@article {890, title = {Thyroid status, cardiovascular risk, and mortality in older adults.}, journal = {JAMA}, volume = {295}, year = {2006}, month = {2006 Mar 01}, pages = {1033-41}, abstract = {

CONTEXT: Previous studies have suggested that subclinical abnormalities in thyroid-stimulating hormone levels are associated with detrimental effects on the cardiovascular system.

OBJECTIVE: To determine the relationship between baseline thyroid status and incident atrial fibrillation, incident cardiovascular disease, and mortality in older men and women not taking thyroid medication.

DESIGN, SETTING, AND PARTICIPANTS: A total of 3233 US community-dwelling individuals aged 65 years or older with baseline serum thyroid-stimulating hormone levels were enrolled in 1989-1990 in the Cardiovascular Health Study, a large, prospective cohort study.

MAIN OUTCOME MEASURES: Incident atrial fibrillation, coronary heart disease, cerebrovascular disease, cardiovascular death, and all-cause death assessed through June 2002. Analyses are reported for 4 groups defined according to thyroid function test results: subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism.

RESULTS: Individuals with overt thyrotoxicosis (n = 4) were excluded because of small numbers. Eighty-two percent of participants (n = 2639) had normal thyroid function, 15\% (n = 496) had subclinical hypothyroidism, 1.6\% (n = 51) had overt hypothyroidism, and 1.5\% (n = 47) had subclinical hyperthyroidism. After exclusion of those with prevalent atrial fibrillation, individuals with subclinical hyperthyroidism had a greater incidence of atrial fibrillation compared with those with normal thyroid function (67 events vs 31 events per 1000 person-years; adjusted hazard ratio, 1.98; 95\% confidence interval, 1.29-3.03). No differences were seen between the subclinical hyperthyroidism group and euthyroidism group for incident coronary heart disease, cerebrovascular disease, cardiovascular death, or all-cause death. Likewise, there were no differences between the subclinical hypothyroidism or overt hypothyroidism groups and the euthyroidism group for cardiovascular outcomes or mortality. Specifically, individuals with subclinical hypothyroidism had an adjusted hazard ratio of 1.07 (95\% confidence interval, 0.90-1.28) for incident coronary heart disease.

CONCLUSION: Our data show an association between subclinical hyperthyroidism and development of atrial fibrillation but do not support the hypothesis that unrecognized subclinical hyperthyroidism or subclinical hypothyroidism is associated with other cardiovascular disorders or mortality.

}, keywords = {Aged, Atrial Fibrillation, Cardiovascular Diseases, Female, Humans, Hyperthyroidism, Hypothyroidism, Male, Proportional Hazards Models, Risk Factors, Thyroid Gland, Thyrotropin}, issn = {1538-3598}, doi = {10.1001/jama.295.9.1033}, author = {Cappola, Anne R and Fried, Linda P and Arnold, Alice M and Danese, Mark D and Kuller, Lewis H and Burke, Gregory L and Tracy, Russell P and Ladenson, Paul W} } @article {940, title = {Association of total insulin-like growth factor-I, insulin-like growth factor binding protein-1 (IGFBP-1), and IGFBP-3 levels with incident coronary events and ischemic stroke.}, journal = {J Clin Endocrinol Metab}, volume = {92}, year = {2007}, month = {2007 Apr}, pages = {1319-25}, abstract = {

CONTEXT: Prior observational studies have demonstrated that the GH/IGF axis is associated with cardiovascular disease. However, this association has not been extensively studied among older adults.

OBJECTIVE: The objective of this study was to assess the association between levels of total IGF-I and IGF binding proteins (IGFBP-1, IGFBP-3) and risk of incident coronary events and ischemic stroke.

DESIGN AND PARTICIPANTS: A case-cohort analysis was conducted among adults 65 yr and older in the Cardiovascular Health Study.

MAIN OUTCOME MEASURES: A total of 534 coronary events [316 nonfatal myocardial infarctions (MIs), 48 fatal MIs, and 170 fatal coronary heart disease events] and 370 ischemic strokes were identified on follow-up. Comparison subjects were 1122 randomly selected participants from the Cardiovascular Health Study.

RESULTS: Mean follow-up time was 6.7 yr for coronary events, 5.6 yr for strokes, and 9.3 yr for comparison subjects. Hazard ratios (95\% confidence intervals) associated with baseline levels of total IGF-I and IGFBPs were estimated using multivariate adjusted Cox proportional hazards models. Neither IGF-I nor IGFBP-1 levels predicted risk of incident coronary events or stroke. IGFBP-3 had an inverse association with risk of coronary events [adjusted hazard ratio per sd=0.88 (0.78-1.00), P=0.05] but was not associated with stroke. Exploratory analyses suggested that low IGF-I and low IGFBP-3 levels were significantly associated with higher risk of nonfatal MI (P<0.05) but not with risk of fatal MI or fatal coronary heart disease.

CONCLUSION: Circulating levels of total IGF-I or IGFBP-1 were not associated with risk of total coronary events or ischemic stroke among older adults, whereas low IGFBP-3 level was associated with increased risk of incident coronary events.

}, keywords = {Aged, Cardiovascular Diseases, Case-Control Studies, Cohort Studies, Coronary Disease, Female, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Male, Multivariate Analysis, Risk Factors, Stroke}, issn = {0021-972X}, doi = {10.1210/jc.2006-1631}, author = {Kaplan, Robert C and McGinn, Aileen P and Pollak, Michael N and Kuller, Lewis H and Strickler, Howard D and Rohan, Tom E and Cappola, Anne R and Xue, XiaoNan and Psaty, Bruce M} } @article {928, title = {Determinants of serum total and free testosterone levels in women over the age of 65 years.}, journal = {J Clin Endocrinol Metab}, volume = {92}, year = {2007}, month = {2007 Feb}, pages = {509-16}, abstract = {

CONTEXT: Little is known about testosterone (T) levels and their determinants in women of late postmenopausal age.

OBJECTIVE: We describe levels of total and free T and selected factors that influence these levels in a random sample of older women.

DESIGN: Levels of serum total T and free T by microdialysis were measured using ultrasensitive assays in 347 community-dwelling women aged 65-98 yr enrolled in the Cardiovascular Health Study. Cross-sectional analyses were performed to define factors associated with total and free T levels.

RESULTS: In adjusted models: 1) total T levels declined with age until 80, whereas free T levels did not vary by age; 2) women with bilateral oophorectomy had 23\% lower total T and 16\% lower free T levels than those with at least one intact ovary; 3) oral estrogen users had total and free T levels that were 47\% lower than never users; 4) obese women had 47\% higher total T and 20\% higher free T levels, and overweight women had 24\% higher total T and 14\% higher free T levels, than normal weight women; and 5) free T levels were 51\% higher in black women. Corticosteroid users had 75\% lower total T and 43\% lower free T levels than nonusers.

CONCLUSIONS: Bilateral oophorectomy, estrogen use, corticosteroid use, and low body mass index are independent risk factors for lower T levels in women aged 65 yr and over. Although highly prevalent in women of this age, the physiological significance of low T levels in late postmenopausal women requires further investigation.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Aging, Body Mass Index, Cross-Sectional Studies, Estrogen Replacement Therapy, Female, Humans, Hypogonadism, Multivariate Analysis, Nonlinear Dynamics, Obesity, Ovariectomy, Ovary, Postmenopause, Predictive Value of Tests, Prevalence, Risk Factors, Testosterone}, issn = {0021-972X}, doi = {10.1210/jc.2006-1399}, author = {Cappola, Anne R and Ratcliffe, Sarah J and Bhasin, Shalender and Blackman, Marc R and Cauley, Jane and Robbins, John and Zmuda, Joseph M and Harris, Tamara and Fried, Linda P} } @article {1035, title = {High insulinlike growth factor binding protein 1 level predicts incident congestive heart failure in the elderly.}, journal = {Am Heart J}, volume = {155}, year = {2008}, month = {2008 Jun}, pages = {1006-12}, abstract = {

BACKGROUND: Low levels of insulinlike growth factor 1 (IGF-I) may influence the development of age-related cardiovascular diseases including congestive heart failure (CHF). Insulinlike growth factor binding protein 1 (IGFBP-1), which increases during catabolic states and inhibits anabolic IGF-I effects, is increased in patients with CHF and has been associated prospectively with increased mortality among older adults and survivors of myocardial infarction. We investigated the association between fasting plasma levels of IGF-I, IGFBP-1, IGFBP-3, and insulin and risk of incident CHF in the prospective Cardiovascular Health Study.

METHODS: From among 5,888 adults 65 years old and older in the Cardiovascular Health Study, we studied 566 incident CHF cases and 1,072 comparison subjects after exclusion of underweight individuals (body mass index <18.5 kg/m(2)) and insulin users. Hazard ratios (HRs) with 95\% CIs for CHF were estimated after adjustment for age, race, sex, hypertension, systolic blood pressure, lipid levels, left ventricular hypertrophy, coronary disease, C-reactive protein, health status, diabetes, and body mass index.

RESULTS: High baseline IGFBP-1 level was a significant predictor of CHF, independent of established CHF risk factors and inflammation markers. The HR per SD of IGFBP-1 was 1.22 (95\% CI 1.07-1.39, P < .01). Relative to the lowest IGFBP-1 tertile, the HR was 1.29 (95\% CI 0.96-1.74, P = .09) for the second IGFBP-1 tertile and 1.47 (95\% CI 1.06-2.04; P = .02) for the highest IGFBP-1 tertile (tertile cut points 19.5 and 35.8 ng/mL). Total IGF-I, IGFBP-3, or insulin levels had no association with CHF after adjustment for CHF risk factors.

CONCLUSIONS: High circulating IGFBP-1 level may be a CHF risk factor among older adults.

}, keywords = {Aged, Aged, 80 and over, Female, Heart Failure, Humans, Incidence, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Male, Predictive Value of Tests, Prospective Studies, Risk Factors}, issn = {1097-6744}, doi = {10.1016/j.ahj.2007.12.031}, author = {Kaplan, Robert C and McGinn, Aileen P and Pollak, Michael N and Kuller, Lewis and Strickler, Howard D and Rohan, Thomas E and Cappola, Anne R and Xue, XiaoNan and Psaty, Bruce M} } @article {991, title = {Insulin-like growth factor-(IGF)-axis, inflammation, and glucose intolerance among older adults.}, journal = {Growth Horm IGF Res}, volume = {18}, year = {2008}, month = {2008 Apr}, pages = {166-73}, abstract = {

Increasing evidence suggests that the insulin-like growth factor (IGF)-axis may play a role in glucose metabolism and may also be associated with systemic inflammation. The aim of this study was to evaluate the association of insulin-like growth factor-1 (IGF-I) and its binding proteins, IGFBP-1 and IGFBP-3, with glucose intolerance and inflammation among older adults. We conducted a cross-sectional analysis in a in a random subsample (n=922) of the Cardiovascular Health Study (CHS), a prospective cohort of men and women > or = 65 years. Mean IGFBP-1 levels were significantly lower in older adults with impaired glucose tolerance (IGT), impaired fasting glucose (IFG) and diabetes compared to those with normal fasting and post-load glucose. High IGFBP-1 was associated with a reduced prevalence of IGT and IFG; the multivariable OR between extreme quartiles of IGFBP-1 was 0.60 (95\% CI: 0.37, 0.95; p-trend: 0.03) for IGT and 0.41 (95\% CI: 0.26, 0.64; p-trend: <0.01) for IFG. We did not find any significant association between IGF-I and glucose intolerance in this study and the association for IGFBP-3 was less clear. However, low levels of IGF-I and IGFBP-3 were associated with increased levels of markers of inflammation including C-reactive protein and interleukin-6 levels. We conclude that among adults > or = 65 years, low IGFBP-1 levels are associated with increased prevalence of glucose intolerance. We did not confirm prior associations of low IGF-I with glucose intolerance in this cohort of older individuals.

