Systematic Review

Assessment of cardiac electrical activity in patients with polycystic ovary syndrome: A systematic review and meta-analysis

Introduction

Polycystic ovary syndrome (PCOS), an intricate genetic condition, is the most prevalent heterogeneous syndrome of clinical and biochemical endocrine disorder among women of reproductive age.¹ The foremost phenotype characteristics of women with PCOS are androgen excess, insulin resistance (IR), hypothalamic-pituitary-ovarian axis dysfunction, and deranged adipokines secretion from the adipose tissue.²

In addition to the fact that PCOS affects fertility and obstetrical conditions of the patients, it brings substantial health outcomes for women, impairing life quality.³ Since it is associated with other correlated lifestyle diseases, this syndrome presents significant metabolic and cardiovascular morbidities.⁴ Women with PCOS are highly susceptible to every component of metabolic syndrome, including dyslipidemia, type 2 diabetes, and hypertension.^5-8 It is ascertained that metabolic syndrome indicates a condition of IR.⁹ Increased insulin level is crucial in promoting theca cells producing excess androgen and forming hyperandrogenism in women with PCOS.¹⁰ Hence, the co-existence of metabolic syndrome with PCOS can lead to greater existing cardiometabolic risk.

Recent studies distinctly claimed that there are significant cardiac conduction system abnormalities in PCOS patients, which can contribute to higher risks for cardiovascular diseases.¹¹ Many studies have revealed that metabolic syndrome and its components can lead to electrocardiographic (ECG) abnormalities, such as longer P-wave duration and prolonged QT interval.¹²

These ECG abnormalities reflect pathologic changes in cardiac electric conduction ¹². In clinical practice, atrial fibrillation (AF) is the most prevalent arrhythmia resulting from an abnormal cardiac conduction system. This abnormality can originate from increased sympathetic activity, high oxidation levels, ischemia, stress, and systemic inflammation.^13-15 It has also been demonstrated that IR is capable of atrial remodeling and is associated with atrial arrhythmogenesis and AF even before diabetes develops.¹⁶ Moreover, gonadal steroids have been found to influence cardiac autonomic function and ion interactions and may lead to cardiac arrhythmias.¹⁷ Some studies were conducted to find possible p-wave and QT abnormalities and changes in the atrium and cardiac conduction system in PCOS patients.^11,18-24

However, the actual relationship between PCOS and cardiac arrhythmia has remained controversial. In this systematic and meta-analysis review, we aim to assess the cardiac electrical activity to determine whether there is a possible elevated risk for cardiac arrhythmias in PCOS.

Methods

This systematic review was prepared using PRISMA reporting guidelines for systematic reviews²⁵ and an a priori protocol registered with PROSPERO, CRD4202233705. During the conduct of the evaluation, we considered the following inclusion criteria.

Eligibility criteria

The overall inclusion criteria for the meta-analysis were as follows: (1) an original research article, (2) a study conducted in case-control, cross-sectional or observational (prospective or retrospective) cohort designs, (3) a study involved clinically and/or para-clinically and/or laboratory diagnosed PCOS, (4) a study reported mean and standard deviation (SD) of at least one of the ECG parameters including p-wave or QT indices or any other parameters measuring cardiac electrical activity other than ECG, (5) a study surveyed the relevant indices both in PCOS participants and control group, (6) a study excluded patients with known cardiovascular disease, thyroid disease, neoplasms, pregnancy or breast-feeding, smoking, chronic alcohol consumption, diabetes mellitus, hypertension, and renal impairment, (7) a study involved adult women in their reproductive age with or without PCOS, (8) no limitation for including articles published in languages other than English will be pursued.

The overall exclusion criteria for the meta-analysis were as follows: (1) abstracts, case reports, case series, any reviews, editorials, and practice guidelines, (2) a study involving menopausal and postmenopausal women with and without PCOS, (3) a study used data reporting forms like median value and interquartile range, (4) a study assessed the cardiac electrical activity in participant only diagnosed with metabolic-syndrome not specifically with PCOS.

