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Therapeutic implications of the gender-specific aspects of cardiovascular disease

Key Points

  • Cardiovascular diseases (CVDs) affect women and men differently, with variations between the sexes in the age at which CVDs manifest and their impact on survival. Diabetes and hypertension are more severe risk factors for CVD in women and sudden death is more frequent in men. It is important that those involved in disease treatment and drug discovery and development are aware of these differences.

  • Differences in the clinical presentation of coronary artery disease are of particular relevance, as they could contribute to a delay in the diagnosis of CVD in women. Women present less frequently with typical exercise angina, and the sensitivity and specificity of diagnostic procedures in women are different from in men.

  • Receptors for the sexual hormones oestrogen, progesterone and androgen (ERs, PRs and ARs, respectively) mediate sex-specific effects in the cardiovascular system. These receptors act by genomic and non-genomic mechanisms. The two known oestrogen receptors, ERα and ERβ, modulate myocardial gene expression, hypertrophic and apoptotic signalling, ion channels, metabolism and function; vascular ERs exert vasoprotective effects, including fast vasodilation via nitric oxide, reduction of leukocyte adhesion and inhibition of vascular smooth-muscle-cell proliferation.

  • Drugs commonly used to treat CVD include digitalis, angiotensin-converting enzyme inhibitors, beta-blockers, aspirin and anti-arrhythmic drugs. However, these drugs have gender-specific side effects, and the incidence of these side effects is higher in women; in particular, QT-interval-prolonging drugs cause more life-threatening arrhythmia in women.

  • There are several differences between women and men in drug pharmacokinetics. These include drug absorption and metabolism, and are frequently related to the cytochrome P450 system. Because lower numbers of women patients are included in cardiovascular trials, there is a lack of safety and efficacy data in women.

  • There is considerable knowledge of the role of gender in CVD and its treatment, and so a systematic search for gender-related differences in the pharmacodynamics and pharmacokinetics of drugs should be integrated into all phases of drug development, from preclinical studies through Phase I and II testing to large-scale clinical trials.

Abstract

The manifestations of cardiovascular diseases differ between men and women, as do outcomes after therapeutic interventions. It is important that those involved in drug discovery and development, as well as disease treatment, are aware of these differences because such variations are likely to have an increasing role in therapeutic decisions in the future. Here, I review gender differences in the most frequent cardiovascular diseases and their underlying sex-dependent molecular pathophysiology, and discuss gender-specific effects of current cardiovascular drugs and the implications for novel strategies for drug development.

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Figure 1: Multiple signalling pathways of oestrogen in cardiovascular cells.
Figure 2: Oestrogen receptors are expressed in the human heart.
Figure 3: Strategies to detect gender-specific effects in drug development.

References

  1. 1

    Barrett-Connor, E. Sex differences in coronary heart disease. Why are women so superior? The 1995 Ancel Keys Lecture. Circulation 95, 252–264 (1997).

    CAS  Google Scholar 

  2. 2

    Mendelsohn, M. E. & Karas, R. H. The protective effects of estrogen on the cardiovascular system. N. Engl. J. Med. 340, 1801–1811 (1999).

    CAS  Google Scholar 

  3. 3

    Reckelhoff, J. F. Gender differences in the regulation of blood pressure. Hypertension 37, 1199–1208 (2001).

    CAS  Google Scholar 

  4. 4

    Dubey, R. K., Oparil, S., Imthurn, B. & Jackson, E. K. Sex hormones and hypertension. Cardiovasc. Res. 53, 688–708 (2002).

    CAS  Google Scholar 

  5. 5

    Regitz-Zagrosek, V., Lehmkuhl, E., Lehmkuhl, H. B. & Hetzer, R. Gender aspects in heart failure. Patho-physiology and medical therapy. Arch. Mal. Coeur. Vaiss. 97, 899–908 (2004).

    CAS  Google Scholar 

  6. 6

    Regitz-Zagrosek, V., Lehmkuhl, E. & Weickert, M. Gender differences in the metabolic syndrome and their role for cardiovascular disease. Clin. Res. Cardiol. 95, 136–147 (2006).

    CAS  Google Scholar 

  7. 7

    Lowel, H. et al. Sex specific trends of sudden cardiac death and acute myocardial infarction: results of the population-based KORA/MONICA-Augsburg register 1985 to 1998. Dtsch. Med. Wochenschr. 127, 2311–2316 (2002).

    CAS  Google Scholar 

  8. 8

    Barrett-Connor, E. L., Cohn, B. A., Wingard, D. L. & Edelstein, S. L. Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? The Rancho Bernardo Study. JAMA 265, 627–631 (1991).

