Academic Editor: Lee Stoner
Objective: Previous literature has suggested that the cardiovascular
risk factors associated with subclinical hypothyroidism (SCH) may be found in
subjects with euthyroidism, but research relating to increased arterial stiffness
(AS) and left ventricular (LV) diastolic dysfunction, which have been proven to
exist in patients with SCH, is limited in patients with euthyroidism. The aim of
this study was to investigate this. Methods: A total of 249
participants with euthyroidism were divided into two groups based on their
thyroid-stimulating
hormone (TSH) levels: Group A (TSH level ranging from 0.49 to 2.5 mIU/L, n =
170) and Group B (TSH level ranging from 2.5 to 4.91 mIU/L, n = 79). The
Cardiovascular Profiling System through brachial-ankle pulse wave velocity
(baPWV) was used to assess AS, and the LV function was evaluated using
Color-Doppler-Echocardiography. The Student’s unpaired t-test and
Pearson’s
Thyroid dysfunction presents as one of the most frequently occurring endocrine diseases [1]. It has been reported that the prevalence of subclinical hypothyroidism (SCH) ranges from 0.4%–20% [2, 3]. Previous studies have suggested that SCH may worsen many risk factors for cardiovascular disease (CVD), including hypertension, atherosclerosis, dyslipidemia, and abnormal endothelial function, and even result in CVD directly, such as pericarditis [4, 5].
Arterial stiffness (AS) appears to be an important risk factor for atherosclerosis and hypertension, as well as in the process of left ventricular (LV) diastolic dysfunction (DD) [6, 7]. A growing number of studies have indicated that patients with SCH exhibit increased AS and impaired LV diastolic function when compared with people with euthyroidism [8, 9].
As noted by the National Health and Nutrition Examination Survey III from the United States of America (USA), the thyroid-stimulating hormone (TSH) upper reference limits may be skewed by thyroperoxidase antibody (TPO-Ab)-negative individuals with occult autoimmune thyroid dysfunction [10]. This may signify that some people with mild hypothyroidism, including SCH, were not identified and were treated as if they had normal thyroid function. Therefore, people with TSH levels close to the upper limit may suffer from similar adverse effects as people with SCH.
The literature revealed that decreased endothelium-dependent vasodilatation (a sign of endothelial dysfunction), increased blood pressure (BP), and dyslipidemia were observed in people with high–normal TSH levels [11, 12, 13]. However, AS and LV DD in patients with high–normal TSH levels have not yet been adequately studied. Pulse wave velocity (PWV) is an index measuring AS by measuring the speed of a pulse wave along an artery. A higher PWV indicates increased stiffness in the arterial wall. Lambrinoudaki et al. [14] reported that a high–normal TSH level is associated with increased PWV, but the study subjects were all healthy postmenopausal women. Sandra et al. [15] suggested that cardiac diastolic abnormalities occur in patients with autoimmune thyroiditis when their serum TSH levels are still within the normal range, but the sample size was small (n = 45).
Subjects with high–normal TSH levels frequently progress to hypothyroidism later in life [16], and an evaluation of AS in this group was warranted. As a result, the present study was conducted to confirm the hypothesis that AS might be greater in people with high–normal TSH levels when compared with people with normal TSH levels, using a simple measurement, i.e., brachial-ankle PWV (baPWV) in a larger sample size. Indices indicating the LV diastolic function were analyzed.
This retrospective study was conducted to examine the AS and the LV diastolic function in subjects with euthyroidism. The participants were collected by searching the computerized database of patients hospitalized in the Department of Endocrinology and Metabolism at our hospital from December 2015 to November 2021. A total of 425 participants who underwent a measurement for AS were included for eligibility assessment. The district in which the study was conducted is not an iodine-deficient district.
The following exclusion criteria were used: (1) incomplete personal medical and
drug treatment history (missing vital data); (2) thyroid function not within the
normal range or a history of thyroid disease or therapy; (3) the use of drugs
known to affect thyroid function, e.g., metformin [17], glucocorticoids, dopamine
agonists, rexinoids, carbamazepine, and metyrapone [18]; (4) a previous history
of serious cardiovascular events, e.g., ischemic heart disease or heart failure,
stroke, or chronic obstructive peripheral arteriopathy (ankle–brachial index
A total of 249 subjects with euthyroidism were included in the final analysis.
