Increased Pulse Wave Velocity in Subclinical Hypothyroidism

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The Journal of Clinical Endocrinology & Metabolism 91(1):154 –158 Copyright © 2006 by The Endocrine Society doi: 10.1210/jc.2005-1342

Increased Pulse Wave Velocity in Subclinical Hypothyroidism Toshiki Nagasaki, Masaaki Inaba, Yasuro Kumeda, Yoshikazu Hiura, Kumi Shirakawa, Shinsuke Yamada, Yasuko Henmi, Eiji Ishimura, and Yoshiki Nishizawa Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan Objective: Subclinical hypothyroidism affects 5–15% of the general population and is associated with increased morbidity from cardiovascular disease. Brachial-ankle pulse wave velocity (baPWV) is a parameter of arterial stiffening and a good independent predictor for the presence of coronary artery disease. This study was performed to assess whether subclinical hypothyroidism might cause enhanced baPWV.

in both subclinical hypothyroid patients and normal subjects. In contrast, there was no significant correlation of baPWV with free T3, free T4, TSH, total, high-density lipoprotein- and low-density lipoproteincholesterol, and the preejection time to ejection time ratio. A comparison of individual values of baPWV and DBP and regression slopes in two groups revealed that baPWV values increase to a larger extent than the increase in DBP in subclinical hypothyroid patients. In both groups, stepwise regression analysis showed a significant and independent association of DBP with baPWV.

Patients and Methods: baPWV was examined in subclinical hypothyroid patients (n ⫽ 50) and normal control subjects (n ⫽ 50).

Conclusions: The present study demonstrated significant increases of baPWV and DBP in subclinical hypothyroid patients. Furthermore, the results suggest that increased DBP might be one of the main factors responsible for increased arterial stiffening in subclinical hypothyroid patients. (J Clin Endocrinol Metab 91: 154 –158, 2006)

Results: Diastolic blood pressure (DBP), a main risk factor for cardiovascular disease, and baPWV were both significantly higher in subclinical hypothyroid patients than normal subjects. baPWV was significantly positively correlated with age and systolic, diastolic, and pulse pressure and significantly negatively correlated with pulse rate

H

YPOTHYROIDISM IS INCREASINGLY recognized as a cardiovascular risk factor (1). Moreover, subclinical hypothyroidism, which occurs in 5–15% of the general population and is highly prevalent in women over 60 yr of age (2, 3), is reported to be a strong indicator for risk of aortic atherosclerosis and myocardial infarction (4 –7), although it is still controversial. Accelerated atherosclerosis in subclinical hypothyroidism occurs due to multiple mechanisms, including increased diastolic blood pressure (DBP) (4) and dyslipidemia (8, 9), but identification of the most important cause of this condition remains controversial. Pulse wave velocity (PWV) is an index of arterial stiffness that is now easily quantitated using a simple device developed for measurement of the brachial-ankle PWV (baPWV) (10). Not only aortic PWV but also baPWV has been shown to be a good independent predictor for the presence of coronary artery disease in men (11, 12). Thus far, we have reported the significance of baPWV in patients with hemiparesis (13). Although subclinical hypothyroidism is a major risk factor for atherosclerosis, few studies have been per-

formed on arterial stiffening using baPWV measurements in subclinical hypothyroid patients. Therefore, it is important to assess baPWV in subclinical hypothyroidism and determine whether known risk factors for cardiovascular disease might be involved in this condition. This background prompted us to examine: 1) whether baPWV might be higher in subclinical hypothyroid patients; 2) whether a significant correlation or association with baPWV might be found in subclinical hypothyroidism among known risk factors for cardiovascular disease, such as serum lipid levels and blood pressures, or among other cardiovascular factors, such as pulse ratio and the preejection time (PET) to left ventricular ejection time (ET) ratio, a parameter of systolic dysfunction reported to be increased in subclinical hypothyroidism (14), although the most common cardiac alteration in subclinical hypothyroidism is diastolic impairment (15) with PET to ET ratio still controversial; and 3) of these factors, which is of most importance in increased arterial stiffening in subclinical hypothyroid patients. Patients and Methods

First Published Online October 18, 2005 Abbreviations: baPWV, Brachial-ankle PWV; BMI, body mass index; DBP, diastolic blood pressure; ET, ejection time; FT3, free T3; FT4, free T4; HDL, high-density lipoprotein; hs-CRP, high-sensitive C-reactive protein; IMT, intima-media thickness; La, path length from the suprasternal notch to the ankle; Lb, path length from the suprasternal notch to the brachium; LDL, low-density lipoprotein; PET, preejection time; PWV, pulse wave velocity; SBP, systolic blood pressure. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.

