Cardiovascular risk in women with uterine fibroids of different ethnic groups
Haan, Y.C.L.
Publication date
2020
Document Version
Other version
License
Other
Link to publication
Citation for published version (APA):
Haan, Y. C. L. (2020). Cardiovascular risk in women with uterine fibroids of different ethnic
groups.
General rights
It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).
Disclaimer/Complaints regulations
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.
Y. C. Haan
I. Oudman
M. E. de Lange
A. Timmermans
W. M. Ankum
G. A. van Montfrans
L. M. Brewster
Hypertension Risk in Dutch Women
With Symptomatic uterine Fibroids
2
ABSTRACT
Background Female-specific risk factors for cardiovascular disease are understudied. We
assessed whether women with uterine fibroids have a greater hypertension risk, independent of the shared risk factors for both conditions.
Methods Blood pressure was measured in women scheduled for fibroid surgery compared
to women scheduled for nonfibroid gynecological surgery and women randomly sampled from the general population. We used multivariable binary logistic regression to assess whether hypertension was more common with surgically treated fibroids, independent of age, body mass index, and African ancestry.
Results We included 1,342 women (542 of African ancestry), of which 272 scheduled for
fibroid surgery, 385 controls scheduled for nonfibroid gynecological surgery, and 685 random population controls, with a mean age (SD) of, respectively, 43.4 (6.6), 41.3 (10.2), and 45.1 (6.6) years; and a mean body mass index (SD) of, respectively, 27.4 (5.3), 25.7 (5.7), and 28.2 (5.6) kg/m2.
Hypertension was found more frequently with surgically treated fibroids, with an occurrence of 41.9% in women with fibroids vs. 27.5% in surgical controls, and 28.3% in population controls (p < 0.001 for fibroids vs. controls). The association with hypertension was independent of age, body mass index, and African ancestry (odds ratio, 2.4; 95% confidence interval, 1.7 to 3.4).
Conclusions Hypertension risk is higher in Dutch women with surgically treated fibroids
than in surgery or population controls, independent of age, body mass index, and African ancestry. Our data add to the body of evidence indicating that women with uterine fibroids are eligible for hypertension screening.
INTRODuCTION
There is a need for strategies to fill the gap in cardiovascular mortality between men and women.1,2 Although the prevalence of cardiovascular disease is declining, the rate of decline is
less pronounced in women than in men, with women even displaying an increase in mortality in the past years.1–3
Hypertension has the highest adjusted estimated population attributable fraction for cardiovascular disease mortality, 40.6% (95% confidence interval, 24.5% to 54.6%).3 Several risk
factors for hypertension have been identified in women, including age, obesity, and African ancestry.1–3 In addition, previous studies indicated an association between hypertension and
uterine fibroids (Table 1), suggesting that women with hypertension have a greater risk to develop fibroids.4–9 However, it was hitherto unclear, whether women with fibroids have a
greater hypertension risk independent of common risk factors, including African ancestry.4,5,7,9–15
Therefore, we assessed whether hypertension is more common in women with a different ancestral background, who are surgically treated for fibroids.
METHODS
Study design and population
Ethical approval for this study was obtained from the local institutional review board. The requirement to obtain informed consent from individual participants was waived because this study used aggregated tables that could not be traced back to individuals.
In this analysis, we included 272 women aged 18–60 years, who were scheduled for surgery for symptomatic uterine fibroids, at the Department of Gynaecology and Obstetrics in the Academic Medical Center, Amsterdam, the Netherlands, from January 2008 to December 2011. The presence of fibroids was confirmed by histopathology.
Controls were 385 women aged 18–60 years, who were scheduled for gynecological surgery at our hospital for other reasons than fibroids, and 691 randomly sampled female population controls, aged 34–60 years, and living in Amsterdam, the Netherlands.17
Hypertension was defined as systolic blood pressure ≥140 mmHg, and/or diastolic blood pressure ≥90 m Hg, or receiving antihypertensive drug therapy. We excluded women without blood pressure data and women with a history of secondary hypertension or malignancy. Finally, controls with a history of fibroids were not included in the primary analysis.