    CAS  Google Scholar 

  9. 9

    Barrett-Connor, E. & Ferrara, A. Isolated postchallenge hyperglycemia and the risk of fatal cardiovascular disease in older women and men. The Rancho Bernardo Study. Diabetes Care 21, 1236–1239 (1998). Groundbreaking study documenting that hyperglycaemia is a risk factor for CVD differences between women and men.

    CAS  Google Scholar 

  10. 10

    Lundberg, V., Stegmayr, B., Asplund, K., Eliasson, M. & Huhtasaari, F. Diabetes as a risk factor for myocardial infarction: population and gender perspectives. J. Intern. Med. 241, 485–492 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Yusuf, S. et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 364, 937–952 (2004). Study of the worldwide risk factors for myocardial infarction and the prominent role of hypertension and diabetes as risk factors for CVD in women and men.

    PubMed  PubMed Central  Google Scholar 

  12. 12

    Chobanian, A. V. et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 289, 2560–2572 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Hayes, S. N. & Taler, S. J. Hypertension in women: current understanding of gender differences. Mayo Clin. Proc. 73, 157–165 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Levy, D., Larson, M. G., Vasan, R. S., Kannel, W. B. & Ho, K. K. The progression from hypertension to congestive heart failure. JAMA 275, 1557–1562 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Levy, D. et al. Long-term trends in the incidence of and survival with heart failure. N. Engl. J. Med. 347, 1397–1402 (2002).

    PubMed  PubMed Central  Google Scholar 

  16. 16

    Albert, C. M., McGovern, B. A., Newell, J. B. & Ruskin, J. N. Sex differences in cardiac arrest survivors. Circulation 93, 1170–1176 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Mieres, J. H. et al. Role of noninvasive testing in the clinical evaluation of women with suspected coronary artery disease: consensus statement from the Cardiac Imaging Committee, Council on Clinical Cardiology, and the Cardiovascular Imaging and Intervention Committee, Council on Cardiovascular Radiology and Intervention, American Heart Association. Circulation 111, 682–696 (2005).

    PubMed  PubMed Central  Google Scholar 

  18. 18

    Vaccarino, V., Parsons, L., Every, N. R., Barron, H. V. & Krumholz, H. M. Sex-based differences in early mortality after myocardial infarction. National Registry of Myocardial Infarction 2 Participants. N. Engl. J. Med. 341, 217–225 (1999). The first large-scale study to document sex-based differences in early mortality and their age dependency.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Antoniucci, D. et al. Sex-based differences in clinical and angiographic outcomes after primary angioplasty or stenting for acute myocardial infarction. Am. J. Cardiol. 87, 289–293 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Schwartz, J. B. Gender-specific implications for cardiovascular medication use in the elderly optimizing therapy for older women. Cardiol. Rev. 11, 275–298 (2003).

    PubMed  PubMed Central  Google Scholar 

  21. 21

    Regitz-Zagrosek, V. et al. Gender as a risk factor in young, not in old, women undergoing coronary artery bypass grafting. J. Am. Coll. Cardiol. 44, 2413–2414 (2004).

    PubMed  PubMed Central  Google Scholar 

  22. 22

    Vaccarino, V., Abramson, J. L., Veledar, E. & Weintraub, W. S. Sex differences in hospital mortality after coronary artery bypass surgery: evidence for a higher mortality in younger women. Circulation 105, 1176–1181 (2002).

    PubMed  PubMed Central  Google Scholar 

  23. 23

    Maron, B. J. et al. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation 92, 785–789 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Wittstein, I. S. et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N. Engl. J. Med. 352, 539–548 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Ueyama, T. Emotional stress-induced Tako-tsubo cardiomyopathy: animal model and molecular mechanism. Ann. NY Acad. Sci. 1018, 437–444 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Carroll, J. D. et al. Sex-associated differences in left ventricular function in aortic stenosis of the elderly. Circulation 86, 1099–1107 (1992). Presents evidence that women with aortic stenosis have a different form of myocardial hypertrophy from men.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Liao, Y., Cooper, R. S., Mensah, G. A. & McGee, D. L. Left ventricular hypertrophy has a greater impact on survival in women than in men. Circulation 92, 805–810 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Cleland, J. G. et al. The EuroHeart Failure survey programme — a survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur. Heart J. 24, 442–463 (2003). The first large-scale survey to show that women with heart failure have frequenttly diastolic dysfunction, whereas, in men, systolic dysfunction is more dominant.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Abi-Gerges, N. et al. Sex differences in ventricular repolarization: from cardiac electrophysiology to Torsades de Pointes. Fundam. Clin. Pharmacol. 18, 139–151 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Stramba-Badiale, M., Locati, E. H., Martinelli, A., Courville, J. & Schwartz, P. J. Gender and the relationship between ventricular repolarization and cardiac cycle length during 24-h Holter recordings. Eur. Heart J. 18, 1000–1006 (1997).