}, keywords = {Aged, Aged, 80 and over, Cohort Studies, Cross-Sectional Studies, Female, Glucose Intolerance, Humans, Inflammation, Insulin-Like Growth Factor Binding Proteins, Male, Signal Transduction, Somatomedins}, issn = {1096-6374}, doi = {10.1016/j.ghir.2007.08.004}, author = {Rajpathak, Swapnil N and McGinn, Aileen P and Strickler, Howard D and Rohan, Thomas E and Pollak, Michael and Cappola, Anne R and Kuller, Lewis and Xue, XiaoNan and Newman, Anne B and Strotmeyer, Elsa S and Psaty, Bruce M and Kaplan, Robert C} } @article {1053, title = {Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study.}, journal = {J Am Coll Cardiol}, volume = {52}, year = {2008}, month = {2008 Sep 30}, pages = {1152-9}, abstract = {

OBJECTIVES: The goal of this study was to determine whether subclinical thyroid dysfunction was associated with incident heart failure (HF) and echocardiogram abnormalities.

BACKGROUND: Subclinical hypothyroidism and hyperthyroidism have been associated with cardiac dysfunction. However, long-term data on the risk of HF are limited.

METHODS: We studied 3,044 adults>or=65 years of age who initially were free of HF in the Cardiovascular Health Study. We compared adjudicated HF events over a mean 12-year follow-up and changes in cardiac function over the course of 5 years among euthyroid participants, those with subclinical hypothyroidism (subdivided by thyroid-stimulating hormone [TSH] levels: 4.5 to 9.9, >or=10.0 mU/l), and those with subclinical hyperthyroidism.

RESULTS: Over the course of 12 years, 736 participants developed HF events. Participants with TSH>or=10.0 mU/l had a greater incidence of HF compared with euthyroid participants (41.7 vs. 22.9 per 1,000 person years, p=0.01; adjusted hazard ratio: 1.88; 95\% confidence interval: 1.05 to 3.34). Baseline peak E velocity, which is an echocardiographic measurement of diastolic function associated with incident HF in the CHS cohort, was greater in those patients with TSH>or=10.0 mU/l compared with euthyroid participants (0.80 m/s vs. 0.72 m/s, p=0.002). Over the course of 5 years, left ventricular mass increased among those with TSH>or=10.0 mU/l, but other echocardiographic measurements were unchanged. Those patients with TSH 4.5 to 9.9 mU/l or with subclinical hyperthyroidism had no increase in risk of HF.

CONCLUSIONS: Compared with euthyroid older adults, those adults with TSH>or=10.0 mU/l have a moderately increased risk of HF and alterations in cardiac function but not older adults with TSH<10.0 mU/l. Clinical trials should assess whether the risk of HF might be ameliorated by thyroxine replacement in individuals with TSH>or=10.0 mU/l.

}, keywords = {Aged, Aged, 80 and over, Cohort Studies, Echocardiography, Female, Heart, Heart Failure, Heart Function Tests, Humans, Hyperthyroidism, Hypertrophy, Left Ventricular, Hypothyroidism, Male, Risk Factors, Time Factors}, issn = {1558-3597}, doi = {10.1016/j.jacc.2008.07.009}, author = {Rodondi, Nicolas and Bauer, Douglas C and Cappola, Anne R and Cornuz, Jacques and Robbins, John and Fried, Linda P and Ladenson, Paul W and Vittinghoff, Eric and Gottdiener, John S and Newman, Anne B} } @article {1067, title = {High frequency of and factors associated with thyroid hormone over-replacement and under-replacement in men and women aged 65 and over.}, journal = {J Clin Endocrinol Metab}, volume = {94}, year = {2009}, month = {2009 Apr}, pages = {1342-5}, abstract = {

CONTEXT: Thyroid hormone use is common in older populations, but the frequency of over- or under-replacement is debated.

OBJECTIVE: We sought to describe the frequency of and factors associated with thyroid hormone over- or under-replacement in a population of older men and women.

DESIGN: Participants were 3678 U.S. community dwelling individuals aged 65 yr or older enrolled in the Cardiovascular Health Study who had thyroid function tests in 1989-1990. Thyroid hormone users (n = 339) were identified and classified into low TSH (<0.45 mU/liter), euthyroid (0.45-4.5 mU/liter), and high TSH (>4.5 mU/liter).

RESULTS: Of the 339 thyroid hormone users, 41\% had a low TSH, 16\% had a high TSH, and 43\% were in the euthyroid range. In multivariable analyses, lower weight (P < 0.001) was independently associated with low TSH status. For every 10 kg lower weight, the likelihood of having low TSH increased by 65\% [odd ratio (OR) 1.65; 95\% confidence interval (CI) 1.31-2.07]. Those with renal insufficiency were less likely to have low TSH levels (P = 0.02). The presence of diabetes was independently associated with having low (OR 3.35; 95\% CI 1.46-7.65) and high TSH levels (OR 2.66; 95\% CI 1.14-6.21).

CONCLUSIONS: There is a very high prevalence of thyroid function testing abnormalities in older people taking thyroid hormone preparations, particularly in those of low weight or with diabetes. Because of potential adverse cardiovascular and skeletal effects from over-replacement, older people represent a key population for increased TSH monitoring on therapy.

}, keywords = {Aged, Body Mass Index, Body Weight, Diabetes Mellitus, Dose-Response Relationship, Drug, Drug Therapy, Combination, Female, Hormone Replacement Therapy, Humans, Male, Multivariate Analysis, Renal Insufficiency, Risk Factors, Thyroid Diseases, Thyroid Hormones, Thyrotropin, Thyroxine, Triiodothyronine}, issn = {1945-7197}, doi = {10.1210/jc.2008-1696}, author = {Somwaru, Lily L and Arnold, Alice M and Joshi, Neha and Fried, Linda P and Cappola, Anne R} } @article {1139, title = {Higher serum testosterone concentration in older women is associated with insulin resistance, metabolic syndrome, and cardiovascular disease.}, journal = {J Clin Endocrinol Metab}, volume = {94}, year = {2009}, month = {2009 Dec}, pages = {4776-84}, abstract = {

CONTEXT: Early postmenopausal women with higher testosterone (T) levels have increased insulin resistance (IR) and cardiovascular risk factors, but whether this translates into increased cardiovascular disease later in life is unknown.

OBJECTIVE: The objective of the study was to determine whether higher T levels are associated with IR, the metabolic syndrome (MetSyn), and coronary heart disease (CHD) in elderly women.

DESIGN: Total T and free T by equilibrium dialysis were measured using ultrasensitive assays in 344 women aged 65-98 yr enrolled in the Cardiovascular Health Study. Cross-sectional analyses were performed to examine the associations between total and free T and IR, MetSyn, and CHD.

RESULTS: There was a stepwise increase in the homeostasis model assessment of insulin resistance with increasing total (P = 0.0.003) and free T (P = 0.02) level and a corresponding decrease in Quantitative Insulin Sensitivity Check Index (P < 0.001 and P = 0.002, respectively). In adjusted models, higher levels of both total and free T were strongly associated with abdominal obesity and high fasting glucose, the two MetSyn components most strongly linked to IR. After adjustment, women in the top quartile of total T levels had a 3-fold greater odds of MetSyn (odds ratio 3.15, 95\% confidence interval 1.57-6.35) than those in the bottom quartile and a 3-fold greater odds of CHD (odds ratio 2.95, 95\% confidence interval 1.2-7.3) than those in second quartile, whereas free T was not significantly associated with MetSyn or CHD.

CONCLUSIONS: Higher levels of T are associated with IR, MetSyn, and CHD in elderly women. Whether T is a marker or mediator of cardiovascular disease in this population merits further investigation.

}, keywords = {Aged, Aged, 80 and over, Blood Glucose, Cardiovascular Diseases, Coronary Disease, Female, Humans, Insulin, Insulin Resistance, Metabolic Syndrome, Odds Ratio, Radioimmunoassay, Socioeconomic Factors, Testosterone, Treatment Outcome}, issn = {1945-7197}, doi = {10.1210/jc.2009-0740}, author = {Patel, Shrita M and Ratcliffe, Sarah J and Reilly, Muredach P and Weinstein, Rachel and Bhasin, Shalender and Blackman, Marc R and Cauley, Jane A and Sutton-Tyrrell, Kim and Robbins, John and Fried, Linda P and Cappola, Anne R} } @article {1123, title = {Trajectories of dehydroepiandrosterone sulfate predict mortality in older adults: the cardiovascular health study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {64}, year = {2009}, month = {2009 Dec}, pages = {1268-74}, abstract = {

BACKGROUND: Dehydroepiandrosterone sulfate (DHEAS) has been proposed as an antiaging hormone, but its importance is unclear. Assessment of an individual{\textquoteright}s ability to maintain a DHEAS set point, through examination of multiple DHEAS levels over time, may provide insight into biologic aging.

METHODS: Using Cox proportional hazard models, we examined the relationship between DHEAS trajectory patterns and all-cause death in 950 individuals aged >or=65 years who were enrolled in the Cardiovascular Health Study and had DHEAS levels measured at three to six time points.

RESULTS: Overall, there was a slight decline in DHEAS levels over time (-0.013 microg/mL/y). Three trajectory components were examined: slope, variability, and baseline DHEAS. When examined individually, a steep decline or extreme variability in DHEAS levels was associated with higher mortality (p < .001 for each), whereas baseline DHEAS level was not. In adjusted models including all three components, steep decline (hazard ratio [HR] 1.75, confidence interval [CI] 1.32-2.33) and extreme variability (HR 1.89, CI 1.47-2.43) remained significant predictors of mortality, whereas baseline DHEAS level remained unpredictive of mortality (HR 0.97 per standard deviation, CI 0.88-1.07). The effect of trajectory pattern was more pronounced in men than in women. Individuals with both a steep decline and extreme variability in DHEAS levels had a significantly higher death rate than those with neither pattern (141 vs 48 deaths per 1,000 person-years, p < .001).

CONCLUSIONS: Our data show significant heterogeneity in the individual trajectories of DHEAS levels and suggest that these trajectories provide important biologic information about the rate of aging, whereas the DHEAS level itself does not.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Biomarkers, Cardiovascular Diseases, Cause of Death, Cohort Studies, Dehydroepiandrosterone Sulfate, Female, Geriatric Assessment, Humans, Longitudinal Studies, Male, Predictive Value of Tests, Proportional Hazards Models, Risk Assessment, Severity of Illness Index, Sex Factors, Survival Analysis, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glp129}, author = {Cappola, Anne R and O{\textquoteright}Meara, Ellen S and Guo, Wensheng and Bartz, Traci M and Fried, Linda P and Newman, Anne B} } @article {1168, title = {Cardiovascular disease is associated with greater incident dehydroepiandrosterone sulfate decline in the oldest old: the cardiovascular health study all stars study.}, journal = {J Am Geriatr Soc}, volume = {58}, year = {2010}, month = {2010 Mar}, pages = {421-6}, abstract = {

OBJECTIVES: To describe cross-sectional and longitudinal associations with dehydroepiandrosterone sulfate (DHEAS) and change in DHEAS with age.

DESIGN: Longitudinal cohort study.

SETTING: Pittsburgh, Pennsylvania.

PARTICIPANTS: Cardiovascular Health Study All Stars study participants assessed in 2005/06 (N=989, mean age 85.2, 63.5\% women, 16.5\% African American).

MEASUREMENTS: Health characteristics were assessed in 2005/06 according to DHEAS level, mean DHEAS and DHEAS change across age categories were tested, and linear and logistic regression was used to identify factors present in 1996/97 associated with continuous and categorical DHEAS change.

RESULTS: Mean +/- standard deviation DHEAS was 0.555 +/- 0.414 microg/mL in 1996/97 and 0.482 +/- 0.449 microg/mL in 2005/06 for women and 0.845 +/- 0.520 microg/mL in 1996/97 and 0.658 +/- 0.516 microg/mL in 2005/06 for men. In 2005/06, DHEAS was lower in women and subjects with cardiovascular disease (CVD) and chronic pulmonary disease and higher for African Americans and subjects with hypertension and high cholesterol. Mean DHEAS change was greater in men (-0.200 microg/mL) than in women (-0.078 microg/mL) (P<.001). Each 1-year increase in age attenuated the effect of male sex by 0.01 microg/mL (P=.009), abolishing the sex difference in DHEAS change by age 79. Presence of CVD before the study period was associated with greater absolute DHEAS change (beta=-0.04 microg/mL, P=.04) and with the fourth quartile of DHEAS change versus the first to third quartiles (odds ratio=1.46, 95\% confidence interval=1.03-2.05).

