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Cardiovascular diseases

Cardiovascular diseases. John C. Stevenson. Risk factors for coronary heart disease (CHD). Genetic Family history Ethnic origin Metabolic Diabetes mellitus Hypertension Obesity Lifestyle Diet Exercise Smoking Socioeconomic status Menopause status.

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Cardiovascular diseases

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  1. Cardiovascular diseases John C. Stevenson

  2. Risk factors forcoronary heart disease (CHD) • Genetic • Family history • Ethnic origin • Metabolic • Diabetes mellitus • Hypertension • Obesity • Lifestyle • Diet • Exercise • Smoking • Socioeconomic status • Menopause status

  3. Prevalence of coronary vascular disease (CVD) and some risk factorsUSA females 2004 www.americanheart.org

  4. CVD and menopausal status Adapted from the Framingham Study, DHEW No 74, 1974

  5. CVD risk factors • Lipids and lipoproteins • Glucose and insulin metabolism • Body fat distribution • Coagulation and fibrinolysis • Homocysteine • Inflammatory markers • Blood pressure • Arterial function

  6. Metabolic syndrome Central obesity Impaired GT Dyslipidemia Insulin resistance Hypertension Coagulation CHD

  7. CHD: metabolic changes • Lower HDL and HDL2 • Lower apolipoprotein AI • Higher triglycerides • Higher insulin response • Lower insulin sensitivity • Lower tissue plasminogen activator (tPA) • Higher PAI-1 • Higher systolic blood pressure • Greater android fat Ley et al. J Am Coll Cardiol 1994;23:377–83

  8. Lipoproteins and CHD • Increased total cholesterol • Increased LDL cholesterol • Decreased HDL and HDL2 cholesterol • Increased triglycerides • Increased lipoprotein(a) • Increased small dense LDL cholesterol • Decreased postprandial lipid clearance • Increased LDL oxidation

  9. Menopause and lipids Cholesterol Triglycerides LDL Apo B HDL HDL2 HDL3 Apo AI Lipoprotein(a) Stevenson et al. Atherosclerosis 1993;98:83–90

  10. Glucose/insulin and CHD • Impaired glucose tolerance • Hyperinsulinemia • Increased insulin response to glucose • Increased insulin resistance • Increased uric acid

  11. Insulin metabolism Incremental pancreatic Insulin secretion Insulin half-life * * Menopause Menopause *p < 0.001 Walton, et al. Eur J Clin Invest 1993;23:466–73

  12. Insulin metabolism Insulin sensitivity Glucose Insulin C-peptide r = 0.20 r = 0.49 r = 0.28 Menopausal age ns p < 0.05 ns Chronological age ns ns ns Body mass index ns p < 0.001 ns IVGTT incremental areas Walton, et al. Eur J Clin Invest 1993;23:466–73; Proudler, et al. Clin Sci 1992;83:489–94

  13. Menopause and diabetes 120 100 80 60 40 20 0 Premenopause Postmenopause Number of women newly diagnosed with diabetes -10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 16 Years from menopause Seige K, et al. 6th Symposium of the German Endocrinological Society: Modern Developments in Progestagenic Hormones in Veterinary Medicine; 1959, 1960; Kiel: Springer Verlag; 1959. p. 274–9

  14. Body composition * * Menopause Menopause *p < 0.001 Ley, et al. Am J Clin Nutr 1992;55:950–54

  15. Menopause and hemostasis • Increased fibrinogen • Increased factor VII • Increased plasminogen activator inhibitor-1 (PAI-1) • Increased antithrombin • ? Increased protein C • Increased tissue plasminogen activator (tPA) Bonithon-Kopp, et al. Int J Epidemiol 1990;19:42–8; Heinrich, et al. Clin Chem 1991;37:1950–4

  16. Endothelial function Flow-mediated dilatation (FMD) * Menopausal *p < 0.01 Arrowood, et al. Circulation 2000;A514

  17. CHD assessments • Ischemia • Exercise ECG • Stress thallium scan • Imaging • Coronary angiography • Multi-slice CT scanning • MRI scanning • Ultrasound IMT • Risk factors • Fasting lipids/lipoproteins • Fasting glucose/insulin • C-reactive protein • Homocysteine

