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Frequency-domain analysis of heart rate variability during rest and stress in adolescents with parental history of diabetes mellitus.

INTRODUCTION

The global prevalence of diabetes mellitus (DM), which is the most common metabolic disorder in all the age group, will be 4.4% by 2030. [1] Genetic component and environmental factors play a role in the development of DM. Population-based Framingham study shows that the risk of developing offspring diabetes is greater when both parents are diabetic and risk increases when mother is diabetic. [2] Twin-based population study demonstrates the role of genetic factor and non-genetic factors in the development of DM. [3] Role of various genes in the development of DM was established. [4]

The study shows that the development of DM is more in monozygotic twins when compared to dizygotics, also genetic component plays an important role in the development of type I DM (T1DM) than type II. [5] Development of T1DM is more in offspring's with positive sibling and parental history of DM. [6] Interaction between multiple genes and environmental factors might lead to the development of DM which is not clearly understood. The common disease-common variant hypothesis proposes that there can be multiple common genetic variants of small effect and also multiple rare variants of large effect. [7,8]

Diabetic cardiac autonomic neuropathy leads to defect in vascular dynamics with features such as orthostasis, postural hypotension, exercise intolerance, and increased incidence of silent myocardial infarction. [9,10]

Beat-to-beat variation in either heart rate or R-R interval is heart rate variability (HRV). It is a practical, non-invasive tool to investigate cardiac autonomic dysfunction and is an indicator of increased risk for cardiac mortality. [11] Reduced HRV with low-frequency (LF) power has strong association with sudden deaths in heart failure patient. [12] One of the complications seen in chronic diabetics with poor glycemic status is autonomic neuropathy. [13] Autonomic function tests such as deep breathing difference, lying-to-standing ratio, and Valsalva ratio were assessed in children with a parental history of diabetes (PHD) by Goel et al. which showed altered response in parasympathetic function tests even before they developed diabetes. These tests mainly assess vagal component of the autonomic activity. The study was not able to prove the sympathovagal balance. [14] Tarek et al. demonstrated sympathovagal imbalance in subjects with family history of T2DM which was explained by dyslipidemia. [15] None of the above study showed the effect of single parent or having both parent diabetics on autonomic balance in the offspring's. Hence, the following was conducted to assess the cardiac autonomic balance in children with PHD.

Mental stress might lead to work-related illness due to alteration in cardiac autonomic activity. [16] Research has shown increased risk of cardiovascular mortality in those who fail to cope up with stress. [17] As there is less work done to assess the response to stress in offspring's of DM, so one more objective of our study is to assess cardiac autonomic balance during acute mental stress in adolescents with a parental history of DM.

MATERIALS AND METHODS

The study was conducted in the Physiology Department, SDMCMS and H, Dharwad, from July to September 2017. Before starting study, the ethical clearance was obtained from the institutional ethical committee. HRV procedure was explained to all participants and written consent was taken. Based on PHD, participants were divided into three groups.

Group I: Controls (negative PHD), Group II: Positive PHD (single-parent diabetic), and Group III: Positive PHD (both parent diabetics).

Exclusion Criteria

Subjects with a history of smoking, those who are currently using medications which can alter autonomic functions, those who have parental H/O hypertension were excluded from the study.

Inclusion Criteria

Sample size was decided based on previous references. 50 subjects in each group (n = 50) (total n = 150) in the age group of 18-25 years participated who were randomly selected.

Study Design

Participants were instructed not to consume coffee, tea, or cola which can alter autonomic activity at least 12 h before the test. Participants attended physiology laboratory at 9 am after having a light breakfast and limited exertion. A standard pro forma was prepared on which sociodemographic details were taken.

HRV Measurement

Electrocardiography (ECG) data acquisition equipment (Niviqure Meditech Systems, Bengaluru, India) was used to collect the ECG data in lead II later HRV analyzed using Kubios software based on non-parametric method of fast Fourier transform. Frequency-domain values such as LF power, high-frequency (HF) power, and total spectral power were recorded. Mental stress was induced by arithmetic mental challenge in which participants were made to rapidly subtract 7 from a three- or four-digit number under time pressure and HRV recorded.

Statistical Analysis

SPSS software version 20 was used for analysis. Student's paired t-test was used to compare the data between rest and mental stress levels. ANOVA was used for intergroup analyses of variables.