CONCLUSION: DHEAS change continues into very old age, is not homogenous, is affected by sex, and is associated with prevalent CVD. Future studies should investigate factors that might accelerate DHEAS decline.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Biomarkers, Cardiovascular Diseases, Cross-Sectional Studies, Dehydroepiandrosterone Sulfate, Female, Humans, Longitudinal Studies, Male, Multivariate Analysis, Regression Analysis, Sex Distribution, United States}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2010.02724.x}, author = {Sanders, Jason L and Boudreau, Robert M and Cappola, Anne R and Arnold, Alice M and Robbins, John and Cushman, Mary and Newman, Anne B} } @article {1231, title = {Subclinical hypothyroidism and the risk of coronary heart disease and mortality.}, journal = {JAMA}, volume = {304}, year = {2010}, month = {2010 Sep 22}, pages = {1365-74}, abstract = {

CONTEXT: Data regarding the association between subclinical hypothyroidism and cardiovascular disease outcomes are conflicting among large prospective cohort studies. This might reflect differences in participants{\textquoteright} age, sex, thyroid-stimulating hormone (TSH) levels, or preexisting cardiovascular disease.

OBJECTIVE: To assess the risks of coronary heart disease (CHD) and total mortality for adults with subclinical hypothyroidism.

DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE and EMBASE (1950 to May 31, 2010) were searched without language restrictions for prospective cohort studies with baseline thyroid function and subsequent CHD events, CHD mortality, and total mortality. The reference lists of retrieved articles also were searched.

DATA EXTRACTION: Individual data on 55,287 participants with 542,494 person-years of follow-up between 1972 and 2007 were supplied from 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan. The risk of CHD events was examined in 25,977 participants from 7 cohorts with available data. Euthyroidism was defined as a TSH level of 0.50 to 4.49 mIU/L. Subclinical hypothyroidism was defined as a TSH level of 4.5 to 19.9 mIU/L with normal thyroxine concentrations.

RESULTS: Among 55,287 adults, 3450 had subclinical hypothyroidism (6.2\%) and 51,837 had euthyroidism. During follow-up, 9664 participants died (2168 of CHD), and 4470 participants had CHD events (among 7 studies). The risk of CHD events and CHD mortality increased with higher TSH concentrations. In age- and sex-adjusted analyses, the hazard ratio (HR) for CHD events was 1.00 (95\% confidence interval [CI], 0.86-1.18) for a TSH level of 4.5 to 6.9 mIU/L (20.3 vs 20.3/1000 person-years for participants with euthyroidism), 1.17 (95\% CI, 0.96-1.43) for a TSH level of 7.0 to 9.9 mIU/L (23.8/1000 person-years), and 1.89 (95\% CI, 1.28-2.80) for a TSH level of 10 to 19.9 mIU/L (n = 70 events/235; 38.4/1000 person-years; P <.001 for trend). The corresponding HRs for CHD mortality were 1.09 (95\% CI, 0.91-1.30; 5.3 vs 4.9/1000 person-years for participants with euthyroidism), 1.42 (95\% CI, 1.03-1.95; 6.9/1000 person-years), and 1.58 (95\% CI, 1.10-2.27, n = 28 deaths/333; 7.7/1000 person-years; P = .005 for trend). Total mortality was not increased among participants with subclinical hypothyroidism. Results were similar after further adjustment for traditional cardiovascular risk factors. Risks did not significantly differ by age, sex, or preexisting cardiovascular disease.

CONCLUSIONS: Subclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Coronary Disease, Female, Humans, Hypothyroidism, Male, Middle Aged, Mortality, Prospective Studies, Risk, Thyrotropin, Young Adult}, issn = {1538-3598}, doi = {10.1001/jama.2010.1361}, author = {Rodondi, Nicolas and den Elzen, Wendy P J and Bauer, Douglas C and Cappola, Anne R and Razvi, Salman and Walsh, John P and Asvold, Bj{\o}rn O and Iervasi, Giorgio and Imaizumi, Misa and Collet, Tinh-Hai and Bremner, Alexandra and Maisonneuve, Patrick and Sgarbi, Jos{\'e} A and Khaw, Kay-Tee and Vanderpump, Mark P J and Newman, Anne B and Cornuz, Jacques and Franklyn, Jayne A and Westendorp, Rudi G J and Vittinghoff, Eric and Gussekloo, Jacobijn} } @article {1246, title = {Subclinical thyroid dysfunction and incident hip fracture in older adults.}, journal = {Arch Intern Med}, volume = {170}, year = {2010}, month = {2010 Nov 22}, pages = {1876-83}, abstract = {

BACKGROUND: Subclinical thyroid dysfunction is common in older adults and affects bone metabolism, but its effects on fracture risk have not been reported. We sought to determine prospectively whether older men and women with subclinical hyperthyroidism or hypothyroidism have an increased risk of hip fracture.

METHODS: Prospective cohort of 3567 US community-dwelling adults, 65 years or older, with biochemically defined subclinical thyroid dysfunction or euthyroidism was enrolled from June 10, 1989, through May 30, 1990, and followed up through 2004. Main outcome measures included incidence and hazard ratios (HRs), with 95\% confidence intervals (CIs), of confirmed incident hip fractures for groups with subclinical hypothyroidism, subclinical hyperthyroidism, and euthyroidism as defined at baseline.

RESULTS: During 39 952 person-years (median follow-up, 13 years), hip fracture incidence (per 1000 men-years) was 13.65 in men with subclinical hyperthyroidism (n = 29) and 10.27 in men with subclinical hypothyroidism (n = 184), both greater than 5.0 in men with euthyroidism (n = 1159). Men with subclinical hypothyroidism had a multivariable-adjusted HR of 2.31 (95\% CI, 1.25-4.27); those with subclinical hyperthyroidism, 3.27 (0.99-11.30). After excluding those with baseline use of thyroid-altering medications, men with endogenous subclinical hyperthyroidism had a higher HR of 4.91 (95\% CI, 1.13-21.27), as did men with endogenous subclinical hypothyroidism (2.45, 1.27-4.73). Hip fracture incidence (per 1000 women-years) was 8.93 in women with subclinical hypothyroidism (n = 359) and 10.90 in women with subclinical hyperthyroidism (n = 142) compared with 10.18 in women with euthyroidism (n = 1694). No clear association between subclinical dysfunction and fracture was observed in women.

CONCLUSIONS: Older men with subclinical hyperthyroidism or hypothyroidism are at increased risk for hip fracture. Whether treatment of the subclinical syndrome reduces this risk is unknown.

}, keywords = {Aged, Female, Follow-Up Studies, Hip Fractures, Humans, Hyperthyroidism, Hypothyroidism, Incidence, Male, Multivariate Analysis, Proportional Hazards Models, Prospective Studies, Risk Factors, Sex Distribution, Thyrotropin, United States}, issn = {1538-3679}, doi = {10.1001/archinternmed.2010.424}, author = {Lee, Jennifer S and B{\r u}zkov{\'a}, Petra and Fink, Howard A and Vu, Joseph and Carbone, Laura and Chen, Zhao and Cauley, Jane and Bauer, Doug C and Cappola, Anne R and Robbins, John} } @article {1266, title = {Higher serum free testosterone concentration in older women is associated with greater bone mineral density, lean body mass, and total fat mass: the cardiovascular health study.}, journal = {J Clin Endocrinol Metab}, volume = {96}, year = {2011}, month = {2011 Apr}, pages = {989-96}, abstract = {

CONTEXT: The physiological importance of endogenous testosterone (T) in older women is poorly understood.

OBJECTIVE: The aim of the study was to determine the association of higher total and free T levels with bone mineral density (BMD), lean body mass, and fat mass in elderly women.

DESIGN: Total and free T were measured using sensitive assays in 232 community-dwelling women aged 67-94 yr who were enrolled in the Cardiovascular Health Study and had dual-energy x-ray absorptiometry scans. Cross-sectional analyses were performed to examine associations between total and free T and BMD and body composition.

RESULTS: In adjusted models, total T was directly associated with BMD at the lumbar spine (P = 0.04) and hip (P = 0.001), but not body composition outcomes, in all women, and after excluding estrogen users and adjusting for estradiol (P = 0.04 and 0.01, respectively). Free T was positively related to hip BMD, lean body mass, and body fat (all P < 0.05), with more than 10\% differences in each outcome between women at the highest and lowest ends of the free T range, with attenuation after excluding estrogen users and adjusting for estradiol.

CONCLUSIONS: In the setting of the low estradiol levels found in older women, circulating T levels were associated with bone density. Women with higher free T levels had greater lean body mass, consistent with the anabolic effect of T, and, in contrast to men, greater fat mass. Mechanistic studies are required to determine whether a causal relationship exists between T, bone, and body composition in this population and the degree to which any T effects are estrogen-independent.

}, keywords = {Adipose Tissue, Aged, Aged, 80 and over, Body Mass Index, Bone Density, Cardiovascular Physiological Phenomena, Cohort Studies, Female, Health, Humans, Organ Size, Osmolar Concentration, Osteoporosis, Postmenopausal, Testosterone, Thinness, Up-Regulation}, issn = {1945-7197}, doi = {10.1210/jc.2010-0926}, author = {Rariy, Chevon M and Ratcliffe, Sarah J and Weinstein, Rachel and Bhasin, Shalender and Blackman, Marc R and Cauley, Jane A and Robbins, John and Zmuda, Joseph M and Harris, Tamara B and Cappola, Anne R} } @article {1293, title = {Predictors of thyroid hormone initiation in older adults: results from the cardiovascular health study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {66}, year = {2011}, month = {2011 Jul}, pages = {809-14}, abstract = {

BACKGROUND: Despite widespread use, there are no data on initiation of thyroid hormone use in older people. We report the prevalence of thyroid hormone use and predictors of thyroid hormone initiation in a population of older men and women.

METHODS: Thyroid hormone medication data were collected annually from 1989 to 2006 in community-dwelling individuals aged 65 years and older enrolled in the Cardiovascular Health Study (N = 5,888). Associations of age, sex, race, body mass index, education, and coronary heart disease with initiation were evaluated using discrete-time survival analysis.

RESULTS: In 1989-1990, 8.9\% (95\% confidence interval 8.1\%-9.7\%) of participants were taking a thyroid hormone preparation, increasing to 20.0\% (95\% confidence interval 8.2\%-21.8\%) over 16 years. The average initiation rate was 1\% per year. The initiation rate was nonlinear with age, and those aged 85 years and older initiated thyroid hormone more than twice as frequently as those aged 65-69 years (hazard ratio = 2.34; 95\% confidence interval 1.43-3.85). White women were more likely to initiate thyroid hormone than any other race and sex group. Higher body mass index was independently associated with higher risk for initiation (p = .002) as was greater education (p = .02) and prevalent coronary heart disease (p = .03).

CONCLUSIONS: Thyroid hormone use is common in older people. The indications and benefits of thyroid hormone use in older individuals with the highest rate of thyroid hormone initiation-the oldest old, overweight and obese individuals, and those with coronary heart disease-should be investigated.

}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Cardiovascular Diseases, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Hypothyroidism, Incidence, Male, Prevalence, Prognosis, Retrospective Studies, Risk Factors, Sex Factors, Thyroid Hormones, Thyroxine, Time Factors, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glr063}, author = {Somwaru, Lily L and Arnold, Alice M and Cappola, Anne R} } @article {1374, title = {Decline in circulating insulin-like growth factors and mortality in older adults: cardiovascular health study all-stars study.}, journal = {J Clin Endocrinol Metab}, volume = {97}, year = {2012}, month = {2012 Jun}, pages = {1970-6}, abstract = {

BACKGROUND: The association between changes in IGF-I and IGF binding protein (IGFBP) levels and mortality in older adults is unknown.

STUDY DESIGN: Participants were 997 persons 77 to 100 yr old enrolled in the Cardiovascular Health Study All Stars Study. Plasma levels of IGF-I, IGFBP-1, and IGFBP-3 were assessed at two study examinations (1996-1997 and 2005-2006). Mortality was assessed between 2006 and 2010.

