident SSS cases were identified by hospital discharge International Classification of Disease-revision 9-Clinical Modification code 427.81 and validated by medical record review.

RESULTS: During an average 17 years of follow-up, 291 incident SSS cases were identified (unadjusted rate 0.8 per 1,000 person-years). Incidence increased with age (hazard ratio [HR]: 1.73; 95\% confidence interval [CI]: 1.47 to 2.05 per 5-year increment), and blacks had a 41\% lower risk of SSS than whites (HR: 0.59; 95\% CI: 0.37 to 0.98). Incident SSS was associated with greater baseline body mass index, height, N-terminal pro-B-type natriuretic peptide, and cystatin C, with longer QRS interval, with lower heart rate, and with prevalent hypertension, right bundle branch block, and cardiovascular disease. We project that the annual number of new SSS cases in the United States will increase from 78,000 in 2012 to 172,000 in 2060.

CONCLUSIONS: Blacks have a lower risk of SSS than whites, and several cardiovascular risk factors were associated with incident SSS. With the aging of the population, the number of Americans with SSS will increase dramatically over the next 50 years.

}, keywords = {African Continental Ancestry Group, Aged, Aged, 80 and over, Cohort Studies, European Continental Ancestry Group, Female, Follow-Up Studies, Humans, Incidence, Male, Middle Aged, Population Surveillance, Prospective Studies, Risk Factors, Sick Sinus Syndrome}, issn = {1558-3597}, doi = {10.1016/j.jacc.2014.03.056}, author = {Jensen, Paul N and Gronroos, Noelle N and Chen, Lin Y and Folsom, Aaron R and deFilippi, Chris and Heckbert, Susan R and Alonso, Alvaro} } @article {6950, title = {Association of Smoking, Alcohol, and Obesity with Cardiovascular Death and Ischemic Stroke in Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study and Cardiovascular Health Study (CHS).}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0147065}, abstract = {

Atrial fibrillation (AF) is associated with an increased risk of ischemic stroke and cardiovascular (CV) death. Whether modifiable lifestyle risk factors are associated with these CV outcomes in AF is unknown. Among Atherosclerosis Risk in Communities (ARIC) study and Cardiovascular Health Study (CHS) participants with incident AF, we estimated the risk of composite endpoint of ischemic stroke or CV death associated with candidate modifiable risk factor (smoking, heavy alcohol consumption, or high body mass index [BMI]), and computed the C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) of incorporating each factor into the CHA2DS2-VASc. Among 1222 ARIC (mean age: 63.4) and 756 CHS (mean age: 79.1) participants with incident AF, during mean follow-up of 6.9 years and 5.7 years, there were 332 and 335 composite events respectively. Compared with never smokers, current smokers had a higher incidence of the composite endpoint in ARIC [HR: 1.65 (1.21-2.26)] but not in CHS [HR: 1.05 (0.69-1.61)]. In ARIC, the addition of current smoking did not improve risk prediction over and above the CHA2DS2-VASc. No significant associations were observed with alcohol consumption or BMI with CVD outcomes in AF patients from either cohort. Smoking is associated with an increased risk of ischemic stroke or CV death in ARIC, which comprised mostly middle-aged to young-old (65-74 years), but not in CHS, which comprised mostly middle-old or oldest-old (>=75 years) adults with AF. However, addition of smoking to the CHA2DS2-VASc score did not improve risk prediction of these outcomes.

}, keywords = {Aged, Alcohol Drinking, Atrial Fibrillation, Cardiovascular Diseases, Female, Humans, Male, Middle Aged, Obesity, Smoking, Stroke}, issn = {1932-6203}, doi = {10.1371/journal.pone.0147065}, author = {Kwon, Younghoon and Norby, Faye L and Jensen, Paul N and Agarwal, Sunil K and Soliman, Elsayed Z and Lip, Gregory Y H and Longstreth, W T and Alonso, Alvaro and Heckbert, Susan R and Chen, Lin Y} } @article {7518, title = {Galectin-3 and Venous Thromboembolism Incidence: the Atherosclerosis Risk in Communities (ARIC) Study.}, journal = {Res Pract Thromb Haemost}, volume = {1}, year = {2017}, month = {2017 Oct}, pages = {223-230}, abstract = {

Background: The inflammatory biomarker galectin-3 contributes to pathologic conditions such as heart failure and stimulates murine thrombogenesis. Its association with venous thromboembolism (VTE) has been sparsely studied.

