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European Heart Journal Advance Access published online on November 13, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn508
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Are serum thyrotropin levels within the reference range associated with endothelial function?

Henry Völzke1,*, Daniel M. Robinson2, Thomas Spielhagen2, Matthias Nauck3, Anne Obst1, Ralf Ewert2, Birger Wolff2,4, Henri Wallaschofski2, Stephan B. Felix2 and Marcus Dörr2

1 Institut für Community Medicine, Ernst-Moritz-Arndt-Universität, Walther Rathenau Str. 48, D-17487 Greifswald, Germany
2 Klinik für Innere Medizin B, Ernst-Moritz-Arndt-Universität, Greifswald, Germany
3 Institut für Klinische Chemie und Laboratoriumsmedizin, Ernst-Moritz-Arndt-Universität, Greifswald, Germany
4 Franz-Volhardt-Klinik, Charité Campus Berlin-Buch, HELIOS Kliniken Berlin, Germany

Received 4 December 2007; revised 11 September 2008; accepted 23 October 2008.

* Corresponding author. Tel: +49 3834 867707, Fax: +49 3834 866684, Email: voelzke{at}uni-greifswald.de


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
Aims: High serum thyrotropin (TSH) levels within the reference range might be associated with an increased cardiovascular risk. In the present study, we investigated the association between serum TSH levels and flow-mediated dilation (FMD) as a measure of endothelial dysfunction.

Methods and results: The study population comprised 1364 subjects (670 women) aged 25–85 years with serum TSH levels between 0.25 and 2.12 mIU/L recruited from 5-year follow-up of the Study of Health in Pomerania. No interventions were performed. Measurements of FMD and nitrate-mediated dilation (NMD) were performed in the supine position using standardized ultrasound techniques. FMD and NMD values below the median of each distribution were considered decreased. Analyses adjusted for age, sex, smoking, and systolic and diastolic blood pressure revealed a non-significant inverse trend between serum TSH levels and FMD (P = 0.130). Subjects with serum TSH levels above the highest quartile had lower median FMD values relative to subjects with serum TSH levels below the lowest quartile (4.86 vs. 5.43%, P < 0.05). A linear inverse trend between serum TSH levels and decreased FMD barely missed statistical significance (P = 0.138). Subjects with high serum TSH levels had higher odds of decreased FMD relative to subjects with low serum TSH levels (odds ratio 1.42; 95% confidence interval 1.02; 1.96; P < 0.05). These associations were more pronounced in men than in women. There were no such associations for NMD.

Conclusion: Serum TSH levels within the upper reference range are associated with impaired endothelial function. Our findings contribute to the discussion on whether the upper TSH reference limit should be redefined.

Key Words: Thyroid function • Endothelial function • Epidemiology


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
Thyroid function has major effects on cardiovascular function. A widened pulse pressure, left ventricular hypertrophy, and cardiac arrhythmias are major clinical signs of overt hyperthyroidism.1 Patients with overt hypothyroidism commonly have a reduced heart rate and an increased risk of atherosclerosis due to impaired lipid metabolism.2 Similar associations were found for subclinical thyroid disorders, but these findings have not always been replicated.1

Significant debate is centred around the correct definition of the upper and lower reference intervals of serum thyrotropin (TSH) levels.3–5 Methodically, reference values are markers of a distribution of test results within a given population. As the distribution of serum TSH levels strongly depends on the underlying iodine supply,6 TSH reference values may substantially vary across populations.7 Against this background, it becomes obvious that TSH reference values might not necessarily be related to clinical diseases or outcomes. Thus, accumulating evidence suggests that serum TSH levels within the upper reference range are related to an increased risk of incident hypothyroidism,8 hypertension,9,10 dyslipidaemia,11 and weight gain,12,13 although not all of these associations were confirmed by other studies.14

Endothelial dysfunction can be assessed as decreased flow-mediated dilation (FMD) using ultrasound and represents a very early stage of atherosclerosis.15 Subjects with decreased FMD share common atherosclerotic risk factors with myocardial infarction or cerebrovascular atherosclerosis patients.16,17 Endothelial dysfunction predicts future cardiovascular morbidity and mortality.18–20 Some smaller studies21–26 have investigated possible associations between thyroid function and FMD. Most of these studies21,23–26 demonstrated high FMD values in subjects with subclinical and overt hyperthyroidism and low FMD values in subjects with subclinical and overt hypothyroidism. One study27 in 35 subjects also demonstrated low FMD values in subjects with serum TSH levels within the upper reference range relative to euthyroid subjects, whereas another study14 in 61 subjects failed to demonstrate an association between thyroid function and endothelial function in euthyroid subjects. Putative associations between thyroid function and FMD over the whole TSH reference range of a general population have not been investigated.