The study was open and prospective. Written informed consent was obtained from each patient, and the study was approved by the ethical committee of Osaka City University Hospital. Newly detected subclinical hypothyroid patients (10 males and 40 females) were enrolled in the present study consecutively during the 24-month period from January 2003 to December 2004. Patients were restricted to those who were both negative for antithyroid antibody (microsome test and thyroid test) and absent for destructive findings on ultrasound analysis, thus negating the presence of any organic thyroid disease causing subclinical hypothyroidism. Normal control subjects who joined Health-Check Program at Osaka City University Hospital were enrolled consecutively to make the

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Nagasaki et al. • Pulse Wave Velocity in Subclinical Hypothyroidism

J Clin Endocrinol Metab, January 2006, 91(1):154 –158

number, age, and male to female ratio become the same as subclinical hypothyroid patients (10 males and 40 females) during the 4-month period from September 2004 to December 2004. The diagnosis of subclinical hypothyroidism was established based on elevation of serum TSH to above the normal upper limit, with normal levels of serum free T4 (FT4) and free T3 (FT3). Measurements of baPWV and biochemical markers were performed for all patients. Fifty healthy control subjects were enrolled from participants in a local health-check program conducted at the Osaka City University Hospital. The control subjects had no past history of thyroid disease, had neither goiter nor an autoimmune antibody titer, and were in a euthyroid state. To avoid confounding by other factors known to affect arteriosclerosis, the following patients were excluded from the study: 1) patients suffering from major diseases known to affect atherosclerosis, such as hypertension (16) and diabetes mellitus; and 2) patients receiving other hormone replacement therapy (17).

Serum parameters Blood was drawn just before an ultrasonography study was performed, after an overnight fast. Total cholesterol, triglyceride, and highdensity lipoprotein (HDL)-cholesterol levels were determined using an autoanalyzer, and the low-density lipoprotein (LDL)-cholesterol level was calculated according to the formula of Friedewald et al. (18). FT4, FT3, and TSH were measured using commercially available kits (19).

PWV An automatic waveform analyzer (model BP-203RPE; Colin Co., Komaki, Japan) was used to measure PWV simultaneously with blood pressure, electrocardiogram, and heart sounds, as we and others have previously described (10, 13). Briefly, subjects were examined in the supine position after 5 min of bed rest, with electrocardiogram electrodes placed on both wrists, a microphone for detecting heart sounds placed on the left edge of the sternum, and cuffs wrapped around the brachium and ankles. The cuffs were connected to a plethysmographic sensor that determines the volume pulse form and an oscillometric pressure sensor that measures blood pressure. PWVs were recorded using a semiconductor pressure sensor (the sample acquisition frequency for the PWV was set at 1200 Hz). Volume waveforms for the brachial and ankle arteries were collected and stored, using a sampling time of 10 sec with automatic gain analysis and quality adjustment. The time interval between the wave front of the brachial waveform and that of the ankle waveform was defined as the time interval between the brachial and ankle arteries. The distance between the brachial and ankle sampling points was calculated automatically, based on the height of the subject. The path length from the suprasternal notch to the bra-

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chium (Lb) was obtained from superficial measurements, and calculated using the following equation: Lb ⫽ 0.2195 ⫻ height of the patient (centimeters) ⫺ 2.0734. The path length from the suprasternal notch to the ankle (La) was obtained from superficial measurements and calculated using the following equation: La ⫽ 0.8129 ⫻ height of the patient (centimeters) ⫹ 12.328. Finally, the following equation was used to obtain the baPWV: baPWV ⫽ (La⫺Lb)/time interval between the brachial and ankle arteries. The reproducibility of the baPWV measurements was evaluated by repeating the measurements in 17 healthy subjects on two different occasions. This analyzer measures baPWV on the both sides at the same time. Because the average coefficient of variation of baPWV was lower on the right side (1.7%) than the left side (2.2%), the value of baPWV on the right side was used as representatives. PET to ET ratio was calculated using the same automatic waveform analyzer as follows: ET was decided from the interval between the open and close of aortic valve, which was determined as the interval between up stroke point and dicrotic notch of the waveform measured on carotid artery. PET was calculated to subtract ET from the interval between the beginning of Q (or R) wave and the onset of II sound (20).

