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Original Article |
Departments of Medicine and Medical Biochemistry (R.J.), University of Wales College of Medicine, Cardiff, United Kingdom CF14 4XN
Address all correspondence and requests for reprints to: Prof. John Lazarus, Department of Medicine, University of Wales College of Medicine, Heath Park, Cardiff, Wales, United Kingdom CF14 4XN.
Abstract
Hypothyroidism is associated with cardiovascular dysfunction. It is increasingly apparent that stiffening of central arteries may lead to increased afterload and cardiac dysfunction. We noninvasively studied the peripheral and central pressure waveforms in 12 untreated hypothyroid patients as well as in 12 age-, sex-, and body mass index-matched controls using the technique of pulse wave analysis from recordings at the radial artery. Indexes of arterial stiffness, augmentation index (AI) and augmentation of central arterial pressure (AG), were derived as well as time of travel of the reflected wave (TR), a direct estimate of aortic pulse wave velocity. At baseline, there were no significant differences between the 2 groups in brachial and aortic blood pressures. Hypothyroid patients had significantly higher AI than controls (mean ± SEM[SCAP], 32.0 ± 3.4% vs. 17.0 ± 2.4%; P < 0.0005) even when corrected for heart rate (AIC; 28.0 ± 3.2% vs. 17.0 ± 2.4%; P < 0.006) and AG (13.0 ± 2.2 vs. 7.0 ± 2.1 mm Hg; P < 0.03) together with a lower TR (132.0 ± 4.1 vs. 142.0 ± 1.5 msec; P < 0.03). After 6 months of therapy with T4, all patients were euthyroid. AIC had decreased in the patient group (23.0 ± 3.2% vs. 28.0 ± 3.2%; P < 0.01) as had AG (9.0 ± 1.5 vs. 13.0 ± 2.2 mm Hg; P < 0.008), but TR was significantly higher (142.0 ± 3.0 vs. 132.0 ± 4.1 msec; P < 0.008). AI correlated with age in all groups (hypothyroid group: r = 0.937; P < 0.0005; control group: r = 0.804; P < 0.0005), but correlated with TSH level only among controls (r = 0.591; P < 0.05).
This study confirms that hypothyroidism is associated with increased cardiovascular risk, as evidenced by increased augmentation of central aortic pressures and central arterial stiffness. Furthermore, these abnormalities are reversed after adequate T4 replacement.
HYPOTHYROIDISM IS ASSOCIATED with cardiovascular dysfunction: decreased cardiac contractility, cardiac output, heart rate, and left ventricular compliance as well as increased total peripheral vascular resistance (1). The presence of hypertension (2) and hypercholesterolemia (1, 3) also contributes to an increased risk of atherogenesis in this condition. Both increased peripheral resistance and arterial stiffening may contribute to the development of hypertension (4, 5). Although increased peripheral resistance has been demonstrated in association with hypothyroidism, there are limited data relating to vascular stiffness.
Central arterial stiffness has been demonstrated in numerous conditions associated with increased cardiovascular risk, including diabetes mellitus (6, 7), hypercholesterolemia (8), and smoking (9, 10). Central arterial stiffening or reduced arterial compliance leads to augmented central blood pressure and increased cardiac afterload and is an independent predictor of cardiac events (11, 12). Diastolic dysfunction and enhanced atherosclerosis contribute to cardiac dysfunction in hypothyroidism (1, 13). Therefore, to clarify a possible role for central arterial stiffness in the cardiovascular risk associated with hypothyroidism, we have studied measures of arterial stiffness in subjects with hypothyroidism before and after treatment with T4.
Subjects and Methods
Twelve hypothyroid subjects (10 females) who had biochemical evidence of primary hypothyroidism were recruited for this study. Two patients had primary autoimmune hypothyroidism, and 10 had been rendered hypothyroid after radioiodine (131I) therapy for Graves’ disease. No patient had received any medication for at least 6 wk before recruitment into the study. Patients with diabetes mellitus, hypertension, renal failure, or established coronary artery disease were excluded from the study. There was 1 smoker each in the patient and control groups. These smokers were closely matched for physical characteristics and smoking history. No change in smoking habits was observed during the study. All patients were studied in the fasting state and, in the case of premenopausal women, in the follicular phase of the menstrual cycle. Twelve euthyroid healthy hospital workers were also studied as controls. The two groups were closely matched for age, sex, body mass index (BMI), and blood pressure. The study was approved by the institutional ethics committee, and all patients gave informed consent to participate in the study.