    CAS  Google Scholar 

  31. 31

    Makkar, R. R., Fromm, B. S., Steinman, R. T., Meissner, M. D. & Lehmann, M. H. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 270, 2590–2597 (1993).

    CAS  Google Scholar 

  32. 32

    Locati, E. H. et al. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation 97, 2237–2244 (1998).

    CAS  Google Scholar 

  33. 33

    Zareba, W. et al. Modulating effects of age and gender on the clinical course of long QT syndrome by genotype. J. Am. Coll. Cardiol. 42, 103–109 (2003).

    Google Scholar 

  34. 34

    Redberg, R. F. et al. Women's Ischemic Syndrome Evaluation: current status and future research directions: report of the National Heart, Lung and Blood Institute workshop: October 2–4, 2002: Section 2: stable ischemia: pathophysiology and gender differences. Circulation 109, e47–49 (2004).

    Google Scholar 

  35. 35

    Buchthal, S. D. et al. Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms. N. Engl. J. Med. 342, 829–835 (2000).

    CAS  Google Scholar 

  36. 36

    Daly, C. et al. Gender differences in the management and clinical outcome of stable angina. Circulation 113, 490–498 (2006).

    Google Scholar 

  37. 37

    Guru, V., Fremes, S. E. & Tu, J. V. Time-related mortality for women after coronary artery bypass graft surgery: a population-based study. J. Thorac. Cardiovasc. Surg. 127, 1158–1165 (2004).

    Google Scholar 

  38. 38

    Redfern, W. S. et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 58, 32–45 (2003).

    CAS  Google Scholar 

  39. 39

    Rodriguez, I., Kilborn, M. J., Liu, X. K., Pezzullo, J. C. & Woosley, R. L. Drug-induced QT prolongation in women during the menstrual cycle. JAMA 285, 1322–1326 (2001).

    CAS  Google Scholar 

  40. 40

    Steinberg, H. O. et al. Type II diabetes abrogates sex differences in endothelial function in premenopausal women. Circulation 101, 2040–2046 (2000).

    CAS  Google Scholar 

  41. 41

    Orio, F., Jr. et al. The cardiovascular risk of young women with polycystic ovary syndrome: an observational, analytical, prospective case-control study. J. Clin. Endocrinol. Metab. 89, 3696–3701 (2004). Study documenting that women with hormonal dysfunction develop arteriosclerosis.

    CAS  Google Scholar 

  42. 42

    Azziz, R. Polycystic ovary syndrome, insulin resistance, and molecular defects of insulin signaling. J. Clin. Endocrinol. Metab. 87, 4085–4087 (2002).

    CAS  Google Scholar 

  43. 43

    Solomon, C. G. et al. Menstrual cycle irregularity and risk for future cardiovascular disease. J. Clin. Endocrinol. Metab. 87, 2013–2017 (2002).

    CAS  Google Scholar 

  44. 44

    Wilson, B. J. et al. Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study. BMJ 326, 845 (2003).

    PubMed  PubMed Central  Google Scholar 

  45. 45

    Williams, C. M. Lipid metabolism in women. Proc. Nutr. Soc. 63, 153–160 (2004).

    CAS  Google Scholar 

  46. 46

    Wajchenberg, B. L. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr. Rev. 21, 697–738 (2000).

    CAS  Google Scholar 

  47. 47

    Vaccarino, V. et al. Gender differences in recovery after coronary artery bypass surgery. J. Am. Coll. Cardiol. 41, 307–314 (2003).

    Google Scholar 

  48. 48

    Mallik, S. et al. Patients with depressive symptoms have lower health status benefits after coronary artery bypass surgery. Circulation 111, 271–277 (2005).

    Google Scholar 

  49. 49

    Mendelsohn, M. E. & Karas, R. H. Molecular and cellular basis of cardiovascular gender differences. Science 308, 1583–1587 (2005).

    CAS  Google Scholar 

  50. 50

    Nordmeyer, J. et al. Upregulation of myocardial estrogen receptors in human aortic stenosis. Circulation 110, 3270–3275 (2004). Reports the first evidence that myocardial oestrogen receptors are upregulated in human myocardial hypertrophy.

    CAS  Google Scholar 

  51. 51

    Mahmoodzadeh, S. et al. Estrogen receptor α upregulation and redistribution in human heart failure. FASEB J. (in the press).