Statistical analysis Data are expressed as means ⫾ se unless otherwise indicated. Statistical analysis was performed with the StatView V system (Abacus Concepts, Berkeley, CA) for the Apple computer. Differences in basal values between subclinical hypothyroid patients and normal controls were examined using a Mann-Whitney U test for assessment of the medians. The difference in male to female ratio between two groups was analyzed by ␹2 test. The Spearman rank correlation was used to examine the correlation between baPWV and other parameters. The difference in regression slopes of the correlation of baPWV with DBP between subclinical hypothyroid patients and normal controls were examined using a t test (21). Stepwise multiple regression analysis with forward elimination was performed to assess independent influences of variables on baPWV. The F value was set as 4.0 at each step. P ⬍ 0.05 was considered to be statistically significant.

Results BaPWV and clinical variables in subclinical hypothyroid patients and normal subjects

The clinical characteristics of the subclinical hypothyroid patients and normal controls are shown in Table 1. As mentioned above, all subclinical hypothyroid patients exhibited

TABLE 1. Baseline characteristics of subclinical hypothyroid subjects and control subjects

No. of subjects Gender (female/male) Age (yr) BMI (kg/m2) Smoking index SBP (mm Hg) DBP (mm Hg) Pulse pressure (mm Hg) Pulse rate (per min) T. Chol (mmol/liter) Triglyceride (mmol/liter) LDL-C (mmol/liter) HDL-C (mmol/liter) LDL-C to HDL-C ratio FT4 (pmol/liter) [range 9.01–24.45] FT3 (pmol/liter) [range 4.00 –7.70] TSH (mIU/liter) [range 0.4 – 4.7] BaPWV (cm/sec) PET to ET ratio

Subclinical hypothyroid patients

Normal controls

P

50 40/10 65.2 ⫾ 2.6 21.7 ⫾ 0.57 121 ⫾ 70 133.2 ⫾ 4.2 78.3 ⫾ 2.3 54.7 ⫾ 2.6 72.3 ⫾ 2.8 5.42 ⫾ 0.27 1.56 ⫾ 0.16 3.42 ⫾ 0.18 1.32 ⫾ 0.07 2.55 ⫾ 0.17 14.2 ⫾ 0.55 4.93 ⫾ 0.26 6.89 ⫾ 0.82 1864.7 ⫾ 78.4 2.98 ⫾ 0.10

50 40/10 64.3 ⫾ 3.1 21.7 ⫾ 0.38 98 ⫾ 61 131.6 ⫾ 3.6 67.3 ⫾ 2.3 56.4 ⫾ 2.5 70.6 ⫾ 2.1 5.52 ⫾ 0.18 1.32 ⫾ 0.27 3.37 ⫾ 0.10 1.58 ⫾ 0.08 2.41 ⫾ 0.21 14.9 ⫾ 0.74 5.01 ⫾ 0.28 2.4 ⫾ 0.51 1381.2 ⫾ 47.5 3.01 ⫾ 0.15

ns ns ns ns ⬍0.005 ns ns ns ns ns ⬍0.05 ns ns ns ⬍0.0001 ⬍0.0001 ns

Data are expressed as means ⫾ SE. The differences between two groups were examined using a Mann-Whitney U test for assessment of the medians. ns, Not significant; T. Chol, total cholesterol; LDL-C, LDL-cholesterol; HDL-C, HDL-cholesterol.