Objectives: To assess the prospective association of plasma galectin-3 and the LGALS3 rs4644 SNP with VTE incidence.

Methods: We measured plasma galectin-3 in 9,916 participants in the Atherosclerosis Risk in Communities (ARIC) study cohort in 1996 - 1998 and identified VTEs through 2013. Using Cox regression, we estimated the hazard ratio associating galectin-3 with incident VTE over a median of 13.9 years. Replication was sought in the Cardiovascular Health Study (CHS).

Results: ARIC included 21.8\% blacks and 56.2\% females with mean baseline age of 62.7 years. The incidence rate of VTE (n=389 events) increased across quintiles of galectin-3, with hazard ratios (95\% CI) of 1 (reference), 1.13 (0.80 - 1.61), 1.00 (0.70 - 1.43), 1.36 (0.96 - 1.91), and 1.55 (1.09 - 2.19) (p-trend = 0.005), adjusted for age, sex, race, body mass index, diabetes status, and renal function. Results did not replicate in the CHS (124 VTE), but meta-analysis of both studies yielded a pooled hazard ratio (95\% CI) for 1 SD increment in log galectin-3 of 1.10 (1.00 - 1.22). In ARIC, the C allele of rs4644 in the LGALS3 gene was associated with higher galectin-3 level, and in whites, with an increased rate of VTE.

Conclusion: Galectin-3 levels were associated positively with VTE incidence.

}, issn = {2475-0379}, doi = {10.1002/rth2.12038}, author = {Fashanu, Oluwaseun E and Heckbert, Susan R and Aguilar, David and Jensen, Paul N and Ballantyne, Christie M and Basu, Saonli and Hoogeveen, Ron C and DeFilippi, Christopher and Cushman, Mary and Folsom, Aaron R} } @article {8105, title = {Plasma Ceramides and Sphingomyelins in Relation to Heart Failure Risk.}, journal = {Circ Heart Fail}, volume = {12}, year = {2019}, month = {2019 Jul}, pages = {e005708}, abstract = {

BACKGROUND: Ceramides exhibit multiple biological activities that may influence the pathophysiology of heart failure. These activities may be influenced by the saturated fatty acid carried by the ceramide (Cer). However, the associations of different circulating Cer species, and their sphingomyelin (SM) precursors, with heart failure have received limited attention.

METHODS AND RESULTS: We studied the associations of plasma Cer and SM species with incident heart failure in the Cardiovascular Health Study. We examined 8 species: Cer and SM with palmitic acid (Cer-16 and SM-16), species with arachidic acid (Cer-20 and SM-20), species with behenic acid (Cer-22 and SM-22), and species with lignoceric acid (Cer-24 and SM-24). During a median follow-up of 9.4 years, we identified 1179 cases of incident heart failure among 4249 study participants. In Cox regression analyses adjusted for risk factors, higher levels of Cer-16 and SM-16 were associated with higher risk of incident heart failure (hazard ratio for one SD increase:1.25 [95\% CI, 1.16-1.36] and 1.28 [1.18-1.40], respectively). In contrast, higher levels of Cer-22 were associated with lower risk of heart failure in multivariable analyses further adjusted for Cer-16 (hazard ratio, 0.85 [0.78-0.92]); and higher levels of SM-20, SM-22 and SM-24 were associated with lower risk of heart failure in analyses further adjusted for SM-16 (hazard ratios, 0.83 [0.77-0.90], 0.81 [0.75-0.88], and 0.83 [0.77-0.90], respectively). No statistically significant interactions with age, sex, black race, body mass index, or baseline coronary heart disease were detected. Similar associations were observed for heart failure with preserved (n=529) or reduced (n=348) ejection fraction.

