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Terapia Sostitutiva e Rischio Cardiovascolare

Terapia Sostitutiva e Rischio Cardiovascolare. Giuseppe M.C. Rosano Dipartimento di Scienze Internistiche Centro di Ricerca Clinica e Sperimentale IRCCS San Raffaele - Roma. Heart rate and life expectancy. Age (years). Heart rate (min -1 ). 140. 1000. Development of life expectancy.

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Terapia Sostitutiva e Rischio Cardiovascolare

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  1. Terapia Sostitutiva e Rischio Cardiovascolare Giuseppe M.C. Rosano Dipartimento di Scienze Internistiche Centro di Ricerca Clinica e Sperimentale IRCCS San Raffaele - Roma

  2. Heart rate and life expectancy Age (years) Heart rate (min-1) 140 1000 Development of life expectancy 600 120 Mouse Hamster Rat 100 300 Monkey Marmot 80 Cat Dog 100 Giraffe 60 Tiger humans 50 Ass Horse Lion 40 Elephant Whale 20 20 Whale 0 20 40 60 80 1000 1200 1400 1600 1800 2000 2200 Year Life expectancy (years) Levine HJ. J Am Coll Cardiol. 1997;30:1104-1106.

  3. Sex Hormones and Atherosclerosis

  4. 1850 1900 1950 2000 2050* Life Expectancy andAge at Menopause Age (years) Age at menopause Date *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at:http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02.US Department of Health and Human Services. Healthy People 2010. Washington DC: January 2000.

  5. Heart Disease* Lung Cancer† Breast Cancer† Colon & Rectal Cancer† Stroke* Endometrial Cancer† 45-54 55-64 65-74 75-84 85 Mortality Rates in Women 6000 5600 Mortality Rate per 100,000 Age (years) *Mean of years 1995-1998; †1994-1998. Eberhardt VMS, et al. Health,United States, 2001. National Center for Health Statistics, 2001:189,192.Ries LAG, et al. SEER Cancer Statistics Review, 1973-1998. National Cancer Institute, 2001.

  6. Annual Incidence of Cardiovascular Disease According to Menopausal Status years From the Framingham Study, 1974;74:599

  7. Systemic Lipid HDL-C LDL-C Lp(a) Triglycerides Nonlipid Coagulation factors Carbohydrate metabolism Inflammation Homocysteine Direct Short-Term/Rapid Vasodilation Nitric oxide availability HDL oxidation Long-Term* Atherosclerosis Vascular injury response Endothelial and smooth muscle cell growth Elastin/collagen production Major Systemic and Direct Effects of Estrogens *Data based on animal studies. HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein(a).

  8. Lipid Differences in Women With CAD Compared to Controls* % Difference compared to controls *controls = women without CAD Eriksson et al. Arterioscler Thromb Vasc Biol. 1999;19:67.

  9. Different HRT Regimens and Plasma Lipids Hänggi W, et al. Br J Obstet Gynecol. 1997;104:708-17.

  10. Age, Estrogens, and Vascular Reactivity The Action of Mammalian Sex Hormones in a Mouse Model Percent Relaxation of Aortic Rings to Estrogen Modified from Williams JK, et al. Menopausal Med. 2002;10:16-9.

  11. Effect of ERT on Coronary Atherosclerosis in Monkeys: Timing of Initiation Premenopausal Years Postmenopausal Years Plaque Area (% of Placebo) Ovariectomy 70%1,2 1. Healthy diet CEE + atherogenic diet 2. 50%3 Atherogenic diet CEE + atherogenic diet Atherogenic diet Healthy diet+ CEE 3. 0%4 Healthy diet ~ 6 Year Human Equivalent Time 1Clarkson TB, et al. J Clin Endocrinol Metab. 1998;83:721-6; 2Adams MR, et al. Arterioscler Thromb Vasc Biol. 1997;17:217-21; 3Clarkson TB, et al. J Clin Endocrinol Metab. 2001;86:41-47; 4Williams JK, et al. Arterioscler Thromb Vas Biol. 1995;15:827-36.

  12. -0.02 -0.07 -0.12 -0.17 -0.22 -0.093 -0.118 -0.094 Progression Change in Min. Diam. (mm) p=0.38 p=0.97 Estrogen E+P Placebo Herrington et al. NEJM 343:522; 2000 ERT/HRT and Progression of Atherosclerosis 222 pts mean age 62.2 yrs Hodis H et al Ann Int Med 2001; 135: 939-953

  13. Aging and Methylation of Estrogen Receptors Post W. et al Am J Cardiol 2001

  14. 110 * * * * * * R=0.23, p=0.52 * * * * * * * * * * * * * 90 * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * % Change in FMD 70 * 50 30 0 5 10 15 20 25 Time since menopause (years) Aging and Vascular Response to HRT R= - 0.56, p<0.05 R= - 0.56, p<0.05 * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * Vitale et al. et al JACC 2003

  15. CRP, Inflammatory Markers and Endothelial Function with Oral HRT 56+6 yrs 64+7 yrs Vitale C, Mercuro G et al et al Menopause 2005

