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High-dose 17β–estradiol treatment prevents development of heart failure post–myocardial infarction in the rat

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Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Objectives

Prognosis of heart failure remains poor despite therapeutic advances, such as angiotensin converting enzyme inhibition or β-receptor blockade. Thus, more effective forms of treatment are urgently needed. Since estrogens have been shown to modulate migration and proliferation of cardiac fibroblasts and to modulate the expression of estrogen receptors of cardiomyocytes we examined whether high-dose estrogen treatment can affect post-myocardial infarction left ventricular remodeling.

Methods

Female rats were treated with 17β-estradiol (7.5 mg/90 d) or placebo for ten weeks, starting two weeks prior to experimental myocardial infarction. Eight weeks after infarction, in vivo echocardiographic and hemodynamic measurements as well as isolated heart perfusion were performed.

Results

In vivo, chronic estrogen treatment almost completely prevented the development of all signs of heart failure that occur in untreated infarcted hearts, such as increased left ventricular diameters (dilatation), reduced fractional shortening (systolic dysfunction) or increased left ventricular end–diastolic pressure (diastolic dysfunction). In vitro, the right- (indicating structural dilatation) and downward (indicating left ventricular dysfunction) shift of left ventricular pressure-volume curves occurring in untreated infarcted hearts was completely prevented by estrogen.

Conclusions

High dose estradiol treatment prevented development of post-MI remodeling, as assessed by in vivo and in vitro parameters of LV dysfunction. Estrogen may hold the potential of becoming a new form of heart failure treatment.However, the mechanisms responsible for this striking and unexpected beneficial action of estrogen in heart failure remain to be elucidated.

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References

  1. Beer S, Reincke M, Kral M, Lie SZ, Steinhauer S, Schmidt HHHW, Allolio B, Neubauer S (2002) Susceptibility to cardiac ischemia/reperfusion injury is modulated by chronic estrogen status. J Cardiovasc Pharmacol 40:420–428

    Article  PubMed  CAS  Google Scholar 

  2. Bittl JA, Ingwall JS (1985) Reaction rates of creatine kinase and ATP synthesis in the isolated rat heart. A 31P NMR magnetization transfer study. J Biol Chem 260:3512–3517

    PubMed  CAS  Google Scholar 

  3. Brutsaert DL (1993) Endocardial and coronary endothelial control of cardiac performance. News Physiol Sci 8:82–86

    Google Scholar 

  4. CIBIS, Investigators and Committees (1994) A randomized trial of b–blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation 90:1765–1773

    Google Scholar 

  5. Cittadini A, Strömer H, Katz SE, Clark R, Moses AC, Morgan JP, Douglas PS (1996) Differential cardiac effects of growth hormone and insulin–like growth factor–1 in the rat. A combined in vivo and in vitro evaluation. Circulation 93:800–809

    PubMed  CAS  Google Scholar 

  6. Dai–Do D, Espinosa E, Liu G, Rabelink TJ, Julmy F, Yang Z, Mahler F, Luscher TF (1996) 17β–estradiol inhibits proliferation and migration of human vascular smooth muscle cells: similar effects in cells from postmenopausal females and in males. Cardiovasc Res 32:980–985

    Article  PubMed  CAS  Google Scholar 

  7. De Simone G, Wallerson DC, Volpe M, Devereux RB (1990) Echocardiographic measurements of left ventricular mass and volume in normotensive and hypertensive rats: necropsy validation. Am J Hypertens 3:688–696

    PubMed  CAS  Google Scholar 

  8. Delyani JA, Murohara T, Nossuli TO, Lefer AM (1996) Protection from myocardial reperfusion injury by acute administration of 17β–estradiol. J Mol Cell Cardiol 28:1001–1008

    Article  PubMed  CAS  Google Scholar 

  9. Gabel SA, Walker VR, London RE, Steenbergen C, Korach KS, Murphy E (2005) Estrogen receptor beta mediates gender differences in ischemia/reperfusion injury. J Mol Cell Cardiol 38:289–297

    Article  PubMed  CAS  Google Scholar 

  10. Gardner JD, Brower GL, Janicki JS (2005) Effects of dietary phytoestrogens on cardiac remodeling secondary to chronic volume overload in female rats. J Appl Physiol 2005:1378–1383

