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Sex differences in myocardial metabolism and cardiac function: an emerging concept

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Abstract

There is substantial evidence that there are dramatic sex-related differences in the incidence of cardiovascular disease, apparently related to the presence of steroid hormones. This is supported by the discovery of steroid hormone receptors in the heart and vasculature. More controversial is the area of sex-related differences in cardiac metabolism and function. A number of human and animal studies have demonstrated that estrogen and testosterone have cardiac metabolic effects. Additionally, research shows females have higher heart rates and various indices of function, including cardiac output and stroke volume, compared with males. However, some controversy exists, as other studies report that function in isolated muscle preparations is lower in females versus males. The reasons for these differences may reflect effects of sex hormones that are dependent on the conditions being studied. Cardiac function is reduced in postmenopausal females, suggesting that female sex hormones, specifically estrogen and progesterone, influence cardiac function. Apart from its well-documented vasodilatory effects, estrogen has also been shown to have negative inotropic effects and to reduce Ca2+ transients in cardiomyocytes. Similar results have been found for progesterone. Several studies show that testosterone administration appears to increase cardiac performance, while others show that it increases the stiffness of the ventricle due to increased collagen synthesis, thereby reducing diastolic performance. This review will discuss current evidence suggesting sex-related differences in cardiac metabolism and its energetics and function and will present the potential role of the principal sex steroid hormones.

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References

  1. Arias-Loza PA, Hu K, Dienesch D, Mehlich AM, Konig S, Jazbutyte V, Neyses L, Hegele-Hartung C, Fritzemeier KH, Pelzer T (2007) Both estrogen receptor subtypes, α and β, attenuate cardiovascular remodeling in aldosterone salt-treated rats. Hypertens 50:432–438

    Article  CAS  Google Scholar 

  2. Ben-Sira D, Sagiv M (1997) The effect of gender on left ventricular function immediately after the wingate test. Euro J Appl Physiol 75:549–553

    Article  CAS  Google Scholar 

  3. Berger E, Borchard U, Hafner D, Pütz I, Weis TM (1997) Effects of 17β-estradiol on action potentials and ionic currents in male rat ventricular myocytes. Naunyn-Schmiedeberg’s Arch Pharmacol 356:788–796

    Article  CAS  Google Scholar 

  4. Beyer ME, Yu G, Hanke H, Hoffmeister HM (2001) Acute gender-specific hemodynamic and inotropic effects of 17β-estradiol on rats. Hypertens 38:1003–1010

    Article  CAS  Google Scholar 

  5. Calovini T, Haase H, Morano I (1995) Steroid-hormone regulation of myosin subunit expression in smooth and cardiac muscle. J Cell Biochem 59:69–78

    Article  PubMed  CAS  Google Scholar 

  6. Campbell SE, Febbraio MA (2001) Effect of ovarian hormones on mitochondrial enzyme activity in the fat oxidation pathway of skeletal muscle. Am J Physiol Endocrinol Metab 281:E803–E808

    PubMed  CAS  Google Scholar 

  7. Camper-Kirby D, Welch S, Walker A, Shiraishi I, Setchell KDR, Schaefer E, Kajstura J, Anversa P, Sussman MA (2001) Myocardial Akt activation and gender. Increased nuclear activity in females versus males. Circ Res 88:1020–1027

    Article  PubMed  CAS  Google Scholar 

  8. Capasso JM, Remily RM, Smithe RH, Sonnenblick EH (1983) Sex differences in myocardial contractility in the rat. Basic Res Cardiol 78:156–171

    Article  PubMed  CAS  Google Scholar 

  9. Cavasin MA, Sakney SS, Yu AL, Menon S, Yang XP (2003) Estrogen and testosterone have opposing effects on chronic cardiac remodeling and function in mice with myocardial infarction. Am J Physiol Heart Circ Physiol 284:H1560–H1569

    PubMed  CAS  Google Scholar 

  10. Chu SH, Goldspink P, Kowalski J, Beck J, Schwertz DW (2006) Effect on estrogen on calcium-handling proteins, β-adrenergic receptors, and function in rat heart. Life Sci 79:1257–1267

