European Journal of Cardiovascular Medicine

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder affecting 5-10% women of reproductive age group. PCOS includes number of symptoms such as irregular menstrual cycles, acne, excessive hair growth (hirsutism), obesity and infertility. Some sets of criteria for diagnosis have been proposed for PCOS, Rotterdam criteria (2003) have been accepted throughout the world. Under these criteria PCOS can be diagnosed when at least two of following three clinical features is present: hyperandrogenism (HA), oligomenorrhea/amenorrhea or anovulation and polycystic ovary morphology ^[1] .

Polycystic ovary syndrome (PCOS) instigates significant alterations in biochemical and hormonal parameters within the body, which in turn disrupt the entire metabolic process and leading to impaired blood sugar level, lipid and hormonal profile. Ultimately this increases the risk of metabolic disorder such as insulin resistance or diabetes mellitus type-2, cardiovascular disease and reproductive disorders.

PCOS is as well interrelated with hyperlipidaemia, abdominal obesity, hypertension ^{[2, 3]} which are report to be related to sympathetic hyperactivity ^{[4, 5]}. Now a days, the correlation between increased sympathetic activity and PCOS has been described, assessed by microneurography, the estimation of nor adrenaline spill over and heart rate variability (HRV). The HRV is most commonly used method to evaluate the modulation of autonomic nervous system ^[6,7] and the interplay between the sympathetic and parasympathetic systems is essential to the maintenance of normal cardio vascular homeostasis and provides the basis for various CV reflexes in beat-to-beat regulation of heart rate ^[8].

HRV refers to variation in time between each heartbeat. In a healthy state, human heart does not beat at regular rate and there occurs a variation from one beat to the next beat. This changes, which is involuntary, is known as heart rate variability. Few studies have reported cardio vascular autonomic involvement in the form of decreased heart rate variability (HRV) and increased sympathetic tone in patients with PCOS.

An interesting hypothesis is that sympathetic hyperactivity may play a role in the development of polycystic ovaries. Increased levels of norepinephrine were noticed in rats with induced multiple cysts in ovaries. In women with polycystic ovaries have spare catecholaminergic nerve fibres than normal ovaries. Furthermore, autonomic dysfunction may influence inappropriate gonadotropin secretion and, in this way, influence the pathogenesis of PCOS ^[9].    

So, in this study, we were aimed to assess the autonomic functions (sympathetic and parasympathetic modulation) by time domain and power spectral analysis of heart rate variability (HRV) in the age matched women with PCOS and in normal control group.

This case control study was conducted in RNT Medical College and Attached Group of Hospital, Udaipur (Rajasthan) after getting approval from IRB and IEC [NO.RNT/ACAD./IEC/2022/289 dated on 13/09/2022]. The sample size of 160 cases of PCOS were included in this study with equal number of the control group. Subjects were recruited with written consent. Subjects were excluded -

• Women who were having history of diabetes mellitus, hypertension, thyroid disorder, cardiovascular disorder, pace maker, pregnant and lactating mother.
• Women who were taking oral contraceptives, hypoglycaemic agents, lipid lowering agent and hormonal medications within previous 10-12 weeks.
• Women who were taking any medication that affects ANS (adrenergic and cholinergic drugs)
• Malignancy or carcinoma of female reproductive system.

HRV was recorded by computerized Physiograph (Exercise physiology system- Ad Company). Heart rate variability is a highly sensitive non-invasive indicator of autonomic functions. In this study, short term analysis of HRV was done.

HRV recording was carried out in the morning to avoid response differences caused by circadian changes. On examination day, after a 15minute rest in the supine position, the subject was interviewed and examined before beginning of the test and blood pressure and heart rate was measured to verify their continued good health and to establish if they had a normal night sleep. HRV was analysed in the 5 min lead– II ECG. In this study, changes in heart rate were interpreted by time domain method and frequency domain method.

(a)Time domain method - One of the simplest methods to perform variations in heart rate. These methods involve finding out either the heart rate at specific points in time or the intervals between successive heartbeats. In a continuous electrocardiographic (ECG) recording, each QRS complex is identified, allowing for the measurement of normal-to-normal (NN) intervals, which are the intervals between adjacent QRS complexes resulting from sinus node depolarization, or the instantaneous heart rate.Simple time–domain variables that can be calculated include the Mean RR interval, standard deviation of normal to normal interval (SDNN), root mean square of differences of successive normal to normal intervals (RMSSD) of HRV etc.

(b)Frequency domain method- The variations in the instantaneous heart rate can be assessed spectrally. RR tachogram is plotted using R-R intervals in the 5 min lead –II ECG. The RR tachogram is a non-periodic signal which is transformed to its frequency spectrum by using fast-fourier transformation (FFT) algorithm or autoregressive modeling (ARM). In this complex mathematical transformation, the distribution of magnitude of variations in different frequency bands corresponds to activity of different physiological systems. The entire frequency spectrum 0-0.4 Hz is divided as follows-

1. A high frequency band (HF) 0.15-0.4 Hz- HF component has been used as an indicator of the vagal drive.
2. A low frequency band (LF) 0.04-0.15 Hz- LF component represents mainly sympathetic power.
3. A very low frequency band (VLF) 0-0.04 Hz- It accounts for all other heart rate changes (humoral and local factors).

