A STUDY OF HEART RATE VARIABILITY (HRV) IN HEALTHY OFFSPRINGS WITH PARENTAL HISTORY OF TYPE 2 DIABETES MELLITUS

We aimed to assess cardiac autonomic funcon using heart rate variability (HRV) parameters in healthy oﬀsprings having parental history of T2DM. A comparave cross-seconal study was carried out in the laboratory of department of Physiology enrolling 30 healthy oﬀsprings of non-diabec parents (Group 1) and 30 healthy oﬀsprings of diabec parents (Group 2). Anthropometric, biochemical and cardiovascular variables were assessed using standard procedures. Time domain and frequency domain parameters of HRV spectrum were assessed using photoplethysmography principle. HRV ﬁndings revealed that markers of sympathec regulaon were signiﬁcantly higher and those of parasympathec funcon were signiﬁcantly reduced in subject group having parental history of T2DM. LF/HF rao was signiﬁcantly increased suggesng sympatho-vagal imbalance in oﬀspring of diabec parents even in their euglycemic state. is in of characterized by reduced vagal and pronounced would of such dysautonomia and reducing the life-threatening eﬀects on oﬀspring having parental history of T2DM. ABSTRACT


Introduc on
Type 2 diabetes mellitus (T2DM) is a heterogeneous polygenic metabolic disease condi on that is caused by insulin resistance leading to hyperglycemia. Since, T2DM is gene cally inherited and autonomic dysfunc on is its major complica ons, healthy offsprings of diabetes parents are highly vulnerable to manifest dysautonomia leading to insulin resistance.

Objec ves
We aimed to assess cardiac autonomic func on using heart rate variability (HRV) parameters in healthy offsprings having parental history of T2DM.

Methodology
A compara ve cross-sec onal study was carried out in the laboratory of department of Physiology enrolling 30 healthy offsprings of non-diabe c parents (Group 1) and 30 healthy offsprings of diabe c parents (Group 2). Anthropometric, biochemical and cardiovascular variables were assessed using standard procedures. Time domain and frequency domain parameters of HRV spectrum were assessed using photoplethysmography principle.

Result
HRV findings revealed that markers of sympathe c regula on were significantly higher and those of parasympathe c func on were significantly reduced in subject group having parental history of T2DM. LF/HF ra o was significantly increased sugges ng sympatho-vagal imbalance in offspring of diabe c parents even in their euglycemic state.

Conclusion
Altera on of cardiovascular autonomic func on is found in healthy offspring of diabe c parents, characterized by reduced vagal ac vity and pronounced sympathe c regula on. Assessment of cardiac autonomic func on would help in mely detec on of such dysautonomia and reducing the life-threatening effects on offspring having parental history of T2DM. factors. Diabe c pa ents have higher probability of having 3 one of his/her parents as diabe c. Even being asymptoma c, non-diabe c offspring of diabe c parents may manifest autonomic neuropathy that support an evidence to the 4,5 evolu on of diabe c spectrum through gene c inheritance. Diabe cs had autonomic nervous system derangement as evidenced by Heart Rate Variability (HRV), which is a well- [6][7][8][9] known risk factor for cardiac events and death. Owing to its inheritable nature, the offspring of diabe c parents are gene cally prone to develop autonomic imbalance and diabetes. Timely assessment of cardio-autonomic func on would be helpful in preven ng and reducing the impact of 10,11 diabetes on global health subserving good quality of life. Therefore, we aimed to find out the early changes in cardiac autonomic regula on among healthy offspring of diabe c parents.

METHODOLOGY
A compara ve cross-sec onal study was conducted in the laboratory of department of physiology of Birat Medical College & Teaching Hospital. We enrolled a total of sixty healthy subjects of either sex, out of which control group consisted of 30 healthy offspring of non-diabe c parents (Group 1) and targeted group consisted of 30 healthy offspring having parental history of type 2 diabetes mellitus (Group 2). Subjects with known history of chronic illness, on any medica ons, consuming alcoholic drinks or tobacco, with endocrine disorders or with any diseases that could alter HRV were excluded from the study. Ethical clearance was obtained from the Ins tu onal ethical review commi ee of the Ins tute. Detailed informa on about research procedures was provided and an informed consent was obtained from subjects for voluntarily par cipa on in the study.
Subjects were requested to come 15 minutes earlier before the commencement of test so as to allow them to familiarize properly with the tes ng environment and a ain baseline res ng condi on. They were requested not to involve in any strenuous physical ac vity on the day of the test and to avoid heavy meal two hours prior to the test session. Detailed medical and family history were taken and anthropometric variables like height, weight, BMI were measured. The subjects were allowed to rest in supine posi on for 15 minutes and cardiovascular variables like systolic&diastolic blood pressure and heart rate were measured.
HRV parameters were assessed (at room temperature 20-24°C) by using validated photoplethysmography applica on, smartphone-based system for real-me pulse-to-pulse (PP) interval me series acquisi on by frame-to-frame camera image processing.The developed smartphone applica on acquires image frames from built-in rear-camera at the maximum available rate (30 Hz) and the smartphone GPU is used by Renderscript API for high performance frame-byframe image acquisi on and compu ng in order to obtain photoplethysmography signal and PP interval me series. [12,13] Time domain measures [mean RR interval (Mean RR), Standard devia on of normal-to-normal RR intervals (SDNN), root mean square successive difference (RMSSD), the propor on of NN50 to the total number of NN intervals (pNN50)] and frequency domain measures [normalized low-frequency power (LFnu), normalized highfrequency power (HFnu), ra o of LFnu to HFnu (LF-HF ra o) and total power (TP)] were measured. Mean RR, SDNN, RMSSD, pNN50 and HFnuare measures ofparasympathe c ac vity. TP shows overall autonomic ac vity, LFnu signifies sympathe c ac vity whereas LH/HF ra oreflects the 12 sympathovagal balance.

