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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Y. C. Haan
F. S. Diemer
L. van der Woude
G. A. van Montfrans
G. P. Oehlers
L. M. Brewster
The risk of hypertension and
cardiovascular disease in women
with uterine fibroids
J Clin Hypertens (Greenwich). 2018 Apr;20(4):718-726
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ABSTRACT
Women with fibroids have a notably high hypertension risk. However, adjusted data regarding other cardiovascular disease (CVD) risk factors are scarce. In this cross-sectional study, CVD risk factors, hemodynamic parameters, and asymptomatic organ damage were analyzed between women with uterine fibroids and controls in a multi-ethnic population. In total, 104 women with self-reported fibroids and 624 controls were included. Women with fibroids had significantly higher odds to have hypertension (OR 3.4; 95% CI 2.2 to 5.2), diabetes (1.7; 1.0 to 2.9), and hypercholesterolemia (1.8; 1.1 to 3.2). After adjustment for confounders, only the odds ratio for hypertension was significant (1.8; 1.1 to 3.1). Asymptomatic organ damage occurred significantly more often in women with fibroids (66.7%; 95% CI 55.8% to 77.6% vs. 42.9%; 38.0 to 47.8 in controls), especially in the younger age group (respectively 48.5%; 31.1% to 65.9% vs. 22.1%; 17.0 to 27.2). In this study, women with fibroids had a remarkably high hypertension risk compared to controls, with more asymptomatic organ damage, in particular young women.
INTRODuCTION
Accounting for approximately 30% of all female deaths, cardiovascular disease (CVD) is the number one cause of death in women.1 Hypertension is the main risk factor for CVD.1 Several
female-specific risk factors for hypertension have been established, including contraceptive use, preeclampsia, and polycystic ovary syndrome.2,3 A novel female-specific risk factor could
be uterine fibroids, which are linked to hypertension in several reports.4-6
Uterine fibroids are most prevalent in women of reproductive age with a two times higher incidence in women of African ancestry.7 Several studies investigated risk factors for uterine
fibroids, mainly focusing on the role of body mass index (BMI).7-9 The majority reported a
modest increase in fibroid prevalence with increasing BMI.7-9 Some authors suggested that
other CVD risk factors, such as diabetes and lipid disorders, also increase the risk to develop uterine fibroids.10-12 Recently, Uimari et al.13 reported a higher fibroid risk in women with
metabolic syndrome, and with increasing low density lipoprotein and triglyceride levels. However, the CVD risk profile of women with fibroids is not well defined. We recently confirmed earlier research demonstrating a high prevalence of hypertension in women with fibroids and showed that this association was independent of age, BMI, and African ancestry.
4-6,14 Data regarding CVD risk factors other than hypertension in women with uterine fibroids
are scarce and not adjusted for confounders.10-12,15-17 Therefore, we assessed the CVD risk profile
in women with fibroids compared to controls, adjusting for known confounders. In addition, asymptomatic organ damage is an important determinant of overall CVD risk, independent of the cardiovascular prediction score.18,19 Therefore, we assessed the prevalence of asymptomatic
organ damage as a secondary outcome.
METHODS AND MATERIALS
Study design and population
Data from the HEalthy LIfe in SURiname (HELISUR) study were used. This large cross-sectional study, which included participants between February 2013 and July 2015, was designed to investigate CVD risk factors among different ethnic groups in Paramaribo, the capital of Suriname. A detailed description of the study is reported elsewhere.20 In brief, 1,800 participants, aged
18–70 years old, were randomly sampled through a household sampling method. The General Bureau of Statistics divided the capital into 1,200 Census enumeration areas, consisting of 100– 150 households, and randomly selected 18 enumeration areas stratified by ancestry. Households were approached consecutively until 100 participants per enumeration area were included. Written informed consent was obtained from all participants. An interview was administered at home. Subsequently, the participant was invited to visit the hospital for an examination. Of the 1,800 sampled participants, 728 women participated in the study (Figure 1).
