Coronary Heart Disease

1. CoronaryHeartDisease The Hormone TherapiesthatPrevent & Relieve Thierry Hertoghe, MD

2. 7 hormone-types => prevent & relieve CHD 6. Oxytocin => also daytime emergencies 7. Melatonin => also nighttime emergencies 2. Thyroid (T3) => Caution :  doses after myocardial infarct 4. IGF-1 (& GH) => Caution :  doses after myocardial infarct 5. DHEA 2 & 3. Estrogens & Testosterone

3. Nr 1 Thyroid Therapy for CHD prevention (& relief?)

4. The importance of Thyroid

5. severe myxoedema

6. severe after2 months myxoedema thyroid treatment

7.  Coronary heart disease => serum thyroid hormones 

8. Subclinical hypothyroidism =>  ischemic heart disease & all-cause mortality 2856 participants (mean age 58.5 yr) 257 subjects with subclinical hypothyroidism (TSH > 5.0 mU/liter) iSubclinical hypothyroidism: • 2.5X  ischemic heart disease indep.of age, systolic BP, BMI, cholesterol, smoking, erythrocyte sedimentation rate,or presence of diabetes mellitus [odds ratio (RR), 2.5; 95% CI: 1.1-5.4 in total subjects & 4X  in men OR, 4.0; 95% CI, 1.4-11.5 in men] but not in women. no association with cerebrovascular disease(OR, 0.9; 95% CI, 0.4-2.4). • In a 10-yr follow-up study : 2x  mortalities from all causes in yr 3-6 after baseline measurement were apparent in men with subclinical hypothyroidism (RR: 1.9-2.1) but not in women, although specific causes of death were not determined.  2293 controls (TSH range 0.6-5.0 mU/liter) Imaizumi M, Akahoshi M, Ichimaru S, Nakashima E, Hida A, Soda M, Usa T, AshizawaK, Yokoyama N, Maeda R, Nagataki S, Eguchi K. Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab. 2004 Jul;89(7):3365-70.

9.  The middle way => avoid too  levels of Thyroid hormones 

10. Excess triiodothyronine as a risk factor of coronary events in patients on emergency admission

11.  Thyroidtreatment for Coronary heart disease 

12. Need for T3 Volume of T3 distribution = 3x that of T4 • Serum T3 concentration = 1/75 x that of T4 • Volume of T3 distribution = 3 x that of T4 20 % T3 < from thyroid gland 80 % T3 < from T4 through conversion in liver, kidney, ... Extracellular Serum T3concentration = 1/75x that of T4 T3 T3 + T4 Serum Intracellular Interstitial T3 = active hormone T4 = prohormone Turnover (utilization) of T3 = 13x that of T4 (Brown J, Chopra IJ et al., Ann Intern Med, 1974, 81(1): 68-81)

13.  CAUTION withthyroid in CHD: veryslowlyincrease • Hypothyroid patient underthyroidtherapy: switch to T3-T4(preferablydesiccated animal) thyroid: 30-150 mg/dayuponawakeningstartingverylow & progressivelyincreasing • Hypothyroid patient not yettakingtherapy: takeT3-T4(preferablydesiccated animal) thyroid: 30-150 mg/day • Patient has adrenaldeficiency: • Addhydrocortisone or prednisolone • OR L-Thyroxinealone Slow Progress: First improvementduring the 2ndmonth, up to 8-12 months for full improvement

14.  CAUTION TIP 1: coronaryheartdisease => remain at lowoften suboptimal doses TIP 2: Myocardialinfarction => No thyroidtreatmentduring 2 months, thenslowly start withverylow doses

15.  Thyroidtreatment =>  coronary heart disease 

16. Adequate thyroxine replacement in hypothyroidism => Prevents coronary artery disease progression

17. Coronary insufficiency & Thyroid hormone therapy Coronary Insufficiency (Yao J et al, Cardiovasc. Res, 1992, 26 (6): 603-7)  improved with T3-therapy in ischemic rat hearts w/ Angina Pectoris  improved with thyroid hormone therapy in humans (Yokohama et al, Cardiology, 1992, 81 (1): 34-45; Israel et al, Am J Dig Dis, 1955, 22 : 161-8)

18. CORONARY BYPASS & THYROID HORMONE THERAPY w/ CORONARY BYPASS improved cardiac recovery with T3-therapy (Myanikov et al, J Atheroscler. Res, 1963; 3: 295)

19. Thyroid Hormones & Arteriosclerosis  ARTERIOSCLEROSIS in thyroid deficiency: =>  regression with T3 treatment in animals (Myanikov, 1963)

