Experimental and clinical studies have clearly demonstrated significant sex differences in myocardial structure and function, both under physiological and pathological conditions. The best example are significant sex differences in the cardiac tolerance to ischemia/reperfusion injury: pre-menopausal adult female hearts are more resistant as compared to the male myocardium. The importance of these findings is supported by the fact that the number of studies dealing with this issue increased significantly in recent years. Detailed molecular and cellular mechanisms responsible for sex differences are yet to be elucidated; however, it has been stressed that the differences cannot be explained only by the effect of estrogens. In recent years, a promising new hypothesis has been developed, suggesting that mitochondria may play a significant role in the sex differences in cardiac tolerance to oxygen deprivation. However, one is clear already today: sex differences are so important that they should be taken into consideration in the clinical practice for the selection of the optimal diagnostic and therapeutic strategy in the treatment of ischemic heart disease. The present review attempts to summarize the progress in cardiovascular research on sex-related differences in cardiac tolerance to oxygen deprivation during the last 40 years, i.e. from the first experimental observation. Particular attention was paid to the sex-related differences of the normal heart, sex-dependent tolerance to ischemia-reperfusion injury, the role of hormones and, finally, to the possible role of cardiac mitochondria in the mechanism of sex-dependent differences in cardiac tolerance to ischemia/reperfusion injury. Key words: Female heart, Cardiac hypoxic tolerance, Ischemia-reperfusion injury, Sex differences.

Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

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Ostadal B, Prochazka J, Pelouch V, Urbanova D, Widimsky J. Comparison of cardiopulmonary responses of male and female rats to intermittent high altitude hypoxia. Physiol Bohemoslov. 1984;33:129–138. PubMed

Ou LC, Sardella GL, Leiter JC, Brinck-Johnsen T, Smith RP. Role of sex hormones in development of chronic mountain sickness in rats. J Appl Physiol (1985) 1994;77:427–433. doi: 10.1152/jappl.1994.77.1.427. PubMed DOI

Kolodgie FD, Farb A, Litovsky SH, Narula J, Jeffers LA, Lee SJ, Virmani R. Myocardial protection of contractile function after global ischemia by physiologic estrogen replacement in the ovariectomized rat. J Mol Cell Cardiol. 1997;29:2403–2414. doi: 10.1006/jmcc.1997.0476. PubMed DOI

Moolman JA. Unravelling the cardioprotective mechanism of action of estrogens. Cardiovasc Res. 2006;69:777–780. doi: 10.1016/j.cardiores.2006.01.001. PubMed DOI

Netuka I, Szarszoi O, Maly J, Riha H, Turek D, Ostadalova I, Ostadal B. Late effect of early hypoxic disturbances in the rat heart: gender differences. Physiol Res. 2010;59:127–131. doi: 10.33549/physiolres.931833. PubMed DOI

Ostadal B, Netuka I, Maly J, Besik J, Ostadalova I. Gender differences in cardiac ischemic injury and protection--experimental aspects. Exp Biol Med (Maywood) 2009;234:1011–1019. doi: 10.3181/0812-MR-362. PubMed DOI

Legato MJ, Leghe JK. Principles of Gender Specific Medicine. New York: Elsevier; 2010. Gender and the heart: sex-specific differences in the normal myocardial anatomy and physiology.

de Simone G, Devereux RB, Daniels SR, Meyer RA. Gender differences in left ventricular growth. Hypertension. 1995;26:979–983. doi: 10.1161/01.HYP.26.6.979. PubMed DOI

Olivetti G, Giordano G, Corradi D, Melissari M, Lagrasta C, Gambert SR, Anversa P. Gender differences and aging: effects on the human heart. J Am Coll Cardiol. 1995;26:1068–1079. doi: 10.1016/0735-1097(95)00282-8. PubMed DOI

Zhang XP, Vatner SF, Shen YT, Rossi F, Tian Y, Peppas A, Resuello RR, Natividad FF, Vatner DE. Increased apoptosis and myocyte enlargement with decreased cardiac mass; distinctive features of the aging male, but not female, monkey heart. J Mol Cell Cardiol. 2007;43:487–491. doi: 10.1016/j.yjmcc.2007.07.048. PubMed DOI PMC

