Advertisement

Gender Differences in Cardiac Hypertrophy

  • Jian WuEmail author
  • Fangjie Dai
  • Chang Li
  • Yunzeng ZouEmail author
Review Article
Part of the following topical collections:
  1. Special Issue: Gender Differences in Cardiovascular Diseases

Abstract

Cardiac hypertrophy is an adaptive response to abnormal physiological and pathological stimuli, which can be classified into concentric and eccentric hypertrophy, induced by pressure overload or volume overload, respectively. In both physiological and pathological scenarios, females generally show a more favorable form of hypertrophy compared with their male counterparts. However once established, cardiac hypertrophy is a stronger risk factor for heart failure in females. Pre-menopausal women are better protected against cardiac hypertrophy compared with men, but this protection is abolished following menopause and is partially restored after estrogen replacement therapy. Estrogen exerts its protection by counteracting pro-hypertrophy signaling pathways, whereas androgen mostly plays an opposite role in cardiac hypertrophy. We here summarize the progress in the understanding of sexual dimorphisms in cardiac hypertrophy and highlight recent breakthroughs in the regulatory role of sex hormones and their intricate molecular networks, in order to shed light on gender-oriented therapeutic efficacy for pathological hypertrophy.

Keywords

Gender Pathological cardiac hypertrophy Physiological cardiac hypertrophy Pressure overload Volume overload 

Notes

Funding Information

This work was supported by National Natural Science Foundation of China (31430039, 81670228, and 81730009), Laboratory Animal Science Foundation of Shanghai Committee of Science and Technology (16140901100), Scientific Research Foundation of Shanghai Municipal Commission of Health (201640044), Foundation for Key Researcher of Zhongshan Hospital (2017ZSYXQN09).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Roth, G. A., Johnson, C., Abajobir, A., Abd-Allah, F., Abera, S. F., Abyu, G., et al. (2017). Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015. Journal of the American College of Cardiology, 70(1), 1–25.  https://doi.org/10.1016/j.jacc.2017.04.052.Google Scholar
  2. 2.
    Zhou, L., Ma, B., & Han, X. (2016). The role of autophagy in angiotensin II-induced pathological cardiac hypertrophy. Journal of Molecular Endocrinology, 57(4), R143–R152.  https://doi.org/10.1530/JME-16-0086.Google Scholar
  3. 3.
    Nakamura, M., & Sadoshima, J. (2018). Mechanisms of physiological and pathological cardiac hypertrophy. Nature Reviews. Cardiology, 15(7), 387–407.  https://doi.org/10.1038/s41569-018-0007-y.Google Scholar
  4. 4.
    McMullen, J. R., & Jennings, G. L. (2007). Differences between pathological and physiological cardiac hypertrophy: novel therapeutic strategies to treat heart failure. [Research Support, Non-U.S. Gov't Review]. Clinical and Experimental Pharmacology & Physiology, 34(4), 255–262.  https://doi.org/10.1111/j.1440-1681.2007.04585.x.Google Scholar
  5. 5.
    Wu, J., You, J., Wang, S., Zhang, L., Gong, H., & Zou, Y. (2014). Insights into the activation and inhibition of angiotensin II type 1 receptor in the mechanically loaded heart. [Research Support, Non-U.S. Gov't]. Circulation Journal, 78(6), 1283–1289.Google Scholar
  6. 6.
    You, J., Wu, J., Zhang, Q., Ye, Y., Wang, S., Huang, J., et al. (2018). Differential cardiac hypertrophy and signaling pathways in pressure versus volume overload. American Journal of Physiology. Heart and Circulatory Physiology, 314(3), H552–H562.  https://doi.org/10.1152/ajpheart.00212.2017.Google Scholar
  7. 7.
    Bernardo, B. C., Weeks, K. L., Pretorius, L., & McMullen, J. R. (2010). Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. [Research Support, Non-U.S. Gov't Review]. Pharmacology & Therapeutics, 128(1), 191–227.  https://doi.org/10.1016/j.pharmthera.2010.04.005.Google Scholar
  8. 8.
    Wende, A. R., O'Neill, B. T., Bugger, H., Riehle, C., Tuinei, J., Buchanan, J., et al. (2015). Enhanced cardiac Akt/protein kinase B signaling contributes to pathological cardiac hypertrophy in part by impairing mitochondrial function via transcriptional repression of mitochondrion-targeted nuclear genes. Molecular and Cellular Biology, 35(5), 831–846.  https://doi.org/10.1128/MCB.01109-14.Google Scholar
  9. 9.