To evaluate the AS and LV functions in relation to the TSH level, all patients
were grouped according to their serum TSH level into the normal TSH group (Group
A, 0.49 mIU/L
The study was conducted in accordance with the declaration of Helsinki and approved by our hospital ethical committee.
The anthropometric indices (body weight and height) were measured by
professional investigators using a standard protocol. Height was assessed to the
nearest 1 cm and body weight with light clothing to the nearest 0.1 kg. The body
mass index (BMI) was calculated as the body weight (kg) divided by the square of
the body height (m). Office BP was measured on the right arm using an automatic
BP monitor (J30 [
The venous blood samples were collected between 6 AM and 8 AM after fasting for
at least 10 h for the measurement of thyroid function, serum lipid profile, and
renal function parameters. Serum concentrations of TSH (normal range: 0.49–4.91
mIU/L), free triiodothyronine (fT
The Cardiovascular Profiling System Colin BP-203RPE III (Omron Healthcare Co.,
Ltd., Dalian, China) operated by well-trained observers was used to assess AS
noninvasively after rest for at least 10 min in a lying position in the
Endocrinology and Metabolism Department ward. Indices reflecting AS were
evaluated through the baPWV (normal range
The LV function was evaluated using color Doppler echocardiography (Epiq 7c, Philips Healthcare, Bothell, WA, USA) at rest by professional medical workers. The parameters involved were as follows: (1) interventricular septum thickness (IVST, cm) and the LV posterior wall thickness (LVPWT, cm); (2) the LV end-diastolic diameter (LVEDD, cm) and the LV end-systolic diameter (cm); (3) the left atrial diameter (cm); (4) the peak early diastolic phase (cm/s) and the late diastolic phase (cm/s) mitral inflow velocities; and (5) the LV ejection fraction (%).
The LV geometry was assessed with the LV mass index (LVMI) (g/m
LV (g) = 0.80
The LV mass was corrected for the body surface area (BSA) to obtain LVMI. The BSA was calculated from height (cm) and weight (kg) using the following equation from DuBois & DuBois [20]:
BSA (m
The RWT was calculated from LVPWT and LVEDD using the following equation [19]:
RWT = (2
The distribution of continuous variables was evaluated using the Shapiro–Wilk test. Data with a normal distribution or approximate normal distribution were expressed as mean and standard deviation, and other data were expressed as median and interquartile range. Categorical variables were presented as absolute numbers with percentages.
For comparing clinical characteristics, the baPWV, and the parameters of the LV
function between the two groups, the Student’s unpaired t-test was
performed for continuous variables and Pearson’s
We used two multivariate regression models. The first model included gender; age; BMI; resting heart rate; BP; antihypertensive, anti-diabetes, or statin treatment; and smoking status. The second model included variables that achieved statistical significance in the first model and the other remaining variables. Due to collinearity, Cr was not included in the model with eGFR. A dummy variable was set for transforming the categorical variable smoking status, and never having smoked was identified as the control. The results of the regression analysis were represented as odds ratios with 95% confidence intervals.
A p value
The clinical characteristics of the two groups are shown in Table 1. The gender,
age, BMI, resting heart rate, diastolic BP (DBP), serum lipid profile, blood
glucose, Cr, and UA were comparable between the groups (p
Normal TSH group (group A) (n = 170) | High-normal TSH group (group B) (n = 79) | p value | ||
Sex, male, n (%) | 105 (61.8%) | 47 (59.5%) | 0.732 | |
Age, years | 48.9 |
