|Year : 2019 | Volume
| Issue : 10 | Page : 1349-1355
Alterations of heart rate variability and turbulence in female patients with hyperthyroidism of various severities
C Tudoran, M Tudoran, M Vlad, M Balas, T Ciocarlie, F Parv
Department VII, Internal Medicine II, University of Medicine and Pharmacy Victor Babes, Timişoara, Romania
|Date of Acceptance||29-May-2019|
|Date of Web Publication||14-Oct-2019|
Dr. M Tudoran
University of Medicine and Pharmacy Victor Babes, Piaţa Eftimie Murgu 2, Timişoara 300041
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objective: The objective of the this study is to document the existence of statistically significant differences between parameters of heart rate variability (HRV) and heart rate turbulence (HRT), determined in women with overt hyperthyroidism (hT), compared to controls and to highlight their correlations with the level of thyroid hormones and the incidence of arrhythmias. Methods: We studied the HRV in time and frequency domain, and the HRT in a group of 113 women with overt hT, without other cardiovascular risk factors or comorbidities, admitted to the endocrinology clinic of our hospital, between 2012 and 2016. Depending on the severity and duration of hT and levels of thyroid hormones, the patients were assigned to three groups: mild and moderate forms, severe hT with thyrotoxicosis and persistent cases with a relapse of hT. We performed 24 h Holter monitoring in all patients. Results: HRV parameters in time domain (TD) were significantly depressed in patients comparing to controls. All patients had abnormal, positive values of turbulence onset (TO) with significant statistically differences (P < 0.0001) comparing to controls. Although positive, the values of turbulence slope (TS) decreased according to the severity of hT. Conclusion: Patients with hT had depressed values of HRV parameters in TD, correlated with the severity of the thyroid disease and with the incidence of arrhythmias. All patients presented pathological values of TO. TS values were positive, but lower compared to controls.
Keywords: Arrhythmias, heart rate turbulence, heart rate variability, hyperthyroidism
|How to cite this article:|
Tudoran C, Tudoran M, Vlad M, Balas M, Ciocarlie T, Parv F. Alterations of heart rate variability and turbulence in female patients with hyperthyroidism of various severities. Niger J Clin Pract 2019;22:1349-55
|How to cite this URL:|
Tudoran C, Tudoran M, Vlad M, Balas M, Ciocarlie T, Parv F. Alterations of heart rate variability and turbulence in female patients with hyperthyroidism of various severities. Niger J Clin Pract [serial online] 2019 [cited 2019 Dec 15];22:1349-55. Available from: http://www.njcponline.com/text.asp?2019/22/10/1349/269025
| Introduction|| |
Overt hyperthyroidism (hT) is a fairly common disorder, with a prevalence of about 0.5% in the general population. It affects predominantly women with an incidence of 5–10 times higher than in men. Its defining feature is a hyperkinetic status, similar to that induced by an excess of catecholamines, characterized by a sympathovagal imbalance. Because in patients with hT, normal or low levels of catecholamines have been determined in serum and urine, it was assumed that the myocardium presents an increased sensitivity to catecholamines, possibly associated with an increased β-receptor density. In these patients, the turnover of catecholamines is reduced. Thyroid hormones in excess alter the coupling of catecholamines to receptors, as well as their affinity for specific receptors. In addition, in the heart, thyroid hormones increase the automatism and the intrinsic activity of the sinus node and reduce the vagal tone. Those changes of the autonomic nervous system (ANS) balance can be documented by modifications of heart rate variability (HRV) and heart rate turbulence (HRT), aspects debated in several studies. HRV describes spontaneous fluctuations in heart rate (HR) and normal RR intervals  and is widely used to characterize the status of the ANS. Its analysis is used in both physiological models and various pathological states for the assessment of cardiovascular risk. HRT studies the sinus rhythm cycle length variation after isolated premature ventricular contractions (PVC).