Mallat Z, Fornes P, Costagliola R, Esposito B, Belmin J, Lecomte D, Tedgui A. Age and gender effects on cardiomyocyte apoptosis in the normal human heart. J Gerontol A Biol Sci Med Sci. 2001;56:M719–723. doi: 10.1093/gerona/56.11.M719. PubMed DOI

Czubryt MP, Espira L, Lamoureux L, Abrenica B. The role of sex in cardiac function and disease. Can J Physiol Pharmacol. 2006;84:93–109. doi: 10.1139/y05-151. PubMed DOI

Burke JH, Goldberger JJ, Ehlert FA, Kruse JT, Parker MA, Kadish AH. Gender differences in heart rate before and after autonomic blockade: evidence against an intrinsic gender effect. Am J Med. 1996;100:537–543. doi: 10.1016/S0002-9343(96)00018-6. PubMed DOI

Bazett HC. An analysis of the time-relations of electrocardiograms. Heart. 1920;7:353–370.

Jochmann N, Stangl K, Garbe E, Baumann G, Stangl V. Female-specific aspects in the pharmacotherapy of chronic cardiovascular diseases. Eur Heart J. 2005;26:1585–1595. doi: 10.1093/eurheartj/ehi397. PubMed DOI

Dubey RK, Oparil S, Imthurn B, Jackson EK. Sex hormones and hypertension. Cardiovasc Res. 2002;53:688–708. doi: 10.1016/S0008-6363(01)00527-2. PubMed DOI

Schwertz DW, Vizgirda V, Solaro RJ, Piano MR, Ryjewski C. Sexual dimorphism in rat left atrial function and response to adrenergic stimulation. Mol Cell Biochem. 1999;200:143–153. doi: 10.1023/A:1007011807383. PubMed DOI

Schwertz DW, Beck JM, Kowalski JM, Ross JD. Sex differences in the response of rat heart ventricle to calcium. Biol Res Nurs. 2004;5:286–298. doi: 10.1177/1099800403262615. PubMed DOI

Machuki JO, Zhang HY, Geng J, Fu L, Adzika GK, Wu L, Shang W, Wu J, Kexue L, Zhao Z, Sun H. Estrogen regulation of cardiac cAMP-L-type Ca(2+) channel pathway modulates sex differences in basal contraction and responses to β(2)AR-mediated stress in left ventricular apical myocytes. Cell Commun Signal. 2019;17:34. doi: 10.1186/s12964-019-0346-2. PubMed DOI PMC

Farrell SR, Ross JL, Howlett SE. Sex differences in mechanisms of cardiac excitation-contraction coupling in rat ventricular myocytes. Am J Physiol Heart Circ Physiol. 2010;299:H36–45. doi: 10.1152/ajpheart.00299.2010. PubMed DOI

Sims C, Reisenweber S, Viswanathan PC, Choi BR, Walker WH, Salama G. Sex, age, and regional differences in L-type calcium current are important determinants of arrhythmia phenotype in rabbit hearts with drug-induced long QT type 2. Circ Res. 2008;102:e86–100. doi: 10.1161/CIRCRESAHA.108.173740. PubMed DOI PMC

Walker CJ, Schroeder ME, Aguado BA, Anseth KS, Leinwand LA. Matters of the heart: Cellular sex differences. J Mol Cell Cardiol. 2021;160:42–55. doi: 10.1016/j.yjmcc.2021.04.010. PubMed DOI PMC

MacDonald JK, Pyle WG, Reitz CJ, Howlett SE. Cardiac contraction, calcium transients, and myofilament calcium sensitivity fluctuate with the estrous cycle in young adult female mice. Am J Physiol Heart Circ Physiol. 2014;306:H938–953. doi: 10.1152/ajpheart.00730.2013. PubMed DOI

Vicencio JM, Ibarra C, Estrada M, Chiong M, Soto D, Parra V, Diaz-Araya G, Jaimovich E, Lavandero S. Testosterone induces an intracellular calcium increase by a nongenomic mechanism in cultured rat cardiac myocytes. Endocrinology. 2006;147:1386–1395. doi: 10.1210/en.2005-1139. PubMed DOI

