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Increased Pulse Wave Velocity in Subclinical Hypothyroidism

Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan

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: inaba-m{at}med.osaka-cu.ac.jp.

	Abstract

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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.

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

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 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 lipoprotein-cholesterol, 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.

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.

	Introduction

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HYPOTHYROIDISM 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, 5, 6, 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 performed 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

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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 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 high-density 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 brachium (Lb) was obtained from superficial measurements, and calculated using the following equation: Lb = 0.2195 x 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 x 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

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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 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, pre- to 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.

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.

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% 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).

View larger version (23K): [in this window] [in a new window]   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.

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

Top Abstract Introduction Patients and Methods Results Discussion References

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 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 (hs-CRP), endothelial dysfunction, and systemic vascular resistance have been reported in subclinical hypothyroidism (25, 26, 27, 28, 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). 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.

	Footnotes

 
The authors have no conflicts of interest.

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.

Received June 16, 2005.

Accepted October 6, 2005.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nagasaki, T. Articles by Nishizawa, Y. Search for Related Content PubMed PubMed Citation Articles by Nagasaki, T. Articles by Nishizawa, Y. Related Collections Thyroid Cardiovascular Endocrinology