Endometriosis associated with an increased risk of cardiovascular outcomes: BJOG

Endometriosis is the abnormal presence and growth of endometrium-like (the inner layer of the uterus) epithelium and stroma in places outside the endometrium and myometrium. The standard for the diagnosis of endometriosis is laparoscopic visualisation, ideally accompanied by histological confirmation. In the UK and several other countries, the average diagnostic delay for endometriosis is 7 years. The exact cause of endometriosis is unclear. Several theories have been postulated.

Ectopic endometrial tissues undergo cyclical proliferation, secretion and sloughing. The result is chronic inflammation and fibrosis. Chronic inflammation triggers endothelial dysfunction and initiates premature atherosclerosis. Moreover, among people with chronic inflammatory disorders, the relative risk of atherosclerotic CVD is greatest in young women. Beyond chronic inflammation, there is increased production of reactive oxygen species from oxidative stress, a known trigger of cardiac arrhythmia.

Given the chronic inflammatory nature of endometriosis, coupled with diagnostic delays, young women with endometriosis may be predisposed to an increase in cardiovascular risk. Using primary care data from the UK, this study done by Okoth K and team aimed to investigate the association between endometriosis and cardiovascular risk, as well as to describe the incidence and prevalence of endometriosis among women of reproductive age in the UK.

To estimate yearly endometriosis prevalence, sequential cross-sectional studies were carried out on 1 January each calendar year from 1998 to 2017. A population-based retrospective cohort study was carried out to assess the risk of long-term cardiovascular outcomes. Women with a diagnosis of endometriosis (exposed) and matched controls from the general population with no diagnosis of endometriosis (unexposed), were identified between 1 January 1995 and 31 December 2018. The rates of cardiovascular outcomes were compared in the exposed and unexposed groups.

The primary outcome was composite cardiovascular disease (CVD) including, ischaemic heart disease (IHD), heart failure (HF) and cerebrovascular disease. Secondary outcomes were arrhythmia, hypertension and allcause mortality.

In all, 56,090 women with endometriosis and 2,23,669 matched controls without endometriosis were included in the analysis of cardiovascular risk.

Compared with women without endometriosis, the aHR for cardiovascular outcomes among women with endometriosis were: composite CVD 1.24; IHD 1.40; cerebrovascular disease 1.19; HF 0.76; arrhythmia 1.26; hypertension 1.12 and all-cause mortality 0.66 .

The incidence of endometriosis was 12.3 per 10,000 person-years in 1998 and 11.5 per 10,000 person-years in 2017. The prevalence of endometriosis increased from 119.7 per 10,000 population in 1998 to 201.3 per 10,000 population in 2017.

This population-based retrospective cohort demonstrated that cardiovascular outcomes were increased among UK women diagnosed with endometriosis compared with those without a diagnosis for endometriosis. Specifically, endometriosis was associated with a higher risk of composite CVD, IHD, cerebrovascular disease, arrhythmia, hypertension, independent of demographic, lifestyle and reproductive confounders. No association was found between endometriosis and heart failure risk. Overall, between 1998 and 2017, the trend in the annual incidence of endometriosis was stable with only minor variations noted between the years. During the same period, there was a steady increase in the annual prevalence of endometriosis.

Several biological mechanisms may explain the observed association between endometriosis and higher cardiovascular risk:

First, chronic inflammation promotes endothelial dysfunction. The systemic inflammatory nature of endometriosis has been demonstrated by several studies that found increased levels of pro-inflammatory markers in the peritoneal fluid and serum of women with endometriosis. Moreover, chronic inflammation may favour the development of cardiac arrhythmia, both directly through altered cardiac electrophysiology and indirectly by the accelerated development of IHD.

Second, biomarkers of oxidative stress have been found to be elevated among women with endometriosis. Prolonged exposure to reactive oxygen species from oxidative stress has been associated with vascular and cardiac myocyte dysfunction, which may lead to cardiac arrhythmias through cardiac fibrosis, ion-channel conduction disturbances, and early and late depolarisations.

Third, various studies have shown that endometriosis is associated with high levels of atherogenic low-density lipoproteins.

Fourth, the oxidation hypothesis may partly explain the association between reproductive risk factors, including endometriosis and increased CVD risk. The hypothesis explains that low-density lipoprotein is not atherogenic on its own; for atherosclerosis to occur, reactive oxygen species must oxidise low-density lipoproteins leading to cell formation, a dysfunctional endothelium and finally atherogenesis.

"In conclusion, this study found an association between endometriosis and a higher risk of cardiovascular outcomes. No association was found between endometriosis and risk of heart failure. Future research should focus on whether early treatment of endometriosis and primary CVD prevention strategies will be effective in reducing CVD risk among young women with endometriosis."

Source: Okoth K, Wang J, Zemedikun D, Thomas GN, Nirantharakumar K, Adderley NJ. Risk of cardiovascular outcomes among women with endometriosis in the United Kingdom: a retrospective matched cohort study. BJOG 2021; 128:1598–1609.