Therapeutic implications of the gender-specific aspects of cardiovascular disease

Nature Reviews Drug Discovery

Volumn 5, Issue 5, 2006, Pages 425-439

  Regitz Zagrosek, Vera ^a  

^a CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLSALICYLIC ACID; AMIODARONE; ANDROGEN; ANGIOTENSIN; ANTIARRHYTHMIC AGENT; ANTICOAGULANT AGENT; BEPRIDIL; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; CALCIUM; DIGITALIS; DIGOXIN; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; DISOPYRAMIDE; DIURETIC AGENT; ERYTHROMYCIN; ESTROGEN; FIBRINOLYTIC AGENT; GESTAGEN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; METOPROLOL; MITOGEN ACTIVATED PROTEIN KINASE; NITRIC OXIDE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PHOSPHATIDYLINOSITOL 3 KINASE; POTASSIUM; PROTEIN KINASE B; QUINIDINE; RENIN; SOTALOL; UNINDEXED DRUG;

ANGIOCARDIOGRAPHY; AWARENESS; BLEEDING; BODY WEIGHT DISORDER; CARDIOVASCULAR DISEASE; CLINICAL FEATURE; CLINICAL TRIAL; CORONARY ARTERY DISEASE; COUGHING; DEPRESSION; DIABETES MELLITUS; DRUG BLOOD LEVEL; DRUG METABOLISM; DRUG RESEARCH; DRUG RESPONSE; ECHOCARDIOGRAPHY; ELECTROCARDIOGRAPHY; ELECTROLYTE DISTURBANCE; FREQUENCY ANALYSIS; HEART ARRHYTHMIA; HEART FAILURE; HEART INFARCTION; HEART VENTRICLE HYPERTROPHY; HUMAN; HYPERTENSION; MEDICAL DECISION MAKING; MOLECULAR MECHANICS; MORTALITY; OBESITY; OUTCOMES RESEARCH; PATHOPHYSIOLOGY; PERCUTANEOUS CORONARY INTERVENTION; PREVALENCE; PRIORITY JOURNAL; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; RESTENOSIS; REVIEW; RISK FACTOR; SENSITIVITY AND SPECIFICITY; SEX DIFFERENCE; SOCIAL PSYCHOLOGY; TACHYCARDIA; X CHROMOSOME;

ANIMALS; CARDIOVASCULAR AGENTS; CARDIOVASCULAR DISEASES; DRUG EVALUATION, PRECLINICAL; FEMALE; HUMANS; MALE; SEX FACTORS;

EID: 33745197797     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd2032     Document Type: Review

References (153)

