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Aim: The study was conducted to assess the sympathovagal balance in patients with polycystic ovary syn- drome (PCOS) using short-term heart rate variability ...

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doi:10.1111/jog.12154

J. Obstet. Gynaecol. Res. Vol. 40, No. 1: 192–199, January 2014

Assessment of cardiovascular autonomic function in patients with polycystic ovary syndrome Kuppusamy Saranya1, Gopal Krushna Pal1, Syed Habeebullah2 and Pravati Pal1 Departments of 1Physiology and 2Obstetrics and Gynaecology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India

Abstract Aim: The study was conducted 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). Methods: Thirty-one newly diagnosed patients with PCOS and 30 age-matched controls were recruited. Body mass index (BMI), waist : hip ratio (WHR), cardiovascular parameters such as basal heart rate (BHR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and rate-pressure product (RPP), and fasting blood glucose (FBG) were measured in both groups. Cardiovascular autonomic functions assessed were spectral analysis of HRV, heart rate and blood pressure response to standing (30:15 ratio), deep breathing (E:I ratio) and isometric handgrip (DDBPihg). Results: The cases had significantly increased BMI, WHR, BHR, SBP, DBP and RPP. Ratio of low-frequency to high-frequency power of HRV (LF-HF ratio), the marker of sympathovagal balance was significantly increased in cases compared to controls. Time-domain indices of HRV and E:I ratio were decreased, and 30:15 ratio, DDBPihg and FBG were increased in cases. Though there was a significant correlation of LF-HF ratio with BMI, WHR, BHR, RPP and FBG, only BHR and RPP had independent contribution to LF-HF ratio. Conclusion: We conclude 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. Key words: autonomic dysfunctions, cardiovascular risks, obesity, polycystic ovary syndrome, sympathovagal imbalance.

Introduction Polycystic ovary syndrome (PCOS) is the most frequent endocrine disorder seen in women of reproductive age, affecting 5–10% of the population.1 It is characterized by menstrual irregularities, biochemical or clinical hyperandrogenism, and polycystic ovary.1 Approximately 50% of the patients are either overweight or obese.1 Obesity is known to cause increased sympathetic activity.2 With obesity as a potent comorbid

factor, PCOS poses a significant cardiovascular risk that warrants an early assessment of cardiovascular health of patients suffering from this condition.3 Autonomic dysfunction in the form of decreased heart rate variability (HRV) has been reported to be associated with adverse cardiovascular events.4 There are very few reports of increased sympathetic activity in patients with PCOS.5,6 Also, attenuated heart rate recovery and exaggerated blood pressure response to exercise depicting decreased vagal and increased

Received: December 13 2012. Accepted: April 16 2013. Reprint request to: Dr Gopal Krushna Pal, Department of Physiology, JIPMER, Puducherry 605006, India. Email: [email protected] Conflict of interest: None.

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Cardiovascular autonomic function in PCOS

sympathetic activity have been reported in these patients.7 However, no studies have been conducted to date to assess the reactivity of the sympathetic and parasympathetic division of the autonomic nervous system in PCOS. Recently, the short-term HRV analysis and conventional autonomic function tests (CAFT) to assess sympathetic and parasympathetic functions, have proved to be effective non-invasive methods of evaluating the cardiovascular risks.8,9 Therefore, in this study, we have attempted to assess the detailed cardiovascular autonomic status in patients with PCOS.

Methods Study design This was an analytical cross-sectional study, conducted in the autonomic function testing (AFT) laboratory, Department of Physiology, JIPMER, Puducherry, India. The approval of the Institute Research Council and Institute Ethics Committee for human studies was obtained prior to the commencement of the study. Subjects Sixty-one subjects were included in the study. Thirtyone cases from the outpatient Department of Obstetrics and Gynaecology of JIPMER, Puducherry, India as per European Society of Human Reproduction and Embryology (ESHRE)/American Society for Reproductive Medicine (ASRM) criteria1 (testosterone levels significantly elevated among the cases as depicted in Table 1) and 30 controls were recruited for the study. The cases included patients with newly diagnosed PCOS in the age group of 15–35 years. Patients already on treatment for PCOS were excluded from the study. Age-matched, healthy, regularly menstruating and nulliparous women were included as controls. Women with menTable 1 Phenotypic presentation among cases (as per ESHRE/ASRM criteria) Parameters