Information sources

To identify the studies, we searched the following electronic databases until January 2023: PubMed, Scopus, Web of Science, and Cochrane, with no restrictions on time and language. We also performed a manual search through references in the found articles.

Search strategy

The search strategy of PubMed was to combine (((((((((((((((((((((“Electrophysiologic Techniques, Cardiac”[Mesh]) OR (“Electrocardiography”[Mesh])) OR (“electric* activity*”)) OR (electric*)) OR (“Heart Conduction System”[Mesh])) OR ((“Cardiac Conduction System Disease”[Mesh])) OR (electromechanical)) OR (“conduction delay”)) OR (“Arrhythmias, Cardiac”[Mesh])) OR (“p wave”)) OR (“p-wave”)) OR (QT*)) OR (“P dispersion”)) OR (“QT dispersion”)) OR (QRS)) OR (“T wave”)) OR (“T-wave”)) OR (atrial)) OR (ventricular)) OR (“left atrium”)) OR (“Atrial Fibrillation”[Mesh])) AND ((“Polycystic Ovary Syndrome”[Mesh]). The search strategy for Scopus, Web of Science, and the Cochrane Library is similar to what we used for searching PubMed (Table S1, Supplementary file 1). Two independent investigators scanned all the studies’ titles and abstracts to select applicable studies. In addition, two investigators manually screened reference lists from systematic reviews and selected studies independently to ensure all relevant studies have been included in this study.

Study selection

All records from the systematic search in the electronic database and reference lists of selected records were evaluated by two authors independently following the eligibility criteria mentioned above. After strict selection and evaluation, we collected the data from the records as follows: ECG indices, study design, numbers of PCOS cases and control group involved, published language, and baseline characteristics, including age, body mass index (BMI), blood pressure, heart rate, waist to hip ratio (WHR), relevant hormone and lipid profile. We categorized the data into two subgroups to assess the cardiac electrical activity in two forms of atrial and ventricular electrical activity in PCOS cases (Table 1).

Data extraction

Two reviewers did data extraction. Data were extracted from each subgroup and collected using Microsoft Excel® sheets. Paper IDs were extracted, including first author, year of publication, study population, and the number of PCOS patients and control groups. We extracted ECG indices and baseline characteristics and added them to the relevant subgroups as follows:

Subgroup 1: Atrial electrical activity and PCOS

ECG parameters: (1) P max, the longest atrial conduction time measured on any of the 12 ECG leads, (2) P min, the shortest atrial conduction time (3) and P dispersion is defined as the difference between P max and P min, (4) Atrial electromechanical coupling (PA) duration, the time interval from the beginning of P-wave on surface ECG to the onset of the late diastolic wave including (1) Lateral PA which is obtained from the lateral mitral annulus, (2) Septal PA is which obtained from the septal mitral annulus, and (3) Tricuspid PA which is obtained from the tricuspid annulus, and (4) Lateral tricuspid PA which is obtained from the lateral tricuspid annulus.

Subgroup 2: Ventricular electrical activity and PCOS

ECG parameters: (1) QT max, the most prolonged QT interval measured on any of the 12 ECG leads, (2) QT min, the shortest QT interval, (3) QT dispersion (QTd.QT dis), the difference between QT max and QT min, (4) Corrected QT (QTc), QT interval.square root of the RR interval and (5) similarly, corrected QT dispersion (QTcd or QTc dis) the difference between QTc max and QTc min.

Risk of bias assessment

Two individuals independently appraised the quality of the eligible studies before inclusion in the review using appraisal instruments from the Joanna Briggs Institute (JBI) for cross-sectional and case-control studies and other comparative studies. After the appraisal, studies that did not meet the methodological criteria were excluded, and reasons for their exclusion are provided in (Table S2).

Outcome quality assessment

The certainty of overall evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method.³⁵ The assessment of evidence certainty for individual outcomes relied on five distinct criteria: (1) limitations of the study design; (2) consistency of results; (3) directness; (4) precision; and (5) potential for publication bias. A decrement of one level in certainty was implemented for each unfulfilled criterion.