Pulse-wave analysis is the study of pulse pressure waveforms within major arteries. At each point in the blood vessel, the pressure waveform is a composite of the forward wave, traveling toward the periphery from the heart, and the reflected wave traveling toward the heart. In normal individuals without central or aortic stiffness, the reflected wave arrives at the aortic root in diastole and thus augments coronary filling. However, in conditions that cause central arterial stiffness, the reflected wave travels faster and arrives back within the systolic portion of the cardiac cycle, resulting in an augmentation of central pressure and increased afterload (14). Peripheral pulse pressure waveforms were recorded noninvasively based on the principle of applanation tonometry, from the radial artery using a pencil-shaped pressure tonometer (SPC-301, Millar Instruments, San Antonio, TX) and the Sphygmocor device (ATCOR Medical, Sydney, Australia) (15). Subjects were supine for 15 min, after which blood pressure was recorded in the dominant arm. The pressure tonometer was then placed perpendicularly on the radial pulse in the same arm resting on a firm surface. Data were excluded if the systolic or diastolic variability exceeded 5% or the pulse height was less than 100 mV. The central pressure waveform was derived by mathematical transformation of the peripheral pressure waveforms using a generalized validated transfer function and closely approximates similar readings gathered from invasive recordings (16). From these data the major indexes of central arterial stiffness were obtained (shown in Fig. 1
). The augmentation of central arterial pressure (AG) is the difference between the first and second systolic peaks of the central pressure waveforms, and the central augmentation index (AI) is the AG expressed as a percentage of the pulse pressure. The time of travel of the reflected wave (TR) may be determined and is a reliable index of aortic pulse wave velocity, a direct estimate of central arterial stiffness (17). In keeping with a higher AI, the reflected wave would return to the aorta quicker, resulting in a lower TR. TR is a direct estimate of aortic pulse wave velocity, another index of arterial stiffness (18).
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Serum concentrations of TSH, free T4, and T3 were measured using an automated immunoassay analyzer (Advia Centaur, Bayer Corp., Newbury, UK). Free T4 and T3 were determined by competitive labeled antibody assays using an acridinium ester as a label and paramagnetic particles as a solid phase, and TSH was measured using a two-site immunochemiluminometric assay. The batch imprecisions of the assays were as follows: free T4, 9.8–23.1 pmol/liter (coefficient of variation, 4%), free T3, 3.5–6.5 pmol/liter (coefficient of variation, 3.1%), and TSH, 0.35–5.50 mU/liter (coefficient of variation, 5.3%).
Serum lipids and plasma glucose were measured using standard techniques, and BMI was recorded as weight (kilograms)/height (meters) squared. All patients were investigated in the fasting state at baseline and after 6 months of thyroid hormone replacement. The dose of T4 that rendered all subjects biochemically euthyroid was 1.5–2.5 µg/kg.
Statistics
Normally distributed data were analyzed using independent and paired t tests. The Mann-Whitney U test and Wilcoxon sign test were used for nonparametric data (SPSS version 7.5 for Windows, SPSS, Inc., Chicago, IL). All results are expressed as the mean ± SEM. P < 0.05 was considered significant.
Results
At baseline, hypothyroid patients and controls did not differ in age, BMI, lipid profiles, or fasting plasma glucose levels (Table 1). There were no significant differences in aortic and peripheral blood pressures between the groups (Table 2). Two patients had diastolic blood pressures above 90 mm Hg (92 and 100 mm Hg, respectively), and after treatment these had dropped to less than 80 mm Hg (70 and 78 mm Hg, respectively). AG and AI were significantly higher in the patient group than in controls at the observed heart rate and when AI was corrected for differences in heart rate (AIC) (17). Figure 2 depicts the reduction in AG in a 66-yr-old hypothyroid patient studied at baseline and when euthyroid at 6 months. Untreated hypothyroids had a lower TR than controls. When biochemically euthyroid at 6 months after thyroid hormone replacement, the AIC had decreased in the patient group, as had AG, but the TR was significantly higher. Figure 3 shows the AI in the patient group before and after treatment and that in controls. No significant changes were noted in lipid profiles. There were no significant correlations between thyroid hormone levels, BMI, blood pressures, and lipid profiles for hypothyroid patients before and after treatment or between this group and control subjects. Significant correlations were noted between AIC and age in the hypothyroid group independent of the thyroid status (r = 0.937; P < 0.0005) and in controls (r = 0.804; P < 0.0005; Fig. 4). Correlation was also noted between TR and AIC in both groups (r = -0.60; P < 0.05). The relationship between thyroid hormone concentrations and AI was examined in three age groups (<45, 45–55, and >55 yr) in the hypothyroid group when hypothyroid and euthyroid as well as in the control group. The only significant correlation in the hypothyroid group was in age less than 45 yr when hypothyroid (r = 0.521; P < 0.03). Within the control group, TSH correlated with AI (r = 0.591; P < 0.05).
