Evaluation of Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio in patients with subclinical hypothyroidism

Abstract

Background:

Prolongation of the peak-to-end interval of the T wave (Tp-e) has been reported as associated with ventricular arrhythmias. The aim of this study was to investigate the ventricular repolarization by using the Tp-e interval, Tp-e/QT ratio and Tp-e/ QTc ratio in patients with subclinical hypothyroidism (SH).

Methods:

We studied 56 volunteers: These were 28 patients with SH (mean age 45 ± 11 years) and 28 healthy subjects (mean age 34 ± 8 years). All basic biochemical parameters were analyzed and electrocardiograms (ECGs) were recorded. RR and QT intervals, QTc, Tp-e intervals and the Tp-e/QT and Tp-e/QTc ratios were calculated. The categorical and numerical variables were compared using the chi-square test and independent t test, respectively. Correlations were analyzed using the Spearman and Pearson correlation tests.

Results:

We found no difference between QT and QTc intervals between groups. In the subjects with SH, the Tp-e intervals (87 ± 5 ms, 66 ± 5 ms, p < 0.01), Tp-e/ QT ratio (0.23 ± 0.03, 0.18 ± 0.01, p < 0.01) and Tp-e/QTc ratio (0.21 ± 0.02, 0.16 ± 0.01, p < 0.01) were increased compared with healthy subjects. We also found positive correlations between levels of thyroid stimulating hormone (TSH) and Tp-e (r = 0.72, p < 0.01), Tp-e/ QT ratio (r = 0.67 p < 0.01), Tp-e/ QTc ratio (r = 0.68, p < 0.01). In the subjects with SH, Left Ventricular Myocardial Performance Index (LV-MPI) was increased compared with the healthy subjects (0.64 ± 0.08, 0.59 ± 0.09, p = 0.066) although it was not significant.

Conclusions:

Compared with healthy subjects, patients with SH demonstrated longer Tp-e intervals, and higher Tp-e/QT and Tp-e/QTc ratios. TSH levels were positively correlated with Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio.

Introduction

Subclinical hypothyroidism (SH) is defined as normal free triiodothyronine (fT3) and free thyroxine (fT4) levels with an isolated elevation of serum thyroid stimulating hormone (TSH) levels (>4 mIU/l), while the clinical findings of overt hypothyroidism are absent. The incidence of SH is high, with reported values ranging from 1% to 10%.¹ Although its effects on the cardiovascular system are well known, it is not yet clear at which levels TSH hormone replacement treatment should be initiated in patients with SH.^2–4

Myocardial repolarization can be evaluated using the QT interval (QT), corrected QT interval (QTc), QT dispersion and transmural repolarization dispersion on electrocardiograms (ECGs). Tp-e interval, defined as the distance between the peak and the end points of the T wave, is considered as the transmural dispersion index of ventricular repolarization.⁵ In addition, the Tp-e/QT and Tp-e/QTc ratios can be used as predictors of ventricular arrhythmogenesis.⁶ QT interval dispersion (QTd) is an indicator of the heterogeneity of ventricular repolarization and is used for the evaluation of cardiovascular risk.⁷ An increased QTd is associated with malign ventricular arrhythmias and sudden cardiac death.⁸

Hypothyroidism prolongs the duration of the action potential and the QT interval.⁹ In the hypothyroid population, correlations between TSH levels and increased QT and QTd have been demonstrated in previous studies.¹⁰ In addition, correlations between TSH levels and increased QT and QTc have been found in patients with SH.¹¹ However, it is not known what potential changes may occur in the Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio in the latter patients. Although recent studies have evaluated ventricular repolarization in this population using the QT interval, no study has investigated the effect of SH on the Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio in comparison with a control group. In this study, we aimed to evaluate ventricular repolarization in patients with SH using the Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio.