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).
2. Mendelsohn, M. E. & Karas, R. H. The protective effects of estrogen on the cardiovascular system. N. Engl. J. Med. 340, 1801-1811 (1999).
3. Reckelhoff, J. F. Gender differences in the regulation of blood pressure. Hypertension 37, 1199-1208 (2001).
4. Dubey, R. K., Oparil, S., Imthurn, B. & Jackson, E. K. Sex hormones and hypertension. Cardiovasc. Res 53, 688-708 (2002).
5. Regitz-Zagrosek, V., Lehmkuhl, E., Lehmkuhl, H. B. & Hetzer, R. Gender aspects in heart failure. Pathophysiology and medical therapy. Arch. Mal. Coeur. Vaiss. 97, 899-908 (2004).
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).
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).
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).
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).
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).
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).
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).
13. Hayes, S. N. & Taler, S. J. Hypertension in women: Current understanding of gender differences. Mayo Clin. Proc. 73, 157-165 (1998).
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).
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).
16. Albert, C. M., McGovern, B. A., Newell, J. B. & Ruskin, J. N. Sex differences in cardiac arrest survivors. Circulation 93, 1170-1176 (1996).
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).
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).
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).
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).
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).
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).
23. Maron, B. J. et al. Prevalence of hypertrophy 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).
24. Wittstein, I. S. et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N. Engl. J. Med. 352, 539-548 (2005).
25. Ueyama, T. Emotional stress-induced Tako-tsubo cardiomyopathy: Animal model and molecular mechanism. Ann. NY Acad. Sci. 1018, 437-444 (2004).
26. Carroll, J. D. et al. Sex-associated differences in left ventricular function in aortic stenosis of the elderly. Circulation 86, 1099-1107 (1992).
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).
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).
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).
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).
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).
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).
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).
34. Redberg, R. F. et al. Women's Ischemic Syndrome Evaluation: Current status and future research directions: Report of the National Heart, Lung Snd Blood Institute workshop: October 2-4, 2002: Section 2: stable ischemia: Pathophysiology and gender differences. Circulation 109, e47-49 (2004).
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).
36. Daly, C. et al. Gender differences in the management and clinical outcome of stable angina. Circulation 113, 490-498 (2006).
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).
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).
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).
40. Steinberg, H. O. et al. Type II diabetes abrogates sex differences in endothelial function in premenopausal women. Circulation 101, 2040-2046 (2000).
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).
42. Azziz, R. Polycystic ovary syndrome, insulin resistance, and molecular defects of insulin signaling. J. Clin. Endocrinol. Metab. 87, 4085-4087 (2002).
43. Solomon, C. G. et al. Menstrual cycle irregularity and risk for future cardiovascular disease. J. Clin. Endocrinol. Metab. 87, 2013-2017 (2002).
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).
45. Williams, C. M. Lipid metabolism in women. Proc. Nutr. Soc. 63, 153-160 (2004).
46. Wajchenberg, B. L. Subcutaneous and visceral adipose tissue: Their relation to the metabolic syndrome. Endocr. Rev. 21, 697-738 (2000).
47. Vaccarino, V. et al. Gender differences in recovery after coronary artery bypass surgery. J. Am. Coll. Cardiol. 41, 307-314 (2003).
48. Mallik, S. et al. Patients with depressive symptoms have lower health status benefits after coronary artery bypass surgery. Circulation 111, 271-277 (2005).
49. Mendelsohn, M. E. & Karas, R. H. Molecular and cellular basis of cardiovascular gender differences. Science 308, 1583-1587 (2005).
50. Nordmeyer, J. et al. Upregulation of myocardial estrogen receptors in human aortic stenosis. Circulation 110, 3270-3275 (2004).
51. Mahmoodzadeh, S. et al. Estrogen receptor α upregulation and redistribution in human heart failure. FASEB J. (in the press).
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).
53. Edwards, D. P. Regulation of signal transduction pathways by estrogen and progesterone. Annu. Rev. Physiol. 67, 335-376 (2005).
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).
55. Mendelsohn, M. E. Genomic and nongenomic effects of 4 estrogen in the vasculature. Am. J. Cardiol. 90, 3F-6F (2002).
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).
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).
58. Dubey R. K., Tofovic, S. P. & Jackson, E. K. Cardiovascular pharmacology of estradiol metabolites. J. Pharmacol. Exp. Ther. 308, 403-409 (2004).
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).
60. Ciana, P. et al. In vivo imaging of transcriptionally active estrogen receptors. Nature Med. 9, 82-86 (2003).
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).
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).
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).
64. van Eickels, M. et al. 17β-estradiol attenuates the development of pressure-overload hypertrophy. Circulation 104, 1419-1423 (2001).
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).
66. Shearman, A. M. et al. Association between estrogen receptor α gene variation and cardiovascular disease. JAMA 290, 2263-2270 (2003).
67. Herrington, D. M. & Howard, T. D. ER-α variants and the cardiovascular effects of hormone replacement therapy. Pharmacogenomics 4, 269-277 (2003).
68. Sudhir, K. & Komesaroff, P. A Clinical review 110: Cardiovascular actions of estrogens in men. J. Clin. Endocrinol. Metab. 84, 3411-3415 (1999).
