Unique Characteristics of Hypertension in Women and Association with to Target Organ Damage

    Authors

    Abstract

    Traditional cardiovascular risk factors for target organ damage are the same in both women and men and include hypertension, hyperlipidemia, diabetes mellitus, smoking, and atrial fibrillation. There are several risk factors that are specific to women, such as differences in sex hormones, exogenous estrogens, and pregnancy. Further investigation into the sex-specific differences in therapeutic utilization and the sex-specific differences in the safety and efficacy of the therapeutic options is required.

    Keywords

    women, risk factors, hypertension

    DOI

    https://doi.org/10.15836/ccar2018.239

    Full Text

    Differences between men and women in hypertension are not recent news. There are well-established differences in prevalence which manifests in age difference (higher prevalence in men up to the fifth decade of life and higher prevalence in women in later ages) as well as higher incidence of white coat hypertension in women; however, the effect of hypertension on target organ damage is less well known, particularly for stroke, which is more common in women than in men (1). Despite a clear biological difference between women and men, there are no guidelines related to the sex differences except for the treatment of hypertension in pregnancy (1). Hypertension in a state of endothelial dysfunction of all blood vessels, and obesity represents the most important factor for the development of heart and kidney disease (2, 3). The overall challenges with female patients are especially emphasized in pregnancy, requiring a multidisciplinary approach. Autoimmune diseases in women, especially systemic lupus types, are often associated with kidney damage, and patients with autoimmune diseases have increased risk of cardiovascular diseases; consequently, the cooperation between different fields of expertise in the treatment of women with autoimmune diseases is especially important (4). Heart failure with preserved ejection fraction is more common in women, and the importance of the link between the heart and the brain is well-know (5). ## The kidney-heart-brain link in women The guiding principle of arterial hypertension treatment, an omnipresent and current preventable causal factor, is the reduction of total mortality. We often forget that stroke is the third leading cause of death for women in the United States of America and the leading cause of incapacitation (5). Beside traditional risk factors for target organ damage that are the same for men and women (arterial hypertension, hyperlipidemia, diabetes, cigarette smoking, atrial fibrillation), there are also specific risk factors present only in women (differences in sex hormones, estrogen supplementation therapy, and pregnancy) (5). Cardiovascular diseases (CVD) are responsible for more than 17 million cases of death per year (6). The overall data show that more women than men die of CVD. This group of diseases is responsible for 45% of all deaths in women and 38% of all deaths in men. In 2013, the World Health Organization published findings showing that arterial hypertension is responsible for at least 45% of cases of death due to heart disease and 51% cases of death due to stroke, and that every tenth person also has chronic kidney disease (CKD) (6). The risk of development of CKD in women is higher than in men (14% vs. 12%) (7). Chronic kidney disease affects approximately 195 million women worldwide and is the 8th leading cause of death in women annually, with 600 000 cases of death (8). Female sex, arterial hypertension, advanced age, and obesity are characteristic for heart failure with preserved ejection fraction (HFpEF) (5, 9). In everyday practice, patients with heart remodeling due to hypertension with atrial fibrillation are common and require adjustment of oral doses of anticoagulation medication depending on the level of CKD, with an increasing prevalence of women of advanced age among them (10). Additionally, HFpEF is often inadequately recognized and managed, and it is associated with numerous comorbid states such as hypertension (60%-80%), ischemic heart disease (35%-70%), diabetes (20%-45%), and atrial fibrillation (15%-40%) (11). Consequently, there have been efforts to raise awareness of the association between CKD, cardiovascular morbidity and mortality, and the possibility of preventive measures recommended by various societies, such as the formation of the Council on Kidney in Cardiovascular Disease as part of the American Heart Association, which approaches the issues of kidney disease as a part of translational medicine with the goal of reducing cardiovascular risk. ## Obesity, kidney damage, and hypertensive disorders in women The prevalence of obesity in Europe is between 4-28% in men and 6.2%-36.5% in