International Journal of Rheumatic Diseases 2014
ORIGINAL ARTICLE
The impact of thyroid autoimmunity on arterial stiffness in postmenopausal patients with fibromyalgia Kyoung Im CHO1 and Ji Hyun LEE2 1 Cardiovascular Research Institute, Kosin University School of Medicine, and 2Division of Rheumatology, Maryknoll Medical Center, Busan, Korea
Abstract Objective: The exact mechanism of arterial stiffness in fibromyalgia (FM) remains unclear. The present study aimed to evaluate the association between thyroid function and markers of arterial function in postmenopausal FM patients. Methods: This study included 163 postmenopausal FM patients without any known cardiovascular diseases and within a normal reference range of thyroid-stimulating hormone (TSH) level. Clinical parameters including the Fibromyalgia Impact Questionnaire (FIQ), the pain visual analogical scale (VAS) and tender point counts were measured. Vascular function was assessed by brachial-ankle pulse wave velocity (baPWV) and flow-mediated dilation (FMD). We evaluated the associations between arterial markers and serum TSH, free thyroxin, as well as serum thyroidperoxidase autoantibody (TPO Ab). Results: Patients with a high baPWV (≥ 1490 cm/s) showed more positive TPO Ab (65% vs. 10%, P = 0.006) than those with a normal baPWV. Additionally, the baPWV values of patients with positive TPO Ab were significantly different from those with negative TPO Ab. Age, FIQ and TPO Ab were significantly correlated with baPWV and FMD (all P < 0.05). Multiple linear regression analysis revealed that the only significant predictors of baPWV were age, FIQ and the presence of TPO Ab after adjustment for traditional risk factors. A significant association was also found between FMD and positive TPO Ab. Conclusion: Age, functional status and presence of TPO Ab were significantly associated with increased arterial stiffness in postmenopausal FM patients. Given the combined thyroid autoimmunity in FM patients, a re-evaluation of the effects on the vasculature may be necessary. Key words: fibromyalgia, flow-mediated dilation, pulse wave velocity, thyroid-stimulating hormone.
INTRODUCTION Fibromyalgia (FM) is a common disorder characterized by chronic widespread musculoskeletal pain and related symptoms along with multiple painful tender points.1,2 In patients with FM, stress and pain may chronically enhance sympathetic activity, which may induce endothelial dysfunction. In some FM patients, dysregulation of pain modulatory systems involves increased sympa-
Correspondence: Dr Ji Hyun Lee, MD, Maryknoll Medical Center, 4–12, Daechung-dong, Jung-gu, Busan, Korea. Email: [email protected]
thetic nervous system (SNS) drive at rest and deficient SNS-mediated responses to certain challenges, such as postural change or exercise.3,4 Thyroid hormones have direct effects on cardiac myocytes, endothelial cells and vascular smooth muscle cells,5,6 resulting in hypertrophy and stiffness of the vessels.7 In addition, there is some evidence of the relationship between thyroid hormones and cardiovascular events. Individuals with ‘high-normal’ thyroid-stimulating hormone (TSH) levels (2.0–4.0 mIU/mL) and positive antithyroid antibodies exhibit elevated levels of total cholesterol.8 Similarly, autoimmune thyroid disorders, such as Hashimoto’s thyroiditis or Graves’ disease,
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
K. I. Cho and J. H. Lee
have been linked to increased rates of hospitalizations for cardiovascular events.9 Muscle symptoms are a frequent finding in thyroid diseases, and it has been recognized that there are significant similarities between noninflammatory arthropathy and symptoms of thyroid dysfunction.10 Some recent reports have found an attenuated response of TSH to thyroidreleasing hormone as well as an increased prevalence of antithyroid antibodies in FM patients.11 Other studies have reported that FM patients had some problems in the production or utilization of thyroid hormones,12 and that there is an association between thyroid autoimmunity and FM.13,14 Our data has also previously demonstrated that euthyroid FM patients had a significantly higher prevalence of positive TPO antibodies.15 Although we previously suggested that a decrease in endothelial function and an increase in arterial stiffness were affected by the clinical parameters of FM,16,17 the exact mechanism is unclear. We performed this study to evaluate the effect of antithyroid antibodies on endothelial function in euthyroid FM patients, using pulse wave velocity (PWV), which assesses arterial stiffness by measuring the status of large and small arteries in the lower extremity,18 and brachial flow mediated dilatation (FMD), a non-invasive measure of endothelial function.
METHODS Subjects One hundred and sixty-three postmenopausal FM patients who met the guidelines outlined by the American College of Rheumatology (ACR) for FM19 were consecutively enrolled in this study from the outpatient clinic of the Rheumatology Division at Maryknoll Medical Center, Busan, Republic of Korea. Fifty healthy female controls were matched to the FM patients according to age, blood pressure (BP), height and cholesterol and glucose levels. Postmenopausal status was defined when there has been amenorrhea for one complete year. Exclusion criteria for both groups included smoking (in the last 5 years), diabetes, dyslipidemia, hypertension, chronic hepatopathy, nephrotic syndrome and obesity with body mass index (BMI) above 26 or abdominal obesity (waist circumference ≥ 90 cm for men and ≥ 85 cm for women). We excluded the cases whose fasting glucose was above 126 mg/dL at the time of entry, or any patients who was taking anti-diabetic medication. The presence of dyslipidemia was assumed if subjects were taking lipid-lowering drugs, or high total cholesterol levels above 200 mg/dL. Hypertension was considered when blood pressure is persistently at or above
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140/90 mmHg. We measured the serum creatinine level at the time of entry, and excluded patients with serum creatinine levels higher than 2.0 mg/dL. Subjects with autoimmune rheumatic diseases with antinuclear antibody (ANA) titers above 1 : 160, history of thyroid diseases, palpable goiter, abnormal free T4 (FT4) and/or TSH levels were also excluded. The local institutional review board approved the study and all subjects gave written informed consent.
Disease-specific evaluation At each visit, subjects were asked to rate their current level of pain on a 10-cm visual analog scale (VAS, 0 = no pain; 10 = worst pain imaginable). Subjects then filled out the fibromyalgia impact questionnaire (FIQ)20 which evaluates physical function, work status, depression, anxiety, sleep, pain, stiffness, fatigue and well-being. A high score indicates a greater impact of the syndrome on the patient. Subjects were then assessed for numbers of positive tender points by digital palpation over the 18 characteristic tender point sites according to ACR diagnostic criteria for FM.
Measurement of arterial stiffness Arterial stiffness was assessed by measuring brachialankle (ba)PWVs using an automatic waveform analyzer (VP-1000; Colin Co., Komaki, Japan).21 The VP-1000 simultaneously records pulse waves, blood pressure (BP; both arms and ankles), ankle-brachial pressure index (ABI), electrocardiogram (ECG) and heart sounds, as described elsewhere.22 ABI was calculated by the ratio of the ankle systolic BP divided by the arm systolic BP, and the lower value of the ankle systolic BP was used for the calculation. For the measurement of baPWV, pulse waves obtained from the brachial and tibial arteries were recorded simultaneously, and the transmission time, which is defined as the time interval between the initial increase in brachial and tibial waveforms, was determined. The transmission distance from the arm to each ankle was calculated according the body height. The baPWV was automatically computed as the transmission distance divided by the transmission time. All participants included in the present study had a normal ABI (> 0.9). A high baPWV was defined as the gender-specific highest quartile of the values among the study subjects (baPWV [the mean of the right and left values] ≥ 1490 cm/s in females).
Brachial artery measurements FMD was performed using 2-dimensional ultrasonography (Vivid 7, General Electric, Horten, Norway) with
International Journal of Rheumatic Diseases 2014
Thyroid autoimmunity postmenopausal FM patients
modification of the methods of Corretti et al.13 Measurements were performed on the subject’s left arm after 10–20 min of rest in the supine position. The brachial artery was scanned longitudinally just above the antecubital crease, using a 10-MHz probe. The diameter of the brachial artery was measured at the interface between the tunica media and tunica adventitia of the anterior and posterior walls. Hyperemia was induced by inflation of a pneumatic cuff to 180–200 mmHg (50 mmHg higher than the systolic blood pressure) for 4 min on the most proximal part of the upper arm. The maximal diameter of the brachial artery was measured after 45– 60 s following sudden deflation of the cuff. Brachial artery percent FMD induced by reactive hyperemia was expressed as the relative change from baseline (% FMD = 100 9 [(diameter after hyperemia-baseline diameter)/baseline diameter]). After 15 min, a third brachial artery scan was recorded again in a resting state with or without a sublingual nitroglycerin (NTG) 0.4 mg tablet, administered if the subject had a systolic blood pressure ≥ 110 mmHg. Relative changes in the brachial artery diameter between baseline and third examination were expressed as endothelium-independent vasodilatation, with or without NTG. We measured each diameter three times during two heart beats, using the mean values for the final analysis. Every diameter was measured at the peak of the R wave of the surface ECG. Measurements were performed by an independent examiner (KI Cho) blinded to the study set-up.
association of TPO Ab with vascular indices, we dichotomized the FM patients with positive TPO Ab and negative TPO Ab. Comparisons of all measurements were made with independent Student’s t-tests for continuous variables and chi-square or the exact Fisher test for qualitative variables of two groups. Correlations between variables were assessed by calculating the correlation coefficient with Pearson correlation tests. Multivariate linear regression was used to determine the sources of variation for vascular indices, using the presence of TPO Ab and selected discrete risk factor traits as covariates. A P-value < 0.05 was considered statistically significant.
