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1.  Subclinical Hypothyroidism and the Risk of Coronary Heart Disease and Mortality 
Data regarding the association between subclinical hypothyroidism and cardiovascular disease outcomes are conflicting among large prospective cohort studies. This might reflect differences in participants’ age, sex, thyroid-stimulating hormone (TSH) levels, or preexisting cardiovascular disease.
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.
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.
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.
PMCID: PMC3923470  PMID: 20858880
2.  Subclinical Thyroid Dysfunction and the Risk of Heart Failure Events: An Individual Participant Data Analysis from Six Prospective Cohorts 
Circulation  2012;126(9):10.1161/CIRCULATIONAHA.112.096024.
ACC/AHA Guidelines for the Diagnosis and Management of Heart Failure (HF) recommend investigating exacerbating conditions, such as thyroid dysfunction, but without specifying impact of different TSH levels. Limited prospective data exist regarding the association between subclinical thyroid dysfunction and HF 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 HF 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 0.45–4.49 mIU/L, subclinical hypothyroidism as TSH 4.5–19.9 mIU/L and subclinical hyperthyroidism as TSH <0.45 mIU/L, both with normal free thyroxine levels. Among 25,390 participants, 2068 had subclinical hypothyroidism (8.1%) and 648 subclinical hyperthyroidism (2.6%). In age- and gender-adjusted analyses, risks of HF events were increased with both higher and lower TSH levels (P for quadratic pattern <0.01): hazard ratio (HR) was 1.01 (95% confidence interval [CI] 0.81–1.26) for TSH 4.5–6.9 mIU/L, 1.65 (CI 0.84–3.23) for TSH 7.0–9.9 mIU/L, 1.86 (CI 1.27–2.72) for TSH 10.0–19.9 mIUL/L (P for trend <0.01), and was 1.31 (CI 0.88–1.95) for TSH 0.10–0.44 mIU/L and 1.94 (CI 1.01–3.72) for TSH <0.10 mIU/L (P for trend = 0.047). Risks remained similar after adjustment for cardiovascular risk factors.
Risks of HF events were increased with both higher and lower TSH levels, particularly for TSH ≥10 mIU/L and for TSH <0.10 mIU/L.
PMCID: PMC3884576  PMID: 22821943
cohort study; epidemiology; heart failure; meta-analysis; thyroid
3.  Subclinical Hyperthyroidism and the Risk of Coronary Heart Disease and Mortality 
Archives of internal medicine  2012;172(10):10.1001/archinternmed.2012.402.
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.
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.
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% for AF 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).
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.
PMCID: PMC3872478  PMID: 22529182
4.  Frailty Status and Altered Glucose-Insulin Dynamics 
We examined women in their 80s and 90s and evaluated the hypothesis that abnormalities in the dynamic response of glucose and insulin to a glucose load are associated with frailty status.
We performed a 75 g oral glucose tolerance test in 73 community-dwelling women aged 84–95 years without known diabetes enrolled in the Women’s Health and Aging Study II. We examined the association of frailty status (nonfrail, prefrail, or frail) with oral glucose tolerance test glucose and insulin levels at 0, 30, 60, 120, and 180 minutes using multiple linear regression models.
Using American Diabetes Association criteria, only 27% of older women had normal glucose status, 48% had prediabetes, and 25% had undiagnosed diabetes. Fasting glucose, fasting insulin, homeostasis model of assessment-insulin resistance, and Matsuda index were similar by frailty status, adjusting for age and body mass index. Conversely, mean oral glucose tolerance test glucose levels were higher at 60 minutes (44.6 ± 18.1 mg/dL higher) and 120 minutes (67.1 ± 23.5 mg/dL higher) and to a lesser extent at 180 minutes (44.3 ± 22.5 mg/dL higher) in frail versus nonfrail women as was integrated glucose area after adjustment. Mean 120-minute insulin level was also higher in frail versus nonfrail women (45.7 ± 22.4 μU/mL higher). Overall, glucose and insulin responses were more exaggerated and prolonged in frail versus nonfrail or prefrail women.
Our data demonstrate dysregulation in response to glucose challenge as a component of physiologic vulnerability associated with frailty in old–old women. Future studies should examine the timing of abnormal glucose–insulin dynamics with respect to the pathogenesis of frailty.
PMCID: PMC3670159  PMID: 21873592
Glucose; Insulin; Dynamics; Elderly; Frailty
5.  Resting Metabolic Rate Among Old-Old Women With and Without Frailty: Variability and Estimation of Energy Requirements 
Resting metabolic rate (RMR) is the largest component of total energy expenditure. It has not been studied in old-old adults living in the community, though abnormalities in RMR may play a critical role in the development of the clinical syndrome of frailty. The objective was to measure RMR and examine the association of measured RMR with frailty status and compare it to expected RMR generated by a predictive equation.