Statistical analysis: All collected data was entered in Microsoft excel 2007 and data analysis was performed using SPSS version 17.0 for windows statistical software. For quantitative data mean, SD were calculated and correlation coefficient for linear relationship between two variables and for statistical inference student “t” test was used for mean difference between two quantitative variables. For qualitative data rate, percentage were calculated and chi square test was used for statistical inference between two attributes. P value <0.001 was consider as statistically significant.

Table: 1 Time domain parameters of HRV-

(The values are expressed as mean ± standard deviation . P<0.001 is considered as highly significant.)

Table no.1 showing time domain parameters of heart rate variability (HRV) of all cases and controls. There was difference in the values of the time domain parameters ( Mean RR , SDNN, RMSSD, pNN50%) in between the groups but the values of pNN50% and RMSSD were significantly (P<0.001) higher in control group than PCOS women.

Table: 2   Frequency domain parameters of HRV-

  (The values are expressed as mean ± standard deviation. P<0.001 is considered as highly significant.)

Table no.2 showing the mean value of frequency domain parameters of HRV in both cases and controls. In the frequency domain, women with PCOS showed significantly higher LF (ms²) and LF/HF ratio (P<0.001) than the control group, whereas power of HF ms²(P<0.001) was significantly higher in control group. 

In this study, we determined the characteristics of cardiac autonomic nervous system by HRV in women with PCOS and compared the results with healthy individuals.

The high HRV score is considered as an indicator of good health. Our result showed, there was difference in the values of the time domain (mean RR, SDNN, RMSSD, pNN50% between the groups and pNN50% (P<0.001) and RMSSD (P=0.001) showed significantly higher values in control group than PCOS women.

Similiarly, de Sa JC et al (2011)⁸ showed difference between the groups, with lower SDNN, RMSSD, pNN50% in PCOS women when compared with control group. Balamurugan M et al (2015)¹⁰ assessed the heart rate variability and lipid profile in non-obese young Indian women with polycystic ovary syndrome and concluded there was significant decrease in Mean RR, SDNN, RMSSD and pNN50% among the patients of PCOS than the controls. Increased LF/HF ratio, shows that there is increased cardiac sympathetic activity even in lean and ideal weight PCOS. Recently Deepa anurekha A. (2021)¹¹ also observed time domain parameters were significantly decreased in women with PCOS that signifies parasympathetic withdrawal in them.

As heart rate variability (HRV) parameters, low frequency (LF) indicates sympathetic activity, high frequency (HF) indicates vagal activity and LF/HF ratio indicates sympathovagal balance.

In the frequency domain, women with PCOS showed significantly higher LF/HF ratio (P<0.001) and LFnu than the control group, Whereas power of HF (P<0.001,) and HFnu (P=0.272) was significantly higher in control group. This high LF/HF ratio is a marker of sympathovagal imbalance playing a major role in increasing the cardiovascular risks and other comorbidities at an early age. Similarly, Yildirir A et al (2006)¹²  concluded that PCOS patients had adverse cardiovascular risk profile than controls. As the HRV parameters, PCOS patients had significantly higher LF nu (P = 0.005) and LF/HF ratio (P = 0.001) and significantly lower HF (P = 0.006) and HF nu (P < 0.001) compared to controls. A study was conducted by Saranya K et al (2014)¹³ to assess the sympathovagal balance in patients with polycystic ovary syndrome (PCOS) using short-term heart rate variability (HRV) analysis and conventional autonomic function tests (CAFT). They also concluded that PCOS patients have altered autonomic modulation in the form of increased sympathetic and decreased parasympathetic reactivity and HRV. The sympathovagal imbalance exposes them to cardiovascular morbidities. This study directly correlates with our findings of HRV where women with PCOS showed significantly higher LF/HF ratio  (P<0.001) than the control group.

Contrast to our study, Ozkececi G et al (2016)¹⁴ concluded there were no significant differences in HRV and HRT parameters between the two groups and cardiac autonomic functions did not differ in PCOS patients compared to controls, possibly due to the absence of concurrent cardiovascular risk factors, indicating an early stage of the disease.

Women with PCOS exhibited altered autonomic function and more pronounced sympathoexcitation than normal healthy women. Therefore PCOS patients had not having favourable profile of cardiac autonomic innervation.

The present study testified sympathovagal imbalance with raised sympathetic activity and parasympathetic withdrawal in PCOS women. The autonomic dysregulation is linked to myocardial performance of PCOS women which can further lead to genesis of hypertension and CV dysfunctions. This study is highlighting clinical significance of HRV assessment and also increasing awareness among women about PCOS and its negative consequences on their health.

Ethical approval and Consent to participate-

This case control study was conducted in RNT Medical College and Attached Group of Hospital, Udaipur (Rajasthan) after getting approval from IRB and IEC [NO.RNT/ACAD./IEC/2022/289  dated on 13/09/2022].Subjects were recruited with written consent.

List of abbreviations- PCOS, ANS, HRV, LF, HF, SDNN, RMSSD, pNN50%

Conflict of Interest-   No conflict of interest

Authors’ contribution-

SC- Study design, definition of intellectual content, literature search, statistical analysis, manuscript preparation and manuscript re- view, and editing.

SS- Data collection and Lab work

NY- literature search and statistical analysis

Acknowledgements-

The efforts and support from the staff of Gynecology Unit of Maharana Bhopal Hospital, Udaipur (Raj.), is greatly appreciated and no specific grant for any funding agency in public.

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