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Figure 1. Flowchart of the study
Outcome
The primary outcome was the adjusted odds ratio for well-known CVD risk factors (ie, hypertension, obesity, diabetes, hypercholesterolemia, smoking, and low physical activity) in women with self-reported fibroids compared to controls. As a secondary outcome, we assessed the prevalence of asymptomatic organ damage.
Sample size calculation
We recently reported the prevalence of hypertension, obesity, diabetes, and dyslipidemia in Paramaribo, Suriname: respectively 39.5%, 36.8%, 14.5%, and 40.9%.21 The sample size
calculation was based on the lowest prevalence (ie, diabetes) and we calculated that at least 690 women were needed to assess a difference in these risk factors with α = 0.05 and 1 – β = 0.80 using multivariable logistic regression analysis with 10 other predictors.
Data collection
Self-reported data on demographic, social, and CVD risk factors were used. Self-reported fibroids were determined by asking: Did a doctor or health professional ever mention that you have uterine fibroids? (yes/no). During physical examination, the participants were weighed in light clothing without shoes. Height was measured without shoes with a measuring tape to the nearest 0.1 cm. All anthropometric measurements were obtained twice, and the means were
1,200 enumeration areas Random selection of 18 enumeration areas Preliminary assessment n= 1,800 Eligible n= 1,483
Did not meet age inclusion criterium (n= 5) Deceased (n= 9) Not retrieved (n= 303) Physical examination n= 1,157 Declined to participate (n= 326) Female n= 728 Male n= 429 Self-reported fibroids n= 104 No fibroidsn= 624
used for the analyses. BMI was calculated as weight in kilograms divided by height in metres squared. Blood pressure was measured twice in a sitting position with an appropriate cuff size supported at heart level (WatchBP Home; Microlife A.G., Widnau, Switzerland). Blood pressure was calculated as the mean of two readings. A 12-lead electrocardiogram was recorded. The aortic pulse wave velocity was estimated twice, non-invasively, in supine position by analysis of the oscillometric pressure curves registered on the right upper arm, using the Arteriograph (TensioMed, Budapest, Hungary). The average of both readings was used. In addition, blood pressure was measured twice on both arms and legs, and the average of both measurements was used. Ankle-brachial index was calculated by dividing the highest of the ankle systolic blood pressures by the highest of the arm systolic blood pressures.22 Blood was collected for
plasma creatinine, fasting plasma glucose, and fasting plasma total cholesterol levels. Morning spot urine was used to determine the presence of proteinuria.
Definitions
According to self-report by the participant, ancestry was classified as African, Asian, or other. Education was determined by the highest self-reported educational level. The levels were grouped according to the International Standard Classification of Education (ISCED): secondary school and less ie, ≤12 years of education [low, ISCED level ≤2], and vocational school and more, ie, >12 years of education [high, ISCED level ≥3]. Smoking was based on current use. Physical activity was based on the International Physical Activity Questionnaire, which assesses physical activity in 4 domains (during transportation, at work, during household and gardening tasks, and during leisure time) and classifies participants into 3 levels of physical activity (low, moderate or vigorous) based on the World Health Organization guideline for physical activity.23,24 Low physical activity was defined as <150 minutes of moderate-intensity
physical activity or <75 minutes of vigorous-intensity physical activity throughout the week, or an equivalent combination of moderate-and vigorous-intensity activity. Use of hormonal contraceptives included oral contraceptive use, or contraception through hormonal injection, or a hormonal intra-uterine device. Postmenopausal status was classified according to the WISE historical algorithm, which includes duration of amenorrhea, previous oophorectomy, and age.25 Obesity was defined as a BMI ≥30.0 kg/m2. Hypertension was defined as systolic
blood pressure (SBP) ≥140 mmHg, and/or diastolic blood pressure (DBP) ≥90 mmHg, or receiving antihypertensive drug therapy. Controlled hypertension included the participants with hypertension using antihypertensive medication with a SBP <140 mmHg and a DBP <90 mmHg. Diabetes mellitus was defined as a fasting plasma glucose ≥7.0 mmol/L, or using glucose-lowering medication. Participants with treated diabetes and a fasting plasma glucose <7.0 mmol/L were defined as controlled. Hypercholesterolemia was defined as a total plasma cholesterol ≥6.20 mmol/L, or receiving cholesterol-lowering medication. Controlled hypercholesterolemia included participants using cholesterol-lowering medication with a fasting plasma cholesterol <6.20 mmol/L.