Physiologic sub-study conducted as a home visit within an observational cohort study.
Baltimore City and County, Maryland.
77 women age 83–93 years enrolled in the Women’s Health and Aging Study II.
RMR with indirect calorimetry; frailty status; fat-free mass; ambient and body temperature; expected RMR via the Mifflin-St. Jeor equation.
Average RMR was 1119 kcal/d (s.d.± 205; range 595–1560). Agreement between observed and expected RMR was biased and very poor (between-subject coefficient of variation 38.0%, 95%CI: 35.1–40.8). Variability of RMR was increased in frail subjects (heteroscedasticity F test P value=0.02). Both low and high RMR were associated with being frail (Odds Ratio 5.4, P value=0.04) and slower self-selected walking speed (P value<0.001) after adjustment for covariates.
Equations to predict RMR that are not validated in old-old adults appear to correlate poorly with measured RMR. RMR values are highly variable among old-old women, with deviations from the mean predicting clinical frailty. These exploratory findings suggest a pathway to clinical frailty through either high or low RMR.
PMCID: PMC3458581  PMID: 22985142
resting metabolic rate; frailty; older adults
6.  Predictors of Thyroid Hormone Initiation in Older Adults: Results From the Cardiovascular Health Study 
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.
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.
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).
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.
PMCID: PMC3143350  PMID: 21628677
Thyroid hormone; Levothyroxine; Elderly population
7.  Relationship of Low-Circulating “Anti-Aging” Klotho Hormone with Disability in Activities of Daily Living among Older Community-Dwelling Adults 
Rejuvenation Research  2012;15(3):295-301.
The aging suppressor gene klotho encodes a single-pass transmembrane protein klotho that in mice is known to extend life span when overexpressed and to resemble accelerated aging, with skeletal muscle atrophy and decreased bone mineral density, when expression is disrupted. We sought to examine the relationship between plasma klotho and disability in activities of daily living (ADL) in older community-dwelling adults. In a cross-sectional study, plasma klotho was measured in a population-based sample of 802 adults, ≥65 years, who participated in the “Invecchiare in Chianti” (Aging in the Chianti Area) (InCHIANTI) study in Tuscany, Italy. The overall proportion of adults with ADL disability was 11.9%. Mean (standard deviation) klotho concentrations were 689 (238) pg/mL. From the lowest to the highest tertile of plasma klotho, 16.1%, 9.7%, and 5.6% of participants, respectively, had ADL disability (p=0.0004). Plasma klotho, per 1 standard deviation increase, was associated with ADL disability (odds ratio=0.57, 95% confidence interval 0.35–0.93, p=0.02) in a multivariate logistic regression model adjusting for age, education, cognition, physical activity, physical performance, total cholesterol, alcohol and tobacco use, and chronic diseases. Low plasma klotho concentrations were independently associated with ADL disability among older community-dwelling men and women.
PMCID: PMC3388499  PMID: 22530731
8.  Serum 25-Hydroxyvitamin D and Pulmonary Function in Older Disabled Community-Dwelling Women 
Recent studies have expanded the functions of vitamin D to a possible role in pulmonary function. Our objective was to examine the relationship between serum 25-hydroxyvitamin D (25[OH]D), serum parathyroid hormone, and pulmonary function in older women.
We examined the relationship of serum 25(OH)D and parathyroid hormone with pulmonary function (forced expiratory volume in one second [FEV1], forced vital capacity [FVC], and FEV1/FVC ratio) in a cross-sectional study of 646 moderately to severely disabled women, 65 years or more, living in the community in Baltimore, Maryland, who participated in the Women’s Health and Aging Study I.
Overall, median (25th, 75th percentile) serum 25-hydroxyvitamin D concentrations were 19.9 (14.7, 26.7) ng/mL. Serum 25(OH)D was positively associated with FEV1 (p = .03), FVC (p = .18), and FEV1/FVC (p = .04) in multivariable linear regression models adjusting for age, race, education, smoking, height, physical activity, cognition, interleukin-6, chronic diseases, and other potential confounders. In the same models, serum parathyroid hormone was not significantly associated with FEV1, FVC, or FEV1/FVC.
These findings support the idea that vitamin D deficiency is independently associated with poor pulmonary function in older disabled women.
