Cardiovascular risk in women with uterine fibroids of different ethnic groups
Haan, Y.C.L.
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2020
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Haan, Y. C. L. (2020). Cardiovascular risk in women with uterine fibroids of different ethnic
groups.
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Summary and
Perspectives
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Historically, women have been underrepresented in studies and have not received similar care for cardiovascular disease as men.1 The phenomenon in which a woman must present “just like a man” in order to receive optimal cardiovascular treatment is known as the Yentl syndrome.2 This syndrome has drawn attention to cardiovascular health care inequality between men and women. As a result, international awareness campaigns and sex-specific guidelines were initiated. Women are now more often included in clinical studies and the gender gap in cardiovascular mortality is gradually closing. However, in young women (≤55 years) admissions for myocardial infarction are rising and mortality rates are still higher than in men.3, 4 Even more worryingly, South Asian and African women have a higher burden of coronary heart disease compared to Caucasian women, and mortality due to heart disease is higher in young African than Caucasian women.5-7 These trends warrant early identification of cardiovascular risk in young women, in particular of South Asian and African ancestry. In order to help clinicians better characterize the cardiovascular risk profile of young women, the search for novel female-specific cardiovascular risk factors should continue.
Apart from female-specific cardiovascular risk factors, the rapid rise in obesity prevalence also contributes to the increased admission rates for myocardial infarction in young women. The worldwide number of adult women with obesity increased from 69 million in 1975 to 390 million in 2016.8 Moreover, the prevalence of morbid obesity is approximately 50% higher among women than men, and nearly twice as high among individuals of African compared to Caucasian ancestry.9 Subjects with obesity are more likely to develop cardiovascular disease and die on average 3.7 years earlier compared to subjects of normal weight.10 South Asian individuals in particular have a higher risk of diabetes and hypertension in the presence of adiposity compared to Caucasians.11 Current public health measures have had little success in attenuating the rise of obesity prevalence. Several mechanisms influence the development of obesity, including genetic and biological factors. A personalized approach by taking into account the individual’s susceptibility to obesity might aid in controlling the obesity epidemic. In this thesis, we investigated new risk factors to reduce cardiovascular mortality in young women, with a focus on African and South Asian women. In the first part of the thesis we focused on a novel female-specific risk factor for cardiovascular disease: the presence of uterine fibroids. Thereafter, we extended the search for markers of susceptibility to obesity. Obesity is the result of a dysbalance in energy intake and expenditure. We explored the potential role of plasma creatine kinase, an enzyme with a central role in energy metabolism, as a marker of susceptibility to obesity.
In Chapter 2, we assessed the association between hypertension and uterine fibroids. Uterine fibroids are benign tumors in the uterus composed of smooth muscle cells and are most prevalent during the reproductive period. As is the case with hypertension, fibroids are more prevalent in Africans and obese women.12 The main symptoms of fibroids are vaginal
bleeding and pelvic pain. In the U.S., the majority of hysterectomies are performed to treat symptomatic fibroids.13 We collected data on 272 women (122 Africans) undergoing surgery for fibroids, and compared these with 385 women (33 Africans) undergoing gynecological surgery for other reasons in the Amsterdam University Medical Centers, location AMC, the Netherlands. These subjects were also compared to 685 controls (387 Africans) from the multi-ethnic population of Amsterdam, the Netherlands. Of the women with fibroids, 41.9% had high blood pressure, compared to 27.5% of the gynecological surgical controls and 28.3% of the population controls (p < 0.001 for comparisons between women with fibroids and controls). The highest prevalence of hypertension was found in women of African ancestry with fibroids. The association between hypertension and fibroids persisted after adjusting for age, body mass index, and African ancestry, with an odds ratio of 2.4 (95% CI 1.7 to 3.4) for hypertension in women with fibroids. These data are in line with the studies of Luoto et al.14, 15 which demonstrated a 1.7 to 2.5 times higher odds of hypertension in Finnish women with fibroids as compared to women without fibroids. However, all these studies were conducted in women with symptomatic fibroids requiring surgery. This may induce selection bias. Therefore, we validated in Chapter 3 in Surinamese women with self-reported fibroids the association between hypertension and fibroids, and we obtained a complete cardiovascular risk profile, including