In the present study, we investigated the association between serum TSH levels and endothelial dysfunction. We hypothesized that subjects with serum TSH levels in the upper reference range have lower FMD values and consequently higher odds of decreased FMD when compared with subjects with serum TSH levels within the lower reference range.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Funding
 Acknowledgements
 References
 
Study population
The Study of Health in Pomerania (SHIP) is a population-based investigation in West Pomerania, a region in the northeastern part of Germany. The study region is a previously iodine-deficient area with a high prevalence of iodine deficiency-related disorders such as goiter, thyroid nodules, and decreased serum TSH levels.28 Study details are given elsewhere.29 In brief, a sample from the population aged 20–79 years was drawn. The SHIP population finally comprised 4310 participants (2193 women), which corresponds to a final response of 68.8%. Baseline examinations (SHIP-0) were conducted between October 1997 and March 2001. Between March 2002 and September 2006, the 5-year follow-up examinations (SHIP-1) were performed and contained 3300 participants (83.6% of still eligible subjects, 1711 women). The study was reviewed by a board of independent scientist and approved by the Ethics Committee of the University of Greifswald. All participants provided written informed consent.

We offered all SHIP-1 participants the opportunity to take part in a substudy with measurements of endothelial function, body plethysmography, and cardiopulmonary exercise testing. Of the 3300 SHIP-1 participants, 1693 subjects (51.3%; 861 women) agreed to take part in the side project. We excluded 172 subjects (103 women) with non-usable ultrasound images, 9 subjects (eight women) who refused blood draws, 148 subjects (80 women) with serum TSH levels outside the reference range, and 4 subjects (3 women) with anti-thyroid medication. This resulted in a final study population of 1360 subjects (667 women) aged 25–85 years, who were available for the present analysis.

Measurements
Sociodemographic and medical characteristics were assessed by computer-assisted personal interviews. According to tobacco consumption, participants were categorized into current (one or more cigarette per day), occasional (less than one cigarette per day), former, and non-smokers. Pack years for current and former smokers were calculated by multiplying the duration of smoking in years with the amount of packs smoked daily (20 cigarettes were defined as one pack). Data on medication were collected using the anatomical therapeutic chemical code. We considered anti-thyroid preparations as exclusion criterion and included anti-hypotensives, peripheral vasodilators, beta-blockers, calcium channel blockers, drugs acting on the renin–angiotensin system, statins, and non-steroidal anti-inflammatory drugs as potential confounders.

Height and weight were measured for the calculation of body mass index [BMI = weight (kg)/height2 (m2)]. After a 5 min rest period, the systolic and diastolic blood pressures were measured three times in the right arm of seated subjects using a digital blood pressure monitor (HEM-705CP, Omron Corporation, Tokyo, Japan), with each reading followed by an additional 3 min rest period. One of two differently sized cuffs was applied according to the circumference of the participant's arm. The mean of the second and third measurements was calculated and used for the present analyses.

Non-fasting blood samples were taken between 7 a.m. and 4 p.m. Serum TSH levels were analysed by immunochemiluminescent procedures [Immulite 2000, Third generation, Diagnostic Products Corporation (DPC), Los Angeles, IL, USA]. We used the serum TSH reference range of 0.25–2.12 mIU/L that has been recently established for this region.7 Serum anti-thyroperoxidase (anti-TPO) was measured by an enzyme immunoassay (VARELISA, Elias Medizintechnik GmbH, Freiburg, Germany). The detection limit of this assay was 1 IU/mL. LDL cholesterol was determined via lipoprotein electrophoresis in agarose gels with subsequent enzymatic cholesterol staining applying the Spife 3000 System from Helena Laboratories (Progen Biotechnik GmbH, Heidelberg, Germany).

