Author + information
- Received October 28, 2013
- Revision received May 20, 2014
- Accepted May 23, 2014
- Published online October 28, 2014.
- Åsa Tivesten, MD, PhD∗∗ (, )
- Liesbeth Vandenput, PharmD, PhD†,
- Daniel Carlzon, MD†,
- Maria Nilsson, MD†,
- Magnus K. Karlsson, MD, PhD‡,
- Östen Ljunggren, MD, PhD§,
- Elizabeth Barrett-Connor, MD‖,
- Dan Mellström, MD, PhD† and
- Claes Ohlsson, MD, PhD†
- ∗Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
- †Centre for Bone and Arthritis Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
- ‡Department of Clinical Sciences and Orthopaedics, Lund University, Malmö, Sweden
- §Department of Medical Sciences, University of Uppsala, Uppsala, Sweden
- ‖Department of Family and Preventive Medicine, School of Medicine, University of California San Diego, La Jolla, California
- ↵∗Reprint requests and correspondence:
Dr. Åsa Tivesten, Wallenberg Laboratory for Cardiovascular and Metabolic Research, Bruna Stråket 16, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden.
Background The adrenal sex hormone dehydroepiandrosterone (DHEA), which is present in serum mainly as the sulfate DHEA-S, is the most abundant steroid hormone in human blood. Its levels decline dramatically with age. Despite the great amount of literature on vascular and metabolic actions of DHEA/-S, evidence for an association between DHEA/-S levels and cardiovascular events is contradictory.
Objectives This study tested the hypothesis that serum DHEA and DHEA-S are predictors of major coronary heart disease (CHD) and/or cerebrovascular disease (CBD) events in a large cohort of elderly men.
Methods We used gas and liquid chromatography-mass spectrometry to analyze baseline levels of DHEA and DHEA-S in the prospective population-based Osteoporotic Fractures in Men study in Sweden (2,416 men, ages 69 to 81 years). Complete cardiovascular clinical outcomes were available from national Swedish registers.
Results During the 5-year follow-up, 302 participants experienced a CHD event, and 225 had a CBD event. Both DHEA and DHEA-S levels were inversely associated with the age-adjusted risk of a CHD event; the hazard ratios and 95% confidence intervals per SD increase were 0.82 (0.73 to 0.93) and 0.86 (0.77 to 0.97), respectively. In contrast, DHEA/-S showed no statistically significant association with the risk of CBD events. The association between DHEA and CHD risk remained significant after adjustment for traditional cardiovascular risk factors, serum total testosterone and estradiol, C-reactive protein, and renal function, and remained unchanged after exclusion of the first 2.6 years of follow-up to reduce reverse causality.
Conclusions Low serum levels of DHEA and its sulfate predict an increased risk of CHD, but not CBD, events in elderly men.
The adrenal sex hormone dehydroepiandrosterone (DHEA) is the most abundant steroid hormone in human blood. It is present in serum mainly as a sulfate ester (DHEA-S) (1,2). DHEA may exert biological effects via peripheral conversion into sex steroids, such as testosterone and estradiol, but other DHEA metabolites may also be biologically active. Direct effects of DHEA have been proposed (1–3).
DHEA/-S levels decline dramatically with age (4); however, the mechanism behind this decline and its consequences for health are unclear (5). DHEA has been hypothesized to be important for body composition, insulin sensitivity, and endothelial function (1,4,6), and DHEA may reduce vascular inflammation and remodeling, platelet aggregation, oxidative stress, and atherosclerosis, which suggests that DHEA may confer vascular protection (1–3,6–9). Consequently, it has been speculated that relative DHEA/-S deficiency with increasing age may contribute to age-related cardiometabolic disease (4). However, although there is a relatively large body of published data on the vascular and metabolic actions of DHEA in experimental models, the relevance of these results for human physiology and pathophysiology is uncertain (4).
Several studies that addressed the association between DHEA/-S levels and cardiovascular disease (CVD) outcomes showed inconsistent findings (6,10–15). In prospective studies, our group and others previously reported an increased risk of both all-cause and CVD mortality among elderly men with the lowest DHEA/-S levels (16–18). However, the data regarding DHEA/-S and CVD mortality in men also conflict (19,20) and may be confounded by DHEA/-S levels that are suppressed in severe illness (21,22). One prospective study reported an association between low DHEA/-S and combined fatal and nonfatal coronary heart disease (CHD) events in men only when self-report of treated CHD and CHD medication were included as events in the analysis (23). Thus, there is a need for large population-based studies to address the potential association between DHEA/-S and CVD outcomes.