data of hypertension, obesity, diabetes, hypercholesterolemia, smoking and physical activity. The study population consisted of women of the HELISUR study, a cross-sectional population-based study conducted in Paramaribo, the capital of Suriname. This middle-income country has a multi-ethnic population, consisting of individuals of mainly African (43%) and Asian (33%) ancestry.16 We analyzed 104 women (55 Africans) with self-reported fibroids and 624 controls (244 Africans). Women with fibroids were on average 10 years older compared to controls. The cardiovascular health of women with fibroids was worse than controls, with a prevalence of 64.1% vs. 34.6% for hypertension, 48.1% vs. 37.9% for obesity and 22.1% vs. 14.1% for diabetes (p < 0.05 for all risk factors). Smoking and physical activity did not differ. In South Asian as well as African women, hypertension and hypercholesterolemia were more common in the presence of fibroids. Again, African women with fibroids had the highest hypertension prevalence. The association between hypertension and fibroids persisted after adjustment for confounders, with 1.8 (95% CI 1.1 to 3.1) higher odds of hypertension in women with fibroids compared to controls. Other risk factors were not significantly associated after adjustment for age, body mass index, African ancestry, use of hormonal contraceptives, parity, postmenopausal status, fasting plasma total cholesterol, fasting plasma glucose, and systolic blood pressure. Whether the increased prevalence of hypertension was accompanied by a higher cardiovascular risk was estimated by assessing the prevalence of asymptomatic organ damage and the Framingham risk score (calculating the 10 year risk of a cardiovascular event). Asymptomatic organ damage was defined as the presence of increased pulse pressure or pulse wave velocity, low ankle-brachial index, electrocardiographic left ventricular hypertrophy, estimated glomerular filtration rate 30-60 mL/min/1.73 m2, or proteinuria. The Framingham risk score is based on age, high-density lipoprotein, total plasma cholesterol, systolic blood
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pressure, use of antihypertensive medication, current smoking, and the presence of diabetes. To our knowledge, we were the first to assess the presence of asymptomatic organ damage in women with fibroids and found that 66.7% of women with fibroids vs. 42.9% of controls (p < 0.05) had asymptomatic organ damage. Alarmingly, up to 45% of women <50 years with fibroids already had asymptomatic organ damage, compared to 22% of controls. The worse cardiovascular health was further demonstrated by a higher 10-year risk of a cardiovascular event: 7.3% in women with fibroids compared to 2.8% in controls (p < 0.05), as assessed by the Framingham risk score.
Taken together, Chapters 2 and 3 demonstrate a worse cardiovascular risk profile in women with fibroids, in particular increased odds of hypertension with more asymptomatic organ damage and a higher 10-year risk of a cardiovascular event. Hypertension was most prevalent in African women with fibroids in the Dutch as well as in the Surinamese study populations. In this thesis, we postulated that the association between fibroids and hypertension is due to a common pathophysiology of smooth muscle proliferation. Several growth factors and vaso-active peptides, such as angiotensin II, stimulate uterine smooth muscle cell proliferation leading to fibroids. In line with this, treatment with an angiotensin II receptor inhibitor and aldosterone antagonists stops fibroid cell proliferation.17, 18 These growth factors are also involved in the development of hypertension causing vascular constriction and remodeling. This vascular remodeling can lead to decreased vascular compliance and thereby a higher speed at which a pulse wave moves through an arterial segment. This is also known as pulse wave velocity, which is a better predictor of future cardiovascular events and all-cause mortality than traditional cardiovascular risk factors and risk scores.19 In order to gain more insight in the pathophysiology of hypertension in women with fibroids and their cardiovascular risk, we assessed in Chapter 4 the pulse wave velocity in 64 women with fibroids and 356 controls from the HELISUR study. As expected, the median pulse wave velocity of women with fibroids was higher than controls (9.2 m/s, IQR 8.1 to 11.4, vs. 7.7 m/s, IQR 6.6 to 9.4, p < 0.05). After adjustment for important confounders and traditional cardiovascular risk factors including hypertension, women with fibroids still had a 1.1 m/s (95% CI 1.02 to 1.12) higher pulse wave velocity compared to controls. These data show that the vascular damage in women with fibroids is not solely dependent on the presence of traditional cardiovascular risk factors. In line with this, 16.4% of women with fibroids with arterial stiffness (pulse wave velocity >10m/s) had a low to moderate cardiovascular risk based on traditional risk factors, compared to 7.4% of controls (p = 0.01). These data show that every one in six women with self-reported fibroids might be untruly classified as low to moderate cardiovascular risk, thereby depriving these women from optimal cardiovascular risk management.