CONCLUSIONS: This study shows associations of higher plasma levels of Cer-16 and SM-16 with increased risk of heart failure and higher levels of Cer-22, SM-20, SM-22, and SM-24 with decreased risk of heart failure.

CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00005133.

}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.118.005708}, author = {Lemaitre, Rozenn N and Jensen, Paul N and Hoofnagle, Andrew and McKnight, Barbara and Fretts, Amanda M and King, Irena B and Siscovick, David S and Psaty, Bruce M and Heckbert, Susan R and Mozaffarian, Dariush and Sotoodehnia, Nona} } @article {8284, title = {Plasma Ceramides and Sphingomyelins in Relation to Atrial Fibrillation Risk: The Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {9}, year = {2020}, month = {2020 Feb 18}, pages = {e012853}, abstract = {

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.

}, issn = {2047-9980}, doi = {10.1161/JAHA.119.012853}, author = {Jensen, Paul N and Fretts, Amanda M and Hoofnagle, Andrew N and Sitlani, Colleen M and McKnight, Barbara and King, Irena B and Siscovick, David S and Psaty, Bruce M and Heckbert, Susan R and Mozaffarian, Dariush and Sotoodehnia, Nona and Lemaitre, Rozenn N} } @article {8922, title = {Association of Trimethylamine N-Oxide and Related Metabolites in Plasma and Incident Type 2 Diabetes: The Cardiovascular Health Study.}, journal = {JAMA Netw Open}, volume = {4}, year = {2021}, month = {2021 Aug 02}, pages = {e2122844}, abstract = {

Importance: Although rodent studies suggest that trimethylamine N-oxide (TMAO) influences glucose homeostasis and risk of type 2 diabetes, evidence in humans is limited.

Objective: To examine the associations of serial measures of plasma TMAO and related metabolite concentrations with incident type 2 diabetes, fasting plasma insulin and glucose levels, and the Gutt insulin sensitivity index (ISI).

Design, Setting, and Participants: This prospective cohort design assessed the association of plasma TMAO and related metabolite concentrations with diabetes outcome, whereas a cross-sectional design assessed the association with insulin and glucose levels and Gutt ISI. The participants were a cohort of older US adults from the Cardiovascular Health Study (CHS). Data from June 1989 to May 1990, from November 1992 to June 1993, and from June 1995 to June 1997 were included, with follow-up through June 2010. Levels of TMAO and related metabolites were measured in CHS plasma samples. Data were analyzed from July 2019 to September 2020.

Exposures: Plasma concentrations of TMAO, carnitine, betaine, choline, crotonobetaine, and γ-butyrobetaine, measured by high-performance liquid chromatography and mass spectrometry.

Main Outcomes and Measures: Linear regression for associations of TMAO and related metabolites with insulin and glucose levels and Gutt ISI, and proportional hazards regression for associations with diabetes.

Results: The study included 4442 participants without diabetes at baseline (mean [SD] age, 73 [6] years at entry; 2710 [61\%] women). In multivariable analyses, plasma TMAO, carnitine, crotonobetaine, and γ-butyrobetaine concentrations were positively associated with fasting insulin level (insulin mean geometric ratio comparing fifth with first quintiles of metabolite concentration: 1.07 [95\% CI, 1.04-1.10] for TMAO; 1.07 [95\% CI, 1.03-1.10] for carnitine; 1.05 [95\% CI, 1.02-1.08] for crotonobetaine; and 1.06 [95\% CI, 1.02-1.09] for γ-butyrobetaine). In contrast, betaine and choline concentrations were associated with greater insulin sensitivity (mean difference in Gutt ISI comparing fifth with first quintiles: 6.46 [95\% CI, 4.32-8.60] and 2.27 [95\% CI, 0.16-4.38], respectively). Incident diabetes was identified in 661 participants during a median 12.1 (interquartile range, 6.9-17.1) years of follow-up. In multivariable analyses, TMAO and metabolites were not significantly associated with type 2 diabetes risk (hazard ratios of diabetes comparing fifth with first quintile: 1.20 [95\% CI, 0.94-1.55] for TMAO; 0.96 [95\% CI, 0.74-1.24] for choline; 0.88 [95\% CI, 0.67-1.15] for betaine; 1.07 [95\% CI, 0.83-1.37] for carnitine; 0.79 [95\% CI, 0.60-1.04] for γ-butyrobetaine; and 1.06 [95\% CI, 0.83-1.35] for crotonobetaine).

