Ageing is associated with changes in cardiac autonomic control as measured by Heart Rate Variability (HRV). Not many studies have explored the influence of gender on age-related changes in cardiac autonomic regulation. This study evaluated the gender differences in age-associated changes in cardiac autonomic nervous activity by assessing HRV using frequency domain analysis of short-term stationary R-R intervals. HRV was studied in healthy males and females ranging in age from 6 to 55 years. Total power and absolute power in High-Frequency (HF) and Low-Frequency (LF) components as well as HF in normalized unit declined significantly with ageing. The HF/LF ratio was significantly higher in the adolescent and adult females compared to male of these age groups. This study suggests that gender differences exist in age-related changes in HRV. The finding that gender differences are limited to adolescent and adult age groups may indicate a role for female sex hormones in cardiac autonomic modulation.
The autonomic nervous system plays a major role in the regulation of the cardiovascular system under both physiological and pathological conditions [
Normal human ageing is associated with changes in the autonomic control of several biological functions. Orthostatic maneuver such as going from supine to standing may trigger dizziness more frequently with ageing, reflecting the diminished cardiovascular sympathetic modulation. Similarly, the recovery of heart rate after exercise becomes blunted with age as a result of sluggish cardiac vagal response to adjust the cardiac activity. The two subsystems sympathetic and parasympathetic of autonomic nervous system mature with time, but degree of the changes due to ageing is different because of their divergent neural pathways. Therefore symaptho-vagal balance also fluctuates with ageing [
There are a few reports on gender-related differences in cardiac autonomic tone. In a population of normal subjects, using short-term and long-term recordings, there was found predominance of parasympathetic over sympathetic tone in women and vice versa in men. It was also demonstrated that the gender-related difference in parasympathetic regulation diminishes after the age of 50, while sympathetic dominance in men disappears significantly later [
A total of 267 healthy volunteers of which 126 males and 141 females between the age group of 6–55 years were recruited. The subjects were from wide range of social and economic classes. The participants were students and faculty of the Institute in Bangalore, South India. Study population was classified into eight groups based on age and gender. That is, men and women are in four age groups: children (6–11 yrs), adolescents (12–19 yrs), Young adults (20–40 yrs), and middle aged (41–55 yrs). Subjects belonging to all the study groups were well nourished based on their body mass Index. The female subjects included in children and middle-aged group were prepubertal and postmenopausal respectively. Menstruating female subjects participated were controlled for menstrual cycle and they were recruited during mid-follicular phase of their menstrual cycle. Subjects were screened after taking detailed medical history and measuring basal blood pressure. Subjects with hypertension and history of diabetes mellitus and any other chronic illness were excluded from the study. Subjects on oral contraceptive pill, hormonal replacement therapy, and drugs that alter the cardiovascular functions were also excluded from the study. Informed written consent was obtained from all participants and in case of children the parental consent was also obtained. The experiment protocol was approved by Ethics committee of the Institute.
All the experiments were conducted in the morning after overnight fasting. Subjects refrained from smoking, caffeinated beverages for at least 12 hours prior to the experiment, and also instructed to avoid strenuous physical activity from the previous evening.
To quantify heart rate, the analog ECG signal was obtained using lead II to obtain a QRS complex of sufficient amplitude and stable base line. ECG signals were conveyed through an A/D converter (Biopac MP 30, Biopac system INC. Santa Barbara, CA) at a sampling frequency of 500 Hz to PC and were analyzed offline after visual checking of abnormal ECG. Heart rate variation during normal breathing for a period of 5 minutes was recorded, with subject supine, awake, and resting. The data gathered was subjected to frequency domain analysis of HRV.
Frequency domain analysis was performed using nonparametric method of Fast Fourier Transformation. Data was edited manually for artifacts and ectopic beats. HRV software used a peak detection algorithm to find the “R” wave, which was done at a resampling rate of “4 Hz”. A minimum of 256 data points was required to perform a spectral analysis. To attain 256 data points a duration of 5 minutes of ECG recording was required. The linear trend was removed from each data set to avoid its contribution to low-frequency power. The power frequency spectrum was subsequently quantified into standard frequency-domain measurements including total variance, HF (0.15–0.4 Hz), LF (0.04–0.15 Hz), and HF/LF ratio.
