David S Siscovick

New York Academy of Medicine, New York City, New York, United States

Are you David S Siscovick?

Claim your profile

Publications (617)5617.45 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with greater risk of cardiovascular events and mortality, especially among people with chronic kidney disease (CKD). Because individuals with CKD are at an increased risk of sudden cardiac death (SCD), we sought to understand whether FGF-23 level is a stronger risk factor for SCD versus non-SCD. Cohort study. 3,244 participants 65 years or older in the community-based Cardiovascular Health Study. Plasma FGF-23 concentrations. We assessed SCD and non-SCD in these analyses. SCD was adjudicated rigorously and was defined as a sudden pulseless condition of cardiac origin in a previously stable person occurring out of hospital or in the emergency department. We estimated associations of baseline FGF-23 concentrations with SCD and non-SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, comorbid conditions, and kidney function. We also tested whether associations differed by CKD status. During a median follow-up of 8.1 years, there were 118 adjudicated SCD and 570 non-SCD events. After multivariable adjustment for demographics, cardiovascular risk factors, comorbid conditions, and parameters of kidney function, higher FGF-23 concentrations were an independent risk factor for non-SCD (HR [per doubling], 1.17; 95% CI, 1.06-1.30). However, elevated FGF-23 concentrations were not associated independently with SCD (HR [per doubling], 1.07; 95% CI, 0.85-1.35). In stratified analysis by CKD status (36.5% of cohort), doubling of FGF-23 concentrations was associated independently with non-SCD (adjusted HR, 1.26; 95% CI, 1.10-1.45). A similar magnitude of association was observed between FGF-23 level and SCD in the CKD subgroup; however, it was not significant (HR, 1.20; 95% CI, 0.89-1.62). Limited power to detect moderate-sized effects between FGF-23 level and SCD in both the primary and stratified analyses. In this population-based study, FGF-23 level elevations were associated independently with non-SCD. Among individuals with CKD, the associations between FGF-23 level and SCD and non-SCD were similar. Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
    American journal of kidney diseases : the official journal of the National Kidney Foundation. 01/2015;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Experimental evidence suggests that hepatic de novo lipogenesis (DNL) affects insulin homeostasis via synthesis of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). Few prospective studies have used fatty acid biomarkers to assess associations with type 2 diabetes.Objectives: We investigated associations of major circulating SFAs [palmitic acid (16:0) and stearic acid (18:0)] and MUFA [oleic acid (18:1n–9)] in the DNL pathway with metabolic risk factors and incident diabetes in community-based older U.S. adults in the Cardiovascular Health Study. We secondarily assessed other DNL fatty acid biomarkers [myristic acid (14:0), palmitoleic acid (16:1n–7), 7-hexadecenoic acid (16:1n–9), and vaccenic acid (18:1n–7)] and estimated dietary SFAs and MUFAs.Design: In 3004 participants free of diabetes, plasma phospholipid fatty acids were measured in 1992, and incident diabetes was identified by medication use and blood glucose. Usual diets were assessed by using repeated food-frequency questionnaires. Multivariable linear and Cox regression were used to assess associations with metabolic risk factors and incident diabetes, respectively.Results: At baseline, circulating palmitic acid and stearic acid were positively associated with adiposity, triglycerides, inflammation biomarkers, and insulin resistance (P-trend < 0.01 each), whereas oleic acid showed generally beneficial associations (P-trend < 0.001 each). During 30,763 person-years, 297 incident diabetes cases occurred. With adjustment for demographics and lifestyle, palmitic acid (extreme-quintile HR: 1.89; 95% CI: 1.27, 2.83; P-trend = 0.001) and stearic acid (HR: 1.62; 95% CI: 1.09, 2.41; P-trend = 0.006) were associated with higher diabetes risk, whereas oleic acid was not significantly associated. In secondary analyses, vaccenic acid was inversely associated with diabetes (HR: 0.56; 95% CI: 0.38, 0.83; P-trend = 0.005). Other fatty acid biomarkers and estimated dietary SFAs or MUFAs were not significantly associated with incident diabetes.Conclusions: In this large prospective cohort, circulating palmitic acid and stearic acid were associated with higher diabetes risk, and vaccenic acid was associated with lower diabetes risk. These results indicate a need for additional investigation of biological mechanisms linking specific fatty acids in the DNL pathway to the pathogenesis of diabetes. This trial was registered at clinicaltrials.gov as NCT00005133.