2
Table 1. Previous studies on the association between hypertension and fibroidsA. Fibroid Risk
Paper Patients Results
Author Year Country Hypertension N Age ANC Fibroid Riska Covar
Faerstein 2001 United
States Hypert SR 712 n.d.
b n.d. 1.7 (1.0 to 2.8) Age, BMI,
ANC Parazzinic 2004 Italy Hypert SR 2,400 21 – 54 Cau 0.9 (0.7 to 1.3) Age
Boynton 2005 United
States Hypert SR 104,233 25 – 42 Multi 1.2 (1.1 to 1.4)
Age, BMI, ANC Takeda 2008 Japan Hypert Diag 372 40 – 49 Jap 5.5 (2.6 to 11.6) None
Radin 2012 United
States Hypert SR 22,530 n.d.
b Afr 1.1 (1.0 to 1.2) Age, BMI
Sivri 2012 Turkey Hypert Diag 378 n.d. n.d. 2.0 (1.3 to 3.3) Age
B. Hypertension Risk
Paper Patients Results
Author Year Country Fibroids N Age ANC Hypertension
Riska
Covar
Luoto 1995 Finland Fibr Diag 3,780 30 – 95 Cau 2.5 (1.6 to 3.9)d Age, BMI
Luoto 2001 Finland Fibr Diag 543 41 – 89 Cau 1.7 (1.1 to 2.7)d Age, BMI
Faerstein 2001 United
States Fibr Diag
e 712 n.d.b n.d. 3.3 (2.1 to 5.2)f None
Parazzinic 2004 Italy Fibr Diag 2,400 21 – 54 Cau 0.8 (0.6 to 1.1)f None
Takeda 2008 Japan Fibr Diag 372 40 – 49 Jap 26.9 (3.6 to 199.4)d,f None
Spies 2010 United
States Fibr Diag 375 30 – 50 Multi 2.8 (1.2 to 6.4)
f None
Lambertino 2011 United
States Fibr SR 577 31 – 82 Cau 1.6 (1.0 to 2.4)f None Sivri 2012 Turkey Fibr Diag 378 n.d. n.d. 1.9 (1.2 to 2.9)d,f None
Aksoy 2014 Turkey Fibr Diag 389 40 – 50 Tur 0.9 (0.6 to 1.3)f None
We only included studies with a minimum of 100 participants. Silver et al.16 is not included in this table, as the number
of participants was not reported. The existing evidence as presented here shows that it has not been established whether hypertension risk in women with fibroids is independent of known risk factors including African ancestry. Abbreviations: Afr, African; ANC, ancestry; BMI, body mass index; Cau, Caucasian; Covar, covariates included in multivariable regression analysis; Fibr Diag, surgically confirmed uterine fibroids; Fibr SR, self-reported history of uterine fibroids; Hypert Diag, hypertension confirmed through blood pressure measurements and/or the use of antihypertensive drugs; Hypert SR, self-reported history of hypertension; Jap, Japanese; Multi, multi-ethnic, including Caucasian, African, Asian, Hispanic/Latin, and patients of other ethnicity; N, number of participants; n.d., no data; Tur, Turkish.
aOdds ratio, except for Radin et al.8 who reported incidence rate ratios. bPremenopausal women.
cParazzini et al.5 included treated hypertension only.
dHypertension risk based on blood pressure measurements and/or the use of antihypertensive drugs. eIncluded sonographically confirmed fibroids.
Primary outcome
The primary outcome was the odds ratio of hypertension in women scheduled for uterine fibroid surgery compared to women scheduled for nonfibroid gynecological surgery and population controls, after adjustment for age, body mass index (BMI), and African ancestry. BMI was calculated as weight in kilograms divided by height in meters squared. We predefined the following subgroups: age categories (arbitrarily defined as <40 vs. ≥40 years), body weight categories (BMI <30 vs. BMI ≥30 kg/m2), and ethno-geographical groups (European vs. African
ancestry).