PMCID: PMC3732158  PMID: 22156439
Aging; Lung function; Parathyroid hormone; Vitamin D; Women
9.  A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function 
Porcu, Eleonora | Medici, Marco | Pistis, Giorgio | Volpato, Claudia B. | Wilson, Scott G. | Cappola, Anne R. | Bos, Steffan D. | Deelen, Joris | den Heijer, Martin | Freathy, Rachel M. | Lahti, Jari | Liu, Chunyu | Lopez, Lorna M. | Nolte, Ilja M. | O'Connell, Jeffrey R. | Tanaka, Toshiko | Trompet, Stella | Arnold, Alice | Bandinelli, Stefania | Beekman, Marian | Böhringer, Stefan | Brown, Suzanne J. | Buckley, Brendan M. | Camaschella, Clara | de Craen, Anton J. M. | Davies, Gail | de Visser, Marieke C. H. | Ford, Ian | Forsen, Tom | Frayling, Timothy M. | Fugazzola, Laura | Gögele, Martin | Hattersley, Andrew T. | Hermus, Ad R. | Hofman, Albert | Houwing-Duistermaat, Jeanine J. | Jensen, Richard A. | Kajantie, Eero | Kloppenburg, Margreet | Lim, Ee M. | Masciullo, Corrado | Mariotti, Stefano | Minelli, Cosetta | Mitchell, Braxton D. | Nagaraja, Ramaiah | Netea-Maier, Romana T. | Palotie, Aarno | Persani, Luca | Piras, Maria G. | Psaty, Bruce M. | Räikkönen, Katri | Richards, J. Brent | Rivadeneira, Fernando | Sala, Cinzia | Sabra, Mona M. | Sattar, Naveed | Shields, Beverley M. | Soranzo, Nicole | Starr, John M. | Stott, David J. | Sweep, Fred C. G. J. | Usala, Gianluca | van der Klauw, Melanie M. | van Heemst, Diana | van Mullem, Alies | H.Vermeulen, Sita | Visser, W. Edward | Walsh, John P. | Westendorp, Rudi G. J. | Widen, Elisabeth | Zhai, Guangju | Cucca, Francesco | Deary, Ian J. | Eriksson, Johan G. | Ferrucci, Luigi | Fox, Caroline S. | Jukema, J. Wouter | Kiemeney, Lambertus A. | Pramstaller, Peter P. | Schlessinger, David | Shuldiner, Alan R. | Slagboom, Eline P. | Uitterlinden, André G. | Vaidya, Bijay | Visser, Theo J. | Wolffenbuttel, Bruce H. R. | Meulenbelt, Ingrid | Rotter, Jerome I. | Spector, Tim D. | Hicks, Andrew A. | Toniolo, Daniela | Sanna, Serena | Peeters, Robin P. | Naitza, Silvia | McCarthy, Mark I.
PLoS Genetics  2013;9(2):e1003266.
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.
Author Summary
Levels of thyroid hormones are tightly regulated by TSH produced in the pituitary, and even mild alterations in their concentrations are strong indicators of thyroid pathologies, which are very common worldwide. To identify common genetic variants associated with the highly heritable markers of thyroid function, TSH and FT4, we conducted a meta-analysis of genome-wide association studies in 26,420 and 17,520 individuals, respectively, of European ancestry with normal thyroid function. Our analysis identified 26 independent genetic variants regulating these traits, several of which are new, and confirmed previously detected polymorphisms affecting TSH (within the PDE8B gene and near CAPZB, MAF/LOC440389, and NR3C2) and FT4 (within DIO1) levels. Gender-specific differences in the genetic effects of several variants for TSH and FT4 levels were identified at several loci, which offer clues to understand the known sexual dimorphism in thyroid function and pathology. Of particular clinical interest, we show that TSH-associated loci contribute not only to normal variation, but also to TSH values outside reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings add to the developing landscape of the regulation of thyroid homeostasis and the consequences of genetic variation for thyroid related diseases.
PMCID: PMC3567175  PMID: 23408906
10.  Relationship of serum fibroblast growth factor 23 with cardiovascular disease in older community-dwelling women 
Although fibroblast growth factor 23 (FGF23) has been implicated in the pathogenesis of cardiovascular disease, the relationship between FGF23 and cardiovascular disease has not been well characterized in the general population. The aim of the study was to determine whether serum FGF23 is independently associated with cardiovascular disease in older community-dwelling women.
Design and methods
A cross-sectional design was used to examine the relationship between serum FGF23 and cardiovascular disease. The subjects consisted of a population-based sample of 659 women, aged 70–79 years, who participated in the Women’s Health and Aging Studies in Baltimore, Maryland. Prevalent cardiovascular disease (coronary heart disease, stroke, congestive heart failure, peripheral artery disease) was assessed through diagnostic algorithms and physician adjudication.
Of the 659 women, 185 (28.1%) had cardiovascular disease. Median (25th, 75th percentile) intact serum FGF23 was 34.6 (25.2, 46.2) pg/mL. The prevalence of cardiovascular disease in the lowest, middle, and highest tertile of serum FGF23 was 22.6%, 24.9%, and 36.7%, respectively (P = 0.002). Serum log FGF23 was associated with cardiovascular disease (Odds Ratio per 1 SD increase = 1.23, 95% Confidence Interval 1.17, 1.30; P <0.0001) in a multivariable logistic regression model, adjusting for age, race, smoking, education, body mass index, cognition, diabetes, hypertension, physical activity, total cholesterol, HDL cholesterol, and renal function.