    American Journal of Clinical Nutrition 01/2015; · 6.50 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite advances in prevention and treatment of cardiovascular disease, sudden cardiac death (SCD) remains a clinical challenge. Risk stratification in the general population is needed. Beat-to-beat spatiotemporal variability in the T vector was measured as the mean angle between consecutive T-wave vectors (mean TT' angle) on standard 12-lead ECGs in 14 024 participants in the Atherosclerosis Risk in Communities (ARIC) study. Subjects with left ventricular hypertrophy, atrial arrhythmias, frequent ectopy, ventricular pacing, or QRS duration ≥120 ms were excluded. The mean spatial TT' angle was 5.21±3.55°. During a median of 14 years of follow-up, 235 SCDs occurred (1.24 per 1000 person-years). After adjustment for demographics, coronary heart disease risk factors, and known ECG markers for SCD, mean TT' angle was independently associated with SCD (hazard ratio 1.089; 95% CI 1.044 to 1.137; P<0.0001). A mean TT' angle >90th percentile (>9.57°) was associated with a 2-fold increase in the hazard for SCD (hazard ratio 2.01; 95% CI 1.28 to 3.16; P=0.002). In a subgroup of patients with T-vector amplitude ≥0.2 mV, the association with SCD was almost twice as strong (hazard ratio 3.92; 95% CI 1.91 to 8.05; P<0.0001). A significant interaction between mean TT' angle and age was found: TT' angle was associated with SCD in participants aged <55 years (hazard ratio 1.096; 95% CI 0.043 to 1.152; P<0.0001) but not in participants aged ≥55 years (Pinteraction=0.009). In a large, prospective, community-based cohort of left ventricular hypertrophy-free participants, increased beat-to-beat spatiotemporal variability in the T vector, as assessed by increasing TT' angle, was associated with SCD. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
    Journal of the American Heart Association. 01/2015; 4(1).
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Short sleep duration has been associated with greater risks of obesity, hypertension, diabetes, and cardiovascular disease. Also, common genetic variants in the human Circadian Locomotor Output Cycles Kaput (CLOCK) show associations with ghrelin and total energy intake. We examined associations between habitual sleep duration, body mass index (BMI), and macronutrient intake and assessed whether CLOCK variants modify these associations. We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations of sleep duration and BMI and macronutrient intake as percentages of total energy as well as interactions with CLOCK variants from 9 cohort studies including up to 14,906 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. We observed a significant association between sleep duration and lower BMI (β ± SE = 0.16 ± 0.04, P < 0.0001) in the overall sample; however, associations between sleep duration and relative macronutrient intake were evident in age- and sex-stratified analyses only. We observed a significant association between sleep duration and lower saturated fatty acid intake in younger (aged 20-64 y) adults (men: 0.11 ± 0.06%, P = 0.03; women: 0.10 ± 0.05%, P = 0.04) and with lower carbohydrate (-0.31 ± 0.12%, P < 0.01), higher total fat (0.18 ± 0.09%, P = 0.05), and higher PUFA (0.05 ± 0.02%, P = 0.02) intakes in older (aged 65-80 y) women. In addition, the following 2 nominally significant interactions were observed: between sleep duration and rs12649507 on PUFA intake and between sleep duration and rs6858749 on protein intake. Our results indicate that longer habitual sleep duration is associated with lower BMI and age- and sex-specific favorable dietary behaviors. Differences in the relative intake of specific macronutrients associated with short sleep duration could, at least in part, explain previously reported associations between short sleep duration and chronic metabolic abnormalities. In addition, the influence of obesity-associated CLOCK variants on the association between sleep duration and macronutrient intake suggests that longer habitual sleep duration could ameliorate the genetic predisposition to obesity via a favorable dietary profile. Trials related to this study were registered at clinicaltrials.gov as NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT01331512 [Invecchiare in Chianti (Aging in the Chianti Area) study], NCT00289237 (Inter99), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis). © 2015 American Society for Nutrition.
