Skip to main content

Advertisement

SpringerLink
Log in

Sex Differences in Cardiovascular Aging and Heart Failure

  • Clinical Heart Failure (TE Meyer, Section Editor)
  • Published:
Current Heart Failure Reports Aims and scope Submit manuscript

Abstract

Purpose of the Review

This review summarizes sex-related changes in the heart and vasculature that occur with aging, both in the presence and absence of cardiovascular disease (CVD).

Recent Findings

In the presence of CVD risk factors and/or overt CVD, sex-specific changes in the number of cardiomyocytes, extent of the myocardial extracellular matrix, and myocellular hypertrophy promote unique patterns of LV remodeling in men and women. In addition, age- and sex-specific vascular stiffening is also well established, driven by changes in endothelial dysfunction, elastin–collagen content, microvascular dysfunction, and neurohormonal signaling. Together, these changes in LV chamber geometry and morphology, coupled with heightened vascular stiffness, appear to drive both age-related increases in systolic function and declines in diastolic function, particularly in postmenopausal women. Accordingly, estrogen has been implicated as a key mediator, given its direct vasodilating properties, association with nitric oxide excretion, and involvement in myocellular Ca2+ handling, mitochondrial energy production, and oxidative stress.

Summary

The culmination of the abovementioned sex-specific cardiac and vascular changes across the lifespan provides important insight into heart failure development, particularly of the preserved ejection fraction variety, while offering promise for future preventive strategies and therapeutic approaches.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Organization WH. Cardiovascular diseases (CVDs) 2017 [Available from: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds).

  2. Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation. 2019;139(10):e56–e528.

    Article  PubMed  Google Scholar 

  3. Salton CJ, Chuang ML, O'Donnell CJ, Kupka MJ, Larson MG, Kissinger KV, et al. Gender differences and normal left ventricular anatomy in an adult population free of hypertension. A cardiovascular magnetic resonance study of the Framingham Heart Study Offspring cohort. J Am Coll Cardiol. 2002;39(6):1055–60.

    Article  PubMed  Google Scholar 

  4. Cheng S, Fernandes VR, Bluemke DA, McClelland RL, Kronmal RA, Lima JA. Age-related left ventricular remodeling and associated risk for cardiovascular outcomes: the Multi-Ethnic Study of Atherosclerosis. Circ Cardiovasc Imaging. 2009;2(3):191–8.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Natori S, Lai S, Finn JP, Gomes AS, Hundley WG, Jerosch-Herold M, et al. Cardiovascular function in multi-ethnic study of atherosclerosis: normal values by age, sex, and ethnicity. AJR Am J Roentgenol. 2006;186(6 Suppl 2):S357–65.

    Article  PubMed  Google Scholar 

  6. Hees PS, Fleg JL, Lakatta EG, Shapiro EP. Left ventricular remodeling with age in normal men versus women: novel insights using three-dimensional magnetic resonance imaging. Am J Cardiol. 2002;90(11):1231–6.

    Article  PubMed  Google Scholar 

  7. Kitzman DW, Scholz DG, Hagen PT, Ilstrup DM, Edwards WD. Age-related changes in normal human hearts during the first 10 decades of life. Part II (Maturity): a quantitative anatomic study of 765 specimens from subjects 20 to 99 years old. Mayo Clin Proc. 1988;63(2):137–46.

    Article  CAS  PubMed  Google Scholar 

  8. Dannenberg AL, Levy D, Garrison RJ. Impact of age on echocardiographic left ventricular mass in a healthy population (the Framingham Study). Am J Cardiol. 1989;64(16):1066–8.

    Article  CAS  PubMed  Google Scholar 

  9. Cheng S, Xanthakis V, Sullivan LM, Lieb W, Massaro J, Aragam J, et al. Correlates of echocardiographic indices of cardiac remodeling over the adult life course: longitudinal observations from the Framingham Heart Study. Circulation. 2010;122(6):570–8.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lieb W, Xanthakis V, Sullivan LM, Aragam J, Pencina MJ, Larson MG, et al. Longitudinal tracking of left ventricular mass over the adult life course: clinical correlates of short- and long-term change in the framingham offspring study. Circulation. 2009;119(24):3085–92.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Petrov G, Dworatzek E, Schulze TM, Dandel M, Kararigas G, Mahmoodzadeh S, et al. Maladaptive remodeling is associated with impaired survival in women but not in men after aortic valve replacement. JACC Cardiovasc Imaging. 2014;7(11):1073–80.

    Article  PubMed  Google Scholar 

  12. Kararigas G, Dworatzek E, Petrov G, Summer H, Schulze TM, Baczko I, et al. Sex-dependent regulation of fibrosis and inflammation in human left ventricular remodelling under pressure overload. Eur J Heart Fail. 2014;16(11):1160–7.

    Article  CAS  PubMed  Google Scholar 

  13. Petrov G, Regitz-Zagrosek V, Lehmkuhl E, Krabatsch T, Dunkel A, Dandel M, et al. Regression of myocardial hypertrophy after aortic valve replacement: faster in women? Circulation. 2010;122(11 Suppl):S23–8.

    PubMed  Google Scholar 

  14. Treibel TA, Kozor R, Schofield R, Benedetti G, Fontana M, Bhuva AN, et al. Reverse myocardial remodeling following valve replacement in patients with aortic stenosis. J Am Coll Cardiol. 2018;71(8):860–71.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Dobson LE, Fairbairn TA, Musa TA, Uddin A, Mundie CA, Swoboda PP, et al. Sex-related differences in left ventricular remodeling in severe aortic stenosis and reverse remodeling after aortic valve replacement: a cardiovascular magnetic resonance study. Am Heart J. 2016;175:101–11.

    Article  PubMed  Google Scholar 

  16. Singh A, Chan DCS, Greenwood JP, Dawson DK, Sonecki P, Hogrefe K, et al. Symptom onset in aortic stenosis: relation to sex differences in left ventricular remodeling. JACC Cardiovasc Imaging. 2019;12(1):96–105.

    Article  PubMed  Google Scholar 

  17. • Miller RJH, Mikami Y, Heydari B, Wilton SB, James MT, Howarth AG, et al. Sex-specific relationships between patterns of ventricular remodelling and clinical outcomes. Eur Heart J Cardiovasc Imaging. 2020. This study confirms that sex differences in LV remodeling have serious adverse implications.

  18. Ho JE, Gona P, Pencina MJ, Tu JV, Austin PC, Vasan RS, et al. Discriminating clinical features of heart failure with preserved vs. reduced ejection fraction in the community. Eur Heart J. 2012;33(14):1734–41.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355(3):251–9.

    Article  CAS  PubMed  Google Scholar 

  20. Shah AM, Shah SJ, Anand IS, Sweitzer NK, O'Meara E, Heitner JF, et al. Cardiac structure and function in heart failure with preserved ejection fraction: baseline findings from the echocardiographic study of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial. Circ Heart Fail. 2014;7(1):104–15.

    Article  CAS  PubMed  Google Scholar 

  21. Gori M, Lam CS, Gupta DK, Santos AB, Cheng S, Shah AM, et al. Sex-specific cardiovascular structure and function in heart failure with preserved ejection fraction. Eur J Heart Fail. 2014;16(5):535–42.

    Article  PubMed  Google Scholar 

  22. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation. 2003;107(2):346–54.