  52. 52

    Forster, C., Kietz, S., Hultenby, K., Warner, M. & Gustafsson, J. A. Characterization of the ERβ−/− mouse heart. Proc. Natl Acad. Sci. USA 101, 14234–14239 (2004).

    Google Scholar 

  53. 53

    Edwards, D. P. Regulation of signal transduction pathways by estrogen and progesterone. Annu. Rev. Physiol. 67, 335–376 (2005).

    CAS  Google Scholar 

  54. 54

    Nuedling, S. et al. Activation of estrogen receptor β is a prerequisite for estrogen-dependent upregulation of nitric oxide synthases in neonatal rat cardiac myocytes. FEBS Lett. 502, 103–108 (2001).

    CAS  Google Scholar 

  55. 55

    Mendelsohn, M. E. Genomic and nongenomic effects of estrogen in the vasculature. Am. J. Cardiol. 90, 3F–6F (2002).

    CAS  Google Scholar 

  56. 56

    Metivier, R. et al. Estrogen receptor-α directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 115, 751–763 (2003). Excellent documentation of the complex and cyclical recruitment of cofactors by oestrogen receptors.

    CAS  Google Scholar 

  57. 57

    Vivacqua, A. et al. The G protein-coupled receptor GPR30 mediates the proliferative effects induced by 17β-estradiol and hydroxytamofen in endometrial cancer cells. Mol. Endocrinol. 20, 631–646 (2005).

    Google Scholar 

  58. 58

    Dubey, R. K., Tofovic, S. P. & Jackson, E. K. Cardiovascular pharmacology of estradiol metabolites. J. Pharmacol. Exp. Ther. 308, 403–409 (2004).

    CAS  Google Scholar 

  59. 59

    Smith, C. L., Conneely, O. M. & O'Malley, B. W. Modulation of the ligand-independent activation of the human estrogen receptor by hormone and antihormone. Proc. Natl Acad. Sci. USA 90, 6120–6124 (1993).

    CAS  Google Scholar 

  60. 60

    Ciana, P. et al. In vivo imaging of transcriptionally active estrogen receptors. Nature Med. 9, 82–86 (2003). Elegant and convincing proof that transcriptional activation of oestrogen receptors can occur without sexual hormones.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Zhai, P., Eurell, T. E., Cooke, P. S., Lubahn, D. B. & Gross, D. R. Myocardial ischemia-reperfusion injury in estrogen receptor-α knockout and wild-type mice. Am. J. Physiol. Heart Circ. Physiol. 278, H1640–H1647 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Pelzer, T. et al. Increased mortality and aggravation of heart failure in estrogen receptor-β knockout mice after myocardial infarction. Circulation 111, 1492–1498 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Korte, T. et al. Female mice lacking estrogen receptor β display prolonged ventricular repolarization and reduced ventricular automaticity after myocardial infarction. Circulation 111, 2282–2290 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    van Eickels, M. et al. 17β-estradiol attenuates the development of pressure-overload hypertrophy. Circulation 104, 1419–1423 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Skavdahl, M. et al. Estrogen receptor-β mediates male-female differences in the development of pressure overload hypertrophy. Am. J. Physiol. Heart Circ. Physiol. 288, H469–H476 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Shearman, A. M. et al. Association between estrogen receptor α gene variation and cardiovascular disease. JAMA 290, 2263–2270 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Herrington, D. M. & Howard, T. D. ER-α variants and the cardiovascular effects of hormone replacement therapy. Pharmacogenomics 4, 269–277 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Sudhir, K. & Komesaroff, P. A. Clinical review 110: Cardiovascular actions of estrogens in men. J. Clin. Endocrinol. Metab. 84, 3411–3415 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Rubanyi, G. M., Kauser, K. & Johns, A. Role of estrogen receptors in the vascular system. Vascul. Pharmacol. 38, 81–88 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Haynes, M. P. et al. Src kinase mediates phosphatidylinositol 3-kinase/Akt-dependent rapid endothelial nitric-oxide synthase activation by estrogen. J. Biol. Chem. 278, 2118–2123 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Simoncini, T. et al. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407, 538–541 (2000). Describes non-genomic oestrogen receptor signalling in endothelial cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Wyckoff, M. H. et al. Plasma membrane estrogen receptors are coupled to endothelial nitric-oxide synthase through Gα(i). J. Biol. Chem. 276, 27071–27076 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Wong, C. W., McNally, C., Nickbarg, E., Komm, B. S. & Cheskis, B. J. Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation cascade. Proc. Natl Acad. Sci. USA 99, 14783–1478 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Li, L., Haynes, M. P. & Bender, J. R. Plasma membrane localization and function of the estrogen receptor α variant (ER46) in human endothelial cells. Proc. Natl Acad. Sci. USA 100, 4807–4812 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Weinberg, E. O. et al. Sex dependence and temporal dependence of the left ventricular genomic response to pressure overload. Physiol. Genomics 12, 113–127 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Grohe, C., Kahlert, S., Lobbert, K. & Vetter, H. Expression of oestrogen receptor α and β in rat heart: role of local oestrogen synthesis. J. Endocrinol. 156, R1–R7 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Camper-Kirby, D. et al. Myocardial Akt activation and gender: increased nuclear activity in females versus males. Circ. Res. 88, 1020–1027 (2001). Describes sex-specific signalling in human myocardium.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    de Jager, T. et al. Mechanisms of estrogen receptor action in the myocardium. Rapid gene activation via the ERK1/2 pathway and serum response elements. J. Biol. Chem. 276, 27873–27880 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Schroeder, C. et al. Phenotypical evidence for a gender difference in cardiac norepinephrine transporter function. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R851–R856 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Nickenig, G. et al. Differential effects of estrogen and progesterone on AT(1) receptor gene expression in vascular smooth muscle cells. Circulation 102, 1828–1833 (2000).