The aim of the present study was to test the hypothesis that serum DHEA and/or DHEA-S levels are predictors of major CHD and/or cerebrovascular disease (CBD) events in a large population-based cohort of elderly men. We used state-of-the-art methodology to assay baseline DHEA and DHEA-S serum levels, and had a complete 5-year follow-up for CHD (including hospitalization for acute myocardial infarction, unstable angina, or revascularization, or death from CHD) and CBD (including hospitalization for stroke or transient ischemic attack, or death from stroke) endpoints.
The multicenter MrOS (Osteoporotic Fractures in Men Study) includes older men in Sweden, Hong Kong, and the United States. Swedish study participants (age 69 to 81 years) were randomly selected from national population registers (24). Eligibility required the ability to walk without walking aids, ability to provide self-reported data, and to understand and sign an informed consent; 45% of those contacted participated in the MrOS Study in Sweden (n = 3,014), which included cohorts in 3 cities: Malmö (n = 1,005), Göteborg (n = 1,010), and Uppsala (n = 999). The ethics committees at Göteborg, Lund, and Uppsala Universities approved the study.
We investigated the associations between serum DHEA and DHEA-S with CHD and/or CBD events in the Swedish MrOS cohort. Serum samples were drawn in the morning (before 10 am; 69% of the cohort) or around noon (between 10 am and 3 pm, average 1 pm; 31%). A sufficient amount of serum for assessment of DHEA by gas chromatography-mass spectroscopy was available for 2,639 men (99% of the participants in the Göteborg cohort, 96% in the Malmö cohort, and 68% in the Uppsala cohort). Of these, 223 participants were excluded for the following reasons: treatment with testosterone, 5alpha-reductase inhibitors, gonadotrophin-releasing hormone agonists, or antiandrogens, or the participants had a history of surgical castration. This left 2,416 men for the present analyses.
Assessment of covariates
We used a standardized questionnaire (25) to gather information about smoking habits and self-reported medical diagnoses (including hypertension, diabetes, and myocardial infarction). Diabetes was defined as a self-reported medical diagnosis of diabetes. Hypertension was defined as a self-reported medical diagnosis with either self-reported antihypertensive treatment or a supine systolic blood pressure of ≥140 mm Hg (measured after a 10-min rest). Standard equipment was used to measure height and weight; body mass index (BMI) was calculated as kilograms (weight)/meters squared (height).
Apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1) were determined by immunoprecipitation enhanced by polyethylene glycol at 340 nm (Thermo Fisher Scientific, Vantaa, Finland). High-sensitivity C-reactive protein (hsCRP) was measured by an ultrasensitive method (Orion Diagnostica, Espoo, Finland). Both analyses were performed on a Konelab 20 autoanalyzer (Thermo Fisher Scientific). Interassay coefficients of variation (CVs) for the Konelab analyses were <5%.
For assessment of the estimated glomerular filtration rate (eGFR), cystatin C was analyzed with polyclonal antibodies against human cystatin C and measured by immunoturbidimetry (Cystatin C Immunoparticles; Dako Denmark A/S, Glostrup, Denmark). The eGFR was calculated using the following formula: GFR = 79.901 × (cystatin C) – 1.4389. This proxy for the GFR has good precision and linearity, and a strong correlation with iohexol clearance (R2 = 0.956) (26).
Serum sex steroids
All samples were frozen at –80°C and shipped on dry ice to 1 laboratory (Laboratory of Molecular Endocrinology, Laval University Hospital Research Center, Québec City, Québec, Canada). A validated gas chromatography-mass spectroscopy system (27–29) was used to analyze DHEA (limit of detection, 0.20 ng/ml; intra-assay CV, 2.0%; interassay CV, 1.9%), testosterone (limit of detection, 0.05 ng/ml; intra-assay CV, 2.9%; interassay CV, 3.4%), and estradiol (limit of detection, 2.00 pg/ml; intra-assay CV, 1.5%; interassay CV, 2.7%) using a 50% phenyl-methyl polysiloxane (DB-17HT) capillary column (30-m × 0.25-mm internal diameter; 0.15-μm film thickness) with helium as the carrier gas. The analytes and the internal standard were detected using a HP5973 quadrupole mass spectrometer equipped with a chemical ionization source. DHEA-S (limit of detection, 0.075 μg/ml; intra-assay CV, 5.2%; interassay CV, 6.3%) was analyzed by a validated liquid chromatography-tandem mass spectroscopy method using turbo ion spray, as previously described (27). To measure the serum sex hormone–binding globulin, we used an immunoradiometric assay (Orion Diagnostics, Espoo, Finland; limit of detection, 1.3 nmol/l; intra-assay CV, 3%; interassay CV, 7%).