Johnson MS, Moore RL, Brown DA. Sex differences in myocardial infarct size are abolished by sarcolemmal KATP channel blockade in rat. Am J Physiol Heart Circ Physiol. 2006;290:H2644–2647. doi: 10.1152/ajpheart.01291.2005. PubMed DOI

Bhupathy P, Babu GJ, Ito M, Periasamy M. Threonine-5 at the N-terminus can modulate sarcolipin function in cardiac myocytes. J Mol Cell Cardiol. 2009;47:723–729. doi: 10.1016/j.yjmcc.2009.07.014. PubMed DOI PMC

Keller KM, Howlett SE. Sex Differences in the Biology and Pathology of the Aging Heart. Can J Cardiol. 2016;32:1065–1073. doi: 10.1016/j.cjca.2016.03.017. PubMed DOI

Sapp DG, Howlett SE. The influence of sex and age on responses of isolated ventricular myocytes to simulated ischemia and reperfusion. In: Ostadal B, Dhalla NS, editors. Sex Differences in Heart Disease . Cham: Springer International Publishing; 2020. pp. 67–85. DOI

Dworatzek E, Baczko I, Kararigas G. Effects of aging on cardiac extracellular matrix in men and women. Proteomics Clin Appl. 2016;10:84–91. doi: 10.1002/prca.201500031. PubMed DOI

Barcena de Arellano ML, Pozdniakova S, Kühl AA, Baczko I, Ladilov Y, Regitz-Zagrosek V. Sex differences in the aging human heart: decreased sirtuins, pro-inflammatory shift and reduced anti-oxidative defense. Aging (Albany NY) 2019;11:1918–1933. doi: 10.18632/aging.101881. PubMed DOI PMC

Steg PG, Greenlaw N, Tardif JC, Tendera M, Ford I, Kääb S, Abergel H, Fox KM, Ferrari R. Women and men with stable coronary artery disease have similar clinical outcomes: insights from the international prospective CLARIFY registry. Eur Heart J. 2012;33:2831–2840. doi: 10.1093/eurheartj/ehs289. PubMed DOI PMC

Tobin JN, Wassertheil-Smoller S, Wexler JP, Steingart RM, Budner N, Lense L, Wachspress J. Sex bias in considering coronary bypass surgery. Ann Intern Med. 1987;107:19–25. doi: 10.7326/0003-4819-107-1-19. PubMed DOI

Steingart RM, Packer M, Hamm P, Coglianese ME, Gersh B, Geltman EM, Sollano J, Katz S, Moyé L, Basta LL, et al. Sex differences in the management of coronary artery disease. Survival and Ventricular Enlargement Investigators. N Engl J Med. 1991;325:226–230. doi: 10.1056/NEJM199107253250402. PubMed DOI

Legato MJ, Colman C. The Female Heart: The Truth about Women and Coronary Artery Disease. Simon & Schuster; 1991.

Duvall WL. Cardiovascular disease in women. Mt Sinai J Med. 2003;70:293–305. PubMed

Bassuk SS, Manson JE. Physical activity and cardiovascular disease prevention in women: a review of the epidemiologic evidence. Nutr Metab Cardiovasc Dis. 2010;20:467–473. doi: 10.1016/j.numecd.2009.12.015. PubMed DOI

Fejfar Z. Prevention against ischaemic heart disease: a critical review. In: Oliver MF, editor. Modern trends in cardiology. London: Butterworths; 1975. pp. 465–495.