Sta s cal Analysis
Independent t-test was done to determine the level of significance between the control group and study group using SPSS version 25. The data were expressed in mean ± SD. The sta s cal probability p< 0.05 was considered to be sta s cally significant.

RESULTS
Basic subject characteris cs, anthropometric, biochemical and cardiovascular parameters of the study group and control group are shown in Table 1. SBP: Systolic blood pressure, DBP: Diastolic blood pressure; * denotes sta s cally significant(p<0.05) Table 1 shows that age, height BMI and blood sugar level were comparable between the groups whereas the parameters like weight, waist-hip ra o, heart rate and systolic blood pressure were found to be sta s cally significant in offspring of diabe c parents when compared to those of non-diabe c parents. Comparison between frequency and me domain parameters of heart rate variability is shown in Table 2 & 3. The results showed sta s cally significant difference in the HRV spectral power between the groups. Mean RR, SDNN, RMSSD, pNN50 and HFnu which are the measures of parasympathe c ac vity were found to be significantly reduced in group 2 reflec ng compromised parasympathe c component of cardiovascular autonomic func on. Similarly, parameters represen ng sympathe c component were found to be significantly increased in offspring of diabe c parents.
Significantly increased LF/HF ra o made the result clearer in understanding that the individuals with the parental history of type II diabetes mellitus have deranged sympathovagal balance.

DISCUSSION
Many extensive researches are carried out to delineate the effect of family history of T2DM on offspring. Altered cardiovascular autonomic func on leading to risk of development of diabetes have been reported among 14,15 healthy offspring of pa ents with T2DM.
Literature suggests that progenies of diabe c parents are more vulnerable to develop diabetes, but early outcome of gene c transmission on such offspring before the 5,16,17 symptoma c onset of disease is overlooked. In our study, we found out that the parameters like age, height, BMI, diastolic BP, blood sugar level were comparable whereas parameters like weight, waist-hip ra o (WHR), heart rate and systolic BP, despite of being within normal range, were found to be differing significantly between the groups. Contrary to our result, a study done by Praveen EP et al. and Samata Padaki et al. showed significantly higher BMI in normoglycemic healthy offspring of T2DM parents when 18,19 compared to those of non-diabe c parents.
However, significantly higher waist to hip ra o was observed in study done by Samata Padaki et al. which was in accordance to our result. Few other studies also have drawn upon inference that central obesity, as measured by the waist to hip ra o, is 20,21 importantly and independently associated with T2DM. WHRbeing more appropriate predic ng parameters than BMI for its associa on with diabetes, significantly higher WHR in our study reflects the level of vulnerability of offspring having parental history of T2DM towards 22 development of diabetes and cardiovascular disease. The HRV findings in our study showed extensive differences in cardiovascular autonomic func on in between the two groups. The me and frequency domains of HRV showed that the vagal ac vity was highly compromised subserving to enhanced sympathe c ou low in subjects having parental history of T2DM. Significantly increased Lfnu revealed that sympathe c component is markedly pronounced whereas significantly reduced HFnu, Mean RR, SDNN, RMSSD, pNN50 and TP reflects diminished parasympathe c component deranging overall cardiovascular autonomic features. Higher LF/HF ra o in targeted group project the inference of altered sympathovagal balance even when gene cally inherited disease outcome is not manifested. These altera ons clearly delineate that subject having family history of T2DM may have underlying autonomic changes predisposing to development of diabetes and cardiovascular autonomic neuropathy. Similar findings like our study were shown by some of the studies, however, F.J Nerves et al. stated that family history of T2DM 14,[24][25][26] have no any influence on HRV spectrum. Some studies reported that even in the absence of insulin resistance, autonomic disturbance may occur whereas few studies correlated the development of autonomic dysfunc on with that of hyperinsulinemia and insulin 27,28 resistance. Central obesity, adiposity and increased free fa y acids level in the body may cause insulin resistance which could lead to hyperinsulinemia predisposing autonomic altera on. Interac on of insulin on hypothalamus leads to ac va on of sympathe c component and suppress the parasympathe c component decreasing the vagal 29 ac vity. Hence, from these observa ons we can deduce that healthy offspring of diabe c parents are at high risk of developing autonomic disorders along with obesity due to gene c inheritance leading to insulin resistance manifes ng diabetes mellitus at later stage.

CONCLUSION
Altera on of cardiovascular autonomic func on is found in healthy offspring of diabe c parents, characterized by reduced vagal ac vity and pronounced sympathe c regula on. Gene c factor may be one of the major causes for the manifesta on of such features which might predispose the popula on to more hazardous complica ons, even before the symptoma c diagnosis of the disease. Assessment of cardiac autonomic func on using modality like HRV would help in early detec on of such dysautonomia and reducing the life-threatening effects on offspring having parental history of T2DM.

LIMITATIONS OF THE STUDY
We have not correlated HRV findings with other biochemical findings.