Following the ECG recording, and daily physical activity level was estimated using a validated physical activity questionnaire which assessed physical activity pattern over the preceding month [
Statistical analysis was performed with an SPSS package (version 10.5). Normality of the distribution was assessed with the Kolmogorov-Smirnov goodness of fit test. Because of skewed distribution of absolute values of spectral powers, they were also analyzed after logarithmic transformation. Data is expressed as mean ± SEM with 95% confidence interval. All the variables were compared between age and gender groups using Two-Way ANOVA, with the test for age and gender effects as well as their interaction. Looking for the overlap of the confidence interval, the study assessed the differences between specific groups. Variables for which age-gender interaction exists and the effect of age amongst the specific groups were compared independently for males and females. For the remaining variables, comparison was done using combined values. In all instances null hypothesis was rejected at
Of the 267 healthy volunteers (126 males and 141 females) originally enrolled in the study, 15 were excluded due to reasons like presence of frequent premature ventricular beats, experience of syncope during ECG recording, and inability of the software to analyse the HRV.
Table
Subject characteristics.
Parameter | Children | Adolescents | Young adults | Middle-aged | ||||
Males | Females | Males | Females | Males | Females | Males | Females | |
( | ( | ( | ( | ( | ( | ( | ( | |
Age (yrs) | ||||||||
Height (cm) | ||||||||
Weight (kg)* | ||||||||
SBP*# | ||||||||
DBP*# | ||||||||
RHR* | ||||||||
BMI* | ||||||||
PAL | N.A@ | N.A@ |
(i) Data expressed as mean ± SE.
(ii) *significantly different across the age group.
(iii) #significantly different between males and females.
(iv) SBP: Systolic blood pressure (mm of Hg).
(v) DBP: Diastolic blood pressure (mm of Hg).
(vi) RHR: Resting heart rate (Beats per minute).
(vii) BMI: Body Mass Index (kg/m2).
(viii) PAL: Physical activity level.
(ix) @Not applicable since standard procedure was not available.
Table
Comparison of heart rate variability spectral power (absolute power) in males and females of different age groups (
Children | Adolescent | Young adults | Middle-aged | |
---|---|---|---|---|
Total power (0–0.4 Hz) (ms2) | ||||
Males | ||||
(2006–3381) | (1446–2697) | (736–1606) | (313–814) | |
Females | ||||
(1756–3110) | (1112–2112) | (846–1456) | (308–448) | |
Total | 2564 ± 234 | 1822 ± 194 | 1158 ± 124*† | 520 ± 72*†‡ |
(2094–3033) | (1434–2209) | (909–1407) | (375–665) | |
Two-way ANOVA: | ||||
High-frequency power (0.15–0.4 Hz) (ms2) | ||||
Males | 1645 ± 209 | 1057 ± 165 | 533 ± 98 | 238 ± 56 |
(1215–2074) | (720–1394) | (331–734) | (121–355) | |
Females | 1561 ± 254 | 999 ± 155 | 628 ± 98 | 209 ± 56 |
(1040–2082) | (683–1314) | (427–825) | (128–289) | |
Total | 1603 ± 163 | 1025 ± 112 | 585 ± 69*† | 223 ± 34*†‡ |
(1250–1931) | (801–1275) | (446–724) | (155–291) | |
Two-way ANOVA: | ||||
Low-frequency power (0.04–0.15 Hz) (ms2) | ||||
Males | 1049 ± 148 | 1001 ± 187 | 638 ± 118 | 325 ± 66 |
(745–1352) | (619–1384) | (396–879) | (188–461) | |
Females | 872 ± 108 | 584 ± 111 | 522 ± 71 | 269 ± 45 |
(650–1093) | (357–812) | (377–666) | (175–363) | |
Total | 960 ± 92 | 760 ± 103 | 573 ± 65*† | 296 ± 39*†‡ |
(776–1144) | (583–997) | (442–703) | (217–376) | |
Two-way ANOVA: |
Data expressed as mean ± SEM and 95% Confidence Intervals.
*Significantly different from children group.
Total power and absolute power in HF and LF components HF in normalized unit as well as HF/LF declined significantly with ageing (
The present study examined the effect of gender on age associated changes in cardiac autonomic activity. Autonomic regulation of heart rate was assessed by frequency domain analysis of short-term HRV at supine resting condition.
The findings of this study indicate that healthy ageing is associated with gradual reduction of overall fluctuation in autonomic input to the heart as well as vagal index of HRV which are reflected by significant decline in total power and HF in absolute power (Table
Reduction in HF nu and the ratio of HF/LF with ageing exhibited a different pattern in males and females (Figures
The figure shows that age-related decline of HF nu across four age groups in both males and females as well as gender-related difference in adolescent age group. *Significantly different from children group; #Significantly different from adult group. $Significantly different from males using two-way ANOVA.