    American Journal of Clinical Nutrition 01/2015; 101(1):135-43. · 6.50 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol16. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl−1. At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase15, 17 and apolipoprotein C-III. Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.
    Nature 12/2014; advance online publication. · 42.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m(2) or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.Kidney International advance online publication, 10 December 2014; doi:10.1038/ki.2014.361.
    Kidney international. 12/2014;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
    Nature Genetics 12/2014; · 29.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Poor vitamin K status is linked to greater risk of several chronic diseases. Age, sex, and diet are determinants of circulating vitamin K; however, there is still large unexplained interindividual variability in vitamin K status. Although a strong genetic component has been hypothesized, this has yet to be examined by a genome-wide association (GWA) study. The objective was to identify common genetic variants associated with concentrations of circulating phylloquinone, the primary circulating form of vitamin K. We conducted a 2-stage GWA meta-analysis of circulating phylloquinone in 2 populations of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium Nutrition Working Group. Circulating phylloquinone was measured by using reversed-phase high-performance liquid chromatography. Results from adjusted cohort-specific discovery GWA analyses were meta-analyzed with inverse variance weights (n = 2138). Associations with circulating phylloquinone at P < 1 × 10(-6) were then evaluated in a second-stage analysis consisting of one independent cohort (n = 265). No significant association was observed for circulating phylloquinone at the genome-wide significance level of 5 × 10(-8). However, from the discovery GWA, there were 11 single-nucleotide polymorphism (SNP) associations with circulating phylloquinone at P < 1 × 10(-6), including a functional variant previously associated with warfarin dose and altered phylloquinone metabolism. These SNPs are on 5 independent loci on 11q23.3, 8q24.3, 5q22.3, 2p12, and 19p13.12, and they fall within or near the candidate genes APOA1/C3/A4/A5 cluster (involved in lipoprotein metabolism), COL22A1, CDO1, CTNAA2, and CYP4F2 (a phylloquinone oxidase), respectively. Second-stage analysis in an independent cohort further suggests the association of the 5q22.3 locus with circulating phylloquinone (P < 0.05). Multiple candidate genes related to lipoprotein and vitamin K metabolism were identified as potential determinants of circulating phylloquinone. Further investigation with a larger sample is warranted to verify our initial findings and identify other loci contributing to circulating phylloquinone. Trials related to this study were registered at clinicaltrials.gov as NCT00005121 (Framingham Offspring Study) and NCT00005487 (Multi-Ethnic Study of Atherosclerosis). © 2014 American Society for Nutrition.
    American Journal of Clinical Nutrition 12/2014; 100(6):1462-9. · 6.50 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann-Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug. METHODS: We sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease. RESULTS: With sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P=0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P=0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%). CONCLUSIONS: Naturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease. (Funded by the National Institutes of Health and others.).
    New England Journal of Medicine 11/2014; 371(22):2072-82. · 54.42 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Context: Aldosterone and parathyroid hormone (PTH) are implicated in the pathogenesis of cardiovascular and skeletal diseases. An expanding body of evidence supports a bidirectional and positive physiologic relationship between aldosterone and PTH. Large population-based studies confirming this relationship, and whether it may be targeted as a potential method to mitigate the clinical consequences associated with excess aldosterone and PTH, are needed. Objective: We hypothesized that higher aldosterone levels would associate with higher PTH, and that the use of renin-angiotensin-aldosterone system (RAAS) inhibitors would predict lower PTH in a large, multi-ethnic, community-based cohort. Design, Setting, Participants: We conducted cross-sectional analyses of participants in the Multi-Ethnic Study of Atherosclerosis without apparent primary hyperparathyroidism or chronic kidney disease (n=5668). We evaluated associations of RAAS inhibitor use with PTH concentration among 1888 treated hypertensive participants. We also tested associations of serum aldosterone concentration with PTH concentration among 1547 participants with these measurements. Outcome: Serum PTH concentration. Results: Higher aldosterone associated with higher PTH (β=0.19 pg/mL per 1 ng/dL of aldosterone, P<0.0001), and this finding was most pronounced among those with a primary hyperaldosteronism-like phenotype. There was a step-wise increment in PTH when comparing untreated normotensives, hypertensives using RAAS inhibitors, untreated hypertensives, and treated hypertensives using non-RAAS inhibitors (40.8, 45.0, 46.2, 47.1 pg/mL, respectively). The use of any RAAS inhibitor independently associated with lower PTH (β= -2.327 pg/mL per use of RAAS inhibitor, P=0.006), when compared to the use of any non-RAAS inhibitor medication. Conclusions: Higher serum aldosterone concentration is associated with higher serum PTH concentration, and the use of RAAS inhibitors is associated with lower PTH concentration. These results extend prior evidence from observational and intervention studies suggesting a potentially important and modifiable relationship between the RAAS and PTH in humans.