RESULTS: Cumulative mortality (CM) was similar among individuals who had at least 10\% decreases over time in IGF-I levels (CM = 29.6\%), individuals who had at least 10\% increases over time in IGF-I levels (CM = 24.7\%), and individuals who had IGF-I levels remaining within {\textpm}10\% over time (CM = 23.5\%). Adjusted for age, sex, race, diabetes, body mass index, creatinine, albumin, and C-reactive protein, decreasing IGF-I level had no significant association with overall cancer mortality or noncancer mortality. Levels of IGFBP-1 increased markedly over time by 38\% (median). Individuals with the largest increases in IGFBP-1 level over time had significantly increased risk of mortality. The adjusted hazard ratio per sd of IGFBP-1 change was 1.40 for overall cancer mortality (95\% confidence interval = 1.10, 1.77; P = 0.01) and 1.14 for noncancer mortality (95\% confidence interval = 1.02, 1.27; P = 0.02). Changes in IGFBP-3 levels were not significantly associated with mortality.

CONCLUSION: Among older adults, decreasing IGF-I level over time does not predict subsequent all-cause mortality, whereas increasing IGFBP-1 predicts increased risk of mortality.

}, keywords = {African Continental Ancestry Group, Aged, Aged, 80 and over, Cardiovascular Diseases, European Continental Ancestry Group, Female, Follow-Up Studies, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Longitudinal Studies, Male, Mortality, Predictive Value of Tests, Risk Factors}, issn = {1945-7197}, doi = {10.1210/jc.2011-2967}, author = {Kaplan, Robert C and B{\r u}zkov{\'a}, Petra and Cappola, Anne R and Strickler, Howard D and McGinn, Aileen P and Mercer, Laina D and Arnold, Alice M and Pollak, Michael N and Newman, Anne B} } @article {1404, title = {Longitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study.}, journal = {J Clin Endocrinol Metab}, volume = {97}, year = {2012}, month = {2012 Nov}, pages = {3944-50}, abstract = {

CONTEXT: Data on thyroid function in the oldest old are sparse, and existing studies show conflicting evidence on the relationship between thyroid function and mortality in this age group.

OBJECTIVE: We describe longitudinal changes in thyroid function in a cohort of elderly individuals and determine the relationship between thyroid function and mortality.

DESIGN, SETTING, AND PARTICIPANTS: Eight hundred forty-three participants in the Cardiovascular Health Study All Stars Study who were not taking thyroid medications and had thyroid function testing in 2005-2006 (mean age 85 yr).

MAIN OUTCOME MEASURE: Thyroid-stimulating hormone (TSH), free T(4) (FT4), total T(3), and thyroid peroxidase antibody status were measured in 1992-1993 and 2005-2006. Deaths were ascertained through February 2011.

RESULTS: There was a statistically significant 13\% increase in TSH, 1.7\% increase in FT4, and 13\% decrease in total T(3) over the 13-yr period. Two hundred eighty-seven deaths occurred over a median follow-up of 5.1 yr. There was no association between subclinical hypothyroidism[hazard ratio (HR) 0.97, 95\% confidence interval (CI) 0.66-1.43], TSH level (HR per milliunits per liter 0.94, 95\% CI 0.88-1.01), or persistent thyroid peroxidase antibody positivity (HR 1.09, 95\% CI 0.62-1.92), and death. However, FT4 was positively associated with death (HR per nanograms per deciliter 2.57, 95\% CI 1.32-5.02).

CONCLUSIONS: TSH increased over time in these older individuals. This elevation was not associated with increased or decreased mortality, although higher FT4 levels were associated with death. These findings raise concern for treatment of mild elevations of TSH in advanced age. Further studies are needed to determine the potential benefit of treating age-related changes in thyroid function.

}, keywords = {Aged, 80 and over, Female, Humans, Longitudinal Studies, Male, Thyroid Diseases, Thyroid Function Tests, Thyroid Gland, Thyrotropin, Thyroxine, Triiodothyronine}, issn = {1945-7197}, doi = {10.1210/jc.2012-2481}, author = {Waring, Avantika C and Arnold, Alice M and Newman, Anne B and B{\r u}zkov{\'a}, Petra and Hirsch, Calvin and Cappola, Anne R} } @article {1373, title = {The natural history of subclinical hypothyroidism in the elderly: the cardiovascular health study.}, journal = {J Clin Endocrinol Metab}, volume = {97}, year = {2012}, month = {2012 Jun}, pages = {1962-9}, abstract = {

CONTEXT: Studies of long-term outcomes of subclinical hypothyroidism have assessed only baseline thyroid function, despite natural transitions to euthyroidism and overt hypothyroidism over time.

OBJECTIVE: We provide estimates of persistence, resolution, and progression of subclinical hypothyroidism over 4 yr, stratified by baseline TSH, anti-thyroid peroxidase antibody (TPOAb) status, age, and sex.

DESIGN, SETTING, AND PARTICIPANTS: Participants were 3996 U.S. individuals at least 65 yr old enrolled in the Cardiovascular Health Study. Subclinical hypothyroidism was detected at baseline in 459 individuals not taking thyroid medication.

MAIN OUTCOME MEASURE: Thyroid function was evaluated at 2 and 4 yr and initiation of thyroid medication annually. Results were stratified by baseline TSH, TPOAb status, age, and sex.

RESULTS: Persistence of subclinical hypothyroidism was 56\% at 2 and 4 yr. At 2 yr, resolution was more common with a TSH of 4.5-6.9 mU/liter (46 vs. 10\% with TSH 7-9.9 mU/liter and 7\% with TSH >=10 mU/liter; P < 0.001) and with TPOAb negativity (48 vs. 15\% for positive; P < 0.001). Higher TSH and TPOAb positivity were independently associated with lower likelihood of reversion to euthyroidism (P < 0.05). TSH of 10 mU/liter or higher was independently associated with progression to overt hypothyroidism (P < 0.05). Transitions between euthyroidism and subclinical hypothyroidism were common between 2 and 4 yr. Age and sex did not affect transitions.

CONCLUSIONS: Subclinical hypothyroidism persists for 4 yr in just over half of older individuals, with high rates of reversion to euthyroidism in individuals with lower TSH concentrations and TPOAb negativity. Future studies should examine the impact of transitions in thyroid status on clinical outcomes.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Autoantibodies, Cardiovascular Diseases, Cohort Studies, Disease Progression, Female, Humans, Hypothyroidism, Iodide Peroxidase, Logistic Models, Longitudinal Studies, Male, Prevalence, Risk Factors, Seroepidemiologic Studies, Severity of Illness Index, Sex Distribution, Thyrotropin}, issn = {1945-7197}, doi = {10.1210/jc.2011-3047}, author = {Somwaru, Lily L and Rariy, Chevon M and Arnold, Alice M and Cappola, Anne R} } @article {1545, title = {Subclinical hyperthyroidism and the risk of coronary heart disease and mortality.}, journal = {Arch Intern Med}, volume = {172}, year = {2012}, month = {2012 May 28}, pages = {799-809}, abstract = {

BACKGROUND: Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting.We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts.

METHODS: Individual data on 52 674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22 437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Euthyroidism was defined as thyrotropin level between 0.45 and 4.49 mIU/L and endogenous subclinical hyperthyroidism as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels, after excluding those receiving thyroid-altering medications.

RESULTS: Of 52 674 participants, 2188 (4.2\%) had subclinical hyperthyroidism. During follow-up, 8527 participants died (including 1896 from CHD), 3653 of 22 437 had CHD events, and 785 of 8711 developed AF. In age- and sex-adjusted analyses, subclinical hyperthyroidism was associated with increased total mortality (hazard ratio[HR], 1.24, 95\% CI, 1.06-1.46), CHD mortality (HR,1.29; 95\% CI, 1.02-1.62), CHD events (HR, 1.21; 95\%CI, 0.99-1.46), and AF (HR, 1.68; 95\% CI, 1.16-2.43).Risks did not differ significantly by age, sex, or preexisting cardiovascular disease and were similar after further adjustment for cardiovascular risk factors, with attributable risk of 14.5\% for total mortality to 41.5\% forAF in those with subclinical hyperthyroidism. Risks for CHD mortality and AF (but not other outcomes) were higher for thyrotropin level lower than 0.10 mIU/L compared with thyrotropin level between 0.10 and 0.44 mIU/L(for both, P value for trend, .03).

CONCLUSION: Endogenous subclinical hyperthyroidism is associated with increased risks of total, CHD mortality, and incident AF, with highest risks of CHD mortality and AF when thyrotropin level is lower than 0.10 mIU/L.

}, keywords = {Adolescent, Adult, Age Distribution, Aged, Aged, 80 and over, Atrial Fibrillation, Cause of Death, Cohort Studies, Coronary Artery Disease, Female, Humans, Hyperthyroidism, Male, Middle Aged, Prognosis, Prospective Studies, Risk Assessment, Severity of Illness Index, Sex Distribution, Survival Analysis, Switzerland, Thyroid Function Tests, Thyrotropin, Young Adult}, issn = {1538-3679}, doi = {10.1001/archinternmed.2012.402}, author = {Collet, Tinh-Hai and Gussekloo, Jacobijn and Bauer, Douglas C and den Elzen, Wendy P J and Cappola, Anne R and Balmer, Philippe and Iervasi, Giorgio and Asvold, Bj{\o}rn O and Sgarbi, Jos{\'e} A and V{\"o}lzke, Henry and Gencer, Bari{\c s} and Maciel, Rui M B and Molinaro, Sabrina and Bremner, Alexandra and Luben, Robert N and Maisonneuve, Patrick and Cornuz, Jacques and Newman, Anne B and Khaw, Kay-Tee and Westendorp, Rudi G J and Franklyn, Jayne A and Vittinghoff, Eric and Walsh, John P and Rodondi, Nicolas} } @article {6087, title = {Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts.}, journal = {Circulation}, volume = {126}, year = {2012}, month = {2012 Aug 28}, pages = {1040-9}, abstract = {

BACKGROUND: American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events.

METHODS AND RESULTS: We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of heart failure events. Individual data on 25 390 participants with 216 248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH of 0.45 to 4.49 mIU/L, subclinical hypothyroidism as TSH of 4.5 to 19.9 mIU/L, and subclinical hyperthyroidism as TSH <0.45 mIU/L, the last two with normal free thyroxine levels. Among 25 390 participants, 2068 (8.1\%) had subclinical hypothyroidism and 648 (2.6\%) had subclinical hyperthyroidism. In age- and sex-adjusted analyses, risks of heart failure events were increased with both higher and lower TSH levels (P for quadratic pattern <0.01); the hazard ratio was 1.01 (95\% confidence interval, 0.81-1.26) for TSH of 4.5 to 6.9 mIU/L, 1.65 (95\% confidence interval, 0.84-3.23) for TSH of 7.0 to 9.9 mIU/L, 1.86 (95\% confidence interval, 1.27-2.72) for TSH of 10.0 to 19.9 mIU/L (P for trend <0.01) and 1.31 (95\% confidence interval, 0.88-1.95) for TSH of 0.10 to 0.44 mIU/L and 1.94 (95\% confidence interval, 1.01-3.72) for TSH <0.10 mIU/L (P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors.

CONCLUSION: Risks of heart failure events were increased with both higher and lower TSH levels, particularly for TSH >=10 and <0.10 mIU/L.