    Dworatzek, E., Mahmoodzadeh, S., Schubert, C., Westphal, C., Leber, J., Kusch, A., et al. (2014). Sex differences in exercise-induced physiological myocardial hypertrophy are modulated by oestrogen receptor beta. Cardiovascular Research, 102(3), 418–428.  https://doi.org/10.1093/cvr/cvu065.Google Scholar
  10. 10.
    Regitz-Zagrosek, V., & Seeland, U. (2011). Sex and gender differences in myocardial hypertrophy and heart failure. Wiener Medizinische Wochenschrift (1946), 161(5–6), 109–116.  https://doi.org/10.1007/s10354-011-0892-8.Google Scholar
  11. 11.
    Blenck, C. L., Harvey, P. A., Reckelhoff, J. F., & Leinwand, L. A. (2016). The Importance of Biological Sex and Estrogen in Rodent Models of Cardiovascular Health and Disease. Circulation Research, 118(8), 1294–1312.  https://doi.org/10.1161/CIRCRESAHA.116.307509.Google Scholar
  12. 12.
    Regitz-Zagrosek, V., & Kararigas, G. (2017). Mechanistic Pathways of Sex Differences in Cardiovascular Disease. Physiological Reviews, 97(1), 1–37.  https://doi.org/10.1152/physrev.00021.2015.Google Scholar
  13. 13.
    Patrizio, M., & Marano, G. (2016). Gender differences in cardiac hypertrophic remodeling. Annali dell'Istituto Superiore di Sanità, 52(2), 223–229.  https://doi.org/10.4415/ANN_16_02_14.Google Scholar
  14. 14.
    Song, J. J., Ma, Z., Wang, J., Chen, L. X., & Zhong, J. C. (2019). Gender Differences in Hypertension. Journal of Cardiovascular Translational Research.  https://doi.org/10.1007/s12265-019-09888-z.
  15. 15.
    Kararigas, G., Dworatzek, E., Petrov, G., Summer, H., Schulze, T. M., Baczko, I., et al. (2014). Sex-dependent regulation of fibrosis and inflammation in human left ventricular remodelling under pressure overload. European Journal of Heart Failure, 16(11), 1160–1167.  https://doi.org/10.1002/ejhf.171.Google Scholar
  16. 16.
    Toyofuku, M., Taniguchi, T., Morimoto, T., Yamaji, K., Furukawa, Y., Takahashi, K., et al. (2017). Sex Differences in Severe Aortic Stenosis- Clinical Presentation and Mortality. Circulation Journal, 81(8), 1213–1221.  https://doi.org/10.1253/circj.CJ-16-1244.Google Scholar
  17. 17.
    Rohde, L. E., Zhi, G., Aranki, S. F., Beckel, N. E., Lee, R. T., & Reimold, S. C. (1997). Gender-associated differences in left ventricular geometry in patients with aortic valve disease and effect of distinct overload subsets. The American Journal of Cardiology, 80(4), 475–480.Google Scholar
  18. 18.
    Avierinos, J. F., Inamo, J., Grigioni, F., Gersh, B., Shub, C., & Enriquez-Sarano, M. (2008). Sex differences in morphology and outcomes of mitral valve prolapse. Annals of Internal Medicine, 149(11), 787–795.Google Scholar
  19. 19.
    Rider, O. J., Lewandowski, A., Nethononda, R., Petersen, S. E., Francis, J. M., Pitcher, A., et al. (2013). Gender-specific differences in left ventricular remodelling in obesity: insights from cardiovascular magnetic resonance imaging. European Heart Journal, 34(4), 292–299.  https://doi.org/10.1093/eurheartj/ehs341.Google Scholar
  20. 20.
    Krumholz, H. M., Larson, M., & Levy, D. (1995). Prognosis of left ventricular geometric patterns in the Framingham Heart Study. Journal of the American College of Cardiology, 25(4), 879–884.  https://doi.org/10.1016/0735-1097(94)00473-4.Google Scholar
  21. 21.
    Gerdts, E., Izzo, R., Mancusi, C., Losi, M. A., Manzi, M. V., Canciello, G., et al. (2018). Left ventricular hypertrophy offsets the sex difference in cardiovascular risk (the Campania Salute Network). International Journal of Cardiology, 258, 257–261.  https://doi.org/10.1016/j.ijcard.2017.12.086.Google Scholar
  22. 22.