Conclusions and Relevance: Plasma TMAO and related metabolites were not significantly associated with type 2 diabetes among older adults. The metabolites TMAO, carnitine, γ-butyrobetaine, and crotonobetaine may be associated with insulin resistance, and betaine and choline may be associated with greater insulin sensitivity, but temporality of the associations was not established.

}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2021.22844}, author = {Lemaitre, Rozenn N and Jensen, Paul N and Wang, Zeneng and Fretts, Amanda M and McKnight, Barbara and Nemet, Ina and Biggs, Mary L and Sotoodehnia, Nona and de Oliveira Otto, Marcia C and Psaty, Bruce M and Siscovick, David S and Hazen, Stanley L and Mozaffarian, Dariush} } @article {8910, title = {Circulating Ceramides and Sphingomyelins and Risk of Mortality: The Cardiovascular Health Study.}, journal = {Clin Chem}, volume = {67}, year = {2021}, month = {2021 Nov 26}, pages = {1650-1659}, abstract = {

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.

}, issn = {1530-8561}, doi = {10.1093/clinchem/hvab182}, author = {Fretts, Amanda M and Jensen, Paul N and Hoofnagle, Andrew N and McKnight, Barbara and Sitlani, Colleen M and Siscovick, David S and King, Irena B and Psaty, Bruce M and Sotoodehnia, Nona and Lemaitre, Rozenn N} } @article {8909, title = {Plasma Ceramides containing Saturated Fatty Acids are Associated with Risk of Type 2 Diabetes.}, journal = {J Lipid Res}, year = {2021}, month = {2021 Sep 20}, pages = {100119}, abstract = {

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.

}, issn = {1539-7262}, doi = {10.1016/j.jlr.2021.100119}, author = {Fretts, Amanda M and Jensen, Paul N and Hoofnagle, Andrew N and McKnight, Barbara and Howard, Barbara V and Umans, Jason and Sitlani, Colleen M and Siscovick, David S and King, Irena B and Djouss{\'e}, Luc and Sotoodehnia, Nona and Lemaitre, Rozenn N} } @article {9171, title = {Plasma epoxyeicosatrienoic acids and diabetes-related cardiovascular disease: The cardiovascular health study.}, journal = {EBioMedicine}, volume = {83}, year = {2022}, month = {2022 Sep}, pages = {104189}, abstract = {

BACKGROUND: Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that may impact atherosclerosis, and animal experimental studies suggest EETs protect cardiac function. Plasma EETs are mostly esterified to phospholipids and part of an active pool. To address the limited information about EETs and CVD in humans, we conducted a prospective study of total plasma EETs (free~+~esterified) and diabetes-related CVD in the Cardiovascular Health Study (CHS).

METHODS: We measured 4 EET species and their metabolites, dihydroxyepoxyeicosatrienoic acids (DHETs), in plasma samples from 892 CHS participants with type 2 diabetes. We determined the association of EETs and DHETs with incident myocardial infarction (MI) and ischemic stroke using Cox regression.