Sample size calculation
To estimate the sample size, we used a previous observation of the unadjusted prevalence of hypertension in women with surgically treated fibroids and controls, 48.6% vs. 24.0%, respectively,16 and calculated that at least 167 women were needed to enter our study to
assess this difference with α = 0.05 and 1 – β = 0.80, in a multivariable logistic regression analysis with 3 other predictors.
Data retrieval
For the primary outcome, we collected data on self-defined European and African ancestry, age, anthropometrics, medical history, drug use, and blood pressure. Blood pressure was measured after 5 minutes of rest with the subject in the sitting position, using an appropriately fitted cuff on the nondominant arm supported at heart level with a Datascope Accutorr Plus monitor (Tascope Corp., Paramus, NJ) in patients scheduled for surgery, and with an oscillometric automated digital blood pressure device (Omron M4 oscillometric device: Omron Healthcare Europe BV, Hoofddorp, the Netherlands) in the population controls. A single reading was performed during the pre-operative assessment 1 month before the surgery, while the mean of 2 readings was analyzed in the population controls as previously reported.17
Statistical analysis
Differences in the occurrence of hypertension between groups were first analyzed using the chi square test. Correlation coefficients of covariates known to influence hypertension were assessed, and those with a significant correlation with blood pressure status (at p < 0.1) were included in the model. We used binary logistic regression analysis to assess whether the odds ratio of hypertension was higher in women with surgically treated fibroids, adjusted for age, BMI, and African ancestry. Model fit was assessed with the appropriate goodness-of-fit test for logistic regression/models. As a sensitivity analysis, we included controls with a history of fibroids in the multivariable regression model. Data were analyzed with SPSS statistical software package for Windows, version 22.0 (SPSS Inc., Chicago, IL). Where applicable a 2-tailed
2
RESuLTS
We included 1,342 women, of which 272 scheduled for fibroid surgery, 385 controls scheduled for nonfibroid gynecological surgery, and 685 random population controls. Participants flow is depicted in Figure 1, with the baseline demographic characteristics in Table 2.
Gynecological controls who were excluded because of missing blood pressure data (n = 84), were significantly younger than the included controls (n = 385), with a mean age (SD) of, respectively, 37.0 (10.0) and 41.3 (10.2) years (p = 0.001). In addition, 31 women with a history of uterine fibroids were excluded from the primary analysis, of whom 9 had surgery for fibroids, with hypertension rates of, respectively, 51.6% and 88.9%. In the population controls, there were no missing blood pressure data, and the prevalence of spontaneously reported fibroids was low, with only 3 women reporting a history of fibroids that were not surgically treated, of whom 1 had hypertension.
Included (n=385) Fibroid Surgery Cases (n=299) Gynaecological Surgery Controls* (n=665) Female Population Controls (n=691) Excluded
No blood pressure data (n=16) Malignancy (n=10) Secondary hypertension (n=1)
Included (n=272)
Excluded
No blood pressure data (n=84) Malignancy (n=159) Secondary hypertension (n=6) History of fibroids (n=31) Included (n=685) Excluded Malignancy (n=2) Secondary hypertension (n=1) History of fibroids (n=3) Hypertension (n=114, 41.9%) Hypertension (n=106, 27.5%) Hypertension (n=194, 28.3%) Figure 1. Hypertension risk in women with fibroids and controls.
Table 2. Characteristics of the participants
Parameters Fibroid Cases Surgery Controls Population Controls
Number of women 272 385 685 Age, yearsa 43.4 (6.6) 41.3 (10.2)b 45.1 (6.6)b BMI, kg/m2a 27.4 (5.3) 25.7 (5.7)b 28.2 (5.6) Obesity, % 72 (26.5) 61 (15.8)b 219 (32.0) African ancestry, %c 122 (44.9) 33 (8.6)b 387 (56.5)d SBP, mmHga 132.2 (17.9) 125.5 (15.8)b 123.1 (20.8)b DBP, mmHga 80.7 (11.1) 75.4 (10.6)b 80.1 (12.0) Hypertension, % 114 (41.9) 106 (27.5)b 194 (28.3)b
Abbreviations: BMI, body mass index; obesity is defi ned as a BMI ≥30 kg/m2; SBP, systolic blood pressure; DBP, diastolic
blood pressure. Hypertension is defi ned as SBP ≥140 mmHg, and/or DBP ≥90 mmHg, or receiving antihypertensive drug therapy.