    Gori, M., Lam, C. S., Gupta, D. K., Santos, A. B., Cheng, S., Shah, A. M., et al. (2014). Sex-specific cardiovascular structure and function in heart failure with preserved ejection fraction. European Journal of Heart Failure, 16(5), 535–542.  https://doi.org/10.1002/ejhf.67.Google Scholar
  23. 23.
    Zhang, M., Wu, J., Sun, R., Tao, X., Wang, X., Kang, Q., et al. (2019). SIRT5 deficiency suppresses mitochondrial ATP production and promotes AMPK activation in response to energy stress. PLoS One, 14(2), e0211796.  https://doi.org/10.1371/journal.pone.0211796.Google Scholar
  24. 24.
    Douglas, P. S., Katz, S. E., Weinberg, E. O., Chen, M. H., Bishop, S. P., & Lorell, B. H. (1998). Hypertrophic remodeling: gender differences in the early response to left ventricular pressure overload. Journal of the American College of Cardiology, 32(4), 1118–1125.Google Scholar
  25. 25.
    Fliegner, D., Schubert, C., Penkalla, A., Witt, H., Kararigas, G., Dworatzek, E., et al. (2010). Female sex and estrogen receptor-beta attenuate cardiac remodeling and apoptosis in pressure overload. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 298(6), R1597–R1606.  https://doi.org/10.1152/ajpregu.00825.2009.Google Scholar
  26. 26.
    Ruppert, M., Korkmaz-Icoz, S., Loganathan, S., Jiang, W., Lehmann, L., Olah, A., et al. (2018). Pressure-volume analysis reveals characteristic sex-related differences in cardiac function in a rat model of aortic banding-induced myocardial hypertrophy. American Journal of Physiology. Heart and Circulatory Physiology, 315(3), H502–H511.  https://doi.org/10.1152/ajpheart.00202.2018.Google Scholar
  27. 27.
    Previlon, M., Pezet, M., Vinet, L., Mercadier, J. J., & Rouet-Benzineb, P. (2014). Gender-specific potential inhibitory role of Ca2+/calmodulin dependent protein kinase phosphatase (CaMKP) in pressure-overloaded mouse heart. PLoS One, 9(6), e90822.  https://doi.org/10.1371/journal.pone.0090822.Google Scholar
  28. 28.
    Scheuermann-Freestone, M., Freestone, N. S., Langenickel, T., Hohnel, K., Dietz, R., & Willenbrock, R. (2001). A new model of congestive heart failure in the mouse due to chronic volume overload. European Journal of Heart Failure, 3(5), 535–543.Google Scholar
  29. 29.
    Gardner, J. D., Brower, G. L., & Janicki, J. S. (2005). Effects of dietary phytoestrogens on cardiac remodeling secondary to chronic volume overload in female rats. Journal of Applied Physiology (Bethesda, MD: 1985), 99(4), 1378–1383.  https://doi.org/10.1152/japplphysiol.01141.2004.Google Scholar
  30. 30.
    Dent, M. R., Tappia, P. S., & Dhalla, N. S. (2010). Gender differences in cardiac dysfunction and remodeling due to volume overload. Journal of Cardiac Failure, 16(5), 439–449.  https://doi.org/10.1016/j.cardfail.2009.12.017.Google Scholar
  31. 31.
    Drolet, M. C., Lachance, D., Plante, E., Roussel, E., Couet, J., & Arsenault, M. (2006). Gender-related differences in left ventricular remodeling in chronic severe aortic valve regurgitation in rats. The Journal of Heart Valve Disease, 15(3), 345–351.Google Scholar
  32. 32.
    Beaumont, C., Walsh-Wilkinson, E., Drolet, M. C., Roussel, E., Arsenault, M., & Couet, J. (2017). Female rats with severe left ventricle volume overload exhibit more cardiac hypertrophy but fewer myocardial transcriptional changes than males. Scientific Reports, 7(1), 729.  https://doi.org/10.1038/s41598-017-00855-9.Google Scholar
  33. 33.
    Dent, M. R., Tappia, P. S., & Dhalla, N. S. (2010). Gender differences in apoptotic signaling in heart failure due to volume overload. Apoptosis, 15(4), 499–510.  https://doi.org/10.1007/s10495-009-0441-8.Google Scholar
  34. 34.
    Dent, M. R., Tappia, P. S., & Dhalla, N. S. (2011). Gender differences in beta-adrenoceptor system in cardiac hypertrophy due to arteriovenous fistula. Journal of Cellular Physiology, 226(1), 181–186.  https://doi.org/10.1002/jcp.22321.Google Scholar
  35. 35.