RESULTS Clinical characteristics of patients Characteristics of FM patients are given in Table 1. There were no significant differences between FM patients and controls in terms of age (51.8 9.0 vs. 50.1 8.9 years) and the other parameters known to
Table 1 Baseline demographic characteristics of the study patients FM patients (n = 163) 51.8 9.0 23.2 2.7 122.8 12.7 76.8 9.2 74.3 8.2 187.7 17.6 1.75 1.06 1.08 0.29 40/163 (24.5%) 0.94 3.6 1.09 0.08 1377.1 206.6 6.13 2.10 11.4 3.78 54.5 21.7 13.5 1.84 48.8 18.7 5.2 5.8 2.08 1.82 47.6 6.10 27/163 (16.6%)
Statistical analysis
Age (years) Body mass index (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (bpm) Total cholesterol (mg/dL) TSH (mIU/L) Free T4 (pmol/L) Positive TPO Ab (%) hsCRP Ankle-brachial index Mean baPWV (cm/s) Reactive FMD NTG FMD Pain VAS Tender point count FIQ Disease duration (years) Duration postmenopause (years) Menopausal age (years) History of hormonal therapy (%)
All data are expressed as the mean standard deviation. Data were analyzed using standard statistical software (SPSS package version 12.0, SPSS Inc., Chicago, IL, USA). In order to further examine the
All values are mean SD. FM, fibromyalgia syndrome; TSH, thyroid stimulating hormone; TPO Ab, thyroidperoxidase autoantibody; hsCRP, highly sensitive C-reactive protein; baPWV, brachial-ankle pulse wave velocity; FMD, flow mediated dilation; NTG, nitroglycerin; VAS, visual analogue scale.
Laboratory evaluation Thyroid function was assessed by measuring levels of FT4 and TSH. FT4 (reference range 9.16–24.9 pmol/L) and TSH (reference range 0.38–4.7 mIU/L) were measured by chemiluminescent microparticle immunoassay (Architect-I 2000, Abbot, Ireland, UK). Thyroperoxidase antibody (TPO Ab) was measured by chemiluminescent immunoassay (ADVIA centaur, Siemens, Munich, Germany). The cut-off value of TPO Ab was 60 IU/mL. Highly sensitive C reactive protein (hsCRP), rheumatoid factor (RF) and ANA were also measured. hsCRP (reference range 0–0.5 mg/L) and RF (reference range 0–15 IU/mL) was measured by turbidometric immunoassay (ADVIA1800, Siemens), while ANA was measured by indirect fluorescent assay.
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affect PWV, including BMI, blood pressure, heart rate and the total cholesterol levels. However, FM patients showed more positive TPO Ab (24.5% vs. 8%, P = 0.03), significantly increased baPWV (1377.1 206.6 vs. 1283.3 185.7 cm/s, P = 0.004) and reduced reactive FMD (6.13 2.10 vs. 7.22 1.35%, P = 0.035) and NTG FMD (11.4 3.78 vs. 14.83 2.65%, P = 0.004) compared to the controls. Although the level of thyroid hormones did not differ significantly between FM patients and controls, the presence of TPO Ab was more prevalent in FM patients. Patients with a high baPWV (≥ 1490 cm/s) had a longer disease duration (P = 0.001), more positive TPO Ab (P = 0.006) and higher FIQ (P = 0.027) than those with a normal baPWV (Table 2).
Clinical characteristics of patients according to the presence of TPO Ab Comparison of the FM patients according to the presence of TPO Ab is presented in Table 3. There was no difference in blood pressure, total cholesterol, hsCRP, free T4, TSH, menopausal status, disease duration or FIQ between FM patients with positive TPO Ab and
Age (years) Duration of disease (years) BMI (kg/m2) Systolic BP (mmHg) Diastolic BP (mmHg) Heart rate (bpm) Total cholesterol (mg/dL) hsCRP TSH (mIU/L) Free T4 (pmol/L) TPO Ab titer Positive TPO (%) Tender point count Pain VAS FIQ ABI Duration postmenopause Menopausal age Reactive FMD NTG FMD
those with negative TPO Ab. However, the baPWV values of those with positive TPO Ab and those with negative TPO Ab (1643.4 306.4 cm/s vs. 1293.3 163.5 cm/s, P < 0.001) were significantly different. In addition, reactive FMD (4.94 1.88 vs. 7.03 3.01%, P < 0.001) and NTG FMD (7.03 3.01 vs. 12.81 2.82%, P < 0.001) were significantly reduced in FM patients with positive TPO Ab compared with those with negative TPO Ab.
Correlation of the vascular indices with clinical features in FM patients Arterial stiffness parameter (baPWV) and endothelial parameters (FMD) were significantly associated with age, functional status of FM (FIQ) and TPO Ab titers in correlation analyses (all P < 0.05, Table 4). However, these parameters showed no significant correlation with disease duration, menopausal age, blood pressure, total cholesterol, TSH, FT4 or inflammatory markers (hsCRP). Multiple regression analysis was used to adjust for any potential confounding influences of age, cholesterol, the duration of the disease and the clinical variables of FM; after adjusting for traditional risk
Table 2 Comparison of FM patients according to baPWV
Normal baPWV (n = 120)
High baPWV (n = 43)
P
50.8 9.2 4.94 5.73 21.5 1.3 125.9 11.8 78.2 9.5 72.8 11.3 193.6 29.8 0.56 1.08 1.83 1.22 1.11 0.21 104.3 440.4 12/120 (10%) 13.30 1.75 47.9 22.3 52.4 21.8 1.07 0.96 2.01 1.78 47.2 6.30 6.72 1.80 12.4 3.06
53.9 11.8 5.82 5.84 22.8 3.2 126.7 12.3 77.9 7.8 70.7 9.8 191.7 32.1 1.05 3.43 1.82 1.46 1.06 0.27 695.7 2050.4 28/43 (65%) 14.14 1.95 60.2 20.8 54.5 19.8 1.09 0.71 2.33 1.94 48.9 5.24 4.49 2.03 8.51 4.17
0.055 0.001 0.313 0.728 0.515 0.578 0.736 0.176 0.793 0.212 0.050 0.006 0.010 0.040 0.027 0.335 0.374 0.081 < 0.001 < 0.001
All values are mean SD. FM, fibromyalgia syndrome; baPWV, brachial-ankle pulse wave velocity; BMI, body mass index; BP, blood pressure; hsCRP, highly sensitive C reactive protein; TSH, thyroid stimulating hormone; TPO Ab, thyroidperoxidase autoantibody; VAS, Visual Analogue Scale; FIQ, Fibromyalgia Impact Questionnaire; ABI, ankle-brachial index; FMD, flow mediated dilation; NTG, nitroglycerin.