    Article  CAS  Google Scholar 

  11. Gaudron P, Hu K, Schamberger R, Budin M, Walter B, Ertl G (1994) Effect of endurance training early or late after coronary artery occlusion on left ventricular remodeling, hemodynamics, and survival in rats with chronic transmural myocardial infarction. Circulation 89:402–412

    PubMed  CAS  Google Scholar 

  12. Grocott–Mason R, Fort S, Lewis MJ, Shah AM (1994) Myocardial relaxant effect of exogenous nitric oxide in isolated ejecting hearts. Am J Physiol 266:H1699–H1705

    PubMed  CAS  Google Scholar 

  13. Grohé C, Kahlert S, Löbber K, Stimpel M, Karas RH, Vetter H, Neyses L (1997) Cardiac myocytes and fibroblasts contain functional estrogen receptors. FEBS Letters 416:107–112

    Article  PubMed  Google Scholar 

  14. Hale S, Birnbaum Y, Kloner R (1996) β– Estradiol, but not α–estradiol, reduces myocardial necrosis in rabbits after ischemia and reperfusion. Am Heart J 132:258–262

    Article  PubMed  CAS  Google Scholar 

  15. Hjalmarson A (2000) Cardioprotection with beta–adrenoceptor blockers. Does lipophilicity matter? Basic Res Cardiol 95:I41–I45

    Article  PubMed  Google Scholar 

  16. Horio T, Nishikimi T, Yoshihara F, Matsuo H, Takishita S, Kangawa K (2000) Inhibitory regulation of hypertrophy by endogenous atrial natriuretic peptide in cultured cardiac mypcytes. Hypertension 35:19–24

    PubMed  CAS  Google Scholar 

  17. Horn M, Neubauer S, Frantz S, Hügel S, Hu K, Gaudron P, Schnackerz K, Ertl G (1996) Preservation of left ventricular mechanical function and energy metabolism in rats after myocardial infarction by the angiotensin–converting enzyme inhibitor quinapril. J Cardiovasc Pharmacol 27:201–210

    Article  PubMed  CAS  Google Scholar 

  18. Hu K, Gaudron P, Ertl G (1998) Longterm effects of beta–adrenergic blocking agent treatment on hemodynamic function and left ventricular remodeling in rats with experimental myocardial infarction. Importance of timing of treatment and infarct size. J Am Coll Cardiol 31:692–700

    Article  PubMed  CAS  Google Scholar 

  19. Hügel S, Horn M, de Groot M, Remkes H, Dienesch C, Hu K, Ertl K, Neubauer S (1999) Effects of angiotensin–converting enzyme inhibition and b–receptorblockade on cardiac energy metabolism in rats post–myocardial infarction. Am J Physiol 277:H2167–H2175

    PubMed  Google Scholar 

  20. Hügel S, Horn M, Remkes H, Dienesch C, Neubauer S (2001) Preservation of cardiac function and energy reserve by the angiotensin–converting enzyme inhibitor quinapril during postmyocardial infarction remodeling in the rat. J Cardiovasc Magnet Res 3:215–225

    Article  Google Scholar 

  21. Hügel S, Reincke M, Strömer H, Winning J, Horn M, Dienesch C, Mora P, Schmidt HHHW, Allolio B, Neubauer S (1999) Evidence against a role of estrogens in post myocardial infarction remodeling. J Am Coll Cardiol 34:1427–1434

    Article  PubMed  Google Scholar 

  22. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E, and for the Heart and Estrogen/Progestin Replacement Study (HERS) Research Group (1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 280:605–613

    Article  PubMed  CAS  Google Scholar 

  23. Kannel WB, Hjortland MC, McNamara PM, Gordon T (1976) Menopause and risk of cardiovascular disease: the Framingham study. Ann Intern Med 85:447–452

    PubMed  CAS  Google Scholar 

  24. Knopp RH, Zhu X, Bonet B (1994) Effects of estrogens on lipoprotein metabolism and cardiovascular disease in women. Atherosclerosis 110(Suppl): S83–S91