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Discussion
Our data demonstrate that subjects with hypothyroidism have increased central arterial stiffness, as evidenced by an increased AI and lower TR. Furthermore, the study shows that these detrimental changes are entirely reversed with appropriate T4 replacement therapy. A similar degree of increased arterial stiffness has been documented in diabetics (6, 7) and also from studies in smokers (9, 10).
Our findings are similar to those of Giannattasio et al. (20), who found evidence of decreased radial arterial compliance in recent-onset hypothyroidism, but did not find similar changes in the carotid artery, using an ultrasound-based technique. That technique has a limited resolution, which can make very small changes in vessel wall diameter difficult to detect. Also, the anatomy of the necks of different patients may limit the accuracy of the results obtained.
There are direct and indirect mechanisms that may underlie the increased central arterial stiffness in untreated hypothyroidism. Thyroid hormones have been shown to cause vascular smooth muscle relaxation as a direct effect. In hypothyroidism the converse is true, implying that an acute deficiency of thyroid hormones may impair smooth muscle relaxation (21), which may lead to increased central arterial stiffness. The recent identification of thyroid hormone receptor isoforms in human aortic vascular smooth muscle (22) would suggest that changes in thyroid hormone concentration may potentially influence aortic vascular smooth muscle relaxation and also central arterial stiffness by regulation of the genes and gene products involved in these processes, although we did not find any consistent correlation between free T4 and AI. Also, hypothyroidism is associated with endothelial dysfunction (23), which is recognized as one of the earliest events in the complex process of atherogenesis (24). Furthermore, hypothyroidism may contribute to decreased cardiac output (1) and sluggish blood flow that together with endothelial dysfunction may predispose to atherosclerosis and increased arterial stiffness.
Dyslipidaemia is associated with hypothyroidism and may contribute to increased vascular risk including accelerated vascular stiffening. However, we found no differences in lipid profiles among our subjects, suggesting that lipids have no role to play in the increased vascular stiffness found in our patients with hypothyroidism. However, this may not entirely be the case, as hypothyroidism may produce qualitative as well as quantitative changes in lipid profiles. Qualitative changes may include a smaller and denser low density lipoprotein molecule that is recognized to be proatherogenic.
As aging is associated with increased central arterial stiffness (25) and the incidence of hypothyroidism (26) and subclinical hypothyroidism (27), correcting thyroid hormone dysfunction may be an important target in modifying cardiovascular risk, especially in elderly patients. Our data, therefore, underpin the an argument for screening for hypothyroidism, especially in the elderly (28).
In conclusion, we have shown that hypothyroid subjects have increased arterial stiffening and that these abnormalities improve after appropriate treatment with T4. Thus, central arterial stiffening may have some etiological role in the development of the cardiovascular effects of hypothyroidism. Furthermore, we might speculate that the age-related increase in overt and subclinical hypothyroidism together with increased vascular stiffness imply that elderly subjects may be particularly vulnerable to increased vascular risk due to the development of untreated hypothyroidism. However, this study suggests that these changes are reversible with prompt and appropriate treatment.
Acknowledgments
We thank Adrienne French and Lyn Taylor for clinical and laboratory help.
Footnotes
This work was supported by Merck, Sharpe, and Dohme.
Abbreviations: AG, Augmentation of central arterial pressure; AI, augmentation index; AIC, augmentation index corrected for heart rate; BMI, body mass index; TR, time of travel of the reflected wave.
Received March 28, 2002.
Accepted July 3, 2002.
References
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