Mathur P, Ostadal B, Romeo F, Mehta JL. Gender-Related Differences in Atherosclerosis. Cardiovasc Drugs Ther. 2015;29:319–327. doi: 10.1007/s10557-015-6596-3. PubMed DOI

Ostadal P, Ostadal B. Women and the management of acute coronary syndrome. Can J Physiol Pharmacol. 2012;90:1151–1159. doi: 10.1139/y2012-033. PubMed DOI

Ostadal B, Ostadal P. Sex-based differences in cardiac ischaemic injury and protection: therapeutic implications. Br J Pharmacol. 2014;171:541–554. doi: 10.1111/bph.12270. PubMed DOI PMC

Kolar F, Ostadal B. Sex differences in cardiovascular function. Acta Physiol (Oxf) 2013;207:584–587. doi: 10.1111/apha.12057. PubMed DOI

Ostadal B, Drahota Z, Houstek J, Milerova M, Ostadalova I, Hlavackova M, Kolar F. Developmental and sex differences in cardiac tolerance to ischemia-reperfusion injury: the role of mitochondria. Can J Physiol Pharmacol. 2019;97:808–814. doi: 10.1139/cjpp-2019-0060. PubMed DOI

Ostadal B, Ostadalova I, Szarszoi O, Netuka I, Olejnickova V, Hlavackova M. Sex-dependent effect of perinatal hypoxia on cardiac tolerance to oxygen deprivation in adults. Can J Physiol Pharmacol. 2021;99:1–8. doi: 10.1139/cjpp-2020-0310. PubMed DOI

Ostadal B, Ostadal P, Neckar J. Sex differences in cardiac ischemia/reperfusion injury. In: Ostadal B, Dhalla NS, editors. Sex differences in heart disease. Switzerland: Springer; 2020. pp. 25–37. DOI

Murphy E, Steenbergen C. Gender-based differences in mechanisms of protection in myocardial ischemia-reperfusion injury. Cardiovasc Res. 2007;75:478–486. doi: 10.1016/j.cardiores.2007.03.025. PubMed DOI

Booth EA, Lucchesi BR. Estrogen-mediated protection in myocardial ischemia-reperfusion injury. Cardiovasc Toxicol. 2008;8:101–113. doi: 10.1007/s12012-008-9022-2. PubMed DOI

Ross JL, Howlett SE. Age and ovariectomy abolish beneficial effects of female sex on rat ventricular myocytes exposed to simulated ischemia and reperfusion. PLoS One. 2012;7:e38425. doi: 10.1371/journal.pone.0038425. PubMed DOI PMC

Bell JR, Porrello ER, Huggins CE, Harrap SB, Delbridge LM. The intrinsic resistance of female hearts to an ischemic insult is abrogated in primary cardiac hypertrophy. Am J Physiol Heart Circ Physiol. 2008;294:H1514–1522. doi: 10.1152/ajpheart.01283.2007. PubMed DOI

Lujan HL, Dicarlo SE. Sex differences to myocardial ischemia and beta-adrenergic receptor blockade in conscious rats. Am J Physiol Heart Circ Physiol. 2008;294:H1523–1529. doi: 10.1152/ajpheart.01241.2007. PubMed DOI

Przyklenk K, Ovize M, Bauer B, Kloner RA. Gender does not influence acute myocardial infarction in adult dogs. Am Heart J. 1995;129:1108–1113. doi: 10.1016/0002-8703(95)90390-9. PubMed DOI

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;106:1681–1691. doi: 10.1161/CIRCRESAHA.109.213645. PubMed DOI PMC

Cross HR, Lu L, Steenbergen C, Philipson KD, Murphy E. Overexpression of the cardiac Na+/Ca2+ exchanger increases susceptibility to ischemia/reperfusion injury in male, but not female, transgenic mice. Circ Res. 1998;83:1215–1223. doi: 10.1161/01.RES.83.12.1215. PubMed DOI

Cross HR, Murphy E, Steenbergen C. Ca(2+) loading and adrenergic stimulation reveal male/female differences in susceptibility to ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2002;283:H481–489. doi: 10.1152/ajpheart.00790.2001. PubMed DOI

Besík J, Szárszoi O, Kunes J, Netuka I, Malý J, Kolár F, Pirk J, Ostádal B. Tolerance to acute ischemia in adult male and female spontaneously hypertensive rats. Physiol Res. 2007;56:267–274. doi: 10.33549/physiolres.930998. PubMed DOI

Clark C, Smith W, Lochner A, du Toit EF. The effects of gender and obesity on myocardial tolerance to ischemia. Physiol Res. 2011;60:291–301. doi: 10.33549/physiolres.931999. PubMed DOI