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Asymptomatic organ damage was based on the 2013 European Society of Hypertension and European Society of Cardiology guidelines for the management of arterial hypertension, and included the presence of at least one of the following: pulse pressure ≥60 mmHg, pulse wave velocity >10 m/s, ankle-brachial index <0.9, electrocardiographic left ventricular hypertrophy (LVH; Sokolow-Lyon criteria: S in V1 or V2 + R in V5 or V6 [whichever is larger] ≥35 mm, or R in aVL ≥11 mm), chronic kidney disease with estimated glomerular filtration rate (eGFR) 30-60 mL/min/1.73 m2, or proteinuria (spot urine).18,26 For calculation of the eGFR we used
the CKD-EPI equation.27 The 10-year risk of a cardiovascular event was calculated using the
Framingham General CVD Risk score as published by D’Agostino et al,28 which includes age,
high-density lipoprotein, total plasma cholesterol, SBP, use of antihypertensive medication, current smoking, and the presence of diabetes. The Framingham General CVD Risk score was used because of the similar discrimination in men and women. In addition, in contrary to some other cardiovascular prediction scores, the Framingham CVD risk score is suitable for African and Asian women, which are the majority of our study population.29-31 Cardiovascular
events included a history of self-reported myocardial infarction or stroke. CVD was defined as the presence of a previous cardiovascular event, history of angina pectoris or coronary bypass surgery, history of a transient ischemic attack, an eGFR <30 mL/min/1.73 m2, or an
ankle brachial index <0.9.
Statistical analyses
First, we assessed the distribution of baseline characteristics and differences between women with fibroids and controls using the chi-square test for proportions, Student’s t-test for normally distributed data, and Mann-Whitney U test for non-normally distributed data. Thereafter, we explored the trend in CVD risk factors between young (<50 years) vs. older women (≥50 years) and different ancestry groups (Asian vs. African). Binary logistic regression analyses were used to assess the odds ratio for CVD risk factors in women with fibroids compared to controls. First, we conducted unadjusted analyses. In Model A, we adjusted for the well-known covariates age, BMI, and African ancestry. Thereafter, we further adjusted for use of hormonal contraceptives, parity, postmenopausal status, fasting plasma total cholesterol, fasting plasma glucose, and SBP. All covariates had a Pearson correlation p < 0.1 for one of the risk factors. As a sensitivity analysis, we repeated the regression analysis with obesity classified as BMI ≥27.5 kg/ m2 in Asians and BMI ≥30.0 kg/m2 in other ancestries. Asians tend to have a lower BMI for the
same percentage of body fat than other ancestry groups, which led to the recommendation by the World Health Organization to use different obesity cut-offs in Asians.32
Model fit was assessed with the appropriate goodness-of-fit test for logistic regression models. We tested the assumptions of linearity and no multicollinearity. Linearity was violated in several models. Therefore, we transformed the continuous variables into categorical variables. Age was divided into <30, 30–34, 35–39, 40–44, 45–49, 50–54, 55–59, 60–64, 65–69, and >69 years.