    Article  PubMed  CAS  Google Scholar 

  25. Kojda G, Kottenberg K, Nix P (1996) Low increase in cGMP induced by organic nitrates and nitrovasodilators improves contractile response of rat ventricular myocytes. Circ Res 78:91–101

    PubMed  CAS  Google Scholar 

  26. Kolodgie FD, Farb A, Litovsky SH, Narula J, Jeffers LA, Lee SJ, Virmani R (1997) Myocardial protection of contractile function after global ischemia by physiologic estrogen replacement in the ovariectomized rat. J Mol Cell Cardiol 29:2403–2414

    Article  PubMed  CAS  Google Scholar 

  27. Kuiper GGJM, Enmark E, Pelto–Huikko M, Nilsson S (1996) Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93:5925–5930

    Article  PubMed  CAS  Google Scholar 

  28. Lee HW, Eghbali–Webb M (1998) Estrogen enhances proliferative capacity of cardiac fibroblasts by estrogen receptor– and mitogen–activated protein kinase– dependent pathways. J Mol Cell Cardiol 30:1359–1368

    Article  PubMed  CAS  Google Scholar 

  29. Leitzbach D, Weckler N, Madajka M, Malinski T, Wiemer G, Linz W (2005) Restoration of endothelial function via enhanced nitric oxide synthesis after long–term treatment of raloxifene in adult hypertensive rats. Arzneimittelforschung 2005:86–92

    Google Scholar 

  30. Leri A, Malhotra A, Liew CC, Kajstura J, Anversa P (2000) Telomerase activity in rat cardiac myocytes is age and gender dependent. J Mol Cell Cardiol 32:385–390

    Article  PubMed  CAS  Google Scholar 

  31. Litwin SE, Katz SE, Morgan JP, Douglas PS (1994) Serial echocardiographic assessment of left ventricular geometry and function after large myocardial infarction in the rat. Circulation 89:345–354

    PubMed  CAS  Google Scholar 

  32. Litwin SE, Morgan JP (1992) Captopril enhances intracellular calcium handling and beta–adrenergic responsiveness of myocardium from rats with postinfarction failure. Circ Res 71:797–807

    PubMed  CAS  Google Scholar 

  33. Nekooeian AA, Pang CC (1998) Estrogen restores role of basal nitric oxide in control of vascular tone in rats with chronic heart failure. Am J Physiol 274:H2094–H2099

    PubMed  CAS  Google Scholar 

  34. Neubauer S, Ertl G, Haas U, Pulzer F, Kochsiek K (1990) Effects of endothelin– 1 in the isolated perfused rat heart. J Cardiovasc Pharmacol 16:1–8

    Article  PubMed  CAS  Google Scholar 

  35. Neubauer S, Horn M, Naumann A, Tian R, Hu K, Laser M, Friedrich J, Gaudron P, Schnackerz K, Ingwall JS, Ertl G (1995) Impairment of energy metabolism in intact residual myocardium of rat hearts with chronic myocardial infarction. J Clin Invest 95:1092–1100

    Article  PubMed  CAS  Google Scholar 

  36. Node K, Kitakaze M, Kosaka H, Minamino T, Funaya H, Hori M (1997) Amelioration of ischemia– and reperfusion– induced myocardial injury by 17β– estradiol. Role of nitric oxide and calcium– activated potassium channels. Circulation 96:1953–1963

    PubMed  CAS  Google Scholar 

  37. Nuedling S, Kahlert S, Loebbert K, Doevendans PA, Meyer R, Vetter H, Grohé C (1999) 17β–Estradiol stimulates expression of endothelial and inducible NO synthase in rat myocardium invitro and in–vivo. Cardiovasc Res 43:666–674

    Article  PubMed  CAS  Google Scholar 

  38. Pelzer T, Loza P–AA, Hu K, Bayer B, Dienesch C, Calvillo L, Couse JF, Korach KS, Neyses L, Ertl G (2005) Increased mortality and aggravation of heart failure in estrogen receptor–b knockout mice after myocardial infarction. Circulation 111:1492–1498

    Article  PubMed  CAS  Google Scholar 

  39. Pelzer T, Schumann M, Neumann M, de– Jager T, Stimpel M, Serfling E, Neyses L (2000) 17β–estradiol prevents programmed cell death in cardiac myocytes. Biochem Biophys Res Com 268:192–200

