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Centre for Endocrine and Diabetes Sciences (P.J.D.O., J.H.L.) and Department of Cardiology (C.R., D.V., T.M., A.G.F.), School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, United Kingdom
Address all correspondence and requests for reprints to: Professor J. H. Lazarus, Centre for Endocrine and Diabetes Sciences, Cardiff University, University Hospital of Wales, Cardiff CF14 4XN, Wales, United Kingdom. E-mail: lazarus{at}cf.ac.uk.
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Abstract |
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Objective: The objective of the study was the assessment of arterial and cardiac function.
Design: The study was a 6-month controlled observational study using pulse wave analysis and tissue Doppler dobutamine stress echocardiography.
Setting: The study was conducted at a thyroid clinic.
Patients: Nineteen female SCH patients with raised TSH, normal free T4, and no cardiovascular disease [aged 49.2 ± 3.8 yr; body mass index (BMI) 29.9 ± 6.7 kg/m2] were recruited from the thyroid clinic, and 10 female controls (aged 50.2 ± 3.4 yr; BMI 29.7 ± 7.2 kg/m2) also participated in the study.
Interventions: Incremental doses of L-thyroxine were used.
Main Outcome Measures: Indices of vascular stiffness and left ventricular echocardiographic function were measured.
Results: Baseline augmentation gradient was elevated in SCH, compared with controls [10.3 ± 5.1 (SD) mm Hg vs. 8.0 ± 4.2, P < 0.05]; when euthyroid (mean T4 dose 114 µg/d), it fell to 8.8 ± 5.3 mm Hg (P < 0.05). Heart rate-corrected augmentation index was 26.7 ± 9.9 vs. 18.8 ± 9.9% (P < 0.02), falling to 19.7 ± 9.6% (P < 0.001) after treatment. Time of travel of the reflected wave was 139.3 ± 11.7 msec, compared with 141.5 ± 8.8 msec in controls (P < 0.05), increasing to 144.9 ± 11.9 msec (P < 0.05). There were no differences in resting global, regional left ventricular function, or regional myocardial velocities during maximal dobutamine stress between SCH patients and controls, or in treated patients, compared with baseline.
Conclusions: Arterial stiffness was increased in SCH and improved with L-thyroxine, which may be beneficial, whereas myocardial functional reserve was similar to controls and remained unaltered after treatment.
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Introduction |
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SCH can be seen as a stage in the development of overt hypothyroidism (OH) (3), and the risk at 1 yr of developing OH with SCH and the presence of thyroid antibodies is 4.3% and 38 times higher than in patients with no antibodies and a TSH level within the reference range (4). Treatment of this early thyroid failure will halt the progression to OH and reduce its associated morbidity. In randomized controlled trials (5, 6, 7), thyroid hormone replacement has been shown to minimize symptoms related to SCH. The association of SCH and dyslipidemia is unclear; some evidence suggests increased total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides with unchanged high-density lipoprotein (HDL) cholesterol and lipoprotein(a) (8), but therapeutic trials have given varying results (9, 10, 11).
Augmentation of central aortic pressure and central arterial stiffness (CAS) are observed in patients with OH, reversing after adequate T4 replacement (12). Increased CAS is an important risk factor for cardiovascular disease, which has been demonstrated in diabetes mellitus, hypercholesterolemia, aging, and smoking (13, 14, 15, 16). Increased CAS or reduced arterial compliance leads to augmented central blood pressure and increased cardiac afterload. Increased arterial stiffness is a determinant of cardiovascular mortality and because reduced arterial elasticity parallels changes in impaired endothelium-dependent vasodilation, reduced arterial elasticity may be used as a noninvasive, indirect measure of endothelial function (17).