}, keywords = {Adult, Aged, Aged, 80 and over, Comorbidity, Female, Follow-Up Studies, Heart Failure, Humans, Hypothyroidism, Male, Middle Aged, Prospective Studies, Risk, Risk Factors, Sensitivity and Specificity, Thyrotropin, Thyroxine}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.112.096024}, author = {Gencer, Bari{\c s} and Collet, Tinh-Hai and Virgini, Vanessa and Bauer, Douglas C and Gussekloo, Jacobijn and Cappola, Anne R and Nanchen, David and den Elzen, Wendy P J and Balmer, Philippe and Luben, Robert N and Iacoviello, Massimo and Triggiani, Vincenzo and Cornuz, Jacques and Newman, Anne B and Khaw, Kay-Tee and Jukema, J Wouter and Westendorp, Rudi G J and Vittinghoff, Eric and Aujesky, Drahomir and Rodondi, Nicolas} } @article {5877, title = {A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.}, journal = {PLoS Genet}, volume = {9}, year = {2013}, month = {2013}, pages = {e1003266}, abstract = {

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10\% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64\% and 2.30\% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

}, keywords = {Female, Genome-Wide Association Study, Humans, Hyperthyroidism, Hypothyroidism, Male, Phenotype, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Sex Characteristics, Signal Transduction, Thyroid Gland, Thyrotropin, Thyroxine}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003266}, author = {Porcu, Eleonora and Medici, Marco and Pistis, Giorgio and Volpato, Claudia B and Wilson, Scott G and Cappola, Anne R and Bos, Steffan D and Deelen, Joris and den Heijer, Martin and Freathy, Rachel M and Lahti, Jari and Liu, Chunyu and Lopez, Lorna M and Nolte, Ilja M and O{\textquoteright}Connell, Jeffrey R and Tanaka, Toshiko and Trompet, Stella and Arnold, Alice and Bandinelli, Stefania and Beekman, Marian and B{\"o}hringer, Stefan and Brown, Suzanne J and Buckley, Brendan M and Camaschella, Clara and de Craen, Anton J M and Davies, Gail and de Visser, Marieke C H and Ford, Ian and Forsen, Tom and Frayling, Timothy M and Fugazzola, Laura and G{\"o}gele, Martin and Hattersley, Andrew T and Hermus, Ad R and Hofman, Albert and Houwing-Duistermaat, Jeanine J and Jensen, Richard A and Kajantie, Eero and Kloppenburg, Margreet and Lim, Ee M and Masciullo, Corrado and Mariotti, Stefano and Minelli, Cosetta and Mitchell, Braxton D and Nagaraja, Ramaiah and Netea-Maier, Romana T and Palotie, Aarno and Persani, Luca and Piras, Maria G and Psaty, Bruce M and R{\"a}ikk{\"o}nen, Katri and Richards, J Brent and Rivadeneira, Fernando and Sala, Cinzia and Sabra, Mona M and Sattar, Naveed and Shields, Beverley M and Soranzo, Nicole and Starr, John M and Stott, David J and Sweep, Fred C G J and Usala, Gianluca and van der Klauw, Melanie M and van Heemst, Diana and van Mullem, Alies and Vermeulen, Sita H and Visser, W Edward and Walsh, John P and Westendorp, Rudi G J and Widen, Elisabeth and Zhai, Guangju and Cucca, Francesco and Deary, Ian J and Eriksson, Johan G and Ferrucci, Luigi and Fox, Caroline S and Jukema, J Wouter and Kiemeney, Lambertus A and Pramstaller, Peter P and Schlessinger, David and Shuldiner, Alan R and Slagboom, Eline P and Uitterlinden, Andr{\'e} G and Vaidya, Bijay and Visser, Theo J and Wolffenbuttel, Bruce H R and Meulenbelt, Ingrid and Rotter, Jerome I and Spector, Tim D and Hicks, Andrew A and Toniolo, Daniela and Sanna, Serena and Peeters, Robin P and Naitza, Silvia} } @article {1551, title = {Persistent subclinical hypothyroidism and cardiovascular risk in the elderly: the cardiovascular health study.}, journal = {J Clin Endocrinol Metab}, volume = {98}, year = {2013}, month = {2013 Feb}, pages = {533-40}, abstract = {

CONTEXT: Use of a single set of thyroid function tests to define subclinical hypothyroidism may lead to misclassification over time and could influence findings from longitudinal studies.

OBJECTIVE: We assessed the risks of coronary heart disease (CHD), heart failure (HF), and cardiovascular (CV) death in older adults with persistent subclinical hypothyroidism.

DESIGN, SETTING, AND PARTICIPANTS: The study included 679 subclinically hypothyroid and 4184 euthyroid U.S. individuals at least 65 yr old enrolled in the Cardiovascular Health Study and not taking thyroid preparations.

MAIN OUTCOME MEASURE: We measured the 10-yr risk of incident CHD, HF, and CV death from persistent subclinical hypothyroidism, overall and stratified by degree of TSH elevation (4.5-6.9, 7.0-9.9, and 10.0-19.9 mU/liter).

RESULTS: There was no association between persistent subclinical hypothyroidism and incident CHD [hazard ratio (HR), 1.12; 95\% confidence interval (CI), 0.93-1.36], HF (HR, 1.05; 95\% CI, 0.97-1.27), or CV death (HR, 1.07; 95\% CI, 0.87-1.31) in adjusted analyses in which subclinical hypothyroidism was modeled as a time-varying exposure using up to four serial thyroid function tests. When subclinical hypothyroidism was stratified by degree of TSH elevation, no significant associations were found in any stratum. Findings were similar in fixed exposure analyses in which only participants with testing 2 yr apart were considered, with no association between persistent or transient subclinical hypothyroidism and incident CHD, HF, or CV death.

CONCLUSIONS: Our data do not support increased risk of CHD, HF, or CV death in older adults with persistent subclinical hypothyroidism.

}, keywords = {Aged, Aged, 80 and over, Coronary Disease, Female, Heart Failure, Humans, Hypothyroidism, Incidence, Longitudinal Studies, Male, Risk, Thyroid Function Tests}, issn = {1945-7197}, doi = {10.1210/jc.2012-2180}, author = {Hyland, Kristen A and Arnold, Alice M and Lee, Jennifer S and Cappola, Anne R} } @article {6000, title = {Do changes in circulating biomarkers track with each other and with functional changes in older adults?}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {69}, year = {2014}, month = {2014 Feb}, pages = {174-81}, abstract = {

BACKGROUND: It is unclear if changes in proposed circulating biomarkers of aging are strongly correlated to each other or functional change. We tested if biomarker changes track with each other and with functional measures over 9 years in older adults.

METHODS: Dehydroepiandrosterone sulfate (DHEAS), adiponectin, insulin-like growth factor 1 (IGF-1), IGF binding proteins 1 (IGFBP-1) and 3 (IGFBP-3), interleukin-6 (IL-6), cholesterol, and function (gait speed, grip strength, Modified Mini Mental Status Exam [3MSE] and Digit Symbol Substitution Test [DSST] scores) were measured in 1996-1997 and 2005-2006 in the Cardiovascular Health Study All Stars study (N = 901, mean [standard deviation, SD] age 85.3 [3.6] years in 2005-2006). Adjusted Pearson correlations illustrated if biomarkers tracked together. Multivariable linear regression demonstrated if biomarker changes tracked with functional changes.

RESULTS: Correlations among biomarker changes were mostly <0.2. In models with each biomarker entered separately, a 1-SD increase biomarker change was associated with change in function as follows: grip strength (DHEAS β = 0.61kg, p = .001; IL-6 β = -0.46kg, p = .012; cholesterol men β = 0.79kg, p = .016); gait speed (DHEAS β = 0.02 meters per second, p = .039; IL-6 β = -0.018 meters per second, p = .049); and DSST score (DHEAS women β = 1.46, p = .004; IL-6 β = -0.83, p = .027). When biomarkers were entered in the same model, significant associations remaining were as follows: grip strength (DHEAS β = 0.54kg, p = .005; IL-6 β = -0.43kg, p = .022); 3MSE score (IGF-1 β = 0.96, p = .04; IGFBP-3 β = -1.07, p = .024); and DSST score (DHEAS women β = 1.27, p = .012; IL-6 β = -0.80, p = .04).

CONCLUSION: Changes in biomarkers were poorly correlated, supporting a model of stochastic, independent change across systems. DHEAS and IL-6 tracked most closely with function, illustrating that changes in inflammation and sex steroids may play dominant roles in changes of these functional outcomes.

}, keywords = {Adiponectin, Aged, Aged, 80 and over, Aging, Biomarkers, Cholesterol, Cognition, Cohort Studies, Dehydroepiandrosterone Sulfate, Female, Gait, Hand Strength, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Interleukin-6, Male, Neuropsychological Tests, Psychomotor Performance, Time Factors}, issn = {1758-535X}, doi = {10.1093/gerona/glt088}, author = {Sanders, Jason L and Ding, Victoria and Arnold, Alice M and Kaplan, Robert C and Cappola, Anne R and Kizer, Jorge R and Boudreau, Robert M and Cushman, Mary and Newman, Anne B} } @article {6213, title = {Subclinical hypothyroidism, weight change, and body composition in the elderly: the Cardiovascular Health Study.}, journal = {J Clin Endocrinol Metab}, volume = {99}, year = {2014}, month = {2014 Apr}, pages = {1220-6}, abstract = {

BACKGROUND: Subclinical hypothyroidism is common in the elderly, yet its relationship with weight and body composition is unclear.

OBJECTIVE: We examined the relationship between subclinical hypothyroidism and weight change and body composition in older adults.

METHODS: A total of 427 subclinically hypothyroid and 2864 euthyroid U.S. individuals >=65 years old enrolled in the Cardiovascular Health Study and not taking thyroid preparations were included. Analyses of 6-year weight change were performed, compared by thyroid status. A cross-sectional analysis of thyroid status and body composition was performed in a subset of 1276 participants who had dual-energy x-ray absorptiometry scans. Models were risk factor-adjusted and stratified by sex.

RESULTS: Overall, participants lost weight during follow-up (-0.38 kg/y in men, -0.37 kg/y in women). Subclinical hypothyroidism, when assessed at a single time point or persisting over 2 years, was not associated with a difference in weight change compared with euthyroidism. Subclinical hypothyroidism was also not associated with differences in lean mass, fat mass, or percent fat compared with euthyroidism. A TSH level 1 mU/L higher within the euthyroid or subclinical hypothyroid range was associated with a 0.51-kg higher baseline weight in women only (P < .001) but not with weight change in either sex. A 1 ng/dL higher free T4 level was associated with lower baseline weight and 0.32 kg/y greater weight loss in women only (P = .003). Baseline weight and weight change did not differ by T3 levels.

CONCLUSIONS: Our data do not support a clinically significant impact of subclinical hypothyroidism on weight status in the elderly.

}, keywords = {Aged, Aged, 80 and over, Asymptomatic Diseases, Body Composition, Body Mass Index, Cohort Studies, Female, Humans, Hypothyroidism, Male, Thyroid Gland, Weight Loss}, issn = {1945-7197}, doi = {10.1210/jc.2013-3591}, author = {Garin, Margaret C and Arnold, Alice M and Lee, Jennifer S and Tracy, Russell P and Cappola, Anne R} } @article {6401, title = {Subclinical thyroid dysfunction and hip fracture and bone mineral density in older adults: the cardiovascular health study.}, journal = {J Clin Endocrinol Metab}, volume = {99}, year = {2014}, month = {2014 Aug}, pages = {2657-64}, abstract = {

BACKGROUND: Subclinical thyroid dysfunction is common in the elderly, yet its relationship with hip fracture and bone mineral density (BMD) is unclear.

OBJECTIVE: We examined the association between endogenous subclinical hyper- and hypothyroidism and hip fracture and BMD in older adults.

METHODS: A total of 4936 US individuals 65 years old or older enrolled in the Cardiovascular Health Study and not taking thyroid preparations were included. Analyses of incident hip fracture were performed by thyroid status, over a median follow-up of 12 years. A cross-sectional analysis of thyroid status and BMD was performed in a subset of 1317 participants who had dual-energy x-ray absorptiometry scans. Models were adjusted for risk factors and stratified by sex.

RESULTS: No association was found between subclinical hypothyroidism and incident hip fracture compared with euthyroidism, when assessed at a single time point or persisting at two time points, in either women [hazard ratio (HR) 0.91, 95\% confidence interval (CI) 0.69-1.20 for a single and HR 0.79, 95\% CI 0.52-1.21 for two time points] or men (HR 1.27, 95\% CI 0.82-1.95 for a single and HR 1.09, 95\% CI 0.57-2.10 for two time points). Likewise, no association was found between subclinical hyperthyroidism and incident hip fracture in either sex (HR 1.11, 95\% CI 0.55-2.25 in women and HR 1.78, 95\% CI 0.56-5.66 in men). No association was found between subclinical thyroid dysfunction and BMD at the lumbar spine, total hip, or femoral neck sites.

CONCLUSIONS: Our data suggest no association between subclinical hypothyroidism or subclinical hyperthyroidism and hip fracture risk or BMD in older men and women. Additional data are needed to improve the precision of estimates for subclinical hyperthyroidism and in men.

}, keywords = {Absorptiometry, Photon, Aged, Aged, 80 and over, Asymptomatic Diseases, Bone Density, Cardiovascular System, Cohort Studies, Cross-Sectional Studies, Female, Hip Fractures, Humans, Male, Osteoporotic Fractures, Risk Factors, Sex Factors, Thyroid Diseases}, issn = {1945-7197}, doi = {10.1210/jc.2014-1051}, author = {Garin, Margaret C and Arnold, Alice M and Lee, Jennifer S and Robbins, John and Cappola, Anne R} } @article {6277, title = {Testosterone and dihydrotestosterone and incident ischaemic stroke in men in the Cardiovascular Health Study.}, journal = {Clin Endocrinol (Oxf)}, volume = {81}, year = {2014}, month = {2014 Nov}, pages = {746-53}, abstract = {

OBJECTIVE: Ischaemic stroke is a major cause of morbidity and mortality in elderly men. Our main objective was to examine whether testosterone (T) or dihydrotestosterone (DHT) was associated with incident ischaemic stroke in elderly men.