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Thyroid autoimmunity postmenopausal FM patients
Table 3 Comparison of arterial stiffness parameters in FM patients according to the presence of TPO Ab
Negative TPO (n = 123) Age (years) Duration of disease (years) BMI (kg/m2) Systolic BP (mmHg) Diastolic BP (mmHg) Heart rate (bpm) Total cholesterol (mg/dL) hsCRP TSH (mIU/L) Free T4 (pmol/L) TPO Ab titer Tender point count Pain VAS FIQ Duration postmenopause Menopausal age ABI Mean baPWV Reactive FMD NTG FMD
50.9 4.96 21.8 126.8 76.9 73.2 192.9 0.66 1.73 1.06 25.7 13.4 53.9 47.9 2.07 47.3 1.08 1293.3 6.52 12.8
8.90 5.75 2.7 10.7 10.1 12.1 28.1 1.12 1.00 0.27 12.1 1.80 22.1 18.6 1.77 6.30 0.07 163.5 2.03 2.82
Positive TPO (n = 40)
P
0.018 0.450 0.287 0.566 0.543 0.243 0.532 0.321 0.749 0.193 0.012 0.142 0.542 0.329 0.847 0.223 0.367 < 0.001 < 0.001 < 0.001
54.7 5.78 22.3 128.2 77.5 72.9 193.8 1.02 1.80 1.12 915.3 13.9 56.3 51.5 2.14 48.6 1.06 1643.4 4.94 7.03
7.80 5.82 3.1 11.9 9.8 10.7 29.1 3.42 1.24 0.21 2131.6 1.91 20.7 18.9 1.99 5.32 0.11 306.4 1.88 3.01
All values are mean SD. FM, fibromyalgia syndrome; BMI, body mass index; BP, blood pressure; hsCRP, highly sensitive C reactive protein; TSH, thyroid stimulating hormone; TPO Ab, thyroidperoxidase autoantibody; VAS, Visual Analogue Scale; FIQ, Fibromyalgia Impact Questionnaire; ABI, ankle-brachial index; baPWV, brachial-ankle pulse wave velocity; FMD, flow mediated dilation; NTG, nitroglycerin.
Table 4 Correlation coefficients between the parameters of arterial stiffness, endothelial function and clinical parameters of the FM group (n = 163)
Age Disease duration Systolic blood pressure Diastolic blood pressure Total cholesterol TPO Ab titer TSH Free T4 Menopausal age hsCRP FIQ
baPWV
Reactive FMD
NTG FMD
0.19 (0.015) 0.13 (0.101) 0.05 (0.758)
0.17 (0.035) 0.05 (0.522) 0.31 (0.030)
0.16 (0.038) 0.01 (0.885) 0.37 (0.008)
0.03 (0.863)
0.17 (0.232)
0.23 (0.111)
0.04 (0.643) 0.30 (< 0.001) 0.008 (0.915) 0.121 (0.125) 0.070 (0.377) 0.05 (0.520) 0.37 (< 0.001)
0.12 (0.325) 0.16 (0.038) 0.06 (0.420) 0.004 (0.959) 0.101 (0.198) 0.07 (0.383) 0.33 (0 < 0.001)
0.19 (0.254) 0.27 (0.001) 0.040 (0.615) 0.013 (0.869) 0.104 (0.187) 0.05 (0.535) 0.29 (0 < 0.001)
All values are mean SD. FM, fibromyalgia syndrome; BMI, body mass index; hsCRP, highly sensitive C reactive protein; TSH, thyroid stimulating hormone; TPO Ab, thyroidperoxidase autoantibody; FIQ, Fibromyalgia Impact Questionnaire; ABI, ankle-brachial index; baPWV, brachial-ankle pulse wave velocity; FMD, flow mediated dilation; NTG, nitroglycerin.
factors, significant predictors of baPWV were age, FIQ and presence of TPO Ab. A significant association was also found between FMD and positive TPO Ab. Although there was a weak association between vascular
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indices and TPO Ab as a continuous variable, the presence of TPO Ab showed a strong impact on vascular indices (Table 5). This relationship remained highly significant after multivariate regression analysis to
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Table 5 Multiple regression analysis between FM functional parameters and vascular parameters Univariate analysis Coefficient (b)
B (95% CI)
Age 0.374 0.004 (0.002 to 0.006) Disease duration 0.157 0.009 ( 0.001 to 0.018) Systolic blood pressure 0.046 0.002 ( 0.003 to 0.004) Diastolic blood pressure 0.025 0.000 ( 0.005 to 0.004) Total cholesterol 0.068 0.001 ( 0.003 to 0.004) hsCRP 0.158 0.005 ( 0.003 to 0.013) FIQ 0.113 1.541 (0.574 to 2.508) Presence of TPO Ab 0.590 3.501 (2.755 to 4.246) baPWV (r2 = 0.363, adjusted r2 = 0.327 in multivariate analysis) Age 0.265 0.039 ( 0.075 to 0.003) Disease duration 0.051 0.018 ( 0.075 to 0.038) Systolic blood pressure 0.005 0.000 ( 0.010 to 0.010) Diastolic blood pressure 0.021 0.001 ( 0.012 to 0.014) Total cholesterol 0.104 0.003 ( 0.006 to 0.013) hsCRP 0.071 0.048 ( 0.061 to 0.158) FIQ 0.117 0.027 ( 0.037 to 0.017) Presence of TPO Ab 0.324 1.579 ( 2.296 to 0.862) Reactive FMD (r2 = 0.264, adjusted r2 = 0.127 in multivariate analysis) Age 0.385 0.125 ( 0.150 to 0.101) Disease duration 0.188 0.041 ( 0.111 to 0.029) Systolic blood pressure 0.172 0.016 ( 0.042 to 0.011) Diastolic blood pressure, 0.196 0.050 ( 0.123 to 0.023) Total cholesterol 0.120 0.007 ( 0.020 to 0.005) hsCRP 0.020 0.008 ( 0.115 to 0.100) FIQ 0.307 0.037 ( 0.070 to 0.004) Presence of TPO Ab 0.656 5.749 ( 6.779 to 4.720) NTG FMD (r2 = 0.503, adjusted r2 = 0.476 in multivariate analysis)
Multivariate analysis 2
P
r
0.003 0.172 0.753 0.863 0.165 0.125 0.007 < 0.001
0.140 0.066 0.002 0.001 0.002 0.209 0.054 0.344
0.105 0.056 0.049 0.048 0.067 0.013 0.250 0.551
0.033 0.443 0.520 0.778 0.497 0.851 0.038 < 0.001
0.035 0.552 0.421 0.233 0.471 0.383 0.002 < 0.001
0.027 0.003 0.000 0.000 0.011 0.005 0.014 0.105
0.127 0.101 0.075 0.052 0.011 0.057 0.185 0.286
0.019 0.212 0.716 0.800 0.693 0.471 0.037 0.001
0.005 0.245 0.232 0.172 0.238 0.889 0.030 0.002
0.081 0.035 0.030 0.094 0.014 0.000 0.039 0.427
0.210 0.010 0.025 0.093 0.061 0.192 0.270 0.702
0.012 0.730 0.907 0.645 0.523 0.262 0.043 < 0.001
Coefficient (b)
P
FM, fibromyalgia syndrome; hsCRP, highly sensitive C reactive protein; TSH, thyroid stimulating hormone; TPO Ab, thyroidperoxidase autoantibody; hsCRP, Highly sensitive C reactive protein; FIQ, Fibromyalgia Impact Questionnaire; baPWV, brachial-ankle pulse wave velocity; FMD, flow mediated dilation; NTG, nitroglycerin.
determine the independent contribution of TPO Ab to baPWV (adjusted r2 = 0.327, P < 0.001), reactive FMD (adjusted r2 = 0.127, P = 0.001) and NTG FMD (adjusted r2 = 0.476, P < 0.001).