  18. CHD prevention • Lipid-lowering drugs • Antihypertensives • Weight reduction • Physical activity • Smoking cessation • ? HRT

  19. HRT and CHD • Lipids and lipoproteins • Glucose and insulin metabolism • Body fat distribution • Coagulation and fibrinolysis • Homocysteine • Inflammatory markers • Blood pressure • Arterial function

  20. Epidemiology: CHD and HRT Hospital case-control Population case-control Prospective internal control Cross-sectional Prospective external control All studies combined Prospective internal control and cross-sectional 0 0.5 1 1.5 2 RR Stampfer and Grodstein. Raven Press, 1994

  21. HRT is beneficial to CVS Primary prevention Secondary prevention Women start HRT around menopause Studies are not randomized Healthy user bias (applies to other outcomes, e.g. osteoporosis) Data can be adjusted for potential biases HRT is not beneficial to CVS Primary prevention Secondary prevention Women start HRT at later ages Problem lies with HRT Dose and type of estrogen Dose and type of progestogen Harm is due to increased thrombogenesis Harm is due to adverse vascular remodelling HRT and CHD Observational studies Randomized trials

  22. Postmenopausal hormone use and CHDNurses Health Study 1976-2000Timing of hormone initiation with respect to age Excluding postmenopausal women with prevalent CHD RR (95% CI) 50–59 years 60+ years 0 0.2 0.4 0.6 0.6 1.0 1.2 1.2 Adjusted for age, body mass index, hypercholesterolemia, hypertension, parental coronary heart disease, diabetes, cigarette smoking, dietary data, husband’s education, alcohol intake, physical activity, vitamin E or multivitamin supplementation, aspirin use Adapted from Grodstein F, et al. J Women’s Health 2006;15:35–44

  23. Effect of HRT-ERT on CHD in PMWTiming of initiation, data from WHI < 10 10–19 > 20 0.56 0.92 1.04 CEE 0 0.5 1.0 1.5 2.0 2.5 Hazard ratio (95% CI) Hazard ratios Years since menopause 0.89 1.22 1.71 < 10 10–19 > 20 CEE + MPA 0 0.5 1.0 1.5 2.0 2.5 LEVEL 1 Hazard ratio (95% CI) IMS Position Statement, Climacteric 2004;7:333–7

  24. WHI: coronary events withET or placebo by age at baseline 50–59 60–69 70–79 Coronary event CHD (MI or coronary death) p = 0.07 p = 0.09 p = 0.09 p = 0.11 CABG or PCI MI, coronary death CABG, and PCI MI, coronary death CABG, PCI and confirmed angina 0 0.5 1 1.5 2 Hazard ratio (95% CI) Hsia J, et al. Arch Intern Med 2006;166:357–65

  25. WHI: coronary heart diseaseHRT and CHD: absolute risk by age 50–59 60–69 70–79 p-value for trend = 0.16 n = 27,347 Taken from Rossouw, et al. J Am Med Assoc 2007;297:1465–77

  26. WHI: HT and absolute risk of cardiovascular disease by years since menopause Years since menopause Hazard ratio CI Absolute excess risk (per 10,000 person-years) < 10 0.76 0.50–1.16 –6 10–19 1.10 0.84–1.45 4 > 20 1.28 1.03–1.58 17 p for trend = 0.02 Adapted from Rossouw, et al. J Am Med Assoc 2007;297:1465–77

  27. ERT and atheroma prevention I/M thickness • 222 healthy postmenopausal women • 17β-estradiol 1 mg daily vs. placebo • Study duration 2 years • Carotid artery intima-media thickness by ultrasound scan Progression Hodis, et al. Ann Intern Med 2001;135:939–53

  28. ERA study Progression p = NS Herrington DM, et al. N Engl J Med 2000

  29. HRT and CHD events • Increased CHD events in elderly women • ? Increased thrombogenesis/adverse remodelling • ? Estrogen dose too high MI / death CABG / PCI 50–59 years composite 70–79 years 0 1 2 HR Hsai, et al. Arch Intern Med 2006;166:357–65

  30. 800 800 600 600 400 400 200 200 0 0 Placebo Estradiol Placebo Estradiol Estradiol and myocardial ichemia Time to 1 mm ST depression Total exercise time ** * Time (sec) Time (sec) *p = 0.01; **p < 0.01 Rosano, et al. Lancet 1993;342:133–6