Subjects and methods

Study population

The study population consisted of 56 volunteers who were admitted to our outpatient clinic between January and March 2016. A total of 28 healthy control subjects (mean age 34 ± 8 years, 19 females) and 28 patients with SH (mean age 45 ± 11 years, 23 females) were enrolled. The patients with SH were not taking any thyroid hormone replacement. The exclusion criteria were coronary artery disease, cardiomyopathy, severe valvular heart disease, any type of arrhythmia, hypertension, diabetes mellitus, chronic lung disease, liver or kidney failure, serum electrolyte abnormalities including hypocalcemia or hypercalcemia, a history of pacemaker or cardioverter defibrillator implantation, the patients with SH using thyroid-hormone replacement, bradycardia (<60 beats/minute), tachycardia (>100 beats/minute), bundle branch block on the ECG, ST-T wave changes and the use of any drugs affecting the cardiac conduction system, including anti-arrhythmics. The study was approved by the Ethics Committee of Sisli Hamidiye Etfal Education and Research Hospital (Ethics Committee No: 593/08.12.2015) and informed consent was obtained from each participant.

Measurements

The arterial blood pressure of all participants was measured using a standard manual sphygmomanometer, with the subject seated and after a 15-minute resting period. At the same time, the pulse rate (beats/minute) was measured from the radial artery during 1 minute and recorded. All participants were normotensive, with a blood pressure <140/90 mmHg on at least two measurements. Venous blood samples were obtained in the morning after a 12-hour fast. The serum TSH, fT3, and fT4 levels were determined by the chemiluminescent microparticle immunoassay method using an Abbott-Architect analyzer (Abbott Laboratories, Abbott Park, III. USA). Secretory capacity of the thyroid gland (SPINA-GT), sum activity of peripheral deiodinases (SPINA-GD) and Jostel’s TSH index (TSHI) were calculated using SPINA Thyr 4.0.1.778 software. Jostel’s TSH index (TSHI = log TSH + 0.1345 × fT4) was used for assessment of thyrotropic pituitary function. The resting ECG (Nihon Kohden 1250 ECG Machine) was recorded at a paper speed of 50 mm per second, a frequency of 512 Hz, and a segment length of 10 seconds. Participants’ ECGs were examined manually. The QT interval was derived from a minimum of six measurements (at least three of them from chest leads). All measurements were performed by the same researcher and because of the well-known difficulties with the definition of the end of T wave, they were reanalyzed by two independent observers. All researchers and observers were blinded to the group assignation.

The RR interval, QRS duration, QT interval, and Tp-e interval were measured manually. Tp-e/QT ratio was calculated from these measurements. The Tp-e interval was measured from the peak of the T wave to the end of the T wave, defined as the intersection of the tangent to the downslope of the T wave with the isoelectric line. The QT interval was defined as the time from the onset of the QRS to the point at which the T wave returned to baseline. The QTc interval was calculated using Bazett’s formula. The Tp-e/QT and Tp-e/QTc ratios were calculated based on the values derived.

Standard M-mode and two-dimensional echocardiography and Doppler blood flow measurements were performed in agreement with the American Society of Echocardiography guidelines.¹² Echocardiographic measurements were performed in participants of the study with Philips iE33 xMATRIX echocardiography device with a 3 MHz transthoracic transducer in the left lateral decubitus position, and all images were saved onto digital media.

Left ventricular (LV) diastolic function parameters were measured using conventional pulsed wave (PW) and continuous wave (CW) Doppler and tissue Doppler imaging. PW Doppler was performed in the apical 4-chamber view to obtain mitral inflow velocities for the assessment of LV filling. The sample volume was placed between the mitral leaflet tips at diastole, and mitral velocity recordings were obtained at a sweep speed of 50 mm/second, averaged over three consecutive cardiac cycles. The measures of mitral diastolic filling included the E-wave and A-wave velocities, the E/A ratio, and the deceleration time of the early filling velocity. The cursor of the CW Doppler was placed in the LV outflow tract to simultaneously display the end of aortic ejection and the onset of mitral inflow to measure and record the isovolumetric relaxation time (IVRT), which is the interval from the closing of the aortic valve to the opening of the mitral valve, and the isovolumetric contraction time (IVCT), which is the interval from the closing of the mitral leaflets to the opening of the aortic valve. The interval between the opening and closing of the aortic valve was measured as the LV ejection time (LVET). The LV myocardial performance index (LV-MPI) was then calculated from the formula LV-MPI = (IVCT + IVRT)/LVET.

Tissue Doppler imaging was performed in the apical four-chamber view to acquire mitral annular velocities. The sample volume was positioned 1 cm inside the septal and lateral insertion sites of the mitral leaflets and annular velocities were obtained at a sweep speed of 50 mm/second at end expiration. The parameters recorded were maximum systolic mitral annular myocardial rate (sm), early diastolic (e’) and late diastolic (a’) velocities, and the e’/a’ ratio. Septal and lateral e’ and a’ were averaged.