51.8 |
0.086 | |
BMI, Kg/m |
27.6 |
27.5 |
0.926 | |
Resting heart rate, beats/min | 74.4 |
75.5 |
0.514 | |
Office SBP, mmHg | 137.2 |
141.8 |
0.046 | |
Office DBP, mmHg | 83.9 |
85.0 |
0.505 | |
Antihypertensive treatment, n (%) | 151 (88.8%) | 67 (84.8%) | 0.372 | |
Anti-diabetes treatment, n (%) | 90 (52.9%) | 48 (60.8%) | 0.248 | |
Statin treatment, n (%) | 95 (55.9%) | 42 (53.2%) | 0.688 | |
Smoking, n (%) | 0.334 | |||
Never | 96 (56.5%) | 50 (63.3%) | ||
Previous | 11 (6.5%) | 7 (8.9%) | ||
Current | 63 (37.1%) | 22 (27.8%) | ||
TC, mmol/L | 5.1 |
5.1 |
0.590 | |
HDL-C, mmol/L | 1.2 |
1.1 |
0.386 | |
LDL-C, mmol/L | 3.0 |
2.9 |
0.546 | |
TGs, mmol/L | 2.0 |
2.1 |
0.537 | |
Cr, umol/L | 80.6 |
81.3 |
0.838 | |
eGFR, mL/min/1.73 m |
93.1 |
87.9 |
0.031 | |
UA, umol/L | 371.0 |
367.2 |
0.797 | |
FBG, mmol/L | 6.0 |
6.1 |
0.632 | |
TSH (mIU/L) | 1.5 |
3.4 |
||
fT3 (pmol/L) | 5.2 |
4.3 |
||
fT4 (pmol/L) | 11.4 |
11.1 |
0.207 | |
TPOAb (+), n (%) | 16 (9.4%) | 12 (15.2%) | 0.179 | |
Data with normal distribution or approximate normal distribution were expressed
as mean BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TGs, triglycerides; Cr, creatinine; eGFR, estimated glomerular filtration rate; UA, uric acid; FBG, fasting blood glucose; TSH, thyroid-stimulating hormone; fT3, free triiodothyronine; fT4, free thyroxine; TPOAb, thyroperoxidases antibody. TPOAb (+) was defined as serum TPOAb higher than their upper limit of reference ranges. |
The data relating to the baPWV and LV functions are illustrated in Table 2. When
compared with the normal group, the baPWV and A wave were significantly higher
and the E/A ratio was lower in the high–normal group (p
Normal TSH group (group A) (n = 170) | High-normal TSH group (group B) (n = 79) | p value | ||
baPWV (m/s) | ||||
left | 16.3 |
18.7 |
||
right | 16.0 |
18.0 |
0.001 | |
IVST (mm) | 10.3 |
10.5 |
0.319 | |
LVPWT (mm) | 9.6 |
9.5 |
0.823 | |
LVEDD (mm) | 46.4 |
46.7 |
0.616 | |
LVESD (mm) | 29.2 |
29.9 |
0.156 | |
LAD (mm) | 36.2 |
36.2 |
0.970 | |
E (cm/s) | 75.1 |
72.7 |
0.326 | |
A (cm/s) | 74.3 |
85.7 |
||
E/A | 1.1 |
0.9 |
0.001 | |
LVEF (%) | 65.4 |
64.3 |
0.090 | |
LVMI (g/m |
85.7 |
88.7 |
0.319 | |
RWT | 0.4 |
0.4 |
0.636 | |
Continuous data with normal distribution or approximate normal distribution were
reported as mean baPWV, brachial-ankle pulse wave velocity; IVST, interventricular septum thickness; LVPWT, left ventricular posterior wall thickness; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; LAD, left atrial diameter; E and A, peak early diastolic phase and late diastolic phase mitral inflow velocities; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; RWT, relative wall thickness. |
The Spearman’s correlation analysis showed baPWV was negatively correlated with
fT
The results of the association between the thyroid function and the baPWV
assessed by multiple logistic regression analysis are represented in Table 3. The
association between the fT
B | EXP(B) | 95% CI of EXP(B) | p value | ||||
TSH | |||||||
Model 1 | |||||||
baPWV (left) | –0.103 | 0.902 | 0.596 | 1.364 | 0.624 | ||
baPWV (right) | –0.329 | 0.720 | 0.450 | 1.152 | 0.170 | ||
Model 2 | |||||||
baPWV (left) | –0.171 | 0.843 | 0.567 | 1.252 | 0.397 | ||
baPWV (right) | –0.307 | 0.736 | 0.474 | 1.143 | 0.173 | ||
fT3 | |||||||
Model 1 | |||||||
baPWV (left) | –1.986 | 0.137 | 0.065 | 0.288 | |||
baPWV (right) | –1.927 | 0.146 | 0.066 | 0.323 | |||
Model 2 | |||||||
baPWV (left) | –1.900 | 0.150 | 0.074 | 0.303 | |||
baPWV (right) | –1.888 | 0.151 | 0.071 | 0.322 | |||
fT4 | |||||||
Model 1 | |||||||
baPWV (left) | –0.069 | 0.933 | 0.731 | 1.192 | 0.580 | ||
baPWV (right) | 0.067 | 1.069 | 0.820 | 1.395 | 0.621 | ||
Model 2 | |||||||
baPWV (left) | –0.031 | 0.969 | 0.769 | 1.222 | 0.791 | ||