DISCUSSION In this study, we evaluated the effect of antithyroid antibodies on arterial stiffness and endothelial function in euthyroid FM patients, using baPWV and FMD. The main findings are: (i) postmenopausal women with FM with increased arterial stiffness showed more positive TPO Ab; (ii) women with FM with TPO Ab showed more increased arterial stiffness and reduced endothelial function than those without TPO Ab; and (iii) linear regression analysis revealed that the only significant predictors of baPWV and FMD were age, FIQ
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and presence of TPO Ab, which suggests a relationship between thyroid autoimmunity and arterial stiffness in euthyroid FM female patients. It has been suggested that chronic stress may promote atherogenesis through the mechanism of autonomic neuropathy-caused sympathetic hyperactivity.23 Sympathetic hyperactivity impairs the autonomic nervous system (ANS) control of the cardiovascular system, and plays a major role in the development of atherosclerosis and endothelial dysfunction.24 Using a nonhuman primate model of atherogenesis, it has been found that psychosocial stress can alter the autonomic balance toward a state of sympathetic arousal leading to the development of coronary artery disease (CAD), perhaps through impairing endothelial function and intensification of endothelium-mediated atherogenic processes.25 Chronic physical pain and mental stress of patients with FM may
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also enhance sympathetic nerve activity, and impair the ANS control of the cardiovascular system. We also previously observed the decrease in endothelial function and increase in arterial stiffness in patients with FM.16,17 Some studies have reported an association between thyroid autoimmunity and FM. The prevalence of thyroid autoantibodies has been observed to be higher in subjects with musculoskeletal complaints.26 The relationships between thyroid autoimmunity and symptoms such as allodynia, dry eyes, sore throat, blurred vision, tension headache and depression have been reported.13,14 There have also been reports of the impact of thyroid autoimmunity on the cardiovascular system. For example, among euthyroid women, the presence of Hashimoto’s thyroiditis was positively associated with arterial stiffness.27 Furthermore, thyroid autoimmunity has been associated with an increase in carotid intima thickness (IMT) in obese women, independent of thyroid function, BMI and cardiovascular risk factors.28 However, thyroid autoimmunity may only affect cardiovascular indices in younger women, whereas the effect may disappear in older women with stronger cardiovascular risk factors. Our previous study demonstrated that FM patients had significantly higher baPWV than controls, and that baPWV was significantly correlated with FIQ,17 indicating that the severity of functional status was correlated with endothelial dysfunction. BaPWV has been reported as a good marker for arterial stiffness, and the results of several studies have shown that baPWV provide similar information to those derived from central arterial stiffness measured with carotid-femoral PWV.29–31 In this study, we tried to investigate other factors that affect endothelial function in patients with FM such as thyroid functional status. We failed to find an association between endothelial dysfunction reflected by higher PWV and TSH levels or thyroid function. However, thyroid autoimmunity was associated with arterial stiffness as represented by the increased baPWV in euthyroid female FM patients. Our finding conflicts with the results of the recent study by Lambrinoudaki et al., who showed that a serum TSH greater than 2.5 mU/mL, but not thyroid autoimmunity, was positively associated with arterial stiffness in postmenopausal women with normal thyroid function.32 The association between thyroid autoimmunity and arterial stiffness has not been consistently reported in previous studies. The Rotterdam study, which evaluated elderly women, showed that thyroid autoimmunity itself was not associated with cardiovascular risk.26 On the contrary, Stamatelopoulos et al.27 reported that the pres-
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ence of Hashimoto’s thyroiditis was positively associated with arterial stiffness, but only in premenopausal women. Another study reported an increase in carotid IMT in obese women with Hashimoto’s thyroiditis.28 In this study, the association of thyroid autoimmunity and the increase in carotid IMT was independent of thyroid function and cardiovascular risk factors. Taken together, Lambrinoudaki et al.32 commented that thyroid autoimmunity may affect cardiovascular indices only in younger women, whereas the effect may disappear in older women with stronger cardiovascular risk factors. However, we found that thyroid autoimmunity was positively associated with arterial stiffness in postmenopausal women with normal thyroid function, possibly because we only included postmenopausal women without cardiovascular risk factors. Moreover, we included euthyroid postmenopausal women with FM, whereas Lambrinoudaki et al. included healthy postmenopausal women. In our study, FM patients showed more positive TPO Ab than controls (24.5% vs. 8%), and previous studies also demonstrated similar higher prevalence of TPO antibodies in FM patients.13,14 However, the prevalence of TPO Ab in the Lambrinoudaki et al. study was only 12.8%, which might not be high enough to enable detection of associations with vascular indices. Although menopausal age has been identified as an independent predictor of subclinical atherosclerosis in postmenopausal women,33 menopausal age in our results was not significantly associated with the vascular indices. There are several limitations to this study. Our patients were on a variety of medications. It is likely that medications may have some effect on endothelial function and arterial stiffness is modulated by pharmacological treatment,34 but we excluded the patients under anti-hypertensive drugs or antidiabetic drugs. However, this study was performed in postmenopausal women, and 27 (16.7%) had hormonal replacement, but we did not account for the effect of exogenous hormones. Despite observational data suggesting the benefits of hormone replacement therapy on endothelial function, data from several randomized trials still failed to support a benefit of hormone therapy on cardiovascular disease.35,36 Therefore, large surveys with sampling of subjects by strict medical examination will be necessary. A second possible limitation is the cross-sectional study design, which cannot demonstrate causal associations. Third, we defined the postmenopausal status when there has been amenorrhea for one complete year, and did not check hormone levels, including estradiol (E2) and gonadotropin, which possibly affect endothelial function. Finally, we did not examine the
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mood status of patients in the control group. We recruited control patients that did not have chronic widespread pain. A report has shown that the mood disturbance score is associated with a decrease in endothelial function,37 so it is likely that mood status would influence baPWV measurements. In conclusion, we demonstrated that combined thyroid autoimmunity is an important predictor of endothelial function and arterial stiffness in euthyroid postmenopausal women with FM. These results support the need to re-evaluate the effects of thyroid autoimmunity on the vasculature of postmenopausal women with FM. However, longitudinal studies that employ a large population will be needed to determine the pathophysiologic and prognostic implications of endothelial dysfunction in FM.
ACKNOWLEDGEMENT The Corresponding author has the right to grant on behalf of the other authors and does grant on behalf of all authors an exclusive license (or non exclusive for government employees) on a worldwide basis to the journal ‘International Journal of Rheumatic diseases’ to permit this article (if accepted) to be published, sublicenses such use and exploits all subsidiary rights, as set out in our license.
DISCLOSURE STATEMENT None of the authors have identified a conflict of interest.
FUNDING None.
REFERENCES 1 Buskila D, Sarzi-Puttini P (2006) Biology and therapy of fibromyalgia. Genetic aspects of fibromyalgia syndrome. Arthritis Res Ther 8 (5), 218. 2 McBeth J (2004) The epidemiology of chronic widespread pain and fibromyalgia. In: Wallace J, Clauw J (eds) Fibromyalgia and Other Central Pain Syndromes, pp. 17–29. Lippincott Williams & Wilkins, Philadelphia. 3 Giske L, Vøllestad NK, Mengshoel AM, Jensen J, Knardahl S, Røe C (2008) Attenuated adrenergic responses to exercise in women with fibromyalgia—a controlled study. Eur J Pain 12, 351–60. 4 Martinez-Lavin M (2007) Biology and therapy of fibromyalgia: stress, the stress response system and fibromyalgia. Arthritis Res Ther 9, 216–22.
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5 Owen J, Sabit R, Lazarus JH (2007) Thyroid disease and vascular function. Thyroid 17, 519–24. 6 Burggraaf J, Lalezari S, Emeis JJ et al. (2001) Endothelial function in patients with hyperthyroidism before and after treatment with propranolol and thiamazol. Thyroid 11, 153–60. 7 Volzke H, Robinson DM, Schminke U et al. (2004) Thyroid function and carotid wall thickness. J Clin Endocrinol Metab 89, 2145–9. 8 Michalopoulou G, Alevizaki M, Piperingos G et al. (1998) High serum cholesterol levels in persons with ‘high-normal’ TSH levels: should one extend the definition of subclinical hypothyroidism? Eur J Endocrinol 138, 141–5. 9 Nyirenda MJ, Clark DN, Finlayson AR et al. (2005) Thyroid disease and increased cardiovascular risk. Thyroid 15, 718–24. 10 Jacobs-Kosmin D, DeHoratius RJ (2005) Musculoskeletal manifestations of endocrine disorders. Curr Opin Rheumatol 17 (1), 64–9. 11 Markenson JA (2010) Rheumatic manifestations of endocrine diseases. Curr Opin Rheumatol 22 (1), 64–71. 12 Garrison RL, Breeding PC (2003) A metabolic basis for fibromyalgia and its related disorders: the possible role of resistance to thyroid hormone. Med Hypotheses 61, 182–9. 13 Bazzichi L, Rossi A, Giuliano T et al. (2007) Association between thyroid autoimmunity and fibromyalgic disease severity. Clin Rheumatol 26, 2115–20. 14 Pamuk ON, Cakir N (2007) The frequency of thyroid antibodies in fibromyalgia patients and their relationship with symptoms. Clin Rheumatol 26, 55–9. 15 Suk JH, Lee JH, Kim JM (2012) Association between thyroid autoimmunity and fibromyalgia. Exp Clin Endocrinol Diabetes 120 (7), 401–4. 16 Cho KI, Lee JH, Kim SM, Lee HG, Kim TI (2011) Assessment of endothelial function in patients with fibromyalgia–cardiac ultrasound study. Clin Rheumatol 30 (5), 647–54. 17 Lee JH, Cho KI, Kim SM, Lee HG, Kim TI (2011) Arterial stiffness in female patients with fibromyalgia and its relationship to chronic emotional and physical stress. Korean Circ J 41 (10), 596–602. 18 Hirsch AT, Criqui MH, Treat-Jacobson D et al. (2001) Peripheral arterial disease detection, awareness, and treatment in the primary care. JAMA 286, 1317–24. 19 Wolfe F, Smythe HA, Yunus MB et al. (1990) The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 33, 160–72. 20 Bae SC, Lee JH (2004) Cross-cultural adaptation and validation of the Korean fibromylagia impact questionnaire in women patients with fibromyalgia for clinical research. Qual Life Res 13 (4), 857–61. 21 Yamashina A, Tomiyama H, Takeda K et al. (2002) Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement. Hypertens Res 25, 359–64.