  31. CHD treatment • Anti-anginal drugs • Statins • Angioplasty + stenting • CABG • ? HRT

  32. HERS trial • 2763 women • Mean age 66.7 years • > 6 months from cardiac event • Conjugated equine estrogens 0.625 mg + MPA 2.5 mg • Event rate 3.3%(estimated 5%) • Mean follow-up 4.1 years (estimated 4.75 years) • No overall benefit seen CHD events Trend p = 0.009 Hulley, et al. J Am Med Assoc 1998;260:605–13

  33. HERS trial Hulley, et al. J Am Med Assoc 1998;260:605–13

  34. WHISP RH 0.68 (CI 0.32–1.46) • 100 postmenopausal women followed up to 12 months • Acute coronary syndrome (majority MI) • Randomized to placebo or HRT 2–28 days post-event • 17β-estradiol 1 mg/NETA 0.5 mg daily • Efficacy • Lipid parameters • (Clinical events) • Safety • Hemostatic parameters Collins, et al. Eur Heart J 2006;27:2046–53

  35. Timing of HRT interventionEffect of estrogens on atherogenesisin non-human primates 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 3. 0%4 Atherogenic diet Healthy diet+ CEE Healthy diet ~ 6-year human equivalent Time 1Clarkson, et al. J Clin Endocrinol Metab 1998;83:721; 2Adams, et al. Arterioscler Thromb Vase Biol 1997;17:217; 3Clarkson, et al. J Clin Endocrinol Metab 2001;86:41; 4Williams, et al. Arterioscler Thromb Vase Biol 1995;15:827

  36. The window of opportunity: hypothetical pathogenetic sequence

  37. Age distribution in WHI population and stage of atherosclerosis progression 0% 10% 20% 45% 25% < 50 yrs 50–54 yrs 55–59 yrs 60–69 yrs 70–79 yrs Endothelial dysfunction Foam Fatty Intermendiate Atheroma Fibrous Complicated cells streak lesion plaque lesion/rupture WHIMS HRTObs. StudiesClinical practice HT RCT 35–45 yrs 45–55 yrs 55–65yrs > 65 yrs Endothelial injury Lipid accumulation Inflammation Estrogens’ preventive action requires healthy tissue

  38. Conclusions: general • CVD is major cause of death in women • Similar risk factors for males and females • Menopause gives additional risk • Prevention and treatment similar for males and females • HRT potentially gives additional benefit

  39. Conclusions: HRT • Biological plausibility for beneficial CVD effects of HRT • Metabolic processes • Arterial function • Clinical studies • Benefit for myocardial ischemia • Benefit for atheroma prevention in healthy women • Population studies • Concordance of benefit in primary prevention • Event studies suggest benefit for secondary prevention • Randomized clinical trials • Early harm followed by later benefit • More benefit seen in younger women – ? therapeutic window of opportunity • More benefit seen with lower dose ± different/no progestogen

  40. HRT and CHD:Misperceptions • HRT increases CHD risk throughout the whole postmenopausal period • HRT causes an increase in coronary events in the first 1–2 years in all women IMS Global Summit 2008. Climacteric 2008;11:267–72

  41. HRT and CHD:Evidence • HRT in women aged 50–59 years does not increase CHD risk in healthy women and may even decrease the risk in this age group • Estrogen-alone therapy in the age group 50–59 years was associated with significantly less coronary calcification (equivalent to a smaller plaque burden), which is consistent with findings of a lower coronary intervention score in women of this age in the WHI study IMS Global Summit 2008. Climacteric 2008;11:267–72

  42. HRT and CHD:Evidence • Early harm (more coronary events during the first 2 years of HRT) was not observed in the early postmenopausal period. The number of CHD events decreased with duration of HRT in both WHI clinical trials • Data derived from randomized controlled trials in the age group 50–59 years are similar to the older observational data, suggesting a protective effect of HRT on coronary disease IMS Global Summit 2008. Climacteric 2008;11:267–72

  43. HRT and CHD:Evidence • Late starters of standard-dose HRT may have a transient, slightly increased risk for coronary events IMS Global Summit 2008. Climacteric 2008;11:267–72

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