Piro M, Della Bona R, Abbate A, Biasucci LM, Crea F. Sex-related differences in myocardial remodeling. J Am Coll Cardiol. 2010;55:1057–1065. doi: 10.1016/j.jacc.2009.09.065. PubMed DOI

Regitz-Zagrosek V, Oertelt-Prigione S, Seeland U, Hetzer R. Sex and gender differences in myocardial hypertrophy and heart failure. Circ J. 2010;74:1265–1273. doi: 10.1253/circj.CJ-10-0196. PubMed DOI

Cavasin MA, Tao Z, Menon S, Yang XP. Gender differences in cardiac function during early remodeling after acute myocardial infarction in mice. Life Sci. 2004;75:2181–2192. doi: 10.1016/j.lfs.2004.04.024. PubMed DOI

Ostadal B, Ostadalova I, Dhalla NS. Development of cardiac sensitivity to oxygen deficiency: comparative and ontogenetic aspects. Physiol Rev. 1999;79:635–659. doi: 10.1152/physrev.1999.79.3.635. PubMed DOI

Netuka I, Szarszoi O, Maly J, Besik J, Neckar J, Kolar F, Ostadalova I, Pirk J, Ostadal B. Effect of perinatal hypoxia on cardiac tolerance to acute ischaemia in adult male and female rats. Clin Exp Pharmacol Physiol. 2006;33:714–719. doi: 10.1111/j.1440-1681.2006.04423.x. PubMed DOI

Humphreys RA, Kane KA, Parratt JR. The influence of maturation and gender on the anti-arrhythmic effect of ischaemic preconditioning in rats. Basic Res Cardiol. 1999;94:1–8. doi: 10.1007/s003950050120. PubMed DOI

Wang M, Crisostomo P, Wairiuko GM, Meldrum DR. Estrogen receptor-alpha mediates acute myocardial protection in females. Am J Physiol Heart Circ Physiol. 2006;290:H2204–2209. doi: 10.1152/ajpheart.01219.2005. PubMed DOI

Song X, Li G, Vaage J, Valen G. Effects of sex, gonadectomy, and oestrogen substitution on ischaemic preconditioning and ischaemia-reperfusion injury in mice. Acta Physiol Scand. 2003;177:459–466. doi: 10.1046/j.1365-201X.2003.01068.x. PubMed DOI

Crisostomo PR, Wang M, Wairiuko GM, Terrell AM, Meldrum DR. Postconditioning in females depends on injury severity. J Surg Res. 2006;134:342–347. doi: 10.1016/j.jss.2006.01.030. PubMed DOI

Lieder HR, Irmert A, Kamler M, Heusch G, Kleinbongard P. Sex is no determinant of cardioprotection by ischemic preconditioning in rats, but ischemic/reperfused tissue mass is for remote ischemic preconditioning. Physiol Rep. 2019;7:e14146. doi: 10.14814/phy2.14146. PubMed DOI PMC

Turcato S, Turnbull L, Wang GY, Honbo N, Simpson PC, Karliner JS, Baker AJ. Ischemic preconditioning depends on age and gender. Basic Res Cardiol. 2006;101:235–243. doi: 10.1007/s00395-006-0585-4. PubMed DOI

Ostadalova I, Ostadal B, Kolár F, Parratt JR, Wilson S. Tolerance to ischaemia and ischaemic preconditioning in neonatal rat heart. J Mol Cell Cardiol. 1998;30:857–865. doi: 10.1006/jmcc.1998.0653. PubMed DOI

Hausenloy DJ, Kharbanda RK, Møller UK, Ramlall M, Aarøe J, Butler R, Bulluck H, et al. Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial. Lancet. 2019;394:1415–1424. doi: 10.1016/S0140-6736(19)32039-2. PubMed DOI PMC

Murphy E. Estrogen signaling and cardiovascular disease. Circ Res. 2011;109:687–696. doi: 10.1161/CIRCRESAHA.110.236687. PubMed DOI PMC