DESIGN: Cohort study.

PARTICIPANTS: Elderly men in the Cardiovascular Health Study who had no history of stroke, heart disease or prostate cancer as of 1994 and were followed until December 2010.

MEASUREMENTS: Adjudicated ischaemic stroke.

RESULTS: Among 1032 men (mean age 76, range 66-97), followed for a median of 10~years, 114 had an incident ischaemic stroke. Total T and free T were not significantly associated with stroke risk, while DHT had a nonlinear association with incident stroke (P~=~0{\textperiodcentered}006) in analyses adjusted for stroke risk factors. The lowest risk of stroke was at DHT levels of 50-75~ng/dl, with greater risk of stroke at DHT levels above 75~ng/dl or below 50~ng/dl. Results were unchanged when SHBG was added to the model. Calculated free DHT had an inverse linear association with incident ischaemic stroke with HR 0{\textperiodcentered}77 (95\% CI, 0{\textperiodcentered}61, 0{\textperiodcentered}98) per standard deviation in analyses adjusted for stroke risk factors.

CONCLUSIONS: Dihydrotestosterone had a nonlinear association with stroke risk in which there was an optimal DHT level associated with the lowest stroke risk. Further studies are needed to confirm these results and to clarify whether there is an optimal androgen range associated with the least risk of adverse outcomes in elderly men.

}, keywords = {Aged, Aged, 80 and over, Brain Ischemia, Cardiovascular Physiological Phenomena, Dihydrotestosterone, Health, Humans, Incidence, Longitudinal Studies, Male, Stroke, Testosterone}, issn = {1365-2265}, doi = {10.1111/cen.12452}, author = {Shores, Molly M and Arnold, Alice M and Biggs, Mary L and Longstreth, W T and Smith, Nicholas L and Kizer, Jorge R and Cappola, Anne R and Hirsch, Calvin H and Marck, Brett T and Matsumoto, Alvin M} } @article {6278, title = {Testosterone, dihydrotestosterone, and incident cardiovascular disease and mortality in the cardiovascular health study.}, journal = {J Clin Endocrinol Metab}, volume = {99}, year = {2014}, month = {2014 Jun}, pages = {2061-8}, abstract = {

CONTEXT: Low testosterone (T) is associated with prevalent cardiovascular disease (CVD) and mortality. DHT, a more potent androgen, may also be associated with CVD and mortality, but few studies have examined this.

OBJECTIVE: The study objective was to examine whether T and DHT are risk factors for incident CVD and mortality.

DESIGN: In a longitudinal cohort study, we evaluated whether total T, calculated free T (cFT), DHT, and calculated free DHT were associated with incident CVD and mortality in men in the Cardiovascular Health Study (mean age 76, range 66-97 years) who were free of CVD at the time of blood collection.

MAIN OUTCOME: The main outcomes were incident CVD and all-cause mortality.

RESULTS: Among 1032 men followed for a median of 9 years, 436 incident CVD events and 777 deaths occurred. In models adjusted for cardiovascular risk factors, total T and cFT were not associated with incident CVD or all-cause mortality, whereas DHT and calculated free DHT had curvilinear associations with incident CVD (P < .002 and P = .04, respectively) and all-cause mortality (P < .001 for both).

CONCLUSIONS: In a cohort of elderly men, DHT and calculated free DHT were associated with incident CVD and all-cause mortality. Further studies are needed to confirm these results and to clarify the underlying physiologic mechanisms.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cause of Death, Dihydrotestosterone, Humans, Incidence, Longitudinal Studies, Male, Mortality, Residence Characteristics, Risk Factors, Testosterone}, issn = {1945-7197}, doi = {10.1210/jc.2013-3576}, author = {Shores, Molly M and Biggs, Mary L and Arnold, Alice M and Smith, Nicholas L and Longstreth, W T and Kizer, Jorge R and Hirsch, Calvin H and Cappola, Anne R and Matsumoto, Alvin M} } @article {6553, title = {Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis.}, journal = {J Clin Endocrinol Metab}, volume = {99}, year = {2014}, month = {2014 Sep}, pages = {3353-62}, abstract = {

CONTEXT: Subclinical hypothyroidism has been associated with increased risk of coronary heart disease (CHD), particularly with thyrotropin levels of 10.0 mIU/L or greater. The measurement of thyroid antibodies helps predict the progression to overt hypothyroidism, but it is unclear whether thyroid autoimmunity independently affects CHD risk.

OBJECTIVE: The objective of the study was to compare the CHD risk of subclinical hypothyroidism with and without thyroid peroxidase antibodies (TPOAbs).

DATA SOURCES AND STUDY SELECTION: A MEDLINE and EMBASE search from 1950 to 2011 was conducted for prospective cohorts, reporting baseline thyroid function, antibodies, and CHD outcomes.

DATA EXTRACTION: Individual data of 38 274 participants from six cohorts for CHD mortality followed up for 460 333 person-years and 33 394 participants from four cohorts for CHD events.

DATA SYNTHESIS: Among 38 274 adults (median age 55 y, 63\% women), 1691 (4.4\%) had subclinical hypothyroidism, of whom 775 (45.8\%) had positive TPOAbs. During follow-up, 1436 participants died of CHD and 3285 had CHD events. Compared with euthyroid individuals, age- and gender-adjusted risks of CHD mortality in subclinical hypothyroidism were similar among individuals with and without TPOAbs [hazard ratio (HR) 1.15, 95\% confidence interval (CI) 0.87-1.53 vs HR 1.26, CI 1.01-1.58, P for interaction = .62], as were risks of CHD events (HR 1.16, CI 0.87-1.56 vs HR 1.26, CI 1.02-1.56, P for interaction = .65). Risks of CHD mortality and events increased with higher thyrotropin, but within each stratum, risks did not differ by TPOAb status.

CONCLUSIONS: CHD risk associated with subclinical hypothyroidism did not differ by TPOAb status, suggesting that biomarkers of thyroid autoimmunity do not add independent prognostic information for CHD outcomes.

}, keywords = {Adult, Aged, Aged, 80 and over, Autoantibodies, Coronary Disease, Female, Humans, Hypothyroidism, Incidence, Male, Middle Aged, Prevalence, Prognosis, Risk Factors, Seroepidemiologic Studies, Severity of Illness Index, Young Adult}, issn = {1945-7197}, doi = {10.1210/jc.2014-1250}, author = {Collet, Tinh-Hai and Bauer, Douglas C and Cappola, Anne R and Asvold, Bj{\o}rn O and Weiler, Stefan and Vittinghoff, Eric and Gussekloo, Jacobijn and Bremner, Alexandra and den Elzen, Wendy P J and Maciel, Rui M B and Vanderpump, Mark P J and Cornuz, Jacques and D{\"o}rr, Marcus and Wallaschofski, Henri and Newman, Anne B and Sgarbi, Jos{\'e} A and Razvi, Salman and V{\"o}lzke, Henry and Walsh, John P and Aujesky, Drahomir and Rodondi, Nicolas} } @article {6800, title = {Subclinical Hypothyroidism and the Risk of Stroke Events and Fatal Stroke: An Individual Participant Data Analysis.}, journal = {J Clin Endocrinol Metab}, volume = {100}, year = {2015}, month = {2015 Jun}, pages = {2181-91}, abstract = {

OBJECTIVE: The objective was to determine the risk of stroke associated with subclinical hypothyroidism.

DATA SOURCES AND STUDY SELECTION: Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data on thyroid function and stroke outcome. Euthyroidism was defined as TSH levels of 0.45-4.49 mIU/L, and subclinical hypothyroidism was defined as TSH levels of 4.5-19.9 mIU/L with normal T4 levels.

DATA EXTRACTION AND SYNTHESIS: We collected individual participant data on 47 573 adults (3451 subclinical hypothyroidism) from 17 cohorts and followed up from 1972-2014 (489 192 person-years). Age- and sex-adjusted pooled hazard ratios (HRs) for participants with subclinical hypothyroidism compared to euthyroidism were 1.05 (95\% confidence interval [CI], 0.91-1.21) for stroke events (combined fatal and nonfatal stroke) and 1.07 (95\% CI, 0.80-1.42) for fatal stroke. Stratified by age, the HR for stroke events was 3.32 (95\% CI, 1.25-8.80) for individuals aged 18-49 years. There was an increased risk of fatal stroke in the age groups 18-49 and 50-64 years, with a HR of 4.22 (95\% CI, 1.08-16.55) and 2.86 (95\% CI, 1.31-6.26), respectively (p trend 0.04). We found no increased risk for those 65-79 years old (HR, 1.00; 95\% CI, 0.86-1.18) or >= 80 years old (HR, 1.31; 95\% CI, 0.79-2.18). There was a pattern of increased risk of fatal stroke with higher TSH concentrations.

CONCLUSIONS: Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.

}, keywords = {Adult, Asymptomatic Diseases, Female, Humans, Hypothyroidism, Incidence, Male, Risk Factors, Stroke, Thyrotropin}, issn = {1945-7197}, doi = {10.1210/jc.2015-1438}, author = {Chaker, Layal and Baumgartner, Christine and den Elzen, Wendy P J and Ikram, M Arfan and Blum, Manuel R and Collet, Tinh-Hai and Bakker, Stephan J L and Dehghan, Abbas and Drechsler, Christiane and Luben, Robert N and Hofman, Albert and Portegies, Marileen L P and Medici, Marco and Iervasi, Giorgio and Stott, David J and Ford, Ian and Bremner, Alexandra and Wanner, Christoph and Ferrucci, Luigi and Newman, Anne B and Dullaart, Robin P and Sgarbi, Jos{\'e} A and Ceresini, Graziano and Maciel, Rui M B and Westendorp, Rudi G and Jukema, J Wouter and Imaizumi, Misa and Franklyn, Jayne A and Bauer, Douglas C and Walsh, John P and Razvi, Salman and Khaw, Kay-Tee and Cappola, Anne R and V{\"o}lzke, Henry and Franco, Oscar H and Gussekloo, Jacobijn and Rodondi, Nicolas and Peeters, Robin P} } @article {6795, title = {Subclinical thyroid dysfunction and fracture risk: a meta-analysis.}, journal = {JAMA}, volume = {313}, year = {2015}, month = {2015 May 26}, pages = {2055-65}, abstract = {

IMPORTANCE: Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking.

OBJECTIVE: To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures.

DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures.

DATA EXTRACTION: Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH >=4.50-19.99 mIU/L) with normal thyroxine concentrations.

MAIN OUTCOME AND MEASURES: The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes.

RESULTS: Among 70,298 participants, 4092 (5.8\%) had subclinical hypothyroidism and 2219 (3.2\%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6\%; 12 studies), any fracture in 2528 participants (9.0\%; 8 studies), nonspine fracture in 2018 participants (8.4\%; 8 studies), and spine fracture in 296 participants (1.3\%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95\% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95\% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95\% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95\% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95\% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95\% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95\% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95\% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95\% CI, 1.19-1.93) for hip fracture, 1.42 (95\% CI, 1.16-1.74) for any fracture, and 1.74 (95\% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk.

CONCLUSIONS AND RELEVANCE: Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Female, Fractures, Bone, Hip Fractures, Humans, Hyperthyroidism, Hypothyroidism, Male, Middle Aged, Risk Factors, Spinal Fractures, Thyrotropin, Young Adult}, issn = {1538-3598}, doi = {10.1001/jama.2015.5161}, author = {Blum, Manuel R and Bauer, Douglas C and Collet, Tinh-Hai and Fink, Howard A and Cappola, Anne R and da Costa, Bruno R and Wirth, Christina D and Peeters, Robin P and Asvold, Bj{\o}rn O and den Elzen, Wendy P J and Luben, Robert N and Imaizumi, Misa and Bremner, Alexandra P and Gogakos, Apostolos and Eastell, Richard and Kearney, Patricia M and Strotmeyer, Elsa S and Wallace, Erin R and Hoff, Mari and Ceresini, Graziano and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Stott, David J and Westendorp, Rudi G J and Khaw, Kay-Tee and Langhammer, Arnuf and Ferrucci, Luigi and Gussekloo, Jacobijn and Williams, Graham R and Walsh, John P and J{\"u}ni, Peter and Aujesky, Drahomir and Rodondi, Nicolas} } @article {6551, title = {Thyroid function in the euthyroid range and adverse outcomes in older adults.}, journal = {J Clin Endocrinol Metab}, volume = {100}, year = {2015}, month = {2015 Mar}, pages = {1088-96}, abstract = {

CONTEXT: The appropriateness of current reference ranges for thyroid function testing in older adults has been questioned.