    Journal of Clinical Endocrinology &amp Metabolism 11/2014; · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To examine the association of body mass index (BMI), waist circumference (WC) and waist hip ratio (WHR) with sudden cardiac death (SCD) in community dwelling individuals. Data from a multicentre, prospective, cohort study of 14 941 men and women (African American, and white), aged 45-64 years, participating in the Atherosclerosis Risk in Communities study was analysed. Obesity measures were assessed at baseline (1987-1989). SCD was adjudicated by a committee. At enrolment mean±SD age of the participants was 54±6 years (55% female; 26% African American). During 12.6±2.5 years of follow-up, 253 SCD occurred (incidence rate 1.34/100 person-years). The association between obesity and SCD differed by smoking status (interaction p≤0.01). In models adjusting for age, sex, race, study centre and education level, SCD risk was positively associated (p<0.001) with BMI, WC and WHR in non-smokers, but not in smokers. WHR was more strongly associated with SCD in non-smokers than was BMI or WC (HR per SD increment (95% CI) 2.00 (1.65 to 2.42); 1.34 (1.15 to 1.56) and 1.49 (1.28 to 1.74), respectively). After adjustment for potential mediators (hypertension, diabetes, lipid profile, prevalent coronary heart disease, heart failure, and LV hypertrophy), non-smokers in the highest WHR category (>0.95 in women; >1.01 in men) had double the risk of SCD (HR 2.03, 95% CI 1.19 to 3.46; incidence rate 1.43/1000 person-years) versus those with normal WHR. General obesity is associated with increased risk of SCD in middle-aged, non-smoking individuals, mediated by traditional cardiovascular risk factors. Central obesity, however, is independently associated with SCD by pathways that remain to be elucidated. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Heart (British Cardiac Society) 11/2014; · 6.02 Impact Factor
  • American Journal of Kidney Diseases 11/2014; · 5.76 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Very long-chain saturated fatty acids (VLSFA) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFA may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFA is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFA by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, SPTLC3 (serine palmitoyl-transferase, long-chain base subunit 3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and CERS4 (ceramide synthase 4). The SPTLC3 variant at rs680379 was associated with higher 20:0 (arachidic acid, p = 5.81x10-13). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (p = 2.65x10-40) and in analyses that adjusted for 20:0, with lower levels of 22:0 (behenic acid, p = 4.22x10-26) and 24:0 (lignoceric acid, p = 3.20x10-21). These novel associations highlight the inter-relationship of circulating VLSFA and sphingolipid synthesis.
    Journal of lipid research. 11/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: To study the independent associations of polycystic ovary syndrome (PCOS), and its 2 components, hyperandrogenism and anovulation, with coronary artery calcification (CAC) and carotid artery intima-media thickness (IMT).
    Arteriosclerosis Thrombosis and Vascular Biology 10/2014; · 5.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Heart failure (HF) is common and is associated with high mortality. We aimed to determine associations of serum parathyroid hormone (PTH) and 25-hydroxyvitamin D (25[OH]D) with incident HF and left ventricular mass. Among 6459 participants in the community-based Multi-Ethnic Study of Atherosclerosis, all of whom were free of prevalent clinical cardiovascular disease, we measured serum concentrations of PTH and 25(OH)D at the baseline examination. In longitudinal analyses, we tested associations of PTH and 25(OH)D with incident HF events, adjudicated by a panel of physicians. In cross-sectional analyses of a subset of 4763 participants, we tested associations of PTH and 25(OH)D with left ventricular mass, measured by cardiac magnetic resonance imaging at baseline. Multivariable Cox proportional hazard and linear regression models were adjusted for demographics, physical examination measures, comorbidity, kidney function, and other mineral metabolism markers. Mean age was 62 years and 53% of participants were female. There were 180 incident HF events over a median (interquartile range) follow-up time of 8.46 (7.67 to 8.63) years. Compared with participants with PTH <65 pg/mL, PTH ≥65 pg/mL was associated with a 50% greater risk of incident HF (95% CI: 3% to 210%) and a 5.3 g higher left ventricular mass (95% CI: 2.6, 7.9 g). In contrast, there was no association of 25(OH)D with risk of incident HF or elevated left ventricular mass. In a racially/ethnically diverse population without prevalent cardiovascular disease, higher serum PTH concentration was associated with increased left ventricular mass and increased risk of incident HF. Further studies should be pursued to determine whether PTH excess may be a modifiable risk factor for HF. © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
    Journal of the American Heart Association. 10/2014; 3(6).