Endothelial dysfunction was assessed by FMD. Examinations were performed in a supine position by two observers. The subject's right arm was comfortably immobilized. The brachial artery diameter was recorded 3–7 cm above the antecubital fossa using a 10 MHz linear array transducer ultrasound system (Cypress, Siemens AG, Erlangen, Germany). After the resting scan, a pneumatic cuff placed around the forearm 10 cm distal to the ultrasound location was inflated above a pressure of 220 mmHg for 5 min. Diameter measurements were repeated 60 s after cuff deflation. FMD was calculated by the ratio between brachial diameters before and after inflation of the pneumatic cuff and is expressed as % diameter. Nitrate-mediated dilation (NMD) was taken 3 min after sublingual administration of nitroglycerin (400 µg) in 1096 subjects (465 women). Examinations were performed and read by two observers. All ultrasound measurements in SHIP underlie strict quality management.30,31 Intra-reader, intra-observer, inter-reader, and inter-observer variabilities are evaluated in certification procedures. Before data collection, 25 images are measured twice by each participating reader, and 12 volunteers are examined twice by each participating observer. Figure 1 gives an example of an inter-observer certification, which was performed before data collection. During data collection, observer certification procedures are repeated semi-annually for six volunteers. At least 24 h is required between two readings and examinations, respectively. The number of images and volunteers, respectively, was arbitrarily defined before the beginning of the study and has been proven satisfactory from experience to demonstrate relevant reader and observer differences. All measurements of intra-reader, intra-observer, inter-reader, and inter-observer agreements with respect to FMD revealed a mean bias of <5% and ±2 SD of bias of <25%. Readers rated the quality of the digitally stored images as excellent, good, and adequate. FMD and NMD values below the median of each distribution were considered decreased.


Figure 1
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  		Figure 1 Example for an inter-observer examination with respect to flow-mediated dilation (FMD) plotted according to Bland and Altman.45 Two observers (OBS1 and OBS2) examined independently from each other the FMD in 12 volunteers. The figure indicates the mean FMD of each volunteer examined by the two observers (x-axis) and the absolute FMD difference measured by the two observers relative to the mean FMD of each volunteer (y-axis). The plot allows assessment for systematic error and its direction by the mean difference (green line) as well as the random error by the 1.96 standard deviation (purple lines). The 95% confidence intervals for each estimate are given as dotted lines.

 
Statistical analysis
The power analysis was based on the assumptions that a total number of 3200 subjects will participate in SHIP-1 and that the response to the subproject will be 55%. This would have resulted in a study population of 1760 participants who were available for the present analysis. Given the size of the study population, it would have been possible to detect a minimum odds ratio (OR) of 1.38 for decreased FMD values when comparing subjects with serum TSH levels within the upper quartile of the reference range with those with lower serum TSH levels (two-sided {chi}2 test, P < 0.05, power >80%).

Data on quantitative characteristics are expressed as mean (SD). Data on qualitative characteristics are expressed as per cent values or absolute numbers as indicated. The study population was divided into four groups using the quartiles of the serum TSH distribution as cut-off (group I TSH 0.25–0.54 mIU/L, group II TSH 0.55–0.78 mIU/L, group III TSH 0.79–1.09 mIU/L, and group IV TSH 1.10–2.12 mIU/L). Inter-group comparisons were made using two-sided {chi}2 test (nominal data) or Student's t-test (interval data). Multivariable statistical analyses were performed using analysis of variance (ANOVA) or logistic regression analysis. All statistical models were adjusted for age and sex. In the final model, we only considered those characteristics as confounders, whose inclusion in the model led to ≥10% change in the coefficient of interest. For this, clinical (smoking, BMI, and blood pressure) and laboratory variables were included in various orders. Thereafter, variables on medication listed in Table 1 entered the model also in various orders. BMI, serum LDL cholesterol and glucose levels, and use of medication did not meet this criterion and were therefore excluded from the final model. The assumptions of ANOVA were met: residuals were normally distributed, the error variances were homogeneous, and there were no patterns in the residual plot as a function of predicted values. In trend analyses, these assumptions were only met after serum TSH levels as continuously distributed independent variables were log-transformed. Post hoc significance in ANOVA was assessed by least significance difference and Bonferroni.32 Adjusted means or OR and their 95% confidence intervals (95% CI) are provided. Natural splines33 were fitted for TSH over the full range. The resulting TSH spline variables were associated with FMD and NMD in the final linear regression models. A value of P < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS software, version 14.0.1 (SPSS GmbH Software, Munich, Germany) and SAS 9.1 (SAS Institute Inc., Cary, NC, USA).


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  		Table 1 Selected characteristics in subjects with different serum thyrotropin levels

 

   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding
 Acknowledgements
 References
 
Subjects with high serum TSH levels within the reference range were older, more commonly non-smokers, and less commonly current smokers and had a higher diastolic blood pressure when compared with those with low serum TSH levels within the reference range. Subjects in the different serum TSH groups were similar with respect to sex, BMI, systolic blood pressure, positive anti-TPO antibodies, and serum LDL cholesterol and glucose levels. With respect to medication, subjects with higher serum TSH levels used more commonly beta-blockers than those with low serum TSH levels. Individuals with serum TSH levels between the second and third quartiles received more often statins relative to those with low serum TSH levels (Table 1).