Synthesis methods

We analyzed the data using RevMan software (version 5.3) with the random effect model and Comprehensive Meta-Analysis software (version 2). Statistical heterogeneity for each pooled estimate was calculated using Cochran’s chi-squared test and presented with the I² statistic. The odds ratio (OR) and mean differences (absolute difference between the mean value in PCOS cases and control group. PCOS - Control) pool the data with 95% confidence intervals (CIs). Publication bias was visually assessed using funnel plots for the overall analysis of all included studies. P values of < 0.05 were considered to be statistically significant.

Results

Study selection

The study flowchart is shown in Figure 1; our search strategy revealed 877 records. After removing duplications, 579 studies went through title assessment. Of these, 107 reports were eligible for abstract review. After surveying abstracts, 22 studies met the inclusion and exclusion criteria and were perused for full text. Finally, 16 studies were qualified to be included in this systematic review and meta-analysis.

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Figure 1.

Flow diagram of study selection

Figure 1.

Flow diagram of study selection

Study characteristics

Sixteen original research articles were retrieved. Of these, nine studies were of a cross-sectional design, and the remaining studies were case-control. Two studies were published in Turkish,^29,32 and the rest were redacted in English. All the studies were conducted in young patients newly diagnosed with PCOS with no medical history of any other health conditions, including cardiovascular disease, thyroid disease, neoplasms, pregnancy or breastfeeding, smoking, chronic alcohol consumption, diabetes mellitus, hypertension, and renal impairment. We divided the articles into two separate subgroups: (1) Atrial electrical activity and PCOS, (2) Ventricular electrical activity and PCOS, in terms of ECG parameters and baseline characteristics shown in Table 1. Among the studies of subgroup 1, all of them reported three P wave indices, including P max, P min, and P dispersion. Four studies also reported atrial electromechanical measures, including lateral PA and septal PA. Among studies of subgroup 2, three articles reported only mean QTc, and the rest reported at least two indices of the QT parameter. Most studies reported baseline characteristics, including age, BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, and lipid and hormone profile of both PCOS cases and controls. Table 1 details the characteristics of all studies, including ECG measures, baseline characteristics, and involved population of PCOS and controls of each study.

Risk of bias assessment of included studies

Among sixteen studies included in this review, nine articles^{11,19,20,23,26,30-32,34} reported on the findings of a cross-sectional study design (Table 2). Seven articles^{18,24,22,27-29,33} reported on the findings of a case-control study design (Table 3). Overall, seven included articles scored 8.8, and two^20,34 scored 6.8 using the scoring method for measuring the methodological qualities of cross-sectionals. Six articles scored 9.10 and one³³ scored 7.10 using the scoring method for measuring the methodological qualities of case controls.

GRADE assessment of outcomes

The GRADE assessment (Table 4) reveals that the certainty of evidence for outcomes related to atrial electrical activity and QT parameters predominantly ranges from Low to Moderate. Atrial electrical activity metrics (e.g., Pmax, PWD, Lateral PA) generally demonstrated Low certainty due to high heterogeneity, moderate risk of bias, or imprecision (confidence intervals crossing zero). Exceptions include P min and Mean QTc, which showed Moderate certainty. Among QT parameters, most outcomes (e.g., QT dispersion, QTc max) had Moderate certainty, while QTc min stood out with High certainty. Key limitations across studies included high inconsistency (heterogeneity), risk of bias in specific trials (e.g., Tasolar et al²⁸), and imprecision from wide confidence intervals. Notably, Lateral Tricuspid PA had Very Low certainty due to an extremely limited number of studies. These findings underscore the need for further high-quality research to strengthen evidence confidence, particularly for outcomes with substantial methodological limitations.

Results of syntheses

We analyzed ECG measures in the form of 2 separate subgroups featuring P wave and QT indices. The clinical characteristics of each subgroup were analyzed separately. Table 5 represents result of ECG synthesis.