Follow-up time was the period between the baseline visit (in 2001 to 2004) and the date of death, first CHD/CBD event, or last data collection (December 31, 2008). Cause-of-death data were collected from the Swedish Causes of Death Register, which is held by the National Board of Health and Welfare in Sweden, in which all deaths in Sweden are registered with International Classification of Diseases (ICD) codes based on information from death certificates. Data were collected from this register from study start until December 31, 2005 and from evaluation of copies of death certificates for deaths occurring after this date up to 2008. Based on the information from the register and/or death certificate, the underlying cause of death was determined and classified for each participant. CHD death was defined by ICD-10 codes I20 to I25 and stroke death by codes I60 to I64. Data on hospitalization for first acute myocardial infarction (ICD-10 codes I21 to I23), unstable angina (ICD-10 codes I20.0 and I24), revascularization procedure (surgery code FN), stroke (ICD-10 codes I60 to I64), or transient ischemic attack (ICD-10 code G45) were collected from the Swedish Hospital Discharge Register between the baseline date and December 31, 2008. The combination of data from the Swedish Causes of Death Register and the Swedish Hospital Discharge Register was shown to be an efficient, validated alternative to hospital discharge notes and death certificates for both CHD and stroke (30). CHD events were defined as a composite endpoint of hospitalization for acute myocardial infarction, unstable angina or revascularization, or death from CHD. CBD events included hospitalization for stroke or transient ischemic attack, or death from stroke. Death due to causes other than CHD (for the analyses of CHD events) or stroke (for the analyses of CBD events) resulted in censoring in the analyses.
The associations between serum log-transformed DHEA and DHEA-S, as well as serum DHEA/-S and total testosterone, estradiol, and sex hormone–binding globulin (log-transformed) were tested by Pearson correlation. Covariates of serum DHEA/-S were studied in a multiple regression model with log-transformed DHEA/-S as the dependent variable; age, morning sample (yes/no), MrOS site (dummy-coded), BMI (log-transformed), the ApoB/A1 ratio, serum hsCRP (log-transformed), eGFR, current smoking status, diabetes, and hypertension were used as the independent variables.
We used Cox proportional hazards regression to analyze the associations between serum DHEA and DHEA-S and CVD outcomes (first CHD or CBD event). The proportional hazard function was tested (using a method developed by Therneau and Grambsch ) and graphically assessed on the basis of Schoenfeld residuals for both CHD and CBD models. No systematic deviations from proportionality were detected. We show the effect estimate for a 1-SD increase (z score) of log-transformed DHEA/-S levels. All estimates were adjusted for age and morning sample (yes/no). Furthermore, all Cox analyses were adjusted for MrOS site (dummy coded), and there were similar associations between DHEA (per SD) and CHD events across the 3 MrOS sites (data not shown). Further adjustments were made for BMI (log-transformed), the ApoB/A1 ratio, serum hsCRP (log-transformed), serum total estradiol and testosterone, serum sex hormone–binding globulin (log-transformed), and eGFR as continuous variables, as well as 3 dichotomous variables (current smoking status, diabetes, and hypertension). We also examined the associations between DHEA/-S and outcomes across the components of the CHD composite endpoint.
Unadjusted Kaplan-Meier survival curves illustrated the association between tertiles of DHEA and CHD, as well as CBD events. The log-rank test assessed statistical significance. DHEA/-S was entered as a quadratic term in the Cox regression analyses to test for possible nonlinearity in the association between DHEA and CHD outcomes. In addition, in the Cox regression analysis, we used a restricted cubic spline approach for a flexible nonlinear assessment of the hazard ratio (HR) in relation to DHEA (32). The positions and the number of knots were selected using the Akaike Information Criterion (33). Five knots positioned at the 10th, 25th, 50th, 75th, and 90th percentiles of log-transformed serum DHEA concentration provided a small Akaike Information Criterion and captured the average curve shape over a systematical assessment of different alternatives. In the analysis that used a spline approach, age and MrOS site were entered as covariates.