BMI was categorized as <18.5, 18.5–24.9, 25.0–29.9, 30.0–34.9, 35.0–39.9, and >39.9 kg/m2. Parity
groups included nulliparous, 1–2, 3–4, and >4 children. Fasting plasma glucose was divided into <6.1, 6.1–6.9, and >6.9 mmol/L and fasting plasma cholesterol into <5.2, 5.2–6.2, and >6.2 mmol/L. SBP was categorized into <120, 120–129, 130–139, 140–149, 150–159, 160–169, 170–179, and >179 mmHg. For the secondary outcome, we calculated the difference in prevalence of asymptomatic organ damage in women with uterine fibroids compared to controls using the chi-square test. In addition, we repeated the regression analyses for asymptomatic organ damage, adjusting for age, BMI, African ancestry, and SBP. Finally, we assessed the 10-year risk of a cardiovascular event in women with fibroids and controls and tested differences using the Mann-Whitney U test. In addition, we conducted analyses stratified by fibroid and hypertension status. Data were analyzed using SPSS statistical software package for Windows, version 22.0.
STROBE guidelines
The STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines were applied to report this cross-sectional study.33
RESuLTS
Of the 728 women, 104 had self-reported uterine fibroids and 624 reported no fibroids (Figure 1). Women with fibroids were significantly older, and more often of African ancestry and postmenopausal. They had an earlier menarche, were less often users of hormonal contraceptives, and had more children compared to controls (Table 1).
Hypertension prevalence was higher in women with fibroids compared to controls (64.1% vs. 34.6%, respectively; p < 0.001). This difference was most prominent in the younger age group (Figure 2). Although the proportion of controlled hypertension was higher in women with fibroids (35.4% vs. 20.5% in controls, p = 0.01), they also more often used ≥3 antihypertensive drugs (21.5% vs. 9.3% in controls, p < 0.01). The most frequently used antihypertensive drugs were calcium channel blockers (29.8% vs. 10.1% in fibroids vs. controls), beta-blockers (21.2% vs. 9.9%, respectively), and ACE inhibitors (17.3% vs. 9.3%, respectively).
Obesity, diabetes, and hypercholesterolemia were more common in women with fibroids. The prevalence of smoking and low physical activity did not differ significantly between women with fibroids and controls (Table 1, Figure 2).
Both women of Asian and of African descent with fibroids had a higher prevalence of hypertension (Figure 3). Although women of African descent more often had obesity and Asian women more often had diabetes, this did not differ between women with fibroids and
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controls. The highest prevalence of hypercholesterolemia (33.3%) was found in Asian women with fibroids compared to 19.5% in Asian women without fibroids. In Africans, the prevalence of hypercholesterolemia was around 10% and slightly higher in women with fibroids (Figure 3). Low physical activity was more prevalent in Asian women with fibroids. Smoking did not differ between women of different ancestries or fibroid status.
Table 1. Baseline characteristics and cardiovascular health of women with and without fibroids Fibroids (n=104) No fibroids (n=624) Baseline characteristics Age, years† 51.1 (9.1)* 41.6 (13.6) Ancestry, % African 52.9* 39.1 Asian 34.6* 43.6 Other 12.5* 17.3
High educational level, % 20.2* 18.1
Married, % 41.3* 34.9
Use of hormonal contraceptives, % 3.8* 19.9 Age of menarche, years† 12.5 (1.7)* 12.9 (1.7)
Parity, n‡ 2.5 (2.0 – 4.0)* 2.0 (1.0 – 4.0)
Postmenopausal, % 51.5* 24.5
Cardiovascular health
Current tobacco smoking, % 4.8* 8.2
Low physical activity, % 18.3* 18.6
Systolic blood pressure, mmHg† 136.5 (19.2)* 127.3 (20.8)
Diastolic blood pressure, mmHg† 83.9 (11.3)* 79.3 (11.0)
Hypertension, % 64.1* 34.6
Treated 72.7* 60.6
Controlled 35.4* 20.5
Body mass index, kg/m2† 30.4 (6.0)* 28.8 (6.5)
Obesity, % 48.1* 37.9
Diabetes, % 22.1* 14.1
Treated 78.3* 85.2
Controlled 21.7* 23.9
Total cholesterol, mmol/L† 5.1 (1.0)* 4.8 (1.1)
Hypercholesterolaemia, % 18.3* 10.9
Treated 36.8* 19.1
Controlled 26.3* 11.9
Asymptomatic organ damage, %§ 66.7* 42.9
Pulse pressure ≥60 mmHg 30.4* 18.1
Pulse wave velocity >10 m/s 47.9* 25.1 Ankle-brachial index <0.9 0.0* 0.8 Left ventricular hypertrophy 0.0* 1.6
Chronic kidney disease or
microalbuminuria 3.9* 4.3
Cardiovascular events, %§ 3.8* 2.4
Cardiovascular disease, %§ 8.1* 6.8
aMean with standard deviation. bMedian with interquartile range.
