10 November 2013: Clinical Research
Left and right ventricular structure and function in subclinical hypothyroidism: The effects of one-year levothyroxine treatment
Sanja Ilic ABCDEF , Marijana Tadic ABCDEF , Branislava Ivanovic ADF , Zorica Caparevic ABF , Bozo Trbojevic AD , Vera Celic ABCG
DOI: 10.12659/MSM.889621
Med Sci Monit 2013; 19:960-968
Abstract
BACKGROUND: The aim of this study was to investigate left ventricular (LV) and right ventricular (RV) structure, function, and mechanics in patients with subclinical hypothyroidism (SHT), and to evaluate the effect of a 1-year levothyroxine treatment.
MATERIAL AND METHODS: We compared 45 untreated women with subclinical hypothyroidism and 35 healthy control women matched by age. All the subjects underwent laboratory analyses, which included a thyroid hormone levels (free T3, free T4, and TSH) test, and a complete 2-dimensional echocardiographic study. All the SHT patients received levothyroxine therapy and were followed for a year after euthyroid state was achieved.
RESULTS: The LV mass index in the SHT participants before and after replacement therapy was significantly higher than in controls. In the SHT patients before the treatment, LV diastolic function and global function estimated by the Tei index were significantly impaired, whereas the LV systolic function was decreased. The results show that LV mechanics was significantly impaired in the SHT patients at baseline. Additionally, the SHT participants before levothyroxine substitution had increased RV wall thickness and significantly impaired RV diastolic and global function in comparison with the controls or the SHT subjects after the treatment. Furthermore, RV mechanics was also significantly deteriorated in the SHT patients before the treatment.
CONCLUSIONS: Subclinical hypothyroidism significantly affected LV and RV structure, systolic, diastolic and global function, and LV and RV mechanics. Levothyroxine replacement therapy significantly improved cardiac structure, function, and mechanics in the SHT patients.
Keywords: Heart Ventricles - drug effects, Echocardiography, Hypothyroidism - drug therapy, Organ Size, Serbia, Thyroxine - therapeutic use, Ventricular Function - drug effects
Background
Thyroid hormones have significant influence on the cardiovascular system [1]. Hypothyroidism is associated with impaired cardiac function [2]; studies have shown that subclinical hypothyroidism (SHT) and mild hypothyroidism are associated with left ventricular (LV) dysfunction, especially diastolic dysfunction [3–8], but the mechanisms of this relationship are still insufficiently investigated. Although researchers revealed that substitution therapy with levothyroxine in the SHT patients could improve LV function and cause reversion of LV diastolic dysfunction [9–12], many controversies remain about the favorable influence of therapy on LV remodeling.
The impact of thyroid hormones on right ventricular (RV) structure and function, especially in the SHT patients, is still unknown. The RV has long been considered as an “insignificant” heart chamber, as long as studies showed that RV hypertrophy and dysfunction are related with cardiovascular morbidity and mortality [13,14]. However, because of its complex geometry, the RV could be very difficult to assess echocardiographically, which is why cardiac MR has long been considered as a gold standard for RV imaging. The estimation of RV function and mechanics became available and reliable after the introduction of new echocardiographic tools such as tissue Doppler and speckle tracking imaging. A few studies have shown that RV remodeling, particularly RV diastolic dysfunction, occurs parallel to LV changes, and that levothyroxine therapy also has favorable influence on reversibility of RV diastolic dysfunction [15,16].
To our knowledge, ours the first study to use 2-dimensional speckle tracking imaging to assess the effect of SHT and levothyroxine replacement therapy on LV and RV mechanics. In the present study, we investigated LV and RV structure, function, and mechanics in SHT patients and evaluated the effect of replacement therapy on LV and RV remodeling.
Material and Methods
ECHOCARDIOGRAPHY:
Echocardiographic examination was performed by using a Vivid 7 ultrasound machine (GE Healthcare, Horten, Norway) equipped with a 2.5 MHz transducer with harmonic capability.
STANDARD TWO-DIMENSIONAL (2DE) ECHOCARDIOGRAPHIC EXAMINATION:
The values of all 2DE parameters were obtained as the average value of 3 consecutive cardiac cycles. The LV end-systolic and end-diastolic (LVEDD) diameters, the left ventricle posterior wall (PWT), and interventricular septum thickness were determined according to the current recommendations [17]. Relative wall thickness was calculated as (2xPWT)/LVEDD. Left ventricular ejection fraction (EF) was estimated by using the biplane method. Left ventricular mass was calculated by using the Devereux formula [18], and was indexed for height powered to 2.7.
