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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1
Introduction and
outline of the thesis
1
11
Introduction
Cardiovascular diseases, such as myocardial infarction and stroke, are the most common preventable causes of death in the Western World.1 They claim more lives each year than cancer
and chronic lung disease combined and are expected to account for over 23.6 million deaths in 2030.2 Although coronary heart disease has traditionally been regarded as a disease of men,
it is also the leading cause of death in women.2 The highest prevalence of cardiovascular
disease is found in women of African ancestry followed by South Asian women, which reflects the substantial differences in cardiovascular disease morbidity and mortality between ethnic groups.3 African and South Asian women have a higher morbidity and mortality from stroke
and coronary heart diseases compared to Caucasian women,3, 4 with increased mortality from
coronary heart disease in South Asian women and from stroke in African women.3, 5 Thus,
women of these ethnic groups are more likely than Caucasians women to die of preventable cardiovascular disease. In addition, in African as well as South Asian women myocardial infarction occurs at an earlier age than Caucasian women.4, 6
In 1997, the American Heart Association conducted a national survey among women, which demonstrated that only 30% were aware that heart disease was their number one killer.7
Alarmingly, African American women have the lowest awareness that heart disease is their leading cause of death.3 With the use of several initiatives such as ‘Go Red for Women’, the
awareness rate had risen to 56% in 2012.7 But even now, public knowledge of the causes and
consequences of cardiovascular disease in women is suboptimal.
For many years, women have been underrepresented or even excluded from studies on cardiovascular disease.8, 9 The interest in sex differences in cardiovascular disease was initiated
in 1991 by Bernadine Healy, the first female director of the U.S. National Institutes of Health. In an issue of the New England Journal of Medicine she summarized two studies revealing sex bias in the management of coronary heart disease.10, 11 One of the studies illustrated the Yentl
syndrome: ‘Women receive equivalent care to men only when they demonstrate that they are
like men by having similar complaints’. This refers to the short story ‘Yentl the Yeshiva Boy’, written by Nobel Prize in Literature Winner Isaac Singer, in which a woman named Yentl had to dress and act like a boy to be able to attend school.10, 11 Currently, the Yentl syndrome still
illustrates the importance of sex differences in cardiovascular disease.11
Although cardiovascular mortality declined in the past decade, ethnic disparities in mortality due to cardiovascular disease has remained,12 with twice the rate of avoidable deaths from
heart disease and stroke in African Americans compared to Caucasians.13 Approximately 80%
of cardiovascular diseases can be prevented through modifiable factors such as not smoking, eating a healthy diet, engaging in physical activity, maintaining a healthy body weight, and controlling blood pressure, diabetes mellitus and lipid levels.2 The main modifiable risk factor
and South-Asian women the hypertension prevalence is higher compared to Caucasians, with the highest prevalence in women of African descent followed by South-Asians. The increased burden of cardiovascular risk factors is largely responsible for the excess mortality among African and South Asian women.2, 5
Women with hypertension have an increased risk to develop target organ damage and have a higher hypertension-related mortality.2, 14 Of the women with hypertension, up to 75% is
aware of their high blood pressure and over 60% is treated. Nevertheless, hypertension in women is controlled in less than 30%.2 Particularly in African women, hypertension is more
severe and less often controlled despite a higher awareness and despite being treated more often compared to Caucasian.2, 4 Also in South Asians, hypertension is less often controlled
compared to Caucasians.15 On top of that, in both ethnic groups hypertension develops at an
earlier age.4 Thus, early identification of hypertension and its risk factors is crucial to reduce
hypertension-related cardiovascular mortality in pre-menopausal women, in particular in South Asian and Africans.16
Although women and men share many cardiovascular risk factors, women also have unique, female-specific risk factors, such as oral contraceptive use.17 Furthermore, the risk
of cardiovascular disease can increase due to pregnancy-related risk factors. Up to 8% of pregnancies are complicated by hypertensive disorders.18 Gestational hypertension and
preeclampsia are well-established female-specific risk factors for hypertension and increase risk of future stroke and coronary heart disease by two-fold.19 The risk of preeclampsia is
higher in women of African ancestry and is accompanied by a three-fold increased risk of future cardiovascular disease in this ethnic group.20 Although the focus has been mainly
on pregnancy-related cardiovascular risk factors, there are other female-specific risk factors such as premature ovarian insufficiency and polycystic ovary syndrome which both have been associated with an increased risk of cardiovascular disease.21 Women with polycystic
ovary syndrome also have an increased risk of developing type 2 diabetes, hypertension and dyslipidaemia.21
Despite this increasing insight and awareness, cardiovascular mortality in young women hardly changed and may actually be on the rise in the past decade.22, 23 Hence, it is vital to help
clinicians better identify women at risk for hypertension and cardiovascular disease, which warrants an extended search for female-specific risk factors. One of the novel risk factors for cardiovascular disease in women that gained increased attention over the past decades is the presence of uterine fibroids.