cAsymptomatic organ damage, cardiovascular events and cardiovascular disease were based on respectively n = 75,
n = 104 and n = 99 women with fibroids and n = 410, n = 604 and n = 617 controls. Cardiovascular events included a history of self-reported myocardial infarction or stroke. Cardiovascular disease was defined as the presence of a previous cardiovascular event, history of angina pectoris or coronary bypass surgery, history of a transient ischemic attack, an eGFR <30 mL/min/1.73 m2, or an ankle-brachial index <0.9.
*p < 0.05 compared to controls.
Fibroids (n=104)
No fibroids (n=624)
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Fi g u re 2 . P re va le nc e o f c ar di ov as cu la r d is eas e r is k f ac to rs by fi br oi d s ta tu s a nd a ge g ro up D at a w er e b as ed o n r esp ec tive ly 4 4 a nd 5 9 w om en w ith u te rin e fib ro id s a nd 4 39 a nd 1 85 c on tr ol s. *p < 0. 05 f or d iffe re nc e b et w ee n w om en w ith fib ro id s a nd c on tr ol sFi g u re 3 . P re va le nc e o f c ar di ov as cu la r d is eas e r is k f ac to rs by fi br oi ds s ta tu s a nd a nc es tr y W e u se d a n a ge r es tr ic tio n o f 3 5– 70 y ea rs i n o rd er t o a vo id s ig ni fic an t a ge d iffe re nc es b et w ee n g ro up s. M ea n a ge w as n ot s ig ni fic an tly d iffe re nt b et w ee n w om en w ith fib ro id s an d co nt ro ls in b ot h an ce st ry gr ou ps . F or A sia n pa rt ic ip an ts , d at a w er e ba se d on 36 w om en w ith fib ro id s an d 19 5 co nt ro ls . F or A fr ic an pa rt ic ip an ts , d at a w er e ba se d on 51 w om en w ith fib ro id s a nd 1 45 c on tr ol s. *p < 0. 05 f or d iffe re nc e b et w ee n w om en w ith fib ro id s a nd c on tr ol s
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In simple logistic regression, fibroids were associated with hypertension, diabetes, and hypercholesterolemia, but not with obesity, smoking, and low physical activity (Table 2). After adjustment for age, BMI, African ancestry, use of hormonal contraceptives, parity, postmenopausal status, fasting plasma total cholesterol, and fasting plasma glucose, the odds ratio for hypertension in women with fibroids was 1.84 (95% CI 1.09 to 3.10). Other CVD risk factors were not significantly different after adjustment (Table 2). Sensitivity analysis with a different BMI cut-off for obesity in Asians in the regression analysis did not alter the results (data not shown). Finally, as a post hoc outcome, we excluded nulliparous controls and controls <35 years of age from the analyses to increase the sensitivity of self-reported fibroids. This did not result in different adjusted odds ratios (Table S1). All the models had a good overall fit and no multicollinearity was detected.