    CAS  Google Scholar 

  81. 81

    Khalil, R. A. Sex hormones as potential modulators of vascular function in hypertension. Hypertension 46, 249–254 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Wu, F. C. & von Eckardstein, A. Androgens and coronary artery disease. Endocr. Rev. 24, 183–217 (2003).

    CAS  Google Scholar 

  83. 83

    Marsh, J. D. et al. Androgen receptors mediate hypertrophy in cardiac myocytes. Circulation 98, 256–261 (1998).

    CAS  Google Scholar 

  84. 84

    Rossouw, J. E. et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288, 321–333 (2002).

    CAS  Google Scholar 

  85. 85

    Anderson, G. L. et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 291, 1701–1712 (2004).

    CAS  Google Scholar 

  86. 86

    Jochmann, N., Stangl, K., Garbe, E., Baumann, G. & Stangl, V. Female-specific aspects in the pharmacotherapy of chronic cardiovascular diseases. Eur. Heart J. 26, 1585–1595 (2005).

    CAS  Google Scholar 

  87. 87

    Anderson, G. D. Sex and racial differences in pharmacological response: where is the evidence? Pharmacogenetics, pharmacokinetics, and pharmacodynamics. J. Womens Health (Larchmt) 14, 19–29 (2005).

    Google Scholar 

  88. 88

    Rathore, S. S., Wang, Y. & Krumholz, H. M. Sex-based differences in the effect of digoxin for the treatment of heart failure. N. Engl. J. Med. 347, 1403–1411 (2002). Retrospective sex-specific analysis of the previously published (1997) 'Dig' study that shows gender differences in digitalis effects for the first time.

    CAS  Google Scholar 

  89. 89

    Rathore, S. S., Curtis, J. P., Wang, Y., Bristow, M. R. & Krumholz, H. M. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 289, 871–878 (2003).

    CAS  Google Scholar 

  90. 90

    Luzier, A. B. et al. Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin. Pharmacol. Ther. 66, 594–601 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    The MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 353, 2001–2007 (1999).

  92. 92

    Packer, M. et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U. S. Carvedilol Heart Failure Study Group. N. Engl. J. Med. 334, 1349–1355 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Simon, T., Mary-Krause, M., Funck-Brentano, C. & Jaillon, P. Sex differences in the prognosis of congestive heart failure: results from the Cardiac Insufficiency Bisoprolol Study (CIBIS II). Circulation 103, 375–380 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    CIBISII1999. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 353, 9–13 (1999).

  95. 95

    Ghali, J. K., Pina, I. L., Gottlieb, S. S., Deedwania, P. C. & Wikstrand, J. C. Metoprolol CR/XL in female patients with heart failure: analysis of the experience in Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF). Circulation 105, 1585–1591 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Garg, R. & Yusuf, S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA 273, 1450–1456 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Wing, L. M. et al. A comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for hypertension in the elderly. N. Engl. J. Med. 348, 583–592 (2003). Shows lack of ACEI effects in older women.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Mackay, F. J., Pearce, G. L. & Mann, R. D. Cough and angiotensin II receptor antagonists: cause or confounding? Br. J. Clin. Pharmacol. 47, 111–114 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Woosley, R. L., Chen, Y., Freiman, J. P. & Gillis, R. A. Mechanism of the cardiotoxic actions of terfenadine. JAMA 269, 1532–1536 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Drici, M. D., Knollmann, B. C., Wang, W. X. & Woosley, R. L. Cardiac actions of erythromycin: influence of female sex. JAMA 280, 1774–1776 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Lehmann, M. H., Hardy, S., Archibald, D., quart, B. & MacNeil, D. J. Sex difference in risk of torsade de pointes with d, l-sotalol. Circulation 94, 2535–2541 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Drici, M. D. & Clement, N. Is gender a risk factor for adverse drug reactions? The example of drug-induced long QT syndrome. Drug Saf. 24, 575–585 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Anthony, M. Male/female differences in pharmacology: safety issues with QT-prolonging drugs. J. Womens Health (Larchmt) 14, 47–52 (2005).