Elevated serum FGF23 concentrations are independently associated with prevalent cardiovascular disease in older community-dwelling women. Further studies are needed to elucidate the potential biological mechanisms by which FGF23 may be involved in the pathogenesis of cardiovascular disease.
PMCID: PMC3486640  PMID: 21873490
aging; cardiovascular disease; fibroblast growth factor 23; women
11.  Plasma klotho and cardiovascular disease in adults 
To determine whether plasma klotho, a recently discovered hormone that has been implicated in atherosclerosis, is related to prevalent cardiovascular disease in adults.
Population-based sample of adults residing in Tuscany, Italy.
One thousand and twenty-three men and women, aged 24–102, participating in the Invecchiare in Chianti (InCHIANTI) study.
Anthropometric measures, plasma klotho, fasting plasma total, high-density lipoprotein (HDL) cholesterol, triglycerides, glucose, creatinine, C-reactive protein. Clinical measures: medical assessment, diabetes mellitus, hypertension, coronary heart disease, heart failure, stroke, peripheral artery disease, cancer, chronic kidney disease. Logistic regression models were used to examine the relationship between plasma klotho and prevalent cardiovascular disease.
Of 1023 participants, 259 (25.3%) had cardiovascular disease. Median (25th, 75th percentile) plasma klotho concentrations were 676 (530, 819) pg/mL. Plasma klotho was correlated with age (r = −0.14, P <0.0001), HDL cholesterol (r = 0.11, P = 0.0004), C-reactive protein (r = −0.10, P = 0.0008), but not systolic blood pressure, fasting plasma glucose, or renal function. Plasma klotho age-adjusted geometric means (95% Confidence Interval [C.I.]) were 626 (601, 658) in participants with cardiovascular disease and 671 (652, 692) pg/mL in those without cardiovascular disease (P = 0.0001). Adjusting for traditional cardiovascular risk factors (age, sex, smoking, total cholesterol, HDL cholesterol, systolic blood pressure, and diabetes), log plasma klotho was associated with prevalent cardiovascular disease (Odds Ratio per 1 standard deviation increase = 0.85, 95% C.I. 0.72, 0.99).
In community-dwelling adults, higher plasma klotho concentrations are independently associated with a lower likelihood of having cardiovascular disease.
PMCID: PMC3486641  PMID: 21883107
aging; atherosclerosis; cardiovascular disease; C-reactive protein; klotho
12.  Relationship of low plasma klotho with poor grip strength in older community-dwelling adults: the InCHIANTI study 
European journal of applied physiology  2011;112(4):1215-1220.
Handgrip strength is a strong indicator of total body muscle strength and is a predictor of poor outcomes in older adults. The aging suppressor gene klotho encodes a single-pass transmembrane protein that is secreted as a circulating hormone. In mice, disruption of klotho expression results in a syndrome that includes sarcopenia, atherosclerosis, osteoporosis, and shortened lifespan, and conversely, overexpression of klotho leads to a greater longevity. The objective was to determine whether plasma klotho levels are related to skeletal muscle strength in humans. We measured plasma klotho in 804 adults, ≥65 years, in the InCHIANTI study, a longitudinal population-based study of aging in Tuscany, Italy. Grip strength was positively correlated with plasma klotho at threshold <681 pg/mL. After adjusting for age, sex, education, smoking, physical activity, cognition, and chronic diseases, plasma klotho (per 1 standard deviation increase) was associated with grip strength (beta = 1.20, standard error = 0.35, P = 0.0009) in adults with plasma klotho <681 pg/mL. These results suggest that older adults with lower plasma klotho have poor skeletal muscle strength.
PMCID: PMC3435096  PMID: 21769735
aging; klotho; muscle strength; sarcopenia
13.  Plasma Klotho and Mortality Risk in Older Community-Dwelling Adults 
The aging-suppressor gene klotho encodes a single-pass transmembrane protein that in mice is known to extend life span when overexpressed and resemble accelerated aging when expression is disrupted. It is not known whether there is a relationship between plasma levels of secreted klotho protein and longevity in humans.
We measured plasma klotho in 804 adults, greater than or equal to 65 years, in the InCHIANTI study, a longitudinal population-based study of aging in Tuscany, Italy.
During 6 years of follow-up, 194 (24.1%) of the participants died. In a multivariate Cox proportional hazards model, adjusting for age, sex, education, body mass index, physical activity, total cholesterol, high-density lipoprotein cholesterol, cognition, 25-hydroxyvitamin D, parathyroid hormone, serum calcium, mean arterial pressure, and chronic diseases, participants in the lowest tertile of plasma klotho (<575 pg/mL) had an increased risk of death compared with participants in the highest tertile of plasma klotho (>763 pg/mL; hazards ratio 1.78, 95% confidence interval 1.20–2.63).