    Wu, C. H., Liu, J. Y., Wu, J. P., Hsieh, Y. H., Liu, C. J., Hwang, J. M., et al. (2005). 17beta-estradiol reduces cardiac hypertrophy mediated through the up-regulation of PI3K/Akt and the suppression of calcineurin/NF-AT3 signaling pathways in rats. Life Sciences, 78(4), 347–356.  https://doi.org/10.1016/j.lfs.2005.04.077. Google Scholar
  36. 36.
    Donaldson, C., Eder, S., Baker, C., Aronovitz, M. J., Weiss, A. D., Hall-Porter, M., et al. (2009). Estrogen attenuates left ventricular and cardiomyocyte hypertrophy by an estrogen receptor-dependent pathway that increases calcineurin degradation. Circulation Research, 104(2), 265–275, 211p following 275.  https://doi.org/10.1161/circresaha.108.190397.Google Scholar
  37. 37.
    van Eickels, M., Grohe, C., Cleutjens, J. P., Janssen, B. J., Wellens, H. J., & Doevendans, P. A. (2001). 17beta-estradiol attenuates the development of pressure-overload hypertrophy. Circulation, 104(12), 1419–1423.Google Scholar
  38. 38.
    Iorga, A., Li, J., Sharma, S., Umar, S., Bopassa, J. C., Nadadur, R. D., et al. (2016). Rescue of Pressure Overload-Induced Heart Failure by Estrogen Therapy. Journal of the American Heart Association, 5(1).  https://doi.org/10.1161/JAHA.115.002482.
  39. 39.
    Gardner, J. D., Murray, D. B., Voloshenyuk, T. G., Brower, G. L., Bradley, J. M., & Janicki, J. S. (2010). Estrogen attenuates chronic volume overload induced structural and functional remodeling in male rat hearts. American Journal of Physiology. Heart and Circulatory Physiology, 298(2), H497–H504.  https://doi.org/10.1152/ajpheart.00336.2009.Google Scholar
  40. 40.
    Pedram, A., Razandi, M., Lubahn, D., Liu, J., Vannan, M., & Levin, E. R. (2008). Estrogen inhibits cardiac hypertrophy: role of estrogen receptor-beta to inhibit calcineurin. Endocrinology, 149(7), 3361–3369.  https://doi.org/10.1210/en.2008-0133.Google Scholar
  41. 41.
    Kilic, A., Javadov, S., & Karmazyn, M. (2009). Estrogen exerts concentration-dependent pro-and anti-hypertrophic effects on adult cultured ventricular myocytes. Role of NHE-1 in estrogen-induced hypertrophy. Journal of Molecular and Cellular Cardiology, 46(3), 360–369.  https://doi.org/10.1016/j.yjmcc.2008.11.018.Google Scholar
  42. 42.
    Gardner, J. D., Brower, G. L., Voloshenyuk, T. G., & Janicki, J. S. (2008). Cardioprotection in female rats subjected to chronic volume overload: synergistic interaction of estrogen and phytoestrogens. American Journal of Physiology. Heart and Circulatory Physiology, 294(1), H198–H204.  https://doi.org/10.1152/ajpheart.00281.2007.Google Scholar
  43. 43.
    Li, Y., Kishimoto, I., Saito, Y., Harada, M., Kuwahara, K., Izumi, T., et al. (2004). Androgen contributes to gender-related cardiac hypertrophy and fibrosis in mice lacking the gene encoding guanylyl cyclase-A. Endocrinology, 145(2), 951–958.  https://doi.org/10.1210/en.2003-0816.Google Scholar
  44. 44.
    Altamirano, F., Oyarce, C., Silva, P., Toyos, M., Wilson, C., Lavandero, S., et al. (2009). Testosterone induces cardiomyocyte hypertrophy through mammalian target of rapamycin complex 1 pathway. The Journal of Endocrinology, 202(2), 299–307.  https://doi.org/10.1677/joe-09-0044.Google Scholar
  45. 45.
    Pirompol, P., Teekabut, V., Weerachatyanukul, W., Bupha-Intr, T., & Wattanapermpool, J. (2016). Supra-physiological dose of testosterone induces pathological cardiac hypertrophy. The Journal of Endocrinology, 229(1), 13–23.  https://doi.org/10.1530/JOE-15-0506.Google Scholar
  46. 46.