    Article  PubMed  CAS  Google Scholar 

  40. Pfeffer MA, Pfeffer JM, Fishbein MC, Fletcher PJ, Spadaro J, Kloner RA, Braunwald E (1979) Myocardial infarct size and ventricular function in rats. Circ Res 44:503–512

    PubMed  CAS  Google Scholar 

  41. Ramaciotti C, Sharkey A, McClellan G, Winegrad S (1992) Endothelial cells regulate cardiac contractility. Proc Acad Sci USA 89:4033–4036

    Article  CAS  Google Scholar 

  42. Sahn DJ, DeMaria A, Kisslo J, Weyman A, and The Committee on M–mode standardization of the American Society of Echocardiography (1978) Recommendations regarding quantitation in M–mode echocardiography: results of a survey of echocardiographic measurements. Circulation 58:1072–1083

    PubMed  CAS  Google Scholar 

  43. Saunders PTK, Maguire SM, Gaughan J, Millar MR (1997) Expression of oestrogen receptor beta (ERb) in multiple rat tissues visualised by immunohistochemistry. J Endocrinol 154:R13–R16

    Article  PubMed  CAS  Google Scholar 

  44. Smith JA, Shah AM, Fort S, Lewis MJ (1992) The influence of endocardial endothelium on myocardial contraction. Trends Pharmacol Sci 13:113–116

    Article  PubMed  CAS  Google Scholar 

  45. Smith PJW, Ornatsky O, Duncan JS, Picard P, Dawood F, Wen WH, Liu PP, Webb DJ, Monge JC (2000) Effects of estrogen replacement on infarct size, cardiac remodeling, and the endothelin system after myocardial infarction in ovariectomized rats. Circulation 102:2983–2989

    PubMed  CAS  Google Scholar 

  46. Smith WHT, Ball SG (2000) ACE inhibitors in heart failure: an update. Basic Res Cardiol 95:I8–I14

    Article  PubMed  Google Scholar 

  47. SOLVD (1991) Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. New Engl J Med 325:293–302

    Article  Google Scholar 

  48. Spinler SA, Hilleman DE, Cheng JWM, Howard PA, Mauro VF, Lopez LM, Munger MA, Gardner SF, Nappi JM (2001) New recommendations from the 1999 American College of Cardiology/ American Heart Association acute myocardial infarction guidelines. Ann Pharmacother 35:589–617

    Article  PubMed  CAS  Google Scholar 

  49. Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH (1991) Postmenopausal estrogen therapy and cardiovascular disease. Ten–year follow–up from the nurses’ health study. New Engl J Med 325:756–762

    Article  PubMed  CAS  Google Scholar 

  50. Tian R, Gaudron P, Neubauer S, Hu K, Ertl G (1995) Alterations of performance and oxygen utilization in chronically infarcted rat hearts. J Mol Cell Cardiol 28:321–330

    Article  Google Scholar 

  51. van Eickels M, Grohé C, Cleutjens JP, Janssen BJ, Wellens HJ, Doevendans PA (2001) 17β–estradiol attenuates the development of pressure–overload hypertrophy. Circulation 104:1419–1423

    PubMed  CAS  Google Scholar 

  52. van Eickels M, Patten RD, Aronovitz MJ, Alsheikh–Ali A, Gostyla K, Celestin F, Grohé C, Mendelsohn ME, Karas RH (2003) 17β–estradiol increases cardiac remodeling and mortality in mice with myocardial infarction. JACC 41:2084–2092

    PubMed  CAS  Google Scholar 

  53. White HD, Norris RM, Brown MA, Brandt PWT, Whitlock RML, Wild CJ (1987) Left ventricular end–systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 76:44–51

    PubMed  CAS  Google Scholar 

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Correspondence to Stephanie Beer MD.

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Beer, S., Reincke, M., Kral, M. et al. High-dose 17β–estradiol treatment prevents development of heart failure post–myocardial infarction in the rat. Basic Res Cardiol 102, 9–18 (2007). https://doi.org/10.1007/s00395-006-0608-1

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  • DOI: https://doi.org/10.1007/s00395-006-0608-1

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