  • [Show abstract] [Hide abstract]
    ABSTRACT: Identifying individuals at risk for sudden cardiac death (SCD) is of critical importance. Electrocardiographic (ECG) deep terminal negativity of P wave in V1 (DTNPV1), a marker of left atrial abnormality, has been associated with increased risk of all-cause and cardiovascular mortality. We hypothesized that DTNPV1 is associated with increased risk of sudden cardiac death (SCD). This analysis included 15 375 participants (54.1±5.8 years, 45% men, 73% whites) from the Atherosclerosis Risk in Communities (ARIC) study. DTNPV1 was defined from the resting 12-lead ECG as presence of biphasic P wave (positive/negative) in V1 with the amplitude of the terminal negative phase >100 μV, or one small box on ECG scale. After a median of 14 years of follow-up, 311 cases of SCD occurred. In unadjusted Cox regression, DTNPV1 was associated with an 8-fold increased risk of SCD (HR 8.21; [95%CI 5.27 to 12.79]). Stratified by race and study center, and adjusted for age, sex, coronary heart disease (CHD), and ECG risk factors, as well as atrial fibrillation (AF), stroke, CHD, and heart failure (HF) as time-updated variables, the risk of SCD associated with DTNPV1 remained significant (2.49, [1.51-4.10]). DTNPV1 improved reclassification: additional 3.4% of individuals were appropriately reclassified into a higher SCD risk group, as compared with traditional CHD risk factors alone. In fully adjusted models DTNPV1 was associated with increased risk of non-fatal events: AF (5.02[3.23-7.80]), CHD (2.24[1.43-3.53]), HF (1.90[1.19-3.04]), and trended towards increased risk of stroke (1.88[0.99-3.57]). DTNPV1 is predictive of SCD suggesting its potential utility in risk stratification in the general population. © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
    Journal of the American Heart Association. 10/2014; 3(6).
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91 462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.Molecular Psychiatry advance online publication, 7 October 2014; doi:10.1038/mp.2014.107.
    Molecular Psychiatry 10/2014; · 15.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Prior studies suggest that circulating n-3 and trans-fatty acids influence the risk of sudden cardiac arrest (SCA). Yet, while other fatty acids also differ in their membrane properties and biological activities which may influence SCA, little is known about the associations of other circulating fatty acids with SCA. The aim of this study was to investigate the associations of 17 erythrocyte membrane fatty acids with SCA risk. We used data from a population-based case-control study of SCA in the greater Seattle, Washington, area. Cases, aged 25–74 years, were out-of-hospital SCA patients, attended by paramedics (n=265). Controls, matched to cases by age, sex and calendar year, were randomly identified from the community (n=415). All participants were free of prior clinically-diagnosed heart disease. Blood was obtained at the time of cardiac arrest by attending paramedics (cases) or at the time of an interview (controls). Higher levels of erythrocyte very long-chain saturated fatty acids (VLSFA) were associated with lower risk of SCA. After adjustment for risk factors and levels of n-3 and trans-fatty acids, higher levels of 20:0 corresponding to 1 SD were associated with 30% lower SCA risk (13%-43%, p=0.001). Higher levels of 22:0 and 24:0 were associated with similar lower SCA risk (ORs for 1 SD-difference: 0.71 [95% CI: 0.57–0.88, p=0.002] for 22:0; and 0.79 [95% CI: 0.63–0.98, p=0.04] for 24:0). These novel findings support the need for investigation of biologic effects of circulating VLSFA and their determinants.