aValues are mean (SD).
bp < 0.05 compared to fi broid cases.
cPrevalence is based on 197 surgically treated fi broids, 230 gynecological controls, and 639 population controls. dRandom population sample with stratifi ed inclusion based on ancestry.
In the included women, the prevalence of hypertension was higher in surgically treated fi broids vs. nonfi broid gynecological surgery and population controls, respectively, 41.9%, 27.5%, and 28.3% (p < 0.001 for the diff erence between women with surgically treated fi broids and controls). The occurrence of hypertension was age dependent, and higher in obese, and in African women (Figure 2).
Figure 2. Hypertension in women with fi broids and controls by age, body mass index, and ancestry.
Vertical bars represent hypertension prevalence in women scheduled for fi broid surgery vs. surgical and population controls, in diff erent age categories (panel A); weight categories (normal weight, body mass index <30 vs. overweight, body mass index ≥30 kg/m2; panel B); and ethno-geographical groups (European vs. African ancestry;
panel C). In this latter panel, data on ancestry were available in only 1,066 out of 1,342 participants. Hypertension prevalence was higher in women with surgically treated fi broids in all subgroups
(*p < 0.05; **p ≤ 0.001). ** * ** * * **
2
The crude odds ratio for hypertension in women with surgically treated fibroids compared to controls was 1.85 (1.41 to 2.44). After adjustment for age, BMI, and African ancestry, the odds ratio became 2.37 (1.67 to 3.38), with surgically treated fibroids as the strongest predictor of hypertension (Table 3). The model had a good overall fit with an overall accuracy rate of 72.3% in the final model, a −2 Log-likelihood of 1132.68, and a model chi-square of 196.00 (df = 4;
p < 0.001). Additionally, Nagelkerke R2 was 0.24; and the Hosmer and Lemeshow test to assess
a lack-of-fit of the model was not significant (chi-square 13.14 (df = 8; p = 0.11)).
Table 3. Multivariable logistic regression analysis of hypertension risk in fibroids Variables Fibroids vs. both
control groups p value Fibroids vs. surgical controls p value Fibroids vs. population controls p value Fibroids 2.37 [1.67 to 3.38] <0.001 1.77 [1.03 to 3.05] 0.04 2.86 [1.97 to 4.15] <0.001 African ancestry 1.64 [1.20 to 2.25] 0.002 0.83 [0.47 to 1.48]a 0.54 2.41 [1.65 to 3.51] <0.001 Age 1.11 [1.08 to 1.13] <0.001 1.13 [1.09 to 1.17] <0.001 1.10 [1.07 to 1.13] <0.001 Body mass index 1.10 [1.07 to 1.13] <0.001 1.16 [1.11 to 1.22] <0.001 1.10 [1.06 to 1.13] <0.001
Data are based on 1,062 women and represent the odds ratio (with confidence interval in square brackets) of hypertension, defined as systolic blood pressure ≥140 mmHg, and/or diastolic blood pressure ≥90 mmHg, or receiving antihypertensive drugs. Model goodness-of-fit: −2, Log-likelihood 1132.68, model chi-square 196.00 (df = 4); p < 0.001.
aBased on 424 women of which 229 surgical controls.
As a sensitivity analysis, we reanalyzed the data with inclusion of the controls with fibroids. The adjusted odds ratio for hypertension in women with fibroids increased to 2.43 (1.72 to 3.43). Finally, as a post hoc outcome, we added diabetes to the model. In European and African participants, we retrieved data on fasting plasma glucose and treatment status in population controls, and on self-reported diabetes in surgery cases and surgery controls, respectively, 7.9%, 4.6%, and 5.7% (p = 0.21 for the differences between groups). In multivariable regression analysis, diabetes was significantly associated with hypertension (odds ratio 1.96 (1.13 to 3.40)), but fibroids was still the strongest predictor of hypertension (odds ratio 2.46 (1.73 to 3.51)).