The figure shows ratio of HF to LF ratio across four age groups in males and females. It depicts the age-related decline in HF/LF ratio in males and females. Females have significantly higher HF/LF ratio as compared to males in the adolescent and adult groups. In the two extreme of ages the ratio is almost similar; *significantly different from children group; #significantly different from adult group; $Significantly different from males of similar age group using two-way ANOVA.
The analysis of gender-related difference in HRV study indicates that HF in relative value (nu) and HF/LF ratio were significantly higher in women. However, HF component of HRV, denoting vagal modulation to heart, was not significantly different between men and women, when expressed in absolute value. Total power of HRV also did not differ between males and females; further LF in normalized and absolute values was significantly lower in females. The data also shows that the gender differences for these indices are age dependent, since differences exist for HF nu, only in adolescent group subjects, and for HF/LF ratio only in adolescent and adult age groups.
The higher HF (nu) and HF/LF ratio observed in the female subjects of this study can be attributed to lower LF in absolute and relative values in females. It has been suggested that normalized powers were superior at detecting the effect of gender and these indices describe a balance, rather than a modulation of individual limbs of ANS [
In this study for the first time the gender differences in cardiac autonomic nervous function in a population of wide age range were studied. Gonadal hormones play an important role in mediating gender differences observed in many physiological parameters. It is assumed that menopause constitutes a significant mile stone in terms of changes in cardiovascular physiology and risk for developing cardiovascular diseases. A gender difference in risk of developing cardiovascular disease tends to diminish in the postmenopausal age groups. Therefore, we chose the postmenopausal age as the upper cut-off for subject recruitment into this study. Further, as this study focused on healthy volunteers, recruitment of subjects above 55 years would have resulted in interference of many altered physiological conditions associated with ageing. It has been reported that autonomic function is modified in altered nutritional status [
Measurements of HRV components, namely, HF in absolute power represent parasympathetic control and the LF represents both sympathetic and parasympathetic modulation to heart. Relative measurements (HF nu, LF nu) provide quantitative evaluation of graded changes in the state of parasympathetic and sympathetic modulation [
The gender-related differences in autonomic nervous system have been studied earlier. Most of the existing data on gender-related differences for power spectral variables belong to the subjects of age group above 40 years [
The mechanism for gender differences in age-associated changes in cardiac autonomic function is obscure. Differences in the autonomic system may be due to differences in afferent receptor stimulation, in central reflex transmission, in the efferent nervous system, and in postsynaptic signaling. At each of these potential sites of difference, there may be effects due to different size or number of neurons, variations in receptors, differences in neurotransmitter content or metabolism, as well as functional differences in the various components of the reflex arc.
Ageing is associated with an increased dependency on sympathetic control of cardiac responses and reduced vagal responsiveness. The blunted vagal modulation of the heart may be related to altered neural vagal discharge to sino-atrial node or to a change in the ability of the cardiac pacemaker itself. Cardiac electrophysiological studies have demonstrated a progressive decline in sino-atrial conduction and sinus node recovery time with age. Studies have revealed an increase in empty Schwan cell bands or reduced number of fibers in the vagus nerve among old subjects [
A few studies have indicated that female sex hormones influence autonomic modulation and estrogen has a facilitating effect on cardiac vagal function [
For assessing gender differences in age-related changes in autonomic modulation, the current study included large sample size subjects from children to middle age, where stratified agewise classification is continuous. As altered nutrition, physical activity level, and phases of menstrual cycle are important confounding variables in measurement of heart rate variability, in the current study, the various study groups were controlled for the above-mentioned factors.
Estimation of gonadal hormones and correlation of its levels with HRV indices would have provided better understanding of influence of hormones on gender differences in age-related changes cardiac autonomic activity. The current study has not estimated the gonadal hormonal levels of the participants. Though menopause is significant mile stone in cardiovascular research, recruitment of subjects above 55 years would better explain age-related changes in autonomic function.
Outcome of this study reveals that the assessment of sympathetic and parasympathetic nervous activity for risk stratification of autonomic related disorder should control for variables like age and gender. Considering physiological differences in evaluation of autonomic dysfunction would be useful for diagnosis and treatment of autonomic-related diseases.
The outcomes of the study indicate that there is scope for further studies on investigation of autonomic nervous activity using sensitive techniques like MSNA and also evaluation of autonomic function in multiple organ systems to provide an index of age-related global autonomic nervous modulation.
This study concludes that gender differences exist in age-related changes in HRV. The finding that gender differences are limited to adolescent and adult age groups may indicate a role for female sex hormones in cardiac autonomic modulation. The exact impact of the neurohormonal axis on the age-related changes in cardiac autonomic nervous system remains to be elucidated.