Number of cases

Anovulation Hyperandrogenemia (laboratory normal, 14–66 ng/dL) Hirsutism PCO (by ultrasonography)

31 22 19 17

Cases, women with polycystic ovary syndrome. ASRM, American Society for Reproductive Medicine; ESHRE, European Society of Human Reproduction and Embryology; PCO, polycystic ovary.

strual irregularities, hypothyroidism, diabetes and women on any hormonal therapy or drugs were excluded. Written informed consent was obtained from all of the subjects prior to the commencement of the study.

Procedure The study was conducted during the follicular phase of the menstrual cycle in control subjects to avoid the influence of ovarian hormones on autonomic function and HRV.10 In the study group, the test was conducted during the amenorrheic period.5 The subjects were asked to report to AFT laboratory at 07.00 hours after overnight fasting.

Anthropometric measurements and metabolic parameters Waist circumference was measured as the circumference of the abdomen at its narrowest point between the lower costal (10th rib) border and the top of the iliac crest. Hip circumference was measured at the level of greatest posterior protuberance of the buttocks. The subject’s height was measured to the nearest millimeter by a wall-mounted stadiometer and weight was measured with a spring balance to the nearest 0.5 kg avoiding zero and parallax errors. Body mass index (BMI) and waist : hip ratio (WHR) were calculated. BMI was calculated by Quetelet’s index. The Asian criterion for BMI was followed for grouping the subjects based on the level of BMI.11 A 2-mL fasting venous blood sample was collected and serum glucose was estimated by glucose oxidase–peroxidase method using a diagnostic kit from Genuine Biosystem (Chennai, India). Baseline cardiovascular parameters After 5 min of sitting rest, basal heart rate (BHR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded by oscillometric method using an Omron MX3 automated blood pressure monitor (Omron Healthcare, Kyoto, Japan). Rate-pressure product (RPP), a determinant of myocardial oxygen consumption and workload was calculated using the formula: RPP = (BHR ¥ SBP) ¥ 10–2.12 Cardiovascular autonomic function tests The tests were explained to the subjects. A room temperature of 23°C with 25–35% humidity was maintained.13

© 2013 The Authors Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology

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Recording of HRV Short-term HRV recording was performed using lead II electrocardiogram (ECG), following the standard procedure as per the recommendation of Task Force.10 The data acquisition was performed using a 16-bit, 16-channel BIOPAC MP100 data acquisition system (BIOPAC, Goleta, CA, USA) with AcqKnowledge ver. 3.8.2 software (BIOPAC). Sampling rate was kept at 500 samples/s per channel. Raw ECG was filtered using a band pass filter (2–40 Hz). HRV analysis of the RR tachogram was performed for frequency domain (by power spectral analysis using fast Fourier transformation) and time domain measures using the software from the Biomedical Signal Analysis Group ver. 1.1 (Kuopio, Finland). The frequency domain indices included low frequency (LF; 0.04–0.15 Hz), high frequency (HF; 0.15–0.4 Hz), total power (TP), LF in normalized units (LFnu), HF in normalized units (HFnu) and the ratio of LF to HF (LF-HF ratio). The time domain measures included mean RR (mean of RR interval), standard deviation of RR interval (SDNN), the square root of the mean of the sum of the squares of the differences between adjacent NN intervals (RMSSD), the number of pairs of adjacent NN intervals differing by more than 50 msec in the entire recording (NN50) and the percentage of NN50 counts, given by NN50 count divided by total number of all NN intervals (pNN50). The HF, HFnu, TP, SDNN, RMSSD, NN50 and PNN50 of HRV indices represent the cardiac parasympathetic drive (vagal tone).9 The LF and LFnu represent sympathetic tone.9 The LF-HF ratio depicts the sympathovagal balance.9 Recording of CAFT The CAFT included HR and BP response to 5 min of active standing, HR response to deep breathing at the rate of 6 breaths/min with inspiratory and expiratory cycles for 5 s each, and DBP response to isometric hand grip (IHG) at one-third of maximum voluntary capacity for 3 min.13 From these tests, the quantification of HR and BP response was performed. During standing, the ratio of longest RR interval at 30th beat to shortest RR interval at 15th beat (30:15 ratio) was computed. From the deep breathing maneuver E:I ratio, the ratio of longest RR interval during expiration to the shortest RR interval during inspiration averaged over 6 cycles of respiration was calculated. During the IHG test, the magnitude of DBP rise during the maneuver given as DDBPihg was calculated. 30:15 ratio and E:I ratio depict