Asymptomatic organ damage (ie, pulse pressure ≥60 mmHg, pulse wave velocity >10 m/s, ankle-brachial index <0.9, electrocardiographic left ventricular hypertrophy, eGFR 30-60 mL/ min/1.73 m2, or proteinuria) was more prevalent in women with fibroids compared to controls,
respectively 66.7% vs. 42.9% (p < 0.001). This was mainly driven by an increased prevalence of high pulse pressure (30.4% vs. 18.1% in women with fibroids compared to controls, p < 0.01) and increased pulse wave velocity (47.9% vs. 25.1% in women with fibroids compared to controls, p < 0.001). Young women in particular had more asymptomatic organ damage in the presence of fibroids (Figure 4).
Figure 4. Prevalence of asymptomatic organ damage by fibroids status and age group
Asymptomatic organ damage included the presence of at least one of the following: pulse pressure ≥60 mmHg, pulse wave velocity >10 m/s, ankle-brachial index <0.9, electrocardiographic left ventricular hypertrophy, eGFR 30-60 mL/min/1.73m2, or proteinuria. Data were based on respectively 33 and 42 women with uterine fibroids and 262
and 148 controls.
In simple logistic regression, women with fibroids had a 2.66 (95% CI 1.58 to 4.47) higher odds to have asymptomatic organ damage. After adjustment for age, BMI, and African ancestry, the odds ratio for asymptomatic organ damage was 1.57 (95% CI 0.84 to 2.94). After further adjustment for SBP, the odds ratio became 1.24 (95% CI 0.60 to 2.56) in women with fibroids compared to controls, indicating that these risk factors contributed to the higher prevalence of asymptomatic organ damage, as expected. The influence of SBP was most prominent in the younger age group. The odds ratio for asymptomatic organ damage in young women with fibroids was 2.18 (95% CI 0.93 to 5.07), after adjustment for age, BMI, and African ancestry, and decreased to 1.22 (95% CI 0.45 to 3.31) after further adjustment for SBP. In the older age group, the odds ratios were respectively 1.18 (95% CI 0.47 to 2.99) and 1.80 (0.54 to 5.97).
According to the Framingham CVD risk score, women with fibroids had a significantly higher 10-year risk of a cardiovascular event; median 7.3% (IQR 3.9% to 15.9%) in women with fibroids and 2.8% (IQR 1.2% to 8.6%) in controls (p < 0.001). The highest median risk of 11.7% (IQR 7.3% to 18.5%) was found in women with fibroids as well as hypertension, compared to 10.0% (IQR 6.3% to 18.5%, p = 0.26) in hypertensive controls. The lowest risk was found in controls without hypertension (median 1.7%, IQR 1.0% to 3.3%), compared to 3.3% (IQR 2.0% to 4.5%, p < 0.001) in women without hypertension but with fibroids.
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Table 2. Odds ratios of cardiovascular disease risk factors in women with fibroids vs. controls Odds ratio [95% CI] Hypertension
Fibroids vs. controls Unadjusted 3.37 [2.18 to 5.21]* Model A 1.90 [1.13 to 3.19]* Model B 1.84 [1.09 to 3.10]*
Obesity
Fibroids vs. controls Unadjusted 1.52 [1.00 to 2.31]^
Model A 1.09 [0.70 to 1.70] Model B 1.10 [0.68 to 1.75]
Diabetes
Fibroids vs. controls Unadjusted 1.72 [1.03 to 2.88]* Model A 1.22 [0.69 to 2.16]^
Model B 1.15 [0.65 to 2.05]^
Hypercholesterolemia
Fibroids vs. controls Unadjusted 1.82 [1.05 to 3.19]* Model A 1.49 [0.82 to 2.70] Model B 1.39 [0.74 to 2.59]
Smoking
Fibroids vs. controls Unadjusted 0.57 [0.22 to 1.46] Model A 0.54 [0.20 to 1.42] Model B 0.53 [0.20 to 1.40]
Low physical activity
Fibroids vs. controls Unadjusted 0.98 [0.57 to 1.67] Model A 0.99 [0.56 to 1.74] Model B 0.92 [0.51 to 1.37]
*p <0.05; Model A is adjusted for age, BMI (except for obesity model) and African ancestry. Model B is adjusted for Model A and use of hormonal contraceptives, parity, postmenopausal status, fasting plasma total cholesterol (except for hypercholesterolemia model), fasting plasma glucose (except for diabetes model), and systolic blood pressure (except for hypertension model).