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22 Tomiyama H, Yamashita A, Arai T, Hirose K, Koji Y, Hinohara S (2003) Influences of age and gender on results of noninvasive brachial-ankle pulse wave velocity measurement – a survey of 12,517 subjects. Atherosclerosis 166, 303–9. 23 Marwah RS, Doux JD, Lee PY et al. (2007) Is atherosclerosis a neurogenic phenomenon? Med Hypotheses 69, 884–7. 24 Dekker JM, Crow RS, Folsom AR et al. (2000) Low heart rate variability in a 2-minute rhythm strip predicts risk of coronary heart disease and mortality from several causes: the ARIC Study. Atherosclerosis risk in communities. Circulation 102, 1239–44. 25 Manuck SB, Kaplan JR, Adams MR et al. (1988) Effects of stress and the sympathetic nervous system on coronary artery atherosclerosis in the cynomolgus macaque. Am Heart J 116, 328–33. 26 Aarflot T, Bruusgaard D (1996) Association between chronic widespread musculoskeletal complaints and thyroid autoimmunity. Results from a community survey. Scand J Prim Health Care 14, 111–5. 27 Stamatelopopoulos KS, Kyrkou K, Chrysochoou E et al. (2009) Arterial stiffness but not intima-media thickness is increased in euthyroid patients with Hashimoto’s thyroiditis: the effect of postmenopausal status. Thyroid 19, 857–62. 28 Ciccone MM, De Pergola G, Porcelli MT et al. (2010) Increased carotid IMT in overweight and obese women affected by Hashimoto’s thyroiditis: an adiposity and autoimmune linkage? BMC Cardiovasc Disord 28 (10), 22.
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29 Sugawara J, Hayashi K, Yokoi T et al. (2005) Brachialankle pulse wave velocity: an index of central arterial stiffness? J Hum Hypertens 19 (5), 401–6. 30 Lee SJ, Park SH (2013) Arterial Ageing. Korean Circ J 43, 73–9. 31 Nagasaki T, Inaba M, Kumeda Y et al. (2007) Central pulse wave velocity is responsible for increased brachialankle pulse wave velocity in subclinical hypothyroidism. Clin Endocrinol 66 (2), 304–8. 32 Lambrinoudaki I, Armeni E, Rizos D et al. (2012) High normal thyroid-stimulating hormone is associated with arterial stiffness in healthy postmenopausal women. J Hypertens 30 (3), 592–9. 33 Lambrinoudaki I, Armeni E, Georgiopoulos G et al. (2013) Subclinical atherosclerosis in menopausal women with low to medium calculated cardiovascular risk. Int J Cardiol 164 (1), 70–6. 34 Boutouyrie P, Lacolley P, Briet M et al. (2011) Pharmacological modulation of arterial stiffness. Drugs 71 (13), 1689–701. 35 Magliano DJ, Rogers SL, Abamson MJ, Tonkin AM (2006) Hormone therapy and cardiovascular disease: a systemic review and meta-analysis. BJOG 113, 5–14. 36 Mosca L, Banka CL, Benjamin EJ et al. (2007) Evidencebased guidelines for cardiovascular disease prevention in women: 2007 update. Circulation 115 (11), 1481–501. 37 Cooper DC (2010) Adverse impact of mood on flowmediated dilatation. Psychosom Med 72 (2), 122–7.
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ORIGINAL ARTICLE
The impact of thyroid autoimmunity on arterial stiffness in postmenopausal patients with fibromyalgia Kyoung Im CHO1 and Ji Hyun LEE2 1 Cardiovascular Research Institute, Kosin University School of Medicine, and 2Division of Rheumatology, Maryknoll Medical Center, Busan, Korea
Abstract Objective: The exact mechanism of arterial stiffness in fibromyalgia (FM) remains unclear. The present study aimed to evaluate the association between thyroid function and markers of arterial function in postmenopausal FM patients. Methods: This study included 163 postmenopausal FM patients without any known cardiovascular diseases and within a normal reference range of thyroid-stimulating hormone (TSH) level. Clinical parameters including the Fibromyalgia Impact Questionnaire (FIQ), the pain visual analogical scale (VAS) and tender point counts were measured. Vascular function was assessed by brachial-ankle pulse wave velocity (baPWV) and flow-mediated dilation (FMD). We evaluated the associations between arterial markers and serum TSH, free thyroxin, as well as serum thyroidperoxidase autoantibody (TPO Ab). Results: Patients with a high baPWV (≥ 1490 cm/s) showed more positive TPO Ab (65% vs. 10%, P = 0.006) than those with a normal baPWV. Additionally, the baPWV values of patients with positive TPO Ab were significantly different from those with negative TPO Ab. Age, FIQ and TPO Ab were significantly correlated with baPWV and FMD (all P < 0.05). Multiple linear regression analysis revealed that the only significant predictors of baPWV were age, FIQ and the presence of TPO Ab after adjustment for traditional risk factors. A significant association was also found between FMD and positive TPO Ab. Conclusion: Age, functional status and presence of TPO Ab were significantly associated with increased arterial stiffness in postmenopausal FM patients. Given the combined thyroid autoimmunity in FM patients, a re-evaluation of the effects on the vasculature may be necessary. Key words: fibromyalgia, flow-mediated dilation, pulse wave velocity, thyroid-stimulating hormone.
INTRODUCTION Fibromyalgia (FM) is a common disorder characterized by chronic widespread musculoskeletal pain and related symptoms along with multiple painful tender points.1,2 In patients with FM, stress and pain may chronically enhance sympathetic activity, which may induce endothelial dysfunction. In some FM patients, dysregulation of pain modulatory systems involves increased sympa-
Correspondence: Dr Ji Hyun Lee, MD, Maryknoll Medical Center, 4–12, Daechung-dong, Jung-gu, Busan, Korea. Email: [email protected]
thetic nervous system (SNS) drive at rest and deficient SNS-mediated responses to certain challenges, such as postural change or exercise.3,4 Thyroid hormones have direct effects on cardiac myocytes, endothelial cells and vascular smooth muscle cells,5,6 resulting in hypertrophy and stiffness of the vessels.7 In addition, there is some evidence of the relationship between thyroid hormones and cardiovascular events. Individuals with ‘high-normal’ thyroid-stimulating hormone (TSH) levels (2.0–4.0 mIU/mL) and positive antithyroid antibodies exhibit elevated levels of total cholesterol.8 Similarly, autoimmune thyroid disorders, such as Hashimoto’s thyroiditis or Graves’ disease,
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
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have been linked to increased rates of hospitalizations for cardiovascular events.9 Muscle symptoms are a frequent finding in thyroid diseases, and it has been recognized that there are significant similarities between noninflammatory arthropathy and symptoms of thyroid dysfunction.10 Some recent reports have found an attenuated response of TSH to thyroidreleasing hormone as well as an increased prevalence of antithyroid antibodies in FM patients.11 Other studies have reported that FM patients had some problems in the production or utilization of thyroid hormones,12 and that there is an association between thyroid autoimmunity and FM.13,14 Our data has also previously demonstrated that euthyroid FM patients had a significantly higher prevalence of positive TPO antibodies.15 Although we previously suggested that a decrease in endothelial function and an increase in arterial stiffness were affected by the clinical parameters of FM,16,17 the exact mechanism is unclear. We performed this study to evaluate the effect of antithyroid antibodies on endothelial function in euthyroid FM patients, using pulse wave velocity (PWV), which assesses arterial stiffness by measuring the status of large and small arteries in the lower extremity,18 and brachial flow mediated dilatation (FMD), a non-invasive measure of endothelial function.