Statistical analysis

The descriptive statistics of the numerical variables obtained in the study are given as mean ± standard deviation (SD). The descriptive statistics of the categorical variables are given as numerical values and percentages. The correlations between the categorical variables were evaluated using the Chi-square test and Fisher’s exact test. The Shapiro–Wilk test was used to test the normality of the numerical variables. The independent t test was used for comparisons between groups regarding the means of the numerical variables, while the Mann–Whitney U test was used for the comparison of medians. The Pearson correlation test was used to evaluate the relationship between parametric continuous variables, while the Spearman correlation test was used for nonparametric continuous variables. As there was a significant difference between the groups with respect to age, the age variable was added to the model as a covariant and the data were reevaluated with the covariant analysis to nullify its effect on the other variables. The accepted limit of significance was p < 0.05 and all calculations were carried out using SPSS (PASW 18) software.

Results

A total of 56 subjects, 28 of whom were patients with SH and 28 of whom were healthy controls, were included in the study. As there was a significant difference between the ages of the patients and the control group, the covariant analysis was performed to nullify its effect on the other variables. Patients and controls were similar in terms of body mass index (BMI), smoking habits, systolic and diastolic blood pressure and biochemical parameters. LV echocardiographic parameters did not differ significantly between the groups. LV-MPI was higher, but not significantly, in the SH group compared with the control group (0.64 ± 0.08, 0.59 ± 0.09, p = 0.066). The baseline characteristics of the study and control groups are presented in Table 1. TSH levels were significantly higher in the SH group (7.26 ± 1.75, 1.87 ± 1.36, p < 0.01). SPINA-GT levels were higher in the control group (3.79 ± 1.80, 1.51 ± 0.19, p < 0.01) and TSHI levels were higher in the SH group (3.87 ± 0.36, 2.47 ± 0.61, p < 0.01). Thyroid function tests of the groups are presented in Table 2. There was no difference between the groups in the QT (p = 0.938) and QTc (p = 0.512) intervals. The Tp-e interval (87 ± 5 ms, 66 ± 5 ms, p < 0.01), Tp-e/QT ratio (0.23 ± 0.03, 0.18 ± 0.01, p < 0.01) and Tp-e/QTc ratio (0.21 ± 0.02, 0.16 ± 0.01, p < 0.01) were significantly higher in the SH group than in the control group. Electrocardiographic measurements of the groups are presented in Table 3. Furthermore, there were significant positive correlations between TSH and Tp-e interval (r = 0.72, p < 0.01) (Figure 1), Tp-e/ QT ratio (r = 0.67, p < 0.01) (Figure 1) and Tp-e/ QTc ratio (r = 0.68, p < 0.01) (Figure 2). FT₄ levels were found to be inversely correlated with Tp-e interval (r = −0.43, p < 0.01), Tp-e/ QT ratio (r = −0.36; p < 0.01) and Tp-e/QTc ratio (r = −0.39, p < 0.01) and FT₃ levels were also found to be inversely correlated with Tp-e interval (r = −0.39, p < 0.01), Tp-e/ QT ratio (r = −0.39, p < 0.01) and Tp-e/QTc ratio (r = −0.43; p < 0.01). There was a negatively significant correlation between SPINA-GT and Tp-e interval (r = −0.54, p < 0.01), Tp-e/ QT ratio (r = −0.49, p < 0.01) and Tp-e/QTc ratio (r = −0.48, p < 0.01). In addition, there was a positively significant correlation between TSHI and Tp-e interval (r = 0.68, p < 0.01) (Figure 2), Tp-e/ QT ratio (r = 0.63, p < 0.01) (Figure 3) and Tp-e/ QTc ratio (r = 0.64, p < 0.01) (Figure 3).

Table 1.

Demographic, biochemical and echocardiographic characteristics of the controls and the patients with subclinical hypothyroidism.