    Article  PubMed  Google Scholar 

  23. Donekal S, Venkatesh BA, Liu YC, Liu CY, Yoneyama K, Wu CO, et al. Interstitial fibrosis, left ventricular remodeling, and myocardial mechanical behavior in a population-based multiethnic cohort: the Multi-Ethnic Study of Atherosclerosis (MESA) study. Circ Cardiovasc Imaging. 2014;7(2):292–302.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Boyle AJ, Shih H, Hwang J, Ye J, Lee B, Zhang Y, et al. Cardiomyopathy of aging in the mammalian heart is characterized by myocardial hypertrophy, fibrosis and a predisposition towards cardiomyocyte apoptosis and autophagy. Exp Gerontol. 2011;46(7):549–59.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lakatta EG, Mitchell JH, Pomerance A, Rowe GG. Human aging: changes in structure and function. J Am Coll Cardiol. 1987;10(2 Suppl A):42A–7A.

    Article  CAS  PubMed  Google Scholar 

  26. Sangaralingham SJ, Huntley BK, Martin FL, McKie PM, Bellavia D, Ichiki T, et al. The aging heart, myocardial fibrosis, and its relationship to circulating C-type natriuretic peptide. Hypertension. 2011;57(2):201–7.

    Article  CAS  PubMed  Google Scholar 

  27. Basso N, Cini R, Pietrelli A, Ferder L, Terragno NA, Inserra F. Protective effect of long-term angiotensin II inhibition. Am J Physiol Heart Circ Physiol. 2007;293(3):H1351–8.

    Article  CAS  PubMed  Google Scholar 

  28. Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, et al. Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest. 2009;119(3):524–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vasan RS, Sullivan LM, D'Agostino RB, Roubenoff R, Harris T, Sawyer DB, et al. Serum insulin-like growth factor I and risk for heart failure in elderly individuals without a previous myocardial infarction: the Framingham Heart Study. Ann Intern Med. 2003;139(8):642–8.

    Article  CAS  PubMed  Google Scholar 

  30. Luong N, Davies CR, Wessells RJ, Graham SM, King MT, Veech R, et al. Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity. Cell Metab. 2006;4(2):133–42.

    Article  CAS  PubMed  Google Scholar 

  31. Li Q, Ceylan-Isik AF, Li J, Ren J. Deficiency of insulin-like growth factor 1 reduces sensitivity to aging-associated cardiomyocyte dysfunction. Rejuvenation Res. 2008;11(4):725–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kessler EL, Rivaud MR, Vos MA, van Veen TAB. Sex-specific influence on cardiac structural remodeling and therapy in cardiovascular disease. Biol Sex Differ. 2019;10(1):7.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Olivetti G, Giordano G, Corradi D, Melissari M, Lagrasta C, Gambert SR, et al. Gender differences and aging: effects on the human heart. J Am Coll Cardiol. 1995;26(4):1068–79.

    Article  CAS  PubMed  Google Scholar 

  34. Kajstura J, Gurusamy N, Ogorek B, Goichberg P, Clavo-Rondon C, Hosoda T, et al. Myocyte turnover in the aging human heart. Circ Res. 2010;107(11):1374–86.

    Article  CAS  PubMed  Google Scholar 

  35. Mallat Z, Fornes P, Costagliola R, Esposito B, Belmin J, Lecomte D, et al. Age and gender effects on cardiomyocyte apoptosis in the normal human heart. J Gerontol A Biol Sci Med Sci. 2001;56(11):M719–23.

    Article  CAS  PubMed  Google Scholar 

  36. Biondi-Zoccai GG, Abate A, Bussani R, Camilot D, Giorgio FD, Marino MP, et al. Reduced post-infarction myocardial apoptosis in women: a clue to their different clinical course? Heart. 2005;91(1):99–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Guerra S, Leri A, Wang X, Finato N, Di Loreto C, Beltrami CA, et al. Myocyte death in the failing human heart is gender dependent. Circ Res. 1999;85(9):856–66.

    Article  CAS  PubMed  Google Scholar 

  38. Gazoti Debessa CR, Mesiano Maifrino LB, Rodrigues de Souza R. Age related changes of the collagen network of the human heart. Mech Ageing Dev. 2001;122(10):1049–58.

    Article  CAS  PubMed  Google Scholar 

  39. Fujimoto N, Hastings JL, Bhella PS, Shibata S, Gandhi NK, Carrick-Ranson G, et al. Effect of ageing on left ventricular compliance and distensibility in healthy sedentary humans. J Physiol. 2012;590(8):1871–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Arbab-Zadeh A, Dijk E, Prasad A, Fu Q, Torres P, Zhang R, et al. Effect of aging and physical activity on left ventricular compliance. Circulation. 2004;110(13):1799–805.

    Article  PubMed  Google Scholar 

  41. Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ, Kass DA. Age- and gender-related ventricular-vascular stiffening: a community-based study. Circulation. 2005;112(15):2254–62.

    Article  PubMed  Google Scholar 

  42. Claessens TE, Rietzschel ER, De Buyzere ML, De Bacquer D, De Backer G, Gillebert TC, et al. Noninvasive assessment of left ventricular and myocardial contractility in middle-aged men and women: disparate evolution above the age of 50? Am J Physiol Heart Circ Physiol. 2007;292(2):H856–65.

    Article  CAS  PubMed  Google Scholar 

  43. Borlaug BA, Redfield MM, Melenovsky V, Kane GC, Karon BL, Jacobsen SJ, et al. Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail. 2013;6(5):944–52.

    Article  PubMed  Google Scholar 

  44. Liu CY, Liu YC, Wu C, Armstrong A, Volpe GJ, van der Geest RJ, et al. Evaluation of age-related interstitial myocardial fibrosis with cardiac magnetic resonance contrast-enhanced T1 mapping: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2013;62(14):1280–7.

    Article  PubMed  Google Scholar 

  45. Tastet L, Kwiecinski J, Pibarot P, Capoulade R, Everett RJ, Newby DE, et al. Sex-related differences in the extent of myocardial fibrosis in patients with aortic valve stenosis. JACC Cardiovasc Imaging. 2020;13(3):699–711.

    Article  PubMed  Google Scholar 

  46. • Nickander J, Themudo R, Sigfridsson A, Xue H, Kellman P, Ugander M. Females have higher myocardial perfusion, blood volume and extracellular volume compared to males - an adenosine stress cardiovascular magnetic resonance study. Sci Rep. 2020;10(1):10380 This novel imaging study raises important questions about sex-specific differences in myocardial perfusion and extracellular volume fraction that needs further investigation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chung AK, Das SR, Leonard D, Peshock RM, Kazi F, Abdullah SM, et al. Women have higher left ventricular ejection fractions than men independent of differences in left ventricular volume: the Dallas Heart Study. Circulation. 2006;113(12):1597–604.

    Article  PubMed  Google Scholar 

  48. Maredziak M, Bengs S, Portmann A, Haider A, Wijnen WJ, Warnock GI, et al. Microvascular dysfunction and sympathetic hyperactivity in women with supra-normal left ventricular ejection fraction (snLVEF). Eur J Nucl Med Mol Imaging. 2020.

  49. Gebhard C, Stahli BE, Gebhard CE, Tasnady H, Zihler D, Wischnewsky MB, et al. Age- and gender-dependent left ventricular remodeling. Echocardiography. 2013;30(10):1143–50.

    Article  PubMed  Google Scholar 

  50. Ruan Q, Rao L, Middleton KJ, Khoury DS, Nagueh SF. Assessment of left ventricular diastolic function by early diastolic mitral annulus peak acceleration rate: experimental studies and clinical application. J Appl Physiol (1985). 2006;100(2):679–84.