In older community-dwelling adults, plasma klotho is an independent predictor of all-cause mortality. Further studies are needed to elucidate the potential biological mechanisms by which circulating klotho could affect longevity in humans.
PMCID: PMC3143348  PMID: 21474560
Aging; Klotho; Longevity; Mortality
14.  Sex Hormones Are Associated with Right Ventricular Structure and Function 
Rationale: Sex hormones have effects on the left ventricle, but hormonal influences on the right ventricle (RV) are unknown.
Objectives: We hypothesized that sex hormones would be associated with RV morphology in a large cohort free of cardiovascular disease.
Methods: Sex hormones were measured by immunoassay and RV ejection fraction (RVEF), stroke volume (RVSV), mass, end-diastolic volume, and end-systolic volume (RVESV) were measured by cardiac magnetic resonance imaging in 1,957 men and 1,738 postmenopausal women. The relationship between each hormone and RV parameter was assessed by multivariate linear regression.
Measurements and Main Results: Higher estradiol levels were associated with higher RVEF (β per 1 ln[nmol/L], 0.88; 95% confidence interval [CI], 0.32 to 1.43; P = 0.002) and lower RVESV (β per 1 ln[nmol/L], −0.87; 95% CI, −1.67 to −0.08; P = 0.03) in women using hormone therapy. In men, higher bioavailable testosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.97; 95% CI, 0.20 to 3.73; P = 0.03) and greater RV mass and volumes (P ≤ 0.01). Higher dehydroepiandrosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.37; 95% CI, 0.15 to 2.59; P = 0.03) and greater RV mass (β per 1 ln[nmol/L], 0.25; 95% CI, 0.00 to 0.49; P = 0.05) and volumes (P ≤ 0.001) in women.
Conclusions: Higher estradiol levels were associated with better RV systolic function in women using hormone therapy. Higher levels of androgens were associated with greater RV mass and volumes in both sexes.
PMCID: PMC3081282  PMID: 20889903
sex; sex hormones; right ventricle
15.  High insulin-like growth factor binding protein-1 (IGFBP-1) level predicts incident congestive heart failure in the elderly 
American Heart Journal  2008;155(6):1006-1012.
Low insulin-like growth factor–1 (IGF-I) may influence the development of age-related cardiovascular diseases including congestive heart failure (CHF). Insulin-like growth factor binding protein-1 (IGFBP-1), which increases during catabolic states and inhibits anabolic IGF-I effects, is increased in CHF patients and has been associated prospectively with increased mortality among older adults and myocardial infarction survivors. 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 (CHS).
From among 5,888 65+ year-old adults in the Cardiovascular Health Study (CHS), we studied 566 incident CHF cases and 1,072 comparison subjects, after exclusion of underweight individuals (BMI < 18.5 kg/m2) and insulin users. Hazard ratios (HR) with 95% confidence intervals (CIs) for CHF were estimated after adjustment for age, race, gender, hypertension, systolic blood pressure, lipid levels, left ventricular hypertrophy, coronary disease, C-reactive protein, health status, diabetes, and BMI.
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 < 0.01). Relative to the lowest IGFBP-1 tertile, the HR was 1.29 (95% CI=0.96–1.74, p=0.09) for the second IGFBP-1 tertile and 1.47 (95% CI=1.06–2.04; p=0.02) for the highest IGFBP-1 tertile (tertile cutpoints 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.
High circulating IGFBP-1 may be a CHF risk factor among older adults.
PMCID: PMC3286655  PMID: 18513511
16.  Relationship of 25-hydroxyvitamin D with all-cause and cardiovascular disease mortality in older community-dwelling adults 
Vitamin D deficiency is associated with cardiovascular disease, osteoporosis, poor muscle strength, falls, fractures, and mortality. Although older adults are at a high risk of vitamin D deficiency, the relationship of serum 25(OH)D with all-cause and cardiovascular disease mortality has not been well characterized in the elderly. We hypothesized that low serum 25(OH)D predicted mortality in older adults.
Serum 25(OH)D and all-cause and cardiovascular disease mortality were examined in 1006 adults, ≥65 years, who participated in the InCHIANTI study, a population-based, prospective cohort study of aging in Tuscany, Italy. Serum 25(OH)D was measured at enrollment in 1998-1999, and participants were followed for mortality.
During 6.5 years of follow-up, 228 (22.7%) participants died, of whom 107 died from cardiovascular disease. Compared with participants in the highest quartile of serum 25(OH)D (>26.5 ng/mL)(to convert to nmol/L, multiply by 2.496), those in the lowest quartile (<10.5 ng/mL) had increased risk of all-cause mortality (Hazards Ratio [H.R.] 2.11, 95% Confidence Interval [C.I.] 1.22 – 3.64, P = 0.007) and cardiovascular disease mortality (H.R. 2.64, 95% C.I. 1.14 – 4.79, P = 0.02), in multivariate Cox proportional hazards models that adjusted for age, sex, education, season, physical activity, and other potential confounders.
