|Year : 2014 | Volume
| Issue : 1 | Page : 26-33
Dyslipidemia and low-grade inflammation are associated with sympathovagal imbalance and cardiovascular risks in subclinical and overt hypothyroidism
Avupati Naga Syamsunder1, Pravati Pal1, Chandrakasan Sadishkumar Kamalanathan2, Subhash Chandra Parija3, Gopal Krushna Pal1, Gopalakrishna Jayakrishnan1, Allampalli Sirisha1, Shanmugavel Karthik1
1 Department of Physiology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
3 Department of Microbiology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
|Date of Submission||10-Oct-2013|
|Date of Decision||24-Dec-2013|
|Date of Acceptance||08-Jan-2014|
|Date of Web Publication||1-Apr-2014|
Department of Physiology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry 605 006
Source of Support: JIPMER as Intramural PhD Research Grant,, Conflict of Interest: None
Background and Aim: Hypothyroidism in both its subclinical and overt form has been reported to be associated with cardiovascular (CV) morbidities. Dyslipidemia, inflammation, and sympathovagal imbalance (SVI) contribute to CV risks. The present study has assessed role of dyslipidemia and inflammation in the genesis of SVI and hypertension status in subclinical hypothyroidism (SCH) and overt hypothyroidism (OH).
Methods: Age-matched 209 females (70 euthyroids, 67 subclinical hypothyroids, and 72 overt hypothyroids) were recruited for this study. Body mass index (BMI), CV parameters, and autonomic function tests (AFT) like spectral analysis of heart rate variability (HRV), heart rate (HR) response to standing, HR response to deep breathing, and blood pressure (BP) response to isometric handgrip were assessed. Thyroid profile, lipid profile, and immunological and inflammatory markers were estimated. The independent association of the ratio of low-frequency to high-frequency (LF-HF ratio) power of HRV and the marker of SVI with various parameters were determined by multiple regression analysis. The prediction of hypertension status by LF-HF ratio was assessed by logistic regression.
Results: CV and AFT parameters, lipid profile, and inflammatory marker were altered and correlated with LF-HF ratio in both SCH and OH groups. Mean arterial pressure, atherogenic index, and high-sensitive C-reactive protein had independent contribution to LF-HF ratio in both the groups. The prediction of hypertension status by LF-HF ratio was more significant in OH groups (odds ratio (OR) 2.15, CI 0.126-5.867, and P = 0.002) compared to SCH group (OR 1.90, CI 1.108-4.352, and P = 0.009).
Conclusion: SVI due to sympathetic activation and vagal withdrawal occurs in SCH that progressively increases from SCH to OH. Dyslipidemia and low-grade inflammation are associated with SVI and CV risks in hypothyroidism.
Keywords: Autonomic imbalance, cardiovascular risks, dyslipidemia, hypothyroidism, inflammation, subclinical hypothyroidism, sympathovagal imbalance
|How to cite this article:|
Syamsunder AN, Pal P, Kamalanathan CS, Parija SC, Pal GK, Jayakrishnan G, Sirisha A, Karthik S. Dyslipidemia and low-grade inflammation are associated with sympathovagal imbalance and cardiovascular risks in subclinical and overt hypothyroidism. Int J Clin Exp Physiol 2014;1:26-33
|How to cite this URL:|
Syamsunder AN, Pal P, Kamalanathan CS, Parija SC, Pal GK, Jayakrishnan G, Sirisha A, Karthik S. Dyslipidemia and low-grade inflammation are associated with sympathovagal imbalance and cardiovascular risks in subclinical and overt hypothyroidism. Int J Clin Exp Physiol [serial online] 2014 [cited 2019 Mar 20];1:26-33. Available from: http://www.ijcep.org/text.asp?2014/1/1/26/129726
| Introduction|| |
Decreased function of the thyroid gland is one of the common endocrine disorders of India, where prevalence of overt hypothyroidism (OH) is 10.95% and subclinical hypothyroidism (SCH) is 8.02%.  OH is defined as a combination of high thyroid stimulating hormone (TSH) with low free thyroxine (fT4), while SCH is defined as a combination of high TSH with normal fT4 levels.  Dyslipidemia and increased inflammatory markers are associated with OH , and SCH. ,,] Increased plasma levels of C-peptide and lipoproteins are reported to increase the risk for cardiovascular (CV) diseases in hypothyroid patients. , Hyperlipidemia, low-grade inflammation and oxidative stress have been reported to increase CV risks in SCH. ,