In 319 subjects (23.5%), the quality of FMD images was rated as excellent, good in 851 subjects (62.6%), and adequate in 190 subjects (14.0%). The respective numbers for NMD images were 268 (24.5%), 665 (60.8%), and 161 (14.7%). In the entire study population, FMD values were 4.23% (2.14%; 6.88%), and NMD values were 13.21% (8.96%; 18.39%). In bivariate analyses, there was no association between serum TSH levels within the reference range and FMD. However, subjects with high serum TSH levels within the reference range had higher unadjusted NMD values compared with those with low serum TSH levels within the reference range (Table 2).


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  		Table 2 Flow- and nitrate-mediated dilation in subjects with different serum thyrotropin levels

 
In age- and sex-adjusted analyses, there was a non-significant linear trend (P = 0.294) towards lower FMD values with increasing serum TSH levels. With analyses adjusted for further confounders, the inverse trend became clearer, but fell short of statistical significance in the final model (P = 0.130). In this model, which included sex, age, smoking status, systolic and diastolic blood pressure as confounders, subjects with serum TSH levels above the highest quartile had lower FMD values relative to those with serum TSH levels below the lowest quartile (Table 3). This difference, however, did not attain statistical significance if adjusted for multiple testing.


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  		Table 3 Association between serum thyrotropin levels in the reference range and flow-mediated dilation (continuous variable) and decreased flow-mediated dilation (nominal variable)

 
Also, there was a non-significant linear inverse trend (P = 0.138) in age- and sex-adjusted analyses for the association between serum TSH levels and decreased FMD. In the final model, this trend narrowly missed statistical significance (P = 0.074). Subjects with high serum TSH levels within the reference range had higher odds for decreased FMD relative to those with low serum TSH levels within the reference range (Table 2). None of the results outlined in Table 3 was substantially affected when positive serum anti-TPO antibodies were added to the final models as further independent variables.

We performed sex-stratified analyses in the full models to explore possible gender differences. In men, the inverse trends between serum TSH levels within the reference range and FMD (P = 0.037) or decreased FMD (P = 0.041) attained statistical significance. Relative to men with serum TSH levels below the lowest quartile, men with high serum TSH levels above the highest quartile had significantly lower FMD values [adjusted mean 3.81 (standard error 0.30) vs. 4.64 (0.30)] and significantly more commonly decreased FMD values [OR 1.61 (95% CI 1.02; 2.55)]. In women, non-significant trends between serum TSH levels and the dependent variables were observed. Compared with women with low serum TSH levels, women with high serum TSH levels had non-significantly lower FMD values [adjusted mean 5.68 (standard error 0.35) vs. 6.13 (0.38)] and non-significantly more commonly decreased FMD values [OR 1.34 (95% CI 0.85; 2.13)].

With respect to NMD, there was no trend over the exposure groups, neither in the age- and sex-adjusted models (P = 0.780) nor in the final model (P = 0.888). Also, inter-group comparisons or sex-stratified analyses did not yield any significant differences. Likewise, there was no association between serum TSH levels and decreased NMD (Table 4).


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  		Table 4 Association between serum thyrotropin levels in the reference range and nitrate-mediated dilation (continuous variable) and decreased nitrate-mediated dilation (nominal variable)

 
In sensitivity analyses, we restricted the full FMD models to 319 subjects with excellent FMD image quality. Linear trends between serum TSH levels and both FMD (P = 0.085) and decreased FMD (P = 0.068) barely missed statistical significance in the final model. Subjects with serum TSH levels above the highest quartile of the reference range had lower FMD values and higher odds for decreased FMD relative to subjects with serum TSH levels below the lowest quartile of the reference range, whereby the mean OR estimate was higher relative to the whole study population. Similar to analyses in the whole population, we did not detect any association of serum TSH levels within the reference range with NMD or decreased NMD in the 269 subjects with excellent NMD image quality (Table 5).


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  		Table 5 Association between serum thyrotropin levels in the reference range, flow-, and nitrate-mediated dilation in subjects with excellent quality rating of images

 
Further sensitivity analyses were performed by varying the scales of independent variables and by replacing the smoking status variable by pack years. In addition, the time point of blood sampling was included in the analysis. All these analyses did not affect the major results materially. Likewise, the inclusion of observers or readers in the multivariable models did neither reveal an association between both variables and FMD or NMD nor a substantial effect on the major results.