FINDINGS: During follow-up (median 7.5 years), we identified 150 MI and 134 ischemic strokes. In primary, multivariable analyses, elevated levels of each EET species were associated with non-significant lower risk of incident MI (for example, hazard ratio for 1 SD higher 14,15-EET: 0.86, 95\% CI: 0.72-1.02; p=0.08). The EETs-MI associations became significant in analyses further adjusted for DHETs (hazard ratio for 1 SD higher 14,15-EET adjusted for 14,15-DHET: 0.76, 95\% CI: 0.63-0.91; p=0.004). Elevated EET levels were associated with higher risk of ischemic stroke in primary but not secondary analyses. Three DHET species were associated with higher risk of ischemic stroke in all analyses.

INTERPRETATION: Findings from this prospective study complement the extensive studies in animal models showing EETs protect cardiac function and provide new information in humans. Replication is needed to confirm the associations.

FUNDING: US National Institutes of Health.

}, keywords = {Animals, Arachidonic Acids, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Eicosanoids, Humans, Ischemic Stroke, Prospective Studies}, issn = {2352-3964}, doi = {10.1016/j.ebiom.2022.104189}, author = {Lemaitre, Rozenn N and Jensen, Paul N and Zeigler, Maxwell and Fretts, Amanda M and Umans, Jason G and Howard, Barbara V and Sitlani, Colleen M and McKnight, Barbara and Gharib, Sina A and King, Irena B and Siscovick, David S and Psaty, Bruce M and Sotoodehnia, Nona and Totah, Rheem A} } @article {9533, title = {Plasma Ceramides and Sphingomyelins and Sudden Cardiac Death in the Cardiovascular Health Study.}, journal = {JAMA Netw Open}, volume = {6}, year = {2023}, month = {2023 Nov 01}, pages = {e2343854}, abstract = {

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.

}, keywords = {Aged, Ceramides, Cohort Studies, Death, Sudden, Cardiac, Eicosanoic Acids, Fatty Acids, Female, Humans, Male, Sphingolipids, Sphingomyelins}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2023.43854}, author = {Bockus, Lee B and Jensen, Paul N and Fretts, Amanda M and Hoofnagle, Andrew N and McKnight, Barbara and Sitlani, Colleen M and Siscovick, David S and King, Irena B and Psaty, Bruce M and Sotoodehnia, Nona and Lemaitre, Rozenn N} } @article {9330, title = {Plasma sphingolipids, lung function and COPD: the Cardiovascular Health Study.}, journal = {ERJ Open Res}, volume = {9}, year = {2023}, month = {2023 Mar}, abstract = {

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.

}, issn = {2312-0541}, doi = {10.1183/23120541.00346-2022}, author = {Gharib, Arya R and Jensen, Paul N and Psaty, Bruce M and Hoofnagle, Andrew N and Siscovick, David and Gharib, Sina A and Sitlani, Colleen M and Sotoodehnia, Nona and Lemaitre, Rozenn N} } @article {9451, title = {Plasma Trimethylamine--Oxide and Incident Ischemic Stroke: The Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis.}, journal = {J Am Heart Assoc}, volume = {12}, year = {2023}, month = {2023 Aug 15}, pages = {e8711}, abstract = {

Background The association of circulating trimethylamine--oxide (TMAO) with stroke has received limited attention. To address this gap, we examined the associations of serial measures of plasma TMAO with incident ischemic stroke. Methods and Results We used a prospective cohort design with data pooled from 2 cohorts. The settings were the CHS (Cardiovascular Health Study), a cohort of older adults, and the MESA (Multi-Ethnic Study of Atherosclerosis), both in the United States. We measured plasma concentrations of TMAO at baseline and again during the follow-up using high-performance liquid chromatography and mass spectrometry. We assessed the association of plasma TMAO with incident ischemic stroke using proportional hazards regression adjusted for risk factors. The combined cohorts included 11 785 participants without a history of stroke, on average 73 (CHS) and 62 (MESA) years old at baseline, including 60\% (CHS) and 53\% (MESA) women. We identified 1031 total incident ischemic strokes during a median 15-year follow-up in the combined cohorts. In multivariable analyses, TMAO was significantly associated with incident ischemic stroke risk (hazard ratios comparing a doubling of TMAO: 1.11 [1.03-1.18], =0.004). The association was linear over the range of TMAO concentrations and appeared restricted to those without diagnosed coronary heart disease. An association with hemorrhagic stroke was not found. Conclusions Plasma TMAO levels are associated with incident ischemic stroke in a diverse population. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00005133.