20. MYOCARDIAL INFARCT& THYROID DEFICIENCY / THERAPY MYOCARDIAL INFARCT humans : the lower  plasma T3(total & free)=> the more severe the infarct Experimental myocardial infarct : => THYROID HORMONE THERAPY ( T3,…) =>  lesions in rats (Holland et al, Ann Thorac Surg, 1992, 54 (2): 301-5) & dogs (Facktor et al, Resuscitation, 1993, 26 (2): 141-62))

21. Ischemic Heart Disease & Thyroid Treatment NORMAL POPULATION New patients w/ ischemic heart disease THYROID TREATED 4 = 0.25 % 72 = 4.6 % figure : number of new patients with ischemic heart disease in 1569 thyroid treated hypothyroid patients over 20 years period (medium treatment period : 5.2 years) compared to the expected number of new cases in a normal population (Framingham study) (Bursos BO, Lancet, 1959, 22 : 149-52)

22.  Thyroidtreatment =>  myocardial infarct 

23. MYOCARDIAL INFARCT& THYROID DEFICIENCY / THERAPY MYOCARDIAL INFARCT humans : the  plasma T3(total & free) => the more severe the infarct experimental myocardial infarct : => THYROID HORMONE THERAPY ( T3, …) =>  lesions in rats(Holland et al, Ann Thorac Surg, 1992, 54 (2): 301-5)& dogs(Facktor et al, Resuscitation, 1993, 26 (2): 141-62) 

25. before after thyroid treatment

26.  Thyroidtreatment =>  cardiac mortality 

27. A  free T3 index/reverse T3 ratio in chronic heart failure patients = highly significant predictor of poor outcome

28. Cardiac patients with  free T3 =>  overall death

29. Cardiac patients +  serum free T3=> High  of cardiac & overall deaths

30. A  free T3 index/reverse T3 ratio in chronic heart failure patients = highly significant predictor of poor outcome

31.  Mechanisms of Thyroidtreatment => Heart 

32. T3 on heart The heart is a major target organ for thyroid hormone action, and marked changesoccur in cardiac function in patients with hypothyroidism or hyperthyroidism. Direct T3 effects result from T3 action in the heart itself and are mediated by nuclear or extranuclear mechanisms. Extranuclear T3 effects, which occur independently of nuclear T3 receptor binding and increases in protein synthesis, =>  transport of amino acids, sugars, & calcium across the cell membrane. Nuclear T3 effects are mediated by the binding of T3 to specific nuclear receptor proteins, which results in  transcription of T3-responsive cardiac genes. The T3 receptor is a member of theligand-activated transcription factor family and is encoded by cellularerythroblastosis A (c-erb A) genes. T3  heart transcription of the myosin heavy chain (MHC) alpha gene &  transcription of the MHCbeta gene=>  myosin V1 &  myosin V3isoenzymes. Myosin V1, which is composed of two MHC alpha, has a  myosinATPase activity than myosin V3, which contains two MHC beta. The globular head of myosin V1, with its higher ATPase activity, leads to a more rapid movement of the globular head of myosin along the thin filament, resulting in an  velocity of contraction. T3 also leads to an increase in the speed of diastolic relaxation, which is caused by the more efficient pumping of the calcium ATPaseof the sarcoplasmic reticulum (SR). This T3 effect results from T3-induced  level of the mRNA coding for the SR calcium ATPase protein, leading to an  number of calcium ATPase pump units in the SR. Overall, T3 =>  ATP consumption in the heart.  Mohr-Kahaly S, Kahaly G, Meyer J.II. Cardiovascular effects of thyroid hormones. Z Kardiol. 1996;85 Suppl 6:219-31. Medizinische Universitatsklinik und Poliklinik, Mainz.

33. Nr 2 Estrogen & ProgesteroneTherapiesin Women for CHD prevention (& relief?)

34. The importance of Estrogens

35. Estrogen deficiency! Dry hair Small wrinkles Dry eyes Eye Pale face Cheeks More hallow face Lip (Vertical wirnkles)

36. Senescence?

37.  Coronary heart disease => serum estrogens 

38.  Women +  serum E2 => risk of coronary disease

39.  Women + Coronary dis. => % of  serum E2

40.  Estrogens in premenopausal women w/ cardiovascular disease Coronary heart disease Healthy controls Healthy controls Plasma estradiol pmol/l (at 6 days after estimated ovulation) Coronary heart disease 24-Hr urinary estrogen pg/pmol creatinine 409 2601 1607 288 n=14 n=14 (1 w/ tubal sterilization) (8 w/ tubal sterilization) Figure: lower estrogen levels in plasma & urine of 14 premenopausal women w/ coronary heart disease Hunke H et al.: Ulm University Germany. Coron Artery Dis 1997; 8(8-9):511-5