Subgroup 1: Atrial electrical activity and PCOS

Among ECG analysis, Pmax, P dispersion were significantly longer in PCOS patients than in controls with effect size of 7.49 (95% CI [0.36, 14.63], p = 0.04) and 10.74 (95% CI [5.96, 15.51], P < 0.0001), respectively (Figure 2). Pmin was significantly shorter in PCOS cases compared to controls with an effect size of -2.23 (95% CI [-4.38, -0.08], P = 0.04) (Figure 2). It was revealed that lateral and septal PA were significantly longer in PCOS cases compared to controls with effect sizes of 16.24 (95% CI [6.29, 26.19], P = 0.001) and 10.76 (95% CI [1.88, 19.55], P = 0.02), respectively(Figure 3). Among baseline characteristics, heart rate tended to be higher in PCOS cases compared to controls, with an effect size of 1.62 (95% CI [0.07, 3.17], P = 0.04) (Table 6). PCOS cases were revealed to have higher BMI and WHR compared to the control group, which indicate obesity state in PCOS with effect size of 2.48 (95% CI [2.00, 2.95], P < 0.00001] and 0.03 (95% CI [0.01, 0.04], P < 0.00001), respectively. Serum testosterone, fasting insulin level and HOMA-IR were significantly higher in PCOS cases than control group with effect sizes of 30.43 (95% CI [24.89, 35.97], P < 0.00001), 5.24 (95% CI [0.49, 9.98], P < 0.00001) and 1.31 (95% CI [0.39, 2.23], P = 0.005) respectively. There were no other significant differences in baseline characteristics between PCOS cases and the control group (Table 6).

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Figure 2.

Atrial electrical activity forest plots indicating A) P minimum, B) P maximum, C) P dispersion

Figure 2.

Atrial electrical activity forest plots indicating A) P minimum, B) P maximum, C) P dispersion

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Figure 3.

Atrial electrical activity forest plots indicating: A) lateral PA, B) Tricuspid PA, C) Septal PA, D) Lateral tricuspid PA

Figure 3.

Atrial electrical activity forest plots indicating: A) lateral PA, B) Tricuspid PA, C) Septal PA, D) Lateral tricuspid PA

Subgroup 2: Ventricular electrical activity and PCOS

It was revealed that mean QTc was significantly lower in PCOS patients compared to the control group, with an effect size of -21.62 (95% CI [-37.70, -5.54], P = 0.008). There were no other significant differences in QT indices (Figure 4). There was a significant difference in FBS levels (effect size of 1.91(95% CI [0.38, 3.44], P = 0.01), serum fasting insulin (effect size of 4.01(95% CI [ 0.67, 7.36], P = 0.02), serum insulin (effect size of 6.37(95% CI [3.49, 9.25], P < 0.0001) and serum testosterone (effect size of 38.57 (95% CI [21.19, 55.96], P < 0.0001) between PCOS cases and controls (Table 6).

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Figure 4.

Ventricular electrical activity forest plots indicating A) QTc minimum, B) QTc maximum, C) Mean QTc, D) QTc dispersion

Figure 4.

Ventricular electrical activity forest plots indicating A) QTc minimum, B) QTc maximum, C) Mean QTc, D) QTc dispersion

Discussion

Atrial electrical activity and PCOS

Atrial remodeling is any atrium changes recognized by poor cellular coupling, inflammation, and fibrosis. Consequently, slowed electric conduction resulting from atrial remodeling develops an arrhythmic condition called AF.³⁶ AF has been discovered as the most prevalent clinically substantial cardiac arrhythmia causing morbidities and mortalities. It is associated with a 5-fold elevated risk for stroke.^37,38 It has been demonstrated that low-grade inflammation is signified in PCOS pathogenesis³⁹. Results from a national Danish registry cohort study conducted by Oliver-Williams et al.⁴⁰ Of 6149 (10.2%) patients with PCOS with a median follow-up of 8.9 years, 138 (0.2%) women developed AF. They reported that women with PCOS were at twice the risk of AF. Inflammation can modify atrial structure and electrophysiology, leading to structural and electrical remodeling, enhancing the vulnerability to AF.⁴¹