baPWV (right) | 0.118 | 1.125 | 0.880 | 1.440 | 0.348 | ||
BaPWV TSH, thyroid-stimulating hormone; fT3, free triiodothyronine; fT4, free thyroxine; baPWV, brachial-ankle pulse wave velocity. Multivariable model 1 was adjusted for sex, age, BMI, resting heart rate, BP, antihypertensive/anti-diabetes/statin treatment and smoking situation; Multivariable model 2 was further adjusted for variables reaching statistical significance in the first model and all the rest variables. |
The multiple logistic regression analysis was conducted to further assess the
association between the baPWV and the E/A ratio, excluding the thyroid function
parameters (see Table 4). The results showed a significant association between
the baPWV and the E/A ratio in both models (p
B | EXP(B) | 95% CI of EXP(B) | p value | |||
baPWV (average) | ||||||
Model 1 | 0.213 | 1.237 | 1.079 | 1.419 | 0.002 | |
Model 2 | 0.240 | 1.272 | 1.108 | 1.459 | 0.001 | |
DBP | ||||||
Model 1 | 0.049 | 1.050 | 0.997 | 1.107 | 0.067 | |
Model 2 | 0.035 | 1.035 | 1.003 | 1.069 | 0.031 | |
E/A ratio The average level of left and right baPWV was calculated and included in the regression analysis. Thyroid function parameters were not included in the regression analysis. baPWV, brachial-ankle pulse wave velocity; DBP, diastolic blood pressure. Multivariable model 1 was adjusted for sex, age, BMI, resting heart rate, BP, antihypertensive/anti-diabetes/statin treatment and smoking situation. Multivariable model 2 was further adjusted for variables reaching statistical significance in the first model and all the rest variables. |
B | EXP(B) | 95% CI of EXP(B) | p value | |||
TSH | ||||||
Model 1 | 0.397 | 1.487 | 1.028 | 2.151 | 0.035 | |
Model 2 | 0.424 | 1.527 | 1.056 | 2.209 | 0.024 | |
fT3 | ||||||
Model 1 | –1.400 | 0.247 | 0.126 | 0.483 | ||
Model 2 | –1.266 | 0.282 | 0.150 | 0.529 | ||
fT4 | ||||||
Model 1 | 0.090 | 1.094 | 0.887 | 1.350 | 0.401 | |
Model 2 | 0.030 | 1.031 | 0.838 | 1.268 | 0.774 | |
baPWV (average) | ||||||
Model 1 | 0.049 | 1.050 | 0.904 | 1.221 | 0.522 | |
Model 2 | 0.088 | 1.091 | 0.940 | 1.267 | 0.250 | |
DBP | ||||||
Model 1 | 0.059 | 1.061 | 1.003 | 1.122 | 0.038 | |
Model 2 | 0.045 | 1.046 | 1.010 | 1.083 | 0.012 | |
E/A ratio Thyroid function parameters were included in the regression analysis. The average level of left and right baPWV was calculated and included in the regression analysis. TSH, thyroid-stimulating hormone; fT3, free triiodothyronine; fT4, free thyroxine; baPWV, brachial-ankle pulse wave velocity; DBP, diastolic blood pressure. Multivariable model 1 was adjusted for sex, age, BMI, resting heart rate, BP, antihypertensive/anti-diabetes/statin treatment and smoking situation; Multivariable model 2 was further adjusted for variables reaching statistical significance in the first model and all the rest variables. |
The main finding of the current study is that, when compared with the normal group, the baPWV was higher and the E/A ratio was lower in the high–normal group. We also provided evidence of the association between the thyroid function, increased AS, and LV DD in subjects with euthyroidism after adjustment for confounders.
The PWV is a critical index for evaluating AS and is widely used for the noninvasive assessment of early atherosclerosis [8], and baPWV could reflect the comprehensive PWV of the thoracic aorta, abdominal aorta, and part of the lower extremity arteries. In recent years, the concept of vascular failure was put forward by Japanese researchers [21]. Regarded as a new physiological diagnostic criterion for vascular failure, the optimal cutoff value of baPWV for predicting CVD was suggested to be 18 m/s [22].
A possible explanation for the elevated baPWV in the high–normal group follows.