These methods are used in studies to estimate the presence of sympathovagal imbalance in patients either with congestive heart failure or after myocardial infarction. Some studies have evidenced that an increased HR, induced by sympathetic hyperactivity, is a negative prognostic factor. The sympatovagal imbalance favors the onset of arrhythmias and increases the risk of sudden death., The significance of HRV and HRT for the assessment of the cardiovascular risk in hyperthyroid patients without other structural heart diseases, except the ones induced by thyroid hormones in excess, is still a subject to debate.,
The main objective of this study is to establish if alterations of HRV and HRT parameters are significantly correlated with levels of thyroid stimulating hormone (TSH), free thyroxin (FT4), or the duration of the disease in women with untreated hT of different severities, compared to controls. Another purpose is to identify, on the 24 h Holter monitoring, the incidence of atrial fibrillation (AF) and to establish if there is any relation with parameters of HRV.
| Methods|| |
In this paper, to characterize the alterations of the ANS in thyroid hyperfunction, we have studied fluctuations of HRV and HRT parameters in female patients with overt hT of various severities, as well as in a group of controls.
Our study group included 113 women with overt hT, admitted to the endocrinology clinic of our hospital, in 4 years (2013–2017). Individuals were aged between 26 and 51 years (mean age = 38.21 ± 6.54 years) and had hT of various etiology, mostly Basedow's disease (100%-88.49%) and toxic adenoma (13%-11.50%). After an initial endocrinologic evaluation (hormonal determinations: TSH, FT4, triiodothyronine, and thyroid sonography) to establish the etiology and severity of thyroid disease, all individuals were examined by the cardiologist.
We ruled out all women with subclinical hT. To prevent the influence of gender, risk factors or associated pathology (excepting cardiothyreosis) on HRV and HRT, we excluded from our study group male patients and all women with diabetes mellitus, neurologic and respiratory pathology or other significant cardiovascular diseases, not related to thyrotoxicosis and also, those with systolic blood pressure values of over 150 mmHg and/or with diastolic of over 90 mmHg. To limit the influence of endocrine status on the ANS imbalance, only women who were not yet in menopause were admitted in this study. In order to avoid the influence of drugs on HRV and HRT, we have not included in this study, patients treated recently with beta-blocker, calcium channel blocker (Verapamil or Diltiazem), or antiarrhythmic drugs. We excluded from the HRT analyze all individuals who were not in sinus rhythm at the moment of the study or those with <5 isolated PVC (at least 2 normal RR intervals before and 15 after the PVC) on the 24 h Holter electrocardiography recording. The results were compared with the ones obtained in an age-matched control group of 29 healthy women.
Depending on the severity and duration of hT and of thyroid hormones levels, individuals were assigned to three groups:
- Mild and moderate forms (46 women) with recent onset of hT and FT4 <40 pmol/L
- Severe hT (34 women) with thyrotoxicosis and
- Persistent cases, with hT diagnosed for over 2 years, with several relapses, which had a new episode of thyrotoxicosis before the enrolment in the study (33 women). These women, for one reason or another, have refused/delayed surgery or therapy with radioactive iodine.
At the time of Holter monitoring, individuals were either still untreated or in the 1st days of therapy with antithyroid drugs.
All patients and controls had 24 h Holter monitoring performed with a Holter Labtech Cardiospy device. For the analysis of the obtained data, we used the Nevrokard Long-Term aHLV (L-aHRV V.5.0.0.) program. Since the presence of PVC was a condition of inclusion in the study, we followed on the 24 h Holter monitoring the appearance of sinus tachycardia and supraventricular arrhythmias: premature supraventricular contractions (PSVC) and especially of paroxysmal AF. Regarding HRV, we studied the following parameters in time domain (TD): The standard deviation of all normal to normal (NN) intervals (SDNN), the standard deviation of all NN intervals occurred in 5 min (SDANN), the radical of the differences of mean squared NN successive intervals (RMSSD), and the HRV index (HRVTI), and in frequency domain (FD): Total power (TP), low frequency (LF), high frequency (HF), and LF/HF ratio. For HRT, we determined the turbulence onset (TO) – early sinus acceleration after a PVC and the turbulence slope (TS) – late sinus deceleration following a PVC.