women. It is incredible that obesity is more common in women than in men. The prevalence of obesity increased with age (25% of persons between 45 and 72 years of age are overweight). What is worrying is the high prevalence of obesity in younger age groups, especially in childhood (8.8%). It is a well-known fact that cardiovascular mortality and morbidity as well as association with uncontrolled hypertension is higher in obese patients (2). The specific characteristic of disorders related to obesity is the mechanism of insulin resistance and ectopic lipid accumulation, which contributes to organ damage in the context of metabolic diseases, indicating that kidney disease associated with obesity is really a state of lipodystrophy and aging process acceleration. The association between lipid-disordered metabolism, insulin resistance, and the activation of inflammatory processes leads to the development of glomerulopathy associated with obesity and heart and vascular remodeling (2). Hypertensive disorders have been recognized as an important risk factor for CVD in women (12). It is important to differentiate between several specific states: 1. Women receiving oral contraceptive therapy Taking oral contraceptives is associated with a small but significant increase in blood pressure (BP) and hypertension in 5% of women receiving oral contraceptive therapy (especially at older ages) (13). The incidence of myocardial infarction and ischemic stroke is low in the age group of women using oral contraceptives. Guidelines do not recommend the use of oral contraceptives in women who have uncontrolled hypertension, and the risk of developing hypertension is reduced with the cessation of oral contraceptives (14). 1. Women on hormone replacement therapy There is a low probability of BP rise in menopausal hypertensive women receiving hormone replacement therapy (15). Hormone replacement therapy and selective estrogen receptor modulators are not recommended for primary and secondary prevention of CVD. 1. Specific characteristics in women and guidelines for hypertension in pregnancy There are no specific guidelines for the treatment of arterial hypertension in women except in pregnancy. The ESH/ESC guidelines for the treatment of hypertension from 2013 recommend commencing antihypertensive treatment at BP values >140/90 mmHg in women with gestational diabetes, preexisting hypertension with the manifestation of gestational diabetes, and in those with hypertension with asymptomatic organ damage or symptoms in any period of the pregnancy (14). The choice of medication for the treatment of hypertension in pregnancy are methyldopa, labetalol, and nifedipine (long-acting). In emergencies such as severe preeclampsia, the medication of choice is the intravenous application of labetalol (14). In women with preeclampsia, the risk of developing hypertension in older age is four times higher in comparison with women who did not have preeclampsia (16). The newest literature lists preeclampsia as an early marker of CVD risk. Women who had preeclampsia have double the risk of developing ischemic heart disease, stroke, and thromboembolic diseases in a period of 5-15 years after pregnancy (17). Complication associated with pregnancy also increase the risk of kidney disease. Preeclampsia, septic abortion, and inflammatory conditions such as acute or chronic pyelonephritis and autoimmune diseases such as lupus nephritis typically manifest in women and are the leading cause of acute kidney damage in women (4). 1. Chronic kidney disease in women Chronic kidney disease, which is currently reaching increasingly pandemic proportions, is an additional risk factor for reduced fertility and unwanted outcomes in pregnancy, and women with CKD are at increased risk of poor outcomes due to greatly increased incidence of hypertension and preterm births (18). The progression of CKD in women, in addition to numerous disorders of other bodily systems, also leads to menstruation disorders, infertility, and early menopause. Women with premature menopause are at higher risk of developing CKD (19). ## Conclusion It is important to note that women are far less represented in a number of cardiovascular studies, especially those related to guidelines (20), which begs the question whether the existing guidelines are adequate for the treatment of women, or only for the treatment of men. Women die more often from CVD than men, and the risk of CKD in women is higher than in men. Even in the early stages, CKD has increased cardiovascular risk, and CVD is basically endothelial dysfunction with simultaneous changes in renal and coronary microcirculation. Further studies are needed to contribute to a better understanding of the unique characteristics related to female health, which have an additional influence on the safety and effectiveness of the treatment options being applied.