    Google Scholar 

  104. 104

    Waldo, A. L. et al. Effect of D-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral D-Sotalol. Lancet 348, 7–12 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Ridker, P. M. et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N. Engl. J. Med. 352, 1293–1304 (2005). Addresses primary prevention of myocardial infarction and stroke by aspirin in women.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Martin, R. M., Biswas, P. N., Freemantle, S. N., Pearce, G. L. & Mann, R. D. Age and sex distribution of suspected adverse drug reactions to newly marketed drugs in general practice in England: analysis of 48 cohort studies. Br. J. Clin. Pharmacol. 46, 505–511 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Gandhi, M., Aweeka, F., Greenblatt, R. M. & Blaschke, T. F. Sex differences in pharmacokinetics and pharmacodynamics. Annu. Rev. Pharmacol. Toxicol. 44, 499–523 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Meibohm, B., Beierle, I. & Derendorf, H. How important are gender differences in pharmacokinetics? Clin. Pharmacokinet. 41, 329–342 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Schwartz, J. B. The influence of sex on pharmacokinetics. Clin. Pharmacokinet. 42, 107–121 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Jamshidi, Y. et al. Peroxisome proliferator — activated receptor α gene regulates left ventricular growth in response to exercise and hypertension. Circulation 105, 950–955 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Cheurfa, N. et al. The Gly482Ser polymorphism in the peroxisome proliferator-activated receptor-γ coactivator-1 gene is associated with hypertension in type 2 diabetic men. Diabetologia 47, 1980–1983 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Valve, R. et al. Two polymorphisms in the peroxisome proliferator-activated receptor-γ gene are associated with severe overweight among obese women. J. Clin. Endocrinol. Metab. 84, 3708–3712 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Simon, I. et al. Pro12Ala substitution in the peroxisome proliferator-activated receptor-γ is associated with increased leptin levels in women with type-2 diabetes mellitus. Horm. Res. 58, 143–149 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Djouadi, F. et al. A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator- activated receptor α-deficient mice. J. Clin. Invest. 102, 1083–1091 (1998). Documents that genetic defects in lipid metabolism can affect myocardial hypertrophy in a gender-related manner.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Nohammer, C. et al. Myocardial dysfunction and male mortality in peroxisome proliferator-activated receptor α knockout mice overexpressing lipoprotein lipase in muscle. Lab. Invest. 83, 259–269 (2003).

    PubMed  PubMed Central  Google Scholar 

  116. 116

    Huss, J. M. & Kelly, D. P. Nuclear receptor signaling and cardiac energetics. Circ. Res. 95, 568–578 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Seto-Young, D. et al. Direct thiazolidinedione action in the human ovary: insulin-independent and insulin-sensitizing effects on steroidogenesis and insulin-like growth factor binding protein-1 (IGFBP-1) production. J. Clin. Endocrinol. Metab. 90, 6099–6105 (2005).

    CAS  Google Scholar 

  118. 118

    Fujita, Y. et al. Sex differences in the pharmacokinetics of pioglitazone in rats. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 136, 85–94 (2003).

    Google Scholar 

  119. 119

    Emoto, M. et al. Troglitazone treatment increases plasma vascular endothelial growth factor in diabetic patients and its mRNA in 3T3-L1 adipocytes. Diabetes 50, 1166–1170 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Dormandy, J. A. et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366, 1279–1289 (2005).

    CAS  Google Scholar 

  121. 121

    van Suylen, R. J. et al. The DD genotype of the angiotensin converting enzyme gene is negatively associated with right ventricular hypertrophy in male patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 159, 1791–1795 (1999).

    CAS  Google Scholar 

  122. 122

    Wittrup, H. H. et al. A common substitution (Asn291Ser) in lipoprotein lipase is associated with increased risk of ischemic heart disease. J. Clin. Invest. 99, 1606–1613 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Linnebank, M., Fliessbach, K., Kolsch, H., Rietschel, M. & Wullner, U. The methionine synthase polymorphism c. 2756A→ G (D919G) is relevant for disease-free longevity. Int. J. Mol. Med. 16, 759–761 (2005).

