Subclinical hypothyroidism (SH) is a generally asymptomatic condition defined as normal serum levels of thyroid hormones and elevated thyroid stimulating hormone (TSH) levels. SH is frequently a laboratory diagnosis, because clinical signs and symptoms are either absent or mild [
Previous studies concerning the cardiovascular effects of SH have shown a decrease in pre-ejection period (PEP) and PEP/LVET (left ventricular ejection time) ratio which is reversible with T4 replacement therapy [
Isovolumetric relaxation time (IVRT) is prolonged and pulsed Doppler-derived transmitral A wave velocity is increased in SH. These findings of diastolic dysfunction (DD) are normalized after T4 replacement therapy [
Myocardial performance index (MPI) is a sensitive parameter that expresses overall left ventricular function [
Tissue Doppler echocardiography (TDE) allows us to measure diastolic mitral annular velocities and thus gather information about diastolic function. Mitral annular velocity measured during diastole reflects the rate of change in LV longitudinal dimension and LV volume. In the presence of abnormal myocardial relaxation, the ratio of mitral annular motion during atrial systole to total diastolic annular motion is increased. Previous TDE studies reported diastolic dysfunction in patients with SH [
Twenty-two consecutive female patients diagnosed with SH in the outpatient clinic of a tertiary care center were enrolled in the study. Criteria for inclusion were being 18 years of age or older, female sex, and a serum TSH level between 4.2 and 9.9 mU/L, and having none of the exclusion criteria listed below. Twenty age-matched, euthyroid female subjects who presented to the outpatient clinic because of symptoms unrelated to the endocrine or cardiovascular systems were included in the study as the control group.
Criteria for exclusion were as follows: age greater than 60 years, atrial fibrillation, diabetes mellitus, systemic arterial hypertension, history of coronary artery disease, moderate to severe valvular heart disease, cardiomyopathy, history of previous hyperthyroidism, previous use of antithyroid agents, and lipid lowering therapy in last 6 months. The same exclusion criteria are applied to the control subjects as well. Subjects older than 60 years of age were excluded because left ventricular diastolic relaxation abnormalities could be observed physiologically.
Also, women with a TSH level of 10 mU/L or greater were not included in the study, because cardiovascular involvement in patients with manifest hypothyroidism (TSH level equal to or greater than 10 mU/L) including diastolic dysfunction and heart failure is well established [
Patients with SH were classifed according to etiology as follows: Hashimoto’s thyroiditis SH due to thyroidectomy SH with negative thyroid auto-antibodies and not due to surgery
Written informed consent was obtained from all participants. The study protocole was approved by the local ethics committee and conforms to the Helsinki Declaration.
L-Thyroxine treatment was administered to patients whose TSH levels were between 4,2 and 10 mIU/L (Levotiron 0,1 mg, Abdi Ibrahim, Istanbul, Turkey). Dose was titrated up every 15 days to a level that achieved and maintained a normal TSH level.
All of the patients and controls underwent laboratory assessment. Baseline hemoglobin, fasting blood glucose, total, LDL, and HDL, cholesterol, triglyceride levels were determined.
Serum-free T3, T4, and TSH were assessed using the microparticular enzyme immunoasssay method (Axsym, Abbott, USA).
Anti-microsomal antibody (anti-M) and anti-thyroglobulin antibody were assessed using radioimmunoassay (RIA). Normal limits were assumed as 0–60 IU/Lt for both antibodies.
An echocardiographic examination was performed before enrollment and three months after euthyroid state was achieved. The cardiologists (A.F.E. and M.C.) who performed and interpreted the echocardiograms were blind to the clinical and treatment status of the patients.
A Vingmed System V echocardiography unit was used (General Electric, Norway). Frequence of the probe was 1.7 MHz and it was capable of harmonic imaging. B-mode, M-mode, continous wave Doppler, and colour Doppler examinations were performed utilising parasternal long axis, parasternal short axis, and apical two- and four-chamber views with the patient in the left lateral decubitus position. Left ventricular end-diastolic and end-systolic diameters, systolic and diastolic thicknesses of the interventricular septum, and the posterior wall were measured during M-mode examination. Left ventricular mass index (LVMI) was calculated according to Devereux’s formula [
Transmitral flow velocities were measured using pulsed-wave Doppler in the apical four-chamber view. A sample volume of 2 mm was placed between the mitral leaflet tips, E and A velocities were measured, and E/A ratio was calculated. E wave deceleration time was measured in milliseconds.