    Article  PubMed  CAS  Google Scholar 

  11. 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. Circ 93:800–809

    Article  CAS  Google Scholar 

  12. Convertino VA (1998) Gender differences in autonomic functions associated with blood pressure regulation. Am J Physiol 275:R1909–R1920

    PubMed  CAS  Google Scholar 

  13. Czubryt MP, Espira L, Lamoureux L, Abrenica B (2006) The role of sex in cardiac function and disease. Can J Physiol Pharmacol 84:93–109

    Article  PubMed  CAS  Google Scholar 

  14. Depre C, Hue L (1994) Cyclic GMP in the perfused rat heart. Effect of ischaemia, anoxia and nitric oxide synthase inhibitor. FEBS Lett 345:241–245

    Article  PubMed  CAS  Google Scholar 

  15. Dodds ML, Kargacin ME, Kargacin GJ (2001) Effects of anti-oestrogens and β-estradiol on calcium uptake by cardiac sarcoplasmic reticulum. Brit J Pharmacol 132:1374–1382

    Article  CAS  Google Scholar 

  16. Du XJ, Riemersma RA, Dart AM (1995) Cardiovascular protection by oestrogen is partly mediated through modulation of autonomic nervous function. Cardiovasc Res 30:161–165

    PubMed  CAS  Google Scholar 

  17. Edén S (1979) Age- and sex-related differences in episodic growth hormone secretion in the rat. Endocrinol 105:555–560

    Article  Google Scholar 

  18. Fuenmayor AJ, Ramirez L, Fuenmayor AM (2000) Left ventricular function and autonomic nervous system balance during two different stages of the menstrual cycle. Int J Cardiol 72:243–246

    Article  PubMed  CAS  Google Scholar 

  19. Greenspan FS, Gardner DG (2004) Greenspan’s basic & clinical endocrinology. Lange Medical Books/McGraw-Hill, New York, p 976

    Google Scholar 

  20. Haring R, John U, Volzke H, Nauck M, Dorr M, Felix SB, Wallaschofski H (2012) Low testosterone concentrations in men contribute to the gender gap in cardiovascular morbidity and mortality. Gend Med 9(6):557–568

    Article  PubMed  Google Scholar 

  21. Hart MV, Hosenpud JD, Hohimer AR, Morton MJ (1985) Hemodynamics during pregnancy and sex steroid administration in guinea pigs. Am J Physiol 249:R179–R185

    PubMed  CAS  Google Scholar 

  22. Haykowsky M, Chan S, Bhambhani Y, Syrotuik D, Quinney H, Bell G (1998) Effects of combined endurance and strength training on left ventricular morphology in male and female rowers. Can J Cardiol 14:387–391

    PubMed  CAS  Google Scholar 

  23. Ho KKL, Pinsky JL, Kannel WB, Levy D (1993) The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol 22(suppl A):6A–13A

    Article  PubMed  CAS  Google Scholar 

  24. Hügel S, Neubauer S, Lie SN, Ernst R, Horn M, Schmidt HHHW, Allolio B, Reincke M (1999) Multiple mechanisms are involved in the acute vasodilatory effect of 17β-estradiol in the isolated perfused rat heart. J Cardiovasc Pharmacol 33:852–858

    Article  PubMed  Google Scholar 

  25. Hulley S, Furberg C, Barrett-Connor E, Cauley J, Grady D, Haskell W, Knopp R, Lowery M, Satterfield S, Schrott H, Vittinghoff E, Hunninghake D (2002) Noncardiovascular disease outcomes during 6.8 years of hormone therapy. J Am Med Assoc 288:58–66

    Article  CAS  Google Scholar 

  26. Ingegno MD, Money SR, Thelmo W, Greene GL, Davidian M, Jaffe BM, Pertschuk LP (1988) Progesterone receptors in the human heart and great vessels. Lab Investig 59:353–356

    PubMed  CAS  Google Scholar 

  27. Johnson MR (1994) Heart failure in women: a special approach? J Heart Lung Transpl 13:S130–S134

    CAS  Google Scholar 

  28. Johnson BD, Zheng W, Korach KS, Scheuer T, Catterall WA, Rubanyi GM (1997) Increased expression of the cardiac L-type calcium channel in estrogen receptor-deficient mice. J Gen Physiol 110:135–140

