Association of endometriosis with cardiovascular disease: Genetic aspects (Review)

The cardiovascular system consists of the heart and its blood vessels. Cardiovascular disease (CVD) is a general term that describes a type of disease that affects any of these components. The majority of the anatomical structures that are related to the cardiovascular system display a common tissue organization, with endothelial cells (ECs), smooth muscle cells (SMCs) and myocardial cells being three of the major cell types at the cellular level. In this context, several types of CVD exist, affecting only the blood vessels or the heart, but most commonly, both of these, either simultaneously as result of a common cause or as a sequalae arising, for example, from one condition that leads to other diseases within the group (e.g., coronary vessel disease that leads to ischemic cardiac disease or arrhythmias) ( 1 ). Endometriosis is a common, benign, estrogen-dependent gynecological disease, associated with chronic pelvic pain and subfertility, defined by the presence of ectopic endometrial glands and stroma outside of the uterine cavity on other organs ( 2 , 3 ). It affects 10 to 15% of women of reproductive age, exhibiting varying symptoms such as severe pelvic pain, irregular menstrual bleeding, heavy menstrual pain, urinary tract and gastrointestinal symptoms and pain during intercourse, and can significantly affect the quality of life of patients ( 4 - 6 ). Notably, endometriosis possesses numerous features that are reminiscent of a benign neoplastic process, which has the potential for malignant transformation. Genetic factors contribute to the development of this condition, in combination with environmental ones, such as toxins and pollution agents ( 3 , 7 ). Although the exact molecular and pathophysiological pathways leading to endometriosis remain unclear, various hypotheses have been suggested thus far, and all cases are not able to be explained by one theory alone ( 8 ). There is strong evidence to suggest the contribution of not only hormonal aspects, but also of multiple immune-mediated processes related to chronic inflammation, increased oxidative stress and an atherogenic lipid profile ( 9 , 10 ). Women with endometriosis, which is a heterogeneous condition, are at a high risk of developing several other chronic diseases, including cancer ( 11 ) and various autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis, rheumatoid arthritis (RA), Crohn's disease, scleroderma, ulcerative colitis, autoimmune thyroid disorder, Sjögren's syndrome, coeliac disease and ankylosing spondylitis ( 12 - 14 ). Of note, previous findings have suggested that endometriosis can increase the susceptibility for cardiovascular disorders in these women, considering that both conditions share pathogenic mechanisms based on hormonal deviations, as well as aberrant immunology and genetic profiles ( 15 - 17 ). Moreover, studies have reported a similar potential association between endometriosis and atherosclerotic CVD, underlying similar pathogenic mechanisms including coronary microvascular dysfunction, endothelial dysfunction and atherogenic lipid profile ( 18 , 19 ). There is an extended amount of literature focusing on the increased risk that women with endometriosis have for developing myocardial infarction, ischemic heart disease, hypertension, atherosclerosis requiring bypass and angioplasty or stenting procedures ( 16 , 20 - 24 ). However, CVD in women with endometriosis remains underdiagnosed and, therefore, detailed studies are required to fully understand the clinical relevance, as well as the underlying pathophysiological mechanisms of the interactions between these conditions. The present review discusses and summarizes the observed increased risk of CVD among women with endometriosis from the genetic point of view, focusing on the potential underlying shared genetic factors that warrant further study. Understanding these associations in depth requires mechanistic and functional genomics research in an effort to determine the causal shared risk factors.

Based on the aforementioned data, a clear identification of a link between endometriosis and lifelong CVD would necessitate a radical shift in public health management. Although endometriosis remains an enigmatic disease and little is understood about the main causes of the disease, it has been associated with various diseases, including CVD, thus suggesting that women with endometriosis may represent a high-risk group for CVD. Of note, Taskin et al ( 225 ) pointed out that endometriosis should be considered as a risk factor for CVD, thus requiring specific counseling and prevention. Key questions that arise from these studies refer to whether gynecologists have to recommend women with endometriosis for a cardiology assessment, as well as the possibility of these findings leading to substantial changes in treatment options. However, it should not be under-recognized that other known risk factors for CVD in women, such as diabetes, LDL-C levels, obesity and hypertension, may have a larger combined effect on the risk of CVD compared to endometriosis alone. Evidently, an in-depth understanding of the association between these conditions may enrich the existing knowledge and may provide new insight into the chronic consequences of endometriosis. Furthermore, given the high prevalence of endometriosis, the development of preventive and early detection guidelines for CVD for women with endometriosis may prove beneficial for public health ( 226 ). Advances in cardiovascular genetics prompted the American Heart Association (AHA) to publish a very recent Scientific Statement for the incorporation of polygenic risk scores to the management of five cardiometabolic diseases (coronary artery disease, hypercholesterolemia, type 2 diabetes, atrial fibrillation, and venous thromboembolic disease) ( 227 ). This report summarizes the dogma for the CVD as a multifactorial and complex one. Despite advancements being made, risk prediction remains imprecise with persistently high rates of incident CVD. Currently, such scores are often used in research, one field being the study the inter-relationship between the risk of CAD and other phenotypes. In an attempt to unravel the mechanisms underlying the risk association between endometriosis and CVD, various possible explanations can be suggested. Thus, it can be hypothesized that endometriosis may cause chronic inflammation, considering that inflammation is the precursor to a number of different disease pathologies, including CVD. To this end, various markers of endothelial function (including common carotid intima-media thickness) can be useful for an evaluation of a preclinical and subclinical risk of atherosclerosis in women with endometriosis, not only in the peritoneal cavity, but also at a systemic level ( 10 ). Notably, a higher risk of CHD has been observed among women who have had a hysterectomy/oophorectomy than in those who have not undergone this surgical procedure and, as a consequence, this fact has to be taken into account before a decision for this invasive treatment ( 15 ). The data presented herein provide evidence of various genetic factors that are shared between endometriosis and CVD, thus demonstrating apparent genetic links between these conditions. Noteworthy, it is beneficial for clinicians to be aware of the possibility of a co-occurrence of these diseases in order to provide suitable medication to women with endometriosis. Given the existing link between endometriosis and early menopause ( 228 ), hormone replacement therapy during perimenopause has shown that estrogen therapy is cardioprotective ( 229 ). However, although estrogens have been found to be generally cardioprotective in women with early atherogenesis, it has been reported that it is potentially harmful in women with established atherosclerosis ( 230 ). In addition, the common treatment of endometriosis by the inhibition of the production of prostaglandins (using drugs such as ibuprofen or naproxen) in an attempt to significantly reduce the symptoms of disease should be avoided, considering that these can lead to an increased cardiovascular risk as an undesirable secondary effect ( 231 ). Future research should attempt to fully unravel the shared molecular pathways underpinning the association between endometriosis and CVD, thus allowing physicians to develop and customize novel therapeutic interventions based on an individual's molecular and clinical profiles.