The obtained numeric variables were expressed as mean values ± standard deviation; independent groups were compared using the unpaired Student's t-test or Mann–Whitney U-test. Statistical analyses were performed using SPSS v.24.0 (Statistical Package for the Social Sciences, Chicago, IL, USA), and statistical significance was defined at P < 0.05. We determined correlations between HRV and HRT parameters and levels of FT4, TSH, and the duration of hT using the Spearman test for nonparametric data.
This study was approved by the ethics committee of our hospital and each patient signed an informed consent form.
| Results|| |
The data obtained in the groups of female patients with hT, as well as in controls, are presented in [Table 1]. Referring to the study groups and to controls, there were no statistically significant differences concerning age and body mass index (P = 0.48 and P = 0.44) between them.
|Table 1: Characteristics and results of HRV and HRT analysis in the study group|
Click here to view
Referring to HRV analysis in TD, all determined parameters (SDNN, SDANN, RMSSD, and HRVTI) were depressed compared to controls [Figure 1]. We observed that the SDNN values were highly depressed, under 10 ms, in patients with severe hT (recently diagnosed and chronic cases) and moderately reduced in those with mild/moderate hT (mean value 90.3 ms) [Table 1] and [Figure 1].
|Figure 1: Heart rate variability analysis in time domain in the study group comparing to controls|
Click here to view
By comparing values of SDNN, SDANN, and HRVTI, determined in each group of patients, with the data found in controls, we noticed that the statistical difference was extremely significant (P < 0.0001) for all three categories of patients. Referring to RMSSD, the difference between patients and controls was also statistically very significant: P < 0.0001, in patients with severe hT (recently diagnosed and chronic cases) and P = 0.0006 in those with mild/moderate hT [Figure 1].
Referring to HRV parameters in FD, the statistically differences between the data determined in patients with hT and in controls were not so conclusive. TP was reduced in patients with severe hT compared to controls, but not in those with mild and moderate forms. LF and HF were higher in patients compared to controls, but the LF/HF ratio was between normal limits, both in patients with hT and in controls, as presented in [Table 1].
On the analysis of HRT parameters, all patients had abnormal, positive values of TO and we found an extremely significant statistically difference (P < 0.0001) compared to controls [Figure 2]. TS values, although normal, of over 2.5 m/RR, both in controls and in patients, were significantly lower in the last category. We determined extremely significant statistically differences between each category of patients and controls (P < 0.0001), [Figure 2].
|Figure 2: Heart rate turbulence analysis in the study group comparing to controls|
Click here to view
Assuming that there may be statistically correlations between HRV or HRT parameters and values of thyroid hormones (TSH and FT4) or the time of evolution of the thyroid disease, we analyzed the obtained data with statistical programs. Regarding SDNN, we found for all individuals, a negative, but extremely significant correlation with FT4 levels (r = −0.73, P < 0.0001), [Figure 3], a positive one, but also extremely significant with TSH values (r = 0.65, P < 0.0001) and a negative, but a very significant one (r = −0.4, P = 0.002) with the duration of hT. Regarding HRVTI, the correlation with FT4 values was negative, but extremely significant (r = −0.7, P < 0.0001), with TSH levels was positive and very significant (r = 0.83, P < 0.0001), and with the duration of hT, negative and very significant (r = −0.39, P = 0.003).