Thyroid hormone is an important regulator of cardiac function (18). OH is accompanied by intrinsic myocardial changes reflected by alterations in contractility and relaxation, causing decreased cardiac contraction, cardiac output, heart rate, and left ventricular compliance as well as an increase in total peripheral resistance, which may be responsible for increased prevalence of hypertension in OH (12). Although there is no clear evidence that SCH causes clinical heart disease (19), changes in thyroid status in SCH are associated with changes in several cardiac parameters manifested by left ventricular dysfunction at rest and systolic dysfunction on effort, an enhanced risk for atherosclerosis, and myocardial infarction. These cardiovascular abnormalities have been shown to regress with L-thyroxine therapy (20, 21, 22). Other studies have, however, shown that cardiac structure and function remain overall normal in SCH (23).
Vitale et al. (24) demonstrated reduced velocities on tissue Doppler echocardiography (TDE) in patients with SCH, compared with healthy control subjects, and Zoncu et al. (25), using TDE, recently demonstrated similar changes in patients who had evidence of borderline hypothyroidism. TDE quantifies myocardial wall motion and allows noninvasive assessment separately of radial and longitudinal, systolic and diastolic regional myocardial velocities. TDE during stress has been reported to be a sensitive method for identifying subclinical left ventricle (LV) dysfunction, but this has not yet been investigated in patients with SCH.
We therefore evaluated both the peripheral arterial function and cardiac function using TDE in patients with SCH before and after 6 months of thyroid hormone therapy, and in control subjects.
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Subjects and Methods |
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Vascular compliance was measured in 10 euthyroid controls, matched for age, sex, and body mass index (BMI). Normal subjects matched as case controls for the dobutamine TDE study were selected from the Myocardial Doppler in Stress Echocardiography database (26). This study was performed in six west European countries and contains digitally stored dobutamine stress echocardiographic studies performed in normal subjects.
Patients were initially started on 50 µg levothyroxine (Synthroid; Abbott Laboratories, Chicago, IL); thyroid function was measured at 0, 6, 12, and 24 wk. TSH was kept within the normal range by dose adjustment, increasing to a maximum dose of 150 µg, and tablet compliance was assessed by regular remaining tablet count. This study was given approval by the local ethics committee and all patients gave informed written consent.
Biochemical measurements
All patients were studied after an overnight fast. Serum concentrations of free T4 (FT4), free T3 (FT3), and TSH were measured using an automated immunoassay analyzer, the Advia Centaur (Bayer Diagnostics Division, Newbury, UK). FT4 was analyzed using a competitive-labeled antibody assay using an acridium ester as a label and paramagnetic particles as a solid phase, and TSH was a two-site immunochemiluminometric assay. The normal ranges of these indices were as follows: FT4, 0.76–1.79 ng/dl (9.8–23.1 
mol/liter); FT3, 0.27–0.51 ng/dl (3.5–6.5 mol/dl); and TSH [0.35–5.50 mU/liter (µU/ml)]. Thyroid peroxidase (TPO) antibodies were measured by an electrochemiluminescence immunoassay method (Roche Diagnostics, Indianapolis, IN). Serum total cholesterol, HDL, LDL, triglycerides, and glucose were measured using standard techniques, and BMI was recorded as weight (kilograms)/height (square meters).
Pulse wave analysis (PWA)
PWA studies pressure waveforms within major arteries. At each point in the blood vessel, the pressure waveform is a composite of the forward traveling wave, moving toward the periphery from the heart and the reflected wave back toward the heart. Normally the reflected wave from the periphery arrives at the central arteries and aortic root in diastole, after the central systolic peak. In conditions that cause CAS, the pulse wave velocity increases and results in the reflected wave arriving back more quickly within the systolic portion of the cardiac cycle, causing augmentation of the central systolic pressure and an increased afterload (12). The elevated central pressure associated with decreased arterial compliance leads to subsequent left ventricular hypertrophy.