Finally, we asked the question whether the association between serum TSH levels and FMD was due to the specific definition of TSH reference range. To answer this question, we re-included all subjects with serum TSH levels outside the reference range. The spline given in Figure 2 did not clearly support this notion. There was no association between TSH and NMD over the whole TSH range (Figure 3).


Figure 2
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  		Figure 2 Association between serum thyrotropin (TSH) levels and flow-mediated dilation (FMD) over the whole TSH range. Natural splines were fitted for TSH over the full range. The resulting TSH spline variables were associated with FMD in the final linear regression model and plotted against the predicted FMD values. The plots display the association between TSH and FMD for a 45-year-old male non-smoker having a blood pressure of 120/80 mmHg.

 

Figure 3
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  		Figure 3 Association between serum thyrotropin (TSH) levels and nitrate-mediated dilation (NMD) over the whole TSH range. Natural splines were fitted for TSH over the full range. The resulting TSH spline variables were associated with NMD in the final linear regression model and plotted against the predicted NMD values. The plots display the association between TSH and NMD for a 45-year-old male non-smoker having a blood pressure of 120/80 mmHg.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 Acknowledgements
 References
 
In the present study, we investigated the association between serum TSH levels within the reference range and endothelial dysfunction. Our hypothesis was partly confirmed. Although there was only a non-significant inverse trend between serum TSH levels and FMD, subjects with serum TSH levels above the upper quartile of the reference range had lower FMD values and higher odds for decreased FMD relative to subjects with serum TSH levels below the lowest quartile of the reference range. These results became clearer when analyses were restricted to subjects with excellent FMD image quality, although in these analyses, the number of included subjects was considerably reduced.

Our results are in good agreement with other studies, which demonstrate that serum TSH levels in the upper reference range are associated with incident hypothyroidism,8 hypertension,9,10 dyslipidaemia,11 and weight gain.12,13 Decreased FMD mirrors endothelial dysfunction, represents a very early stage of atherogenesis and plaque formation,34 and is highly associated with progression and prognosis of generalized atherosclerosis.35 Moreover, endothelial dysfunction predicts cardiovascular outcome.36 Together, these findings indicate that serum TSH levels within the upper reference range are markers for clinically relevant disorders and outcomes.

As discussed previously,3 the serum TSH reference range that has been recently established for our region is relatively shifted towards the left. Reasons for this shift include the previous status of iodine deficiency, the strict criteria used to select a reference population, which included thyroid ultrasound, and the specific laboratory method used for analysing TSH values. In the present study, the association between serum TSH levels and decreased FMD was observed, although we used our relatively low upper TSH reference value. Taking this knowledge into account, our results support the notion that currently generally accepted upper TSH reference values of 4.0 mIU/L37 might be too high, as they include a thyroid status that is already associated with significant cardiovascular alterations.

The present findings indirectly support previous studies,21,23–26 which demonstrate high FMD values in patients with hyperthyroidism and low FMD values in those with hypothyroidism. These findings, however, have not always been confirmed.14,22 Divergent results might be explained by the low number of participants recruited for former studies, ranging from 4226 to 221 patients.22 Together, 660 subjects were investigated by previous studies14,21–27 on the association between thyroid and endothelial function. Thus, with 1364 subjects recruited, our study represents by far the largest study in this field to date.

The inverse association between serum TSH levels within the reference range and FMD was more pronounced in men than in women, thereby suggesting that endothelial function in males is more sensitive for thyroid hormone action than in females. This is in good agreement with other studies,38,39 which demonstrated that the negative effects of known cardiovascular risk factors on endothelial function are more pronounced in men than in women. It is a matter of current research to answer the question whether these disparities can be mainly explained by gender-related differences in accumulated atherosclerotic risk factors, divergent hormonal levels, or simply by distinct diameters of the brachial artery.38,40,41

In contrast to FMD, NMD is a marker of endothelium-independent vasodilation.42 Although there was an association between serum TSH levels within the reference range and FMD in our study, we did not find such association for NMD. This strengthens the hypothesis that thyroid hormones affect endothelial function via the NO system. Thus, experimental evidence suggests that the administration of thyroid hormones reduces endothelium-dependent NO in rats.43 In addition, the treatment of rats with propylthiouracil gives rise to diminished responsiveness in response to phenylnephrine, an effect that might be mediated by enhanced NO production of the endothelium.44