    Article  PubMed  CAS  Google Scholar 

  29. Koenig H, Fan CC, Goldstone AD, Lu CY, Trout JJ (1989) Polyamines mediate androgenic stimulation of calcium fluxes and membrane transport in rat heart myocytes. Circ Res 64:415–426

    Article  PubMed  CAS  Google Scholar 

  30. Leblanc N, Chartier D, Gosselin H, Rouleau JL (1998) Age and gender differences in excitation-contraction coupling of the rat ventricle. J Physiol 511:553–548

    Article  Google Scholar 

  31. LeGros T, McConnell D, Murry T, Edavettal M, Racey-Burns LA, Shepherd RE, Burns AH (2000) The effects of 17α-methyltestosterone on myocardial function in vitro. Med Sci in Sports Exercise 32:897–903

    Article  CAS  Google Scholar 

  32. Lerner DJ, Kannel WB (1986) Patterns of coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population. Am Heart J 111:383–390

    Article  PubMed  CAS  Google Scholar 

  33. Lev EI, Pines A, Drory Y, Rotmensch HH, Tenenbaum A, Fisman EZ (1998) Exercise-induced aortic flow parameters in early postmenopausal women and middle-aged men. J Internal Med 243:275–280

    Article  PubMed  CAS  Google Scholar 

  34. Li HY, Bian JS, Kwan YW, Wong TM (2000) Enhanced responses to 17β-estradiol in rat hearts treated with isoproterenol: involvement of a cyclic AMP-dependent pathway. J Pharmacol Exp Ther 293:592–598

    PubMed  CAS  Google Scholar 

  35. Light KC, Hinderliter AL, West SG, Grewen KM, Steege JF, Sherwood A, Girdler SS (2001) Hormone replacement improves hemodynamic profile and left ventricular geometry in hypertensive and normotensive postmenopausal women. J Hypertens 19:269–278

    Article  PubMed  CAS  Google Scholar 

  36. Lin AL, Schultz JJ, Brenner RM, Shain SA (1990) Sexual dimorphism characterized baboon myocardial androgen receptors but not myocardial estrogen and progesterone receptors. J Steroid Biochem Mol Biol 37:85–95

    Article  PubMed  CAS  Google Scholar 

  37. Liu L, Fan QI, El-Zaru MR, Vanderpool K, Hines RN, Marsh JD (2000) Regulation of DHP receptor expression by elements in the 5′-flanking sequence. Am J Physiol 278:H1153–H1162

    CAS  Google Scholar 

  38. Lopaschuk GD, Kelly DP (2008) Signalling in cardiac metabolism. Cardiovasc Res 79:205–207

    Article  PubMed  CAS  Google Scholar 

  39. Luczak ED, Leinwand LA (2009) Sex-based cardiac physiology. Annu Rev Physiol 71:1–18

    Article  PubMed  CAS  Google Scholar 

  40. MacLellan WR, Schneider MD (1997) Death by design. Programmed cell death in cardiovascular biology and disease. Circ Res 81:137–144

    Article  PubMed  CAS  Google Scholar 

  41. Magness RR, Rosenfeld CR (1989) Local and systemic estradiol-17β: effects on uterine and systemic vasodilation. Am J Physiol 256:E536–E542

    PubMed  CAS  Google Scholar 

  42. Marsh JD, Lehmann MH, Ritchie RH, Gwathmey JK, Green GE, Schiebinger RJ (1998) Androgen receptors mediate hypertrophy in cardiac myocytes. Circ 98:256–261

    Article  CAS  Google Scholar 

  43. Mendelsohn ME (2000) Mechanisms of estrogen action in the cardiovascular system. J Steroid Biochem Mol Biol 74:337–343

    Article  PubMed  CAS  Google Scholar 

  44. Mendoza J, De Mello WC (1974) Influence of progesterone on membrane potential and peak tension of myocardial fibres. Cardiovasc Res 8:352–361

    Article  PubMed  CAS  Google Scholar 

  45. Merz CNB, Moriel M, Rozanski A, Klein J, Berman DS (1996) Gender-related differences in exercise ventricular function among healthy subjects and patients. Am Heart J 131:704–709