PWA was performed noninvasively using applanation tonometry at the radial artery (SPC-301; Millar Instruments, San Antonio, TX) and the Sphygmocor apparatus (ATCOR Medical, Sydney, Australia) (27). Patients were asked to lie supine for 10 min, a brachial blood pressure measurement was recorded, and a pencil-shaped tonometer was placed on the radial artery. Peripheral pressure waveforms were recorded, and via a validated transfer factor central pressure waveforms were generated (28). Indices of central arterial stiffness are calculated from these waveforms: augmentation gradient (AG), augmentation index (AI), and time of travel of the reflected wave (TR). TR is a reliable index of aortic pulse wave velocity, a direct estimate of central arterial stiffness, and an independent predictor of cardiovascular mortality (29).
PWA was performed by one observer who was not blinded to the study. The computer software allowed quality control parameters to be used and waveforms were only analyzed if there was less than 5% variance between successive waves. The reproducibility data for paired measurements by a single observer showed a mean difference ± SD of 0.69 ± 4.1% [95% confidence interval (–0.79 to 1.92)], which compares favorably with published data (30).
Echocardiography
Complete echocardiographic studies (31) were obtained at baseline in patients and before and after 6 months of treatment with T4, using the Vingmed System 5 (GE, Horten, Norway) with a 2.5-MHz transducer and an integrated digitizing system (EchoPAC, version 6.3.1b2 and EPAC-TVI). These included cross-sectional imaging, spectral Doppler, color Doppler, pulsed tissue Doppler of the lateral mitral annulus, and color tissue Doppler of the LV in three apical views (four-chamber, two-chamber, and three-chamber). An M-mode study of the LV in the parasternal long-axis view was obtained for measuring LV dimensions, LV end diastolic dimension (LVEDD), end systolic dimension, and fractional shortening. Spectral and color Doppler were used to assess valves. Color M-mode of LV inflow was used to measure the velocity of flow propagation, after modifying the Nyquist limit (32) to obtain a distinct color border of the propagation velocity that extends well into the distal third of the LV cavity. Pulsed Doppler of mitral inflow was measured, keeping the sample volume at the tips of the mitral leaflets. Mitral E velocity (E), A velocity (A), E deceleration time, and A duration were measured.
Isovolumic relaxation time (IVRT) was measured using pulsed or continuous wave Doppler, keeping the sample volume between the left ventricular outflow tract and mitral inflow, as the interval between the end of aortic forward flow and the onset of the mitral E wave. Pulmonary venous Doppler was recorded with the sample volume 1 cm into the right upper pulmonary vein. Pulmonary venous A reversal velocity and the duration of A reversal (A dur) were measured. Preejection period (PEP) was measured from the beginning of the QRS to the beginning of aortic ejection. Isovolumetric contraction time (IVCT) was measured from the end of mitral inflow to the beginning of left ventricular outflow. Ejection time (ET) was measured from the aortic outflow Doppler trace, and PEP/ET was calculated. Myocardial performance index was calculated from the formula IVRT+ IVCT/ET. Pulsed tissue Doppler of the lateral mitral annulus was recorded at baseline and measurements of the peak systolic annular velocity (Vs), peak early diastolic velocity (Ve), and peak late diastolic velocity were performed. Precontraction time was measured from QRS onset to the beginning of Vs. Contraction time was measured from the beginning of Vs to the end of Vs. Relaxation time was measured from the end of Vs to the onset of Ve. Values of two-dimensional echo parameters were compared with historic reference values (33).
After the baseline study, all the patients underwent stress echocardiography with iv dobutamine (31) given in incremental doses of 5, 10, 20, 30, and 40 µg/kg/min; patients who failed to achieve a target heart rate [>85% of (220 – patient’s age)] or became hypotensive were given atropine while continuing their final dobutamine dose. Two-beat color tissue Doppler loops of the LV in apical four-chamber, two-chamber, and three-chamber views were recorded at the end of each stage and during recovery and analyzed off-line by a cardiologist. Regional myocardial velocities in the six basal segments (basal septal and basal lateral in the four-chamber view, basal inferior and basal anterior in the two-chamber view, basal posterior and basal anteroseptal in the three-chamber view) were measured and compared with control values (Myocardial Doppler in Stress Echocardiography database). Isovolumic acceleration was measured as the slope of the isovolumic contraction wave. The echocardiographers were all blind as to the patient status.