Furthermore, IR is shown to cause discordant autonomic nerve function, microvascular changes, and impaired blood glucose levels. Mentioned conditions can lead to myocardial fibrosis as a remodeling change that can cause atrial enlargement, leading to a prolonged conduction time.³⁹ Moreover, elevated testosterone levels, a prominent diagnostic feature of PCOS, have increased the risk for AF and ischemic stroke.^42,43

The meta-analysis of this study revealed that maximum p-wave duration (Pmax) was significantly higher in PCOS patients than in controls. Following this finding, Akdag et al,²⁶ Zehir et al,²⁴ Bayir et al,²³ and Erdogan et al²² have reported significant longer Pmax in PCOS patients compared to controls; however, the absolute mean values of Pmax in the PCOS population of both included studies and this meta-analysis were within the normal range, which is considered to be less than 110 ms.^44-46 In other words, the Pmax duration in PCOS patients is tuned in normal upper limits compared to non-PCOS. It can be assumed that being chronically in IR and hyperandrogenism states can lead to higher stages of atrial remodeling over time, slowed electric conduction, and longer P-wave duration. Our studied PCOS population was young and, therefore, might be in the early stages of PCOS and probably were not sufficiently exposed to IR and hyperandrogenism states to manifest noticeable and pathological atrial remodeling changes.

P dispersion (Pd) is a non-invasive ECG marker presenting intra- and inter-atrial conduction heterogeneity.⁴⁷ Increased atrial heterogenic electrical activity by inducing atrial reentry leads to the development of cardiac arrhythmias (mostly AF and atrial flutter).²² Moreover, P-wave dispersion (Pd) is associated with IR independently but not with other factors such as BMI, waist circumference, LA size, LV diastolic function, and blood pressure.⁴⁸ This meta-analysis revealed that Pd was significantly higher in PCOS patients than in controls, suggesting an increased susceptibility to develop AF compared to women without PCOS. Increased Pd in PCOS patients compared to controls were reported in all included studies in this meta-analysis.^22-24,26-28 Heart rate was also significantly higher in PCOS patients than in controls. In a systematic review and meta-analysis that Wang et al⁴⁸ conducted, it was concluded that there might be evidences of cardiovascular autonomic dysfunction in women with PCOS with increased sympathetic tone and decreased parasympathetic activity; in IR states, the sympathetic nervous system is hyperactive, which results in a significant prolongation of P-wave duration and Pd and increased heart rate.

Atrial electromechanical delay can also be measured from the onset of the P wave on ECG to the commencement of atrial contraction determined by pulsed-wave tissue Doppler imaging (TDI).^15,49,50 In this meta-analysis, lateral PA and septal PA durations were significantly higher in PCOS patients than in controls, showing a possible electromechanical delay in the atrial conduction system; hence, we can say that longer Pmax duration, presence of P dispersion, and inter and delayed intra-atrial conduction define sinus impulses to have inhomogeneous propagation. This is a well-known ECG characteristic of the atrium that is likely to develop AF.^51,52

In addition, enlargement and increased pressure of the atrium are known to affect P-wave disturbances.^53-55 A larger left atrium (LA) diameter suggests early adverse cardiac modeling. Previous studies revealed that women with PCOS have greater left atrial dimensions than healthy controls.^23,28,56,57 Zehir et al²⁴ reported that prolonged atrial conduction time significantly correlated with IR, chronic inflammation, Pd, Left ventricular (LV) diastolic function parameters, and greater LA diameter.

LV diastolic dysfunction is an early echocardiographic manifestation of cardiomyopathy in patients with cardiovascular risk factors.⁵⁸ There is evidence that patients with PCOS have elevated cardiovascular risk compared with age-matched controls. Higher incidence of obesity, impaired glucose tolerance, diabetes mellitus, and metabolic syndrome in PCOS patients define this association.⁵⁹

Previous studies recommended that endothelial and LV diastolic dysfunction develops in patients with PCOS due to IR and hyperandrogenism.^60,61 It is established that IR is associated with left ventricular (LV) remodeling independent from obesity and type-2 diabetes; LV remodeling leads to LV diastolic dysfunction.^62,63