    CAS  Google Scholar 

  124. 124

    Reiner, A. P. et al. Common promoter polymorphisms of inflammation and thrombosis genes and longevity in older adults: the cardiovascular health study. Atherosclerosis 181, 175–183 (2005).

    CAS  Google Scholar 

  125. 125

    Muller-Thomsen, T. et al. Depression in Alzheimer's disease might be associated with apolipoprotein Eε4 allele frequency in women but not in men. Dement. Geriatr. Cogn. Disord. 14, 59–63 (2002).

    Google Scholar 

  126. 126

    Kokubo, Y. et al. Association analysis between hypertension and CYBA, CLCNKB, and KCNMB1 functional polymorphisms in the Japanese population — the Suita Study. Circ. J. 69, 138–142 (2005).

    CAS  Google Scholar 

  127. 127

    Carrel, L. & Willard, H. F. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434, 400–404 (2005). Reports that 15% of X-linked genes escape inactivation to some degree, which suggests an unsuspected degree of gene-expression heterogeneity among females.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Deinum, J., van Gool, J. M., Kofflard, M. J., ten Cate, F. J. & Danser, A. H. Angiotensin II type 2 receptors and cardiac hypertrophy in women with hypertrophic cardiomyopathy. Hypertension 38, 1278–1281 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Okumura, M. et al. Sex difference in vascular injury and the vasoprotective effect of valsartan are related to differential AT2 receptor expression. Hypertension 46, 577–583 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Leinwand, L. A. Sex is a potent modifier of the cardio-vascular system. J. Clin. Invest. 112, 302–307 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Du, X. J. Gender modulates cardiac phenotype development in genetically modified mice. Cardiovasc. Res. 63, 510–519 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Xin, H. B. et al. Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy. Nature 416, 334–338 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Corsetti, J. P., Sparks, J. D., Peterson, R. G., Smith, R. L. & Sparks, C. E. Effect of dietary fat on the development of non-insulin dependent diabetes mellitus in obese Zucker diabetic fatty male and female rats. Atherosclerosis 148, 231–241 (2000).

    CAS  Google Scholar 

  134. 134

    Stauffer, B. L., Konhilas, J. P., Luczak, E. D. & Leinwand, L. A. Soy diet worsens heart disease in mice. J. Clin. Invest. 116, 209–216 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Boudikova, B., Szumlanski, C., Maidak, B. & Weinshilboum, R. Human liver catechol-O-methyltransferase pharmacogenetics. Clin. Pharmacol. Ther. 48, 381–389 (1990).

    CAS  Google Scholar 

  136. 136

    Wang, Y. R., Yen, C. H., Sun, Y. F. & Laun, Y. T. Gender-dependent response in blood pressure changes following the inhibition of nitric oxide synthase. Chin. J. Physiol. 46, 91–94 (2003).

    Google Scholar 

  137. 137

    Jayachandran, M. et al. Sex-specific changes in platelet aggregation and secretion with sexual maturity in pigs. J. Appl. Physiol. 97, 1445–1452 (2004).

    CAS  Google Scholar 

  138. 138

    Khetawat, G. et al. Human megakaryocytes and platelets contain the estrogen receptor β and androgen receptor (AR): testosterone regulates AR expression. Blood 95, 2289–2296 (2000).

    CAS  Google Scholar 

  139. 139

    Braunstein, J. B. et al. Interaction of hemostatic genetics with hormone therapy: new insights to explain arterial thrombosis in postmenopausal women. Chest 121, 906–920 (2002).

    PubMed  PubMed Central  Google Scholar 

  140. 140

    Patrono, C., Coller, B., FitzGerald, G. A., Hirsh, J. & Roth, G. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126, 234S–264S (2004).

    CAS  Google Scholar 

  141. 141

    Herrington, D. M. et al. Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N. Engl. J. Med. 346, 967–974 (2002).

    CAS  Google Scholar 

  142. 142

    Schwartz, J. B. Gender-specific implications for cardiovascular medication use in the elderly optimizing therapy for older women. Cardiol. Rev. 11, 275–298 (2003).

