Jacobijn Gussekloo

Meta-analysis: Subclinical Thyroid Dysfunction and the Risk for Coronary Heart Disease and Mortality

Context Is subclinical thyroid dysfunction associated with increased risk for coronary heart disease and mortality? Contribution This systematic review of 12 prospective cohort studies found that both subclinical hypothyroidism and hyperthyroidism were possibly associated with a small increased risk for coronary heart disease and mortality. Caution Data were uncertain. Confidence intervals around risk estimates were wide, particularly for those related to subclinical hyperthyroidism. Higher-quality studies showed lower estimates of risk than lower-quality studies. Implication Randomized trials testing the efficacy of thyroxine replacement and antithyroid medications for subclinical hypothyroidism and subclinical hyperthyroidism are needed. The Editors Subclinical thyroid dysfunction refers to patients who have an abnormal thyrotropin (thyroid-stimulating hormone [TSH]) level and a normal free thyroxine (T4) level (1). The prevalence of subclinical hypothyroidism is about 4.3% in adults (0.7% for subclinical hyperthyroidism), and prevalence is higher in older adults and women (25). Controversy persists about whether screening and treating subclinical thyroid dysfunction is warranted (1, 57) because current evidence about the risks is limited (1, 5) and randomized, controlled trials on relevant clinical outcomes have not been done (5, 8). Subclinical hypothyroidism has been associated with elevated cholesterol levels (911) and increased risk for atherosclerosis (12, 13). Yet, data on the relationship between subclinical hypothyroidism and coronary heart disease (CHD) events are conflicting (12, 1417). In a previous meta-analysis (18), we found that subclinical hypothyroidism was associated with a 1.65-fold increased risk (CI, 1.28 to 2.12) for CHD. However, that meta-analysis included several cross-sectional and casecontrol studies and only 5 small prospective studies. Recently, 3 large prospective studies on this issue have been published (14, 16, 17), with somewhat inconsistent results. Because these new data include many additional CHD events, data are now sufficient to do a meta-analysis that includes only prospective studies, which provide greater validity. Data on the association between subclinical hypothyroidism and mortality are also conflicting (14, 17, 19, 20). The consequences of subclinical hyperthyroidism have been less frequently studied than those of subclinical hypothyroidism. Subclinical hyperthyroidism has been associated with cardiovascular and total mortality (15), but with conflicting data (14, 17). Two of the 3 recent, large prospective studies (14, 17) also examined CHD and mortality in subclinical hyperthyroid participants. To summarize prospective evidence about the relationship between subclinical thyroid dysfunction and CHD and mortality, we did a systematic review of prospective cohort studies. Methods We followed a standardized protocol and conducted and reported this analysis according to the guidelines of the Meta-analysis Of Observational Studies in Epidemiology group (21). Data Sources and Searches We conducted a systematic literature search of MEDLINE for articles in any language on the association between subclinical thyroid dysfunction (both subclinical hypothyroidism and hyperthyroidism) and CHD or mortality (cardiovascular and total) published from 1950 to January 2008. To avoid missing any relevant study, we also searched the bibliographies of key articles in the field and those included in this review. We did our search on an Ovid (MEDLINE) server by using broadly defined Medical Subject Headings, such as thyroid diseases, hypothyroidism, hyperthyroidism, thyroid hormones, thyrotropin, mortality, myocardial ischemia, survival, and cardiovascular diseases and such keywords as subclinical hypothyroidism, subclinical hyperthyroidism, subclinical dysthyroidism, and subclinical thyroid, combined with the filter designed by knowledge information specialists from BMJ to select prospective studies (MEDLINE cohort-study filter) (22) but without their year limitation. Study Selection Two reviewers independently screened the abstracts and titles of the search results and eliminated articles only if they did not clearly study the association between subclinical thyroid dysfunction and CHD or mortality (cardiovascular or total) in a prospective design. The same 2 reviewers independently evaluated the remaining full-text articles for eligibility on the basis of a predefined set of eligibility criteria. Disagreements were resolved by consensus. We included only full-text, published, longitudinal cohort studies that measured thyroid function and followed persons prospectively, assessed CHD or mortality, and provided risk estimates or sufficient data to calculate risk estimates associated with subclinical thyroid dysfunction compared with normal thyroid function. Subclinical hypothyroidism was defined as elevated TSH levels