    Article  Google Scholar 

  51. Kaku K, Takeuchi M, Otani K, Sugeng L, Nakai H, Haruki N, et al. Age- and gender-dependency of left ventricular geometry assessed with real-time three-dimensional transthoracic echocardiography. J Am Soc Echocardiogr. 2011;24(5):541–7.

    Article  PubMed  Google Scholar 

  52. Wang TJ, Evans JC, Benjamin EJ, Levy D, LeRoy EC, Vasan RS. Natural history of asymptomatic left ventricular systolic dysfunction in the community. Circulation. 2003;108(8):977–82.

    Article  PubMed  Google Scholar 

  53. Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA. 2003;289(2):194–202.

    Article  PubMed  Google Scholar 

  54. Mosterd A, Hoes AW, de Bruyne MC, Deckers JW, Linker DT, Hofman A, et al. Prevalence of heart failure and left ventricular dysfunction in the general population. The Rotterdam Study Eur Heart J. 1999;20(6):447–55.

    Article  CAS  PubMed  Google Scholar 

  55. McDonagh TA, Morrison CE, Lawrence A, Ford I, Tunstall-Pedoe H, McMurray JJ, et al. Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet. 1997;350(9081):829–33.

    Article  CAS  PubMed  Google Scholar 

  56. Davies M, Hobbs F, Davis R, Kenkre J, Roalfe AK, Hare R, et al. Prevalence of left-ventricular systolic dysfunction and heart failure in the Echocardiographic Heart of England Screening study: a population based study. Lancet. 2001;358(9280):439–44.

    Article  CAS  PubMed  Google Scholar 

  57. Devereux RB, Roman MJ, Paranicas M, Lee ET, Welty TK, Fabsitz RR, et al. A population-based assessment of left ventricular systolic dysfunction in middle-aged and older adults: the Strong Heart Study. Am Heart J. 2001;141(3):439–46.

    Article  CAS  PubMed  Google Scholar 

  58. Hayashi S, Yamada H, Nishio S, Hotchi J, Bando M, Takagawa Y, et al. Age- and gender-specific changes of tricuspid annular motion velocities in normal hearts. J Cardiol. 2015;65(5):397–402.

    Article  PubMed  Google Scholar 

  59. Hoshida S, Shinoda Y, Ikeoka K, Fukuoka H, Inui H, Watanabe T. Age- and sex-related differences in diastolic function and cardiac dimensions in a hypertensive population. ESC Heart Fail. 2016;3(4):270–7.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Hayward CS, Kalnins WV, Kelly RP. Gender-related differences in left ventricular chamber function. Cardiovasc Res. 2001;49(2):340–50.

    Article  CAS  PubMed  Google Scholar 

  61. Celentano A, Palmieri V, Arezzi E, Mureddu GF, Sabatella M, Di Minno G, et al. Gender differences in left ventricular chamber and midwall systolic function in normotensive and hypertensive adults. J Hypertens. 2003;21(7):1415–23.

    Article  CAS  PubMed  Google Scholar 

  62. Gruner Svealv B, Fritzon G, Andersson B. Gender and age related differences in left ventricular function and geometry with focus on the long axis. Eur J Echocardiogr. 2006;7(4):298–307.

    Article  PubMed  Google Scholar 

  63. Foll D, Jung B, Schilli E, Staehle F, Geibel A, Hennig J, et al. Magnetic resonance tissue phase mapping of myocardial motion: new insight in age and gender. Circ Cardiovasc Imaging. 2010;3(1):54–64.

    Article  PubMed  Google Scholar 

  64. Yoneyama K, Gjesdal O, Choi EY, Wu CO, Hundley WG, Gomes AS, et al. Age, sex, and hypertension-related remodeling influences left ventricular torsion assessed by tagged cardiac magnetic resonance in asymptomatic individuals: the multi-ethnic study of atherosclerosis. Circulation. 2012;126(21):2481–90.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Hung CL, Goncalves A, Shah AM, Cheng S, Kitzman D, Solomon SD. Age- and sex-related influences on left ventricular mechanics in elderly individuals free of prevalent heart failure: the ARIC study (Atherosclerosis Risk in Communities). Circ Cardiovasc Imaging. 2017;10(1):e004510.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Nio AQX, Stohr EJ, Shave RE. Age-related differences in left ventricular structure and function between healthy men and women. Climacteric. 2017;20(5):476–83.

    Article  CAS  PubMed  Google Scholar 

  67. Ayaz O, Howlett SE. Testosterone modulates cardiac contraction and calcium homeostasis: cellular and molecular mechanisms. Biol Sex Differ. 2015;6:9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Machuki JO, Zhang HY, Geng J, Fu L, Adzika GK, Wu L, et al. Estrogen regulation of cardiac cAMP-L-type Ca(2+) channel pathway modulates sex differences in basal contraction and responses to beta2AR-mediated stress in left ventricular apical myocytes. Cell Commun Signal. 2019;17(1):34.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Parks RJ, Bogachev O, Mackasey M, Ray G, Rose RA, Howlett SE. The impact of ovariectomy on cardiac excitation-contraction coupling is mediated through cAMP/PKA-dependent mechanisms. J Mol Cell Cardiol. 2017;111:51–60.

    Article  CAS  PubMed  Google Scholar 

  70. Ren J, Hintz KK, Roughead ZK, Duan J, Colligan PB, Ren BH, et al. Impact of estrogen replacement on ventricular myocyte contractile function and protein kinase B/Akt activation. Am J Physiol Heart Circ Physiol. 2003;284(5):H1800–7.

    Article  CAS  PubMed  Google Scholar 

  71. Turdi S, Huff AF, Pang J, He EY, Chen X, Wang S, et al. 17-beta estradiol attenuates ovariectomy-induced changes in cardiomyocyte contractile function via activation of AMP-activated protein kinase. Toxicol Lett. 2015;232(1):253–62.

    Article  CAS  PubMed  Google Scholar 

  72. Ribeiro RF Jr, Pavan BM, Potratz FF, Fiorim J, Simoes MR, Dias FM, et al. Myocardial contractile dysfunction induced by ovariectomy requires AT1 receptor activation in female rats. Cell Physiol Biochem. 2012;30(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  73. Paigel AS, Ribeiro RF Jr, Fernandes AA, Targueta GP, Vassallo DV, Stefanon I. Myocardial contractility is preserved early but reduced late after ovariectomy in young female rats. Reprod Biol Endocrinol. 2011;9:54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bupha-Intr T, Wattanapermpool J, Pena JR, Wolska BM, Solaro RJ. Myofilament response to Ca2+ and Na+/H+ exchanger activity in sex hormone-related protection of cardiac myocytes from deactivation in hypercapnic acidosis. Am J Phys Regul Integr Comp Phys. 2007;292(2):R837–43.

    CAS  Google Scholar 

  75. Wu Q, Zhao Z, Sun H, Hao YL, Yan CD, Gu SL. Oestrogen changed cardiomyocyte contraction and beta-adrenoceptor expression in rat hearts subjected to ischaemia-reperfusion. Exp Physiol. 2008;93(9):1034–43.

    Article  CAS  PubMed  Google Scholar 

  76. Curl CL, Wendt IR, Canny BJ, Kotsanas G. Effects of ovariectomy and 17 beta-oestradiol replacement on [Ca2+]i in female rat cardiac myocytes. Clin Exp Pharmacol Physiol. 2003;30(7):489–94.

    Article  CAS  PubMed  Google Scholar 

  77. Kam KW, Kravtsov GM, Liu J, Wong TM. Increased PKA activity and its influence on isoprenaline-stimulated L-type Ca2+ channels in the heart from ovariectomized rats. Br J Pharmacol. 2005;144(7):972–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Araujo AB, O'Donnell AB, Brambilla DJ, Simpson WB, Longcope C, Matsumoto AM, et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab. 2004;89(12):5920–6.