Transmitral Doppler inflow and tissue-pulsed Doppler were obtained in the apical 4-chamber view. Pulsed Doppler measurements included the transmitral early diastolic peak flow velocity (E), late diastolic flow velocity (A), their ratio (E/A), and E velocity deceleration time (DT) [19]. Tissue Doppler imaging was used to obtain left ventricular myocardial velocities in the apical 4-chamber view, with a sample volume placed at the septal segment of the mitral annulus during early and late diastole (e’ and a’) and systole (s). Using tissue Doppler, we also determined early diastolic velocity across a lateral segment of the mitral annulus and computed the average early diastolic relaxation velocity (e’av) of the septal and lateral mitral annulus; this was used for further calculation of the E/e’av ratio.
The parameters necessary for calculating the Tei index were obtained by the tissue Doppler in the apical 4-chamber view. A 2-mm sample volume was placed at the lateral corner of the mitral annulus. Isovolumic contraction time (IVCT) and isovolumic relaxation time (IVRT) were measured from the end of the mitral annular velocity pattern to the onset of the systolic wave, and from the end of the systolic wave to the onset of the mitral annular velocity pattern, respectively. The ejection time (ET) was defined as the duration of the left ventricle outflow Doppler velocity profile. The Tei index was then calculated according to the formula: Tei index = (IVCT + IVRT)/ET [20].
TWO-DIMENSIONAL LEFT VENTRICULAR STRAIN:
2DE strain imaging was performed by using 3consecutive cardiac cycles of 2DE LV images in apical (long-axis 4-chamber view) [21]. The frame rate ranged between 50 and 70Hz. A commercially available software, 2DE Auto LVQ software (EchoPAC 110.1.2, GE-Healthcare, Horten, Norway), was used for 2DE strain analysis. The 2DE longitudinal strain and strain rate were calculated by averaging all 6 values of the regional peak longitudinal strain obtained in 4-chamber apical view. We separately estimated peak longitudinal strain of the LV, interventricular septum, and LV lateral wall.
RIGHT VENTRICLE AND ATRIUM:
The RV internal end-diastolic diameter was measured in M-mode in the parasternal long-axis view [22]. RV end-diastolic thickness was measured in the subcostal view [22]. Two-dimensional RV volumes and ejection fraction were calculated by using the modified Simpson’s rule [22]. The right atrial (RA) diameters were measured in the apical 4-chamber view at the ventricular end-systole [22].
Pulsed Doppler measurements across the tricuspid annulus included early and late diastolic flow velocity, their ratio (E/At), and deceleration time (DTt). Tissue Doppler imaging was used to obtain the RV myocardial velocities in the apical 4-chamber view with a sample volume placed at the lateral segment of the tricuspid annulus [22]. Acquisition was performed at end-expiration during quite breathing. RV global systolic function was assessed as the tricuspid annular plane systolic excursion (TAPSE) [22].
The parameters necessary for calculation of the Tei index of the right ventricle were obtained by the tissue Doppler in the apical 4-chamber view. The RV Tei index was calculated similarly as for the LV, according to the current guidelines [22].
RV systolic blood pressure (SPAP) was assessed in a subset of patients with minimal/mild tricuspid regurgitation.
TWO-DIMENSIONAL RIGHT VENTRICULAR STRAIN:
Two-dimensional strain imaging was performed by using 3 consecutive cardiac cycles in the apical 4-chamber view [22]. The frame rate ranged between 60 and 80 frames/s. EchoPAC 110.1.2 (GE-Healthcare, Horten, Norway) commercially available software was used for the 2DE strain analysis. Longitudinal peak strain was the variable used for evaluation of systolic function and contractility. We separately estimated peak strains of the RV and free wall.
STATISTICAL ANALYSIS:
Normal distribution of all variables was verified using the Kolmogorov-Smirnov test. Continuous variables are presented as mean ± standard deviation (SD) and were compared by using the 2-tailed t-test. Comparisons between the controls and the patients were performed by an independent-samples t-test. The data before and after L-thyroxin therapy were compared by a paired-samples t-test. The differences in proportions were compared by using the χ2 test. The correlations were determined by the Pearson rank correlation test. Inter- and intra-observer variability was examined by using Bland-Altmann analysis. We reported relation coefficients, 95% confidence intervals, and percent errors. P-value <0.05 was considered statistically significant.
Results
LEFT VENTRICULAR STRUCTURE, FUNCTION, AND MECHANICS:
The LV diameters and volumes were similar among the SHT patients and the controls (Table 2), but LV EF was lower in the SHT patients at baseline in comparison with the controls and the SHT patients after the therapy. IVS and PWT were significantly increased in the SHT patients before the therapy in comparison with the controls (Table 2). The LV mass index was significantly increased in the SHT patients before the therapy in comparison with the controls and the treated SHT subjects (Table 2). There was no important difference in LA diameter between the SHT patients and the controls. Transmitral E/A and e’/a’ ratios were decreased in the SHT patients before the therapy in comparison with the controls and the SHT patients after therapy. Additionally, DTm and IVRTm were significantly prolonged, and E/e’av was increased, in the SHT patients before the treatment (Table 2). Mitral s was significantly decreased, whereas the LV Tei index was increased in the patients before substitution therapy.