and normal T4 levels (1). Several reviews suggest a TSH upper limit cutoff of 4.5 to 5.0 mU/L (1, 5), but others suggest decreasing the upper limit of the TSH range to 2.5 to 3.0 mU/L (23, 24). In the absence of consensus, we did not prespecify a TSH cutoff value to define subclinical hypothyroidism and did a sensitivity analysis by limiting the analysis to studies with a TSH cutoff of 4.5 mU/L or greater (5). Because most adults with elevated TSH levels have subclinical and not overt hypothyroidism (2), we included 2 studies with participants who had elevated TSH levels without a T4 measurement report (25, 26) and did a sensitivity analysis excluding those studies. For subclinical hyperthyroidism, we did not specify a TSH cutoff value (in the absence of consensus), but all studies had a cutoff value close to 0.3 to 0.5 mU/L. We included 1 study with participants who had low TSH levels without a reported T4 measurement (26) and did a sensitivity analysis excluding this study. For CHD, we considered myocardial infarction, angina, the acute coronary syndrome, revascularization (coronary artery surgery, percutaneous transluminal coronary angioplasty), and significant coronary stenosis (defined as 50%) (27). We also considered death due to CHD or cardiovascular disease and did a sensitivity analysis excluding studies that only included the latter. We assessed methods and criteria used for adjudication of those outcomes. The agreement between the 2 reviewers was 99.5% for the first screen (titles and abstracts; = 0.79) and 100% for the full-text screen (= 1.00). Data Extraction and Quality Assessment Two reviewers independently abstracted data on participant characteristics, criteria used to define subclinical thyroid dysfunction, CHD and mortality data, and study results with adjustment factors by using a standardized data collection form. Discrepancies in data extraction between reviewers were resolved by consensus. We systematically assessed key indicators of study quality (28): methods of outcome adjudication and ascertainment that account for confounders and completeness of follow-up ascertainment. Similar to our previous meta-analysis (18), study populations were considered either a convenience or a population-based sample (defined as a random sample of the general population) (29). Methods of outcome adjudication were categorized as use of formal adjudication procedures and adjudication without knowledge of thyroid status. A formal adjudication procedure was defined as having clear criteria for the outcomes that were reviewed by experts for each potential case (29) (for example, specific electrocardiogram or cardiac enzyme modifications for CHD). We did not consider CHD adjudication based only on death certificates as a formal adjudication procedure. If an article did not clearly mention 1 of these criteria, we considered that it had not been done. We contacted the authors of 7 studies (12, 14, 15, 19, 26, 30, 31) that met inclusion criteria but did not provide specific data on the associations between subclinical thyroid dysfunction and CHD or mortality. We obtained risk estimates and CIs for cardiovascular and total mortality from cohort studies in the United Kingdom (15) and the Netherlands (19), as well as specific data for CHD mortality from a cohort of cardiac patients in Italy (31). Authors of a cohort study that published data about the relationship between autoimmune thyroid disease and CHD (30) provided us with data specific to subclinical hypothyroidism that were available for a subgroup of the participants. Three studies provided us with specific numbers of outcomes in each thyroid group (12, 14, 26). We used the most adjusted risk estimates available (the model containing the greatest number of covariates), unless a separate model further adjusted for thyroid antibodies, because thyroid autoimmunity has been hypothesized to be a mediator in the association between subclinical hypothyroidism and CHD (20). We did a sensitivity analysis without the studies that adjusted for cholesterol because high cholesterol might be on the causal pathway. When risk estimates and CIs were not provided but raw data were available (25, 30, 32), we calculated relative risks (RRs) and CIs by using the Woolf method (3335). Data Synthesis and Analysis We first qualitatively synthesized data, paying particular attention to which definitions of subclinical thyroid dysfunction were used and which outcomes were measured. To calculate summary estimates and CIs of the risk for subclinical thyroid dysfunction, we pooled both RRs and hazard ratios (HRs) by using random-effects models based on the variance model developed by DerSimonian and Laird (36). Analyses were repeated by using fixed-effects models for comparison. The presence of heterogeneity across studies was evaluated by using the Q statistic with a conservative P value of 0.10 (37). We also calculated the I 2 statistic, which describes the total variation across studies attributable to heterogeneity rather than chance; an I