    Article  PubMed  CAS  Google Scholar 

  46. Modena MG, Muia N Jr, Aveta P, Molinari R, Rossi R (1999) Effects of transdermal 17β-estradiol on left ventricular anatomy and performance in hypertensive women. Hypertens 34:1041–1046

    Article  CAS  Google Scholar 

  47. Nillson SE, Fransson E, Brismar K (2009) Relationship between serum progesterone concentrations and cardiovascular disease, diabetes, and mortality in elderly Swedish men and women: an 8-year prospective study. Gend Med 6(3):433–443

    Article  Google Scholar 

  48. Pasanen S, Ylikomi T, Syvälä H, Tuohimaa P (1997) Distribution of progesterone receptor in chicken: novel target organs for progesterone and estrogen action. Mol Cell Endocrinol 135:79–91

    Article  PubMed  CAS  Google Scholar 

  49. Patterson E, Ma L, Szabo B, Robinson CP, Thadani U (1998) Ovariectomy and estrogen-induced alterations in myocardial contractility in female rabbits: role of the L-type calcium channel. J Pharmacol Exp Ther 284:586–591

    PubMed  CAS  Google Scholar 

  50. Pelzer T, Jazbutyte V, Hu K, Segrer S, Nahrendorf M, Nordbeck P, Bonz AW, Much J, Fritzemeier KH, Hegele-Hartung C, Ertl G, Neyses L (2005) The estrogen receptor-α agonist 16α-LE2 inhibits cardiac hypertrophy and improves hemodynamic function in estrogen-deficient spontaneously hypertensive rats. Cardiovasc Res 1:604–612

    Article  Google Scholar 

  51. 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 Comm 268:192–200

    Article  PubMed  CAS  Google Scholar 

  52. Peterson LR, Soto PF, Herrero P, Schechtman KB, Dence C, Gropler RJ (2007) Sex differences in myocardial oxygen and glucose metabolism. J Nucl Cardiol 14(4):573–581

    Article  PubMed  Google Scholar 

  53. Prelevic GM, Beljic T (1994) The effect of oestrogen and progestogen replacement therapy on systolic flow velocity in healthy postmenopausal women. Maturitas 20:37–44

    Article  PubMed  CAS  Google Scholar 

  54. Raddino R, Manca C, Poli E, Bolognesi R, Visioli O (1986) Effect of 17β-estradiol on the isolated rabbit heart. Arch Int Pharmacodyn 281:57–65

    PubMed  CAS  Google Scholar 

  55. Raddino R, Poli E, Pelà G, Manca C (1989) Action of steroid sex hormones on the isolated rabbit heart. Pharmacol 38:185–190

    Article  CAS  Google Scholar 

  56. Re M, Gemelli A, Falcone M, Gulluni S, Ciriaco O, Sorcini G, Pepe M, D’Arezzo A, Canova R, Clemenzia G (1986) A study of cardiac function in relation to the menstrual cycle. Panminerva Medica 28:11–14

    PubMed  CAS  Google Scholar 

  57. Ren J, Samson WK, Sowers JR (1999) Insulin-like growth factor 1 as a cardiac hormone: physiological and pathophysiological implications in heart disease. J Mol Cell Cardiol 31:2049–2061

    Article  PubMed  CAS  Google Scholar 

  58. Scheuer J, Malhotra A, Schaible TG, Capasso J (1987) Effects of gonadectomy and hormonal replacement on rat hearts. Circ Res 61:12–19

    Article  PubMed  CAS  Google Scholar 

  59. Schillaci G, Verdecchia P, Borgioni C, Ciucci A, Porcellati C (1998) Early cardiac changes after menopause. Hypertens 32:764–769

    Article  CAS  Google Scholar 

  60. Sites CK, Tischler MD, Blackman JA, Niggel J, Fairbank JT, O'Connell M, Ashikaga T (1999) Effect of short-term hormone replacement therapy on left ventricular mass and contractile function. Fertil Steril 71:137–143

    Article  PubMed  CAS  Google Scholar 

  61. Sitzler G, Lenz O, Kitler H, La Rosee K, Böhm M (1996) Investigation of the negative inotropic effects of 17β-oestradiol in human isolated myocardial tissues. Br J Pharmacol 119:43–48

