Endometriosis and CV Risk: Link Needs Further Attention and Research

Endometriosis may heighten cardiovascular risk in women over the long-term but doesn’t appear to increase the risk of all-cause death, according to new Danish data.

A chronic disease that affects around one in 10 women of reproductive age, endometriosis can cause complications like systemic inflammation, endothelial dysfunction, oxidative stress, as well as increases in LDL cholesterol and triglycerides, all of which can consequently affect cardiovascular disease risk.

Research linking endometriosis with long-term CV outcomes is limited, lead author Eva Havers-Borgersen, MD (Rigshospitalet, Copenhagen University Hospital, Denmark), told TCTMD, so investigation into any possible relationship was long overdue.

And find one they did. Comparing more than 60,000 women with endometriosis with more than 242,000 matched controls, the researchers demonstrated an adjusted 15% greater risk of the composite outcome of acute MI and ischemic stroke in those with the disease.

“I was surprised by the magnitude of the relative risk differences we found,” Havers-Borgersen said. “And I was also surprised that the results held true in all of the sensitivity analyses, even though we tried to take everything we could into account to see if there was something underlying driving these associations. We were not able to adjust out of the difference.”

Commenting on the study for TCTMD, Garima Sharma, MD (Inova Health System, Fairfax, VA), called the findings “hypothesis generating” but said they nevertheless serve as a reminder that endometriosis is a sex-specific risk factor worth consideration. “Asking for a reproductive and gynecological history is important,” she said in an email. “There are other symptoms that patients complain of and clinicians often miss the signs. This should be a part of regular female-specific history.”

The findings were presented as a poster at the 2024 European Society of Cardiology Congress last month and simultaneously published in the European Heart Journal.

Increased Risks With Endometriosis

For the study, Havers-Borgersen and colleagues included 60,508 women with endometriosis (median age 37.3 years) diagnosed in Denmark between 1977 and 2021 as well as a matched-control population of 242,032 women without evidence of endometriosis. Women in the study group had more comorbidities, used more medications, and had a higher socioeconomic standing.

Over a median follow-up period of 16.1 years, the rate of the primary endpoint (acute MI and ischemic stroke) was 5.9% in women with endometriosis and 4.9% in those without. The 40-year cumulative incidence of this endpoint was higher for women with endometriosis (17.5%) compared with controls (15.3%), translating into a significantly higher adjusted risk (HR 1.15; 95% CI 1.11-1.20).

It’s time we open our eyes to these sex-specific and especially female-specific risk factors that haven't been examined previously as much. Eva Havers-Borgersen

Individual adjusted risks for both acute MI (6.8% vs 6.1%; HR 1.35; 95% CI 1.31-1.40) and ischemic stroke (12.4% vs 10.5%; HR 1.18; 95% CI 1.12-1.23) also were slightly higher among women with endometriosis, as were the risks for arrhythmias (25.4% vs 22.2%; HR 1.21; 95% CI 1.17-1.25) and heart failure (9.7% vs 9.3%; HR 1.11; 95% CI 1.05-1.18).

Interestingly, women with endometriosis had a lower incidence of adjusted all-cause death in the study compared with controls (HR 0.93; 95% CI 0.91-0.96). When the mortality analysis was limited to women who had a primary endpoint event, there was no longer a difference observed (HR 0.92; 95% CI 0.81-1.05).

The secondary endpoint of acute MI, ischemic stroke, and all-cause mortality remained significantly higher for women with endometriosis (P = 0.01).

Several sensitivity analyses supported the overall findings, including analyses that excluded women who had primary endpoint events prior to the study; adjusted for education, income, and cancer; looked only at women diagnosed after the year 2000; used hysterectomy and oophorectomy as well as hormone therapy as time-dependent variables; and stratified women by decade of diagnosis.

Sex-Specific Risk Factors

The findings cannot elucidate the reasons behind the link between endometriosis and CV risk, though “I would think that the main mechanism is inflammation and the oxidative stress and endothelial dysfunction and the proatherogenic lipid profile associated with the condition,” Havers-Borgersen said. “But we need more research to examine the exact underlying mechanism driving this association.”

Sharma agreed that increased inflammation with endometriosis is likely the culprit here. “Future studies might want to incorporate assessment of the inflammatory milieu and endothelial dysfunction in patients with endometriosis,” she suggested.

One puzzling finding was the increased risk of each endpoint in the study with endometriosis except for death, Sharma noted. “[That’s] hard to explain,” she said. “Increased survival rates in patients with endometriosis might be due the heightened self-awareness in these patients, and more of these patients might interface with clinicians leading to better screening and monitoring of chronic disease and symptoms and cardiovascular health assessments.”

In the meantime, Havers-Borgersen urged cardiologists to focus more closely on risk factors, like endometriosis, that solely affect women. “We have come so far in describing in all traditional risk factors that are common for men and women, but my opinion is that we have to delve further down and look into the sex-specific risk factors to come even further and understand sex-specific differences in detail,” she said. “It’s time we open our eyes to these sex-specific and especially female-specific risk factors that haven't been examined previously as much.”

Previous partnerships between cardiologists and ob-gyns with regard to preeclampsia, for example, have a proven track record in improving care for patients, Havers-Borgersen said, adding that this model could potentially be used for endometriosis as well.

Going forward, Sharma said she would like to see more studies look at this topic in “more racially and ethnically diverse populations.” Also, things like quality of life, patient-centered outcomes such as lived experiences, and the psychological impact of endometriosis-related comorbidities are “of great importance,” she said. “What social and environmental drivers of health impact the diagnosis?”