The LV global longitudinal strain was significantly decreased in the SHT patients at baseline in comparison with the controls and the SHT patients after the levothyroxine therapy (Table 2). Similar results were obtained for septal and LV lateral wall strain.
RIGHT VENTRICULAR STRUCTURE, FUNCTION, AND MECHANICS:
The RV diameter and volumes did not differ between the SHT patients and the controls, regardless of therapy; whereas RV wall thickness was significantly increased in the SHT patients before the treatment (Table 3). Interestingly, RV EF assessed by the biplanes rule was lower in the SHT patients before the treatment in comparison with the controls.
The RA diameters were similar between the controls and the SHT patients (Table 3). Tricuspid E/A and e’/a’ ratio were decreased in the SHT patients before the therapy in comparison with the controls or with the SHT patients after the therapy. There was no difference in E/e’t, st, TAPSE, and SPAP between the SHT patients and the controls (Table 3). Global RV function obtained by the Tei index was significantly impaired in the SHT patients before the therapy in comparison with the SHT participants after the therapy or the controls (Table 3).
Longitudinal RV strain was decreased in the untreated SHT patients in comparison with treated SHT subjects or healthy volunteers (Table 3). Similar results were obtained for free wall strain (Table 3).
CORRELATION AND REGRESSION ANALYSES:
Considering the entire study population (the SHT patients before and after levothyroxine therapy, and controls), TSH level correlated with LV mass index (r=0.47, p<0.01), E/Am ratio (r=−0.32, p<0.01), E/e’m ratio (r=0.37, p<0.01), LV Tei index (r=0.43, p<0.01), and LV global longitudinal strain (r=−0.51, p<0.01) among LV parameters; and also correlated with E/At ratio (r=−0.28, p=0.02), E/e’t (r=0.39, p<0.01), RV Tei index (r=0.4, p<0.01), and RV global longitudinal strain (r=−0.48, p<0.01) among RV parameters. However, after adjustment for LV mass index and RV wall thickness, in the whole study population, TSH was associated only with LV Tei index (β=0.39, p<0.01), LV longitudinal strain (β=−0.47, p<0.01), and RV longitudinal strain (β=−0.32, p=0.025).
INTEROBSERVER VARIABILITY:
Bland-Altman analyses was: Mitral E/e’av (95% CI ±2.7; percentage error 5.1%); LV Tei index (95% CI ±2.4; percentage error 4.5%); global LV strain (95% CI ±2; percentage error 4.1%); Tricuspid E/e’ (95% CI ±2.9; percentage error 5.5%); RV Tei index (95% CI ±3.1; percentage error 5.8%); Global RV strain (95% CI ±2.9; percentage error 5.4%).
INTRAOBSERVER VARIABILITY:
Bland-Altman analyses was: Mitral E/e’av (95% CI ±2.1; percentage error 4.1%); LV Tei index (95% CI ±1.8; percentage error 3.9%); Global LV strain (95% CI ±1.5; percentage error 3.4%); Tricuspid E/e’ (95% CI ±2.2; percentage error 4.7%); RV Tei index (95% CI ±2.4; percentage error 5.2%); Global RV strain (95% CI ±2.2; percentage error 4.6%).
Discussion
LIMITATIONS:
Our study has several limitations. Firstly, the relatively small number of patients could be a limitation to our study. Secondly, our investigation included only women (SHT is mostly seen in females, which is why we decided to include only women), which restricts our results to this population. Thirdly, the existence of coronary artery disease (CAD) was not excluded by coronary angiography; however, our study included young females without other cardiovascular risk factors and expected prevalence of CAD in this population is very low.
Conclusions
LV and RV structure and systolic, diastolic, and global function are impaired in SHT patients. LV and RV mechanics are also damaged in the SHT subjects. Impairments in LV and RV function and mechanics were reversed after adequate treatment with levothyroxine, whereas structural cardiac damage did not significantly improve. This shows that a longer time of treatment is probably needed to achieve this kind of improvement. TSH level correlates with LV and RV structure, diastolic and global function, and LV and RV mechanics. However, after adjustment for LV and RV hypertrophy, TSH was associated only with LV global function and LV and RV mechanics. Further longitudinal analyses with a greater number of patients are needed to validate the possible impact of LV and RV mechanical changes on morbidity and mortality in SHT subjects.
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