Ventricular filling pressure reflects LV diastolic function, and LA function is a significant determinant of LV diastolic filling. LA passive emptying volume depends on increased LV end-diastolic pressure.^64,65

Multiple studies have assessed LV function in PCOS with echocardiographic parameters.^{23,24,27,28,49,56,57,66-69} It was revealed that there were significant differences in LV diastolic echo parameters between PCOS patients and control groups. The majority of these studies reported increased isovolumetric relaxation time (IVRT), deceleration time of early phase of mitral valve flow (DT), and a lower ratio of peak early and late diastolic flow velocities (E.A ratio) in PCOS patients compared to control group.^{22-24,28,56,68-70}. Tíras et al reported a reverse correlation between insulin levels and the E.A ratio, suggesting that PCOS patients are probably more susceptible to developing diastolic dysfunction.⁶⁸

In a study by Orio et al,⁵⁷ PCOS women showed an increased LV mass index (LVMI) independent of body weight and hypertension. Moreover, De Jong et al⁶⁶ and Yildirim et al⁶⁷ also reported higher LVIM mass index in PCOS patients compared to control groups, suggesting PCOS could be considered an aggravating factor leading to LV hypertrophy and, therefore, to the early cardiovascular diseases in PCOS.

It is possible to say that changes in LV diastolic function indexes (IVRT, E.A ratio, DT, and LVMI) could be responsible for greater LA diameter and longer Pmax, Pd, inter, and intra-atrial conduction times in PCOS.

Obesity and IR are frequently seen in women with PCOS.⁷¹ By the high incidence of obesity and IR in PCOS, our results showed that PCOS patients have significantly higher BMI, HOMA-IR, and serum insulin levels than controls. In the study conducted by Bayir et al, it was revealed that there was a significant correlation between atrial conduction parameters and BMI in patients with PCOS despite a relatively lower range of BMI values in their study.²³

Ventricular electrical activity and PCOS

Ventricular arrhythmia is defined as conditions that can range a spectrum of different abnormal cardiac rhythms from single premature ventricular complexes to polymorphic ventricular tachycardia and ventricular fibrillation. They are one of the most common causes of sudden cardiac death.^72,73 Identifying the risk factors that generate Ventricular arrhythmias is essential. Using QT parameters, particularly QT dispersion, is a non-invasive method to measure ventricular electrical inhomogeneity.⁷⁴ QTc interval has been proven to be related to cardiac arrhythmia and sudden death,⁷⁵ same as QT dispersion.^76,77 Çağlı et al⁷⁸ reported that QT dispersion shows the heterogeneity of ventricular refractoriness, and prolonged QT dispersion has been correlated with the risk of arrhythmic death in various disorders (cardiac and non-cardiac). Also, a higher QRS-T angle can predict an increased risk of sudden cardiac death and other cardiovascular diseases.^79,80 A study has described abnormal QRS-T angle as a probable predictor of ventricular arrhythmia.⁸¹ Through this, Topaloğlu et al⁸² assessed the QRS-T angle in women with PCOS and discovered abnormal degrees of QRS-T angle only in a small percentage of PCOS patients; interestingly, this abnormal angle turned out to be strongly correlated with mean ovarian volume (MOV). They concluded that MOV is a good predictor of abnormal QRS-T angle and cardiovascular diseases, considering that combined effects of IR and other hormonal parameters can influence MOV.

Gonadal steroids are essential determinants of gender-related differences in ventricular repolarization.^83-85 It has been proven that by the onset of puberty, marked by increased testosterone concentration, the QTc interval starts to shorten in males, while in females, it stays unchanged.⁸⁶ Testosterone appeared responsible for this sex difference by reducing action potential duration as its underlying mechanism.⁸⁷ Vrtovec et al³⁴ and Meden Vrtovec et al³³ reported an inverse association between QT and QTc intervals and serum testosterone levels in PCOS patients, which means that they had shorter QTc intervals compared to controls. Huang et al¹¹ concluded that although there was no significant difference between QT indices of PCOS patients and non-PCOS women, PCOS patients with androgen excess had shorter QT intervals in comparison with PCOS patients without androgen excess. On the other hand, Orio et al and Alpaslan et al reported that there were no significant differences in QT intervals and QT dispersion between PCOS patients and controls.^18,19

This meta-analysis revealed no significant differences in QT parameters between the two groups of PCOS and controls except for the mean QTc parameter, which was significantly lower in PCOS patients compared to controls. Based on the testosterone effect on shortening QTc, this meta-analysis’s lower QTc interval in PCOS patients was probably associated with excess testosterone levels, significantly higher in PCOS patients than controls.

