Study On The Relationship Between Thyroid Stimulating Hormone And Cardiovascular Events

BackgroundOvert hypothyroidism is known to predispose patients to cardiovascular diseases. However, controversies exist regarding whether subclinical hypothyroidism (SCH), defined as a serum thyroid stimulating hormone (TSH) concentration above the normal range with normal scrum FT4and FT3concentration, is associated with coronary artery disease (CAD) and its mortality. Some studies showed a positive association between them.But these findings were not conformed by other studies. Recently, these associations have been further investigated among individuals with normal thyroid function. High levels of TSH with the reference range were showed to be associated with hypercholesterolemia. hypertension, impaired endothelial function, arterial stiffness.metabolic syndrome and renal dysfunction. One prospective study indicated TSH levels within the reference range were positively and linearly associated with cardiovascular mortality in women and two cross-sectional studies reported that relatively high normal TSH levels within the reference range was associated with the presence of CAD, while others did not confirm these findings.It has been reported that age influences the relationship between SCH and CAD. with increased risks for CAD in younger but not older individuals. However, few studies have explored the role of age in the link between thyroid function and CAD in euthyroid subjects so far.Objective1. To investigate the relationship between TSII within the reference range and CAD. 2. To investigate the modification effect of age on the relationship between TSH withinthe reference range and CAD.Methods1. Patients who underwent coronary angiography because of chest pain were retrospectively reviewed. The exclusion criteria were as follows:Abnormal serum levels of TSH, T4or T3; History of thyroid dysfunction or under treatment with thyroid medication; Acute or past myocardial infarction; History of revascularization of coronary artery; Severe cardiac, hepatic or renal dysfunction; Medication with amiodarone, sex hormones and steroid hormones. Finally, a total of318subjects were included.2. Information of past medications and risk factors for CAD, including smoking, hypertension, diabetes, body mass index, lipid profile, blood glucose, creatinine, thyroid hormones and coronary angiographic findings were recorded.3. Data were represented as mean±tandard deviation. Inter-group analysis was done by using independent t test, Mann-Whitney U test and chi-square test. Analysis of covariance was performed to adjust for age and sex. Multivariate logistic regression analysis was done to determine risk factors relating to CAD. Statistical significance was set at p<0.05. All the above analyses were conducted with the use of SPSS software in version17.0.ResultsLevels of TSH, T3and T4were similar between CAD and non-CAD group (TSH:1.77±0.99vs1.89±0.98mIU/L.T3:1.45±0.36vs1.51±0.35nmol/L, T4:100.06±20.49vs103.95±24.06nmol/L, respectively) when analysis was performed among all subjects. TSH levels between the group with single-vessel CAD and multivessel CAD also did not differ significantly.When analysis was restricted to participants younger than65years, levels of TSH were significantly higher in CAD group than in non-CAD group (2.03±0.94vs1.75±0.97mlU/L, adjusted p=0.024). Levels of T3and T4did not differ between two groups.Multiple logistic regression analysis showed elevated TSH level was an independent risk factor for CAD, with an adjusted odds ratio (OR) of1.512(95%CI:1.100-2.078, p=0.011).Among subjects older than65years, no significant differences in TSH, T3and T4between CAD group and non-CAD group were observed (TSH:1.66±1.0vs1.89±1.09mlU/L, adjusted p=0.772; T3:1.52±0.39vs1.35±0.36nmol/L, adjusted p=0.145; T4:103.83±22.89vs101.96±18.32nmol/L, adjusted p=0.524; respectively).Multiple logistic regression analysis showed TSH level was not an independent risk factor for CAD (OR:1.099, p=0.767).Conclusions1. High levels of TSH within the reference range were independently associated with the presence of CAD among subjects younger than65years of age.2. Among subjects older than65years of age, no significant relationship between high levels of TSH within the reference range and the presence of CAD was observed.3. The findings suggested a modification effect of age on the relationship between high levels of TSH within the reference range and CAD. BackgroundSubclinical hyperthyroidism, defined as a serum TSH concentration below the normal range with normal levels of thyroid hormones, is a mild form of hyperthyroidism. Whether subclinical hyperthyroidism leads to adverse clinical outcomes and should be treated remains controversial. Subclinical hyperthyroidism has been found to be associated with a higher risk of atrial fibrillation, hypertension, osteoporosis and dementia compared with euthyroid subjects in some but not all studies. Similarly, the findings from the cohort studies on the association of subclinical hyperthyroidism and cardiovascular disease (CVD), cardiovascular and all-cause mortality were also inconsistent. Lack of randomized clinical trials answering the question whether long-term health outcomes are improved by treatment of subclinical hyperthyroidism made this issue more elusive.Several meta-analyses assessing the relationship between CVI). cardiovascular mortality and all-cause mortality have been performed previously, providing somewhat conflicting results. These meta-analyses had low power to detect this association precisely with availability of only a small number of studies. Since the latest meta-analysis had been performed, a total of eleven new large prospective studies on this issue have been published. Now data is sufficient to update the meta-analysis.Objective1. To investigate the relationship between subclinical hyperthyroidism and cardiovascular diseases.2. To investigate the relationship between subclinical hyperthyroidism and cardiovascular mortality.3. To investigate the relationship between subclinical hyperthyroidism and all-cause mortality.Methods1. Search strategy and Study selection. PubMed and Embase database were searched