    Article  CAS  PubMed  Google Scholar 

  79. Oskui PM, French WJ, Herring MJ, Mayeda GS, Burstein S, Kloner RA. Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. J Am Heart Assoc. 2013;2(6):e000272.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Pluchino N, Carmignani A, Cubeddu A, Santoro A, Cela V, Errasti T. Androgen therapy in women: for whom and when. Arch Gynecol Obstet. 2013;288(4):731–7.

    Article  CAS  PubMed  Google Scholar 

  81. Mitchell GF, Parise H, Benjamin EJ, Larson MG, Keyes MJ, Vita JA, et al. Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart Study. Hypertension. 2004;43(6):1239–45.

    Article  CAS  PubMed  Google Scholar 

  82. Vaitkevicius PV, Fleg JL, Engel JH, O'Connor FC, Wright JG, Lakatta LE, et al. Effects of age and aerobic capacity on arterial stiffness in healthy adults. Circulation. 1993;88(4 Pt 1):1456–62.

    Article  CAS  PubMed  Google Scholar 

  83. Kelly R, Hayward C, Avolio A, O'Rourke M. Noninvasive determination of age-related changes in the human arterial pulse. Circulation. 1989;80(6):1652–9.

    Article  CAS  PubMed  Google Scholar 

  84. Smulyan H, Asmar RG, Rudnicki A, London GM, Safar ME. Comparative effects of aging in men and women on the properties of the arterial tree. J Am Coll Cardiol. 2001;37(5):1374–80.

    Article  CAS  PubMed  Google Scholar 

  85. Gatzka CD, Kingwell BA, Cameron JD, Berry KL, Liang YL, Dewar EM, et al. Gender differences in the timing of arterial wave reflection beyond differences in body height. J Hypertens. 2001;19(12):2197–203.

    Article  CAS  PubMed  Google Scholar 

  86. Hayward CS, Kelly RP. Gender-related differences in the central arterial pressure waveform. J Am Coll Cardiol. 1997;30(7):1863–71.

    Article  CAS  PubMed  Google Scholar 

  87. Avolio AP, Deng FQ, Li WQ, Luo YF, Huang ZD, Xing LF, et al. Effects of aging on arterial distensibility in populations with high and low prevalence of hypertension: comparison between urban and rural communities in China. Circulation. 1985;71(2):202–10.

    Article  CAS  PubMed  Google Scholar 

  88. Chen CH, Nakayama M, Nevo E, Fetics BJ, Maughan WL, Kass DA. Coupled systolic-ventricular and vascular stiffening with age: implications for pressure regulation and cardiac reserve in the elderly. J Am Coll Cardiol. 1998;32(5):1221–7.

    Article  CAS  PubMed  Google Scholar 

  89. Little WC, Cheng CP. Left ventricular-arterial coupling in conscious dogs. Am J Phys. 1991;261(1 Pt 2):H70–6.

    CAS  Google Scholar 

  90. Burkhoff D, de Tombe PP, Hunter WC, Kass DA. Contractile strength and mechanical efficiency of left ventricle are enhanced by physiological afterload. Am J Phys. 1991;260(2 Pt 2):H569–78.

    CAS  Google Scholar 

  91. van der Velde ET, Burkhoff D, Steendijk P, Karsdon J, Sagawa K, Baan J. Nonlinearity and load sensitivity of end-systolic pressure-volume relation of canine left ventricle in vivo. Circulation. 1991;83(1):315–27.

    Article  PubMed  Google Scholar 

  92. Saba PS, Ganau A, Devereux RB, Pini R, Pickering TG, Roman MJ. Impact of arterial elastance as a measure of vascular load on left ventricular geometry in hypertension. J Hypertens. 1999;17(7):1007–15.

    Article  CAS  PubMed  Google Scholar 

  93. Sengupta PP, Khandheria BK, Narula J. Twist and untwist mechanics of the left ventricle. Heart Fail Clin. 2008;4(3):315–24.

    Article  PubMed  Google Scholar 

  94. Lumens J, Delhaas T, Arts T, Cowan BR, Young AA. Impaired subendocardial contractile myofiber function in asymptomatic aged humans, as detected using MRI. Am J Physiol Heart Circ Physiol. 2006;291(4):H1573–9.

    Article  CAS  PubMed  Google Scholar 

  95. Bianco CM, Farjo PD, Ghaffar YA, Sengupta PP. Myocardial mechanics in patients with normal LVEF and diastolic dysfunction. JACC Cardiovasc Imaging. 2020;13(1 Pt 2):258–71.

    Article  PubMed  Google Scholar 

  96. Szelenyi Z, Fazakas A, Szenasi G, Tegze N, Fekete B, Molvarec A, et al. The mechanism of reduced longitudinal left ventricular systolic function in hypertensive patients with normal ejection fraction. J Hypertens. 2015;33(9):1962–9 discussion 9.

    Article  CAS  PubMed  Google Scholar 

  97. Bell V, McCabe EL, Larson MG, Rong J, Merz AA, Osypiuk E, et al. Relations between aortic stiffness and left ventricular mechanical function in the community. J Am Heart Assoc. 2017;6(1):e004903.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Yoshida Y, Nakanishi K, Daimon M, Ishiwata J, Sawada N, Hirokawa M, et al. Sex-specific difference in the association between arterial stiffness and subclinical left ventricular dysfunction. Eur Heart J Cardiovasc Imaging. 2020.

  99. Takeuchi M, Nakai H, Kokumai M, Nishikage T, Otani S, Lang RM. Age-related changes in left ventricular twist assessed by two-dimensional speckle-tracking imaging. J Am Soc Echocardiogr. 2006;19(9):1077–84.

    Article  PubMed  Google Scholar 

  100. Buchalter MB, Rademakers FE, Weiss JL, Rogers WJ, Weisfeldt ML, Shapiro EP. Rotational deformation of the canine left ventricle measured by magnetic resonance tagging: effects of catecholamines, ischaemia, and pacing. Cardiovasc Res. 1994;28(5):629–35.

    Article  CAS  PubMed  Google Scholar 

  101. Rosen BD, Edvardsen T, Lai S, Castillo E, Pan L, Jerosch-Herold M, et al. Left ventricular concentric remodeling is associated with decreased global and regional systolic function: the Multi-Ethnic Study of Atherosclerosis. Circulation. 2005;112(7):984–91.

    PubMed  Google Scholar 

  102. Nikitin NP, Witte KK, Thackray SD, de Silva R, Clark AL, Cleland JG. Longitudinal ventricular function: normal values of atrioventricular annular and myocardial velocities measured with quantitative two-dimensional color Doppler tissue imaging. J Am Soc Echocardiogr. 2003;16(9):906–21.

    Article  PubMed  Google Scholar 

  103. Fujimoto N, Borlaug BA, Lewis GD, Hastings JL, Shafer KM, Bhella PS, et al. Hemodynamic responses to rapid saline loading: the impact of age, sex, and heart failure. Circulation. 2013;127(1):55–62.

    Article  CAS  PubMed  Google Scholar 

  104. Okura H, Takada Y, Yamabe A, Kubo T, Asawa K, Ozaki T, et al. Age- and gender-specific changes in the left ventricular relaxation: a Doppler echocardiographic study in healthy individuals. Circ Cardiovasc Imaging. 2009;2(1):41–6.