|Figure 3: Heart rate variability analysis: Correlations between normal to normal intervals and heart rate variability index and free thyroxin levels|
Click here to view
Regarding HRT analysis, considering the presence of a correlation between TO and FT4 levels, we found a positive and extremely significant one (r = 0.72, P < 0.0001), [Figure 4]; with TSH a negative, extremely significant correlation (r = −0.68, P < 0.0001) and with the duration of hT a positive, significant one (r = 0.32, P = 0.01). Referring to the correlation between TS and FT4, it was negative, but significant (r = −0.27, P = 0.02) [Figure 4]; with TSH, it was positive and extremely significant (r = 0.71, P < 0.0001); with the duration of hT, it was negative, but not significant (r = −0.2, P = 0.14).
|Figure 4: Heart rate turbulence analysis: Correlations between turbulence onset and turbulence slope and free thyroxin levels|
Click here to view
Concerning the occurrence of arrhythmias, sinus tachycardia was a common finding in individuals with hT but occurred in only 20.68% of controls. It was present in 56.52% of patients with mild and moderate hT, in 76.47% of those with severe hT and 54.54% of women with persistent forms. PSVC were detected with a higher incidence in patients with hT (41.3%, 61.76%, respectively, 48.48%) comparing to controls (24.13%). Paroxysmal AF was detected quite frequently in patients with thyrotoxicosis (new forms – 26.47% and persistent forms – 27.27%), also in individuals with mild and moderate forms – 15.21%, but not in controls [Table 1] and [Figure 5].
|Figure 5: Incidence of arrhythmias in hyperthyroid female patients and in controls|
Click here to view
By comparing HRV parameters determined in hyperthyroid patients with and without paroxysmal AF on the 24 h Holter monitoring, we observed that SDNN values were lower in those with arrhythmia (P < 0.0001) independent of hT severity. Thus, for women with severe hT, newly diagnosed, SDNN was 5.33 ± 0.5 ms, in those who presented AF and 6.28 ± 1.42 ms in the ones without AF. The difference was even bigger in patients with severe persistent hT: 5.44 ± 1.01 ms in patients with AF and 8.03 ± 1.53 ms in those without AF. In individuals with mild and moderate hT, in those with AF SDNN were 81.71 ± 5.7 ms and 101.48 ± 16.2 ms in the ones without AF.
| Discussion|| |
In this paper, we have studied HRV and HRT parameters in a group of 113 women, with hT of various severities: mild/moderate and severe forms first diagnosed, but also in persistent forms with a relapse of the disease. In the moment of the study, all patients were either untreated or in an early stage of therapy with antithyroid drugs. From over 500 patients with hT, admitted to the endocrinology clinic of our hospital over a period of 4 years (2012–2016), only 113 patients fulfilled all the inclusion and exclusion criteria. We have compared the obtained values of HRV and HRT parameters with the ones determined in age-matched controls. To the best of our knowledge, this is the first paper where the patients are divided into groups, according to the severity and duration of hT.
We performed the analysis of HRT and HRV, in both time and FD to determine a possible correlation between these parameters and the severity and duration of hT. Referring to HRV analysis in TD, we documented in all patients with hT depressed levels of SDNN, SDANN, RMSSD, and HRVTI similar to those presented by other authors., The depression of these parameters indicates an increased sympathetic and a reduced vagal activity. Our study evidenced a statistically significant depression of all mentioned parameters, between the controls and all three categories of patients. We determined also significant correlations between these parameters and the severity of the thyroid disease, expressed by the levels of FT4 and TSH [Figure 3], as well as with the duration of hT. On the HRV analysis performed in FD, HF reflects the parasympathetic activity, and LF represents a marker for the sympathetic modulation when expressed in normalized units. LF/HF ratio is considered to reflect the sympathetic modulation. In our study, the differences between values measured in patients with hT and in controls were not so conclusive. TP was reduced only in women with severe hT compared to controls. LF and HF were higher in patients compared to controls, but their ratio was in normal limits for all studied individuals.