Older community-dwelling adults with low serum 25(OH)D are at higher risk of all-cause and cardiovascular disease mortality.
PMCID: PMC3277831  PMID: 19953106
Aging; all-cause mortality; cardiovascular disease mortality; vitamin D
17.  Examining Faculty Awards for Gender Equity and Evolving Values 
Awards given to medical school faculty are one important mechanism for recognizing what is valued in academic medicine. There have been concerns expressed about the gender distribution of awards, and there is also a growing appreciation for the evolving accomplishments and talents that define academic excellence in the 21st century and that should be considered worthy of award recognition.
Examine faculty awards at our institution for gender equity and evolving values.
Recipient data were collected on awards from 1996 to 2007 inclusively at the University of Pennsylvania School of Medicine (SOM). Descriptions of each award also were collected. The female-to-male ratio of award recipients over the time span was reviewed for changes and trends. The title and text of each award announcement were reviewed to determine if the award represented a traditional or a newer concept of excellence in academic medicine.
There were 21 annual awards given to a total of 59 clinical award recipients, 60 research award recipients, and 154 teaching award recipients. Women received 28% of research awards, 29% of teaching awards and 10% of clinical awards. Gender distribution of total awards was similar to that of SOM full-time faculty except in the clinical awards category. Only one award reflected a shift in the culture of individual achievement to one of collaboration and team performance.
Examining both the recipients and content of awards is important to assure they reflect the current composition of diverse faculty and the evolving ideals of leadership and excellence in academic medicine.
PMCID: PMC2811595  PMID: 19727968
faculty awards; gender equity; female-to-male ratio; leadership; excellence
18.  Trajectories of Dehydroepiandrosterone Sulfate Predict Mortality in Older Adults: The Cardiovascular Health Study 
Dehydroepiandrosterone sulfate (DHEAS) has been proposed as an antiaging hormone, but its importance is unclear. Assessment of an individual’s ability to maintain a DHEAS set point, through examination of multiple DHEAS levels over time, may provide insight into biologic aging.
Using Cox proportional hazard models, we examined the relationship between DHEAS trajectory patterns and all-cause death in 950 individuals aged ≥65 years who were enrolled in the Cardiovascular Health Study and had DHEAS levels measured at three to six time points.
Overall, there was a slight decline in DHEAS levels over time (−0.013 μg/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).
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.
PMCID: PMC2773814  PMID: 19713299
DHEA; DHEAS; Mortality; Aging; Elderly
19.  Nonlinear Multisystem Physiological Dysregulation Associated With Frailty in Older Women: Implications for Etiology and Treatment 
Frailty in older adults, defined as a constellation of signs and symptoms, is associated with abnormal levels in individual physiological systems. We tested the hypothesis that it is the critical mass of physiological systems abnormal that is associated with frailty, over and above the status of each individual system, and that the relationship is nonlinear.
Using data on women aged 70–79 years from the Women’s Health and Aging Studies I and II, multiple analytic approaches assessed the cross-sectional association of frailty with eight physiological measures.
Abnormality in each system (anemia, inflammation, insulin-like growth factor-1, dehydroepiandrosterone-sulfate, hemoglobin A1c, micronutrients, adiposity, and fine motor speed) was significantly associated with frailty status. However, adjusting for the level of each system measure, the mean number of systems impaired significantly and nonlinearly predicted frailty. Those with three or more systems impaired were most likely to be frail, with odds of frailty increasing with number of systems at abnormal level, from odds ratios (ORs) of 4.8 to 11 to 26 for those with one to two, three to four, and five or more systems abnormal (p < .05 for all). Finally, two subgroups were identified, one with isolated or no systems abnormal and a second (in 30%) with multiple systems abnormal. The latter group was independently associated with being frail (OR = 2.6, p < .05), adjusting for confounders and chronic diseases and then controlling for individual systems.
Overall, these findings indicate that the likelihood of frailty increases nonlinearly in relationship to the number of physiological systems abnormal, and the number of abnormal systems is more predictive than the individual abnormal system. These findings support theories that aggregate loss of complexity, with aging, in physiological systems is an important cause of frailty. Implications are that a threshold loss of complexity, as indicated by number of systems abnormal, may undermine homeostatic adaptive capacity, leading to the development of frailty and its associated risk for subsequent adverse outcomes. It further suggests that replacement of any one deficient system may not be sufficient to prevent or ameliorate frailty.