Clinical data indicates that both endogenous and exogenous estrogen can cause prolongation in QT interval and QT dispersion. Estrogens impact the activity of cardiac calcium currents, which determines the cardiac electrical cycle and the length of the action potentials and, thus, the QT interval length.^84,88 Experimental animal studies revealed that estrogen prolongs the action potential’s QT interval and repolarization phase by depressing the potassium current expression.^88,89 Studies show that hormone replacement therapy with estrogens in postmenopausal women prolonged QT intervals.^90-92 Gazi et al reported significantly elevated serum estrogen and testosterone levels in PCOS patients that may explicate the prolonged QT dispersion in PCOS patients of their study.³¹ Both experimental and clinical findings support that estrogen and testosterone influence QTc. Estradiol levels were not significantly different between PCOS patients and controls in this meta-analysis; however, only 4 included studies evaluated estradiol levels in participants.

Some studies showed that hyperinsulinemia could prolong the QTc interval.^93,94 Also, IR, a state of compensatory hyperinsulinemia, can persist QTc lengthening even when obesity, diabetes, and autonomic neuropathy are absent.^95,96 QTc max, QTc min, and QT dispersion were longer in patients with metabolic syndrome.⁹⁷ IR is involved in subclinical LV remodeling and dysfunction independent of traditional metabolic risk factors and can explain some impacts of BMI on concentric LV remodeling.⁶² Besides, it has been shown that LV remodeling alone is associated with malignant ventricular arrhythmias.⁹⁸ Gazi et al reported that in patients with PCOS, HOMA-IR and insulin were associated with QTc prolongation despite the patients being non-obese.³¹ In our meta-analysis, serum insulin levels and HOMA-IR were significantly higher in PCOS patients compared to controls despite the non-significant difference in QT dispersion and shorter QTc interval in PCOS patients. Out of eleven studies enrolled in the meta-analysis, only five and three articles assessed HOMA-IR and serum insulin levels, respectively. It is good to mention that IR is not present in all patients with PCOS. Incidence of IR in PCOS has been reported up to 64% according to the HOMA-IR measurement.⁹⁹

It is important to acknowledge certain limitations when comparing the provided reports. Firstly, the existing body of evidence on the relationship between cardiac electrical activity and PCOS in is still limited, with a relatively small number of studies available, most of which have been conducted before 2020.As a result, the certainty of evidence for the outcomes reported in this review is not yet high, and more original studies are needed to strengthen the conclusions.The limited number of studies included in the meta-analysis not only reduced the statistical power but also hindered the reliability of Egger’s and Begg’s tests and funnel plots for assessing publication bias.

Conclusion

This systematic review and meta-analysis demonstrate that PCOS is associated with impaired atrial electrical activity, evidenced by prolonged P-wave duration, increased P-wave dispersion, and delayed atrial electromechanical conduction. These findings suggest a heightened susceptibility to atrial arrhythmias, potentially driven by IR, chronic inflammation, and hyperandrogenism. In contrast, ventricular electrical parameters, including QT intervals and dispersion, showed no significant abnormalities, indicating no elevated risk of ventricular arrhythmias in PCOS. While the GRADE assessment highlighted variability in evidence certainty, these results underscore the need for further longitudinal studies to clarify long-term cardiovascular risks and mechanistic pathways in women with PCOS.

Competing Interests

The authors have no conflicts of interest to declare.

Ethical Approval

The protocol for this work was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (identifier: CRD42022337050).

Supplementary Files

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