}, keywords = {Aged, Atherosclerosis, Female, Humans, Ischemic Stroke, Methylamines, Oxides, Prospective Studies, Risk Factors, Stroke, United States}, issn = {2047-9980}, doi = {10.1161/JAHA.122.029230}, author = {Lemaitre, Rozenn N and Jensen, Paul N and Wang, Zeneng and Fretts, Amanda M and Sitlani, Colleen M and Nemet, Ina and Sotoodehnia, Nona and de Oliveira Otto, Marcia C and Zhu, Weifei and Budoff, Matt and Longstreth, W T and Psaty, Bruce M and Siscovick, David S and Hazen, Stanley L and Mozaffarian, Dariush} } @article {9747, title = {Trimethylamine -Oxide and Related Gut Microbe-Derived Metabolites and Incident Heart Failure Development in Community-Based Populations.}, journal = {Circ Heart Fail}, volume = {17}, year = {2024}, month = {2024 Aug}, pages = {e011569}, abstract = {

BACKGROUND: Growing evidence indicates that trimethylamine -oxide, a gut microbial metabolite of dietary choline and carnitine, promotes both cardiovascular disease and chronic kidney disease risk. It remains unclear how circulating concentrations of trimethylamine -oxide and its related dietary and gut microbe-derived metabolites (choline, betaine, carnitine, γ-butyrobetaine, and crotonobetaine) affect incident heart failure (HF).

METHODS: We evaluated 11 768 participants from the Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis with serial measures of metabolites. Cox proportional hazard models were used to examine the associations between metabolites and incident HF, adjusted for cardiovascular disease risk factors.

RESULTS: In all, 2102 cases of HF occurred over a median follow-up of 15.9 years. After adjusting for traditional risk factors, higher concentrations of trimethylamine -oxide (hazard ratio, 1.15 [95\% CI, 1.09-1.20]; <0.001), choline (hazard ratio, 1.44 [95\% CI, 1.26-1.64]; <0.001), and crotonobetaine (hazard ratio, 1.24 [95\% CI, 1.16-1.32]; <0.001) were associated with increased risk for incident HF. After further adjustment for renal function (potential confounder or mediator), these associations did not reach Bonferroni-corrected statistical significance (=0.01, 0.049, and 0.006, respectively). Betaine and carnitine were nominally associated with a higher incidence of HF (<0.05). In exploratory analyses, results were similar for subtypes of HF based on left ventricular ejection fraction, and associations appeared generally stronger among Black and Hispanic/Latino versus White adults, although there were no interactions for any metabolites with race.

CONCLUSIONS: In this pooled analysis of 2 well-phenotyped, diverse, community-based cohorts, circulating concentrations of gut microbe-derived metabolites such as trimethylamine -oxide, choline, and crotonobetaine were independently associated with a higher risk of developing HF.

REGISTRATION: URL: https://www.clinicaltrials.gov/; Unique identifiers: NCT00005133 and NCT00005487.

}, keywords = {Aged, Aged, 80 and over, Betaine, Biomarkers, Carnitine, Choline, Female, Gastrointestinal Microbiome, Heart Failure, Humans, Incidence, Male, Methylamines, Middle Aged, Risk Factors, United States}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.124.011569}, author = {Tang, W H Wilson and Lemaitre, Rozenn N and Jensen, Paul N and Wang, Meng and Wang, Zeneng and Li, Xinmin S and Nemet, Ina and Lee, Yujin and Lai, Heidi T M and de Oliveira Otto, Marcia C and Fretts, Amanda M and Sotoodehnia, Nona and DiDonato, Joseph A and B{\"a}ckhed, Fredrik and Psaty, Bruce M and Siscovick, David S and Budoff, Matthew J and Mozaffarian, Dariush and Hazen, Stanley L} }