    Article  PubMed  Google Scholar 

  105. Daimon M, Watanabe H, Abe Y, Hirata K, Hozumi T, Ishii K, et al. Gender differences in age-related changes in left and right ventricular geometries and functions. Echocardiography of a healthy subject group. Circ J. 2011;75(12):2840–6.

    Article  PubMed  Google Scholar 

  106. Sudhir K, Chou TM, Mullen WL, Hausmann D, Collins P, Yock PG, et al. Mechanisms of estrogen-induced vasodilation: in vivo studies in canine coronary conductance and resistance arteries. J Am Coll Cardiol. 1995;26(3):807–14.

    Article  CAS  PubMed  Google Scholar 

  107. Reis SE, Gloth ST, Blumenthal RS, Resar JR, Zacur HA, Gerstenblith G, et al. Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. Circulation. 1994;89(1):52–60.

    Article  CAS  PubMed  Google Scholar 

  108. Caulin-Glaser T, Garcia-Cardena G, Sarrel P, Sessa WC, Bender JR. 17 beta-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2+ mobilization. Circ Res. 1997;81(5):885–92.

    Article  CAS  PubMed  Google Scholar 

  109. Lantin-Hermoso RL, Rosenfeld CR, Yuhanna IS, German Z, Chen Z, Shaul PW. Estrogen acutely stimulates nitric oxide synthase activity in fetal pulmonary artery endothelium. Am J Phys. 1997;273(1 Pt 1):L119–26.

    CAS  Google Scholar 

  110. Bassani JW, Bassani RA, Bers DM. Relaxation in rabbit and rat cardiac cells: species-dependent differences in cellular mechanisms. J Physiol. 1994;476(2):279–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bers D Excitation-contraction coupling and cardiac contractile force: Springer Science & Business Media; 2001.

  112. Alencar AK, da Silva JS, Lin M, Silva AM, Sun X, Ferrario CM, et al. Effect of age, estrogen status, and late-life GPER activation on cardiac structure and function in the Fischer344xBrown Norway Female Rat. J Gerontol A Biol Sci Med Sci. 2017;72(2):152–62.

    Article  CAS  PubMed  Google Scholar 

  113. Wang H, Jessup JA, Lin MS, Chagas C, Lindsey SH, Groban L. Activation of GPR30 attenuates diastolic dysfunction and left ventricle remodelling in oophorectomized mRen2.Lewis rats. Cardiovasc Res. 2012;94(1):96–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Michalson KT, Groban L, Howard TD, Shively CA, Sophonsritsuk A, Appt SE, et al. Estradiol treatment initiated early after ovariectomy regulates myocardial gene expression and inhibits diastolic dysfunction in female cynomolgus monkeys: potential roles for calcium homeostasis and extracellular matrix remodeling. J Am Heart Assoc. 2018;7(21):e009769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Maslov PZ, Kim JK, Argulian E, Ahmadi A, Narula N, Singh M, et al. Is cardiac diastolic dysfunction a part of post-menopausal syndrome? JACC Heart Fail. 2019;7(3):192–203.

    Article  PubMed  Google Scholar 

  116. Ayaz O, Banga S, Heinze-Milne S, Rose RA, Pyle WG, Howlett SE. Long-term testosterone deficiency modifies myofilament and calcium-handling proteins and promotes diastolic dysfunction in the aging mouse heart. Am J Physiol Heart Circ Physiol. 2019;316(4):H768–H80.

    Article  CAS  PubMed  Google Scholar 

  117. Golden KL, Marsh JD, Jiang Y. Testosterone regulates mRNA levels of calcium regulatory proteins in cardiac myocytes. Horm Metab Res. 2004;36(4):197–202.

    Article  CAS  PubMed  Google Scholar 

  118. Pouleur H. Diastolic dysfunction and myocardial energetics. Eur Heart J. 1990;11(Suppl C):30–4.

    Article  PubMed  Google Scholar 

  119. Aggarwal NR, Patel HN, Mehta LS, Sanghani RM, Lundberg GP, Lewis SJ, et al. Sex differences in ischemic heart disease: advances, obstacles, and next steps. Circ Cardiovasc Qual Outcomes. 2018;11(2):e004437.

    Article  PubMed  Google Scholar 

  120. Sobhani K, Nieves Castro DK, Fu Q, Gottlieb RA, Van Eyk JE, Noel Bairey Merz C. Sex differences in ischemic heart disease and heart failure biomarkers. Biol Sex Differ. 2018;9(1):43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Nelson MD, Szczepaniak LS, Wei J, Haftabaradaren A, Bharadwaj M, Sharif B, et al. Diastolic dysfunction in women with signs and symptoms of ischemia in the absence of obstructive coronary artery disease: a hypothesis-generating study. Circ Cardiovasc Imaging. 2014;7(3):510–6.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Nelson MD, Sharif B, Shaw JL, Cook-Wiens G, Wei J, Shufelt C, et al. Myocardial tissue deformation is reduced in subjects with coronary microvascular dysfunction but not rescued by treatment with ranolazine. Clin Cardiol. 2017;40(5):300–6.

    Article  PubMed  Google Scholar 

  123. Zamani SK, Samuel TJ, Wei J, Thomson LEJ, Tamarappoo B, Sharif B, et al. Left atrial stiffness in women with ischemia and no obstructive coronary artery disease: novel insight from left atrial feature tracking. Clin Cardiol. 2020.

  124. Brown DA, Perry JB, Allen ME, Sabbah HN, Stauffer BL, Shaikh SR, et al. Expert consensus document: mitochondrial function as a therapeutic target in heart failure. Nat Rev Cardiol. 2017;14(4):238–50.

    Article  CAS  PubMed  Google Scholar 

  125. Kumar AA, Kelly DP, Chirinos JA. Mitochondrial dysfunction in heart failure with preserved ejection fraction. Circulation. 2019;139(11):1435–50.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Lagranha CJ, Deschamps A, Aponte A, Steenbergen C, Murphy E. Sex differences in the phosphorylation of mitochondrial proteins result in reduced production of reactive oxygen species and cardioprotection in females. Circ Res. 2010;106(11):1681–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Lancaster TS, Jefferson SJ, Hunter JC, Lopez V, Van Eyk JE, Lakatta EG, et al. Quantitative proteomic analysis reveals novel mitochondrial targets of estrogen deficiency in the aged female rat heart. Physiol Genomics. 2012;44(20):957–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Liu H, Yanamandala M, Lee TC, Kim JK. Mitochondrial p38beta and manganese superoxide dismutase interaction mediated by estrogen in cardiomyocytes. PLoS One. 2014;9(1):e85272.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Fliegner D, Schubert C, Penkalla A, Witt H, Kararigas G, Dworatzek E, et al. Female sex and estrogen receptor-beta attenuate cardiac remodeling and apoptosis in pressure overload. Am J Phys Regul Integr Comp Phys. 2010;298(6):R1597–606.

    CAS  Google Scholar 

  130. Chen Y, Zhang Z, Hu F, Yang W, Yuan J, Cui J, et al. 17beta-estradiol prevents cardiac diastolic dysfunction by stimulating mitochondrial function: a preclinical study in a mouse model of a human hypertrophic cardiomyopathy mutation. J Steroid Biochem Mol Biol. 2015;147:92–102.

    Article  CAS  PubMed  Google Scholar 

  131. Silberman GA, Fan TH, Liu H, Jiao Z, Xiao HD, Lovelock JD, et al. Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction. Circulation. 2010;121(4):519–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Wang H, Kohr MJ, Traynham CJ, Wheeler DG, Janssen PM, Ziolo MT. Neuronal nitric oxide synthase signaling within cardiac myocytes targets phospholamban. Am J Phys Cell Phys. 2008;294(6):C1566–75.

