European Journal of Cardiovascular Medicine

Menopause is the time of cessation of ovarian function resulting in permanent amenorrhea. Menopause literally means the "end of monthly cycles".¹  The main pathophysiology of menopause is cessation of ovarian activity and fall in estrogen level, which causes a rebound increase in Follicle stimulating hormone (FSH) and Luteinizing hormone (LH) secretion by anterior pituitary gland. The loss of estrogen often causes marked early and late physiological changes in the women. Early changes are hot flashes, sweating, insomnia, irritability, psychological symptoms etc. and late changes are arthritis, osteoporosis, bone fracture, cardiovascular accidents etc. ²

Postmenopausal women have alteration in their autonomic status with higher sympathetic and lower vagal tone compared with premenopausal women. Epidemiological evidence suggests that the hormonal changes during this period, particularly the decline in estrogen, are primary factors contributing to the increased risk of CVDs.³     

Heart rate variability is defined as cyclic changes or fluctuations of heart periods (R-R intervals) around the mean heart rate over time. The amount of short- and long-term variability in heart rate provides a measurement of autonomic nervous system (ANS) balance.⁴

HRV has been utilized in scientific research to characterize the cardiac control mechanism of the ANS. The ANS is divided into two major divisions, sympathetic and parasympathetic. Activation of the sympathetic division results in cardiac responses of vasoconstriction, increased force and rate of cardiac contractility, and increased conduction velocity in the myocardium. Exerting an antagonistic response to sympathetic function, the parasympathetic division of the ANS induces selective vasodilation of blood vessels and decreases the rate and force of cardiac contractility.⁵

The power spectrum of HRV has two components. They are high frequency (HF) component and low frequency (LH) components. HF component is indicative of parasympathetic activity and LF component is indicative of sympathetic activity. LF/HF ratio reflects sympathovagal balance. There is also another parameter called total power, which is indicative of parasympathetic activity. Increased HF, reduced LF, and LF/HF ratio indicate parasympathetic predominance whereas reduced HF, increased LF, and LF/HF ratio indicate sympathetic predominance. Predominant parasympathetic activity favors good cardiovascular health. Predominant sympathetic activity is an important cardiovascular risk factor.⁶Menopause causes an imbalance of the autonomic nervous control of the cardiovascular system that shifts toward sympathetic hyperactivity.

Epidemiological studies have indicated that women have a lower incidence of cardiovascular disease compared to their male counterparts but this difference decreases after menopause.^8,9 Although many Western studies have shown that there is sympathetic hyperactivity in postmenopausal women compared to pre-menopausal women, very few studies have been conducted in Indian population. Hence the aim of the present study was to compare HRV between premenopausal (reproductive) and postmenopausal women among Indian population.

Though menopausal status is associated with autonomic changes, there are very few studies on the detailed autonomic functions in non-hypertensives, non-diabetics postmenopausal women.

Therefore, the present study aimed to assess the heart rate variability in early postmenopausal and late premenopausal women of 40-55 years and compared the parameters between them and relationship between heart rate variability and menopausal symptoms.A

The present study was a hospital based cross sectional study undertaken to compare heart rate variability between pre- and post- menopausal women. The study was approved by the Ethical Committee of the Medical College. The study period was June 2018 to June 2021.

The study involved 140 women who were divided into two groups:

Group I - pre menopausal women of age group 40- 55 years (n= 70)

Group II – post menopausal women of age group 40-55 years (n=70)

A detailed medical and personal history and clinical examination of the women (Annexure B) was carried out and those who met the criteria were selected for the study. Written informed consent (Annexure D) was taken before the clinical examination and data collection. The women were selected by Simple Random Technique from the women attending the Gynaecology OPD in our institute/ from general population fulfilling the following inclusion and exclusion criteria.

INCLUSION CRITERIA:

• Premenopausal Group: apparently normal women of age group 40-55 years with regular menstrual cycles.
• Postmenopausal Group: apparently normal women of age group 40-55 years whose menstruation stopped at least one year before.

EXCLUSION CRITERIA:

• Women having hypertension, diabetes, heart disease, asthma, family history of CAD
• Any chronic disease or associated factors that may affect the autonomic reflexes, neurological or psychiatric diseases.

• Chronic alcoholics, smokers
• Women receiving hormone replacement therapy and any medication that have been reported to affect autonomic function (like autonomic blockers eg. Prazosin, Atenolol Hexamethonium)
• Perimenopausal women (having irregular menstrual cycles)
• Women who underwent surgical menopause.