Statistical analysis
All data were analyzed using SPSS (version 11.0 for Windows; SPSS Inc., Chicago, IL). Results are expressed as mean ± SD for normally distributed data except TSH, which is expressed as a median value (range). P < 0.05 was considered as significant. Normally distributed data were analyzed using independent and paired t tests, and Mann-Whitney U test was used for nonparametric data. The correlation between variables was evaluated using Spearman’s and Pearson’s correlation coefficients and stepwise regression analysis.
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Results |
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. There were no significant differences in age, BMI, or fasting plasma glucose levels between the control and patient groups initially. Total cholesterol and LDL levels were significantly lower in controls, compared with the patient group initially (P < 0.01). TPO antibodies were detected in 17 subjects, and two were smokers who did not change their smoking habits during the trial.
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Vascular function, including AG, AI, and corrected AI (AIc) were significantly increased in SCH patients, compared with controls and fell to control levels after 6 months of treatment. Figure 1, A and B, shows the response to treatment on AG, AI, and AIc and FT4, FT3, and TSH, respectively. The fall in AIc is shown in Fig. 2 during treatment at 0, 6, 12, and 24 wk. The TR, an indirect estimate of pulse wave velocity, increased significantly after T4 therapy from 139.3 ± 11.7 to 144.9 ± 11.9 msec (P < 0.05). Diastolic brachial and aortic blood pressures decreased significantly with treatment, but there were no significant changes in brachial and aortic systolic blood pressures after treatment (Fig. 3). The resting heart rate (beats per minute) showed no difference at baseline, compared with controls (71.9/min vs. 72.8, P = ns) and remained unchanged after treatment (70.0 vs. 71.9, P = ns).
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Myocardial function
The baseline assessment of LV systolic and diastolic function is shown in Table 2, together with posttreatment. Standard two-dimensional echocardiography showed that after 6 months of treatment with L-T4, parameters measuring systolic and diastolic function did not alter significantly. In addition, with the exception of IVRT, values were not different from standard reference values. The IVRT was longer than the accepted range in our patients.
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for patients both at rest and after maximal dobutamine stress together with a mean value of all six sites in patients. Values for control subjects are available for only four sites as shown (BL, BS, BA, BI), and these are compared with the same four sites in patients before and after treatment with dobutamine, with the mean of these four sites also shown. There were no significant alterations comparing the average velocities of four or six sites, before or after treatment with L-thyroxine or compared with controls.
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Discussion |
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Hypothyroidism is associated with decreased endothelium-dependent vasodilation, and animal studies have indicated that thyroid status alters capacities for both formation and response to nitric oxide (34). Patients with SCH are characterized by endothelial dysfunction resulting from a reduction in nitric oxide availability. This alteration is partially independent of dyslipidemia and reversed by levothyroxine supplementation (35).
Detecting early carotid artery wall alterations via measurement of the intima-media thickness (IMT) has shown SCH patients to have higher IMT, compared with control subjects, and with L-T4 treatment IMT improves this parameter as well as the lipoprotein profile, suggesting that lipid infiltration of the arterial wall may be an underlying mechanism for IMT in SCH (9). Recently significantly elevated brachial-ankle pulse wave velocity, a parameter of arterial stiffening and a predictor for the presence of coronary heart disease, has been demonstrated in SCH (36).
Thyroid hormone’s effect on peripheral vascular smooth muscle is via T3 converted from T4 via types 1 and 2 deiodinases; the presence of the latter has been detected in rat aorta media (37). Experiments involving aortic endothelial and vascular smooth muscle cells exposed to tension revealed relaxation in response to exposure to T3 and further suggested that T3 acted directly on the vascular smooth muscle cells to cause vascular relaxation (38). In this regard it is interesting that significant but weak correlations were found between thyroid hormones and indices of vascular function, a feature noted by other workers (9).