OBJECTIVE: This study aimed to determine the relationship between thyroid function tests within the euthyroid range and adverse outcomes in older adults not taking thyroid medication.

DESIGN, SETTING, AND PARTICIPANTS: US community-dwelling adults years of older (n = 2843) enrolled onto the Cardiovascular Health Study with TSH, free T4 (FT4), and total T3 concentrations in the euthyroid range.

MAIN OUTCOME MEASURES: Incidence of atrial fibrillation, coronary heart disease, heart failure, hip fracture, dementia, and all-cause death were measured.

RESULTS: No departures from linearity were detected. Higher TSH was negatively associated (P = .03) and higher FT4 was positively associated (P = .007) with mortality. Higher FT4 was associated with atrial fibrillation (P < .001) and heart failure (P = .004). Compared with the first quartile, individuals with TSH in the fourth quartile had a 9.6 per 1000 person-year lower incidence of dementia (P < .05) and those with FT4 in the fourth quartile had higher incidences of atrial fibrillation, coronary heart disease, heart failure, and mortality (11.0, 8.0, 7.8, and 14.3 per 1000 person-years, respectively, all P < .05). Total T3 was not associated with any outcome.

CONCLUSIONS: Higher TSH and lower FT4 concentrations within the euthyroid range are associated with lower risk of multiple adverse events in older people, including mortality. This suggests tolerance for lower thyroid hormone levels in this age group. Clinical trials are needed to evaluate the risk-benefit profile of new thresholds for initiating treatment and optimal target concentrations for thyroid hormone replacement in older people.

}, keywords = {Aged, Aged, 80 and over, Aging, Atrial Fibrillation, Cause of Death, Coronary Disease, Dementia, Female, Heart Failure, Hip Fractures, Humans, Incidence, Male, Prognosis, Reference Values, Survival Analysis, Thyroid Function Tests, Thyroid Gland}, issn = {1945-7197}, doi = {10.1210/jc.2014-3586}, author = {Cappola, Anne R and Arnold, Alice M and Wulczyn, Kendra and Carlson, Michelle and Robbins, John and Psaty, Bruce M} } @article {6798, title = {Thyroid function within the normal range and risk of coronary heart disease: an individual participant data analysis of 14 cohorts.}, journal = {JAMA Intern Med}, volume = {175}, year = {2015}, month = {2015 Jun}, pages = {1037-47}, abstract = {

IMPORTANCE: Some experts suggest that serum thyrotropin levels in the upper part of the current reference range should be considered abnormal, an approach that would reclassify many individuals as having mild hypothyroidism. Health hazards associated with such thyrotropin levels are poorly documented, but conflicting evidence suggests that thyrotropin levels in the upper part of the reference range may be associated with an increased risk of coronary heart disease (CHD).

OBJECTIVE: To assess the association between differences in thyroid function within the reference range and CHD risk.

DESIGN, SETTING, AND PARTICIPANTS: Individual participant data analysis of 14 cohorts with baseline examinations between July 1972 and April 2002 and with median follow-up ranging from 3.3 to 20.0 years. Participants included 55,412 individuals with serum thyrotropin levels of 0.45 to 4.49 mIU/L and no previously known thyroid or cardiovascular disease at baseline.

EXPOSURES: Thyroid function as expressed by serum thyrotropin levels at baseline.

MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) of CHD mortality and CHD events according to thyrotropin levels after adjustment for age, sex, and smoking status.

RESULTS: Among 55,412 individuals, 1813 people (3.3\%) died of CHD during 643,183 person-years of follow-up. In 10 cohorts with information on both nonfatal and fatal CHD events, 4666 of 48,875 individuals (9.5\%) experienced a first-time CHD event during 533,408 person-years of follow-up. For each 1-mIU/L higher thyrotropin level, the HR was 0.97 (95\% CI, 0.90-1.04) for CHD mortality and 1.00 (95\% CI, 0.97-1.03) for a first-time CHD event. Similarly, in analyses by categories of thyrotropin, the HRs of CHD mortality (0.94 [95\% CI, 0.74-1.20]) and CHD events (0.97 [95\% CI, 0.83-1.13]) were similar among participants with the highest (3.50-4.49 mIU/L) compared with the lowest (0.45-1.49 mIU/L) thyrotropin levels. Subgroup analyses by sex and age group yielded similar results.

CONCLUSIONS AND RELEVANCE: Thyrotropin levels within the reference range are not associated with risk of CHD events or CHD mortality. This finding suggests that differences in thyroid function within the population reference range do not influence the risk of CHD. Increased CHD risk does not appear to be a reason for lowering the upper thyrotropin reference limit.

}, keywords = {Cohort Studies, Coronary Disease, Humans, Hypothyroidism, Thyrotropin}, issn = {2168-6114}, doi = {10.1001/jamainternmed.2015.0930}, author = {Asvold, Bj{\o}rn O and Vatten, Lars J and Bj{\o}ro, Trine and Bauer, Douglas C and Bremner, Alexandra and Cappola, Anne R and Ceresini, Graziano and den Elzen, Wendy P J and Ferrucci, Luigi and Franco, Oscar H and Franklyn, Jayne A and Gussekloo, Jacobijn and Iervasi, Giorgio and Imaizumi, Misa and Kearney, Patricia M and Khaw, Kay-Tee and Maciel, Rui M B and Newman, Anne B and Peeters, Robin P and Psaty, Bruce M and Razvi, Salman and Sgarbi, Jos{\'e} A and Stott, David J and Trompet, Stella and Vanderpump, Mark P J and V{\"o}lzke, Henry and Walsh, John P and Westendorp, Rudi G J and Rodondi, Nicolas} } @article {7238, title = {Thyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis.}, journal = {J Clin Endocrinol Metab}, volume = {101}, year = {2016}, month = {2016 Nov}, pages = {4270-4282}, abstract = {

CONTEXT: The currently applied reference ranges for thyroid function are under debate. Despite evidence that thyroid function within the reference range is related with several cardiovascular disorders, its association with the risk of stroke has not been evaluated previously.

DESIGN AND SETTING: We identified studies through a systematic literature search and the Thyroid Studies Collaboration, a collaboration of prospective cohort studies. Studies measuring baseline TSH, free T4, and stroke outcomes were included, and we collected individual participant data from each study, including thyroid function measurements and incident all stroke (combined fatal and nonfatal) and fatal stroke. The applied reference range for TSH levels was between 0.45 and 4.49 mIU/L.

RESULTS: We collected individual participant data on 43 598 adults with TSH within the reference range from 17 cohorts, with a median follow-up of 11.6 years (interquartile range 5.1-13.9), including 449 908 person-years. Age- and sex-adjusted pooled hazard ratio for TSH was 0.78 (95\% confidence interval [CI] 0.65-0.95 across the reference range of TSH) for all stroke and 0.83 (95\% CI 0.62-1.09) for fatal stroke. For the free T4 analyses, the hazard ratio was 1.08 (95\% CI 0.99-1.15 per SD increase) for all stroke and 1.10 (95\% CI 1.04-1.19) for fatal stroke. This was independent of cardiovascular risk factors including systolic blood pressure, total cholesterol, smoking, and prevalent diabetes.

CONCLUSION: Higher levels of TSH within the reference range may decrease the risk of stroke, highlighting the need for further research focusing on the clinical consequences associated with differences within the reference range of thyroid function.

}, issn = {1945-7197}, doi = {10.1210/jc.2016-2255}, author = {Chaker, Layal and Baumgartner, Christine and den Elzen, Wendy P J and Collet, Tinh-Hai and Ikram, M Arfan and Blum, Manuel R and Dehghan, Abbas and Drechsler, Christiane and Luben, Robert N and Portegies, Marileen L P and Iervasi, Giorgio and Medici, Marco and Stott, David J and Dullaart, Robin P and Ford, Ian and Bremner, Alexandra and Newman, Anne B and Wanner, Christoph and Sgarbi, Jos{\'e} A and D{\"o}rr, Marcus and Longstreth, W T and Psaty, Bruce M and Ferrucci, Luigi and Maciel, Rui M B and Westendorp, Rudi G and Jukema, J Wouter and Ceresini, Graziano and Imaizumi, Misa and Hofman, Albert and Bakker, Stephan J L and Franklyn, Jayne A and Khaw, Kay-Tee and Bauer, Douglas C and Walsh, John P and Razvi, Salman and Gussekloo, Jacobijn and V{\"o}lzke, Henry and Franco, Oscar H and Cappola, Anne R and Rodondi, Nicolas and Peeters, Robin P} } @article {7550, title = {Thyroid Function Within the Normal Range, Subclinical Hypothyroidism, and the Risk of Atrial Fibrillation.}, journal = {Circulation}, volume = {136}, year = {2017}, month = {2017 Nov 28}, pages = {2100-2116}, abstract = {

BACKGROUND: Atrial fibrillation (AF) is a highly prevalent disorder leading to heart failure, stroke, and death. Enhanced understanding of modifiable risk factors may yield opportunities for prevention. The risk of AF is increased in subclinical hyperthyroidism, but it is uncertain whether variations in thyroid function within the normal range or subclinical hypothyroidism are also associated with AF.

METHODS: We conducted a systematic review and obtained individual participant data from prospective cohort studies that measured thyroid function at baseline and assessed incident AF. Studies were identified from MEDLINE and EMBASE databases from inception to July 27, 2016. The euthyroid state was defined as thyroid-stimulating hormone (TSH) 0.45 to 4.49 mIU/L, and subclinical hypothyroidism as TSH 4.5 to 19.9 mIU/L with free thyroxine (fT4) levels within reference range. The association of TSH levels in the euthyroid and subclinical hypothyroid range with incident AF was examined by using Cox proportional hazards models. In euthyroid participants, we additionally examined the association between fT4 levels and incident AF.

RESULTS: Of 30 085 participants from 11 cohorts (278 955 person-years of follow-up), 1958 (6.5\%) had subclinical hypothyroidism and 2574 individuals (8.6\%) developed AF during follow-up. TSH at baseline was not significantly associated with incident AF in euthyroid participants or those with subclinical hypothyroidism. Higher fT4 levels at baseline in euthyroid individuals were associated with increased AF risk in age- and sex-adjusted analyses (hazard ratio, 1.45; 95\% confidence interval, 1.26-1.66, for the highest quartile versus the lowest quartile of fT4; P for trend <=0.001 across quartiles). Estimates did not substantially differ after further adjustment for preexisting cardiovascular disease.

CONCLUSIONS: In euthyroid individuals, higher circulating fT4 levels, but not TSH levels, are associated with increased risk of incident AF.

}, keywords = {Adult, Aged, Aged, 80 and over, Asymptomatic Diseases, Atrial Fibrillation, Biomarkers, Chi-Square Distribution, Female, Humans, Hypothyroidism, Incidence, Male, Middle Aged, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Risk Assessment, Risk Factors, Thyroid Function Tests, Thyroid Gland, Thyrotropin, Thyroxine, Time Factors, Young Adult}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.117.028753}, author = {Baumgartner, Christine and da Costa, Bruno R and Collet, Tinh-Hai and Feller, Martin and Floriani, Carmen and Bauer, Douglas C and Cappola, Anne R and Heckbert, Susan R and Ceresini, Graziano and Gussekloo, Jacobijn and den Elzen, Wendy P J and Peeters, Robin P and Luben, Robert and V{\"o}lzke, Henry and D{\"o}rr, Marcus and Walsh, John P and Bremner, Alexandra and Iacoviello, Massimo and Macfarlane, Peter and Heeringa, Jan and Stott, David J and Westendorp, Rudi G J and Khaw, Kay-Tee and Magnani, Jared W and Aujesky, Drahomir and Rodondi, Nicolas} } @article {7584, title = {Trajectories of IGF-I Predict Mortality in Older Adults: The Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2017}, month = {2017 Jul 23}, abstract = {

Background: Disruption of insulin-like growth factor-I (IGF-I) increases health and life span in animal models, though this is unconfirmed in humans. If IGF-I stability indicates homeostasis, the absolute level of IGF-I may be less clinically relevant than maintaining an IGF-I setpoint.