    Duran, J., Oyarce, C., Pavez, M., Valladares, D., Basualto-Alarcon, C., Lagos, D., et al. (2016). GSK-3beta/NFAT Signaling Is Involved in Testosterone-Induced Cardiac Myocyte Hypertrophy. PLoS One, 11(12), e0168255.  https://doi.org/10.1371/journal.pone.0168255.Google Scholar
  47. 47.
    Duran, J., Lagos, D., Pavez, M., Troncoso, M. F., Ramos, S., Barrientos, G., et al. (2017). Ca(2+)/Calmodulin-Dependent Protein Kinase II and Androgen Signaling Pathways Modulate MEF2 Activity in Testosterone-Induced Cardiac Myocyte Hypertrophy. Frontiers in Pharmacology, 8, 604.  https://doi.org/10.3389/fphar.2017.00604.Google Scholar
  48. 48.
    Mishra, J. S., More, A. S., Gopalakrishnan, K., & Kumar, S. (2019). Testosterone plays a permissive role in angiotensin II-induced hypertension and cardiac hypertrophy in male rats. Biology of Reproduction, 100(1), 139–148.  https://doi.org/10.1093/biolre/ioy179.Google Scholar
  49. 49.
    Regitz-Zagrosek, V., Oertelt-Prigione, S., Seeland, U., & Hetzer, R. (2010). Sex and gender differences in myocardial hypertrophy and heart failure. Circulation Journal, 74(7), 1265–1273.Google Scholar
  50. 50.
    de Kat, A. C., Dam, V., Onland-Moret, N. C., Eijkemans, M. J., Broekmans, F. J., & van der Schouw, Y. T. (2017). Unraveling the associations of age and menopause with cardiovascular risk factors in a large population-based study. BMC Medicine, 15(1), 2.  https://doi.org/10.1186/s12916-016-0762-8.Google Scholar
  51. 51.
    Rossouw, J. E., Prentice, R. L., Manson, J. E., Wu, L., Barad, D., Barnabei, V. M., et al. (2007). Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA, 297(13), 1465–1477.  https://doi.org/10.1001/jama.297.13.1465.Google Scholar
  52. 52.
    Miya, Y., Sumino, H., Ichikawa, S., Nakamura, T., Kanda, T., Kumakura, H., et al. (2002). Effects of hormone replacement therapy on left ventricular hypertrophy and growth-promoting factors in hypertensive postmenopausal women. Hypertension Research, 25(2), 153–159.Google Scholar
  53. 53.
    Dash, R., Schmidt, A. G., Pathak, A., Gerst, M. J., Biniakiewicz, D., Kadambi, V. J., et al. (2003). Differential regulation of p38 mitogen-activated protein kinase mediates gender-dependent catecholamine-induced hypertrophy. Cardiovascular Research, 57(3), 704–714.  https://doi.org/10.1016/s0008-6363(02)00772-1.Google Scholar
  54. 54.
    Shen, T., Ding, L., Ruan, Y., Qin, W., Lin, Y., Xi, C., et al. (2014). SIRT1 functions as an important regulator of estrogen-mediated cardiomyocyte protection in angiotensin II-induced heart hypertrophy. Oxidative Medicine and Cellular Longevity, 2014, 713894.  https://doi.org/10.1155/2014/713894.Google Scholar
  55. 55.
    Bhuiyan, M. S., Shioda, N., & Fukunaga, K. (2007). Ovariectomy augments pressure overload-induced hypertrophy associated with changes in Akt and nitric oxide synthase signaling pathways in female rats. American Journal of Physiology. Endocrinology and Metabolism, 293(6), E1606–E1614.  https://doi.org/10.1152/ajpendo.00246.2007.Google Scholar
  56. 56.
    Sasaki, H., Nagayama, T., Blanton, R. M., Seo, K., Zhang, M., Zhu, G., et al. (2014). PDE5 inhibitor efficacy is estrogen dependent in female heart disease. The Journal of Clinical Investigation, 124(6), 2464–2471.  https://doi.org/10.1172/JCI70731.Google Scholar
  57. 57.
    Redfield, M. M., Chen, H. H., Borlaug, B. A., Semigran, M. J., Lee, K. L., Lewis, G., et al. (2013). Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA, 309(12), 1268–1277.  https://doi.org/10.1001/jama.2013.2024.Google Scholar
  58. 58.
    Zou, Y., Liang, Y., Gong, H., Zhou, N., Ma, H., Guan, A., et al. (2011). Ryanodine receptor type 2 is required for the development of pressure overload-induced cardiac hypertrophy. Hypertension, 58(6), 1099–1110.  https://doi.org/10.1161/HYPERTENSIONAHA.111.173500.Google Scholar
  59. 59.