Hutson DD, Gurrala R, Ogola BO, Zimmerman MA, Mostany R, Satou R, Lindsey SH. Estrogen receptor profiles across tissues from male and female Rattus norvegicus. Biol Sex Differ. 2019;10:4. doi: 10.1186/s13293-019-0219-9. PubMed DOI PMC

Chen JQ, Yager JD, Russo J. Regulation of mitochondrial respiratory chain structure and function by estrogens/estrogen receptors and potential physiological/pathophysiological implications. Biochim Biophys Acta. 2005;1746:1–17. doi: 10.1016/j.bbamcr.2005.08.001. PubMed DOI

Gabel SA, Walker VR, London RE, Steenbergen C, Korach KS, Murphy E. Estrogen receptor beta mediates gender differences in ischemia/reperfusion injury. J Mol Cell Cardiol. 2005;38:289–297. doi: 10.1016/j.yjmcc.2004.11.013. PubMed DOI

Deschamps AM, Murphy E. Activation of a novel estrogen receptor, GPER, is cardioprotective in male and female rats. Am J Physiol Heart Circ Physiol. 2009;297:H1806–1813. doi: 10.1152/ajpheart.00283.2009. PubMed DOI PMC

Bopassa JC, Eghbali M, Toro L, Stefani E. A novel estrogen receptor GPER inhibits mitochondria permeability transition pore opening and protects the heart against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2010;298:H16–23. doi: 10.1152/ajpheart.00588.2009. PubMed DOI PMC

Knowlton AA, Lee AR. Estrogen and the cardiovascular system. Pharmacol Ther. 2012;135:54–70. doi: 10.1016/j.pharmthera.2012.03.007. PubMed DOI PMC

Sun J, Picht E, Ginsburg KS, Bers DM, Steenbergen C, Murphy E. Hypercontractile female hearts exhibit increased S-nitrosylation of the L-type Ca2+ channel alpha1 subunit and reduced ischemia/reperfusion injury. Circ Res. 2006;98:403–411. doi: 10.1161/01.RES.0000202707.79018.0a. PubMed DOI

Tong H, Imahashi K, Steenbergen C, Murphy E. Phosphorylation of glycogen synthase kinase-3beta during preconditioning through a phosphatidylinositol-3-kinase--dependent pathway is cardioprotective. Circ Res. 2002;90:377–379. doi: 10.1161/01.RES.0000012567.95445.55. PubMed DOI

Lee TM, Su SF, Tsai CC, Lee YT, Tsai CH. Cardioprotective effects of 17 beta-estradiol produced by activation ofmitochondrial ATP-sensitive K(+)Channels in canine hearts. J Mol Cell Cardiol. 2000;32:1147–1158. doi: 10.1006/jmcc.2000.1167. PubMed DOI

Bae S, Zhang L. Gender differences in cardioprotection against ischemia/reperfusion injury in adult rat hearts: focus on Akt and protein kinase C signaling. J Pharmacol Exp Ther. 2005;315:1125–1135. doi: 10.1124/jpet.105.090803. PubMed DOI

Xu Y, Williams SJ, O’Brien D, Davidge ST. Hypoxia or nutrient restriction during pregnancy in rats leads to progressive cardiac remodeling and impairs postischemic recovery in adult male offspring. Faseb J. 2006;20:1251–1253. doi: 10.1096/fj.05-4917fje. PubMed DOI

Yu Y, Wei SG, Weiss RM, Felder RB. Sex differences in the central and peripheral manifestations of ischemia-induced heart failure in rats. Am J Physiol Heart Circ Physiol. 2019;316:H70–h79. doi: 10.1152/ajpheart.00499.2018. PubMed DOI PMC

Apaijai N, Chattipakorn SC, Chattipakorn N. The Roles of Testosterone in Cardiac Ischemia/Reperfusion Injury. In: Ostadal B, Dhalla NS, editors. Sex Differences in Heart Disease. Cham: Springer International Publishing; 2020. pp. 39–65. DOI

van der Wall EE. Testosterone bad for men, good for women? Neth Heart J. 2011;19:1–2. doi: 10.1007/s12471-010-0058-0. PubMed DOI PMC