    PubMed  PubMed Central  Google Scholar 

  143. 143

    Benton, R. E., Sale, M., Flockhart, D. A. & Woosley, R. L. Greater quinidine-induced QTc interval prolongation in women. Clin. Pharmacol. Ther. 67, 413–418 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Brower, G. L., Gardner, J. D. & Janicki, J. S. Gender mediated cardiac protection from adverse ventricular remodeling is abolished by ovariectomy. Mol. Cell. Biochem. 251, 89–95 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Brown, D. A. et al. Susceptibility of the heart to ischaemia-reperfusion injury and exercise-induced cardioprotection are sex-dependent in the rat. J. Physiol. 564, 619–630 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Litwin, S. E., Katz, S. E., Litwin, C. M., Morgan, J. P. & Douglas, P. S. Gender differences in postinfarction left ventricular remodeling. Cardiology 91, 173–183 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Tatchum-Talom, R., Eyster, K. M. & Martin, D. S. Sexual dimorphism in angiotensin II-induced hypertension and vascular alterations. Can. J. Physiol. Pharmacol. 83, 413–422 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Fortepiani, L. A. & Reckelhoff, J. F. Role of oxidative stress in the sex differences in blood pressure in spontaneously hypertensive rats. J. Hypertens. 23, 801–805 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Maris, M. E., Melchert, R. B., Joseph, J. & Kennedy, R. H. Gender differences in blood pressure and heart rate in spontaneously hypertensive and Wistar-Kyoto rats. Clin. Exp. Pharmacol. Physiol. 32, 35–39 (2005).

    PubMed  PubMed Central  Google Scholar 

  150. 150

    Graham, D., Hamilton, C., Beattie, E., Spiers, A. & Dominiczak, A. F. Comparison of the effects of omapatrilat and irbesartan/hydrochlorothiazide on endothelial function and cardiac hypertrophy in the stroke-prone spontaneously hypertensive rat: sex differences. J. Hypertens. 22, 329–337 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Hennes, M. M., McCune, S. A., Shrago, E. & Kissebah, A. H. Synergistic effects of male sex and obesity on hepatic insulin dynamics in SHR/Mcc-cp rat. Diabetes 39, 789–795 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Rodrigues, B. & McNeill, J. H. Comparison of cardiac function in male and female diabetic rats. Gen. Pharmacol. 18, 421–423 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Konhilas, J. P. et al. Sex modifies exercise and cardiac adaptation in mice. Am. J. Physiol. Heart Circ. Physiol. 287, H2768–H2776 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I thank S. Brokat for help with Figure 1, S. Eder and S. Mahmoodzadeh for Figure 2, E. Lehmkuhl for literature research and evaluation and A. M. Gale, Editor in the Life Sciences, for editorial assistance. My warm thanks go to M. Prescott, Novartis, New Jersey, USA, for many fruitful discussions and suggestions and to E. Zagrosek for very helpful thoughts. The support of the Deutsche Forschungsgemeinschaft, the BMBF (Competence Network Heart Failure) and the Centre for Gender in Medicine (GiM) in Berlin, Germany, is gratefully acknowledged. I also would like to acknowledge the work of many authors whose original work, due to space restrictions, could not be referenced and had to be quoted as being discussed in earlier reviews.

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DATABASES

OMIM

Type 2 diabetes

Glossary

QT interval

The QT interval represents the time for electrical activation and inactivation of the ventricles, the pumping chambers of the heart. Prolongation of the QT interval can result in potentially lethal arrhythmias (some of which are known as torsades de pointes).

Angina

A narrowing of the coronary arteries, frequently as a result of arteriosclerosis, that leads to the chest pains known as angina pectoris.

Echocardiography

The use of ultrasound to image structural and functional abnormalities of the heart.

Cardiac catheterization

A procedure in which a catheter is introduced into the heart and contrast material is injected to visualize the right and left ventricles, as well as the coronary arteries.

Myocardial hypertrophy

Physiological (pregnancy, training) or pathological growth of the myocardium. Pathological myocardial hypertrophy is a major risk factor for heart failure.

Diastolic heart failure

A condition in which the heart contracts normally, but the ventricle does not distend correctly and so filling of the heart is impaired.

Systolic heart failure

A condition in which inadequate contraction of the heart leads to reduced cardiac output.

Autosomal dominant

A mode of inheritance that requires that the mutation of a single gene be present on either of the paternally and maternally derived alleles for the clinical phenotype to be expressed.

Population-attributable risk

The percentage of risk that can be attributed to a given risk factor in a population.

Android obesity

Obesity typically seen in males, which is characterized by visceral fat accumulation.

Hyponatraemia

A deficiency of sodium in the blood.

Hypokalaemia

A deficiency of potassium in the blood.

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Regitz-Zagrosek, V. Therapeutic implications of the gender-specific aspects of cardiovascular disease. Nat Rev Drug Discov 5, 425–439 (2006). https://doi.org/10.1038/nrd2032

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