METHODS Subjects One hundred and sixty-three postmenopausal FM patients who met the guidelines outlined by the American College of Rheumatology (ACR) for FM19 were consecutively enrolled in this study from the outpatient clinic of the Rheumatology Division at Maryknoll Medical Center, Busan, Republic of Korea. Fifty healthy female controls were matched to the FM patients according to age, blood pressure (BP), height and cholesterol and glucose levels. Postmenopausal status was defined when there has been amenorrhea for one complete year. Exclusion criteria for both groups included smoking (in the last 5 years), diabetes, dyslipidemia, hypertension, chronic hepatopathy, nephrotic syndrome and obesity with body mass index (BMI) above 26 or abdominal obesity (waist circumference ≥ 90 cm for men and ≥ 85 cm for women). We excluded the cases whose fasting glucose was above 126 mg/dL at the time of entry, or any patients who was taking anti-diabetic medication. The presence of dyslipidemia was assumed if subjects were taking lipid-lowering drugs, or high total cholesterol levels above 200 mg/dL. Hypertension was considered when blood pressure is persistently at or above
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140/90 mmHg. We measured the serum creatinine level at the time of entry, and excluded patients with serum creatinine levels higher than 2.0 mg/dL. Subjects with autoimmune rheumatic diseases with antinuclear antibody (ANA) titers above 1 : 160, history of thyroid diseases, palpable goiter, abnormal free T4 (FT4) and/or TSH levels were also excluded. The local institutional review board approved the study and all subjects gave written informed consent.
Disease-specific evaluation At each visit, subjects were asked to rate their current level of pain on a 10-cm visual analog scale (VAS, 0 = no pain; 10 = worst pain imaginable). Subjects then filled out the fibromyalgia impact questionnaire (FIQ)20 which evaluates physical function, work status, depression, anxiety, sleep, pain, stiffness, fatigue and well-being. A high score indicates a greater impact of the syndrome on the patient. Subjects were then assessed for numbers of positive tender points by digital palpation over the 18 characteristic tender point sites according to ACR diagnostic criteria for FM.
Measurement of arterial stiffness Arterial stiffness was assessed by measuring brachialankle (ba)PWVs using an automatic waveform analyzer (VP-1000; Colin Co., Komaki, Japan).21 The VP-1000 simultaneously records pulse waves, blood pressure (BP; both arms and ankles), ankle-brachial pressure index (ABI), electrocardiogram (ECG) and heart sounds, as described elsewhere.22 ABI was calculated by the ratio of the ankle systolic BP divided by the arm systolic BP, and the lower value of the ankle systolic BP was used for the calculation. For the measurement of baPWV, pulse waves obtained from the brachial and tibial arteries were recorded simultaneously, and the transmission time, which is defined as the time interval between the initial increase in brachial and tibial waveforms, was determined. The transmission distance from the arm to each ankle was calculated according the body height. The baPWV was automatically computed as the transmission distance divided by the transmission time. All participants included in the present study had a normal ABI (> 0.9). A high baPWV was defined as the gender-specific highest quartile of the values among the study subjects (baPWV [the mean of the right and left values] ≥ 1490 cm/s in females).
Brachial artery measurements FMD was performed using 2-dimensional ultrasonography (Vivid 7, General Electric, Horten, Norway) with
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Thyroid autoimmunity postmenopausal FM patients
modification of the methods of Corretti et al.13 Measurements were performed on the subject’s left arm after 10–20 min of rest in the supine position. The brachial artery was scanned longitudinally just above the antecubital crease, using a 10-MHz probe. The diameter of the brachial artery was measured at the interface between the tunica media and tunica adventitia of the anterior and posterior walls. Hyperemia was induced by inflation of a pneumatic cuff to 180–200 mmHg (50 mmHg higher than the systolic blood pressure) for 4 min on the most proximal part of the upper arm. The maximal diameter of the brachial artery was measured after 45– 60 s following sudden deflation of the cuff. Brachial artery percent FMD induced by reactive hyperemia was expressed as the relative change from baseline (% FMD = 100 9 [(diameter after hyperemia-baseline diameter)/baseline diameter]). After 15 min, a third brachial artery scan was recorded again in a resting state with or without a sublingual nitroglycerin (NTG) 0.4 mg tablet, administered if the subject had a systolic blood pressure ≥ 110 mmHg. Relative changes in the brachial artery diameter between baseline and third examination were expressed as endothelium-independent vasodilatation, with or without NTG. We measured each diameter three times during two heart beats, using the mean values for the final analysis. Every diameter was measured at the peak of the R wave of the surface ECG. Measurements were performed by an independent examiner (KI Cho) blinded to the study set-up.
association of TPO Ab with vascular indices, we dichotomized the FM patients with positive TPO Ab and negative TPO Ab. Comparisons of all measurements were made with independent Student’s t-tests for continuous variables and chi-square or the exact Fisher test for qualitative variables of two groups. Correlations between variables were assessed by calculating the correlation coefficient with Pearson correlation tests. Multivariate linear regression was used to determine the sources of variation for vascular indices, using the presence of TPO Ab and selected discrete risk factor traits as covariates. A P-value < 0.05 was considered statistically significant.
RESULTS Clinical characteristics of patients Characteristics of FM patients are given in Table 1. There were no significant differences between FM patients and controls in terms of age (51.8 9.0 vs. 50.1 8.9 years) and the other parameters known to
Table 1 Baseline demographic characteristics of the study patients FM patients (n = 163) 51.8 9.0 23.2 2.7 122.8 12.7 76.8 9.2 74.3 8.2 187.7 17.6 1.75 1.06 1.08 0.29 40/163 (24.5%) 0.94 3.6 1.09 0.08 1377.1 206.6 6.13 2.10 11.4 3.78 54.5 21.7 13.5 1.84 48.8 18.7 5.2 5.8 2.08 1.82 47.6 6.10 27/163 (16.6%)
Statistical analysis
Age (years) Body mass index (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (bpm) Total cholesterol (mg/dL) TSH (mIU/L) Free T4 (pmol/L) Positive TPO Ab (%) hsCRP Ankle-brachial index Mean baPWV (cm/s) Reactive FMD NTG FMD Pain VAS Tender point count FIQ Disease duration (years) Duration postmenopause (years) Menopausal age (years) History of hormonal therapy (%)
All data are expressed as the mean standard deviation. Data were analyzed using standard statistical software (SPSS package version 12.0, SPSS Inc., Chicago, IL, USA). In order to further examine the
All values are mean SD. FM, fibromyalgia syndrome; TSH, thyroid stimulating hormone; TPO Ab, thyroidperoxidase autoantibody; hsCRP, highly sensitive C-reactive protein; baPWV, brachial-ankle pulse wave velocity; FMD, flow mediated dilation; NTG, nitroglycerin; VAS, visual analogue scale.
Laboratory evaluation Thyroid function was assessed by measuring levels of FT4 and TSH. FT4 (reference range 9.16–24.9 pmol/L) and TSH (reference range 0.38–4.7 mIU/L) were measured by chemiluminescent microparticle immunoassay (Architect-I 2000, Abbot, Ireland, UK). Thyroperoxidase antibody (TPO Ab) was measured by chemiluminescent immunoassay (ADVIA centaur, Siemens, Munich, Germany). The cut-off value of TPO Ab was 60 IU/mL. Highly sensitive C reactive protein (hsCRP), rheumatoid factor (RF) and ANA were also measured. hsCRP (reference range 0–0.5 mg/L) and RF (reference range 0–15 IU/mL) was measured by turbidometric immunoassay (ADVIA1800, Siemens), while ANA was measured by indirect fluorescent assay.
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affect PWV, including BMI, blood pressure, heart rate and the total cholesterol levels. However, FM patients showed more positive TPO Ab (24.5% vs. 8%, P = 0.03), significantly increased baPWV (1377.1 206.6 vs. 1283.3 185.7 cm/s, P = 0.004) and reduced reactive FMD (6.13 2.10 vs. 7.22 1.35%, P = 0.035) and NTG FMD (11.4 3.78 vs. 14.83 2.65%, P = 0.004) compared to the controls. Although the level of thyroid hormones did not differ significantly between FM patients and controls, the presence of TPO Ab was more prevalent in FM patients. Patients with a high baPWV (≥ 1490 cm/s) had a longer disease duration (P = 0.001), more positive TPO Ab (P = 0.006) and higher FIQ (P = 0.027) than those with a normal baPWV (Table 2).
Clinical characteristics of patients according to the presence of TPO Ab Comparison of the FM patients according to the presence of TPO Ab is presented in Table 3. There was no difference in blood pressure, total cholesterol, hsCRP, free T4, TSH, menopausal status, disease duration or FIQ between FM patients with positive TPO Ab and
Age (years) Duration of disease (years) BMI (kg/m2) Systolic BP (mmHg) Diastolic BP (mmHg) Heart rate (bpm) Total cholesterol (mg/dL) hsCRP TSH (mIU/L) Free T4 (pmol/L) TPO Ab titer Positive TPO (%) Tender point count Pain VAS FIQ ABI Duration postmenopause Menopausal age Reactive FMD NTG FMD
those with negative TPO Ab. However, the baPWV values of those with positive TPO Ab and those with negative TPO Ab (1643.4 306.4 cm/s vs. 1293.3 163.5 cm/s, P < 0.001) were significantly different. In addition, reactive FMD (4.94 1.88 vs. 7.03 3.01%, P < 0.001) and NTG FMD (7.03 3.01 vs. 12.81 2.82%, P < 0.001) were significantly reduced in FM patients with positive TPO Ab compared with those with negative TPO Ab.