69. Rubanyi, G. M., Kauser, K. & Johns, A. Role of estrogen receptors in the vascular system. Vascul. Pharmacol. 38, 81-88 (2002).
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).
71. Simoncini, T. et al. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407, 538-541 (2000).
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).
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).
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).
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).
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).
77. Camper-Kirby, D. et al. Myocardial Akt activation and gender: Increased nuclear activity in females versus males. Circ. Res. 88, 1020-1027 (2001).
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).
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).
80. Nickenig, G. et al. Differential effects of estrogen and progesterone on AT(1) receptor gene expression in vascular smooth muscle cells. Circulation 102, 1 828-1833 (2000).
81. Khalil, R. A. Sex hormones as potential modulators of vascular function in hypertension. Hypertension 46, 249-254 (2005).
82. Wu, F. C. & van Eckardstein, A. Androgens and coronary artery disease. Endocr. Rev. 24, 183-217 (2003).
83. Marsh, J. D. et al. Androgen receptors mediate hypertrophy in cardiac myocytes. Circulation 98, 256-261 (1998).
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).
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).
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).
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).
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).
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).
90. Luzier, A. B. et al. Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin. Pharmacol. Ther. 66, 594-601 (1999).
91. TheMERIT-HFStudyGroup. 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. 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).
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).
94. CIBISII1999. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial. Lancet 353, 9-13 (1999).
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).
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).
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).
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).
99. Woosley, R. L., Chen, Y., Freiman, J. P. & Gillis, R. A. Mechanism of the cardiotoxic actions of terfenadine. JAMA 269, 1532-1536 (1993).
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).
101. Lehmann, M. H., Hardy, S., Archibald, D., quart, B. & MacNeil, D. J. Sex difference in risk of torsade de pointes with d, I-sotalol. Circulation 94, 2535-2541 (1996).
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).
103. Anthony, M. Male/female differences in pharmacology: Safety issues with QT-prolonging drugs. J. Womens Health (Larchmt) 14, 47-52 (2005).
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).
105. Ridker, P. M. et al. A randomized trial of low-pose aspirin in the primary prevention of cardiovascular disease in women. N. Engl. J. Med. 352, 1293-1304 (2005).
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).
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).
108. Meibohm, B., Beierle, I. & Derendorf, H. How important are gender differences in pharmacokinetics? Clin. Pharmacokinet. 41, 329-342 (2002).
109. Schwartz, J. B. The influence of sex on pharmacokinetics. Clin. Pharmacokinet. 42, 107-121 (2003).
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).
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. Diabetologio 47, 1980-1983 (2004).
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).
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).
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).
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).
116. Huss, J. M. & Kelly D. P. Nuclear receptor signaling and cardiac energetics. Circ. Res. 95, 568-578 (2004).
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).
118. Fujita, V. et al. Sex differences in the pharmacokinetics of pioglitazone in rats. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 136, 85-94 (2003).
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).
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).
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).
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).
123. Linnebank, M., Fliessbach, K, Kolsch, H., Rietschel, M. & Wullner, U. The methionine synthase polymorphism c. 2756A→ G (D919C) is relevant for disease-free longevity. Int. J. Mol. Med. 16, 759-761 (2005).
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).
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).
126. Kokubo, Y. et al. Association analysis between hypertension and CYBA, CLCNKB, and KCNMB 1 functional polymorphisms in the Japanese population - the Suita Study. Circ. J. 69, 138-142 (2005).
127. Carrel, L. & Willard, H. F. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434, 400-404 (2005).
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 hypertrophy cardiomyopathy. Hypertension 38, 1278-1281 (2001).
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).
130. Leinwand, L. A. Sex is a potent modifier of the cardiovascular system. J. Clin. Invest. 112, 302-307 (2003).
131. Du, X. J. Gender modulates cardiac phenotype development in genetically modified mice. Cardiovasc. Res. 63, 510-519 (2004).
132. Xin, H. B. et al. Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy. Nature 416, 334-338 (2002).
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).
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).
135. Boudikova, B., Szumlanski, C., Maidak, B. & Weinshilboum, R. Human liver catechol-O-methyltransferase pharmacokenetics. Clin. Pharmacol. Ther. 48, 381-389 (1990).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
149. Maris, M. E., Melchert, R. S., 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).
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).
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).
152. Rodrigues, B. & McNeill, J. H. Comparison of cardiac function in male and female diabetic rats. Gen. Pharmacol. 18, 421-423 (1987).
153. Konhilas, J. P. et al. Sex modifies exercise and cardiac adaptation in mice. Am. J. Physiol. Heart Circ. Physiol. 287, H2768-H2776 (2004).