Current literature shows that measurement of pulse wave velocity improves the identification of individuals with high cardiovascular risk beyond traditional risk factors.19 We propose that the increased pulse wave velocity we observed in women with fibroids is a result of vascular
remodeling due to hypertension. In addition, we postulate a role for endothelial dysfunction. The endothelium modulates vascular tone through substances such as nitric oxide, which is important for vasorelaxation. However, nitric oxide does not only modulate vascular tone leading to hypertension, but is also capable of modulating vascular compliance.20 Moreover, angiotensin II, which plays a role in hypertension and fibroid growth, also promotes oxidative stress and decreased nitric oxide bioavailability leading to endothelial dysfunction.18 In addition, increased levels of endothelin-121 and decreased levels of adiponectin22 are found in women with fibroids, which is associated with endothelial dysfunction.23, 24
Although the higher pulse wave velocity in women with fibroids implies there is an increased risk of cardiovascular disease, literature is limited. Therefore, we assessed in Chapter 5 the cardiovascular disease burden of women with fibroids using data from NHANES, a nationally representative survey of the U.S. population conducted by the National Center for Health Statistics. This is a multi-ethnic sample, which mainly consists of women from Caucasian (46%), Hispanic (29%) and African (21%) ancestry. We analyzed data from 700 women with reported fibroids and 4,847 controls. In line with our previous studies, women with self-reported fibroids had higher odds of hypertension after adjustment for confounders (odds ratio 1.6, 95% CI 1.3 to 2.0). The prevalence of cardiovascular disease was higher in women with fibroids compared to controls (5.2 vs. 3.3%). Women with fibroids had a 1.6 (95% CI 1.1 to 2.4) times higher adjusted odds of cardiovascular disease. To assess whether this was all attributable to hypertension, we further adjusted for hypertension status, which did not change the outcome. Some studies suggest that a hysterectomy, which is one of the main therapies for symptomatic fibroids, is associated with an increased cardiovascular risk.13, 25, 26 Therefore, we excluded women with a hysterectomy from the analyses, which did not alter the association between presence of fibroids and cardiovascular disease.
In conclusion, Chapters 1 to 5 illustrate that women with fibroids have an increased cardiovascular risk and cardiovascular disease burden. The association between hypertension and fibroids was confirmed in multi-ethnic samples of the Netherlands, Suriname and the U.S. Fibroids occur more often in women of African ancestry.12 Although African women already have the highest burden of hypertension and hypertension-related cardiovascular morbidity and mortality in the world,12 the presence of fibroids further increased the prevalence of hypertension in African women. Also in South Asian women, who are already prone to cardiovascular disease, and in Caucasians, the hypertension prevalence increased in the presence of fibroids. Hypertension does not seem to be the only factor contributing to the increased cardiovascular risk in women with fibroids. In addition, women with fibroids had a higher pulse wave velocity and cardiovascular disease prevalence, which remained even after adjusting for hypertension and other traditional risk factors. Clinicians should be aware of the increased hypertension and cardiovascular risk of women with fibroids, in particular in African women, and be assertive in screening for hypertension and target organ damage.