Conventional autonomic function tests (CAFT) and power spectral analysis of heart rate variability (HRV) are useful tools to measure cardiac autonomic activity and sympathovagal balance. ,, OH is associated with decreased sympathovagal modulation of heart rate (HR).  Though hypothyroidism is a hypometabolic state, sympathovagal imbalance (SVI) due to increased sympathetic activity and decreased parasympathetic activity has been reported in OH. ,, The cardiac autonomic activity is also altered in SCH.  Hyperlipidemia and inflammation have been reported to cause SVI, , and SVI has been observed to be associated with increased CV risks. , Recently, we have reported SVI in the form of sympathetic overactivity and vagal inhibition, which is linked to hypertension status in hypothyroidism patients.  However, till date the pathophysiology of SVI in SCH has not been adequately studied. Moreover, the cause and progression of SVI from the state of SCH to OH and its link to increased CV risks in these conditions have not been elucidated. Therefore, in the present study we have assessed the association of dyslipidemia, inflammatory markers with SVI, hypertension status, and CV risks in subclinical and overt hypothyroid patients.
| Materials and Methods|| |
The present study was conducted in the Department of Physiology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India. After obtaining approval of the project plan from research and ethics committees of JIPMER, 209 female subjects (70 euthyroid, 67 subclinical hypothyroid, and 72 overt hypothyroid patients) were recruited from the Endocrinology Clinic of JIPMER Hospital. Euthyroidism was defined as a serum TSH level of 0.35-5.50 µIU/mL with normal fT4 concentration (0.89-1.76 ng/dL). OH was defined as a serum fT4 concentrations <0.89 ng/dL with serum TSH level >5.50 µIU/mL. SCH was defined as a serum TSH level of >5.50 µIU/mL with normal fT4 concentrations. Written informed consent was obtained from all the participants prior to initiation of the study. Subjects of study groups were freshly diagnosed untreated female subclinical and overt hypothyroid patients.
Female patients freshly diagnosed as subclinical hypothyroids and overt hypothyroids, before initiation of the treatment were included for the study. Control group had age-matched healthy euthyroid females.
Patients, who were already on treatment for SCH or hypothyroidism, known cases of diabetes mellitus, hypertension, heart diseases, autonomic failure, or endocrine disorders and those receiving chronic medications, were excluded from the study. Females receiving oral contraceptives, females in the perimenopausal age and who had attained menopause were also excluded from the study.
The subjects reported to polygraph laboratory of physiology department at about 8 AM without breakfast. Height and weight were measured to calculate body mass index (BMI). After 10 min of supine rest in polygraph laboratory (room temperature maintained at 25°C), the following recordings were done.
Recording of baseline CV and HRV parameters
Baseline HR and blood pressure (BP) were recorded in the left arm after 10 min of rest in the supine position using automatic BP monitor (Omron Healthcare Co. Ltd, Kyoto, Japan). For recording of short-term HRV, the procedure as described earlier,  and recommendation of the Task Force on HRV was followed.  For the purpose, electrocardiogram (ECG) electrodes were connected and Lead II ECG was acquired at a rate of 250 samples/s during supine rest using BioHarness 2 data acquisition system (BIOPAC Inc, Goleta, CA, USA). The data was transferred from BioHarness to a windows-based PC with AcqKnowledge software version 4.1.0. Ectopics and artefacts were removed from the recorded ECG tachogram [Figure 1]. HRV analysis was done using the HRV analysis software version 1.1 (Bio-signal Analysis group, Kuopio, Finland). Frequency domain indices such as total power (TP), low-frequency power expressed in normalized unit (LFnu), high-frequency power expressed in normalized unit (HFnu), ratio of LF to HF power (LF-HF ratio), and time domain indices (TDI) such as mean RR, square root of the mean squared differences of successive normal to normal intervals (RMSSD), standard deviation of normal to normal interval (SDNN), the number of interval differences of successive NN intervals greater than 50 ms (NN50), and the proportion derived by dividing NN50 by the total number of NN intervals (pNN50) were recorded.