Telomere length in white blood cells is not associated with morbidity or mortality in the oldest old: a population‐based study

Cross‐sectional studies have repeatedly suggested peripheral blood monocyte telomere length as a biomarker of aging. To test this suggestion in a large population‐based follow‐up study of the oldest old, we measured telomere length at baseline in 598 participants of the Leiden 85‐plus Study (mean age at baseline 89.8 years). We also obtained second telomere measurements from 81 participants after an average time span of between 3.9 and 12.9 years. Telomere length at baseline was not predictive for mortality (P > 0.40 for all‐cause, cardiovascular causes, cancer or infectious diseases, Cox regression for gender‐adjusted tertiles of telomere length) or for the incidence of dementia (P = 0.78). Longitudinally, telomere length was highly unstable in a large fraction of participants. We conclude that blood monocyte telomere length is not a predictive indicator for age‐related morbidity and mortality at ages over 85 years, possibly because of a high degree of telomere length instability in this group.

Use of Framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study.

Objectives To investigate the performance of classic risk factors, and of some new biomarkers, in predicting cardiovascular mortality in very old people from the general population with no history of cardiovascular disease. Design The Leiden 85-plus Study (1997-2004) is an observational prospective cohort study with 5 years of follow-up. Setting General population of the city of Leiden, the Netherlands. Participants Population based sample of participants aged 85 years (215 women and 87 men) with no history of cardiovascular disease; no other exclusion criteria. Main measurements Cause specific mortality was registered during follow-up. All classic risk factors included in the Framingham risk score (sex, systolic blood pressure, total and high density lipoprotein cholesterol, diabetes mellitus, smoking and electrocardiogram based left ventricular hypertrophy), as well as plasma concentrations of the new biomarkers homocysteine, folic acid, C reactive protein, and interleukin 6, were assessed at baseline. Results During follow-up, 108 of the 302 participants died; 32% (35/108) of deaths were from cardiovascular causes. Classic risk factors did not predict cardiovascular mortality when used in the Framingham risk score (area under receiver operating characteristic curve 0.53, 95% confidence interval 0.42 to 0.63) or in a newly calibrated model (0.53, 0.43 to 0.64). Of the new biomarkers studied, homocysteine had most predictive power (0.65, 0.55 to 0.75). Entering any additional risk factor or combination of factors into the homocysteine prediction model did not increase its discriminative power. Conclusions In very old people from the general population with no history of cardiovascular disease, concentrations of homocysteine alone can accurately identify those at high risk of cardiovascular mortality, whereas classic risk factors included in the Framingham risk score do not. These preliminary findings warrant validation in a separate cohort.

Handgrip strength as a predictor of functional, psychological and social health. A prospective population-based study among the oldest old

BACKGROUND muscle wasting is associated with a detrimental outcome in older people. Muscle strength measurements could be useful as part of a clinical evaluation of oldest old patients to determine who are most at risk of accelerated decline in the near future. OBJECTIVE this study aimed to assess if handgrip strength predicts changes in functional, psychological and social health among oldest old. DESIGN the Leiden 85-plus Study is a prospective population-based follow-up study. SUBJECTS five-hundred fifty-five, all aged 85 years at baseline, participated in the study. METHODS handgrip strength was measured with a handgrip strength dynamometer. Functional, psychological and social health were assessed annually. Baseline data on chronic diseases were obtained from the treating physician, pharmacist, electrocardiogram and blood sample analysis. RESULTS at age 85, lower handgrip strength was correlated with poorer scores in functional, psychological and social health domains (all, P < 0.001). Lower baseline handgrip strength predicted an accelerated decline in activities of daily living (ADL) and cognition (both, P <or= 0.001), but not in social health (P > 0.30). CONCLUSION poor handgrip strength predicts accelerated dependency in ADL and cognitive decline in oldest old. Measuring handgrip strength could be a useful instrument in geriatric practice to identify those oldest old patients at risk for this accelerated decline.