    Literature

    1. Delles C, Currie G. Sex differences in hypertension and other cardiovascular diseases. J Hypertens. 2018 Apr;36(4):768–70. https://doi.org/10.1097/HJH.0000000000001655
    2. Prkačin I. Multiple obesity related mechanisms of kidney disease. Cardiol Croat. 2017;12(7-8):315–8. https://doi.org/10.15836/ccar2017.315
    3. Prkačin I, Vrdoljak P, Cavrić G, Vazanić D, Pervan P, Nesek Adam V. Resistant Hypertension and Cardiorenovascular Risk. BANTAO Journal. 2017;15(1):6–9. https://doi.org/10.1515/bj-2017-0002
    4. Valetić AM, Kisić M, Markeljević J, Valetić J, Ljubanović-Galešić D, Prkačin I. Trudnoća u bolesnice s lupusnim nefritisom. Acta Med Croatica. 2017;71 Suppl 1:57–61.
    5. Demel SL, Kittner S, Ley SH, McDermott M, Rexrode KM. Stroke Risk Factors Unique to Women. Stroke. 2018 Mar;49(3):518–23. https://doi.org/10.1161/STROKEAHA.117.018415
    6. World Health Organization. A Global Brief on Hypertension. 2013. Available at: (May 25, 2018). http://www.who.int/iris/bitstream/10665/79059/1/WHO_DCO_WHD_2013.2_eng.pdf?ua=1
    7. Hill NR, Fatoba ST, Oke JL, Hirst JA, O’Callaghan CA, Lasserson DS, et al. Global Prevalence of Chronic Kidney Disease - A Systematic Review and Meta-Analysis. PLoS One. 2016 Jul 6;11(7):e0158765. https://doi.org/10.1371/journal.pone.0158765
    8. Data on prevalence and mortality in women taken from GBD website: (May 25, 2018). https://vizhub.healthdata.org/gbd-compare/
    9. van Heerebeek L, Paulus WJ. Impact of comorbidities on myocardial remodeling and dysfunction in heart failure with preserved ejection fraction. SOJ Pharm Pharm Sci. 2014;1(2):20. https://doi.org/10.15226/2374-6866/1/2/00112
    10. Prkačin I, Cavrić G, Nesek-Adam V, Balenović D, Horvat I, Đermanović-Dobrota V. Oral anticoagulants in patients with chronic kidney disease and atrial fibrillation. Signa Vitae. 2016;11 Suppl 2:41–3. https://doi.org/10.22514/SV112.062016.8
    11. Ziaeian B, Heidenreich PA, Xu H, DeVore AD, Matsouaka RA, Hernandez AF, et al. Race/ethnic differences in outcomes among hospitalized Medicare patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2017 Jul;5(7):483–93. https://doi.org/10.1016/j.jchf.2017.02.012
    12. Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, Lloyd-Jones DM, et al. American Heart Association. Effectiveness-based guidelines for the prevention of cardiovascular disease in women: 2011 update: a guideline from the American Heart Association. J Am Coll Cardiol. 2011 Mar 22;57(12):1404–23. https://doi.org/10.1016/j.jacc.2011.02.005
    13. Vitale C, Fini M, Speziale G, Chierchia S. Gender differences in the cardiovascular effects of sex hormones. Fundam Clin Pharmacol. 2010 Dec;24(6):675–85. https://doi.org/10.1111/j.1472-8206.2010.00817.x
    14. Mancia G, Fagard R, Narkiewicz K, Redón J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013 Jul;31(7):1281–357. https://doi.org/10.1097/01.hjh.0000431740.32696.cc
    15. Mueck AO, Seeger H. Effect of hormone therapy on BP in normotensive and hypertensive postmenopausal women. Maturitas. 2004 Nov 15;49(3):189–203. https://doi.org/10.1016/j.maturitas.2004.01.010
    16. McDonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ. Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses. Am Heart J. 2008 Nov;156(5):918–30. https://doi.org/10.1016/j.ahj.2008.06.042
    17. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Preeclampsia and risk of cardiovascular disease and cancer in later life: systematic reviewand meta-analysis. BMJ. 2007 Nov 10;335(7627):974. https://doi.org/10.1136/bmj.39335.385301.BE
    18. Smyth A, Radovic M, Garovic VD. Women, kidney disease, and pregnancy. Adv Chronic Kidney Dis. 2013;20:402–10. https://doi.org/10.1053/j.ackd.2013.06.004
    19. Muka T, Oliver-Williams C, Kunutsor S, Laven JS, Fauser BC, Chowdhury R, et al. Association of age at onset of menopause and time since onset of menopause with cardiovascular outcomes, intermediate vascular traits, and all-cause mortality: a systematic review and meta-analysis. JAMA Cardiol. 2016;1:767–76. https://doi.org/10.1001/jamacardio.2016.2415
    20. Westerman S, Wenger NK. Women and heart disease, the underrecognized burden:sex differemces, biases, and unmet clinical and research challenges. Clin Sci (Lond). 2016 Apr;130(8):551–63. https://doi.org/10.1042/CS20150586
    Cardiologia Croatica
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    Unique Characteristics of Hypertension in Women and Association with to Target Organ Damage