DISCuSSION
Women with fibroids from this multi-ethnic random population had a worse CVD risk profile, including higher blood pressures, higher fasting plasma cholesterol and glucose levels, and more asymptomatic organ damage. After adjustment for age, BMI, African ancestry, hormonal contraceptive use, parity, postmenopausal status, and cholesterol and glucose levels, their odds to have hypertension remained significantly higher compared to controls. In young women in particular, the high hypertension prevalence may have an impact on the presence of asymptomatic organ damage.
To our knowledge, we are the first to assess the presence of asymptomatic organ damage in women with fibroids. One study that investigated subclinical atherosclerosis found a higher ankle brachial index and a trend toward a higher pulse wave velocity in Chinese women with fibroids.16 We assessed a large spectrum of asymptomatic organ damage, including
measures of arterial stiffness (ie, pulse pressure and pulse wave velocity), cardiac involvement (electrocardiographic left ventricular hypertrophy), and kidney damage (eGFR 30-60 mL/ min/1.73 m2 or proteinuria). As asymptomatic organ damage was a secondary outcome, this
study was not powered to detect differences in this outcome. There was a trend toward more asymptomatic organ damage in women with fibroids, in particular in the younger age group. High pulse pressure and pulse wave velocity were the main manifestations of asymptomatic organ damage. Antihypertensive drugs, in particular ACE inhibitors, but also calcium channel blockers and beta-blockers, are known to reduce pulse wave velocity significantly compared to placebo.34 In our sample, treated hypertension was more common in women with fibroids.
In addition, women with fibroids used calcium channel blockers, beta-blockers, and ACE inhibitors more often. This may have led to a reduction of pulse wave velocity in the women with fibroids and therefore underestimated the association. Future studies should focus on the presence of early vascular ageing and cardiovascular events in women with fibroids.
The co-occurrence of hypertension and fibroids could be related to a common pathophysiology of enhanced smooth muscle proliferation in uterine tissue and the vascular wall induced by growth factors, vasoactive peptides, and enzymes.4 One enzyme that is suggested to be
involved is creatine kinase (CK), which promotes vascular as well as uterine smooth muscle proliferation by rapidly providing ATP for trophic responses.35,36 In line with this, Hoag et al.37
found higher CK levels in uterine fibroid tissue compared to adjacent myometrium. Importantly, CK has been causally implicated in hypertension, as the enzyme also provides ATP for vascular contractility.35,38,39 Thus, the CK system, which influences other growth factors and vasoactive
peptides, could explain the co-occurrence between fibroids and hypertension. Other studies proposed that hypertension and fibroids often co-occur due to similarities between fibroids and atherosclerotic plaques.13,15,16,40 Both are of monoclonal origin and the result of proliferation
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release, promoting the proliferation of smooth muscle cells in the vascular wall as well as in the uterine wall.11,13,15 This proliferation can also be induced by other atherosclerotic risk factors,
such hyperinsulinemia and upregulation of insulin-like growth factor-1 (IGF-1),41 thereby
connecting obesity, diabetes, and hypertension to uterine fibroids.10 On the contrary, a trend
toward lower insulin resistance was found in women with fibroids.12,42,43 Some studies suggest
higher IGF-1 levels in fibroid tissue compared to myometrium,44 but no difference in serum
IGF-1 was found between women with and without fibroids.43 Currently, the mechanism for
the co-occurrence between fibroids and hypertension remains uncertain.