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an increase in serum TSH above the normal upper limit, with serum FT4 and FT3 within their respective normal ranges. There was no significant difference in age, gender ratio, preto postmenopausal ratio in females (5:35), body weight, body mass index (BMI), smoking index (daily number of cigarettes multiplied by the number of years of smoking), systolic blood pressure (SBP), pulse pressure, and pulse rate. Among the hemodynamic factors, DBP was significantly higher in subclinical hypothyroid patients than normal controls, as previously reported (4). Serum levels of total cholesterol, LDL-cholesterol and triglyceride, and LDL to HDL ratio did not differ significantly between the two groups. Among lipid profiles, HDL-cholesterol was lower in subclinical hypothyroid patients than normal controls. BaPWV was significantly higher in subclinical hypothyroid patients than normal controls. Correlation between baPWV and other parameters in subclinical hypothyroid patients and normal subjects

The baPWV was significantly positively correlated with age, SBP and DBP, and pulse pressure and significantly negatively correlated with pulse rate in both subclinical hypothyroid patients and normal control subjects (Table 2). In both groups, baPWV was not significantly correlated with FT3; FT4; TSH; total, HDL- and LDL-cholesterol; LDL to HDL ratio; and the PET to ET ratio. Individual values of baPWV in comparison with DBP in subclinical hypothyroid patients

Figure 1A shows the correlation between baPWV and DBP in 50 normal controls. The solid and dotted lines represent the mean and the 95% confidence lines of the baPWV values, respectively, based on the DBP. Forty-nine of the 50 normal controls (98%) showed baPWV values within the confidence line. Figure 1B shows the individual values of baPWV in comparison with DBP in the subclinical hypothyroid patients. The solid and dotted lines indicate the mean and the 95% TABLE 2. Correlation between baPWV and other parameters in subclinical hypothyroid patients and control subjects Subclinical hypothyroid patients

Age (yr) BMI SBP DBP Pulse pressure Pulse rate T. Chol Triglyceride LDL-C HDL-C LDL-C to HDL-C ratio FT4 FT3 TSH PET to ET ratio

Normal controls

Rho

P

Rho

P

0.759 0.084 0.610 0.349 0.571 ⫺0.422 0.152 0.138 0.136 ⫺0.147 ⫺0.061 0.040 0.148 ⫺0.055 0.052

⬍0.0001 ns 0.0001 0.0271 0.0005 0.0180 ns ns ns ns ns ns ns ns ns

0.656 0.084 0.755 0.451 0.643 ⫺0.448 0.134 0.153 0.150 ⫺0.477 0.251 0.052 0.102 ⫺0.078 0.082

0.0003 ns ⬍0.0001 0.0134 0.0004 0.0141 ns ns ns ns ns ns ns ns ns

Data are expressed as means ⫾ SE. Spearman correlation coefficients were used. ns, Not significant; T. Chol, total cholesterol; LDL-C, LDL-cholesterol; HDL-C, HDL-cholesterol.

FIG. 1. A, Individual values of baPWV plotted against DBP in 50 normal controls. The solid and dotted lines represent the mean and (95%) confidence lines for the baPWV values, based on the individual DBP. These regression lines were calculated by Pearson’s analysis (r ⫽ 0.378, P ⫽ 0.0361) between baPWV and DBP in normal controls. Forty-nine of the 50 normal controls (98%) showed baPWV values within the confidence lines. B, Individual values of baPWV plotted against DBP in 50 subclinical hypothyroid patients. The solid and dotted lines represent the mean and confidence lines for the baPWV values in normal control subjects, based on the individual DBP. The thick solid line represents the regression line by Pearson’s analysis (r ⫽ 0.364, P ⫽ 0.0192) for the relationship between baPWV and DBP in subclinical hypothyroid patients. Among the 50 subclinical hypothyroid patients, 38 (76%) patients showed baPWV values within the confidence lines of normal controls.

confidence lines of the baPWV values in normal controls as depicted in Fig. 1A. The thick solid line in Fig. 1B is the regression line for the relationship between baPWV and DBP in subclinical hypothyroid patients. Although 38 of the 50 patients (76%) showed baPWV values within the confidence line for normal controls, 12 (24%) subclinical hypothyroid patients had baPWV values above the 95% confidence line of normal controls. Therefore, these data suggest that the increase of baPWV values might be larger than that of DBP in subclinical hypothyroid patients. Moreover, the difference in the regression slopes of the correlation of baPWV with DBP between subclinical hypothyroid patients and normal controls reached statistical significance (P ⬍ 0.001).