We performed the restricted cubic spline analysis using SAS (version 9.2, SAS Institute, Cary, North Carolina), and the other statistical analyses were performed using SPSS for Windows (version 19.0, SPSS, Chicago, Illinois).
At baseline, the mean age of the cohort (n = 2,614) was 75.4 years (Table 1). Serum levels of DHEA and DHEA-S in the cohort were highly collinear (r = 0.73; p < 0.001), but their covariates differed slightly (Tables 2 and 3⇓⇓). The covariates of DHEA and DHEA-S levels in a multiple regression model (Table 3) were age, BMI, hsCRP, and diabetes. Together with these factors, DHEA, but not DHEA-S, levels were also highly influenced by the time of blood sampling and renal function.
During follow-up, a total of 302 participants experienced a CHD event (rate of 2.5 per 100 person-years at risk), and 225 participants had a CBD event (1.9 per 100 person-years at risk). The median follow-up time (to death, first event, or last data collection) was 5.2 years (12.070 person-years) for CHD events and 5.2 years (12.137 person-years) for CBD events. Except for 3 participants who moved abroad, there was no loss of follow-up.
In prospective analyses, DHEA and DHEA-S levels were both inversely associated with the age-adjusted risk of CHD events when analyzed as continuous variables (Table 4, Model 1). In contrast, there was no statistically significant association between DHEA or DHEA-S and CBD events in the corresponding analyses (Table 4). After adjustment for traditional cardiovascular risk factors (age, BMI, smoking, diabetes, hypertension, and the ApoB/A1 ratio; Model 2), the associations between DHEA/-S and CHD risk remained significant (Table 4). Spline and quadratic models did not support a nonlinear association between DHEA level and CHD risk (Figure 1, and data not shown).
Because DHEA/-S may modulate immune responses (7), we addressed inflammation as a potential mediator between a lower DHEA/-S level and increased CHD risk. Adjustment of the association for hsCRP level did not materially change the association between DHEA/-S and CHD risk (Table 4).
Both DHEA and DHEA-S levels were directly associated with renal function as assessed by eGFR (Table 2). Therefore, we adjusted the association between DHEA/-S and CHD risk for eGFR and found that the point estimates for CHD risk did not materially change (Table 4).
DHEA/-S is a precursor hormone for testosterone and estradiol (4). DHEA showed an association with serum testosterone (r = 0.21; p < 0.001) and estradiol (r = 0.14; p < 0.001) that was slightly stronger than the association between DHEA-S and testosterone (r = 0.05; p = 0.010) and estradiol (r = 0.06; p = 0.005), respectively. After the adjustment of the association between low DHEA/-S and CHD risk for serum total testosterone and estradiol, the associations remained unchanged (Table 4).
We also examined the association between DHEA/-S and the sex hormone–binding globulin, which has an important role in sex hormone biology (34). Sex hormone–binding globulin levels were significantly associated with DHEA-S (r = –0.09; p < 0.001), but these levels were not associated with DHEA (r = 0.03; p = 0.095). Adjustment for the sex hormone–binding globulin level did not change the association between DHEA/-S and CHD events (Table 4).
In a subanalysis, we examined the associations between DHEA/-S and outcomes across the components of the CHD composite endpoint (Online Table S1). We found that the point estimates for the DHEA/-S association with CHD death, hospitalization for myocardial infarction, hospitalization for unstable angina, and hospitalization for revascularization were all in the same direction; the strongest point estimates were for CHD death and hospitalization for unstable angina, and the weakest point estimates were for revascularization procedures.
To illustrate the association between DHEA status and CVD risk, we plotted unadjusted Kaplan-Meier curves of CHD and CBD event-free survival stratified by DHEA tertiles. These plots illustrated that men with relatively lower DHEA levels had a statistically significantly increased risk of a CHD event (Figure 2A), but did not have an increased risk of a CBD event (Figure 2B).
DHEA levels are suppressed in severe illness (21,22). Therefore, general health status is a potential confounder of observed associations. To study the role of subclinical diseases, we performed an analysis that excluded men with a short follow-up time, which is indicative of poor health at the baseline examination. After exclusion of men with a follow-up of 2.6 years or less (one-half of the median follow-up time), the age-adjusted association between low DHEA levels and CHD risk was not attenuated (Table 5). Similarly, the association between DHEA and CHD risk remained following the exclusion of men with reduced renal function (eGFR ≤45 ml/min/1.73 m2) and men without morning samples. Furthermore, the association between DHEA and CHD risk remained after exclusion of men with a baseline history of myocardial infarction.
