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Purpose Although thyroid hormones are irrefutably implicated in cardiovascular physiology, the impact of within-reference range variations of thyroid function on cardiovascular disease (CVD) remains unclear. Elucidating this is important, since it could foster preventive treatment and reduce global CVD burden. We therefore investigated the impact of within-reference range variations of thyroid function on all-cause and cardiovascular mortality. Methods We included community-dwelling individuals aged 28–75 years from a prospective cohort study, without known use of thyroid-affecting therapy and with thyrotropin within reference range. Associations of thyroid function with mortality were quantified using Cox models and adjusted for sociodemographic and cardiovascular risk factors. Results Mean (SD) age of the 6,054 participants (52.0% male) was 53.3 (12.0) years. During 47,594 person-years of follow-up, we observed 380 deaths from all causes and 103 from CVDs. Although higher thyrotropin was not associated with all-cause mortality (adjusted HR 1.02, 95% CI 0.92–1.14), point estimates for cardiovascular mortality diverged toward increased risk in younger (4) was associated with all-cause mortality (1.18, 1.07–1.30) and with cardiovascular mortality only in elderly (1.61, 1.19–2.18), but not in younger participants (1.03, 0.78–1.34). Higher free triiodothyronine (FT3) was associated with all-cause mortality in females only (1.18, 1.02–1.35). FT3 was not associated with cardiovascular mortality (0.91, 0.70–1.18). Conclusions Community-dwelling elderly individuals with high-normal thyroid function are at increased risk of all-cause and cardiovascular mortality, reinforcing the need of redefining the current reference ranges of thyroid function.

// Na Hu 1, 2, * , Zhan-Ming Li 3, * , Jin-Feng Liu 1, 2 , Zhen-Zhen Zhang 1, 2 , Li-Shun Wang 1 1 Institute of Biomedical Sciences, Minhang Hospital, Fudan University, Shanghai, P.R. China 2 School of Public Health Taishan Medical University, Shandong, P.R. China 3 Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, P.R. China * These authors contributed equally to this work Correspondence to: Li-Shun Wang, email: lishunwang@fudan.edu.cn Keywords: thyroid cancer, serum thyrotropin, meta-analysis, differentiated thyroid carcinoma, papillary thyroid carcinoma Received: December 16, 2015 Accepted: June 12, 2016 Published: June 24, 2016 ABSTRACT Thyrotropin (TSH) is thought as a risk factor for thyroid cancer. However, the effect of serum TSH might depend on histological types of thyroid cancer. We searched for related studies including serum TSH as an exposure and thyroid cancer as a result in PUBMED, EMBASE and Chinese National Knowledge Infrastructure up to April 21, 2016. This meta-analysis included 22 articles with 53,538 participants. When comparing all histological thyroid cancer, the pooled odds ratios of thyroid cancer in patients with nodules was found to increase significantly with higher serum TSH concentrations for differentiated thyroid carcinoma (1.88 vs .1.48, P = 0.0000) and papillary thyroid carcinoma (2.08 vs. 1.48, P = 0.0006). Each 1 mU/L increase of serum TSH was associated with 14% greater risk of thyroid cancer for all histological thyroid cancer, 16% for differentiated thyroid carcinoma and 22% for papillary thyroid carcinoma. In addition, high serum TSH was associated with a reduced risk for follicular thyroid carcinoma (OR = 0.73, 95% CI: 0.52, 1.02). This meta-analysis suggested high serum TSH concentration is risky for papillary thyroid carcinoma but not for follicular thyroid carcinoma.

Background: Hypothyroidism, the most common endocrine disease, induces cardiac electrical remodeling that creates a substrate for ventricular arrhythmias. Recent studies report that high thyrotropin (TSH) levels are related to cardiac electrical abnormalities and increased mortality rates. The aim of the present work was to investigate the direct effects of TSH on the heart and its possible causative role in the increased incidence of arrhythmia in hypothyroidism. Methods: A new rat model of central hypothyroidism (low TSH levels) was created and characterized together with the classical propylthiouracil-induced primary hypothyroidism model (high TSH levels). Electrocardiograms were recorded in vivo, and ionic currents were recorded from isolated ventricular myocytes in vitro by the patch-clamp technique. Protein and mRNA were measured by Western blot and quantitative reverse transcription polymerase chain reaction in rat and human cardiac myocytes. Adult human action potentials were simulated in silico to incorporate the experimentally observed changes. Results: Both primary and central hypothyroidism models increased the L-type Ca2+ current (ICa-L) and decreased the ultra-rapid delayed rectifier K+ current (IKur) densities. However, only primary but not central hypothyroidism showed electrocardiographic repolarization abnormalities and increased ventricular arrhythmia incidence during caffeine/dobutamine challenge. These changes were paralleled by a decrease in the density of the transient outward K+ current (Ito) in cardiomyocytes from animals with primary but not central hypothyroidism. In vitro treatment with TSH for 24 hours enhanced isoproterenol-induced spontaneous activity in control ventricular cells and diminished Ito density in cardiomyocytes from control and central but not primary hypothyroidism animals. In human myocytes, TSH decreased the expression of KCND3 and KCNQ1, Ito, and the delayed rectifier K+ current (IKs) encoding proteins in a protein kinase A–dependent way. Transposing the changes produced by hypothyroidism and TSH to a computer model of human ventricular action potential resulted in enhanced occurrence of early afterdepolarizations and arrhythmia mostly in primary hypothyroidism, especially under b-adrenergic stimulation. Conclusions: The results suggest that suppression of repolarizing K+ currents by TSH underlies most of the electrical remodeling observed in hypothyroidism. This work demonstrates that the activation of the TSHreceptor/protein kinase A pathway in the heart is responsible for the cardiac electrical remodeling and arrhythmia generation seen in hypothyroidism., Centro de Investigaciones Cardiovasculares

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 T-4, 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.

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 T-4 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 personyears). 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.

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 T-4 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 personyears). 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.

The negative impact of subclinical hypothyroidism (sHT) on cardiovascular risk, widely recognized in young adults (aged55-60 y), is still debated in the elderly (65 y), especially in the oldest olds (80 y).We searched Medline for reports published with the following search terms: "hypothyroidism," "subclinical hypothyroidism," "ageing," "elderly," "L-thyroxin," "thyroid," "guidelines," "treatment," "quality of life," "cardiovascular risk," "heart failure," "coronary heart disease" (CHD), "atherosclerosis," and "endothelial dysfunction." We limited our search to reports in English published after 1980, although we incorporated some reports published before 1980. We supplemented the search with records from personal files, textbooks, and relevant articles. Analyzed parameters included the epidemiology of thyroid failure, the effect of thyroid hormone on the aging process, cardiovascular function, and CHD risk factors. We also included the potential benefits of L-T4 therapy on the quality of life, cardiovascular events, and survival.TSH levels increase with age, even in older people without thyroid disease. Most longitudinal studies show an increased risk for CHD events and mortality in sHT participants. This increase is less evident in the elderly, mainly in cases of serum TSH values above 10 mIU/L. Lower mortality rate in a cohort of the oldest olds (85 y) has been reported.sHT in older people should be not regarded as a unique condition, and moderately old patients (aged70-75 y) could be considered clinically similar to the adult population, albeit with a higher optimal TSH target value. Conversely, the oldest old subjects should be carefully followed with a wait-and-see strategy, generally avoiding hormonal treatment. The decision to treat elderly people is still an unresolved clinical challenge--first, due to a lack of appropriately powered randomized controlled trials of L-T4 in sHT patients, examining cardiovascular hard endpoints in various classes of age; and second, because of the negative effects of possible overtreatment.