    Johnson, B. D., Zheng, W., Korach, K. S., Scheuer, T., Catterall, W. A., & Rubanyi, G. M. (1997). Increased expression of the cardiac L-type calcium channel in estrogen receptor-deficient mice. The Journal of General Physiology, 110(2), 135–140.Google Scholar
  60. 60.
    Jovanovic, S., Jovanovic, A., Shen, W. K., & Terzic, A. (2000). Low concentrations of 17beta-estradiol protect single cardiac cells against metabolic stress-induced Ca2+ loading. Journal of the American College of Cardiology, 36(3), 948–952.Google Scholar
  61. 61.
    Skavdahl, M., Steenbergen, C., Clark, J., Myers, P., Demianenko, T., Mao, L., et al. (2005). Estrogen receptor-beta mediates male-female differences in the development of pressure overload hypertrophy. American Journal of Physiology. Heart and Circulatory Physiology, 288(2), H469–H476.  https://doi.org/10.1152/ajpheart.00723.2004.Google Scholar
  62. 62.
    Babiker, F. A., Lips, D., Meyer, R., Delvaux, E., Zandberg, P., Janssen, B., et al. (2006). Estrogen receptor beta protects the murine heart against left ventricular hypertrophy. Arteriosclerosis, Thrombosis, and Vascular Biology, 26(7), 1524–1530.  https://doi.org/10.1161/01.atv.0000223344.11128.23.Google Scholar
  63. 63.
    Cavasin, M. A., Sankey, S. S., Yu, A. L., Menon, S., & Yang, X. P. (2003). Estrogen and testosterone have opposing effects on chronic cardiac remodeling and function in mice with myocardial infarction. American Journal of Physiology. Heart and Circulatory Physiology, 284(5), H1560–H1569.  https://doi.org/10.1152/ajpheart.01087.2002.Google Scholar
  64. 64.
    Zwadlo, C., Schmidtmann, E., Szaroszyk, M., Kattih, B., Froese, N., Hinz, H., et al. (2015). Antiandrogenic therapy with finasteride attenuates cardiac hypertrophy and left ventricular dysfunction. Circulation, 131(12), 1071–1081.  https://doi.org/10.1161/circulationaha.114.012066.Google Scholar
  65. 65.
    Baltatu, O., Cayla, C., Iliescu, R., Andreev, D., & Bader, M. (2003). Abolition of end-organ damage by antiandrogen treatment in female hypertensive transgenic rats. Hypertension, 41(3 Pt 2), 830–833.  https://doi.org/10.1161/01.hyp.0000048702.55183.89.Google Scholar
  66. 66.
    Ziemens, B., Wallaschofski, H., Volzke, H., Rettig, R., Dorr, M., Nauck, M., et al. (2013). Positive association between testosterone, blood pressure, and hypertension in women: longitudinal findings from the Study of Health in Pomerania. Journal of Hypertension, 31(6), 1106–1113.  https://doi.org/10.1097/HJH.0b013e3283603eb1.Google Scholar
  67. 67.
    Zhabyeyev, P., Gheblawi, M., & Oudit, G. Y. (2019). Testosterone and Cardiac Remodeling: Why are Older Men Susceptible to Heart Disease? American Journal of Physiology. Heart and Circulatory Physiology.  https://doi.org/10.1152/ajpheart.00046.2019.
  68. 68.
    Rhoden, E. L., & Morgentaler, A. (2004). Risks of testosterone-replacement therapy and recommendations for monitoring. The New England Journal of Medicine, 350(5), 482–492.  https://doi.org/10.1056/NEJMra022251.Google Scholar
  69. 69.
    Hwang, K., & Miner, M. (2015). Controversies in testosterone replacement therapy: testosterone and cardiovascular disease. Asian Journal of Andrology, 17(2), 187–191.  https://doi.org/10.4103/1008-682X.146968.Google Scholar
  70. 70.
    Goodale, T., Sadhu, A., Petak, S., & Robbins, R. (2017). Testosterone and the heart. Methodist DeBakey Cardiovascular Journal, 13(2), 68–72.  https://doi.org/10.14797/mdcj-13-2-68.Google Scholar
  71. 71.