for relevant studies assessing the association between subclinical hyperthyroidism and CVD or mortality (cardiovascular and all-cause). Studies were considered eligible if they met the following criteria:1) the study design was a cohort study (its definition was as follows:exposure is measured at baseline and the occurrence of outcomes is assessed after a certain time span of follow-up);2) thyroid function was measured at baseline;3) the outcome of interest was CVD, cardiovascular or all-cause mortality; and4) relative risk (RR) or hazard ratio (HR) and the corresponding95%confidence interval (CI)(or data to calculate them) were reported.2. Data extraction. The following data were abstracted:the first author’s name; the publication year; the country of origin; the number, mean age, and sex of the participants; the definition of subclinical hyperthyroidism and cardiovascular events, based on the information as provided in the primary studies; the prevalence of subclinical hyperthyroidism; the study design details, including population source, starting year of study, and study duration; whether the reported RR or HR was adjusted for potential confounders; and losses to follow-up.3. Statistical analyses. The study-specific maximally adjusted RR or HR was used to compute a summary RR and its95%CI. HRs were directly considered as RRs. Heterogeneity across studies was tested by using the Q and I2statistic. The combined risk estimates were computed using either fixed-effects models or random-effects models with the presence of heterogeneity. A subgroup analysis was conducted to explore the potential effect modification of variables on outcomes. Meta-regression was used to explore possible contributors to heterogeneity. We also investigated the influence of a single study on the overall risk estimate by omitting1study in each turn. Potential publication bias was assessed by Egger’s test and Begg’s test to evaluate publication bias. All analyses were performed using STATA version11.0. A P value<0.05was considered statistically significant, except where otherwise specified.Results1. Study characteristics and Quality assessment. The characteristics of17cohort studies were included. These studies were published between2001and2011. The mean length of follow-up ranged from2to20years. In most studies participants were recruited from communities and participants of five studies derived from convenience sample. All studies used second or third generation method for TSH assay. Most studies had a TSH cutoff value of0.25to0.5mU/L with normal FT4level. The prevalence of subclinical hyperthyroidism ranged from1.4%to14.7%. Seven studies repeatedly measured thyroid functions over follow-up and the others made single baseline measurements. Most studies defined cardiovascular events as a combined endpoint. All outcome assessments were from medical record and hospital database. Most studies adjusted for a group of conventional risk factors for CVD. Losses to follow-up were lower than5%in most studies. The Newcastle-Ottawa Scale was adopted for quality assessment and all studies scored6or higher.2. Subclinical hyperthyroidism and risk of CVD.Eleven eligible studies on the association between subclinical hyperthyroidism and CVD were pooled. The summary RR from the fixed-effects model was1.19(95%CI:1.10to1.28) with no evidence of heterogeneity (P=0.48,I2-=0.0%). When only combining studies from community sample the summary RR was1.30(95%CI:1.16to1.47.P=0.00).3. Subclinical hyperthyroidism and risk of cardiovascular mortality. Twelve eligible studies on the association between subclinical hyperthyroidism and cardiovascular mortality were combined. The summary RR for cardiovascular mortality was1.52(95%CI:1.08to2.13) with a moderate degree of heterogeneity (P=0.084,I2=38.5%). Sub-analysis by sample source showed that the summary RR was1.26(95%CI:0.94to 1.68) when restricting to studies from community sample and3.21(95%CI:1.66to6.21) when restricting to those from convenience sample.4. Subclinical hyperthyroidism and risk of All-cause mortality. Twelve studies were pooled to calculate the overall RR for all-cause mortality. A borderline significant association was observed when combining all studies (RR:1.2595%CI:1.00to1.55, P=0.05) with presence of heterogeneity (P=0.03,I2=48.0%). Significant difference between subclinical hyperthyroidism and reference group disappeared when combining studies from community samples (RR:1.13[95%CI:0.91to1.41]; P=0.26) but existed when pooling those from convenience samples (RR:1.84[95%CI:1.05to3.25]; P=0.03).5. Exploration of the sources of heterogeneity. Exploratory univariate meta-regression was performed with age, sample source, publication year, length of follow-up, ethnicity and sample size as the potential sources of between-study heterogeneity. Sample source was a key contributor to the heterogeneity among studies on the association between subclinical hyperthyroidism and cardiovascular mortality. None of variables abovementioned was identified as a potentially important source of between-study heterogeneity in combining RRs for total mortality. Stratified analysis by assessment of thyroid function (repeated or not) and mean age barely changed the results among studies from community sample.6. Sensitivity analysis. Omission of the study by Robert W. Flynnhad moderate influence on the combined RRs of subclinical hyperthyroidism for risk of CVD, changing the summary RR to1.29(95%CI:1.15to1.44). No evidence of any individual study having excessive influence on the pooled effect in combining risk estimates of subclinical hyperthyroidism for cardiovascular mortality or all-cause mortality was observed.7. Publication bias. The Begg’s funnel plot and Egger s regression test did not indicate evidence of publication bias.Conclusions1. Subclinical hyperthyroidism was associated with an increased risk of CVD for general individuals, independent of conventional CVD risk factors, including age, diabetes, hypertension, smoking, BMI and hypercholesterolemia et al.2. Subclinical hyperthyroidism was associated with an increased risk of cardiovascular and all-cause mortality only for sick individuals, but not for general individuals.