Factors for baPWV in subclinical hypothyroid patients

Table 3 shows the results of stepwise multiple regression analysis of the association of various clinical variables with baPWV in subclinical hypothyroid patients. Parameters analyzed included age, SBP, DBP, pulse pressure, and pulse rate, which showed significant correlation with baPWV in Table 2. Among these parameters, age, SBP, DBP, and pulse pressure were found to be significant factors that were positively associated with baPWV, although pulse rate did not emerge as a significant factor associated with baPWV. In normal controls, age, SBP, DBP, and pulse pressure were significantly and positively associated with baPWV, and pulse rate failed to be a significant factor associated with baPWV (data not shown). Discussion

In the present study, we demonstrated that baPWV and DBP were significantly higher in subclinical hypothyroid patients than normal controls (Table 1) and that there is a significant positive correlation and independent association of baPWV with age, SBP and DBP, and pulse pressure and a significant negative correlation with pulse rate in subclinical hypothyroid patients and controls (Tables 2 and 3). Although subclinical hypothyroid patients retained a significant and positive correlation between baPWV and DBP, baPWV increased to a greater extent than DBP, as reflected by an increased number of subclinical hypothyroid patients with baPWV values above the confidence line of normal control subjects (Fig. 1) and an increased regression slope of the correlation of baPWV with DBP in subclinical hypothyroid patients. These findings suggest that elevation of DBP may contribute to the increase in baPWV in subclinical hypothyroid patients but that it does not solely account for the extent of the increase of baPWV. Taken collectively, the results suggest that, at least in part, increased DBP may explain the acceleration of arterial stiffening in subclinical hypothyroid patients. Luboshitzky et al. (4) reported that increased DBP may be the main risk factor for cardiovascular disease in subclinical hypothyroidism because mean values of lipids and SBP in subclinical hypothyroid patients did not differ from those in controls. Our data further support the importance of increased DBP for progression of atherosclerosis in subclinical hypothyroid patients. Higher levels of baPWV have been reported previously in 28 subclinical hypothyroid patients, but no correlation of baPWV with DBP was found (22), although a significant correlation of baPWV with age and SBP was apparent, which TABLE 3. Stepwise multiple regression analysis to evaluate the association of baPWV and other parameters in subclinical hypothyroid patients Dependent variables

Independent variables

␤

F value

baPWV

Age SBP DBP Pulse pressure

0.725 0.603 0.481 0.492

39.81 20.00 10.52 11.15

Parameters assayed included age, SBP, DBP, pulse pressure, and pulse rate. ␤, Standard regression coefficient; R2 ⫽ 0.525 (P ⬍ 0.0001).


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is consistent with our results. The reason for the discrepancy is unclear, but the smaller numbers of subjects enrolled in the earlier study might account for the lack of correlation between baPWV and DBP. The lack of correlation of baPWV with FT3, FT4, and TSH may suggest that reductions in the serum levels of thyroid hormone might increase baPWV values not by direct mechanism but by indirect mechanisms such as alterations in hemodynamics. However, further examination to monitor the changes of baPWV during restoration of euthyroidism by levothyroxine therapy would be needed to elucidate the possible mechanism of subclinical hypothyroidism on increased arterial stiffening. Although Monzani et al. (23) recently reported increased arterial thickening by increased arterial intima-media thickness (IMT) in subclinical hypothyroid patients, it was very difficult to demonstrate a subtle increase of IMT in our hand (data not shown) because the precision of the IMT measurement is much lower than that for the automatic waveform analyzer system for measurement of baPWV. Together with their data and the present results, it was suggested that subclinical hypothyroid patients exhibited increases in both arterial stiffening and arterial thickening. Dagre et al. (24) also reported that changes in arterial stiffness in hypothyroidism, even in the subclinical stage, may be caused from detrimental effects on left ventricular function and coronary perfusion. Therefore, it would be worthwhile to assess the correlation of baPWV with left ventricular function and coronary perfusion. A limitation of the present study was that the stepwise multiple regression model in Table 3 explains only from 52.5% of the baPWV, indicating the possible presence of other regulatory factors that lead to elevation of baPWV in subclinical hypothyroid patients. Supportive of this notion is the higher increase in baPWV, compared with that of DBP. Therefore, other factors besides an increase in DBP may contribute significantly to increased arterial stiffening in subclinical hypothyroid patients. Thus far, alterations in various markers and aspects of atherosclerosis such as high-sensitive C-reactive protein (hsCRP), endothelial dysfunction, and systemic vascular resistance have been reported in subclinical hypothyroidism (25– 29). Although many investigators reported higher levels of serum hs-CRP in subclinical hypothyroid patients, it is still controversial whether CRP can be a risk factor in cardiovascular events because levothyroxine replacement therapy did not decrease hs-CRP serum levels (25, 26). Other reports showed impairment of endothelial function and nitric oxide availability in subclinical hypothyroidism and its reversal to normal levels with levothyroxine replacement (27, 28). Furthermore, increased systemic vascular resistance in subclinical hypothyroid patients is also reported to improve with levothyroxine replacement (29). Hence, it is of importance to further examine whether these newly detected atherosclerotic markers are associated with baPWV in subclinical hypothyroidism. It was reported that the male subclinical hypothyroid patients were associated with ischemic heart disease independent of age, SBP, BMI, cholesterol, smoking, or presence of diabetes mellitus but not with cerebrovascular disease (6).