Methods: Participants were 945 U.S. community-dwelling individuals aged >=65 years enrolled in the Cardiovascular Health Study with IGF-I levels at 3-6 timepoints. We examined the association of baseline IGF-I level, trajectory slope, and variability around the trajectory with mortality.

Results: There were 633 deaths over median 11.3 years of follow-up. Lower IGF-I levels, declining or increasing slope, and increasing variability were each individually associated with higher mortality (all p < .001). In an adjusted model including all three trajectory parameters, baseline IGF-I levels <70 ng/mL (hazard ratio [HR] 1.58, 95\% CI 1.28-1.96 relative to IGF-I levels of 170 ng/mL), steep declines and steep increases in trajectory slope (HR 2.22, 1.30-3.80 for a 15\% decline; HR 1.40, 1.07-1.84 for a 10\% decline; HR 1.80, 1.12-2.89 for a 15\% increase; HR 1.31, 1.00-1.72 for a 10\% increase, each vs no change), and variability >=10\% (HR 1.59, 1.09-2.32 for >= 30\%; HR 1.36, 1.06-1.75 for 20\%; and HR 1.17, 1.03-1.32 for 10\% variability, each vs 0\%) in IGF-I levels were independently associated with mortality.

Conclusions: In contrast to data from animal models, low IGF-I levels are associated with higher mortality in older humans. Irrespective of the actual IGF-I level, older individuals with stability of IGF-I levels have lower mortality than those whose IGF-I levels fluctuate over time.

}, issn = {1758-535X}, doi = {10.1093/gerona/glx143}, author = {Sanders, Jason L and Guo, Wensheng and O{\textquoteright}Meara, Ellen S and Kaplan, Robert C and Pollak, Michael N and Bartz, Traci M and Newman, Anne B and Fried, Linda P and Cappola, Anne R} } @article {7671, title = {Association of biomarker and physiologic indices with mortality in older adults: Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2018}, month = {2018 Apr 12}, abstract = {

Background: A goal of gerontology is discovering aging phenotypes that reflect biological aging distinct from disease pathogenesis. Biomarkers strongly and independently associated with mortality and which statistically attenuate chronologic age could be used to define such a phenotype. We determined the association of a Biomarker Index (BI) with mortality and compared it to a validated Physiologic Index (PI) in older adults.

Methods: The indices were constructed in the Cardiovascular Health Study, mean (SD) age 74.5 (5.1) years. The BI incorporated circulating levels of new biomarkers, including insulin-like growth factor (IGF)-1, IGF binding protein 3, amino-terminal pro-B-type natriuretic peptide, dehydroepiandrosterone sulfate, and interleukin-6, and was built in test (N=2197) and validation (N=1124) samples. The PI included carotid intima-media thickness, pulmonary capacity, brain white matter grade, cystatin-C, and fasting glucose. Multivariable Cox proportional hazards models predicting death were calculated with 10 years of follow-up.

Results: In separate age-adjusted models, the hazard ratio (HR) for mortality per point of the BI was 1.30 (95\% CI 1.25, 1.34) and the BI attenuated age by 25\%. The HR for the PI was 1.28 (1.24, 1.33) (29\% age attenuation). In the same model, the HR for the BI was 1.23 (1.18, 1.28) and for the PI was 1.22 (1.17, 1.26), and age was attenuated 42.5\%. Associations persisted after further adjustment.

Conclusions: The BI and PI were significantly and independently associated with mortality. Both attenuated the age effect on mortality substantially. The indices may be feasible phenotypes for developing interventions hoping to alter the trajectory of aging.

}, issn = {1758-535X}, doi = {10.1093/gerona/gly075}, author = {Sanders, Jason L and Arnold, Alice M and Boudreau, Robert M and Hirsch, Calvin H and Kizer, Jorge R and Kaplan, Robert C and Cappola, Anne R and Cushman, Mary and Jacob, Mini E and Kritchevsky, Stephen B and Newman, Anne B} } @article {7805, title = {Low thyroid function is not associated with an accelerated deterioration in renal function.}, journal = {Nephrol Dial Transplant}, year = {2018}, month = {2018 Apr 18}, abstract = {

Background: Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups.

Methods: Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models.

Results: A total of 72~856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95\% confidence interval) -4.07 (-6.37 to -1.78) and -2.40 (-3.78 to -1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66~542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50-4.52) mL/min/1.73 m2 higher. During 329~713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function.

Conclusions: Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.

}, issn = {1460-2385}, doi = {10.1093/ndt/gfy071}, author = {Meuwese, Christiaan L and van Diepen, Merel and Cappola, Anne R and Sarnak, Mark J and Shlipak, Michael G and Bauer, Douglas C and Fried, Linda P and Iacoviello, Massimo and Vaes, Bert and Degryse, Jean and Khaw, Kay-Tee and Luben, Robert N and Asvold, Bj{\o}rn O and Bj{\o}ro, Trine and Vatten, Lars J and de Craen, Anton J M and Trompet, Stella and Iervasi, Giorgio and Molinaro, Sabrina and Ceresini, Graziano and Ferrucci, Luigi and Dullaart, Robin P F and Bakker, Stephan J L and Jukema, J Wouter and Kearney, Patricia M and Stott, David J and Peeters, Robin P and Franco, Oscar H and V{\"o}lzke, Henry and Walsh, John P and Bremner, Alexandra and Sgarbi, Jos{\'e} A and Maciel, Rui M B and Imaizumi, Misa and Ohishi, Waka and Dekker, Friedo W and Rodondi, Nicolas and Gussekloo, Jacobijn and den Elzen, Wendy P J} } @article {7817, title = {The relation between thyroid function and anemia: a pooled analysis of individual participant data.}, journal = {J Clin Endocrinol Metab}, year = {2018}, month = {2018 Aug 02}, abstract = {

Context: Anemia and thyroid dysfunction often co-occur and both increase with age. Human data on the relationship between thyroid disease and anemia are scarce.

Objective: To investigate the cross-sectional and longitudinal associations between clinical thyroid status and anemia.

Design: Individual participant data meta-analysis.

Setting: Sixteen cohorts participating in the Thyroid Studies Collaboration (n=42 162).

Main outcome measures: Primary outcome measure was anemia (hemoglobin <130 g/L in men and <120 g/L in women).

Results: Cross-sectionally, participants with abnormal thyroid status had an increased risk of having anemia compared with euthyroid participants (overt hypothyroidism, pooled odds ratio 1.84 [95\% CI: 1.35-2.50], subclinical hypothyroidism 1.21 [1.02-1.43], subclinical hyperthyroidism 1.27 [1.03-1.57], overt hyperthyroidism 1.69 [1.00-2.87]). Hemoglobin levels were lower in all groups compared to participants with euthyroidism. In the longitudinal analyses (n=25,466 from 14 cohorts), the pooled hazard ratio for the risk of development of anemia was 1.38 [95\% CI: 0.86-2.20] for overt hypothyroidism, 1.18 [1.00-1.38] for subclinical hypothyroidism, 1.15 [0.94-1.42] for subclinical hyperthyroidism and 1.47 [0.91-2.38] for overt hyperthyroidism. Sensitivity analyses excluding thyroid medication or high levels of C-reactive protein yielded similar results. No differences in mean annual change in hemoglobin levels were observed between the thyroid hormone status groups.

Conclusion: Higher odds of having anemia were observed in both participants with hypothyroid function and hyperthyroid function. In addition, reduced thyroid function at baseline showed a trend of increased risk of developing anemia during follow-up. It remains to be assessed in a randomized controlled trial whether treatment is effective in reducing anemia.

}, issn = {1945-7197}, doi = {10.1210/jc.2018-00481}, author = {Wopereis, Daisy M and Du Puy, Robert S and van Heemst, Diana and Walsh, John P and Bremner, Alexandra and Bakker, Stephan J L and Bauer, Douglas C and Cappola, Anne R and Ceresini, Graziano and Degryse, Jean and Dullaart, Robin P F and Feller, Martin and Ferrucci, Luigi and Floriani, Carmen and Franco, Oscar H and Iacoviello, Massimo and Iervasi, Georgio and Imaizumi, Misa and Jukema, J Wouter and Khaw, Kay-Tee and Luben, Robert N and Molinaro, Sabrina and Nauck, Matthias and Patel, Kushang V and Peeters, Robin P and Psaty, Bruce M and Razvi, Salman and Schindhelm, Roger K and van Schoor, Natasja M and Stott, David J and Vaes, Bert and Vanderpump, Mark P J and V{\"o}lzke, Henry and Westendorp, Rudi G J and Rodondi, Nicolas and Cobbaert, Christa M and Gussekloo, Jacobijn and den Elzen, Wendy P J} } @article {7973, title = {Assessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation: A Mendelian Randomization Study.}, journal = {JAMA Cardiol}, year = {2019}, month = {2019 Jan 23}, abstract = {

Importance: Increased free thyroxine (FT4) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear.

Objective: To evaluate the potential direct involvement of thyroid traits on AF.

Design, Setting, and Participants: Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55 114 AF cases and 482 295 referents, all of European ancestry.

Exposures: Genomewide significant variants were used as instruments for standardized FT4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT3):FT4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data.

Main Outcomes and Measures: Prevalent and incident AF.

Results: The study-level analysis included 7679 individuals with AF and 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7\%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT4 levels (nanograms per deciliter) for incident AF was 1.55 (95\% CI, 1.09-2.20; P = .02; I2 = 76\%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95\% CI, 1.41-5.54; P = .003; I2 = 64\%) in multivariable-adjusted analyses. The FT4 genetic risk score was associated with an increase in FT4 by 0.082 SD (standard error, 0.007; P < .001) but not with incident AF (risk ratio, 0.84; 95\% CI, 0.62-1.14; P = .27) or prevalent AF (OR, 1.32; 95\% CI, 0.64-2.73; P = .46). Similarly, in summary-level inverse-variance weighted random-effects MR, gene-based FT4 within the reference range was not associated with AF (OR, 1.01; 95\% CI, 0.89-1.14; P = .88). However, gene-based increased FT3:FT4 ratio, increased thyrotropin within the reference range, and hypothyroidism were associated with AF with inverse-variance weighted random-effects OR of 1.33 (95\% CI, 1.08-1.63; P = .006), 0.88 (95\% CI, 0.84-0.92; P < .001), and 0.94 (95\% CI, 0.90-0.99; P = .009), respectively, and robust to tests of horizontal pleiotropy. However, the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels were not associated with AF. Gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31 (95\% CI, 1.05-1.63; P = .02) with evidence of horizontal pleiotropy (P = .045).

Conclusions and Relevance: Genetically increased FT3:FT4 ratio and hyperthyroidism, but not FT4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.

}, issn = {2380-6591}, doi = {10.1001/jamacardio.2018.4635}, author = {Ellervik, Christina and Roselli, Carolina and Christophersen, Ingrid E and Alonso, Alvaro and Pietzner, Maik and Sitlani, Collen M and Trompet, Stella and Arking, Dan E and Geelhoed, Bastiaan and Guo, Xiuqing and Kleber, Marcus E and Lin, Henry J and Lin, Honghuang and Macfarlane, Peter and Selvin, Elizabeth and Shaffer, Christian and Smith, Albert V and Verweij, Niek and Weiss, Stefan and Cappola, Anne R and D{\"o}rr, Marcus and Gudnason, Vilmundur and Heckbert, Susan and Mooijaart, Simon and M{\"a}rz, Winfried and Psaty, Bruce M and Ridker, Paul M and Roden, Dan and Stott, David J and V{\"o}lzke, Henry and Benjamin, Emelia J and Delgado, Graciela and Ellinor, Patrick and Homuth, Georg and K{\"o}ttgen, Anna and Jukema, Johan W and Lubitz, Steven A and Mora, Samia and Rienstra, Michiel and Rotter, Jerome I and Shoemaker, M Benjamin and Sotoodehnia, Nona and Taylor, Kent D and van der Harst, Pim and Albert, Christine M and Chasman, Daniel I} }