    Professional Article
    Issue7-8
    Published
    Pages239-242
    PDF via DOIhttps://doi.org/10.15836/ccar2018.239
    women
    risk factors
    hypertension

    Authors

    Ingrid Prkačin*ORCIDMedicinski fakultet Sveučilišta u Zagrebu, Zagreb, Hrvatska
    Martina Lovrić BenčićORCIDMedicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, Hrvatska
    Domagoj MarkovićORCIDSplit, Croatia

    *Correspondence email: ingrid.prkacin@gmail.com

    Abstract

    Traditional cardiovascular risk factors for target organ damage are the same in both women and men and include hypertension, hyperlipidemia, diabetes mellitus, smoking, and atrial fibrillation. There are several risk factors that are specific to women, such as differences in sex hormones, exogenous estrogens, and pregnancy. Further investigation into the sex-specific differences in therapeutic utilization and the sex-specific differences in the safety and efficacy of the therapeutic options is required.

    Full Text

    Differences between men and women in hypertension are not recent news. There are well-established differences in prevalence which manifests in age difference (higher prevalence in men up to the fifth decade of life and higher prevalence in women in later ages) as well as higher incidence of white coat hypertension in women; however, the effect of hypertension on target organ damage is less well known, particularly for stroke, which is more common in women than in men (1).

    Despite a clear biological difference between women and men, there are no guidelines related to the sex differences except for the treatment of hypertension in pregnancy (1). Hypertension in a state of endothelial dysfunction of all blood vessels, and obesity represents the most important factor for the development of heart and kidney disease (2, 3). The overall challenges with female patients are especially emphasized in pregnancy, requiring a multidisciplinary approach.

    Autoimmune diseases in women, especially systemic lupus types, are often associated with kidney damage, and patients with autoimmune diseases have increased risk of cardiovascular diseases; consequently, the cooperation between different fields of expertise in the treatment of women with autoimmune diseases is especially important (4). Heart failure with preserved ejection fraction is more common in women, and the importance of the link between the heart and the brain is well-know (5).

    The kidney-heart-brain link in women

    The guiding principle of arterial hypertension treatment, an omnipresent and current preventable causal factor, is the reduction of total mortality. We often forget that stroke is the third leading cause of death for women in the United States of America and the leading cause of incapacitation (5). Beside traditional risk factors for target organ damage that are the same for men and women (arterial hypertension, hyperlipidemia, diabetes, cigarette smoking, atrial fibrillation), there are also specific risk factors present only in women (differences in sex hormones, estrogen supplementation therapy, and pregnancy) (5).

    Cardiovascular diseases (CVD) are responsible for more than 17 million cases of death per year (6). The overall data show that more women than men die of CVD. This group of diseases is responsible for 45% of all deaths in women and 38% of all deaths in men. In 2013, the World Health Organization published findings showing that arterial hypertension is responsible for at least 45% of cases of death due to heart disease and 51% cases of death due to stroke, and that every tenth person also has chronic kidney disease (CKD) (6). The risk of development of CKD in women is higher than in men (14% vs. 12%) (7). Chronic kidney disease affects approximately 195 million women worldwide and is the 8th leading cause of death in women annually, with 600 000 cases of death (8). Female sex, arterial hypertension, advanced age, and obesity are characteristic for heart failure with preserved ejection fraction (HFpEF) (5, 9). In everyday practice, patients with heart remodeling due to hypertension with atrial fibrillation are common and require adjustment of oral doses of anticoagulation medication depending on the level of CKD, with an increasing prevalence of women of advanced age among them (10). Additionally, HFpEF is often inadequately recognized and managed, and it is associated with numerous comorbid states such as hypertension (60%-80%), ischemic heart disease (35%-70%), diabetes (20%-45%), and atrial fibrillation (15%-40%) (11).

    Consequently, there have been efforts to raise awareness of the association between CKD, cardiovascular morbidity and mortality, and the possibility of preventive measures recommended by various societies, such as the formation of the Council on Kidney in Cardiovascular Disease as part of the American Heart Association, which approaches the issues of kidney disease as a part of translational medicine with the goal of reducing cardiovascular risk.