The main strength of this study is that we extensively assessed the CVD risk profile of women with fibroids, including hemodynamic parameters and asymptomatic organ damage in women of different ancestry. Furthermore, we adjusted the outcome for important confounders. Finally, CVD risk factor prevalence was based on physical examination, blood pressure measurement, and laboratory studies instead of self-reported data. A main limitation of our study is that the presence of uterine fibroids was self-reported. Unfortunately we do not have data on pelvic ultrasound. The specificity of self-reported fibroids is relatively high, ranging from 86% in younger women to 98% in women above 35 years of age.45 However,
the sensitivity of self-reported fibroids is often <50%.45 In this population sample 104 of the
728 participants (14.3%) had self-reported fibroids, which might be lower than expected in African women and therefore might have led to an overestimation or underestimation of the effect due to possible unknown cases in the control group.43,45 The sensitivity of self-reported
fibroids increases with age and is up to 2.9 times higher in parous women.45 Increasing the
sensitivity of self-reported fibroids by excluding nulliparous controls and controls <35 years of age from the analyses did not result in a different outcome. In addition, previous literature showed that the sensitivity of self-reported fibroids is higher in women with large fibroids.45
Interestingly, Radin et al.46 found a higher prevalence of hypertension in hysterectomy
confirmed compared to ultrasound confirmed fibroids, respectively 27.2% and 19.7%, which indicates there might be a “dose-response” relationship between fibroids and blood pressure. Unfortunately, we lack data on surgical menopause, serum hormone levels, and the use of hormone replacement therapy. Although we could not define postmenopausal status based on serum hormone levels, we did use the WISE historical algorithm which has a specificity of 97% with a predictive value of 79% for postmenopausal status.25 Adjusting for hormonal
contraceptives and postmenopausal status did not change the outcome. Another limitation is the use of electrocardiographic criteria for the detection of LVH. The majority of the subjects are obese, in which electrocardiographic criteria are less applicable.47,48 On the other hand,
we also included pulse wave velocity which is strongly associated with left ventricular mass in African women.49,50 Finally, due to the cross-sectional design of the study, causal inferences
CONCLuSION
In conclusion, our data indicate that women with self-reported fibroids have a worse CVD risk profile compared to controls, including an increased hypertension risk, which remains after adjustment for age and other confounders. In young women in particular, the higher hypertension prevalence may play an important role in the presence of asymptomatic organ damage. Thus, fibroids may not be the innocent bystander they are hitherto thought to be.
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SuPPLEMENTAL MATERIAL
Supplemental Table 1. Regression analyses after excluding nulliparous controls and controls <35 years of
age (in order to increase sensitivity of self-reported fibroids)
Risk factors Unadjusted OR (total group) Unadjusted OR (excluding controls) Fully adjusted OR (total group) Fully adjusted OR (excluding controls) Hypertension 3.37 [2.18 to 5.21]* 1.99 [1.27 to 3.12]* 1.83 [1.09 to 3.09]* 1.91 [1.10 to 3.32]* Obesity 1.52 [1.00 to 2.31] 1.31 [0.84 to 2.02] 1.11 [0.70 to 1.78] 1.20 [0.73 to 1.98] Diabetes 1.72 [1.03 to 2.88]* 1.07 [0.63 to 1.81] 1.19 [0.67 to 2.12] 1.13 [0.63 to 2.03] Hypercholesterolemia 1.82 [1.05 to 3.19]* 1.31 [0.74 to 2.33] 1.39 [0.75 to 2.58] 1.31 [0.68 to 2.52] Smoking 0.57 [0.22 to 1.46] 0.52 [0.20 to 1.36] 0.53 [0.20 to 1.41] 0.51 [0.19 to 1.42] Low physical activity 0.98 [0.57 to 1.67] 1.14 [0.65 to 2.01] 0.88 [0.49 to 1.58] 1.09 [0.59 to 2.03]