DISCuSSION
The data presented in this study indicate that hypertension risk is 2.4 times higher in Dutch women with surgically treated uterine fibroids than in women scheduled for nonfibroid gynecological surgery and population controls, independent of age, BMI, and African ancestry. The association between these 2 conditions might be due to a common pathophysiology, related to enhanced uterine and vascular smooth muscle proliferation and vascular contractility
Figure 3. Common pathways involved in hypertension risk in uterine fibroids.
Summary of the main pathways potentially involved in hypertension and uterine fibroids. Several growth factors and vasoactive peptides, such as insulin-like growth factor-1, platelet-derived growth factor, endothelin-1, angiotensin II, transforming growth factor-ß, and creatine kinase, stimulate smooth muscle proliferation as well as vascular contractility, which might lead to uterine fibroids and hypertension.18-32 In addition, studies hypothesized
that the smooth muscle proliferation in fibroids is, analogous to atherosclerotic changes in smooth muscle, a result of stimulated transforming growth factor-ß due to smooth muscle injury by hypertension.4,5,7,33,34 Others proposed
that fibroids promote hypertension through local uterine synthesis of angiotensinogenase, which hydrolyzes angiotensinogen.35
In our view, the clinical relevance of the association lies in the early identification of hypertension in women presenting with fibroids. Our data show that women with surgery for fibroids have greater hypertension risk, independent of common risk factors including African ancestry. To our knowledge, prospective data on the actual development of hypertension in index cases with fibroids are lacking. Nonetheless, based on the aggregated body of evidence on this matter as presented in this paper and in Table 1, women with fibroids should be offered screening for hypertension.
The main strength of our study is that we present well controlled and adjusted data, with population and surgery controls, adjustment for ancestry, and in-person blood pressure measurements instead of the self-reported hypertension used in many papers.4,5,10–12,15 Our
data and analyses are limited by the small numbers of persons of African ancestry and women with self-reported fibroids in, respectively, the surgical and population controls. In addition, the gynecological controls excluded because of missing blood pressure data were younger than the included controls, which might have overestimated the crude hypertension rate in the latter, as hypertension rates increase with age. However, the mean age in this control group was comparable with the cases, and we adjusted for age and ancestry in the regression analysis. Also, the low number of fibroids in the population controls might have affected the
Uterine fibroids Hypertension
Vascular contractility Vascular remodeling Smooth muscle proliferation Growth factors and vasoactive peptides
2
pressure reading in both surgery cases and surgery controls might have led to misclassification of the hypertension status in either direction,36 but hypertension rates in surgical cases were
also significantly different from surgery controls. Finally, although hypertension is the main independent risk factor for premature cardiovascular death,3 and we included age, BMI, African
ancestry, and diabetes as other risk factors in the analysis, we lacked data on smoking status, physical activity, lipid spectrum, hormone use, menopausal status, gestational hypertension, or target organ damage. Of note, other studies addressing these risk factors13,14 confirmed the
independent hypertension risk with fibroids.
In summary, women have a high risk of cardiovascular disease, nonetheless female-specific risk factors appear to be understudied. We provide Dutch data indicating that women with surgically treated fibroids have a greater hypertension risk, which is independent of age, BMI, and ancestry. Our data add to the existing body of evidence suggesting that women with fibroids are eligible for hypertension screening.
REFERENCES
1. Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, Lloyd-Jones DM, Newby LK, Pina HL, Roger VL, Shaw LJ, Zhao D, Beckie TM, Bushnell C, D’Armiento J, Kris-Etherton PM, Fang J, Ganiats TG, Gomes AS, Gracia CR, Haan CK, Jackson EA, Judelson DR, Kelepouris E, Lavie CL, Moore A, Nussmeier NA, Ofili E, Oparil S, Ouyang P, Pinn VW, Sherif K, Smith SC, Sopko G Jr, Chandra Strobos N, Urbina EM, Vaccarino V, Wenger NK. Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the American Heart Association. Circulation 2011; 123:1243–1262.