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parasympathetic modulation.13 The DDBPihg represents the sympathetic modulation.13

Statistical analysis Sample size was calculated using PS program ver. 3.0.43. Sample size was estimated for three parameters: LFnu, HFnu and LF-HF ratio. The calculation with LFnu yielded the highest sample size of 30, with an expected mean difference of 13 from the previous study performed for a power of 0.8 and type I error of 0.1.5 Statistical analysis was performed using SPSS ver. 19 (SPSS, Chicago, IL, USA). For data analysis, all values were expressed as mean ⫾ standard deviation. The data were subjected to Kolmogorov–Smirnov normality test. The intergroup differences between the controls and cases were compared using Student’s unpaired t-test for normally distributed data and Mann–Whitney U-test for non-parametric data. Association of various factors with LF-HF ratio was assessed by Pearson correlation for parametric data and Spearman’s rank correlation coefficient for non-parametric data. Multiple regression analysis was done to assess the contribution of individual factors to sympathovagal imbalance (alteration in LF-HF ratio). P < 0.05 was considered statistically significant.

Results Phenotypic presentation of the patients with PCOS Among the 31 cases included for study as per the ESHRE/ASRM criteria, all of them had anovulatory cycles (Table 1). Twenty-two patients had hyperandrogenemia (testosterone levels more than normal range of 14–66 ng/dL). Nineteen patients presented with hirsutism and ultrasonographic evidence of polycystic ovary was observed in 17 patients. Age, anthropometric, basal cardiovascular and metabolic parameters Both the cases and control subjects belonged to the same mean age group (P = 0.0864) (Table 2). The cases had significantly high (P < 0.001) BMI and WHR compared to that of controls. The cardiovascular baseline parameters (i.e. SBP, DBP and BHR) were significantly high (P < 0.001) in cases compared to those of controls. The RPP was found to be significantly high (P < 0.001) in the cases. The fasting blood glucose (FBG) was significantly high (P = 0.048) in cases compared to the controls.

© 2013 The Authors Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology

Cardiovascular autonomic function in PCOS

Table 2 Comparison of age, anthropometric and basal sitting cardiovascular parameters between controls and cases Parameters

Controls (n = 30)

Cases (n = 31)

P-value

Age (years) BMI (kg/m2) WHR BHR (b.p.m.) SBP (mmHg) DBP (mmHg) RPP Testosterone (ng/dL) FBG (mg/dL)

24.733 ⫾ 2.935 21.98 ⫾ 2.512 0.740 ⫾ 0.048 65.40 ⫾ 9.016 97.633 ⫾ 7.686 68.266 ⫾ 5.936 72.133 ⫾ 13.541 38.727 ⫾ 13.650 69.267 ⫾ 7.315

23.129 ⫾ 4.129 27.093 ⫾ 6.543*** 0.831 ⫾ 0.049*** 78.322 ⫾ 10.55*** 107.935 ⫾ 9.483*** 78.677 ⫾ 9.796*** 93.807 ⫾ 16.968*** 74.61 ⫾ 18.42*** 73.355 ⫾ 8.435*

0.0864

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