FMD and NMD measurements were potentially prone to observer bias. In the daily practice of study quality management, the wish to measure potential observer differences with high precision has to be weighed up against practicability. We usually examine 12 volunteers to assess intra- and inter-observer variabilities for a priori certifications of ultrasound observers. This procedure does not take >2 days and is by experience sufficient to detect major observer differences. Thus, although the confidence intervals in the exemplary certification examination displayed in Figure 1 do not overlap, the estimates of observer differences are relatively imprecise, reflecting the limitation of the procedure. However, we do not suspect a relevant systematic observer bias in the present study, because in multivariable analyses, the observer variable neither was related to FMD and NMD nor did substantially change the results with respect to the association of interest. We certainly cannot unequivocally exclude misclassification in the definition of FMD and NMD variables due to random errors. An incorrect labelling of FMD status, however, should bias our results towards the null, thus strengthening our positive findings. The fact that the association between serum TSH levels within the reference range and FMD became clearer in subjects with excellent FMD reading quality argues for a certain underestimation of this association in the entire study population. Small NMD differences across the serum TSH groups and the lack of a dose–response relation make it unlikely that we missed a significant association between serum TSH levels within the reference range and NMD.

We conclude that serum TSH levels within the upper reference range are associated with impaired endothelial function. Our findings significantly contribute to the current discussion on whether the upper TSH reference limit should be redefined.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
Acknowledgements
 References
 
This study is funded by the Federal Ministry of Education and Research, the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. This work was further supported by the German Research Foundation (DFG Vo 955/5-1).


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
References
 
This work is part of the Community Medicine Research net (CMR) of the University of Greifswald, Germany. The CMR encompasses several research projects that share population-based data from the Study of Health in Pomerania (SHIP; http://ship.community-medicine.de). We thank Christian Schwahn and Till Ittermann, University of Greifswald, for statistical advice.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 