2. Papakonstantinou NA, Stamou MI, Baikoussis NG, Goudevenos J, Apostolakis E. Sex differentiation with regard to coronary artery disease. J Cardiol 2013; 62:4–11.
3. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Judd SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid DJ, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER III, Moy CS, Mussolino ME, Neumar RW, Nichol G, Pandey DK, Paynter NP, Reeves MJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Wong ND, Woo D, Turner MB; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation 2014; 129:e28–e292.
4. Faerstein E, Szklo M, Rosenshein NB. Risk factors for uterine leiomyoma: a practice-based case control study. II. Atherogenic risk factors and potential sources of uterine irritation. Am J Epidemiol 2001; 153:11–19.
5. Parazzini F, Chiaffarino F, Polverino G, Chiantera V, Surace M, La Vecchia C. Uterine fibroids risk and history of selected medical conditions linked with female hormones. Eur J Epidemiol 2004; 19:249– 253.
6. Boynton-Jarrett R, Rich-Edwards J, Malspeis S, Missmer SA, Wright R. A prospective study f hypertension and risk of uterine leiomyomata. Am J Epidemiol 2005; 161:628–638.
7. Takeda T, Sakata M, Isobe A, Miyake A, Nishimoto F, Ota Y, Kamiura S, Kimura T. Relationship between metabolic syndrome and uterine leiomyomas: a case-control study. Gynecol Obstet Invest 2008; 66:14–17.
8. Radin RG, Rosenberg L, Palmer JR, Cozier YC, Kumanyika SK, Wise LA. Hypertension and risk of uterine leiomyomata in US black women. Hum Reprod 2012; 27:1504–1509.
9. Sivri N, Yalta T, Sayın C, Yalta K, Ozpuyan F, Taotekin E, Yetkin E. Evaluation of cardiovascular risk factors in women with uterine leimyoma: is there a link with atherosclerosis? Balkan Med J 2012; 29:320–323.
10. Aksoy Y, Sivri N, Karaoz B, Sayın C, Yetkin E. Carotid intima-media thickness: a new marker of patients with uterine leiomyoma. Eur J Obstet Gynecol Reprod Biol 2014; 175:54–57.
11. Lambertino A, Turyk M, Anderson H, Freels S, Persky V. Uterine leiomyomata in a cohort of Great Lakes sport fish consumers. Environ Res 2011; 111:565–572.
2
13. Luoto R, Kaprio J, Reunanen A, Rutanen EM. Cardiovascular morbidity in relation to ovarian functionafter hysterectomy. Obstet Gynecol 1995; 85:515–522.
14. Luoto R, Rutanen EM, Auvinen A. Fibroids and hypertension. A cross-sectional study of women undergoing hysterectomy. J Reprod Med 2001; 46:359–564.
15. Spies JB, Bradley LD, Guido R, Maxwell GL, Levine BA, Coyne K. Outcomes from leiomyoma therapies: comparison with normal controls. Obstet Gynecol 2010; 116:641–652.
16. Silver MA, Raghuvir R, Fedirko B, Elser D. Systemic hypertension among women with uterine leiomyomata: potential final common pathways of target end-organ remodeling. J Clin Hypertens 2005; 7:664–668.
17. Brewster LM, Mairuhu G, Bindraban NR, Koopmans RP, Clark JF, van Montfrans GA. Creatine kinase activity is associated with blood pressure. Circulation 2006; 114:2034–2039.
18. Ciarmela P, Islam MS, Reis FM, Gray PC, Bloise E, Petraglia F, Vale W, Castellucci M. Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications. Hum Reprod
Update 2011; 17:772–790.