	Controls (n = 28)	SH (n = 28)	p
Age (year)	34 ± 8	45 ± 11	<0.01
Sex (male/female)	9/19	5/23	0.217
BMI (kg/m2)	25.6 ± 4.7	27.8 ± 5.7	0.443
Smoking	20/8	14/14	0.101
SBP (mmHg)	115 ± 15	122 ± 12	0.569
DBP (mmHg)	73 ± 8	76 ± 7	0.500
Cholesterol (mg/dl)	174 ± 39	197 ± 43	0.457
Triglycerides (mg/dl)	120 ± 93	163 ± 75	0.512
HDL (mg/dl)	50 ± 13	51 ± 11	0.768
LDL (mg/dl)	100 ± 35	119 ± 32	0.505
Creatinine (mg/dl)	0.8 ± 0.1	0.8 ± 0.2	0.683
Hemoglobin (g/dl)	13.7 ± 1.4	13.1 ± 1.7	0.467
Glucose (mg/dl)	90 ± 9	100 ± 26	0.786
LVEF (%)	69 ± 4	68 ± 4	0.555
E (cm/s)	82 ± 15.3	72.9 ± 17.1	0.695
A (cm/s)	63.8 ± 16.2	69.7 ± 11.2	0.518
DT (ms)	169 ± 28	175 ± 32	0.716
IVRT (ms)	91 ± 10.8	92.9 ± 10.1	0.534
IVCT (ms)	65.8 ± 12.9	73.2 ± 12.9	0.050
E/A ratio	1.35 ± 0.37	1.06 ± 0.27	0.203
LV-MPI	0.59 ± 0.09	0.64 ± 0.08	0.066
e’ (cm/s)	14.6 ± 3.4	12.1 ± 4.0	0.985
a’ (cm/s)	9.1 ± 2.6	10.1 ± 2.4	0.518
e’/a’ ratio	1.73 ± 0.65	1.26 ± 0.47	0.309
E/e’ ratio	5.83 ± 1.34	6.38 ± 1.61	0.929

Values are presented as mean ± standard deviation. BMI, body mass index; SBP, systolic blood pressure; DSP, diastolic blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LVEF, left ventricular ejection fraction; E, peak early filling velocity; A, late diastolic filling velocity; DT, E wave deceleration time; IVRT, isovolumetric relaxation time; IVCT, isovolumetric contraction time; LV-MPI, left ventricular myocardial performance index; e’, early diastolic mitral annular velocity; a’, late diastolic mitral annular velocity.

Table 2.

Thyroid function tests of the controls and the patients with subclinical hypothyroidism.

	Controls (n = 28)	SH (n = 28)	p
TSH	1.87 ± 1.36	7.26 ± 1.75	<0.01
FT4	1.20 ± 0.18	1.04 ± 0.19	0.02
FT3	3.35 ± 0.51	2.82 ± 0.49	0.06
SPINA-GT	3.79 ± 1.80	1.51 ± 0.19	<0.01
SPINA-GD	31.12 ± 6.44	28.48 ± 5.15	0.11
TSHI	2.47 ± 0.61	3.87 ± 0.36	<0.01

SH, subclinical hypothyroidism; TSH (0.27–4.2 µIU/ml), thyroid stimulating hormone; FT4 (0.8–1.67 ng/dl), Free T4; FT3 (1.64–4.42 pg/ml), Free T3; SPINA-GT (1.41–8.67 pmol/second), thyroid’s secretory capacity; SPINA-GD (20–40 nmol/second), the sum activity of peripheral deiodinases; TSHI (1.3–4.1), Jostel’s TSH index; values are presented as mean ± standard deviation.

Table 3.

Electrocardiographic measurements of the controls and the patients with subclinical hypothyroidism.

	Controls (n = 28)	SH (n = 28)	p
Tp-e (ms)	66 ± 5	87 ± 5	<0.01
QT (ms)	363 ± 21	377 ± 32	0.938
QTc (ms)	406.5 ± 19.3	413.4 ± 19.4	0.512
Tp-e/QT	0.18 ± 0.01	0.23 ± 0.03	<0.01
Tp-e/QTc	0.16 ± 0.01	0.21 ± 0.02	<0.01

Values are presented as mean ± standard deviation.

SH, subclinical hypothyroidism.

Figure 1.

Correlation between Tp-e and TSH (A).

Correlation between Tp-e /QT ratio and TSH (B).

Figure 2.

Correlation between Tp-e/QTc and TSH (C).

Correlation between Tp-e and Jostel’s TSH index (D).

Figure 3.