|Figure 1: Tachogram of HRV recording by AcqKnowledge software version 4.1.0|
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Other autonomic function tests
Three CAFTs were performed following the standard procedures: 
Lying to standing test
In this test, HR and BP response to standing was assessed. The BP and ECG were recorded in supine position. The subject was instructed to stand up in 3 s. The ECG was continuously recorded during the procedure. The BP was recorded every 40 s by automatic BP monitor (Omron, SEM-1, Kyoto, Japan) till 5 th min. 30:15 ratio (ratio of maximum RR interval at 30 th beat to minimum RR interval at 15 th beat following standing) was calculated.
Deep breathing test
The subject in sitting posture, the HR, and respiration monitoring was done from ECG recording and stethographic respiratory tracings recorded respectively, on the multichannel polygraph (Nihon-Kohden, Tokyo, Japan). A baseline recording of ECG and respiration was taken for 30 s. The subject was asked to take slow and deep inspiration followed by slow and deep expiration such that each breathing cycle lasted for 10 s, consisting of six breathing cycles per min. E:I ratio (ratio of average RR interval during expiration to average RR interval during inspiration in six cycles of deep breathing) was calculated from ECG tracing.
Isometric handgrip test
The baseline BP was recorded. The subject was asked to press handgrip dynamometer at 30% of maximum voluntary contraction for 2 min. The BP was recorded at 1 st and 2 nd min of contraction. ∆DBP IHG (maximum rise in diastolic BP above baseline) was noted.
Measurement of biochemical parameters
Five ml of fasting blood sample was collected. The serum was separated from the blood samples of all the subjects for estimation of biochemical parameters. Free triiodothyronine (fT3), fT4, and TSH were assayed by chemiluminiscence method using the kits from Siemens Healthcare Diagnostics Inc, USA. Lipid profile (total cholesterol (TC), triglycerides (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), and very low density lipoproteins (VLDL)) were assessed using fully automated analyzer (AU400, Olympus, USA). Anti-thyroperoxidase antibody (anti-TPO Ab), anti-thyroglobulin antibody (anti-TG Ab) and immunoglobulin E (Ig E) were estimated by indirect immunoenzymatic colorimetric method using enzyme-linked immunosorbent assay (ELISA) kits (Dia Metra, Segrate, Italy). The high-sensitive C-reactive protein (hsCRP) was estimated by using ELISA kits (dbc Diagnostics Biochem Canada Inc, Canada).
Statistical Package for Social Sciences (SPSS) version 19 (SPSS Software Inc, Chicago, IL, USA) and GraphPad InStat softwares (GraphPad Software Inc, San Diego, CA, USA) were used for statistical analysis. All the data were presented as mean ± SD. Normality of data was tested by Kolmogorov Smirnov test. For parametric data, the level of significance between the groups was tested by Student's unpaired 't' test and for nonparametric data, the Welch's corrected t test was used. The association between LF-HF and various parameters was assessed by Pearson's correlation analysis. The independent contribution of various factors to LF-HF ratio was assessed by multiple regression analysis. Bivariate logisitc regression was performed for the prediction of BP status in control subjects and hypertension status in subclinical and overt hypothyroid patients by LF-HF ratio. The P values less than 0.05 was considered statistically significant.