General Protocol:

 Women attending Gynaecology OPD or were accompanying with patient were explained everything about the study in detail and query if any. Detailed history was taken of these women and was explained about the investigations and study. Appointment was given of later date to women fulfilling criteria and we’re asked to come after a sound sleep and to avoid caffeinated drink on day of examination. On the day of examination data was obtained by clinical history and physical examination was done after 15 minutes of rest and was transferred to specific designed questionnaire-Menopausal rating scale. Later a detailed investigation for ECG and HRV was done of women following standard protocol. Standing height was measured. Weight was measured in kg with KRUPS weighing machine in light weight garments without foot wears. BMI was calculated as weight in (kg) / height (m2) Resting heart rate was recorded in supine position. The blood pressure (BP) was measured with sphygmomanometer by the standard auscultatory Riva-Rocci method from the right upper arm in supine position. Baseline ECG was recorded in lead II with the help of Lab chart 8.0 of AD instrument. Women were asked to lie down comfortably on the wooden table in supine position under optimum environmental conditions in quiet surrounding. They were asked to keep aside all electronic devices and metallic objects. After five minutes rest, three limb leads were attached on the extremities with conduction jelly and continuous ECG was recorded in supine position. Heart rate variability parameters were measured including SDRR (Standard deviation of RR interval), RMSSD (Root mean square of successive differences), pRR50 (percentage of successive RR interval), VLF (Very low frequency), HF (High frequency), LF (Low frequency), LF/HF ratio (Low frequency/High frequency ratio)

Data Entry and Analysis: Data entered using Microsoft excel 2007 and analysed using STATA Version 14.0

Data was summarized as frequency tables and histogram. Categorical variables were reported as proportion. Continuous data were described as mean (standard deviation) or medians (interquartile range) depending on the distribution of data. The student t- test and ANOVA were applied in the following results. P<0.05 was considered statistically significant.

Table 1: Distribution of parameters of Heart rate variability Heart rate variability among two groups:

(* P value >0.05 statistically not significant (NS) by un paired T test)

The difference in mean SDRR, RMSSD, pRR50, VLF and HF among women in two groups was statistically significant. (P<0.05)

Similarly, LF and LF/HF ratio in post-menopausal women was increased compared to pre-menopausal women and this difference in mean LF and LF/HF ratio among women in two groups was statistically significant. (P<0.05)

Table 2: Distribution of parameters of Heart rate variability among asymptomatic and symptomatic women in post-menopausal group:

The various heart rate variability parameters like SDRR, RMSSD, pRR50, VLF and HF(nu) in symptomatic post-menopausal women was decreased compared to asymptomatic post-menopausal women and this difference in mean SDRR, RMSSD, pRR50, VLF and HF among women in two groups was statistically significant. (P<0.05)

Similarly, LF and LF/HF ratio in symptomatic post-menopausal women was increased compared to asymptomatic post-menopausal women and this difference in mean LF(nu) and LF/HF ratio among women in two groups was statistically significant. (P<0.05)

Table 3: Distribution of parameters of Heart rate variability in Post menopausal symptomatic women by severity of Hot flashes:

(* P value >0.05 statistically not significant (NS) by ANOVA test)

According to menopausal rating scale, as the severity of hot flashes increased from mild to severe among symptomatic women, the heart rate variability parameters like VLF, HF(nu) decreased. This difference in mean VLF and HF(nu) was statistically significant. (P<0.05)

Table 4: Distribution of parameters of Heart rate variability in Post menopausal symptomatic women by severity of sleep problems:

(* P value >0.05 statistically not significant (NS) by un paired T test)

The difference in mean SDRR, RMSSD, pRR50, VLF,HF(nu) and LF/HF ratio was statistically significant. (P<0.05)

Table 5: Distribution of parameters of Heart rate variability in Post menopausal symptomatic women by severity of depression:

(* P value >0.05 statistically not significant (NS) by un paired T test)

The difference in mean SDRR, RMSSD, pRR50, VLF, LF (nu),HF(nu) and LF/HF ratio was statistically significant. (P<0.05)

Menopause is the physiological phenomenon which a woman undergoes as she ages. The menstruation stops because of complete loss of ovarian functions. Scientifically menopause is defined as permanent cessation of menstruation for 12 months. During this phase of menopause transition woman undergoes certain social, psychological, reproductive and physical changes.¹⁰These changes has implications on their health such that they become susceptible for certain ailments earlier than similar age men. Changes in the neuroendocrine system due to the loss of ovarian function at menopause are widely studied and includes changes in mood, memory, cognition, behaviour, immune function, locomotor system, and cardiovascular functions. ¹¹

The present study was a conducted to study heart rate variability in pre- and post-menopausal women and its association with menopausal Symptoms in a tertiary care institute. The results of the study suggested that there was significant difference in HRV between postmenopausal and premenopausal women. It was observed that post-menopausal women had a significantly reduced fluctuation in Heart rate, which is reflected by HF (nu). There was shift in of cardiac autonomic tone towards sympathetic dominance in post-menopausal women as the study showed higher LF (nu) and ratio of LF to HF in postmenopausal women.