    Obesity, kidney damage, and hypertensive disorders in women

    The prevalence of obesity in Europe is between 4-28% in men and 6.2%-36.5% in women. It is incredible that obesity is more common in women than in men. The prevalence of obesity increased with age (25% of persons between 45 and 72 years of age are overweight). What is worrying is the high prevalence of obesity in younger age groups, especially in childhood (8.8%). It is a well-known fact that cardiovascular mortality and morbidity as well as association with uncontrolled hypertension is higher in obese patients (2).

    The specific characteristic of disorders related to obesity is the mechanism of insulin resistance and ectopic lipid accumulation, which contributes to organ damage in the context of metabolic diseases, indicating that kidney disease associated with obesity is really a state of lipodystrophy and aging process acceleration. The association between lipid-disordered metabolism, insulin resistance, and the activation of inflammatory processes leads to the development of glomerulopathy associated with obesity and heart and vascular remodeling (2). Hypertensive disorders have been recognized as an important risk factor for CVD in women (12).

    It is important to differentiate between several specific states:

    1. Women receiving oral contraceptive therapy

    Taking oral contraceptives is associated with a small but significant increase in blood pressure (BP) and hypertension in 5% of women receiving oral contraceptive therapy (especially at older ages) (13). The incidence of myocardial infarction and ischemic stroke is low in the age group of women using oral contraceptives. Guidelines do not recommend the use of oral contraceptives in women who have uncontrolled hypertension, and the risk of developing hypertension is reduced with the cessation of oral contraceptives (14).

    1. Women on hormone replacement therapy

    There is a low probability of BP rise in menopausal hypertensive women receiving hormone replacement therapy (15). Hormone replacement therapy and selective estrogen receptor modulators are not recommended for primary and secondary prevention of CVD.

    1. Specific characteristics in women and guidelines for hypertension in pregnancy

    There are no specific guidelines for the treatment of arterial hypertension in women except in pregnancy. The ESH/ESC guidelines for the treatment of hypertension from 2013 recommend commencing antihypertensive treatment at BP values >140/90 mmHg in women with gestational diabetes, preexisting hypertension with the manifestation of gestational diabetes, and in those with hypertension with asymptomatic organ damage or symptoms in any period of the pregnancy (14). The choice of medication for the treatment of hypertension in pregnancy are methyldopa, labetalol, and nifedipine (long-acting). In emergencies such as severe preeclampsia, the medication of choice is the intravenous application of labetalol (14). In women with preeclampsia, the risk of developing hypertension in older age is four times higher in comparison with women who did not have preeclampsia (16). The newest literature lists preeclampsia as an early marker of CVD risk. Women who had preeclampsia have double the risk of developing ischemic heart disease, stroke, and thromboembolic diseases in a period of 5-15 years after pregnancy (17). Complication associated with pregnancy also increase the risk of kidney disease. Preeclampsia, septic abortion, and inflammatory conditions such as acute or chronic pyelonephritis and autoimmune diseases such as lupus nephritis typically manifest in women and are the leading cause of acute kidney damage in women (4).

    1. Chronic kidney disease in women

    Chronic kidney disease, which is currently reaching increasingly pandemic proportions, is an additional risk factor for reduced fertility and unwanted outcomes in pregnancy, and women with CKD are at increased risk of poor outcomes due to greatly increased incidence of hypertension and preterm births (18). The progression of CKD in women, in addition to numerous disorders of other bodily systems, also leads to menstruation disorders, infertility, and early menopause. Women with premature menopause are at higher risk of developing CKD (19).

    Conclusion

    It is important to note that women are far less represented in a number of cardiovascular studies, especially those related to guidelines (20), which begs the question whether the existing guidelines are adequate for the treatment of women, or only for the treatment of men. Women die more often from CVD than men, and the risk of CKD in women is higher than in men. Even in the early stages, CKD has increased cardiovascular risk, and CVD is basically endothelial dysfunction with simultaneous changes in renal and coronary microcirculation. Further studies are needed to contribute to a better understanding of the unique characteristics related to female health, which have an additional influence on the safety and effectiveness of the treatment options being applied.