RESULTS

The study involves 50 participants with positive PHD with one parent diabetic (n = 50), 50 participants with positive PHD having both parent diabetics (n = 50), and 50 healthy control participants without PHD (n = 50). HRV parameters at rest in participants with a parental history and without PHD are shown in Table 1 (n = 150). Total power (P = 0.00) and HF (nu) (P = 0.00) were significantly reduced and LF (nu) (P = 0.00) and LF/HF ratio (P = 0.00) were significantly increased in subjects with positive PHD in comparison to those without PHD. Frequency-domain HRV parameters during acute mental stress in subjects with and without PHD are shown in Table 2. Total power (P = 0.00), HF (nu) (P = 0.00), and LF (m[s.sup.2]) (P = 0.00) were significantly reduced and a significant increase in LF (nu) (P = 0.00) and LF/HF ratio (P = 0.00) were found in subjects with positive PHD in comparison to those without PHD.

Frequency-domain HRV parameters during rest and stress in subjects with negative PHD are shown in Table 3 (n = 50). LF (m[s.sup.2]) (P = 0.00) is significantly increased and HF (nu) (P = 0.01) is significantly reduced during stress when compared to rest. Frequency-domain HRV parameters during rest and stress in subjects with one parent diabetic are shown in Table 4 (n = 50). LF (m[s.sup.2]) (P = 0.00) is significantly increased and HF (nu) (P = 0.01) is significantly reduced during stress when compared to rest.

HRV parameters during rest and stress in subjects with both parent diabetics are shown in Table 5 (n = 50). Total power (P = 0.041), HF (m[s.sup.2]) (P = 0.00), and HF (nu) (P = 0.00) were significantly reduced and LF (m[s.sup.2]) (P = 0.02), LF (nu) (P = 0.003), and LF/HF ratio (P = 0.00) significantly increased during stress when compared to rest.

DISCUSSION

This study assesses frequency-domain analysis of HRV during rest and stress in adolescents with a parental history of DM. Our study demonstrates reduced total power (m[s.sup.2]) (P = 0.00) and HF nu (HF) (P = 0.00) during rest in adolescents of both the parent diabetics when compared to controls having negative PHD, which is statistically significant showing altered cardiac autonomic modulation during rest with reduced parasympathetic activity. The study also demonstrates elevated LF nu (LF) during rest in adolescents of both the parent diabetics when compared to controls having negative PHD and also adolescents having single-parent diabetic, which is statistically significant showing increased sympathetic activity (P = 0.00).

The results are comparable to the study done by Tarek et al. who assessed frequency-domain HRV parameters in dyslipidemic adults with PHD which showed frequency-domain indices such as total power and HF (nu) were significantly (P = 0.05) decreased and LF (nu) and LF/HF ratio were significantly (P = 0.05) increased. [15] Goel compared the parasympathetic functions using deep breathing difference, immediate response to standing, and Valsalva ratio in adults whose parents are diabetics. Even though the study shows a decrease in parasympathetic function tests in adults with PHD, results were not statistically significant. [14] Tuppad studied parasympathetic function tests in subjects with a parental history of DM in relation to glycemic status. They found subclinical cardiac dysfunction in adults with PHD, which is not related to glycemic level. [18] Foss et al. also observed subjects with PHD showed reduced HRV in relation to altered diurnal variation of BP. [19] The possible mechanism behind parasympathetic dysfunction associated with increased cardiovascular morbidity is its association with insulin resistance and increased glucose production, leading to atherosclerosis. [14] Our study also demonstrates frequency-domain HRV parameters recorded during rest and acute stress in adolescents with parents having diabetes. Our study demonstrates that total power (P = 0.00) and HF (nu) (P = 0.00) are significantly reduced and LF (nu) (P = 0.00) is significantly elevated in subjects with positive PHD in comparison to those without PHD, which is statistically significant showing altered cardiac autonomic modulation, reduced parasympathetic activity, and also increased sympathetic activity which is augmented response to stress in offspring's having both parents diabetic. We compared the HRV parameters in all three groups during rest and stress. Our study shows that total power and HF (nu) are significantly reduced and LF nu is significantly increased during stress when compared to rest in both the adolescents with one parent and both parents diabetic, but augmented response was seen in them having both parents diabetic. In response to chronic stress, inadequate activation of stress system can lead to altered milieu interieur. After hypoglycemia, HRV recorded during rest and stress showed reduced baroreflex sensitivity and sympathetic activity. [20] Reduced HRV is seen in patients recovered from acute myocardial infarction due to increased sympathetic and reduced parasympathetic activity. [21] The above studies explain that reduced cardiac autonomic modulation is a better predictor of increased cardiovascular mortality. [22] Risk of developing CAN is also more in adolescents with a parental history of DM as they show altered HRV which can be due to elevated blood glucose levels, dyslipidemia, and obesity. [23]