Using continous-wave Doppler tracings obtained at the apical five-chamber view, isovolumetric contraction time (ICT), isovolumetric relaxation time (IVRT), and aortic ejection time (ET) were measured. Myocardial performance index (MPI) was calculated by dividing the sum of ICT and IVRT by ET.
Tissue Doppler was employed to measure systolic and diastolic mitral annular velocities. Tissue Doppler sample volume was placed on septal and lateral localizations of the mitral annulus in the apical four-chamber view and the anterior and inferior localizations in the apical two-chamber view. Systolic (S) and diastolic (E′ and A′) velocities of the annulus were measured Pulsed wave Doppler-derived E wave velocity/tissue Doppler-derived E′ velocity ratio (E/E′).
Data was analyzed using SPSS 12 software package. Results were expressed as mean ± standard deviation. The normal distribution of variables was verified with the Shapiro-Wilk test. As the distribution was normal, Student’s
Baseline characteristics and biochemical examinations were not different between the SH group and the euthyroid control group.
As expected, mean serum TSH level in the SH group (
Patients with subclinical hypothyroidism received THRT as described in the methods section and euthyroidism was achieved in all subjects. Thyroid function tests before and after treatment, are given in Table
Thyroid function tests before and after thyroid hormone replacement therapy (THRT).
Before THRT | After THRT | ||
---|---|---|---|
fT3 (pg/mL) | 2.62 ± 0.39 | 2.67 ± 0.44 | 0.07 |
fT4 (ng/dL) | 0.89 ± 0.13 | 1.02 ± 0.12 | |
TSH ( | 7.17 ± 1.74 | 2.28 ± 0.63 |
fT3: free triiodothyronine; fT4: free thyroxine; TSH: thyroid stimulating hormone
Table
Two-dimensional (2D) echocardiographic findings.
SH | Control | ||
---|---|---|---|
LVEF (%) | 71.72 (4,61) | 74.2 (4,68) | 0.09 |
IVS (cm) | 0.97 (0,12) | 0.88 (0,1) | |
Posterior wall (cm) | 1.0 (0,13) | 0.92 (0,13) | |
LVEDD (cm) | 4,61 (0.34) | 4.73 (0.35) | 0.29 |
LVESD (cm) | 2.92 (0.26) | 2.90 (0.32) | 0.84 |
LVEF: Left ventricular ejection fraction; IVS: interventricular septum; LVEDD: Left ventricular end-diastolic diameter; LVESD: Left ventricular end-systolic diameter.
All results are expressed as mean values and numbers in brackets denote Standard Deviation.
Mean left ventricular mass index calculated according to the Devereux formula was similar among the SH and control groups (
The mean left atrial diameter corrected according to the body surface area in the subclinical hypothyroidism (SH) patients was statistically significantly higher when compared to the healthy controls (2.1 cm/m2 versus 1.8 cm/m2,
Table
Pulsed wave Doppler-derived parameters.
SH | Control | ||
---|---|---|---|
E vel (cm/sn) | 84 (0.14) | 86 (0.13) | 0.67 |
A vel (cm/sn) | 64 (0.16) | 60 (0.11) | 0.37 |
E/A | 1.39 (0.33) | 1.44 (0.15) | 0.58 |
DT (msn) | 178.86 (41.98) | 169.26 (23.68) | 0.37 |
ET (msn) | 297.68 (21.10) | 298.20 (19.83) | 0.93 |
MPI | 0.27 (0.08) | 0.22 (0.06) |
E vel: E wave velocity; A vel: A wave velocity; DT: Deceleration time (of mitral E wave); ET: Ejection time; MPI: Myocardial performance index.
All results are expressed as mean values and numbers in brackets denote Standard Deviation.
Tissue Doppler echocardiography parameters are given in Table
Tissue Doppler-derived parameters.