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Moreover, the report indicated increased mortalities from all causes. This report further supports the possibility of unknown risk factors to affect increased cardiovascular morbidities in the male subclinical hypothyroid patients. In summary, this study demonstrated that subclinical hypothyroid patients exhibit increased baPWV and DBP, compared with normal controls. Furthermore, the significant association of DBP with baPWV suggests that increased DBP might be one of the main contributory factors associated with increased baPWV in subclinical hypothyroid patients. Acknowledgments Received June 16, 2005. Accepted October 6, 2005. Address all correspondence and requests for reprints to: Masaaki Inaba, M.D., Department of Metabolism, Endocrinology, and Molecular Medicine, Internal Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. E-mail: [email protected]. The authors have no conflicts of interest.

References 1. Cappola AR, Ladenson PW 2003 Hypothyroidism and atherosclerosis. J Clin Endocrinol Metab 88:2438 –2444 2. Evered DC, Tunbridge WM, Hall R, Appleton D, Brewis M, Clark F, Manuel P, Young E 1978 Thyroid hormone concentrations in a large scale community survey. Effect of age, sex, illness and medication. Clin Chim Acta 83:223–229 3. Sawin CT, Chopra D, Azizi F, Mannix JE, Bacharach P 1979 The aging thyroid. Increased prevalence of elevated serum thyrotropin levels in the elderly. JAMA 242:247–250 4. Luboshitzky R, Aviv A, Herer P, Lavie L 2002 Risk factors for cardiovascular disease in women with subclinical hypothyroidism. Thyroid 12:421– 425 5. Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC 2000 Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med 132:270 –278 6. Imaizumi M, Akahoshi M, Ichimaru S, Nakashima E, Hida A, Soda M, Usa T, Ashizawa K, Yokoyama N, Maeda R, Nagataki S, Eguchi K 2004 Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab 89:3365–3370 7. Biondi B, Klein I 2004 Hypothyroidism as a risk factor for cardiovascular disease. Endocrine 24:1–13 8. Althaus BU, Staub JJ, Ryff-De Leche A, Oberhansli A, Stahelin HB 1998 LDL/HDL-changes in subclinical hypothyroidism: possible risk factors for coronary heart disease. Clin Endocrinol (Oxf) 28:157–163 9. Mya MM, Aronow WS 2002 Subclinical hypothyroidism is associated with coronary artery disease in older persons. J Gerontol A Biol Sci Med Sci 57: M658 –M659 10. Yamashina A, Tomiyama H, Takeda K, Tsuda H, Arai T, Hirose K, Koji Y, Hori S, Yamamoto Y 2002 Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement. Hypertens Res 25:359 –364 11. Blacher J, Asmar R, Djane S, London GM, Safar ME 1999 Aortic pulse wave


12. 13. 14.

15. 16. 17. 18. 19. 20. 21. 22. 23.

24. 25.

26.

27.