Parker MW, Thompson PD. Anabolic-androgenic steroids: worse for the heart than we knew? Circ Heart Fail. 2010;3:470–471. doi: 10.1161/CIRCHEARTFAILURE.110.957720. PubMed DOI

Jones TH, Kelly DM. Randomized controlled trials - mechanistic studies of testosterone and the cardiovascular system. Asian J Androl. 2018;20:120–130. doi: 10.4103/aja.aja_6_18. PubMed DOI PMC

Maldonado O, Ramos A, Guapillo M, Rivera J, Palma I, Rubio-Gayosso I, Ramirez-Sanchez I, Najera N, Ceballos G, Mendez-Bolaina E. Effects of chronic inhibition of Testosterone metabolism on cardiac remodeling after ischemia/reperfusion-induced myocardial damage in gonadectomized rats. Biol Open. 2019:8. doi: 10.1242/bio.041905. PubMed DOI PMC

Ghimire A, Bisset ES, Howlett SE. Ischemia and reperfusion injury following cardioplegic arrest is attenuated by age and testosterone deficiency in male but not female mice. Biol Sex Differ. 2019;10:42. doi: 10.1186/s13293-019-0256-4. PubMed DOI PMC

Cavasin MA, Tao ZY, Yu AL, Yang XP. Testosterone enhances early cardiac remodeling after myocardial infarction, causing rupture and degrading cardiac function. Am J Physiol Heart Circ Physiol. 2006;290:H2043–2050. doi: 10.1152/ajpheart.01121.2005. PubMed DOI

Tsang S, Wu S, Liu J, Wong TM. Testosterone protects rat hearts against ischaemic insults by enhancing the effects of alpha(1)-adrenoceptor stimulation. Br J Pharmacol. 2008;153:693–709. doi: 10.1038/sj.bjp.0707624. PubMed DOI PMC

Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science. 2005;308:1583–1587. doi: 10.1126/science.1112062. PubMed DOI

Bonora M, Bononi A, De Marchi E, Giorgi C, Lebiedzinska M, Marchi S, Patergnani S, Rimessi A, Suski JM, Wojtala A, Wieckowski MR, Kroemer G, Galluzzi L, Pinton P. Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition. Cell Cycle. 2013;12:674–683. doi: 10.4161/cc.23599. PubMed DOI PMC

Ventura-Clapier R, Moulin M, Piquereau J, Lemaire C, Mericskay M, Veksler V, Garnier A. Mitochondria: a central target for sex differences in pathologies. Clin Sci (Lond) 2017;131:803–822. doi: 10.1042/CS20160485. PubMed DOI

Drahota Z, Endlicher R, Kučera O, Rychtrmoc D, Červinková Z. Factors affecting the function of the mitochondrial membrane permeability transition pore and their role in evaluation of calcium retention capacity values. Physiol Res. 2020;69:491–499. doi: 10.33549/physiolres.934391. PubMed DOI PMC

Colom B, Oliver J, Roca P, Garcia-Palmer FJ. Caloric restriction and gender modulate cardiac muscle mitochondrial H2O2 production and oxidative damage. Cardiovasc Res. 2007;74:456–465. doi: 10.1016/j.cardiores.2007.02.001. PubMed DOI

Moulin M, Piquereau J, Mateo P, Fortin D, Rucker-Martin C, Gressette M, Lefebvre F, Gresikova M, Solgadi A, Veksler V, Garnier A, Ventura-Clapier R. Sexual dimorphism of doxorubicin-mediated cardiotoxicity: potential role of energy metabolism remodeling. Circ Heart Fail. 2015;8:98–108. doi: 10.1161/CIRCHEARTFAILURE.114.001180. PubMed DOI

Ribeiro RF, Jr, Ronconi KS, Morra EA, Do Val Lima PR, Porto ML, Vassallo DV, Figueiredo SG, Stefanon I. Sex differences in the regulation of spatially distinct cardiac mitochondrial subpopulations. Mol Cell Biochem. 2016;419:41–51. doi: 10.1007/s11010-016-2748-4. PubMed DOI