In the present large, population-based cohort study of elderly men followed for 5 years, we found that baseline serum levels of DHEA and DHEA-S predicted future CHD events (Central Illustration). In contrast, DHEA/-S showed no statistically significant association with the risk of CBD events. The association between DHEA and CHD risk remained significant after adjustment for traditional cardiovascular risk factors, serum testosterone and estradiol levels, hsCRP, and renal function. Furthermore, the association between DHEA and CHD risk was not materially changed in the analyses that excluded the first 2.6 years of follow-up.
Previous epidemiological evidence of an association between DHEA/-S levels and CVD outcomes in men are contradictory (10–20,23,35). A prospective, nested case–control study reported lower DHEA-S levels among fatal CHD cases (10), but several smaller prospective case–control studies of fatal and/or nonfatal CHD events (13–15) found no association with DHEA-S levels. In larger prospective cohort studies, we and others previously found an increased risk of both all-cause and CVD mortality among elderly men with the lowest DHEA/-S levels (16–18), but other large studies found no association between DHEA-S and CVD mortality in men (19,20). In addition, a population-based study reported no association between DHEA-S levels and incident CVD in 2,084 middle-aged men (mean age 55 years) (35). The Massachusetts Male Aging Study found no significant association between low DHEA/-S levels and 9-year CHD mortality in 1,167 men age 40 to 70 years. However, this study did find an association between low DHEA/-S levels and combined fatal and nonfatal CHD events (151 events), but only when self-report of treated CHD and CHD medication were included as events in the analysis (23). Taken together, previous data are conflicting, and there is a paucity of large prospective analyses on this topic. Our study represents the largest study to date (302 men with CHD events and 225 men with CBD events in 2,416 men at risk), and strongly supports an association between DHEA/-S levels and CHD risk in (elderly) men.
Experimental in vitro and rodent studies suggest that DHEA/-S may modulate lipid and/or glucose metabolism, systemic inflammation, vascular endothelial function, and vascular remodeling via different mechanisms, such as peroxisome proliferator-activated receptor-alpha activation, activation of a G-protein–coupled receptor, or conversion to downstream DHEA metabolites (1–3,9). However, because adult rodents do not produce DHEA/-S in measurable amounts due to lack of adrenal expression of the enzyme CYP17 (36), results from rodent studies must be interpreted with caution. Short-term trials on the effect of DHEA therapy on vascular endothelial function in humans have reported both improvement (37,38) and no effect (39,40). Similarly, 4 longer (6 months to 2 years) trials of DHEA therapy in elderly persons showed conflicting results on the effects on body composition and insulin action (41–45). Notably, the association between DHEA/-S and CHD risk in the present study was unaffected by adjustment for traditional vascular risk factors. Moreover, our results do not support systemic inflammation as a mediator, because adjustment for hsCRP level had no impact. Furthermore, we found that the association between DHEA/-S and CHD risk was not materially changed after adjustment for serum testosterone and estradiol levels. Importantly, this does not exclude a pivotal role for androgens or estrogens produced locally by DHEA metabolism (4). The findings of the present study should encourage further mechanistic studies, preferably performed in humans or other primates. These studies should particularly address the possible direct actions of DHEA on the vascular wall, for example, on endothelial function and/or regeneration (2,36,46,47) and the proliferation of vascular smooth muscle cells (3,48,49).
Although collinear, the covariates of DHEA and DHEA-S differed slightly. In line with previous findings that DHEA secretion follows a diurnal rhythm similar to that of cortisol (2,16), DHEA was associated with the time of blood sampling, whereas DHEA-S did not show such an association, as expected from its significantly longer half-life (2). Importantly, DHEA, but not DHEA-S, was associated with renal function in the multivariable models. It is conceivable that a “low DHEA status” is not properly reflected by DHEA-S levels, especially when renal function is reduced, because of reduced renal clearance of the conjugated (sulfated), and therefore, water soluble form of the hormone. Thus, the impact of any systemic disease on DHEA-S levels may be counteracted by concomitant renal dysfunction (50). Nevertheless, adjustment for renal function had no major impact on the association between DHEA or DHEA-S and CHD risk in our study.