  1. Dorr M, Volzke H. Cardiovascular morbidity and mortality in thyroid dysfunction. Minerva Endocrinol (2005) 30:199–216.[Medline]
  2. Rodondi N, Aujesky D, Vittinghoff E, Cornuz J, Bauer DC. Subclinical hypothyroidism and the risk of coronary heart disease: a meta-analysis. Am J Med (2006) 119:541–551.[CrossRef][Web of Science][Medline]
  3. Brabant G, Beck-Peccoz P, Jarzab B, Laurberg P, Orgiazzi J, Szabolcs I, Weetman AP, Wiersinga WM. Is there a need to redefine the upper normal limit of TSH? Eur J Endocrinol (2006) 154:633–637.[Abstract/Free Full Text]
  4. Surks MI, Goswami G, Daniels GH. The thyrotropin reference range should remain unchanged. J Clin Endocrinol Metab (2005) 90:5489–5496.[Abstract/Free Full Text]
  5. Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab (2005) 90:5483–5488.[Abstract/Free Full Text]
  6. Laurberg P, Pedersen KM, Hreidarsson A, Sigfusson N, Iversen E, Knudsen PR. Iodine intake and the pattern of thyroid disorders: a comparative epidemiological study of thyroid abnormalities in the elderly in Iceland and in Jutland, Denmark. J Clin Endocrinol Metab (1998) 83:765–769.[Abstract/Free Full Text]
  7. Volzke H, Alte D, Kohlmann T, Ludemann J, Nauck M, John U, Meng W. Reference intervals of serum thyroid function tests in a previously iodine-deficient area. Thyroid (2005) 15:279–285.[CrossRef][Web of Science][Medline]
  8. Teng W, Shan Z, Teng X, Guan H, Li Y, Teng D, Jin Y, Yu X, Fan C, Chong W, Yang F, Dai H, Yu Y, Li J, Chen Y, Zhao D, Shi X, Hu F, Mao J, Gu X, Yang R, Tong Y, Wang W, Gao T, Li C. Effect of iodine intake on thyroid diseases in China. N Engl J Med (2006) 354:2783–2793.[Abstract/Free Full Text]
  9. Volzke H, Alte D, Dorr M, Wallaschofski H, John U, Felix SB, Rettig R. The association between subclinical hyperthyroidism and blood pressure in a population-based study. J Hypertens (2006) 24:1947–1953.[Web of Science][Medline]
  10. Asvold BO, Bjoro T, Nilsen TI, Vatten LJ. Association between blood pressure and serum thyroid-stimulating hormone concentration within the reference range: a population-based study. J Clin Endocrinol Metab (2007) 92:841–845.[Abstract/Free Full Text]
  11. Asvold BO, Vatten LJ, Nilsen TI, Bjoro T. The association between TSH within the reference range and serum lipid concentrations in a population-based study. The HUNT Study. Eur J Endocrinol (2007) 156:181–186.[Abstract/Free Full Text]
  12. Knudsen N, Laurberg P, Rasmussen LB, Bulow I, Perrild H, Ovesen L, Jorgensen T. Small differences in thyroid function may be important for body mass index and the occurrence of obesity in the population. J Clin Endocrinol Metab (2005) 90:4019–4024.[Abstract/Free Full Text]
  13. Fox CS, Pencina MJ, D'Agostino RB, Murabito JM, Seely EW, Pearce EN, Vasan RS. Relations of thyroid function to body weight: cross-sectional and longitudinal observations in a community-based sample. Arch Intern Med (2008) 168:587–592.[Abstract/Free Full Text]
  14. Balletshofer BM, Rittig K, Rett K, Haring HU, Nawroth PP. Flow associated (endothelium dependent) vasodilation and TSH-levels in young normotensive and normoglycemic subjects. VASA Zeitschrift fur Gefasskrankheiten (2001) 30:97–100.
  15. Faulx MD, Wright AT, Hoit BD. Detection of endothelial dysfunction with brachial artery ultrasound scanning. Am Heart J (2003) 145:943–951.[CrossRef][Web of Science][Medline]
  16. Clarkson P, Celermajer DS, Powe AJ, Donald AE, Henry RM, Deanfield JE. Endothelium-dependent dilatation is impaired in young healthy subjects with a family history of premature coronary disease. Circulation (1997) 96:3378–3383.[Abstract/Free Full Text]
  17. Juonala M, Viikari JS, Laitinen T, Marniemi J, Helenius H, Ronnemaa T, Raitakari OT. Interrelations between brachial endothelial function and carotid intima–media thickness in young adults: the cardiovascular risk in young Finns study. Circulation (2004) 110:2918–2923.[Abstract/Free Full Text]
  18. Shimbo D, Grahame-Clarke C, Miyake Y, Rodriguez C, Sciacca R, Di Tullio M, Boden-Albala B, Sacco R, Homma S. The association between endothelial dysfunction and cardiovascular outcomes in a population-based multi-ethnic cohort. Atherosclerosis (2007) 192:197–203.[CrossRef][Medline]
  19. Heitzer T, Baldus S, von Kodolitsch Y, Rudolph V, Meinertz T. Systemic endothelial dysfunction as an early predictor of adverse outcome in heart failure. Arterioscler Thromb Vasc Biol (2005) 25:1174–1179.[Abstract/Free Full Text]
  20. Gokce N, Keaney JF Jr, Hunter LM, Watkins MT, Nedeljkovic ZS, Menzoian JO, Vita JA. Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Col Cardiol (2003) 41:1769–1775.[Abstract/Free Full Text]
  21. Cikim AS, Oflaz H, Ozbey N, Cikim K, Umman S, Meric M, Sencer E, Molvalilar S. Evaluation of endothelial function in subclinical hypothyroidism and subclinical hyperthyroidism. Thyroid (2004) 14:605–609.[CrossRef][Web of Science][Medline]