41.  Estrogen & Progesterone treatments for Coronary heart disease 

42.  Postmenopausalwomenwithcoronaryheartdisease 25 first days of eachmonth or or Estra-diol gel 1-3 mg/day of transdermal estradiol + 100 mg micronizedprogesterone 1-2 mg/day of oral estradiol valerate + 100 mg micronizedprogesterone 1-2 mg/day of oral estradiol valerate + 100 mg micronizedprogesterone Proges-terone Slow Progress: After 1-2 months: First heartimprovement, thennext 8-12 months: Furtherimprovements

43.  Estrogentreatment =>  coronary heart disease 

44.   Female thormone therapy =>  coronary artery disease in female monkeys

45. Coronary dilation of athero-sclerotic arteries only if plasma estradiol > 60 pg/mL. BACKGROUND: The purpose of this study was to identify determinants of coronaryartery reactivity among premenopausal female monkeys. Estrogen replacementtherapy in postmenopausal females modulates reactivity of atherosclerotic coronary arteries. However, no studies have evaluated the factors that modulatecoronary artery reactivity among premenopausal females. METHODS AND RESULTS:Twenty-five adult premenopausal female monkeys were fed an atherogenic diet for32 months. During this time, monkeys were housed in small social groups anddetermined to be socially dominant (associated with normal ovarian function) orsubordinate (associated with impaired ovarian function). After 32 months,coronary artery vasomotor responses to intracoronary acetylcholine,nitroglycerin, and serotonin were assessed by computer-assisted quantitativecoronary angiography. Coronary arteries of dominant monkeys dilated (+9 +/- 2%),whereas those of subordinate monkeys constricted (-6 +/- 2%) in response toacetylcholine (P < .05). There was no effect of social status on vascularresponse to nitroglycerin or serotonin (P > .10). Vascular responses toacetylcholine were independent of social status effects on plasma lipids, bloodpressure, and atherosclerosis extent. The correlation between acetylcholineresponses and plasma estradiol concentration measured on the day of angiographywas r = .7 (P = < .01). Furthermore, dilation occurred only if plasma estradiolconcentrations were greater than 60 pg/mL. CONCLUSIONS: Psychosocial factors and endogenous estrogen production are important modulators ofacetylcholine-mediated dilation of atherosclerotic coronary arteries amongpremenopausal female monkeys.PMID: 8044971 [PubMed - indexed for MEDLINE] Williams JK, Shively CA, Clarkson TB. Determinants of coronary artery reactivity in premenopausal female cynomolgus monkeys with diet-induced atherosclerosis. Circulation. 1994 Aug;90(2):983-7 Department of Comparative Medicine, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27157-1040.

46.  EStradiol => endothelium endothelium-dependent & coronary vasomotion in postmenopausal women

47.  Estrogens treatment=>  myocardial infarct 

48. MYOCARDIAL INFARCT& ESTROGENS MYOCARDIAL INFARCT • ESTROGEN THERAPY in 48.470 postmenopausal women followed during 10 yrs •  - 44 % of myocardial infarct mortality (Stampfer MJ et al, New Engl J Med, 1991, 325: 756-62)

49. Estradiol => Cardiac Ischemia During reperfusion after 15' ischemia 2 weeks of 17-ß-Estradiol treatment Increase in left anterior descending coronary artery flow to ach Before ischemia 151 % Placebo 100 % 60 % Before ischemia During reperfusion after 15' ischemia Endothelium dependent relaxation in vitro 17-b-Estradiol 100 % Placebo 42 % 24 % figure : 17-beta-estradiol protects against endothelial & myocardial dysfunction resulting from brief ischemic perfusion(Kim YD et al, Circulation, 1996, 94 (11) : 290/-8)

50. 17 - BETA - ESTRADIOL PROTECTS AGAINST ACUTE MYOCARDIAC ISCHEMIA SALINE SOLUTION (or 17--E2) SALINE Cardiac necrosis area 17--E2 neutrophil adherence to coronary vascular endothelium 17--E2 17--E2 33 % 86 % 79 % 17 % 44 % figure : 17--estradiol (given i.v. 30 min. prior to reperfusion) protects against myocardial ischemia (90') / reperfusion (270'), in part, by attenuating polymorphonuclear infiltration in necrotic tissue and subsequent injury due to PMN mediator release. (Delgani JA et al, J Mol Cell Cardiol, 1996; 28 (5) : 1001-8)