Strength of Study

This is the first study to record the influence of parental DM on frequency-domain HRV parameters during acute stress.

Limitation of Study

Blood glucose levels of the adolescents with a parental history of DM were not estimated. The study can be further extended by assessing blood glucose levels and insulin resistance and correlating its value with the autonomic function tests.

CONCLUSION

Adolescents having a strong parental history of DM exhibit an altered cardiac autonomic modulation even before they develop the disease. They exhibit sympathetic overdrive and reduced parasympathetic activities during rest. They also exhibit an augmented response to acute mental stress when compared to those who have negative parental history of DM.

REFERENCES

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[5.] Kaprio J, Tuomilehto J, Koskenvuo M, Romanov K, Reunanen A, Eriksson J, et al. Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia 1992;35:1060-7.

[6.] Tillil H, Kobberling J. Age-corrected empirical genetic risk estimates for first-degree relatives of IDDM patients. Diabetes 1987;36:93-9.

[7.] Gibson G. Rare and common variants: Twenty arguments. Nat Rev Genet 2012;13:135-45.

[8.] Stranger BE, Stahl EA, Raj T. Progress and promise of genome-wide association studies for human complex trait genetics. Genetics 2011;187:367-83.

[9.] Vinik AI, Zeigler D. Diabetic cardiovascular autonomic neuropathy. Circulation 2007;115:387-97.

[10.] Albers AR, Krichavsky MZ, Balady GJ. Stress testing in patients with diabetes mellitus: Diagnostic and prognostic value. Circulation 2006;113:583-92.

[11.] Billman GE. Heart rate variability - A historical perspective. Front Physiol 2011;2:86.

[12.] La Rovere MT, Pinna GD, Maestri R, Mortara A, Capomolla S, Febo O, et al. Short-term heart rate variability strongly predicts sudden cardiac death in chronic heart failure patients. Circulation 2003;107:565-70.

[13.] Nagalakshmi V, Smruthi V, Shama, Rathnakarashetty G, Nallulwar SC. Cardiac autonomic neuropathy in type II diabetes mellitus patients and its association with the age of the patient, duration of disease and glycemic control. Indian J Physiol Pharmacol 2016;60:222-29.

[14.] Charu G, Tanu A, Syed NH, Deepankar, Salman SS, Bhawana S, et al. A case-control study of cardiovascular parasympathetic function tests in offspring's of Type 2 diabetes mellitus parents. Natl J Physiol Pharm Pharm 2016;6:364-7.

[15.] Tarek MA, Yousri MH, Ahmad AE. Heart rate variability in non-diabetic dyslipidemic young Saudi adult offspring of Type 2 diabetic patients. Natl J Physiol Pharm Pharm 2016;6:215-21.

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[17.] Chida Y, Steptoe A. Greater cardiovascular responses to laboratory mental stress are associated with poor subsequent cardiovascular risk status: A meta-analysis of prospective evidence. Hypertension 2010;55:1026-32.

[18.] Tuppad S, Aithala M, Bagali S. A study of glycemic status and parasympathetic functions in nondiabetic offspring's of Type 2 diabetes mellitus. Int J Biomed Adv Res 2013;3:887-90.

[19.] Foss CH, Vestbo E, Froland A, Gjessing HJ, Mogensen CE, Damsgaard EM, et al. Autonomic neuropathy in nondiabetic offspring of Type 2 diabetic subjects is associated with urinary albumin excretion rate and 24-h ambulatory blood pressure: The Fredericia study. Diabetes 2001;50:630-6.