The study population selected was in the narrow range of age so as to avoid the confounding effect on autonomic function within narrow range to minimize the effect of age on autonomic function.

In present study, it was found that SDRR, RMSSD & pRR50 was significantly reduced in post-menopausal women suggesting decrease in vagal tone in postmenopausal women. The study done by Subhashri et al ¹² showed RMSSD significantly less (P< 0.00) in post-menopausal group compared to premenopausal group. These findings were similar to present study, whereas SDNN (P= 0.27) and pNN50 (P= 0.30) showed no statistical difference between the groups which was in contrast to present study. Studies done by Neves VF et al ⁷ and Ribeiro TF et al ¹³ showed significant decrease in RMSSD in post-menopausal women which was similar to our study.

The frequency domain parameters included HF, LF and LF/HF ratio. HF reflects the parasympathetic activity, LF reflects sympathetic and LF/HF ratio tells about sympathovagal balance⁶. In present study, HF(nu) was statistically lower in post-menopausal women compared to pre-menopausal women while LF(nu) and LF/HF ratio were significantly higher in post-menopausal women. LF: HF ratio was significantly raised in the postmenopausal group which suggest sympathovagal balance shifting to sympathetic overactivity. Atreya Tanu et al¹⁴ also conducted study on Pre and Post Menopausal Women from Health Care Profession and found significantly lower high frequency power and higher low frequency power (LF) and LF/HF Ratio significantly higher among post-menopausal women which is similar to our study.

The secondary objective of this study was to find the correlation heart rate variability and menopausal symptoms. In present study, the various heart rate variability parameters like SDRR, RMSSD, pRR50 and HF in asymptomatic post-menopausal women were compared with symptomatic women and it was found that these parameters were statistically different in two groups(p<0.05). Lee JO et al¹⁵ studied correlation of menopausal symptoms with heart rate variability (HRV) observed Low frequency/high frequency (LF/HF) ratio was significantly higher in symptomatic women, compared with asymptomatic women (P < 0.05). This finding was similar to present study. Similarly in a study reported by Ahn et al¹⁶. which applied HRV as a standard of climacteric(menopausal) symptoms reported that in the group with severe menopausal symptoms, the SDNN and the RMSSD were reduced. Lee JO et al¹⁵ studied correlation of menopausal symptoms with heart rate variability (HRV) observed LF/HF ratio of HRV parameters showed a significant increase in moderate or severe degree of "hot flashes" (P < 0.05). Freedman RR et al¹⁷, Hoikkala H et al¹⁸ showed an increase in low frequency HRV, a measure of sympathetic function, during hot flashes.

Several studies suggest that hot flashes induce wakefulness during sleep, resulting in chronic sleep deprivation and fatigue¹⁹. Consequently, deterioration of the sleep quality lowers the level of activity of the parasympathetic nerves. When the autonomic nervous system, which maintains the electrical stability of heart, is impaired, the probability of arrhythmia or consequent death may increase²⁰. Our study found that the level of imbalance of the autonomic nervous system was present suggested by less HF(nu) and this is seen as the severity of hot flashes or sleep disorder symptoms increased.

The relation of various heart rate variability parameters like SDRR, RMSSD, pRR50, VLF and HF among symptomatic post-menopausal women and severity of depression showed statistically significant difference. (P<0.05) The study done by Chin K. Kim et al²¹, showed all the time domain indexes namely SDNN, ASDNN, SDANN of HRV were significantly lower in participants with depressive symptoms compared with those without depressive symptom

Taulant Muka et al²² observed presence of vasomotor symptoms and other menopausal symptoms are generally associated with an increased risk of cardiovascular disease, which is mainly explained by changes observed in cardiovascular risk factors.

The present study concludes that, HRV is a non-invasive approach that is used to provide information about the autonomic regulation of heart in pre and postmenopausal women. The results of present study objectively adds to the evidences that menopausal transition are associated with fluctuations in cardiac autonomic activity.

Menopause shifts the autonomic sympathovagal balance towards sympathetic predominance in post-menopausal women.

The study suggest that postmenopausal symptoms are associated with altered autonomic control of heart rate. In particular, hot flashes and sleep problems in moderate or severe degree are related to increase of sympathetic nerve activity.

So, menopausal symptoms and their severity may predict the susceptibility of a women to cardiac morbidity in future. Early interventions and screening may help in improving the women’s health status after menopause

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