  16. 0 0.5 1.0 2.0 10 Summary of Observational Studies of ERT/HRT and CVD Stampfer et al, 1985 Wilson et al, 1985 Bush et al, 1987 Petitti et al, 1987 Boysen et al, 1998 Criqui et al, 1988 Henderson et al, 1988 van der Giezen et al, 1990 Wolfe et al, 1991 Falkeborn et al, 1992 Psaty et al, 1994 Folsom et al, 1995 Relative Risk

  17. Outcome • HRT • n (%)* • Placebo • n (%)* • Hazard Ratio • Nominal 95% CI • Adjusted 95% CI • CHD • 164 (0.37) • 122 (0.30) • 1.29 • 1.02-1.63 • 0.85-1.97 • CHD death • 33 (0.07) • 26 (0.06) • 1.18 • 0.70-1.97 • 0.47-2.98 • Nonfatal MI • 133 (0.30) • 96 (0.23) • 1.32 • 1.02-1.72 • 0.82-2.13 • CABG/PTCA • 183 (0.42) • 171 (0.41) • 1.04 • 0.84-1.28 • 0.71-1.51 • Stroke • 127 (0.29) • 85 (0.21) • 1.41 • 1.07-1.85 • 0.86-2.31 • Fatal • 16 (0.04) • 13 (0.03) • 1.20 • 0.58-2.50 • 0.32-4.49 • Nonfatal • 94 (0.21) • 59 (0.14) • 1.50 • 1.08-2.08 • 0.83-2.70 • VTE disease • Deep vein thrombosis • Pulmonary embolism • Total CVD • 151 (0.34) • 115 (0.26) • 70 (0.16) • 694 (1.57) • 67 (0.16) • 52 (0.13) • 31 (0.08) • 546 (1.32) • 2.11 • 2.07 • 2.13 • 1.22 • 1.58-2.82 • 1.49-2.87 • 1.39-3.25 • 1.09-1.36 • 1.26-3.55 • 1.14-3.74 • 0.99-4.56 • 1.00-1.49 WHI Results: CVD Outcomes *n = number of patients; (%) = annualized % calculated from average exposure over 60 months. Nominal = variability based on simple trial for single outcome; adjusted = corrects variability for multiple analyses over time. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.

  18. POPULATION CHARACTERISTICS

  19. Icarus Study POPULATION CHARACTERISTICS

  20. Women’s HOPE Study and the Menopause Study Group Trial • Two (2) large prospective clinical trials of 4,397 patients revealed only one single CHD event in a placebo subject

  21. Women’s Health Initiative (WHI)first primary prevention RCT in predominantly healthy women • ……………..Prevalence of prior CVD was low and levels of cardiovascular risk factors were consistent with a generally healthy population of postmenopausal women. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.

  22. Estrogen plus Progestin and the Risk of Coronary Heart Disease n engl j med 349;6 www.nejm.org august 7,2003

  23. Hypertension: Prevalence by Age and Sex

  24. CHD Mortality by Gender and Blood Pressure

  25. Receptor level Effect of Progestins on the Renin-Angiotensin-Aldosterone System (RAAS) Estrogens Angiotensinogen Angiotensin I Angiotensin II Adrenal gland Aldosterone + Progestins Sodium- and water retention Drospirenone - Increased plasma volume - Rise of blood pressure in susceptibles - Water retention-related symptoms (edema, bloating, weight gain) Progesterone

  26. 0 0.5 1.0 2.0 10 Summary of Observational Studies of ERT/HRT and CVD Stampfer et al, 1985 Wilson et al, 1985 Bush et al, 1987 Petitti et al, 1987 Boysen et al, 1998 Criqui et al, 1988 Henderson et al, 1988 van der Giezen et al, 1990 Wolfe et al, 1991 Falkeborn et al, 1992 Psaty et al, 1994 Folsom et al, 1995 Relative Risk

  27. WHI: Effect of CEE with and without MPA on Risk of CHD Hazard ratio for CHD Manson JE, et al. N Engl J Med. 2003;349:523-34.

  28. J GEN INTERN MED 2004;19:791–804

  29. Short-term Symptoms Long-term Diseases Long-term Diseases Development of subclinical disease Estrogen Secretion Hot flushes Hot flushes Mood, sleep, and/or acute cognitive changes Night sweats, sleep disturbances, and mood changes Urogenital symptoms Urogenital symptoms Cardiovascular disease Cardiovascular disease Osteoporosis (Osteopenia) Osteoporosis Cognitive decline (Alzheimer’s disease) Cognitive decline 40 45 50 55 60 65 70 75 Age (years) Estrogen Loss and Manifestations of Health Risks Over Time HRT 40 45 50 55 60 65 70 75 >80 Age (years)

  30. Conclusion • Menopause is associated with an increased cardiovascular risk because of the unfavourable changes of ovarian deficiency on CV risk factors. • Estrogens improve the cardiovascular risk profile of menopausal women but the beneficial effect of estrogens are often abolished by concurrent progestin administration. • Hormone replacement therapy if started early in postmenopause may improve cardiovasclar risk and reduce events. The choice of progestins to use in HRT schemes is crucial in order to maximise the beneficial cardiovascular effects of ERT

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