19. Li Y, Levesque LO, Anand-Srivastava MB. Epidermal growth factor receptor transactivation by endogenous vasoactive peptides contributes to hyperproliferation of vascular smooth muscle cells of SHR. Am J Physiol Heart Circ Physiol 2010; 299:H1959–H1967.
20. Eude I, Dallot E, Vacher-Lavenu MC, Chapron C, Ferre F, Breuiller-Fouche M. Potentiation response of cultured human uterine leiomyoma cells to various growth factors by endothelin-1: role of protein kinase C. Eur J Endocrinol 2001; 144:543–548.
21. Isobe A, Takeda T, Sakata M, Miyake A, Yamamoto T, Minekawa R, Nishimoto F, Okamoto Y, Walker CL, Kimura T. Dual repressive effect of angiotensin II-type 1 receptor blocker telmisartan on angiotensin II-induced and estradiol-induced uterine leiomyoma cell proliferation. Hum Reprod 2008; 23:440– 446.
22. Bouallegue A, Vardatsikos G, Srivastava AK. Involvement of insulin-like growth factor 1 receptor transactivation in endothelin-1-induced signaling in vascular smooth muscle cells. Can J Physiol
Pharmacol 2010; 88:501–509.
23. Kimura C, Konishi S, Hasegawa M, Oike M. Development of vascular smooth muscle contractility by endothelium-derived transforming growth factor β proteins. Pflugers Arch 2014; 466:369 380. 24. Batenburg WW, Jansen PM, van den Bogaerdt AJ, J Danser AH. Angiotensin II-aldosterone interaction
in human coronary microarteries involves GPR30, EGFR, and endothelial NO synthase. Cardiovasc Res 2012; 94:136–43.
25. Batchu SN, Korshunov VA. Novel tyrosine kinase signaling pathways: implications in vascular remodeling. Curr Opin Nephrol Hypertens 2012; 21:122–7.
26. Brewster LM, Clark JF, van Montfrans GA. Is greater tissue activity of creatine kinase the genetic factor increasing hypertension risk in black people of sub-Saharan African descent? J Hypertens 2000; 18:1537–1544.
28. Somjen D, Kohen F, Jaffe A, Amir-Zaltsman Y, Knoll E, Stern N. Effects of gonadal steroids and their antagonists on DNA synthesis in human vascular cells. Hypertension 1998; 32:39–45.
29. Brewster LM, Coronel CM, Sluiter W, Clark JF, van Montfrans GA. Ethnic differences in tissue creatine kinase activity: an observational study. PLoS One 2012; 7:e32471.
30. Salvadori A, Fanari P, Ruga S, Brunani A, Longhini E. Creatine kinase and creatine kinase-MB isoenzyme during and after exercise testing in normal and obese young people. Chest 1992; 102:1687–1689. 31. Hoag GN, Franks CR, Smith C, DeCoteau WE. Creatine kinase isoenzyme patterns in normal smooth
muscle and smooth muscle neoplasms. Clin Biochem 1980; 13:149–150.
32. Brewster LM, Taherzadeh Z, Volger S, Clark JF, Rolf T, Wolf H, VanBavel E, van Montfrans GA. Ethnic differences in resistance artery contractility of normotensive pregnant women. Am J Physiol Heart
Circ Physiol 2010; 299:H431-H436.
33. Moss NS, Benditt EP. Human atherosclerotic plaque cells and leiomyoma cells. Comparison of in vitro growth characteristics. Am J Pathol 1975; 78:175–190.
34. Stewart EA, Nowak RA. New concepts in the treatment of uterine leiomyomas. Obstet Gynecol 1998; 92:624–627.
35. Ganten D, Schelling P, Vecsei P, Ganten U. Iso-renin of extrarenal origin. “The tissue angiotensinogenase systems”. Am J Med 1976; 60:760–772.
36. Handler J, Zhao Y, Egan BM. Impact of the number of blood pressure measurements on blood pressure classification in US adults: NHANES 1999–2008. J Clin Hypertens (Greenwich) 2012;14:751–9.