Correlation between Tp-e/QT and Jostel’s TSH index (E).

Correlation between Tp-e/QTc and Jostel’s TSH index (F).

Discussion

The present study showed that the Tp-e interval, and the Tp-e/QT and Tp-e/QTc ratios were prolonged in patients with SH when compared with the control group. Moreover, we found positive correlations between TSH levels and Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio. The Tp-e interval and Tp-e/QT ratio are well-known electrocardiographic markers of an increase in the dispersion of ventricular repolarization.^5,6 Thus, the fact that the patients with SH in this study had a longer Tp-e interval and higher Tp-e/QT and Tp-e/QTc ratios is important. We have shown for the first time that these parameters differ significantly between SH patients and controls. These differences may contribute to an increased prevalence of ventricular arrhythmias in patients with SH as a result of a greater heterogeneity of ventricular repolarization.

Many studies have shown that increased dispersion of repolarization might predispose to ventricular arrhythmias.^13–15 Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio may be used as electrocardiographic indexes of ventricular arrhythmogenesis and sudden cardiac death.¹⁶ Sicouri and colleagues¹⁷ demonstrated an association between prolongation of the Tp–e interval and ventricular arrhythmogenesis. The earliest part of repolarization is repolarization of the epicardial action potential, which coincides with the peak of the T wave. The last part of repolarization is repolarization of the M cells which coincides with the end of the T wave. Thus, the QT interval and the Tp-e interval are indexes of the transmural dispersion of repolarization.¹⁸ Previous studies reported that prolongation of the Tp-e interval was associated with increased mortality in patients with Brugada syndrome, long-QT syndrome, hypertrophic cardiomyopathy and myocardial infarction.^13–15

As far as we know, there is no other study in the literature concerning the association between SH and Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio, though a recent study demonstrated that SH can alter the autonomic modulation of heart rate and cause increased heterogeneity of ventricular recovery times.¹⁹

Bakiner and colleagues¹¹ demonstrated that QT and QTc intervals are prolonged in SH patients and that a return of serum TSH levels to values within the reference range resulted in QTc normalization. In our study, the QT and QTc intervals did not differ between the SH and control groups. However, we found that Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio were increased in patients with SH.

LV systolic function is normal at rest but impaired during exercise in patients with SH when compared with euthyroid controls.²⁰ Exercise-induced systolic dysfunction has been attributed to diastolic dysfunction at rest; the impairment of LV relaxation may lead to impaired ventricular filling and thus systolic dysfunction that becomes manifest only during exercise.²¹ IVRT is prolonged and PW Doppler-derived transmitral A-wave velocity is increased in SH. It has been shown that these findings of diastolic dysfunction are normalized after fT₄ replacement therapy.²²

LV-MPI, a sensitive parameter that expresses overall LV function, is increased in patients with SH.^{23, 24} Sauer and colleagues²⁵ showed that increased Tp-e is associated with both resting and exercise- induced diastolic dysfunction, while electromechanical coupling may reflect a pathophysiological link between the transmural dispersion of repolarization and abnormal mechanical myocardial relaxation. In our study, diastolic parameters did not differ between the SH and control groups. However, LV-MPI was higher in SH patients even though the difference was nonsignificant.

We have shown for first time that the Tp-e interval is prolonged and the Tp-e/QT ratio and Tp-e/QTc ratio are increased in patients with SH, and that there is a positive correlation between Tp-e interval and TSH. Further studies are required to determine the relation between Tp-e interval, Tp-e/QT ratio, Tp-e/QTc ratio, and ventricular arrhythmias in patients with SH.

Limitations

The most important limitation of our study is the small number of patients. Another limitation is that we did not assess the association between ventricular arrhythmias and Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio, since the study population could not be followed up prospectively for episodes of ventricular arrhythmias. Large-scale prospective studies are needed to determine the predictive value of a prolonged Tp-e interval and increased Tp-e/QT and Tp-e/QTc ratios in this population. Our results may contribute to elucidating the pathophysiological mechanisms of the increased prevalence of ventricular arrhythmias by indicating an increase in the heterogeneity of ventricular repolarization in these patients.

Conclusion

This study showed that SH is associated with a prolonged Tp-e interval and increased Tp-e/QT and Tp-e/QTc ratios. Furthermore, TSH levels are positively correlated with the Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio.