Polycystic ovary syndrome as a novel risk factor for atrial fibrillation: results from a national Danish registry cohort study

Abstract

Risk factors for atrial fibrillation (AF), including type 2 diabetes and obesity, are highly prevalent in women with polycystic ovary syndrome (PCOS),^1,2 an endocrinological condition affecting up to 18% of women.² Furthermore, raised levels of testosterone, a cardinal symptom of PCOS, are associated with a greater risk of AF and ischaemic stroke in women.³ We assessed the association between PCOS and AF risk using nationwide registries.

We identified women from 1994 to 2015 using the Danish National Assisted Reproductive Technology (ART)-Couple II (DANAC II) Cohort, linked to the National Patient Register, the Civil Registration System and the Medical Birth Register. Women with cardiovascular disease at baseline were excluded (n = 2325), resulting in 60,574 women. Women with PCOS were identified in DANAC II using International Classification of Diseases (ICD-10) code E28.2 from 2006 onwards. Before 2006, the register-specific code ‘ovulation defect’ was used to indicate PCOS. As 90–95% of anovulatory women presenting to fertility clinics have PCOS, ovulation defect is an appropriate proxy.² Incident AF was identified in the National Patient Register using ICD-10 code I48.

The study was approved by the Danish Data Protection Agency and the Health Data Authority. Patient informed consent and ethics committee approval were not required.

Women were followed from their initial ART treatment and censored at the first of the following: (a) AF diagnosis; (b) death; (c) emigration; or (d) 31 December 2015 (end of follow-up). Baseline characteristics and outcomes, presented as medians and interquartile intervals or numbers and percentages, were tabulated for women with PCOS and women without PCOS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models with age as the underlying time scale. The model included age, year of first ART treatment, parity before first ART treatment, relationship status and education. As body mass index (BMI), hypertension and diabetes were considered to be potential mediators of the relationship, they were not included in the statistical models.

Of the 60,574 women, 6149 (10.2%) had PCOS. Median follow-up was 8.9 years (interquartile range 4.2–14.8) and 138 (0.2%) women developed AF. Table 1 reports the characteristics of the cohort at baseline. Women with PCOS were at twice the risk of AF (Figure 1). The results were robust when women with PCOS were compared: (a) to women receiving ART treatment due to non-anovulatory female factor infertility (HR 2.22, 95% CI 1.38–3.57); or (b) to women referred for male factor infertility (HR 1.75, 95% CI 1.09–2.81), a reproductively healthy subcohort.

Table 1.

Characteristics of women receiving ART treatment by polycystic ovary syndrome diagnosis, Denmark, 1994–2015.

	Women without PCOS		Women with PCOS		Total
N, %	54,426	89.9	6149	10.2	60,575	100.0
Sociodemographic factors
Age at entry, median and IQI (years)	33.1	29.9–36.7	31.0	28.3–34.5	32.9	29.7–36.5
Age at censoring, median and IQI (years)	42.5	37.2–48.5	42.6	36.6–48.6	42.5	37.2–48.5
Duration of follow-up, median and IQI (years)	8.7	3.97–14.6	11.9	6.0–15.7	8.9	4.2–14.8
Year of first ART treatment, median and IQI	2006	2000–2011	2003	1999–2007	2005	2000–2010
Marital status, N (%)
Married	25,531	47.2	3153	51.4	28,684	47.6
Cohabiting	21,368	39.5	2454	40.0	23,822	39.5
Single	7241	13.4	527	8.6	7768	12.9
Education, N (%)
Low	11,327	21.6	1394	23.2	12,727	21.8
Medium	19,706	37.7	2248	37.4	21,954	37.6
High	14,174	27.1	1623	27.0	15,797	27.1
Highest	7131	13.6	749	12.5	7880	13.5
Parity at baseline, N (%)
0	43,129	79.2	5229	85.0	48,358	79.8
1	8495	15.6	797	12.5	9262	15.3
2	1925	3.5	129	2.1	2054	3.4
3	640	1.2	20	0.3	660	1.1
4+	237	0.4	4	0.1	241	0.4
Health and medical factors
BMI, median and IQR (kg/m²)*	23.1	21.0–26.1	23.5	20.8–27.5	23.1	21.0–26.1
Alcohol, median and IQR (units/week)*	0	0–2	0	0–2	0	0–2
Current smoker, N (%)*	2558	10.9	147	9.5	2705	10.8
Hypertension, N (%)	618	1.1	104	1.7	722	1.2
Gestational diabetes, N (%)	224	3.6	1003	1.8	1227	2.0
Outcomes
Atrial fibrillation, N (%)	111	0.2	27	0.4	138	0.2
Died, N (%)	428	0.8	39	0.6	467	0.8
Migrated, N (%)	1152	2.1	112	1.8	1264	2.1

ART treatment: assisted reproductive technology treatment; BMI: body mass index; IQI: interquartile interval; PCOS: polycystic ovary syndrome.

*Available after 2006.

Missing data – education: 2223 (4.6%); relationship status: 301 (0.5%); BMI: 5285 (17.5%); alcohol: 6277 (20.8%); smoking: 5292 (17.5%).

Figure 1.

Hazard ratios and 95% confidence intervals for atrial fibrillation in women diagnosed with polycystic ovary syndrome, Denmark, 1994-2015.

To our knowledge, this is the first study to investigate the association between PCOS and hospital-diagnosed AF, building on prior research.^4,5 Insulin resistance and BMI may potentially explain the association between PCOS and AF. Women with PCOS are at a greater risk of type 2 diabetes and insulin resistance compared to BMI-matched controls,⁶ and diabetes is a risk factor for AF.¹ Raised BMI is also common among women with PCOS⁶ and is associated with greater AF risk,¹ including for women.⁷

Another plausible mechanism may be raised levels of sex steroid hormones. In women, higher levels of endogenous bioavailable testosterone may be associated with the risk of AF and ischaemic stroke (a composite outcome).³ Although this has not been replicated in all cohorts,⁸ the current analysis supports a potential role of sex hormones in AF development. Up to 90% of women with PCOS may have excessive levels of male sex hormones.⁶ If there is a threshold above which levels of bioavailable testosterone contribute to adverse atrial remodelling, and thus AF risk, then women with PCOS will be at increased AF risk.

Our study has several limitations. PCOS is a heterogenous condition. Diagnosis required two or more of the following: (a) menstrual irregularity; (b) hyperandrogenism (excess male hormones); and (c) polycystic ovaries.² Women with PCOS in our cohort may represent more severe PCOS cases as their fertility was affected. Our cohort was also relatively young (median age at censoring (interquartile range) 42.5 (37.2–48.5)). Therefore, AF events are rare. Residual confounding from smoking and alcohol consumption may have occurred, due to limited data on these factors.

Finally, we studied women receiving ART treatment, which may limit the generalisability of the findings. However, risk estimates were robust when comparing women with PCOS to women accessing ART treatment due to male factor infertility, who are a reproductively healthy subcohort.

In conclusion, PCOS was associated with greater AF risk. Adverse hormonal and cardiometabolic profiles that may predispose women with PCOS to subsequent AF require further investigation.

Footnotes

Data sharing

On request, the analytical methods will be made available for other researchers for purposes of reproducing the results or procedures. The data are available through the Danish Data Protection Agency to approved researchers affiliated with a Danish institute.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial spport for the research, authorship, and/or publication of this article: This work was funded by the British Heart Foundation (RE/13/6/30180), a doctoral research grant to DV from the Faculty of Health and Medical Sciences, University of Copenhagen (Copenhagen, Denmark), a research fellowship to COW from Homerton College, University of Cambridge, a travel fellowship to COW from the European Society of Human Reproduction and Embryology and ReproUnion, and this article is part of the ReproUnion collaborative study, co-financed by the European Union, Intereg V Öresund-Kattegat-Skagerrak.

References

Lau

Nattel

Kalman

, et al. Modifiable risk factors and atrial fibrillation. Circulation 2017; 136: 583–596.

Teede

Deeks

Moran

Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Med 2010; 8: 41.

Zeller

Schnabel

Appelbaum

, et al. Low testosterone levels are predictive for incident atrial fibrillation and ischaemic stroke in men, but protective in women – results from the FINRISK study. Eur J Prev Cardiol 2018; 25: 1133–1139.

Zehir

Karabay

Kocabay

, et al. Assessment of atrial conduction time in patients with polycystic ovary syndrome. J Interv Card Electrophysiol 2014; 41: 137–143.

Taşolar

Mete

Balli

, et al. Assessment of atrial electromechanical delay in patients with polycystic ovary syndrome in both lean and obese subjects. J Obstet Gynaecol Res 2014; 40: 1059–1066.

Glintborg

Rubin

Nybo

, et al. Morbidity and medicine prescriptions in a nationwide Danish population of patients diagnosed with polycystic ovary syndrome. Eur J Endocrinol 2015; 172: 627–638.

Di Benedetto

Michels

Luben

, et al. Individual and combined impact of lifestyle factors on atrial fibrillation in apparently healthy men and women: the EPIC-Norfolk prospective population study. Eur J Prev Cardiol 2018; 25: 1374–1383.

O’Neal

Nazarian

Alonso

, et al. Sex hormones and the risk of atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis (MESA). Endocrine 2017; 58: 91–96.