    Prostaglandins Leukotrienes and Essential Fatty Acids 10/2014; · 1.98 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: The associations of some risk factors with cardiovascular disease (CVD) are attenuated in older age; whereas others appear robust. The present study aimed to compare CVD risk factors across older age. Methods: Participants (n = 4883) in the Cardiovascular Health Study free of prevalent CVD, were stratified into three age groups: 65-74, 75-84, 85+ years. Traditional risk factors included systolic blood pressure (BP), LDL-cholesterol, HDL-cholesterol, obesity, and diabetes. Novel risk factors included kidney function, C-reactive protein (CRP), and N-terminal pro-B-type natriuretic peptide (NT pro-BNP). Results: There were 1498 composite CVD events (stroke, myocardial infarction, and cardiovascular death) over 5 years. The associations of high systolic BP and diabetes appeared strongest, though both were attenuated with age (p-values for interaction = 0.01 and 0.002, respectively). The demographic-adjusted hazard ratios (HR) for elevated systolic BP were 1.79 (95% confidence interval: 1.49, 2.15), 1.59 (1.37, 1.85) and 1.10 (0.86, 1.41) in participants aged 65-74, 75-84, 85+, and for diabetes, 2.36 (1.89, 2.95), 1.55 (1.27, 1.89), 1.51 (1.10, 2.09). The novel risk factors had consistent associations with the outcome across the age spectrum; low kidney function: 1.69 (1.31, 2.19), 1.61 (1.36, 1.90), and 1.57 (1.16, 2.14) for 65-74, 75-84, and 85+ years, respectively; elevated CRP: 1.54 (1.28, 1.87), 1.33 (1.13, 1.55), and 1.51 (1.15, 1.97); elevated NT pro-BNP: 2.67 (1.96, 3.64), 2.71 (2.25, 3.27), and 2.18 (1.43, 3.45). Conclusions: The associations of most traditional risk factors with CVD were minimal in the oldest old, whereas diabetes, eGFR, CRP, and NT pro-BNP were associated with CVD across older age.
    Atherosclerosis 09/2014; 237(1):336-342. · 3.71 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target. Methods We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis. Findings Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05–0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18–0·43), waist circumference (0·32 cm, 0·16–0·47), plasma insulin concentration (1·62%, 0·53–2·72), and plasma glucose concentration (0·23%, 0·02–0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00–1·05); the rs12916-T allele association was consistent (1·06, 1·03–1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18–1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10–0·38 in all trials; 0·33 kg, 95% CI 0·24–0·42 in placebo or standard care controlled trials and −0·15 kg, 95% CI −0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9–6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06–1·18 in all trials; 1·11, 95% CI 1·03–1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04–1·22 in intensive-dose vs moderate dose trials). Interpretation The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition. Funding The funding sources are cited at the end of the paper.
    The Lancet. 09/2014;

Publication Stats

29k Citations
5,617.45 Total Impact Points

Institutions

  • 2014
    • New York Academy of Medicine
      New York City, New York, United States
  • 1996–2014
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 1994–2014
    • University of Washington Seattle
      • • Department of Medicine
      • • Department of Epidemiology
      • • Department of Biostatistics
      • • Cardiovascular Health Research Unit (CHRU)
      • • Division of Nephrology
      Seattle, Washington, United States
  • 2013
    • National Institute on Aging
      Baltimore, Maryland, United States
    • Massachusetts Department of Public Health
      Boston, Massachusetts, United States
    • Genome Institute of Singapore
      Tumasik, Singapore
    • Queensland Institute of Medical Research
      Brisbane, Queensland, Australia
    • University of Western Australia
      Perth City, Western Australia, Australia
  • 2010–2013
    • University of Eastern Finland
      • Institute of Public Health and Clinical Nutrition
      Kuopio, Eastern Finland Province, Finland
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Angeles, CA, United States
    • Wellcome Trust Sanger Institute
      Cambridge, England, United Kingdom
    • Wake Forest School of Medicine
      Winston-Salem, North Carolina, United States
    • University of Michigan
      Ann Arbor, Michigan, United States
  • 2009–2013
    • University of Vermont
      Burlington, Vermont, United States
    • University of California, Berkeley