SH | Control | ||
---|---|---|---|
Septal S | 7.68 (0.97) | 8.14 (0.99) | 0.14 |
Lateral S | 9.52 (1.73) | 9.42 (1.50) | 0.83 |
Anterior S | 8.83 (1.94) | 8.32 (0.90) | 0.29 |
Inferior S | 8.21 (1.13) | 8.49 (0.96) | 0.40 |
Septal E′ | 11.45 (3.24) | 13.24 (2.44) | |
Lateral E′ | 15.70 (3.97) | 16.89 (2.74) | 0.27 |
Anterior E′ | 13.20 (3.87) | 15.65 (2.43) | |
Inferior E′ | 13.47 (3.77) | 14.94 (2.10) | 0.13 |
Septal A′ | 9.15 (2.28) | 8.65 (1.39) | 0.40 |
Lateral A′ | 10.14 (2.74) | 9.85 (1.61) | 0.67 |
Anterior A′ | 9.70 (2.94) | 9.22 (1.24) | 0.49 |
Inferior A′ | 9.92 (2.08) | 9.25 (1.45) | 0.24 |
Mean E′ | 13.70 (3.39) | 15.12 (2.26) | 0.12 |
Mean A′ | 9.63 (2.27) | 9.24 (0.97) | 0.47 |
E′/A′ | 1.52 (0.58) | 1.63 (0.25) | 0.43 |
E/E′ | 6.13 (1.12) | 5.09 (1.08) | 0.15 |
All results are expressed as mean values and numbers in brackets denote Standard Deviation.
Table
Response of 2D and M-Mode echocardiographic parameters to thyroid hormone replacement therapy.
Before treatment | After treatment | ||
---|---|---|---|
LVEF (%) | 71,72 (4,61) | 72,77 (4,67) | 0,50 |
DIASTOLIC SEPTUM THICKNESS (cm) | 0,97 (0,12) | 0,93 (0,10) | 0,21 |
DIASTOLIC POSTERIOR WALL THICKNESS (cm) | 1,0 (0,13) | 0,92 (0,11) | |
LV EDD (cm) | 4,61 (0,34) | 4,64 (0,40) | 0,71 |
LV ESD (cm) | 2,92 (0,26) | 2,95 (0,34) | 0,70 |
LVMI (gr/m2) | 77,34 (2,14) | 77,21 (2,27) | 0,43 |
LVEF: Left ventricular ejection fraction; LVEDD: Left ventricular end-diastolic diameter; LVESD: Left ventricular end-systolic diameter; LVMI: Left venticular mass index.
All results are expressed as mean values and numbers in brackets denote Standard Deviation.
Relative wall thickness (RWT), which is the basis for diagnosis of concentric remodeling, was 0.43 at baseline in SH patients, slightly above the cut-off value of 0.42. After 3 months of THRT, RWT was nomalized (0.39).
Pulsed wave Doppler-derived conventional diastolic indices did not differ before and after treatment.
As seen in Table
The response of tissue Doppler-derived parameters to thyroid hormone replacement therapy.
Before treatment | After treatment | ||
---|---|---|---|
SEPTAL S VELOCITY (cm/sn) | 7,68 (0,97) | 7,63 (0,99) | 0,85 |
LAT S VELOCITY (cm/sn) | 9,52 (1,73) | 8,86 (1,19) | 0,11 |
ANT S VELOCITY (cm/sn) | 8,83 (1,94) | 8,17 (1,10) | 0,16 |
INF S VELOCITY (cm/sn) | 8,21 (1,13) | 8,22 (0,83) | 0,97 |
SEP E′ VELOCITY (cm/sn) | 11,45 (3,24) | 11,94 (2,89) | 0,45 |
LAT E′ VELOCITY (cm/sn) | 15,70 (3,97) | 16,43 (3,12) | 0,19 |
ANT E′ VELOCITY (cm/sn) | 13,20 (3,87) | 14,53 (2,75) | |
INF E′ VELOCITY (cm/sn) | 13,47 (3,77) | 14,38 (2,95) | 0,14 |
SEP A′ VELOCITY (cm/sn) | 9,15 (2,28) | 8,59 (1,78) | 0,25 |
LAT A′ VELOCITY (cm/sn) | 10,14 (2,74) | 9,72 (1,66) | 0,36 |
ANT A′ VELOCITY (cm/sn) | 9,70 (2,94) | 9,17 (2,19) | 0,40 |
INF A′ VELOCITY (cm/sn) | 9,92 (2,08) | 9,40 (1,34) | 0,14 |
MEAN E′ VELOCITY (cm/sn) | 13,70 (3,39) | 14,45 (2,52) | 0,13 |
MEAN A′ VELOCITY (cm/sn) | 9,63 (2,27) | 9,19 (1,35) | 0,22 |
E′/A′ | 1,52 (0,58) | 1,60 (0,39) | 0,31 |
E/E′ | 6,13 (1,12) | 6,2 (1,01) | 0,63 |
All results are expressed as mean values and numbers in brackets denote Standard Deviation.