Regarding HRT analysis, all patients had abnormal, positive values of TO, with statistically significant differences compared to controls [Figure 2]. TS values, although normal, in controls and patients, were significantly lower in the last category, aspects debated also in other studies., We have determined extremely significant statistically differences between each category of patients and controls [Figure 2]. We also have demonstrated the existence of statistically significant correlations between TO and TS values and the levels of FT4 and TSH, [Figure 4], and with the duration of hT.
HRV depression is considered an independent risk factor for the apparition of severe arrhythmias in patients after acute myocardial infarction and in those with heart failure., Comparing to them, patients with hT, although presenting a sympatovagal imbalance, are prone to a lesser extent to ventricular arrhythmias, but mostly to supraventricular ones, especially to AF. It is a clinically relevant topic to document in what extent the sympathovagal imbalance, encountered in patients with hT, can predict the risk of developing AF. Although we have selected in our study only younger women, without cardiovascular diseases and have excluded those with previous arrhythmias, we detected in all patients on the 24 h Holter monitoring a fairly high incidence of paroxysmal AF related to the severity of hT. We documented also in women with AF a significant reduction of SDNN (P < 0.0001) compared to those without this arrhythmia, regardless of the severity of hT. This aspect was debated by other authors ,,, in their articles.
The study of HRV and HRT is a highly debated topic in the literature and is used to ascertain the influences of the ANS on the heart. Several scientific papers have been written about their significance in various physiological states  and in pathological conditions., Fluctuations of HRV and HRT parameters were observed in thyroid disorders. Some authors, have studied their evolution in hypothyroidism , and others , in hT and have evidenced, on the short- and long-term Holter monitoring, a sympatovagal imbalance in treated and untreated patients.
The hyperkinetic state encountered in hT  is similar to that induced by the excess of catecholamines, characterized by a sympathovagal imbalance. In one study, it is documented that all parameters, measured in TD and FD, decreased progressively from euthyroid individuals to patients with subclinical hT (P < 0.001). These data highlight the reduction in the vagal tone and the increase of the sympathetic cardiac control in hT, with important clinical implications taking into account that a decreased HRV signifies an increased risk for arrhythmias. Other studies have reported a decreased parasympathetic cardiac activity in hT,, effect that can be attributed to the interference between peripheral neuroeffector mechanisms and central inhibitory effects on cardiac baroreflexes. Jin-Long Chen  and Kabir  described in their studies an increased sympathetic activity in patients with hT.
Taking into account that improvements or even normalizing of HRV and HRT in patients with hT after achieving the euthyroid state, has been discussed in some studies , we have not debated the evolution of these parameters in our paper.
| Conclusion|| |
In our study, we have documented in female patients with hT depressed values of HRV parameters in TD, which were correlated with the severity of the thyroid disease. TO values, determined in our study group were pathological, in relation with the severity of hT. Although positive, TS values were lower in patients compared to controls. The incidence of supraventricular arrhythmias, especially of paroxysmal AF, was high in women with overt hT (new forms or persistent) and was associated with severely depressed values of SDNN.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Madariaga AG, Palacios SS, Guillen-Grima F, Galofre JC. The incidence and prevalence of thyroid disfunction in Europe: A meta-analysis. J Clin Endocrinol Metab 2014;3:923-31.
Florea VG, Cohn JN. The autonomic nervous system and heart failure. Circ Res 2014;114:1815-26.
Chu Duc H, Nguyen Phan K, NguyenViet D. A review of heart rate variability and its applications. APCBEE Procedia 2013;7:80-85.
Bairey Merz CN, Elboudwarej O, Mehta P. The autonomic nervous system and cardiovascular health and disease: A complex balancing act. JACC Heart Fail 2015;3:383-5.
Shpak LV, Volkova IA. Heart rate variability in patients with thyrotoxicosis before and after thyroid resection. Ter Arkh 2009;81:58-62.
Bauer A, Malik M, Schmidt G, Barthel P, Bonnemeier H, Cygankiewicz I, et al.