| Results|| |
There was no significant difference in age of control, subclinical and overt hypothyroid patients [Table 1]. BMI of subclinical and overt hypothyroid patients were significantly more compared to that of controls (P < 0.001). The basal HR (BHR) was significantly less (P < 0.05) only in overt hypothyroid patients compared to controls. The DBP (P < 0.001) and mean arterial pressure (MAP) (P < 0.001) were significantly more in subclinical and overt hypothyroid patients compared to the controls [Table 1]. BMI (P < 0.001), DBP (P < 0.001), and MAP (P < 0.05) were significantly more in overt hypothyroid patients compared to that of subclinical hypothyroid patients.
|Table 1: Age, BMI, basal cardiovascular, HRV and CAFT parameters of control group, SCH group and OH group|
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There was significant reduction in TP (P < 0.001) and HFnu (P < 0.01) and significant increase in LFnu (P < 0.01) and LF-HF ratio (P < 0.001) in subclinical hypothyroid patients compared to the controls [Table 1]. TP and HFnu reduced significantly (P < 0.001) and LFnu and LF-HF ratio increased significantly (P < 0.001) in overt hypothyroid patients compared to the controls [Table 1] and [Figure 2]. Also, TP and HFnu were significantly (P < 0.001) less and LFnu and LF-HF ratio were significantly (P < 0.001) more in overt hypothyroid patients compared to subclinical hypothyroid patients [Table 1]. The TDI of HRV (RMSSD, SDNN, NN50, and pNN50) were significantly decreased (P < 0.001) in overt hypothyroid patients compared to the control group. In subclinical hypothyroid patients compared to controls, there was significant reduction in SDNN, pNN50 (P < 0.001) and in RMSSD and NN50 (P < 0.05). All TDI except RMSSD decreased significantly (P < 0.01) in overt hypothyroid patients compared to subclinical hypothyroid patients. The 30:15 ratio and ΔDBP IHG were significantly increased (P < 0.001) and E:I ratio was significantly decreased (P < 0.001) in subclinical and overt hypothyroid patients compared to controls and in OH patients compared to subclinical hypothyroid patients [Table 1].
|Figure 2: This picture depicts the power spectral analysis (Auto Regression model) of heart rate variability of one sample subject each from control, subclinical and overt hypothyroid groups. The LF power and HF power were almost 50:50 in control subject; LF power was more than HF power in subclinical hypothyroid subject; LF power was maximum and HF power was minimum in overt hypothyroid subject|
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There was a significant decrease (P < 0.01) in fT4 and increase in TSH (P < 0.05) in subclinical hypothyroid patients compared to control group [Table 2]. There was a significant decrease (P < 0.001) in fT3 and fT4 and increase in TSH (P < 0.001) in overt hypothyroid patients compared to control group and subclinical hypothyroid patients [Table 2]. TC, TG, LDL, and VLDL were increased (P < 0.001) and HDL (P < 0.001) was decreased in subclinical and overt hypothyroid patients compared to control group and in overt hypothyroid patients compared to subclinical hypothyroid patients. All the lipid risk factors were significantly high (P < 0.001) in subclinical and overt hypothyroid patients compared to controls and in overt hypothyroid patients compared to subclinical hypothyroid patients. Levels of anti-TPO antibody, anti-TG antibody and hsCRP were increased (P < 0.001) in subclinical and overt hypothyroid patients and in overt hypothyroid patients compared to SCH patients [Table 2].
LF-HF ratio was not significantly correlated with any of the parameter in control group and with BMI in any of the groups [Table 3]. In subclinical and overt hypothyroid patients, there was a significant correlation of LF-HF ratio with BHR, MAP, TSH, lipid profile parameters, lipid risk factors, and inflammatory and immunological markers except Anti-Tg Ab [Table 3]. Multiple regression analysis revealed independent contribution of MAP (β 0.878, P = 0.000 in SCH and β 0.510, P = 0.011 in OH), atherogenic index (AI) (β 0.786, P = 0.002 in SCH and β 1.152, P = 0.000 in OH) and hsCRP (β 0.568, P = 0.012 in SCH and β 0.625, P = 0.005 in OH) to LH-HF ratio [Table 4]. Bivariate logistic regression [Table 5] showed significant prediction of LF-HF to hypertension status in SCH (odds ratio (OR) 1.90, CI 1.108-4.352, P = 0.009) and OH (OR 2.15, CI 0.126-5.867, P = 0.002) patients.