In the present study, both DHEA and DHEA-S blood levels predicted CHD events. The relative biological importance and pathways of DHEA and DHEA-S are unclear, and the collinearity between DHEA and DHEA-S precludes firm conclusions from statistical analyses. The concentration of circulating DHEA is approximately 350 times lower than that of DHEA-S, but because it is more readily converted to downstream tissue metabolites, DHEA may be equally important (1,2). Other data suggest that DHEA-S is back-converted to DHEA only to a minor degree (2,51). DHEA sulfation and desulfation are actively catalyzed by sulfotransferase and sulfatase, respectively, which may be regulated by different intraindividual and/or environmental factors and disease states (52,53). Gaining further insight into the biological role of the conjugated versus nonconjugated form of DHEA and how DHEA sulfation is regulated are important tasks for future studies.
Because any systemic disease and general poor health may lower DHEA/-S (22), comorbidity might explain associations between DHEA/-S and CHD events. Those who have poor general health (of any cause) at baseline are more likely to die and/or experience a CHD or non-CHD event soon after baseline. Therefore, our finding that the association between DHEA and CHD risk was unchanged following exclusion of the first 2.6 years of follow-up argues against comorbidities confounding the observed association.
The results of several small DHEA supplementation studies are inconclusive (1). Although available data does not support DHEA supplementation to elderly people, there is widespread, nonsupervised use of DHEA as a dietary supplement. Our results highlight the need for further and larger trials of the cardiometabolic consequences of DHEA therapy in elderly subjects and/or subjects with low DHEA/-S levels.
If DHEA/-S is cardioprotective, drugs that target its synthesis may adversely affect CHD risk. Abiraterone acetate, which inhibits the enzyme CYP17, which then leads to inhibition of both DHEA and testosterone biosynthesis, is a new therapy for advanced prostate cancer. Abiraterone acetate was recently shown to increase short-term overall survival in patients with metastatic prostate cancer (54), but concerns about potential cardiovascular side effects may be raised due to its pronounced DHEA-lowering effect.
The results were based on single measurements of DHEA and DHEA-S, which might underestimate true associations. Because of the diurnal variation in serum DHEA levels (16), the use of some non-morning samples might have contributed to increased variability, but the hour of day was adjusted for in the analyses, and excluding the participants without morning samples did not materially change the results. Another limitation was that baseline covariates were partly self-reported, which is a potential source of residual confounding. Older adults are often also treated with more CVD medications, some of which could alter cardiovascular risk and/or DHEA/-S levels. Our study also had notable strengths, including the mass spectrometry DHEA/-S methodology, a large well-characterized sample, complete follow-up, fatal and nonfatal outcomes, and the documented accuracy of classification in nationwide Swedish registers (30).
Low-serum levels of DHEA and its sulfate predicted the risk of CHD, but not the risk of CBD, events in elderly men.
COMPETENCY IN MEDICAL KNOWLEDGE: The sulfated form of DHEA is the most abundant steroid hormone in human blood. The exact physiological role of DHEA/-S has not been defined, but DHEA/-S levels are lower in the elderly, in patients with Addison’s disease, and in those with certain other conditions.
COMPETENCY IN PATIENT CARE: The safety and efficacy of routine DHEA supplementation have not been established.
TRANSLATIONAL OUTLOOK: Properly designed clinical trials are needed to evaluate the cardiometabolic effects, safety, and efficacy of DHEA supplementation in clearly defined study cohorts.
The authors thank the MrOS study personnel for their excellent research assistance.
This study was supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, the Avtal om Läkarutbildning och Forskning research grant in Gothenburg, the Swedish Heart-Lung Foundation, the Marianne and Marcus Wallenberg Foundation, the Lundberg Foundation, the Torsten and Ragnar Söderberg's Foundation, Petrus and Augusta Hedlund’s Foundation, AFA Insurance, and the Novo Nordisk Foundation. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- apolipoprotein A1
- apolipoprotein B
- body mass index
- cerebrovascular disease
- coronary heart disease
- coefficient of variation
- cardiovascular disease
- dehydroepiandrosterone sulfate
- estimated glomerular filtration rate
- high-sensitivity C-reactive protein
- International Classification of Diseases
- Received October 28, 2013.
- Revision received May 20, 2014.
- Accepted May 23, 2014.
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