    CAS  Google Scholar 

  133. Ziolo MT, Kohr MJ, Wang H. Nitric oxide signaling and the regulation of myocardial function. J Mol Cell Cardiol. 2008;45(5):625–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Zhang YH, Zhang MH, Sears CE, Emanuel K, Redwood C, El-Armouche A, et al. Reduced phospholamban phosphorylation is associated with impaired relaxation in left ventricular myocytes from neuronal NO synthase-deficient mice. Circ Res. 2008;102(2):242–9.

    Article  CAS  PubMed  Google Scholar 

  135. Moens AL, Takimoto E, Tocchetti CG, Chakir K, Bedja D, Cormaci G, et al. Reversal of cardiac hypertrophy and fibrosis from pressure overload by tetrahydrobiopterin: efficacy of recoupling nitric oxide synthase as a therapeutic strategy. Circulation. 2008;117(20):2626–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: Part II: causal mechanisms and treatment. Circulation. 2002;105(12):1503–8.

    Article  PubMed  Google Scholar 

  137. Jessup JA, Zhang L, Presley TD, Kim-Shapiro DB, Wang H, Chen AF, et al. Tetrahydrobiopterin restores diastolic function and attenuates superoxide production in ovariectomized mRen2.Lewis rats. Endocrinology. 2011;152(6):2428–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Jespersen L, Hvelplund A, Abildstrom SZ, Pedersen F, Galatius S, Madsen JK, et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J. 2012;33(6):734–44.

    Article  PubMed  Google Scholar 

  139. Bairey Merz CN, Shaw LJ, Reis SE, Bittner V, Kelsey SF, Olson M, et al. Insights from the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study: Part II: gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease. J Am Coll Cardiol. 2006;47(3 Suppl):S21–9.

    Article  PubMed  Google Scholar 

  140. Shaw LJ, Bairey Merz CN, Pepine CJ, Reis SE, Bittner V, Kelsey SF, et al. Insights from the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study: Part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies. J Am Coll Cardiol. 2006;47(3 Suppl):S4–S20.

    Article  PubMed  Google Scholar 

  141. Chantler PD, Lakatta EG, Najjar SS. Arterial-ventricular coupling: mechanistic insights into cardiovascular performance at rest and during exercise. J Appl Physiol (1985). 2008;105(4):1342–51.

    Article  Google Scholar 

  142. Borlaug BA, Melenovsky V, Redfield MM, Kessler K, Chang HJ, Abraham TP, et al. Impact of arterial load and loading sequence on left ventricular tissue velocities in humans. J Am Coll Cardiol. 2007;50(16):1570–7.

    Article  PubMed  Google Scholar 

  143. Gorski PA, Ceholski DK, Hajjar RJ. Altered myocardial calcium cycling and energetics in heart failure--a rational approach for disease treatment. Cell Metab. 2015;21(2):183–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Ikonomidis I, Aboyans V, Blacher J, Brodmann M, Brutsaert DL, Chirinos JA, et al. The role of ventricular-arterial coupling in cardiac disease and heart failure: assessment, clinical implications and therapeutic interventions. A consensus document of the European Society of Cardiology Working Group on Aorta & Peripheral Vascular Diseases, European Association of Cardiovascular Imaging, and Heart Failure Association. Eur J Heart Fail. 2019;21(4):402–24.

    Article  PubMed  Google Scholar 

  145. Tritakis V, Tzortzis S, Ikonomidis I, Dima K, Pavlidis G, Trivilou P, et al. Association of arterial stiffness with coronary flow reserve in revascularized coronary artery disease patients. World J Cardiol. 2016;8(2):231–9.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Ikonomidis I, Lekakis J, Papadopoulos C, Triantafyllidi H, Paraskevaidis I, Georgoula G, et al. Incremental value of pulse wave velocity in the determination of coronary microcirculatory dysfunction in never-treated patients with essential hypertension. Am J Hypertens. 2008;21(7):806–13.

    Article  PubMed  Google Scholar 

  147. van Schinkel LD, Auger D, van Elderen SG, Ajmone Marsan N, Delgado V, Lamb HJ, et al. Aortic stiffness is related to left ventricular diastolic function in patients with diabetes mellitus type 1: assessment with MRI and speckle tracking strain analysis. Int J Card Imaging. 2013;29(3):633–41.

    Article  Google Scholar 

  148. Pandey A, Khan H, Newman AB, Lakatta EG, Forman DE, Butler J, et al. Arterial stiffness and risk of overall heart failure, heart failure with preserved ejection fraction, and heart failure with reduced ejection fraction: the Health ABC Study (Health, Aging, and Body Composition). Hypertension. 2017;69(2):267–74.

    Article  CAS  PubMed  Google Scholar 

  149. Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, et al. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995;26(5):1235–41.

    Article  CAS  PubMed  Google Scholar 

  150. Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Deanfield JE. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol. 1994;24(2):471–6.

    Article  CAS  PubMed  Google Scholar 

  151. Skaug EA, Aspenes ST, Oldervoll L, Morkedal B, Vatten L, Wisloff U, et al. Age and gender differences of endothelial function in 4739 healthy adults: the HUNT3 Fitness Study. Eur J Prev Cardiol. 2013;20(4):531–40.

    Article  PubMed  Google Scholar 

  152. Moreau KL, Hildreth KL, Meditz AL, Deane KD, Kohrt WM. Endothelial function is impaired across the stages of the menopause transition in healthy women. J Clin Endocrinol Metab. 2012;97(12):4692–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Moreau KL, Stauffer BL, Kohrt WM, Seals DR. Essential role of estrogen for improvements in vascular endothelial function with endurance exercise in postmenopausal women. J Clin Endocrinol Metab. 2013;98(11):4507–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Yim SF, Lau TK, Sahota DS, Chung TK, Chang AM, Haines CJ. Prospective randomized study of the effect of "add-back" hormone replacement on vascular function during treatment with gonadotropin-releasing hormone agonists. Circulation. 1998;98(16):1631–5.

    Article  CAS  PubMed  Google Scholar 

  155. Lew R, Komesaroff P, Williams M, Dawood T, Sudhir K. Endogenous estrogens influence endothelial function in young men. Circ Res. 2003;93(11):1127–33.

    Article  CAS  PubMed  Google Scholar 

  156. Lieberman EH, Gerhard MD, Uehata A, Walsh BW, Selwyn AP, Ganz P, et al. Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann Intern Med. 1994;121(12):936–41.

    Article  CAS  PubMed  Google Scholar 

  157. Saitta A, Altavilla D, Cucinotta D, Morabito N, Frisina N, Corrado F, et al. Randomized, double-blind, placebo-controlled study on effects of raloxifene and hormone replacement therapy on plasma no concentrations, endothelin-1 levels, and endothelium-dependent vasodilation in postmenopausal women. Arterioscler Thromb Vasc Biol. 2001;21(9):1512–9.

    Article  CAS  PubMed  Google Scholar 

  158. Meendering JR, Torgrimson BN, Miller NP, Kaplan PF, Minson CT. Estrogen, medroxyprogesterone acetate, endothelial function, and biomarkers of cardiovascular risk in young women. Am J Physiol Heart Circ Physiol. 2008;294(4):H1630–7.