    Literature

    1. 1.
      Delles C, Currie G. Sex differences in hypertension and other cardiovascular diseases. J Hypertens. 2018 Apr;36(4):768–70.DOI
    2. 2.
      Prkačin I. Multiple obesity related mechanisms of kidney disease. Cardiol Croat. 2017;12(7-8):315–8.DOI
    3. 3.
      Prkačin I, Vrdoljak P, Cavrić G, Vazanić D, Pervan P, Nesek Adam V. Resistant Hypertension and Cardiorenovascular Risk. BANTAO Journal. 2017;15(1):6–9.DOI
    4. 4.
      Valetić AM, Kisić M, Markeljević J, Valetić J, Ljubanović-Galešić D, Prkačin I. Trudnoća u bolesnice s lupusnim nefritisom. Acta Med Croatica. 2017;71 Suppl 1:57–61.
    5. 5.
      Demel SL, Kittner S, Ley SH, McDermott M, Rexrode KM. Stroke Risk Factors Unique to Women. Stroke. 2018 Mar;49(3):518–23.DOI
    6. 6.
      World Health Organization. A Global Brief on Hypertension. 2013. Available at: (May 25, 2018).Link
    7. 7.
      Hill NR, Fatoba ST, Oke JL, Hirst JA, O’Callaghan CA, Lasserson DS, et al. Global Prevalence of Chronic Kidney Disease - A Systematic Review and Meta-Analysis. PLoS One. 2016 Jul 6;11(7):e0158765.DOI
    8. 8.
      Data on prevalence and mortality in women taken from GBD website: (May 25, 2018).Link
    9. 9.
      van Heerebeek L, Paulus WJ. Impact of comorbidities on myocardial remodeling and dysfunction in heart failure with preserved ejection fraction. SOJ Pharm Pharm Sci. 2014;1(2):20.DOI
    10. 10.
      Prkačin I, Cavrić G, Nesek-Adam V, Balenović D, Horvat I, Đermanović-Dobrota V. Oral anticoagulants in patients with chronic kidney disease and atrial fibrillation. Signa Vitae. 2016;11 Suppl 2:41–3.DOI
    11. 11.
      Ziaeian B, Heidenreich PA, Xu H, DeVore AD, Matsouaka RA, Hernandez AF, et al. Race/ethnic differences in outcomes among hospitalized Medicare patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2017 Jul;5(7):483–93.DOI
    12. 12.
      Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, Lloyd-Jones DM, et al. American Heart Association. Effectiveness-based guidelines for the prevention of cardiovascular disease in women: 2011 update: a guideline from the American Heart Association. J Am Coll Cardiol. 2011 Mar 22;57(12):1404–23.DOI
    13. 13.
      Vitale C, Fini M, Speziale G, Chierchia S. Gender differences in the cardiovascular effects of sex hormones. Fundam Clin Pharmacol. 2010 Dec;24(6):675–85.DOI
    14. 14.
      Mancia G, Fagard R, Narkiewicz K, Redón J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013 Jul;31(7):1281–357.DOI
    15. 15.
      Mueck AO, Seeger H. Effect of hormone therapy on BP in normotensive and hypertensive postmenopausal women. Maturitas. 2004 Nov 15;49(3):189–203.DOI
    16. 16.
      McDonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ. Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses. Am Heart J. 2008 Nov;156(5):918–30.DOI
    17. 17.
      Bellamy L, Casas JP, Hingorani AD, Williams DJ. Preeclampsia and risk of cardiovascular disease and cancer in later life: systematic reviewand meta-analysis. BMJ. 2007 Nov 10;335(7627):974.DOI
    18. 18.
      Smyth A, Radovic M, Garovic VD. Women, kidney disease, and pregnancy. Adv Chronic Kidney Dis. 2013;20:402–10.DOI
    19. 19.
      Muka T, Oliver-Williams C, Kunutsor S, Laven JS, Fauser BC, Chowdhury R, et al. Association of age at onset of menopause and time since onset of menopause with cardiovascular outcomes, intermediate vascular traits, and all-cause mortality: a systematic review and meta-analysis. JAMA Cardiol. 2016;1:767–76.DOI
    20. 20.
      Westerman S, Wenger NK. Women and heart disease, the underrecognized burden:sex differemces, biases, and unmet clinical and research challenges. Clin Sci (Lond). 2016 Apr;130(8):551–63.DOI