[20.] Adler GK, Bonyhay I, Failing H, Waring E, Dotson S, Freeman R, et al. Antecedent hypoglycemia impairs autonomic cardiovascular function: Implications for rigorous glycemic control. Diabetes 2009;58:360-6.

[21.] Kleiger RE, Miller JP, Bigger JT Jr., Moss AJ. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 1987;59:256-62.

[22.] Szykowna I, Wasikowa R. Evaluation of the risk of diabetes in the offspring of patients with diagnosis of Type 2 diabetes. Pediatr Endocrinol Diabetes Metab 2009;15:71-83.

[23.] Law JR, Stafford JM, D'Agostino RB Jr., Badaru A, Crume TL, Dabelea D, et al. Association of parental history of diabetes with cardiovascular disease risk factors in children with Type 2 diabetes. J Diabetes Complications 2015;29:534-9.

Nagalakshmi Vijaykumar (1), Sanjivani Jadhav (1), Vandana Kattimani (2), Vitthal Khode (1)

(1) Department of Physiology, SDM College of Medical Sciences and Hospital, Dharwad, Karnataka, India, (2) MBBS Student, SDM College of Medical Sciences and Hospital, Dharwad, Karnataka, India

Correspondence to: Sanjivani Jadhav, E-mail: sanjuj03@gmail.com

Received: November 28, 2018; Accepted: January 20, 2019

Source of Support: Nil, Conflict of Interest: None declared.

DOI: 10.5455/njppp.2019.9.1135621012019
Table 1: Frequency-domain HRV parameters recorded during rest in
adolescents with and without a parental history of DM (n=150)

HRV parameters               Group I (n=50)         Group II (n=50)

Total power (m[s.sup.2])  3714.94[+ or -]101.39  3084.91[+ or -]52.67
LF (m[s.sup.2])           1035.32[+ or -]24.14   1060.87[+ or -]53.73
LF (nu)                     43.52[+ or -]2.94      45.90[+ or -]0.63
HF (m[s.sup.2])           2086.28[+ or -]75.12   1985.16[+ or -]800.12
HF (nu)                     56.54[+ or -]4.44      53.83[+ or -]5.11
LF/HF ratio                  0.76[+ or -]0.18       0.858[+ or -]0.01

HRV parameters              Group III (n=50)       F value     P value

Total power (m[s.sup.2])  2139.96[+ or -]94.78     2180.76     0.000 (*)
LF (m[s.sup.2])            547.96[+ or -]44.73        3.05     0.039 (*)
LF (nu)                     46.53[+ or -]1.02       303.586    0.00 (*)
HF (m[s.sup.2])            946.52[+ or -]360.12       3.073    0.062
HF (nu)                     53.03[+ or -]0.52       232.65     0.00 (*)
LF/HF ratio                  0.877[+ or -]0.02452   456.172    0.00 (*)

(*) P<0.05: Statistically significant difference, Group I: Negative
PHD, Group II: Positive PHD one parent DM, Group III: Positive PHD both
parents DM, Values expressed as mean[+ or -]SD. DM: Diabetes mellitus,
HRV: Heart rate variability, PHD: Parental history of diabetes, LF: Low
frequency, HF: High frequency, SD: Standard deviation

Table 2: Frequency-domain HRV parameter recorded during acute stress in
adolescents with and without a parental history of DM (n=150)

HRV parameters       Group I (n=50)         Group II (n=50)

Total power      3398.00[+ or -]101.23  2868.15[+ or -]194.42
LF (m[s.sup.2])  1310.35[+ or -]75.59   1543.67[+ or -]675.34
LF (nu)            45.28[+ or -]2.98      46.67[+ or -]1.08
HF (m[s.sup.2])  1593.43[+ or -]94.23    987.34[+ or -]563.98
HF (nu)            51.43[+ or -]8.69      45.79[+ or -]1.2
LF/HF ratio         0.88[+ or -]0.012      1.02[+ or -]0.04

HRV parameters     Group III (n=50)        F value   P value

Total power      965.54[+ or -]116.91     3665.653  0.00 (*)
LF (m[s.sup.2])  664.34[+ or -]56.78       350.957  0.00 (*)
LF (nu)           56.94[+ or -]4.06        350.957  0.00 (*)
HF (m[s.sup.2])  275.56[+ or -]12.11      2567.98   0.00 (*)
HF (nu)           42.82[+ or -]4.06        203.663  0.00 (*)
LF/HF ratio        1.3419[+ or -]0.16055   337.207  0.00 (*)