The necessity of thyroid hormone replacement in SH is controversial [
It has been established that SH also has cardiovascular manifestations. Rotterdam study reported that SH is a strong independent predictor for aortic atherosclerosis and myocardial infarction in elderly women. It was shown in this study that positive thyroid antibodies were associated with increased cardiovascular risk only when accompanied by SH [
In a recent reanalysis of the Whickham survey, an association was found between incident ischemic heart disease (IHD) events and IHD-related mortality with SH over the 20 years of follow-up. Treatment of SH with levothyroxine seems to attenuate IHD-related morbidity and mortality, and the authors conclude that properly designed controlled trials of treatment of SH are required to clarify this issue [
Vitale et al. were the first to report myocardial dysfunction in SH patients using tissue Doppler echocardiography [
In the present study, other potential causes of diastolic dysfunction such as hypertension, obesity, and coronary artery disease were excluded. Left ventricular ejection fraction and cavity diameters were not different among the groups.
Mean left ventricular posterior wall thickness and interventricular septum thickness were slightly yet significantly increased in SH. However, left ventricular mass index was not different between the groups. Echocardiographic follow-up three months after the achievement of euthyroid state displayed a mild yet significant decrease in left ventricular posterior wall thickness. These findings suggest that SH may cause concentric remodeling rather than hypertrophy, and concentric remodeling may be reversible with THRT. Mild left ventricular hypertrophy is an established feature of cardiovascular involvement of overt hypothyroidism [
The mean left atrial diameter corrected according to the body surface area in the subclinical hypothyroidism (SH) patients was statistically significantly higher when compared to the healthy controls (2.1 cm/m2 versus 1.8 cm/m2,
Our study did not show any difference in terms of pulsed-wave Doppler-derived diastolic indices such as E and A velocities, E/A ratio, and E wave deceleration time between the SH and control groups. This may be due to the fact that diastolic dysfunction is relatively mild in SH and conventional indices may not be sensitive enough to detect this degree of dysfunction.
Myocardial performance index (MPI), calculated by dividing the sum of isovolumetric contraction time (ICT) and isovolumetric relaxation time (IVRT) by aortic ejection time (ET), is a parameter which displays both systolic and diastolic (global) performance of the ventricle. Mean MPI was 0.27 ± 0.08 in the patient group and 0,22 ± 0,06 in the control group
We observed no change in MPI after thyroid hormone replacement therapy in subjects with SH. In a study by Yazici et al. [
On the other hand, evaluation of regional diastolic function employing tissue Doppler echocardiography (TDE) revealed significantly decreased mitral annular E′ velocities in septal and anterior localizations in the SH group compared to euthyroid controls. Regional diastolic dysfunction in SH had been reported by Vitale et al. previously [
The main limitations of this study are the small sample size and relatively short follow-up period. The exclusion of patients older than 60 years may also be considered as a limitation.
We conclude that SH is associated with mild left ventricular diastolic dysfunction, which is reversible with thyroid hormone replacement therapy. While it is generally agreed upon that therapy is indicated for patients in whom serum TSH levels are greater than 10 mIU/mL, initiating thyroid hormone replacement therapy for patients whose TSH levels are between 4,2 and 10 mIU/mL is controversial. In this study, improvement of left ventricular diastolic function in SH with thyroid hormone replacement therapy was shown using tissue Doppler. This finding may contribute to justification of treating patients whose TSH levels are between 4,2 and 10 mIU/mL, considering that diastolic dysfunction has been consistently reported in this patient group. Findings of this study also suggest that TDE may be a sensitive and useful tool to detect diastolic dysfunction and its response to thyroid hormone replacement therapy in patients (especially women) with SH.
There is no financial support for this research.
G. Erkan and S. Karaahmetoglu screened and recruited the patients. G. Erkan also contributed in study design, implementation, and the preparation of the manuscript. M. Cemri and A. F. Erkan performed the echocardiographic examinations. A. F. Erkan also contributed in analysis and preparation of the manuscript. A. Cengel contributed in the study design and analysis. M. Cesur contributed in the study design and preparation of the manuscript.
All authours have no conflict of interest to disclose.