|Table 3: Correlation of LH-HF ratio with various parameters of control, SCH and OH subjects|
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| Discussion|| |
In the present study, LH-HF ratio, a sensitive indicator of SVI, , was significantly increased in subclinical and overt hypothyroid patients compared to controls and the increase in LF-HF ratio was more significant in overt hypothyroid group . As increase in LF-HF ratio indicates increased sympathetic drive to the heart, , it is evident that cardiac sympathetic drive was more in both subclinical and overt hypothyroid patients, which was more accentuated in overt hypothyroids. Further, LFnu that primarily reflects sympathetic modulation of heart,  was significantly increased in subclinical and overt hypothyroid patients, especially more prominent in overt hypothyroid group [Table 1]. In addition, DBP was significantly increased in subclinical and overt hypothyroid patients compared to controls, which indicates increased sympathetic activity in these patients as DBP is the reflection of sympathetic vasoconstrictor tone.  The HRV parameters like TP, HFnu, and all TDI (RMSSD, SDNN, NN50, and pNN50) represent parasympathetic drive to the heart.  In hypothyroid patients, all these parameters were significantly decreased indicating reduced parasympathetic activity. In addition, these parasympathetic indices were more prominently reduced in overt hypothyroid patients compared to subclinical hypothyroid patients. Thus, there was increased sympathetic and decreased parasympathetic activity leading to SVI in these patients, which was more intense in overt hypothyroid patients. This indicates that the autonomic imbalance could be proportionate with the degree of thyroid hormone deficiency. HRV analysis has been used as a marker for the progression of CV disease in several high-risk populations,  and also as a predictor of sudden cardiac death. 
Among CAFT parameters, increase in 30:15 ratio (HR response to standing) and decrease in E:I ratio (deep breathing) indicate lower parasympathetic reactivity and increase in BP response to isometric handgrip (ΔDBP IHG ) indicates higher sympathetic reactivity.  There was decreased vagal and increased sympathetic reactivity in subclinical and overt hypothyroid patients [Table 1], and the changes were more significant in overt hypothyroid patients. Thus, findings of the present study suggest that the SVI in subclinical and overt hypothyroid patients is due to decreased parasympathetic activity and reactivity, along with increased sympathetic activity and reactivity. However, the degree of SVI was more in overt hypothyroids compared to subclinical hypothyroid patients.
There was significant dyslipidemia (hypercholesterolemia, triglyceridemia, high LDL-hypercholesterolemia, high VLDL-hypercholesterolemia, and low HDL-cholesterolemia) and increased lipid risk factors [Table 2] in subclinical and overt hypothyroid patients compared to the controls, and the degree of dyslipidemia was more marked in overt hypothyroid group compared to the subclinical hypothyroid group. All lipid parameters were significantly correlated with LF-HF ratio [Table 3]. However, the degree of correlation was more in overt hypothyroid patients compared to subclinical hypothyroid patients. Besides AI, which is a better indicator of CV risk, had significant independent contribution to LF-HF ratio [Table 4], and its contribution was more in overt hypothyroid patients compared to subclinical hypothyroid patients. As dyslipidemia significantly impairs endothelial dysfunction and increases sympathetic drive,  the rising dyslipidemia contributes significantly to SVI in a gradual manner from subclinical to overt hypothyroid condition.