  22. Fernandez-Real JM, Lopez-Bermejo A, Castro A, Casamitjana R, Ricart W. Thyroid function is intrinsically linked to insulin sensitivity and endothelium-dependent vasodilation in healthy euthyroid subjects. J Clin Endocrinol Metab (2006) 91:3337–3343.[Abstract/Free Full Text]
  23. Guang-da X, Hong-yan C, Xian-mei Z. Changes in endothelium-dependent arterial dilation before and after subtotal thyroidectomy in subjects with hyperthyroidism. Clin Endocrinol (2004) 61:400–404.[Medline]
  24. Ho WJ, Chen ST, Tsay PK, Wang CL, Hsu TS, Kuo CT, Chen WJ. Enhancement of endothelium-dependent flow-mediated vasodilation in hyperthyroidism. Clin Endocrinol (2007) 67:505–511.[Medline]
  25. Razvi S, Ingoe L, Keeka G, Oates C, McMillan C, Weaver JU. The beneficial effect of L-thyroxine on cardiovascular risk factors, endothelial function, and quality of life in subclinical hypothyroidism: randomized, crossover trial. J Clin Endocrinol Metab (2007) 92:1715–1723.[Abstract/Free Full Text]
  26. Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L, Salvetti A, Ferrannini E, Monzani F. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab (2003) 88:3731–3737.[Abstract/Free Full Text]
  27. Lekakis J, Papamichael C, Alevizaki M, Piperingos G, Marafelia P, Mantzos J, Stamatelopoulos S, Koutras DA. Flow-mediated, endothelium-dependent vasodilation is impaired in subjects with hypothyroidism, borderline hypothyroidism, and high-normal serum thyrotropin (TSH) values. Thyroid (1997) 7:411–414.[Web of Science][Medline]
  28. Volzke H, Ludemann J, Robinson DM, Spieker KW, Schwahn C, Kramer A, John U, Meng W. The prevalence of undiagnosed thyroid disorders in a previously iodine-deficient area. Thyroid (2003) 13:803–810.[CrossRef][Web of Science][Medline]
  29. John U, Greiner B, Hensel E, Ludemann J, Piek M, Sauer S, Adam C, Born G, Alte D, Greiser E, Haertel U, Hense HW, Haerting J, Willich S, Kessler C. Study of Health In Pomerania (SHIP): a health examination survey in an east German region: objectives and design. Soz Praventivmed (2001) 46:186–194.[CrossRef][Web of Science][Medline]
  30. Dorr M, Wolff B, Robinson DM, John U, Ludemann J, Meng W, Felix SB, Volzke H. The association of thyroid function with cardiac mass and left ventricular hypertrophy. J Clin Endocrinol Metab (2005) 90:673–677.[Abstract/Free Full Text]
  31. Volzke H, Robinson DM, Schminke U, Ludemann J, Rettig R, Felix SB, Kessler C, John U, Meng W. Thyroid function and carotid wall thickness. J Clin Endocrinol Metab (2004) 89:2145–2149.[Abstract/Free Full Text]
  32. SPSS Statistical Algorithms. (1997) Chicago, Il: SPSS Inc. p572–580.
  33. Stone C, Koo CY. Additive Splines in Statistics. (1985) Washington, DC: American Statistical Association.
  34. Rundek T, Hundle R, Ratchford E, Ramas R, Sciacca R, Di Tullio MR, Boden-Albala B, Miyake Y, Elkind MS, Sacco RL, Homma S. Endothelial dysfunction is associated with carotid plaque: a cross-sectional study from the population based Northern Manhattan Study. BMC Cardiovasc Disord (2006) 6:35.[CrossRef][Medline]
  35. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, Nour KR, Quyyumi AA. Prognostic value of coronary vascular endothelial dysfunction. Circulation (2002) 106:653–658.[Abstract/Free Full Text]
  36. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation (2001) 104:2673–2678.[Abstract/Free Full Text]
  37. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab (2002) 87:489–499.[Abstract/Free Full Text]
  38. Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Deanfield JE. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol (1994) 24:471–476.[Abstract]
  39. Juonala M, Viikari JS, Ronnemaa T, Helenius H, Taittonen L, Raitakari OT. Elevated blood pressure in adolescent boys predicts endothelial dysfunction: the cardiovascular risk in young Finns study. Hypertension (2006) 48:424–430.[Abstract/Free Full Text]
  40. Khalil RA. Sex hormones as potential modulators of vascular function in hypertension. Hypertension (2005) 46:249–254.[Abstract/Free Full Text]
  41. Mizia-Stec K, Gasior Z, Mizia M, Haberka M, Holecki M, Zwolinska W, Katarzyna K, Skowerski M. Flow-mediated dilation and gender in patients with coronary artery disease: arterial size influences gender differences in flow-mediated dilation. Echocardiography (Mount Kisco, NY) (2007) 24:1051–1057.
  42. Neunteufl T, Katzenschlager R, Abela C, Kostner K, Niederle B, Weidinger F, Stefenelli T. Impairment of endothelium-independent vasodilation in patients with hypercalcemia. Cardiovasc Res (1998) 40:396–401.[Abstract/Free Full Text]
  43. McAllister RM, Albarracin I, Price EM, Smith TK, Turk JR, Wyatt KD. Thyroid status and nitric oxide in rat arterial vessels. J Endocrinol (2005) 185:111–119.[Abstract/Free Full Text]
  44. Grieve DJ, Fletcher S, Pitsillides AA, Botham KM, Elliott J. Effects of oral propylthiouracil treatment on nitric oxide production in rat aorta. Br J Pharmacol (1999) 127:1–8.[CrossRef][Web of Science][Medline]
  45. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet (1986) 307–310.

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