    Ayaz, O., Banga, S. E., Heinze-Milne, S., Rose, R. A., Pyle, W. G., & Howlett, S. E. (2019). Long term testosterone deficiency modifies myofilament and calcium handling proteins and promotes diastolic dysfunction in the aging mouse heart. American Journal of Physiology. Heart and Circulatory Physiology.  https://doi.org/10.1152/ajpheart.00471.2018.
  72. 72.
    Ikeda, Y., Aihara, K., Sato, T., Akaike, M., Yoshizumi, M., Suzaki, Y., et al. (2005). Androgen receptor gene knockout male mice exhibit impaired cardiac growth and exacerbation of angiotensin II-induced cardiac fibrosis. The Journal of Biological Chemistry, 280(33), 29661–29666.  https://doi.org/10.1074/jbc.M411694200.Google Scholar
  73. 73.
    Ventura-Clapier, R., Dworatzek, E., Seeland, U., Kararigas, G., Arnal, J. F., Brunelleschi, S., et al. (2017). Sex in basic research: concepts in the cardiovascular field. Cardiovascular Research, 113(7), 711–724.  https://doi.org/10.1093/cvr/cvx066.Google Scholar
  74. 74.
    Rohini, A., Agrawal, N., Koyani, C. N., & Singh, R. (2010). Molecular targets and regulators of cardiac hypertrophy. Pharmacological Research, 61(4), 269–280.  https://doi.org/10.1016/j.phrs.2009.11.012.Google Scholar
  75. 75.
    de Simone, G., Devereux, R. B., Daniels, S. R., & Meyer, R. A. (1995). Gender differences in left ventricular growth. Hypertension, 26(6 Pt 1), 979–983.Google Scholar
  76. 76.
    Luczak, E. D., & Leinwand, L. A. (2009). Sex-based cardiac physiology. Annual Review of Physiology, 71, 1–18.  https://doi.org/10.1146/annurev.physiol.010908.163156.Google Scholar
  77. 77.
    Grandi, A. M., Venco, A., Barzizza, F., Scalise, F., Pantaleo, P., & Finardi, G. (1992). Influence of age and sex on left ventricular anatomy and function in normals. Cardiology, 81(1), 8–13.  https://doi.org/10.1159/000175770.Google Scholar
  78. 78.
    Sullivan, M. J., Cobb, F. R., & Higginbotham, M. B. (1991). Stroke volume increases by similar mechanisms during upright exercise in normal men and women. The American Journal of Cardiology, 67(16), 1405–1412.Google Scholar
  79. 79.
    Petersen, S. E., Hudsmith, L. E., Robson, M. D., Doll, H. A., Francis, J. M., Wiesmann, F., et al. (2006). Sex-specific characteristics of cardiac function, geometry, and mass in young adult elite athletes. Journal of Magnetic Resonance Imaging, 24(2), 297–303.  https://doi.org/10.1002/jmri.20633.Google Scholar
  80. 80.
    Higginbotham, M. B., Morris, K. G., Coleman, R. E., & Cobb, F. R. (1984). Sex-related differences in the normal cardiac response to upright exercise. Circulation, 70(3), 357–366.Google Scholar
  81. 81.
    Foryst-Ludwig, A., & Kintscher, U. (2013). Sex differences in exercise-induced cardiac hypertrophy. Pflügers Archiv, 465(5), 731–737.  https://doi.org/10.1007/s00424-013-1225-0.Google Scholar
  82. 82.
    Gertz, E. W., Wisneski, J. A., Stanley, W. C., & Neese, R. A. (1988). Myocardial substrate utilization during exercise in humans. Dual carbon-labeled carbohydrate isotope experiments. The Journal of Clinical Investigation, 82(6), 2017–2025.  https://doi.org/10.1172/jci113822.Google Scholar
  83. 83.
    Dorn, G. W., 2nd. (2007). The fuzzy logic of physiological cardiac hypertrophy. Hypertension, 49(5), 962–970.  https://doi.org/10.1161/hypertensionaha.106.079426.Google Scholar
  84. 84.
    Horton, T. J., Dow, S., Armstrong, M., & Donahoo, W. T. (2009). Greater systemic lipolysis in women compared with men during moderate-dose infusion of epinephrine and/or norepinephrine. Journal of Applied Physiology (Bethesda, MD: 1985), 107(1), 200–210.  https://doi.org/10.1152/japplphysiol.90812.2008.Google Scholar
  85. 85.
    Carter, S. L., Rennie, C., & Tarnopolsky, M. A. (2001). Substrate utilization during endurance exercise in men and women after endurance training. American Journal of Physiology. Endocrinology and Metabolism, 280(6), E898–E907.  https://doi.org/10.1152/ajpendo.2001.280.6.E898.Google Scholar
  86. 86.