First, it is well known that dyslipidemia is an important factor leading to
atherosclerosis and lipid homeostasis is influenced by thyroid hormones [23].
Previous studies have indicated correlations between TSH and dyslipidemia in
subjects with euthyroidism [12]. Second, Lekakis revealed that flow-mediated
vasodilatation is impaired in patients with high–normal serum TSH levels, which
would influence the elastic behavior of the arteries and
result
in increased AS [11, 24]. Third, as noted in the National Health and Nutrition
Examination Survey III [10], the prevalence of TPO-Ab increases with an increase
in the TSH level. However, even when TSH was
The present research proceeded to study the indices relating to the LV diastolic function. The PWV and AS increase under the influence of aging, hypertension, and atherosclerosis, which leads to an increase in the BP, pulse pressure, and LV load with hypertrophy and LV DD [25, 26]. An increase in the A wave and a decrease in E/A ratio might reflect early LV DD [27]. Studies on the diastolic function in patients with SCH have showed an increased A wave, reduced E/A ratio, and prolonged isovolumic relaxation time when compared with healthy subjects [28, 29]. The current study showed an increased A wave and a decreased E/A ratio in the high–normal TSH group, which is supported by the underlying mechanism and is in accordance with the study in patients with SCH.
The effect of the thyroid gland on the cardiovascular system is primarily
exerted through biologically active T
In the present study, fT
The association between cardiovascular events, cardiovascular mortality, and all-cause mortality with the baPWV has been proven in several studies, even after adjustments for the conventional risk factors, including age, gender, brachial SBP, history of use of antihypertensive agents, hemoglobin A1c, BMI, TC, HDL-C, and current smoking habits [34, 35]. The result of our analysis of the association between the baPWV and the E/A ratio without the thyroid function index was consistent with previous studies; however, the baPWV was not a significant variable after the thyroid function was included in the regression analysis. We are inclined to think that the effect of the thyroid on the pathophysiological process of LV DD was stronger in this investigation. Further studies are required.
This study had several limitations. First, it was a single-center study, and the applicability of these results to other centers needs to be confirmed. Causal relationships could not be established due to the nature of the observational study, and the influence of unknown confounding factors and potential reverse causality could not be excluded. A strictly designed prospective study may be required to verify the conclusions. Second, the blood samples were drawn between 6 AM and 8 AM after fasting for at least 10 hours, and the intra- and inter-assay coefficient variations were below 5%, but it is important to note that the influences of diurnal variation and assay variation could not be excluded completely. Another confounder that could not be neglected was the state of the menopausal stage, which was not included in the current study. Further study is needed. Third, previous literature revealed patients with SCH present LV DD at rest and systolic and DD under effort [36, 37]. Our investigation in subjects with high–normal TSH levels showed LV DD at rest, but the assessment of systolic and diastolic function under effort is required. Because the E/A ratio would be influenced by many factors and might be pseudo-normal in patients with DD, or even with severe DD, E/e’ ratio is an important indicator for evaluating the type of DD and should be employed in future in the analysis of correlation between the thyroid function, AS, and DD. Other more valuable indices including the left atrial function and volume should also be measured in future. Finally, replacement therapy was not included in the current investigation. Levothyroxine therapy appears to ameliorate AS and cardiac dysfunction, but age, the presence of CVD, and the presence of autoimmune antibodies may influence the decision to conduct replacement therapy in subjects with high–normal TSH levels and its curative effect [37, 38].
In conclusion, this study may signify the association between the thyroid function, increased AS, and LV DD in subjects with euthyroidism after adjustment for confounders. It would be helpful to evaluate the benefit of replacement therapy in people with high–normal TSH levels, especially in the presence of TPO-Ab in future large, multicenter, randomized trials.
All participants signed a document of informed consent.
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.
Conception and design of the research—LJY, HT, YZ. Acquisition of data—LJY, XQS. Analysis and interpretation of the data—LJY, HT, YZ. Statistical analysis—LJY, XQS. Obtaining financing—None. Writing of the manuscript—LJY, XQS. Critical revision of the manuscript for intellectual content—HT, YZ. All authors read and approved the final draft.
The study was conducted in accordance with the declaration of Helsinki and approved by the Beijing Anzhen Hospital Ethical Committee (No. 2022053X). Written informed consent was obtained from all participants.
Not applicable.
This research received no external funding.
The authors declare no conflict of interest.