PMCID: PMC2737590  PMID: 19567825
Frailty etiology; Aging
20.  Relationship Between Higher Estradiol Levels and 9-Year Mortality in Older Women: The Invecchiare in Chianti Study 
To investigate the relationship between total estradiol (E2) levels and 9-year mortality in older postmenopausal women not taking hormone replacement therapy (HRT).
Population-based study of persons living in the Chianti geographic area (Tuscany, Italy).
A representative sample of 509 women aged 65 and older with measures of total E2.
Serum total E2 was measured at the University of Parma using ultrasensitive radioimmunoassay (RIA).
Women who died (n = 135) during 9 years of follow up were older; had higher total E2 levels; and were more likely to have evidence of stroke, hypertension, diabetes mellitus, and congestive heart failure at baseline than survivors. Higher E2 levels were associated with a greater likelihood of death (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 1.01–1.06), and the relationship was independent of age, waist:hip ratio, C-reactive protein, education, cognitive function, physical activity, caloric intake, smoking, and chronic disease (HR = 1.08 pg/mL, 95% CI = 1.03–1.13, P = .003). The excessive risk of death associated with higher total E2 was not attenuated after adjustment for total testosterone (HR = 1.12, 95% CI = 1.02–1.18, P<.001) and after further adjustment for insulin resistance evaluated using the homeostasis model assessment (HR = 1.07, 95% CI = 1.03–1.17, P<.001).
Total E2 was highly predictive of death after more than 5 years (HR = 1.42: CI 1.01–1.91, P = .04) and not predictive of death for less than 5 years (P = .78).
Higher total E2 concentration predicts mortality in older women not taking HRT.
PMCID: PMC2798148  PMID: 19737330
estradiol; older postmenopausal women; mortality
21.  Low serum 25-hydroxyvitamin D concentrations are associated with greater all-cause mortality in older community-dwelling women 
Vitamin D deficiency is associated with osteoporosis, poor muscle strength, falls, and fractures. The relationship between serum vitamin D concentrations and mortality in older, community-dwelling women has not been well characterized. We hypothesized that women with lower 25-hydroxyvitamin D (25[OH]D) concentrations were at higher risk of mortality. We examined the association between serum 25[OH]D concentrations and all-cause mortality in a prospective, population-based study of 714 community-dwelling women, aged 70-79 years, the Women's Health and Aging Studies I and II in Baltimore, Maryland. The studies were originally designed to evaluate the causes and course of physical disability in older women living in the community. Vital status was determined through follow-up interviews and matching with the National Death Index. During a median 72 months of follow-up, 100 (14%) of 714 women died. Women in the lowest quartile of 25(OH)D (<15.3 ng/mL or 38.2 nmol/L) were at higher risk of death (Hazards Ratio 2.45, 95% Confidence Interval 1.12-5.36, P = 0.02) compared to women in the highest quartile (>27.0 ng/mL or 67.4 nmol/L) of 25(OH)D in a multivariate Cox proportional hazards model adjusting for demographics, season, and conventional risk factors. Older community-dwelling women with low 25(OH)D levels are at an increased risk of death.
PMCID: PMC2789316  PMID: 19761886
aging; mortality; survival; vitamin D; women
22.  Cardiovascular Disease Is Associated with Greater Incident Dehydroepiandrosterone Sulfate Decline in the Oldest Old: The Cardiovascular Health Study All Stars Study 
To describe cross-sectional and longitudinal associations with dehydroepiandrosterone sulfate (DHEAS) and change in DHEAS with age.
Longitudinal cohort study.
Pittsburgh, Pennsylvania.
Cardiovascular Health Study All Stars study participants assessed in 2005/06 (N =989, mean age 85.2, 63.5% women, 16.5% African American).
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.
Mean ± standard deviation DHEAS was 0.555 ± 0.414 μg/mL in 1996/97 and 0.482 ± 0.449 μg/mL in 2005/06 for women and 0.845 ± 0.520 μg/mL in 1996/97 and 0.658 ± 0.516 μg/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 μg/mL) than in women (− 0.078 μg/mL) (P<.001). Each 1-year increase in age attenuated the effect of male sex by 0.01 μg/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 (β = − 0.04 μg/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).
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.
PMCID: PMC2880808  PMID: 20163485
dehydroepiandrosterone sulfate; cardiovascular disease; gender; aging
23.  Subclinical Thyroid Dysfunction, Cardiac Function and the Risk of Heart Failure: The Cardiovascular Health Study 
The goal of this study was to determine whether subclinical thyroid dysfunction was associated with incident heart failure (HF) and echocardiogram abnormalities.
Subclinical hypothyroidism and hyperthyroidism have been associated with cardiac dysfunction. However, long-term data on the risk of HF are limited.
We studied 3044 adults ≥65 years initially free of HF in the Cardiovascular Health Study (CHS). We compared adjudicated HF events over a mean 12-year follow-up and changes in cardiac function over 5 years among euthyroid participants, those with subclinical hypothyroidism (subdivided by TSH levels: 4.5–9.9, ≥10.0 mU/L), and those with subclinical hyperthyroidism.