1
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Introduction
OuTLINE OF THE THESIS
In the search for novel female-specific risk factors for cardiovascular disease, this thesis focuses on the potential role of uterine fibroids. Fibroids are the most common benign tumors in women, and are hormone dependent, thereby being mainly developed during the reproductive period of a woman’s life.24 In the past decades, several studies suggested
that women with uterine fibroids have a higher prevalence of hypertension.25, 26 Fibroids are
most common in African women and this ethnic group develops fibroids earlier in life. The prevalence of fibroids is comparable in women of South Asian and Caucasian ancestry.27
Moreover, uterine fibroids in African women are often larger and cause more severe symptoms compared to other ethnic groups.28 Interestingly, African women are also disproportionally
often affected by hypertension and cardiovascular disease.29 Previous studies on fibroids and
hypertension did not adjust for ancestry or other important confounders such as age and body mass index. Therefore, as a first step, we assessed in Chapter 2 the association between hypertension and uterine fibroids in African and Caucasian women undergoing surgery for uterine fibroids in the Netherlands, adjusted for important confounders.
Hypertension often clusters with other cardiovascular risk factors such as glucose intolerance and dyslipidemia, which has a multiplicative effect on cardiovascular risk. In order to gain more insight in the cardiovascular risk profile of women with fibroids, we assessed in Chapter 3 the prevalence of hypertension, obesity, diabetes, hypercholesterolemia, smoking and physical activity in African and South Asian women with and without fibroids living in Suriname. In addition, we investigated the prevalence of asymptomatic organ damage, which refers to structural or functional changes caused by these cardiovascular risk factors. Asymptomatic organ damage is a sign of preclinical cardiovascular disease and an important independent marker of increased cardiovascular risk.30, 31
One of the main hypotheses of the co-occurrence of hypertension and uterine fibroids is a common pathophysiology of smooth muscle proliferation in the uterus as well as the vascular wall.32 The smooth muscle proliferation is stimulated by several growth factors and vasoactive
peptides that are upregulated in hypertension as well as uterine fibroids, such as angiotensin II, endothelin-1, transforming growth factor-β, and creatine kinase. Smooth muscle proliferation might promote the formation of uterine fibroids in the myometrial wall and remodeling of the vascular wall, which in turn could lead to hypertension and stiffening of the arteries.33 This so
called arterial stiffness can be determined by non-invasive measurement of the pulse wave velocity, which is the velocity at which the pressure waves propagate along the arterial tree. With increasing stiffness, the pulse wave velocity increases which is an important predictor of cardiovascular events.31 We assessed in Chapter 4 the pulse wave velocity in women with
Until now, it was unknown whether the increased hypertension risk in women with fibroids was accompanied by a higher cardiovascular burden. Current literature contains only a few case reports of strokes in women with fibroids and one cohort study reported a six-fold increased risk of myocardial infarction in women undergoing surgery for fibroids compared to hysterectomy for other indications.34-38 These data are unadjusted for confounders, such
as age, body mass index and ancestry. Therefore, we assessed in Chapter 5 whether women from the U.S. with fibroids have a higher prevalence of cardiovascular disease, adjusted for cardiovascular risk factors. In this large sample of women of different ethnic groups, we also assessed the cardiovascular risk profile and the accompanying 10-year risk of fatal cardiovascular disease.
Another important risk factor for cardiovascular disease is obesity. The increase in obesity rates among young women parallels the increase in myocardial infarction and stroke among middle-aged women.7 In 2016, 41.1% of U.S. women were obese, compared to 37.9% of men.
The difference in prevalence was even more pronounced for morbid obesity (BMI ≥40 kg/m2):
9.9% of women versus 5.5% of men, with the highest prevalence of 16.8% in African American women.2 South Asians have a greater amount of body fat compared with Caucasians for a
given level of body mass index or waist circumference, which is strongly associated with hypertension and diabetes in this ethnic group.39, 40
Susceptibility to adiposity is driven by an interaction between environmental, genetic and biological factors.2, 41 One of these biological factors is the skeletal muscle fiber composition.42, 43 Skeletal muscles consist of type I and type II muscle fibers. These type II muscle fibers display
high cytosolic creatine kinase activity and are designed for burst activity by enhancing glycolysis instead of lipid oxidation, thereby promoting the storage of fatty acids.42, 43 Predominance of
type II muscle fibers is associated with obesity and type 2 diabetes, and might therefore be a marker of susceptibility to obesity.42, 43 The gold standard to assess fiber type distribution is an
invasive skeletal muscle biopsy, which is not suitable for large scale screening. However, total plasma creatine kinase after rest accurately reflects tissue creatine kinase in skeletal muscle fibers.44, 45 Therefore, we assessed in Chapter 6 whether plasma creatine kinase is associated
with various measures of obesity in a multi-ethnic population.
In conclusion, in this thesis we examined whether the presence of uterine fibroids in associated with hypertension, target organ damage and a higher cardiovascular burden in women of different ethnic groups across the world. This research adds to the existing knowledge regarding uterine fibroids as a risk factor for hypertension and cardiovascular disease in reproductive
1
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Introduction
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