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With the current obesity epidemic, it is no surprise that women develop heart disease at younger ages, which is largely preventable through lifestyle modifications and searching for novel female-specific risk factors. Obesity prevention strategies should aim for a personalized approach. The individual’s susceptibility for obesity is a result of how the body regulates energy intake, expenditure, and storage. An important factor in energy handling is the composition of skeletal muscles. There are two types of muscle fibers: slow type I and fast type II fibers. These type I fibers use mitochondrial oxidation of fatty acids to generate ATP, while fast type II muscle fibers mainly rely on glycolysis and the creatine kinase system for their ATP.27 Due to attenuated mitochondrial oxidation, type II fibers promote storage of fatty acids rather than their oxidation. In line with this, in several studies type II muscle fiber predominance is associated with obesity.28, 29 As predominance of type II fibers represents an important part of energy expenditure and energy storage, it might be a marker of susceptibility for obesity. The gold standard to assess fiber composition is a muscle biopsy, which is an invasive procedure. However, total plasma creatine kinase after rest accurately reflects tissue creatine kinase in skeletal muscle fibers. Therefore, in Chapter 6 we assessed whether resting plasma creatine kinase is a good marker of obesity. We analyzed 528 men and 783 women that were included in the SUNSET study, a multi-ethnic population study conducted in Amsterdam, the Netherlands. There was a positive correlation between plasma creatine kinase levels and waist circumference, waist-to-hip ratio and body mass index. Plasma creatine kinase levels are higher in men and Africans. Therefore, we adjusted for these and other important confounders and found that plasma creatine kinase was associated with all three measures of adiposity. This is in line with unadjusted reports on plasma creatine kinase levels and anthropometric measures.30, 31 Moreover, animal studies using creatine-deficient and creatine kinase-knockout mice showed that these mice had a lower body weights and total body fat content.32, 33 In addition, rodents receiving the creatine kinase inhibitor beta-guanidinopropionic acid demonstrated a shift from type II to type I fiber predominance, which resulted in greater glucose and fatty acid oxidation and a reduction in body weight.34 These findings suggests a role of the creatine kinase system in weight regulation and obesity. Therefore, plasma creatine kinase might be used as a non-invasive marker of obesity susceptibility. Interestingly, African individuals have more type II muscle fibers and higher creatine kinase levels.35, 36 In addition, creatine kinase is associated with hypertension,37 which might explain the excessive burden of hypertension and obesity in this ethnic group.
Perspectives
The window of opportunity to prevent cardiovascular disease in women is in the pre-menopausal years. In this thesis, we showed that women with uterine fibroids have a worse cardiovascular risk compared to controls. Moreover, although African women already have the highest prevalence of hypertension and hypertension-related cardiovascular morbidity and mortality, this is further increased in the presence of uterine fibroids. As uterine fibroids are highly common in Africans, early cardiovascular risk identification is warranted especially in
this group. A recent study among gynecologists in the U.S. demonstrated that less than 50% screened their patients for cardiovascular risk factors,38 a proportion that should be improved. A good predictor of cardiovascular risk is pulse wave velocity, which was increased in women with fibroids, even in the absence of traditional cardiovascular risk factors. Thus, assessing pulse wave velocity as a marker of cardiovascular risk may be especially important in women with fibroids. The presence of fibroids, as a potential novel cardiovascular risk factor, offers several new ways of reducing the cardiovascular disease risk in young women. For example, arterial stiffness can be improved by antihypertensive drugs, in particular angiotensin-converting-enzyme (ACE) inhibitors.39 Interestingly, even in the absence of hypertension, ACE inhibitors can improve pulse wave velocity.40 This means that further studies should assess whether women with fibroids and arterial stiffness could benefit from treatment with ACE inhibitors, independent of their blood pressure status. This approach would be similar to the treatment of myocardial infarction in diabetic women, in which an ACE inhibitor therapy is started independently of blood pressure to improve cardiac remodeling.41
With the rising cardiovascular mortality in young women, the search for female-specific risk factors is ongoing. Accumulating evidence points towards an increased cardiovascular risk in women with fibroids, in particular in African women. In this thesis, we further strengthened the knowledge about cardiovascular risk in women with fibroids. The finding of fibroids as a novel risk factor might provide opportunities to reduce cardiovascular morbidity and mortality in young women.
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