      • Division of Epidemiology
      Berkeley, CA, United States
  • 2004–2013
    • San Francisco VA Medical Center
      San Francisco, California, United States
    • University of California, San Francisco
      • • Department of Surgery
      • • Division of Hospital Medicine
      • • Division of General Internal Medicine
      • • Veterans Affairs Medical Center
      San Francisco, California, United States
  • 2001–2013
    • Beth Israel Deaconess Medical Center
      • • Division of General Medicine and Primary Care
      • • CardioVascular Institute
      • • Department of Medicine
      Boston, MA, United States
  • 1998–2013
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem District, Israel
  • 1984–2013
    • University of North Carolina at Chapel Hill
      • • Department of Epidemiology
      • • Department of Nutrition
      Chapel Hill, NC, United States
  • 2012
    • University of California, San Diego
      • Department of Medicine
      San Diego, CA, United States
    • University of Texas Southwestern Medical Center
      • Division of Nephrology
      Dallas, TX, United States
    • San Diego Regenerative Medicine Institute
      San Diego, California, United States
    • University of Alabama at Birmingham
      • Department of Medicine
      Birmingham, AL, United States
    • Harvard University
      • Department of Epidemiology
      Cambridge, MA, United States
    • McGill University
      • Department of Epidemiology, Biostatistics and Occupational Health
      Montréal, Quebec, Canada
  • 2011–2012
    • Weill Cornell Medical College
      • Division of Hospital Medicine
      New York City, New York, United States
    • Yeungnam University
      • Department of Food and Nutrition
      Daikyū, Daegu, South Korea
    • University of California, Los Angeles
      Los Angeles, California, United States
    • University of Alabama
      Tuscaloosa, Alabama, United States
    • University of San Francisco
      San Francisco, California, United States
    • Montreal Heart Institute
      Montréal, Quebec, Canada
    • The Ohio State University
      Columbus, Ohio, United States
    • National University (California)
      San Diego, California, United States
    • Johns Hopkins Bloomberg School of Public Health
      • Department of Epidemiology
      Baltimore, MD, United States
    • Massachusetts Eye and Ear Infirmary
      • Department of Ophthalmology
      Boston, MA, United States
  • 2010–2012
    • University of Pennsylvania
      • • Department of Pharmacology
      • • Division of Cardiovascular Medicine
      Philadelphia, PA, United States
  • 2005–2012
    • Tufts Medical Center
      • • Division of Nephrology
      • • Department of Medicine
      Boston, Massachusetts, United States
    • University of Maryland, Baltimore
      • Division of Nephrology
      Baltimore, MD, United States
  • 2002–2012
    • Brigham and Women's Hospital
      • • Department of Medicine
      • • Division of Preventive Medicine
      Boston, MA, United States
  • 2004–2011
    • University of Pittsburgh
      • Department of Epidemiology
      Pittsburgh, PA, United States
  • 2007–2010
    • Northwestern University
      • Department of Preventive Medicine
      Evanston, IL, United States
  • 2004–2010
    • University of Texas Health Science Center at Houston
      • Brown Foundation Institute of Molecular Medicine
      Houston, TX, United States
  • 2008
    • Wake Forest University
      Winston-Salem, North Carolina, United States
    • Oregon Health and Science University
      • Division of Nephrology & Hypertension
      Portland, OR, United States
    • University of Groningen
      • Department of Cardiology
      Groningen, Province of Groningen, Netherlands
    • Beverly Hospital, Boston MA
      Beverly, Massachusetts, United States
  • 2007–2008
    • Columbia University
      • Institute for Social and Economic Research and Policy
      New York City, NY, United States
  • 2006–2008
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1998–2008
    • Kaiser Permanente
      Oakland, California, United States
    • Leiden University Medical Centre
      • Department of Clinical Epidemiology
      Leiden, South Holland, Netherlands
  • 2003
    • Singapore Eye Research Institute
      Tumasik, Singapore
  • 2000
    • Virginia Commonwealth University
      • Department of Internal Medicine
      Richmond, VA, United States
  • 1997
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 1990–1991
    • Swedish Medical Center Seattle
      Seattle, Washington, United States