Heart rate turbulence: Standards of measurement, physiological interpretation, and clinical use: International society for holter and noninvasive electrophysiology consensus. J Am Coll Cardiol 2008;52:1353-65.
Sassi R, Cerutti S, Lombardi F, Malik M, Huikuri HV, Peng CK, et al.
Advances in heart rate variability signal analysis: Joint position statement by the e-cardiology ESC working group and the European Heart Rhythm Association Co-Endorsed by the Asia Pacific Heart Rhythm Society. Europace 2015;17:1341-53.
Kaminski G, Makowski K, Michałkiewicz D, Kowal J, Ruchala M, Szczepanek E, et al.
The influence of subclinical hyperthyroidism on blood pressure, heart rate variability, and prevalence of arrhythmias. Thyroid 2012;22:454-60.
Osman F, Franklyn JA, Daykin J, Chowdhary S, Holder RL, Sheppard MC, et al.
Heart rate variability and turbulence in hyperthyroidism before, during, and after treatment. Am J Cardiol 2004;94:465-9.
Kabir R, Begum N, Ferdousi S, Begum S, Ali T. Relationship of thyroid hormones with heart rate variability. J Bangladesh Soc Physiol 2010;5:20-6.
Galetta F, Franzoni F, Fallahi P, Tocchini L, Braccini L, Santoro G, et al.
Changes in heart rate variability and QT dispersion in patients with overt hypothyroidism. Eur J Endocrinol 2008;158:85-90.
Kabir R, Begum N, Ferdousi S, Begum S, Ali T. Heart Rate Variability in Hyperthyroidism J Bangladesh Soc Physiol 2009;4:51-7.
Celik A, Aytan P, Dursun H, Koc F, Ozbek K, Sagcan M, et al.
Heart rate variability and heart rate turbulence in hypothyroidism before and after treatment. Ann Noninvasive Electrocardiol 2011;16:344-50.
Bettoni M, Zimmermann M. Autonomic tone variations before the onset of paroxysmal atrial fibrillation. Circulation 2002;105:2753-9.
Wustmann K, Kucera JP, Zanchi A, Burow A, Stuber T, Chappuis B, et al.
Activation of electrical triggers of atrial fibrillation in hyperthyroidism. J Clin Endocrinol Metab 2008;93:2104-8.
Bielecka-Dabrowa A, Mikhailidis DP, Rysz J, Banach M. The mechanisms of atrial fibrillation in hyperthyroidism. Thyroid Res 2009;2:4.
Zhang Y, Dedkov EI, Teplitsky D, Weltman NY, Pol CJ, Rajagopalan V, et al.
Both hypothyroidism and hyperthyroidism increase atrial fibrillation inducibility in rats. Circ Arrhythm Electrophysiol 2013;6:952-9.
Chen JL, Chiu HW, Tseng YJ, Chu WC. Hyperthyroidism is characterized by both increased sympathetic and decreased vagal modulation of heart rate: Evidence from spectral analysis of heart rate variability. Clin Endocrinol (Oxf) 2006;64:611-6.
Esco MR, Flatt AA. Ultra-short-term heart rate variability indexes at rest and post-exercise in athletes: Evaluating the agreement with accepted recommendations. J Sports Sci Med 2014;13:535-41.
Yildiz C, Yildiz A, Tekiner F. Heart rate turbulence analysis in subclinical hypothroidism heart rate turbulence in hypothyroidism. Acta Cardiol Sin 2015;31:444-8.
Chen JL, Tseng YJ, Chiu HW, Hsiao TC, Chu WC. Nonlinear analysis of heart rate dynamics in hyperthyroidism. Physiol Meas 2007;28:427-37.
Kabir R, Begum N, Ferdousi S, Begum S, Ali T. Heart Rate Variability in Hyperthyroidism. J Bangladesh Soc Physiol 2009;4:51-7.
Klein I, Danzi S. Thyroid disease and the heart. Circulation 2007;116:1725-35.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]