28. 29.

velocity as a marker of cardiovascular risk in hypertensive patients. Hypertension 33:1111–1117 Imanishi R, Seto S, Toda G, Yoshida M, Ohtsuru A, Koide Y, Baba T, Yano K 2004 High brachial-ankle pulse wave velocity is an independent predictor of the presence of coronary artery disease in men. Hypertens Res 27:71–78 Okabe R, Inaba M, Sakai S, Ishimura E, Moriguchi A, Shoji T, Nishizawa Y 2004 Increased arterial stiffening and thickening in the paretic lower limb in patients with hemiparesis. Clin Sci 106:613– 618 Monzani F, Di Bello V, Caraccio N, Bertini A, Giorgi D, Giusti C, Ferrannini EJ 2001 Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J Clin Endocrinol Metab 86:1110 –1115 Fazio S, Palmieri EA, Lombardi G, Biondi B 2004 Effects of thyroid hormone on the cardiovascular system. Recent Prog Horm Res 59:31–50 Takami T, Shigemasa M 2003 Efficacy of various antihypertensive agents as evaluated by indices of vascular stiffness in elderly hypertensive patients. Hypertens Res 26:609 – 614 Miura S, Tanaka E, Mori A, Toya M, Takahashi K, Nakahara K, Ohmichi M, Kurachi H 2003 Hormone replacement therapy improves arterial stiffness in normotensive postmenopausal women. Maturitas 45:293–298 Friedewald WT, Levy RI, Fredrickson DS 1972 Estimation of the concentration of low-density lipoprotein in plasma without use of preparative ultracentrifuge. Clin Chem 18:499 Christofides ND, Sheehan CD 1995 Enhanced chemiluminescence labeledantibody immunoassay (Amerlite-MAB) for free thyroxine: design, development, and technical validation. Clin Chem 41:17–23 Kelly B, Hayward C, Avolio A, O’Rourke M 1989 Noninvasive determination of age-related changes in the human arterial pulse. Circulation 80:1652–1659 Ichihara K 1990 Comparison of two regression parameters. In: Ichihara K, ed. Statistics for bioscience—practical technique and theory. Tokyo: Nankodo; 218 –223 Hamano K, Inoue M 2005 Increased risk for atherosclerosis estimated by pulse wave velocity in hypothyroidism and its reversal with appropriate thyroxine treatment. Endocr J 52:95–101 Monzani F, Caraccio N, Kozakowa M, Dardano A, Vittone F, Virdis A, Taddei S, Palombo C, Ferrannini E 2004 Effect of levothyroxine replacement on lipid profile and intima-media thickness in subclinical hypothyroidism: a double-blind, placebo-controlled study. J Clin Endocrinol Metab 89:2099 –2106 Dagre AG, Lekakis JP, Papaioannou TG, Papamichael CM, Koutras DA, Stamatelopoulos SF, Alevizaki M 2005 Arterial stiffness is increased in subjects with hypothyroidism. Int J Cardiol 103:1– 6 Christ-Crain M, Meier C, Guglielmetti M, Huber PR, Riesen W, Staub JJ, Muller B 2003 Elevated C-reactive protein and homocysteine values: cardiovascular risk factors in hypothyroidism? A cross-sectional and a double-blind, placebo-controlled trial. Atherosclerosis 166:379 –386 Perez A, Cubero JM, Sucunza N, Ortega E, Arcelus R, Rodriguez-Espinosa J, Ordonez-Llanos J, Blanco-Vaca F 2004 Emerging cardiovascular risk factors in subclinical hypothyroidism: lack of change after restoration of euthyroidism. Metabolism 53:1512–1515 Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L, Salvetti A, Ferrannini E, Monzani F 2003 Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab 88:3731–3737 Cikim AS, Oflaz H, Ozbey N, Cikim K, Umman S, Meric M, Sencer E, Molvalilar S 2004 Evaluation of endothelial function in subclinical hypothyroidism and subclinical hyperthyroidism. Thyroid 14:605– 609 Faber J, Petersen L, Wiinberg N, Schifter S, Mehlsen J 2002 Hemodynamic changes after levothyroxine treatment in subclinical hypothyroidism. Thyroid 12:319 –324

JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community.