Handgrip strength and mortality in the oldest old population: the Leiden 85-plus study

Background: Poor muscular strength has been shown to be associated with increased morbidity and mortality in diverse samples of middle-aged and elderly people. However, the oldest old population (i.e., over 85 years) is underrepresented in such studies. Our objective was to assess the association between muscular strength and mortality in the oldest old population. Methods: We included 555 participants (65% women) from the Leiden 85-plus study, a prospective population-based study of all 85-year-old inhabitants of Leiden, Netherlands. We measured the handgrip strength of participants at baseline and again at age 89 years. We collected baseline data on comorbidities, functional status, levels of physical activity, and adjusted for potential confounders. During the follow-up period, we collected data on mortality. Results: During a follow-up period of 9.5 years (range 8.5–10.5 years), 444 (80%) participants died. Risk for all-cause mortality was elevated among participants in the lowest tertile of handgrip strength at age 85 years (hazard ratio [HR] 1.35, 95% confidence interval [CI] 1.00–1.82, p = 0.047) and the lowest two tertiles of handgrip strength at age 89 years (HR 2.04, CI 1.24–3.35, p = 0.005 and HR 1.73, CI 1.11–2.70, p = 0.016). We also observed significantly increased mortality among participants in the tertile with the highest relative loss of handgrip strength over four years (HR 1.72, CI 1.07–2.77, p = 0.026). Interpretation: Handgrip strength, a surrogate measurement of overall muscular strength, is a predictor of all-cause mortality in the oldest old population and may serve as a convenient tool for prognostication of mortality risk among elderly people.

A high response is not essential to prevent selection bias: Results from the Leiden 85-plus study

We tested the hypothesis that an additional effort to increase the response rate would diminish selection bias in a community-based cohort study. In the Leiden 85-plus Study, all subjects of the town of Leiden who had reached their 85th birthday were informed of the study by mail and then asked to participate by telephone. In an additional recruitment stage, those subjects who did not participate directly were visited and personally asked to participate. When these subjects refused, some nonresponse questions were asked. In this way we collected data on the whole source population. Of 691 eligible elderly subjects, 511 subjects (74%) participated directly. Of those who did not participate directly, 88 subjects participated after the additional effort. The response rate increased from 74% to 87%. Compared to the 511 subjects who directly participated, the 88 subjects who entered the study after the additional effort had poorer health and lower survival. The subjects who refused were more healthy and had poorer mood. The direct sample did not differ from the source population with respect to socio-demographics, health, and mortality. In conclusion, we showed that given a moderately high direct response the additional effort was effective in increasing the response rate, but was also selective and was not necessary to prevent selection bias.

Subclinical Thyroid Dysfunction and the Risk of Heart Failure Events An Individual Participant Data Analysis From 6 Prospective Cohorts

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.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. # Clinical Perspective {#article-title-42}