(**) P<0.05: Statistically significant difference, Group I: Negative
PHD, Group II: Positive PHD one parent DM, Group III: Positive PHD both
parents DM, DM: Diabetes mellitus, HRV: Heart rate variability, PHD:
Parental history of diabetes, LF: Low frequency, HF: High frequency

Table 3: Frequency-domain HRV parameters during rest and stress in
adolescents with negative parental history of DM using paired t-test
(n=50)

HRV parameters        Rest                   Stress             t value

Total power      3714.94[+ or -]101.39  3398.00[+ or -]101.23    0.263
LF (m[s.sup.2])  1035.32[+ or -]24.14   1310.35[+ or -]75.59    63.92
LF (nu)            43.52[+ or -]2.94      45.28[+ or -]2.98      2.635
HF (m[s.sup.2])  2086.28[+ or -]75.12   1593.43[+ or -]94.23     0.530
HF (nu)            56.54[+ or -]4.44      51.43[+ or -]8.69      6.667
LF/HF ratio         0.76[+ or -]0.18       0.88[+ or -]0.012   -27.66

HRV parameters   P value

Total power      0.609
LF (m[s.sup.2])  0.00 (*)
LF (nu)          0.108
HF (m[s.sup.2])  0.468
HF (nu)          0.011 (*)
LF/HF ratio      0.062

(*) P<0.05: Statistically significant difference. DM: Diabetes
mellitus, HRV: Heart rate variability, LF: Low frequency, HF: High
frequency

Table 4: Frequency-domain HRV parameters during rest and stress in
adolescents with one parent diabetic (n=50)

HRV parameters        Rest                   Stress             t value

Total power      3084.91[+ or -]52.67   2868.15[+ or -]194.42    7.609
LF (m[s.sup.2])  1060.87[+ or -]53.73   1543.67[+ or -]675.34  -27.66
LF (nu)            45.90[+ or -]0.63      46.67[+ or -]1.08     -4.35
HF (m[s.sup.2])  1985.16[+ or -]800.12   987.34[+ or -]563.98    2.635
HF (nu)            53.83[+ or -]5.11      45.79[+ or -]1.2      43.58
LF/HF ratio         0.858[+ or -]0.01      1.02[+ or -]0.04    -26.78

HRV parameters   P value

Total power      0.000 (*)
LF (m[s.sup.2])  0.062
LF (nu)          0.02 (*)
HF (m[s.sup.2])  0.108
HF (nu)          0.00 (*)
LF/HF ratio      0.000 (*)

(*) P<0.05: Statistically significant difference. HRV: Heart rate
variability, LF: Low frequency, HF: High frequency

Table 5: Frequency-domain HRV parameters during rest and stress in
adolescents with both parent diabetics (n=50)

HRV parameters          Rest                     Stress

Total power      2139.96[+ or -]94.78     965.54[+ or -]116.91
LF (m[s.sup.2])   547.96[+ or -]44.73     664.34[+ or -]56.78
LF (nu)            46.53[+ or -]1.02       56.94[+ or -]4.06
HF (m[s.sup.2])   946.52[+ or -]360.12    275.56[+ or -]12.11
HF (nu)            53.03[+ or -]0.52       42.82[+ or -]4.06
LF/HF ratio         0.877[+ or -]0.02452    1.3419[+ or -]0.16055

HRV parameters   t value     P value

Total power       64.572    0.041 (*)
LF (m[s.sup.2])   -4.35     0.02 (*)
LF (nu)            9.499    0.003 (*)
HF (m[s.sup.2])    7.609    0.00 (*)
HF (nu)           17.609    0.000 (*)
LF/HF ratio      -20.211    0.000 (*)

(*) P<0.05: Statistically significant difference. HRV: Heart rate
variability, LF: Low frequency, HF: High frequency
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Title Annotation:RESEARCH ARTICLE
Author:Vijaykumar, Nagalakshmi; Jadhav, Sanjivani; Kattimani, Vandana; Khode, Vitthal
Publication:National Journal of Physiology, Pharmacy and Pharmacology
Date:Mar 1, 2019
Words:3477
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