    Article  PubMed  CAS  Google Scholar 

  62. Snabes MC, Payne JP, Kopelen HA, Dunn JK, Young RL, Zoghbi WA (1997) Physiologic estradiol replacement therapy and cardiac structure and function in normal postmenopausal women: a randomized, double-blind, placebo-controlled, crossover trial. Obstet Gynecol 89:332–339

    Article  PubMed  CAS  Google Scholar 

  63. Stanley WC, Recchia RA, Lopaschuk GD (2005) Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 85:1093–1129

    Article  PubMed  CAS  Google Scholar 

  64. Tannenbaum GS, Martin JB (1976) Evidence for an endogenous utradian rhythm governing growth hormone secretion in the rat. Endocrinol 98:562–570

    Article  CAS  Google Scholar 

  65. Taylor AH, Al-Azzawi F (2000) Immunolocalisation of oestrogen receptor beta in human tissues. J Mol Endocrinol 24:145–155

    Article  PubMed  CAS  Google Scholar 

  66. The Writing Group for the PEPI Trial (1995) Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. J Am Med Assoc 273:199–208

    Article  Google Scholar 

  67. Vanhaesebroeck B, Alessi DR (2000) The PI3K-PDK1 connection: more than just a road to PKB. Biochem J 346:561–576

    Article  PubMed  CAS  Google Scholar 

  68. Villari B, Campbell SE, Schneider J, Vassalli G, Chiarello M, Hess OM (1995) Sex-dependent differences in left ventricular function and structure in chronic pressure overload. Eur Heart J 16:1410–1419

    PubMed  CAS  Google Scholar 

  69. Voutilainen S, Hippeläinen M, Hulkko S, Karppinen K, Ventilä M, Kupari M (1993) Left ventricular diastolic function by Doppler echocardiography in relation to hormonal replacement therapy in healthy postmenopausal women. Am J Cardiol 71:614–617

    Article  PubMed  CAS  Google Scholar 

  70. Wallen WJ, Cserti C, Belanger MP, Wittnich C (2000) Gender-differences in myocardial adaptation to afterload in normotensive and hypertensive rats. Hypertens 36:774–779

    Article  CAS  Google Scholar 

  71. Wang SN, Wyeth RP, Kennedy RH (1998) Effects of gender on the sensitivity of rat cardiac muscle to extracellular Ca2+. Eur J Pharmacol 361:73–77

    Article  PubMed  CAS  Google Scholar 

  72. Younis LT, Melin JA, Robert AR, Detry JMR (1990) Influence of age and sex on left ventricular volumes and ejection fraction during upright exercise in normal subjects. Eur Heart J 11:916–924

    PubMed  CAS  Google Scholar 

  73. Zabalgoitia M, Rahman NU, Haley WE, Oneschuk L, Yarows S, Yunis C, Lucas C, Linn W, Krause L, Amerena J (1996) Gender dimorphism in cardiac adaptation to hypertension is unveiled by prior treatment and efficacy. Am J Cardiol 78:838–840

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Physiology, University of Toronto, 1 King’s College Circle, Medical Sciences Bldg. Room 7256, Toronto, ON, M5S 1A8, Canada

    Carin Wittnich, Luke Tan, Jack Wallen & Michael Belanger

  2. Department of Surgery, University of Toronto, 1 King’s College Circle, Medical Sciences Bldg. Room 7256, Toronto, ON, M5S 1A8, Canada

    Carin Wittnich

  3. The Cardiovascular Sciences Collaborative Program, University of Toronto, Toronto, M5S 1A8, Canada

    Carin Wittnich, Luke Tan & Jack Wallen

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  1. Carin Wittnich
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  2. Luke Tan
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  4. Michael Belanger
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Correspondence to Carin Wittnich.

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This article is published as part of the special issue on sex differences in health and disease: brain and heart connections.

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Wittnich, C., Tan, L., Wallen, J. et al. Sex differences in myocardial metabolism and cardiac function: an emerging concept. Pflugers Arch - Eur J Physiol 465, 719–729 (2013). https://doi.org/10.1007/s00424-013-1232-1

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  • DOI: https://doi.org/10.1007/s00424-013-1232-1

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