The T3-induced changes in cardiac function may result from direct or indirect actions. Directly, the effect in cardiac myocytes is achieved through binding to specific thyroid hormone nuclear receptors, increasing the transcription of T3-responsive cardiac genes, by increasing protein synthesis, thereby influencing transport of amino acids and calcium across the cell membrane. The nongenomic effects include the effects of thyroid hormone on heart rate by specific ion channel proteins in the sinus node of the left atrium thyroid hormone markedly influencing contractile and electrical activity (39, 40).
Reduced cardiac preload has been shown by cardiac magnetic imaging in patients with SCH (1) together with increased afterload. After a period of L-T4 therapy in these patients, these hemodynamic alterations reversed. In our study using estimates of preload (LVEDD and E/Ve), there were no alterations. We have no explanation for the increased IVRT, but this value did not change in response to treatment.
Mean systolic velocities as measured by tissue Doppler are the most reproducible parameter of LV function and are very sensitive to ischemia. Subtle systolic and diastolic dysfunction in euthyroid patients who had evidence of autoimmune thyroiditis has recently been shown by TDE (25). However, in this present study, using TDE to quantify regional myocardial function in patients before and after treatment with dobutamine stress, no significant differences between patients and historic controls at baseline or after treatment were found. (It was deemed inappropriate to perform TDE with dobutamine stress in SCH patients who may have received only placebo therapy.)
Previous authors evaluating the effect of L-T4 therapy on cardiovascular function have concluded that SCH affects both myocardial structure and contractility with hormone replacement reversing these abnormalities (41). However, no prior studies of SCH have compared cardiac and vascular parameters at the same time intervals in response to treatment, and this study suggests there may be differential sensitivities to a mild deficiency of T4 between cardiac and peripheral vessels; this may raise the possibility of further mechanisms that may be directly or indirectly affecting vascular function via action on vascular thyroid hormone or other receptors.
We therefore conclude, because of extensive evaluation in our patients with SCH, that increased arterial stiffness was evident and treatment with L-thyroxine was beneficial. However, no convincing decrement in cardiac function or myocardial reserve was found, compared with controls, and this did not change after treatment. It would be beneficial to evaluate SCH patients in further large randomized trials to confirm potential benefits of treatment, especially at high normal TSH levels, especially if TPO antibodies are present.
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Footnotes |
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First Published Online March 14, 2006
Abbreviations: A, A velocity; A dur, duration of A reversal; AG, augmentation gradient; AI, augmentation index; AIc, corrected AI; BA, basal anterior; BI, basal inferior; BL, basal lateral; BMI, body mass index; BS, basal septal; CAS, central arterial stiffness; E, E velocity; ET, ejection time; FT3, free T3; FT4, free T4; HDL, high-density lipoprotein; IMT, intima-media thickness; IVCT, isovolumetric contraction time; IVRT, isovolumic relaxation time; LDL, low-density lipoprotein; LV, left ventricle; LVEDD, LV end diastolic dimension; OH, overt hypothyroidism; PEP, preejection period; PWA, pulse wave analysis; SCH, subclinical hypothyroidism; TDE, tissue Doppler echocardiography; TPO, thyroid peroxidase; TR, time of travel of the reflected wave; Ve, early diastolic velocity; Vs, systolic annular velocity.
Received September 21, 2005.
Accepted March 8, 2006.
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, P < 0.0001, pretreatment TSH, compared with controls; 
, P < 0.002, pretreatment, compared with posttreatment for FT3 and pretreatment, compared with controls; •, P < 0.05, pretreatment, compared with posttreatment for AG, and pretreatment, compared with controls; 
, P < 0.001, pretreatment, compared with controls, for AI; 
, P < 0.001, pretreatment, compared with posttreatment, for AIc; 
, P < 0.002, pretreatment, compared with controls, for AIc.