Correlation of the vascular indices with clinical features in FM patients Arterial stiffness parameter (baPWV) and endothelial parameters (FMD) were significantly associated with age, functional status of FM (FIQ) and TPO Ab titers in correlation analyses (all P < 0.05, Table 4). However, these parameters showed no significant correlation with disease duration, menopausal age, blood pressure, total cholesterol, TSH, FT4 or inflammatory markers (hsCRP). Multiple regression analysis was used to adjust for any potential confounding influences of age, cholesterol, the duration of the disease and the clinical variables of FM; after adjusting for traditional risk
Table 2 Comparison of FM patients according to baPWV
Normal baPWV (n = 120)
High baPWV (n = 43)
P
50.8 9.2 4.94 5.73 21.5 1.3 125.9 11.8 78.2 9.5 72.8 11.3 193.6 29.8 0.56 1.08 1.83 1.22 1.11 0.21 104.3 440.4 12/120 (10%) 13.30 1.75 47.9 22.3 52.4 21.8 1.07 0.96 2.01 1.78 47.2 6.30 6.72 1.80 12.4 3.06
53.9 11.8 5.82 5.84 22.8 3.2 126.7 12.3 77.9 7.8 70.7 9.8 191.7 32.1 1.05 3.43 1.82 1.46 1.06 0.27 695.7 2050.4 28/43 (65%) 14.14 1.95 60.2 20.8 54.5 19.8 1.09 0.71 2.33 1.94 48.9 5.24 4.49 2.03 8.51 4.17
0.055 0.001 0.313 0.728 0.515 0.578 0.736 0.176 0.793 0.212 0.050 0.006 0.010 0.040 0.027 0.335 0.374 0.081 < 0.001 < 0.001
All values are mean SD. FM, fibromyalgia syndrome; baPWV, brachial-ankle pulse wave velocity; BMI, body mass index; BP, blood pressure; hsCRP, highly sensitive C reactive protein; TSH, thyroid stimulating hormone; TPO Ab, thyroidperoxidase autoantibody; VAS, Visual Analogue Scale; FIQ, Fibromyalgia Impact Questionnaire; ABI, ankle-brachial index; FMD, flow mediated dilation; NTG, nitroglycerin.
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Thyroid autoimmunity postmenopausal FM patients
Table 3 Comparison of arterial stiffness parameters in FM patients according to the presence of TPO Ab
Negative TPO (n = 123) Age (years) Duration of disease (years) BMI (kg/m2) Systolic BP (mmHg) Diastolic BP (mmHg) Heart rate (bpm) Total cholesterol (mg/dL) hsCRP TSH (mIU/L) Free T4 (pmol/L) TPO Ab titer Tender point count Pain VAS FIQ Duration postmenopause Menopausal age ABI Mean baPWV Reactive FMD NTG FMD
50.9 4.96 21.8 126.8 76.9 73.2 192.9 0.66 1.73 1.06 25.7 13.4 53.9 47.9 2.07 47.3 1.08 1293.3 6.52 12.8
8.90 5.75 2.7 10.7 10.1 12.1 28.1 1.12 1.00 0.27 12.1 1.80 22.1 18.6 1.77 6.30 0.07 163.5 2.03 2.82
Positive TPO (n = 40)
P
0.018 0.450 0.287 0.566 0.543 0.243 0.532 0.321 0.749 0.193 0.012 0.142 0.542 0.329 0.847 0.223 0.367 < 0.001 < 0.001 < 0.001
54.7 5.78 22.3 128.2 77.5 72.9 193.8 1.02 1.80 1.12 915.3 13.9 56.3 51.5 2.14 48.6 1.06 1643.4 4.94 7.03
7.80 5.82 3.1 11.9 9.8 10.7 29.1 3.42 1.24 0.21 2131.6 1.91 20.7 18.9 1.99 5.32 0.11 306.4 1.88 3.01
All values are mean SD. FM, fibromyalgia syndrome; BMI, body mass index; BP, blood pressure; hsCRP, highly sensitive C reactive protein; TSH, thyroid stimulating hormone; TPO Ab, thyroidperoxidase autoantibody; VAS, Visual Analogue Scale; FIQ, Fibromyalgia Impact Questionnaire; ABI, ankle-brachial index; baPWV, brachial-ankle pulse wave velocity; FMD, flow mediated dilation; NTG, nitroglycerin.
Table 4 Correlation coefficients between the parameters of arterial stiffness, endothelial function and clinical parameters of the FM group (n = 163)
Age Disease duration Systolic blood pressure Diastolic blood pressure Total cholesterol TPO Ab titer TSH Free T4 Menopausal age hsCRP FIQ
baPWV
Reactive FMD
NTG FMD
0.19 (0.015) 0.13 (0.101) 0.05 (0.758)
0.17 (0.035) 0.05 (0.522) 0.31 (0.030)
0.16 (0.038) 0.01 (0.885) 0.37 (0.008)
0.03 (0.863)
0.17 (0.232)
0.23 (0.111)
0.04 (0.643) 0.30 (< 0.001) 0.008 (0.915) 0.121 (0.125) 0.070 (0.377) 0.05 (0.520) 0.37 (< 0.001)
0.12 (0.325) 0.16 (0.038) 0.06 (0.420) 0.004 (0.959) 0.101 (0.198) 0.07 (0.383) 0.33 (0 < 0.001)
0.19 (0.254) 0.27 (0.001) 0.040 (0.615) 0.013 (0.869) 0.104 (0.187) 0.05 (0.535) 0.29 (0 < 0.001)
All values are mean SD. FM, fibromyalgia syndrome; BMI, body mass index; hsCRP, highly sensitive C reactive protein; TSH, thyroid stimulating hormone; TPO Ab, thyroidperoxidase autoantibody; FIQ, Fibromyalgia Impact Questionnaire; ABI, ankle-brachial index; baPWV, brachial-ankle pulse wave velocity; FMD, flow mediated dilation; NTG, nitroglycerin.
factors, significant predictors of baPWV were age, FIQ and presence of TPO Ab. A significant association was also found between FMD and positive TPO Ab. Although there was a weak association between vascular
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indices and TPO Ab as a continuous variable, the presence of TPO Ab showed a strong impact on vascular indices (Table 5). This relationship remained highly significant after multivariate regression analysis to
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Table 5 Multiple regression analysis between FM functional parameters and vascular parameters Univariate analysis Coefficient (b)
B (95% CI)
Age 0.374 0.004 (0.002 to 0.006) Disease duration 0.157 0.009 ( 0.001 to 0.018) Systolic blood pressure 0.046 0.002 ( 0.003 to 0.004) Diastolic blood pressure 0.025 0.000 ( 0.005 to 0.004) Total cholesterol 0.068 0.001 ( 0.003 to 0.004) hsCRP 0.158 0.005 ( 0.003 to 0.013) FIQ 0.113 1.541 (0.574 to 2.508) Presence of TPO Ab 0.590 3.501 (2.755 to 4.246) baPWV (r2 = 0.363, adjusted r2 = 0.327 in multivariate analysis) Age 0.265 0.039 ( 0.075 to 0.003) Disease duration 0.051 0.018 ( 0.075 to 0.038) Systolic blood pressure 0.005 0.000 ( 0.010 to 0.010) Diastolic blood pressure 0.021 0.001 ( 0.012 to 0.014) Total cholesterol 0.104 0.003 ( 0.006 to 0.013) hsCRP 0.071 0.048 ( 0.061 to 0.158) FIQ 0.117 0.027 ( 0.037 to 0.017) Presence of TPO Ab 0.324 1.579 ( 2.296 to 0.862) Reactive FMD (r2 = 0.264, adjusted r2 = 0.127 in multivariate analysis) Age 0.385 0.125 ( 0.150 to 0.101) Disease duration 0.188 0.041 ( 0.111 to 0.029) Systolic blood pressure 0.172 0.016 ( 0.042 to 0.011) Diastolic blood pressure, 0.196 0.050 ( 0.123 to 0.023) Total cholesterol 0.120 0.007 ( 0.020 to 0.005) hsCRP 0.020 0.008 ( 0.115 to 0.100) FIQ 0.307 0.037 ( 0.070 to 0.004) Presence of TPO Ab 0.656 5.749 ( 6.779 to 4.720) NTG FMD (r2 = 0.503, adjusted r2 = 0.476 in multivariate analysis)
Multivariate analysis 2
P
r
0.003 0.172 0.753 0.863 0.165 0.125 0.007 < 0.001
0.140 0.066 0.002 0.001 0.002 0.209 0.054 0.344
0.105 0.056 0.049 0.048 0.067 0.013 0.250 0.551
0.033 0.443 0.520 0.778 0.497 0.851 0.038 < 0.001
0.035 0.552 0.421 0.233 0.471 0.383 0.002 < 0.001
0.027 0.003 0.000 0.000 0.011 0.005 0.014 0.105
0.127 0.101 0.075 0.052 0.011 0.057 0.185 0.286
0.019 0.212 0.716 0.800 0.693 0.471 0.037 0.001
0.005 0.245 0.232 0.172 0.238 0.889 0.030 0.002
0.081 0.035 0.030 0.094 0.014 0.000 0.039 0.427
0.210 0.010 0.025 0.093 0.061 0.192 0.270 0.702
0.012 0.730 0.907 0.645 0.523 0.262 0.043 < 0.001
Coefficient (b)
P
FM, fibromyalgia syndrome; hsCRP, highly sensitive C reactive protein; TSH, thyroid stimulating hormone; TPO Ab, thyroidperoxidase autoantibody; hsCRP, Highly sensitive C reactive protein; FIQ, Fibromyalgia Impact Questionnaire; baPWV, brachial-ankle pulse wave velocity; FMD, flow mediated dilation; NTG, nitroglycerin.