Over 12 years, 736 participants developed HF events. Participants with TSH≥10.0 mU/L had a greater incidence of HF compared to euthyroid participants (41.7 vs. 22.9/1000 person years, p=0.01, adjusted hazard ratio=1.88, 95% confidence interval 1.05–3.34). Baseline peak E velocity, an echocardiographic measurement of diastolic function associated with incident HF in the CHS cohort, was higher in those with TSH≥10.0 compared to euthyroid participants (0.80 vs. 0.72 m/sec, p=0.002). Over 5 years, left ventricular mass increased among those with TSH≥10.0, but other echocardiographic measurements were unchanged. Those with TSH 4.5–9.9 or with subclinical hyperthyroidism had no increase in risk of HF.
Compared to euthyroid older adults, those with a TSH≥10.0 mU/L have a moderately elevated risk of HF and alterations in cardiac function, but not older adults with TSH<10. Clinical trials should assess whether the risk of HF might be ameliorated by thyroxine replacement in individuals with TSH≥10.0 mU/L.
PMCID: PMC2874755  PMID: 18804743
Subclinical Thyroid Dysfunction; Heart Failure; Echocardiography; Cohort Study
24.  White Blood Cell Counts, Insulinlike Growth Factor-1 Levels, and Frailty in Community-Dwelling Older Women 
Elevated white blood cell (WBC) counts and decreased insulin-like growth factor-1 (IGF-1) levels are individually associated with frailty in older adults. WBC subpopulations are known to produce IGF-1 and express IGF-1 receptors in vitro. However, in vivo relationships between WBC and IGF-1 and their joint contribution to frailty have not been investigated.
Baseline data from 696 community-dwelling older women in the Women’s Health and Aging Study I were included in this cross-sectional analysis. Multivariate linear regression analysis was performed to assess the relationship between WBC counts and IGF-1 levels. Odds ratios (ORs) for frailty were evaluated across tertiles of WBC counts and IGF-1 levels, adjusting for age, race, education, body mass index, and smoking.
WBC counts correlated with IGF-1 levels (Spearman coefficient: .10, p < .01). Compared with participants in the low WBC and high IGF-1 tertiles (reference group), those in the low WBC and low IGF-1 tertiles had OR of 2.33 for frailty (95% confidence interval [CI]: 1.04–3.65, p < .05), those in the high WBC and high IGF-1 tertiles had OR of 3.86 (95% CI: 1.13–4.07, p < .01), and those in the high WBC and low IGF-1 tertiles had OR of 3.61 (95% CI: 1.64–4.97, p < .01), adjusting for covariates.
These findings demonstrate in vivo correlation between WBC and IGF-1. They suggest U-shaped joint associations of WBC and IGF-1 with frailty, with the strongest association at adverse levels of both. They also provide a basis for further investigation into the complex immune–endocrine dysregulations in frailty.
PMCID: PMC2657176  PMID: 19251912
Frailty; WBC; IGF-1
25.  Multiple Hormonal Deficiencies in Anabolic Hormones Are Found in Frail Older Women: The Women's Health and Aging Studies 
Alterations in anabolic hormones are theorized to contribute to aging and frailty, with most studies focusing on the relationship between individual hormones and specific age-associated diseases. We hypothesized that associations with frailty would most likely manifest in the presence of deficits in multiple anabolic hormones.
The relationships of serum levels of total IGF-1, DHEAS, and free testosterone (T) with frailty status (nonfrail, prefrail, or frail) were analyzed in 494 women aged 70–79 years enrolled in the Women's Health and Aging Studies I or II. Using multivariate polytomous regression, we calculated the odds of frailty for deficiency in each hormone (defined as the bottom quartile of the hormone) individually, as well as for a count of the hormones.
For each hormone, in adjusted analyses, those with the deficiency were more likely to be frail than those without the deficiency, although this did not achieve statistical significance (IGF-1: odds ratio [OR] 1.82, confidence interval [CI] 0.81–4.08; DHEAS: OR 1.68, CI 0.77–3.69; free T: OR 2.03, CI 0.89–4.64). Compared with those with no hormonal deficiencies, those with one deficiency were not more likely to be frail (OR 1.15, CI 0.49–2.68), whereas those with two or three deficiencies had a very high likelihood of being frail (OR 2.79, CI 1.06–7.32), in adjusted models.
The absolute burden of anabolic hormonal deficiencies is a stronger predictor of frailty status than the type of hormonal deficiency, and the relationship is nonlinear. These analyses suggest generalized endocrine dysfunction in the frailty syndrome.
PMCID: PMC2655016  PMID: 19182229
Hormones; Aging; Elderly; Women; Frailty; IGF-1; DHEAS; Testosterone

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