    Article  CAS  PubMed  Google Scholar 

  159. Miner JA, Martini ER, Smith MM, Brunt VE, Kaplan PF, Halliwill JR, et al. Short-term oral progesterone administration antagonizes the effect of transdermal estradiol on endothelium-dependent vasodilation in young healthy women. Am J Physiol Heart Circ Physiol. 2011;301(4):H1716–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Akishita M, Hashimoto M, Ohike Y, Ogawa S, Iijima K, Eto M, et al. Low testosterone level is an independent determinant of endothelial dysfunction in men. Hypertens Res. 2007;30(11):1029–34.

    Article  CAS  PubMed  Google Scholar 

  161. Empen K, Lorbeer R, Dorr M, Haring R, Nauck M, Glaser S, et al. Association of testosterone levels with endothelial function in men: results from a population-based study. Arterioscler Thromb Vasc Biol. 2012;32(2):481–6.

    Article  CAS  PubMed  Google Scholar 

  162. Makinen JI, Perheentupa A, Irjala K, Pollanen P, Makinen J, Huhtaniemi I, et al. Endogenous testosterone and brachial artery endothelial function in middle-aged men with symptoms of late-onset hypogonadism. Aging Male. 2011;14(4):237–42.

    Article  PubMed  CAS  Google Scholar 

  163. Corrigan FE 3rd, Al Mheid I, Eapen DJ, Hayek SS, Sher S, Martin GS, et al. Low testosterone in men predicts impaired arterial elasticity and microvascular function. Int J Cardiol. 2015;194:94–9.

    Article  PubMed  Google Scholar 

  164. Sansone A, Rastrelli G, Cignarelli A, de Rocco PM, Condorelli RA, Giannetta E, et al. Effect of treatment with testosterone on endothelial function in hypogonadal men: a systematic review and meta-analysis. Int J Impot Res. 2019;32(4):379–86.

    Article  PubMed  CAS  Google Scholar 

  165. Somani YB, Pawelczyk JA, De Souza MJ, Kris-Etherton PM, Proctor DN. Aging women and their endothelium: probing the relative role of estrogen on vasodilator function. Am J Physiol Heart Circ Physiol. 2019;317(2):H395–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Moreau KL. Intersection between gonadal function and vascular aging in women. J Appl Physiol (1985). 2018;125(6):1881–7.

    Article  CAS  Google Scholar 

  167. Moreau KL. Modulatory influence of sex hormones on vascular aging. Am J Physiol Heart Circ Physiol. 2019;316(3):H522–H6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Moreau KL, Babcock MC, Hildreth KL. Sex differences in vascular aging in response to testosterone. Biol Sex Differ. 2020;11(1):18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Haynes WG. Endothelins as regulators of vascular tone in man. Clin Sci (Lond). 1995;88(5):509–17.

    Article  CAS  Google Scholar 

  170. Ishikawa K, Ihara M, Noguchi K, Mase T, Mino N, Saeki T, et al. Biochemical and pharmacological profile of a potent and selective endothelin B-receptor antagonist, BQ-788. Proc Natl Acad Sci U S A. 1994;91(11):4892–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. • Kuczmarski AV, Shoemaker LN, Hobson JC, Edwards DG, Wenner MM. Altered endothelial ETB receptor expression in postmenopausal women. Am J Physiol Heart Circ Physiol. 2020;319(1):H242–H7 This study provides novel data demonstrating attenuated endothelial ETB receptor expression in postmenopausal women, providing mechanistic insight into vascular endothelial dysfunction in the population, with important potential therapeutic implications.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Kitada K, Ohkita M, Matsumura Y. Pathological importance of the endothelin-1/ET(B) receptor system on vascular diseases. Cardiol Res Pract. 2012;2012:731970.

    Article  PubMed  PubMed Central  Google Scholar 

  173. Ergul A, Shoemaker K, Puett D, Tackett RL. Gender differences in the expression of endothelin receptors in human saphenous veins in vitro. J Pharmacol Exp Ther. 1998;285(2):511–7.

    CAS  PubMed  Google Scholar 

  174. Donato AJ, Gano LB, Eskurza I, Silver AE, Gates PE, Jablonski K, et al. Vascular endothelial dysfunction with aging: endothelin-1 and endothelial nitric oxide synthase. Am J Physiol Heart Circ Physiol. 2009;297(1):H425–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Westby CM, Weil BR, Greiner JJ, Stauffer BL, DeSouza CA. Endothelin-1 vasoconstriction and the age-related decline in endothelium-dependent vasodilatation in men. Clin Sci (Lond). 2011;120(11):485–91.

    Article  CAS  Google Scholar 

  176. Wenner MM, Sebzda KN, Kuczmarski AV, Pohlig RT, Edwards DG. ETB receptor contribution to vascular dysfunction in postmenopausal women. Am J Phys Regul Integr Comp Phys. 2017;313(1):R51–R7.

    Google Scholar 

  177. Li Z, Froehlich J, Galis ZS, Lakatta EG. Increased expression of matrix metalloproteinase-2 in the thickened intima of aged rats. Hypertension. 1999;33(1):116–23.

    Article  CAS  PubMed  Google Scholar 

  178. O'Rourke MF, Hashimoto J. Mechanical factors in arterial aging: a clinical perspective. J Am Coll Cardiol. 2007;50(1):1–13.

    Article  PubMed  Google Scholar 

  179. Jacob MP. Extracellular matrix remodeling and matrix metalloproteinases in the vascular wall during aging and in pathological conditions. Biomed Pharmacother. 2003;57(5-6):195–202.

    Article  CAS  PubMed  Google Scholar 

  180. Qiu H, Depre C, Ghosh K, Resuello RG, Natividad FF, Rossi F, et al. Mechanism of gender-specific differences in aortic stiffness with aging in nonhuman primates. Circulation. 2007;116(6):669–76.

    Article  PubMed  Google Scholar 

  181. Cattell MA, Anderson JC, Hasleton PS. Age-related changes in amounts and concentrations of collagen and elastin in normotensive human thoracic aorta. Clin Chim Acta. 1996;245(1):73–84.

    Article  CAS  PubMed  Google Scholar 

  182. Spina M, Garbisa S, Hinnie J, Hunter JC, Serafini-Fracassini A. Age-related changes in composition and mechanical properties of the tunica media of the upper thoracic human aorta. Arteriosclerosis. 1983;3(1):64–76.

    Article  CAS  PubMed  Google Scholar 

  183. Andreotti L, Bussotti A, Cammelli D, di Giovine F, Sampognaro S, Sterrantino G, et al. Aortic connective tissue in ageing--a biochemical study. Angiology. 1985;36(12):872–9.

    Article  CAS  PubMed  Google Scholar 

  184. Maurel E, Shuttleworth CA, Bouissou H. Interstitial collagens and ageing in human aorta. Virchows Arch A Pathol Anat Histopathol. 1987;410(5):383–90.

    Article  CAS  PubMed  Google Scholar 

  185. Hosoda Y, Kawano K, Yamasawa F, Ishii T, Shibata T, Inayama S. Age-dependent changes of collagen and elastin content in human aorta and pulmonary artery. Angiology. 1984;35(10):615–21.

    Article  CAS  PubMed  Google Scholar 

  186. Bairey Merz CN. Women and ischemic heart disease: paradox and pathophysiology. JACC Cardiovasc Imaging. 2011;4(1):74–7.

    Article  PubMed  Google Scholar 

  187. Bairey Merz CN, Pepine CJ, Walsh MN, Fleg JL. Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade. Circulation. 2017;135(11):1075–92.