determine the independent contribution of TPO Ab to baPWV (adjusted r2 = 0.327, P < 0.001), reactive FMD (adjusted r2 = 0.127, P = 0.001) and NTG FMD (adjusted r2 = 0.476, P < 0.001).
DISCUSSION In this study, we evaluated the effect of antithyroid antibodies on arterial stiffness and endothelial function in euthyroid FM patients, using baPWV and FMD. The main findings are: (i) postmenopausal women with FM with increased arterial stiffness showed more positive TPO Ab; (ii) women with FM with TPO Ab showed more increased arterial stiffness and reduced endothelial function than those without TPO Ab; and (iii) linear regression analysis revealed that the only significant predictors of baPWV and FMD were age, FIQ
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and presence of TPO Ab, which suggests a relationship between thyroid autoimmunity and arterial stiffness in euthyroid FM female patients. It has been suggested that chronic stress may promote atherogenesis through the mechanism of autonomic neuropathy-caused sympathetic hyperactivity.23 Sympathetic hyperactivity impairs the autonomic nervous system (ANS) control of the cardiovascular system, and plays a major role in the development of atherosclerosis and endothelial dysfunction.24 Using a nonhuman primate model of atherogenesis, it has been found that psychosocial stress can alter the autonomic balance toward a state of sympathetic arousal leading to the development of coronary artery disease (CAD), perhaps through impairing endothelial function and intensification of endothelium-mediated atherogenic processes.25 Chronic physical pain and mental stress of patients with FM may
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also enhance sympathetic nerve activity, and impair the ANS control of the cardiovascular system. We also previously observed the decrease in endothelial function and increase in arterial stiffness in patients with FM.16,17 Some studies have reported an association between thyroid autoimmunity and FM. The prevalence of thyroid autoantibodies has been observed to be higher in subjects with musculoskeletal complaints.26 The relationships between thyroid autoimmunity and symptoms such as allodynia, dry eyes, sore throat, blurred vision, tension headache and depression have been reported.13,14 There have also been reports of the impact of thyroid autoimmunity on the cardiovascular system. For example, among euthyroid women, the presence of Hashimoto’s thyroiditis was positively associated with arterial stiffness.27 Furthermore, thyroid autoimmunity has been associated with an increase in carotid intima thickness (IMT) in obese women, independent of thyroid function, BMI and cardiovascular risk factors.28 However, thyroid autoimmunity may only affect cardiovascular indices in younger women, whereas the effect may disappear in older women with stronger cardiovascular risk factors. Our previous study demonstrated that FM patients had significantly higher baPWV than controls, and that baPWV was significantly correlated with FIQ,17 indicating that the severity of functional status was correlated with endothelial dysfunction. BaPWV has been reported as a good marker for arterial stiffness, and the results of several studies have shown that baPWV provide similar information to those derived from central arterial stiffness measured with carotid-femoral PWV.29–31 In this study, we tried to investigate other factors that affect endothelial function in patients with FM such as thyroid functional status. We failed to find an association between endothelial dysfunction reflected by higher PWV and TSH levels or thyroid function. However, thyroid autoimmunity was associated with arterial stiffness as represented by the increased baPWV in euthyroid female FM patients. Our finding conflicts with the results of the recent study by Lambrinoudaki et al., who showed that a serum TSH greater than 2.5 mU/mL, but not thyroid autoimmunity, was positively associated with arterial stiffness in postmenopausal women with normal thyroid function.32 The association between thyroid autoimmunity and arterial stiffness has not been consistently reported in previous studies. The Rotterdam study, which evaluated elderly women, showed that thyroid autoimmunity itself was not associated with cardiovascular risk.26 On the contrary, Stamatelopoulos et al.27 reported that the pres-
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ence of Hashimoto’s thyroiditis was positively associated with arterial stiffness, but only in premenopausal women. Another study reported an increase in carotid IMT in obese women with Hashimoto’s thyroiditis.28 In this study, the association of thyroid autoimmunity and the increase in carotid IMT was independent of thyroid function and cardiovascular risk factors. Taken together, Lambrinoudaki et al.32 commented that thyroid autoimmunity may affect cardiovascular indices only in younger women, whereas the effect may disappear in older women with stronger cardiovascular risk factors. However, we found that thyroid autoimmunity was positively associated with arterial stiffness in postmenopausal women with normal thyroid function, possibly because we only included postmenopausal women without cardiovascular risk factors. Moreover, we included euthyroid postmenopausal women with FM, whereas Lambrinoudaki et al. included healthy postmenopausal women. In our study, FM patients showed more positive TPO Ab than controls (24.5% vs. 8%), and previous studies also demonstrated similar higher prevalence of TPO antibodies in FM patients.13,14 However, the prevalence of TPO Ab in the Lambrinoudaki et al. study was only 12.8%, which might not be high enough to enable detection of associations with vascular indices. Although menopausal age has been identified as an independent predictor of subclinical atherosclerosis in postmenopausal women,33 menopausal age in our results was not significantly associated with the vascular indices. There are several limitations to this study. Our patients were on a variety of medications. It is likely that medications may have some effect on endothelial function and arterial stiffness is modulated by pharmacological treatment,34 but we excluded the patients under anti-hypertensive drugs or antidiabetic drugs. However, this study was performed in postmenopausal women, and 27 (16.7%) had hormonal replacement, but we did not account for the effect of exogenous hormones. Despite observational data suggesting the benefits of hormone replacement therapy on endothelial function, data from several randomized trials still failed to support a benefit of hormone therapy on cardiovascular disease.35,36 Therefore, large surveys with sampling of subjects by strict medical examination will be necessary. A second possible limitation is the cross-sectional study design, which cannot demonstrate causal associations. Third, we defined the postmenopausal status when there has been amenorrhea for one complete year, and did not check hormone levels, including estradiol (E2) and gonadotropin, which possibly affect endothelial function. Finally, we did not examine the
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K. I. Cho and J. H. Lee
mood status of patients in the control group. We recruited control patients that did not have chronic widespread pain. A report has shown that the mood disturbance score is associated with a decrease in endothelial function,37 so it is likely that mood status would influence baPWV measurements. In conclusion, we demonstrated that combined thyroid autoimmunity is an important predictor of endothelial function and arterial stiffness in euthyroid postmenopausal women with FM. These results support the need to re-evaluate the effects of thyroid autoimmunity on the vasculature of postmenopausal women with FM. However, longitudinal studies that employ a large population will be needed to determine the pathophysiologic and prognostic implications of endothelial dysfunction in FM.
ACKNOWLEDGEMENT The Corresponding author has the right to grant on behalf of the other authors and does grant on behalf of all authors an exclusive license (or non exclusive for government employees) on a worldwide basis to the journal ‘International Journal of Rheumatic diseases’ to permit this article (if accepted) to be published, sublicenses such use and exploits all subsidiary rights, as set out in our license.
DISCLOSURE STATEMENT None of the authors have identified a conflict of interest.
FUNDING None.
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