Inflammation and Stroke The Leiden 85-Plus Study

Background— Experimental evidence indicates that interleukin-10 (IL-10) deficiency is associated with the development of cardiovascular and cerebrovascular disease. We analyzed the relation between low IL-10 production levels, history of stroke, and incident fatal stroke. Summary of Report— All 85-year-old inhabitants of Leiden, Netherlands (n=599) were visited at their place of residence (response rate, 87%). Production levels of the anti-inflammatory cytokine IL-10 were assessed in a whole blood assay whereby lipopolysaccharide was used as a stimulus. Plasma concentrations of C-reactive protein (CRP) were also used as a marker of inflammation. A history of stroke was obtained at baseline (prevalence, 10%). The number of fatal strokes was prospectively obtained for a median follow-up of 2.6 years (incidence, 1.82 per 100 person-years at risk). Subjects with a history of stroke had significantly lower median IL-10 production levels at baseline than subjects without stroke (558 versus 764 pg/mL;P <0.05). They also had significantly higher median CRP concentrations (6 versus 3 mg/L;P <0.05). The odds ratio for a history of stroke increased to 2.30 (95% CI, 1.12 to 4.72) over strata representing decreasing production levels of IL-10. The relative risk for incident fatal stroke was 2.94 (95% CI, 1.01 to 8.53) when we compared subjects with low or intermediate baseline IL-10 production levels to those with high production levels of IL-10. Conclusions— Our data support the hypothesis that subjects with low IL-10 production levels have an increased risk of stroke.

C-Reactive Protein Is a Strong but Nonspecific Risk Factor of Fatal Stroke in Elderly Persons

An elevated level of C-reactive protein is a strong predictor of cardiovascular events in elderly persons. Whether C-reactive protein has direct adverse vascular effects or is a marker of aspecific systemic inflammation remains to be determined. The aim of this study was to investigate the relation between C-reactive protein and the occurrence of fatal strokes in elderly persons. In the Leiden 85-Plus Study, a population-based prospective follow-up study, we studied the levels of C-reactive protein in 80 participants who died from stroke within the first 5 years of follow-up. Levels of C-reactive protein were determined in serum samples at baseline. Levels of C-reactive protein were also determined in 82 control subjects who survived for the first 5 years of follow-up and in 83 participants who died from noncardiovascular causes. Mortality risks were estimated with logistic regression and adjusted for differences in age, sex, smoking, medication, total cholesterol, history of diabetes or hypertension, and previous cardiovascular events. Levels of C-reactive protein at baseline were 2-fold higher in subjects who died from stroke than in control subjects (median 5.7 versus 2.7 mg/L, P<0.005). The levels of C-reactive protein in subjects who died from stroke or from noncardiovascular causes were similar (median 5.7 versus 4.9 mg/L, P=0.7). The risk of death from stroke as well as from noncardiovascular causes increased linearly up to 10-fold in subjects with the highest levels of C-reactive protein at baseline (P<0.001). The levels of C-reactive protein were lower when more time had elapsed between blood sampling and time of death during follow-up (P=0.01). C-reactive protein is a strong but nonspecific risk factor of fatal stroke in old persons. The data do not support the idea that C-reactive protein has direct vascular effects that underlie fatal cerebrovascular disease.

The metabolic syndrome is associated with decelerated cognitive decline in the oldest old

Background: The metabolic syndrome is a cluster of risk factors including hypertension, obesity, dyslipidemia, and impaired glucose metabolism, associated with cardiovascular disease. The metabolic syndrome also appears to predispose to cognitive dysfunction and dementia. In this study the association between the metabolic syndrome and cognitive function was examined in a population of the oldest old. Methods: The Leiden 85-Plus Study is a population-based study of 599 persons from age 85 onward. Cognitive function was assessed annually from age 85 to 90 by means of four neuropsychological tests. The presence (n = 237) or absence (n = 325) of the metabolic syndrome was recorded at baseline. Cross-sectional and prospective associations between the metabolic syndrome and cognitive function were analyzed with linear mixed models, adjusted for sex and level of education. Results: At age 85 the metabolic syndrome was not associated with lower cognitive performance. The metabolic syndrome was associated with a decelerated cognitive decline from age 85 to 90 on the Mini-Mental State Examination (additional annual effect 0.18 [0.07], p = 0.01), the Stroop Test (−1.49 [0.59], p = 0.01), and the Letter Digit Coding Test (0.26 [0.09], p = 0.005). This effect was mainly attributable to glucose, body mass index, and, to a lesser extent, blood pressure. Conclusion: The association between the metabolic syndrome and accelerated cognitive decline, which has been reported in persons up to age 75, is not evident in a population of the oldest old. The concept of the metabolic syndrome may be less valid in this age group.