Low-grade inflammation and altered immunological status have been reported in both SCH and OH. , In the present study hsCRP, anti-TPO Ab, and anti-TG Ab were significantly increased in subclinical and overt hypothyroid patients compared to controls and in overt hypothyroid patients compared to subclinical hypothyroid patients. The LF-HF ratio was significantly correlated with hsCRP and anti-TPO Ab in subclinical and overt hypothyroid patients with the significance being more for overt hypothyroid patients [Table 3]. However, only hsCRP had significant independent contribution to LF-HF ratio and the contribution was more in overt hypothyroid patients compared to subclinical hypothyroid patients [Table 5]. Therefore, alteration in SVI in SCH and OH appears to be directly linked to the level of hsCRP. It has been reported that CRP is an independent predictor for carotid artery intima-media thickness progression in asymptomatic younger adults.  Therefore, gradually elevated hsCRP from subclinical to overt hypothyroid condition plays a role in progression of SVI and adds to the CV risk.
|Table 4: Multiple regression analysis of LF-HF ratio (as dependent variable) with various other associated factors (as independent variables) in SCH and OH group|
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|Table 5: Bivariate logistic regression for assessment of link of hypertension status (as dependent variable) with LF-HF ratio (as independent variable) in SCH group and OH group after adjusting for age and BMI|
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Dyslipidemia, inflammation, , and SVI  are known CV risk factors, which are increased in SCH  and OH. , In the present study, SVI was associated with dyslipidemia and inflammation, and the risk factors were observed to be increasingly more with decrease in thyroid function. Furthermore, increased MAP was significantly associated with LF-HF ratio (SVI) in subclinical and overt hypothyroid patients [Table 4]. Recently, we have reported the association of SVI with hypertension status that increases CV risks in hypothyroid patients.  In the present study, LF-HF ratio had significant prediction for hypertension status in both subclinical and overt hypothyroid patients, which was more prominent in OH [Table 5]. Therefore, the findings of the present study demonstrate that considerable SVI, sustained hyperlipidemia, and chronic low-grade inflammation in both subclinical and overt hypothyroid patients predispose them to increased risk of CV morbidity and mortality, and SVI could be the physiological basis of CV risks in these patients.
In the present study, LF-HF ratio had more independent contribution to MAP in subclinical compared to overt hypothyroids [Table 4], indicating that SVI profoundly contribute to rise in BP in SCH. As such, usually SCH is clinically less symptomatic, and these abnormalities may remain undetected for several years during which these patients could be susceptible to greater CV risks. SCH has been reported to be associated with impaired left ventricular diastolic function, mild systolic dysfunction and enhanced risk for atherosclerosis and myocardial infarction.  Further, subclinical hypothyroid patients have an increased risk for all-cause mortality and CV disease death. , Also, SCH may progress to OH in approximately 2-5% cases annually.  As AI and hsCRP had independent association with SVI, further research should evaluate the cause-effect relationship among these factors, and should also assess if hypolipidemic and anti-inflammatory therapy can improve sympathovagal balance in SCH and OH. Moreover, subclinical and overt hypothyroid patients should also be encouraged to adapt nonpharmacological therapies such as pranayamic breathing exercises and yoga, as reports from our laboratory and others have documented reduction of sympathetic activity and improvement of vagal activity following practice of such life style modification programs. ,
Limitations of the study
In the present study we have not assessed cardiac dysfunctions directly by radioimaging techniques and their possible correlation with SVI in subclinical and overt hypothyroid patients.
| Conclusion|| |
In this study, HRV was found to be grossly reduced in subclinical and overt hypothyroid patients predisposing them to CV morbidities, which was more intense in overt hypothyroids. SVI in SCH was due to the concomitant increased sympathetic and decreased vagal activities, which was proportionately accentuated in OH. SVI was associated with dyslipidemia and low-grade inflammation. SVI was linked to hypertension status in these patients. As chronic SVI, hypertension, hyperlipidemia, and inflammation are known CV risk factors, further research should be conducted to assess if improvement in cardiometabolic functions and attainment of sympathovagal homeostasis can improve the CV health in subclinical and overt hypothyroid patients.
| Acknowledgments|| |
We acknowledge the intramural financial assistance from JIPMER as Intramural PhD Research Grant for supporting this study.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]