    Article  PubMed  Google Scholar 

  188. Nelson MD. Left ventricular diastolic dysfunction in women with nonobstructive ischemic heart disease: insights from magnetic resonance imaging and spectroscopy. Am J Physiol Regul Integr Comp Physiol. 2017;313(4):R322–r9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Shah SJ, Lam CSP, Svedlund S, Saraste A, Hage C, Tan R-S, et al. Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF. Eur Heart J. 2018;39(37):3439–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Borlaug BA, Olson TP, Lam CSP, Flood KS, Lerman A, Johnson BD, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2010;56(11):845–54.

    Article  PubMed  PubMed Central  Google Scholar 

  191. Wei J, Nelson MD, Sharif B, Shufelt C, Bairey Merz CN. Why do we care about coronary microvascular dysfunction and heart failure with preserved ejection fraction: addressing knowledge gaps for evidence-based guidelines. Eur Heart J. 2018;39(37):3451–3.

    Article  PubMed  PubMed Central  Google Scholar 

  192. Nelson MD, Wei J, Bairey Merz CN. Coronary microvascular dysfunction and heart failure with preserved ejection fraction as female-pattern cardiovascular disease: the chicken or the egg? Eur Heart J. 2018;39(10):850–2.

    Article  PubMed  PubMed Central  Google Scholar 

  193. Lipecz A, Miller L, Kovacs I, Czakó C, Csipo T, Baffi J, et al. Microvascular contributions to age-related macular degeneration (AMD): from mechanisms of choriocapillaris aging to novel interventions. Geroscience. 2019;41(6):813–45.

    Article  PubMed  PubMed Central  Google Scholar 

  194. Ikonomidis I, Pavlidis G, Thymis J, Birba D, Kalogeris A, Kousathana F, et al. Effects of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and their combination on endothelial glycocalyx, arterial function, and myocardial work index in patients with type 2 diabetes mellitus after 12-month treatment. J Am Heart Assoc. 2020;9(9):e015716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Pranskunas A, Tamosuitis T, Balciuniene N, Damanskyte D, Sneider E, Vitkauskiene A, et al. Alterations of conjunctival glycocalyx and microcirculation in non-septic critically ill patients. Microvasc Res. 2018;118:44–8.

    Article  PubMed  Google Scholar 

  196. Machin DR, Bloom SI, Campbell RA, Phuong TTT, Gates PE, Lesniewski LA, et al. Advanced age results in a diminished endothelial glycocalyx. Am J Physiol Heart Circ Physiol. 2018;315(3):H531–H9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. • Rosenberry R, Trojacek D, Chung S, Cipher DJ, Nelson MD. Interindividual differences in the ischemic stimulus and other technical considerations when assessing reactive hyperemia. Am J Phys Regul Integr Comp Phys. 2019;317(4):R530–R8 This study raises important methodological considerations regarding reactive hyperemia, a common measures of peripheral microvascular function. The considerations raised have direct implications for sex and age related differences previously reported.

    CAS  Google Scholar 

  198. Rosenberry R, Nelson MD. Reactive hyperemia: a review of methods, mechanisms, and considerations. Am J Phys Regul Integr Comp Phys. 2020;318(3):R605–R18.

    Google Scholar 

  199. Ganzeboom KS, Colman N, Reitsma JB, Shen WK, Wieling W. Prevalence and triggers of syncope in medical students. Am J Cardiol. 2003;91(8):1006–8 A8.

    Article  PubMed  Google Scholar 

  200. Fu Q, Arbab-Zadeh A, Perhonen MA, Zhang R, Zuckerman JH, Levine BD. Hemodynamics of orthostatic intolerance: implications for gender differences. Am J Physiol Heart Circ Physiol. 2004;286(1):H449–57.

    Article  CAS  PubMed  Google Scholar 

  201. Christou DD, Jones PP, Jordan J, Diedrich A, Robertson D, Seals DR. Women have lower tonic autonomic support of arterial blood pressure and less effective baroreflex buffering than men. Circulation. 2005;111(4):494–8.

    Article  PubMed  Google Scholar 

  202. Hart EC, Charkoudian N, Wallin BG, Curry TB, Eisenach JH, Joyner MJ. Sex differences in sympathetic neural-hemodynamic balance: implications for human blood pressure regulation. Hypertension. 2009;53(3):571–6.

    Article  CAS  PubMed  Google Scholar 

  203. Hart EC, Charkoudian N, Wallin BG, Curry TB, Eisenach J, Joyner MJ. Sex and ageing differences in resting arterial pressure regulation: the role of the beta-adrenergic receptors. J Physiol. 2011;589(Pt 21):5285–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Kneale BJ, Chowienczyk PJ, Brett SE, Coltart DJ, Ritter JM. Gender differences in sensitivity to adrenergic agonists of forearm resistance vasculature. J Am Coll Cardiol. 2000;36(4):1233–8.

    Article  CAS  PubMed  Google Scholar 

  205. Narkiewicz K, Phillips BG, Kato M, Hering D, Bieniaszewski L, Somers VK. Gender-selective interaction between aging, blood pressure, and sympathetic nerve activity. Hypertension. 2005;45(4):522–5.

    Article  CAS  PubMed  Google Scholar 

  206. Harvey RE, Barnes JN, Charkoudian N, Curry TB, Eisenach JH, Hart EC, et al. Forearm vasodilator responses to a beta-adrenergic receptor agonist in premenopausal and postmenopausal women. Phys Rep. 2014;2(6):e12032.

    Article  CAS  Google Scholar 

  207. Harvey RE, Ranadive SM, Limberg JK, Baker SE, Nicholson WT, Curry TB, et al. Forearm vasodilatation to a beta2 -adrenergic receptor agonist in premenopausal and postmenopausal women. Exp Physiol. 2020;105(5):886–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Briant LJ, Burchell AE, Ratcliffe LE, Charkoudian N, Nightingale AK, Paton JF, et al. Quantifying sympathetic neuro-haemodynamic transduction at rest in humans: insights into sex, ageing and blood pressure control. J Physiol. 2016;594(17):4753–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by National Institutes of Health grant nos. R01HL136601, HL090957, R01HL146158, N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, U01 64829, U01 HL649141, U01 HL649241, R03 AG032631, and R01HL146158.

Author information

Authors and Affiliations

  1. Applied Physiology and Advanced Imaging Lab, University of Texas at Arlington, 655 West Mitchell St, Arlington, TX, 76010, USA

    Andrew Oneglia & Michael D. Nelson

  2. Barbra Streisand Women’s Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, 127 S San Vicente Blvd, AHSP Suite A3206, Los Angeles, CA, 90048, USA

    Michael D. Nelson & C. Noel Bairey Merz

Authors
  1. Andrew Oneglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael D. Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Noel Bairey Merz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Noel Bairey Merz.

Ethics declarations

Conflict of Interest

C.N.B.M receives funding from Abbott Diagnostics, Sanofi (paid through CSMC) and serves as Board of Directors for iRhythm. Andrew Oneglia and Dr. Michael Nelson declare that they have no conflict of interest. Dr. Bairey Merz reports personal fees from iRhythm, personal fees from Med Intelligence, personal fees from Bayer Advisory Board, grants from California Institute for Precision Medicine, grants from CDMRP Department of Defense, grants from NHLBI subcontract to Research Triangle Institute (RTI) International, grants from the NIH, and grants from Sanofi, outside the submitted work.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Clinical Heart Failure

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Oneglia, A., Nelson, M.D. & Merz, C.N.B. Sex Differences in Cardiovascular Aging and Heart Failure. Curr Heart Fail Rep 17, 409–423 (2020). https://doi.org/10.1007/s11897-020-00487-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11897-020-00487-7

Keywords

Search

Navigation