    Soto, P. F., Herrero, P., Schechtman, K. B., Waggoner, A. D., Baumstark, J. M., Ehsani, A. A., et al. (2008). Exercise training impacts the myocardial metabolism of older individuals in a gender-specific manner. American Journal of Physiology. Heart and Circulatory Physiology, 295(2), H842–H850.  https://doi.org/10.1152/ajpheart.91426.2007.Google Scholar
  87. 87.
    Vega, R. B., Konhilas, J. P., Kelly, D. P., & Leinwand, L. A. (2017). Molecular Mechanisms Underlying Cardiac Adaptation to Exercise. Cell Metabolism, 25(5), 1012–1026.  https://doi.org/10.1016/j.cmet.2017.04.025.Google Scholar
  88. 88.
    Foryst-Ludwig, A., Kreissl, M. C., Sprang, C., Thalke, B., Bohm, C., Benz, V., et al. (2011). Sex differences in physiological cardiac hypertrophy are associated with exercise-mediated changes in energy substrate availability. American Journal of Physiology. Heart and Circulatory Physiology.  https://doi.org/10.1152/ajpheart.01222.2010.
  89. 89.
    Schaible, T. F., & Scheuer, J. (1979). Effects of physical training by running or swimming on ventricular performance of rat hearts. Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology, 46(4), 854–860.  https://doi.org/10.1152/jappl.1979.46.4.854.Google Scholar
  90. 90.
    Schaible, T. F., & Scheuer, J. (1981). Cardiac function in hypertrophied hearts from chronically exercised female rats. Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology, 50(6), 1140–1145.  https://doi.org/10.1152/jappl.1981.50.6.1140.Google Scholar
  91. 91.
    Strom, C. C., Aplin, M., Ploug, T., Christoffersen, T. E., Langfort, J., Viese, M., et al. (2005). Expression profiling reveals differences in metabolic gene expression between exercise-induced cardiac effects and maladaptive cardiac hypertrophy. The FEBS Journal, 272(11), 2684–2695.  https://doi.org/10.1111/j.1742-4658.2005.04684.x.Google Scholar
  92. 92.
    Honda, S., Harada, N., Ito, S., Takagi, Y., & Maeda, S. (1998). Disruption of sexual behavior in male aromatase-deficient mice lacking exons 1 and 2 of the cyp19 gene. Biochemical and Biophysical Research Communications, 252(2), 445–449.Google Scholar
  93. 93.
    Haines, C. D., Harvey, P. A., & Leinwand, L. A. (2012). Estrogens mediate cardiac hypertrophy in a stimulus-dependent manner. Endocrinology, 153(9), 4480–4490.  https://doi.org/10.1210/en.2012-1353.Google Scholar
  94. 94.
    Ewer, M. S., & Gluck, S. (2009). A woman's heart: the impact of adjuvant endocrine therapy on cardiovascular health. Cancer, 115(9), 1813–1826.  https://doi.org/10.1002/cncr.24219.Google Scholar
  95. 95.
    Mahmoodzadeh, S., Eder, S., Nordmeyer, J., Ehler, E., Huber, O., Martus, P., et al. (2006). Estrogen receptor alpha up-regulation and redistribution in human heart failure. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 20(7), 926–934.Google Scholar
  96. 96.
    Power, R. F., Mani, S. K., Codina, J., Conneely, O. M., & O'Malley, B. W. (1991). Dopaminergic and ligand-independent activation of steroid hormone receptors. Science, 254(5038), 1636–1639.Google Scholar
  97. 97.
    Lehman, J. J., & Kelly, D. P. (2002). Gene regulatory mechanisms governing energy metabolism during cardiac hypertrophic growth. Heart Failure Reviews, 7(2), 175–185.Google Scholar
  98. 98.
    Arany, Z., He, H., Lin, J., Hoyer, K., Handschin, C., Toka, O., et al. (2005). Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle. Cell Metabolism, 1(4), 259–271.  https://doi.org/10.1016/j.cmet.2005.03.002.Google Scholar
  99. 99.
    Grohe, C., Kahlert, S., Lobbert, K., & Vetter, H. (1998). Expression of oestrogen receptor alpha and beta in rat heart: role of local oestrogen synthesis. The Journal of Endocrinology, 156(2), R1–R7.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical SciencesFudan UniversityShanghaiChina

Personalised recommendations