Cao Y, Vergnes L, Wang YC, Pan C, Chella Krishnan K, Moore TM, Rosa-Garrido M, Kimball TH, Zhou Z, Charugundla S, Rau CD, Seldin MM, Wang J, Wang Y, Vondriska TM, Reue K, Lusis AJ. Sex differences in heart mitochondria regulate diastolic dysfunction. Nat Commun. 2022;13:3850. doi: 10.1038/s41467-022-31544-5. PubMed DOI PMC

Morkuniene R, Arandarcikaite O, Ivanoviene L, Borutaite V. Estradiol-induced protection against ischemia-induced heart mitochondrial damage and caspase activation is mediated by protein kinase G. Biochim Biophys Acta. 2010;1797:1012–1017. doi: 10.1016/j.bbabio.2010.03.027. PubMed DOI

Pavón N, Martínez-Abundis E, Hernández L, Gallardo-Pérez JC, Alvarez-Delgado C, Cerbón M, Pérez-Torres I, Aranda A, Chávez E. Sexual hormones: effects on cardiac and mitochondrial activity after ischemia-reperfusion in adult rats. Gender difference. J Steroid Biochem Mol Biol. 2012;132:135–146. doi: 10.1016/j.jsbmb.2012.05.003. PubMed DOI

Arieli Y, Gursahani H, Eaton MM, Hernandez LA, Schaefer S. Gender modulation of Ca(2+) uptake in cardiac mitochondria. J Mol Cell Cardiol. 2004;37:507–513. doi: 10.1016/j.yjmcc.2004.04.023. PubMed DOI

Williams GS, Boyman L, Lederer WJ. Mitochondrial calcium and the regulation of metabolism in the heart. J Mol Cell Cardiol. 2015;78:35–45. doi: 10.1016/j.yjmcc.2014.10.019. PubMed DOI PMC

Chweih H, Castilho RF, Figueira TR. Tissue and sex specificities in Ca2+ handling by isolated mitochondria in conditions avoiding the permeability transition. Exp Physiol. 2015;100:1073–1092. doi: 10.1113/EP085248. PubMed DOI

Halestrap AP. A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection. Biochem Soc Trans. 2010;38:841–860. doi: 10.1042/BST0380841. PubMed DOI

Drahota Z, Milerova M, Endlicher R, Rychtrmoc D, Cervinkova Z, Ostadal B. Developmental changes of the sensitivity of cardiac and liver mitochondrial permeability transition pore to calcium load and oxidative stress. Physiol Res. 2012;61:S165–172. doi: 10.33549/physiolres.932377. PubMed DOI

Halestrap AP, Richardson AP. The mitochondrial permeability transition: a current perspective on its identity and role in ischaemia/reperfusion injury. J Mol Cell Cardiol. 2015;78:129–141. doi: 10.1016/j.yjmcc.2014.08.018. PubMed DOI

Di Lisa F, Bernardi P. Mitochondrial function as a determinant of recovery or death in cell response to injury. Mol Cell Biochem. 1998;184:379–391. doi: 10.1023/A:1006810523586. PubMed DOI

Halestrap AP. Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans. 2006;34:232–237. https://doi.org/10.1042/BST20060232, https://doi.org/10.1042/BST0340232. PubMed DOI

Ong SB, Kalkhoran SB, Cabrera-Fuentes HA, Hausenloy DJ. Mitochondrial fusion and fission proteins as novel therapeutic targets for treating cardiovascular disease. Eur J Pharmacol. 2015;763:104–114. doi: 10.1016/j.ejphar.2015.04.056. PubMed DOI PMC

Alam MR, Baetz D, Ovize M. Cyclophilin D and myocardial ischemia-reperfusion injury: a fresh perspective. J Mol Cell Cardiol. 2015;78:80–89. doi: 10.1016/j.yjmcc.2014.09.026. PubMed DOI

Mewton N, Dernis A, Bresson D, Zouaghi O, Croisille P, Flocard E, Douek P, Bonnefoy-Cudraz E. Myocardial biomarkers and delayed enhanced cardiac magnetic resonance relationship in clinically suspected myocarditis and insight on clinical outcome. J Cardiovasc Med (Hagerstown) 2015;16:696–703. doi: 10.2459/JCM.0000000000000024. PubMed DOI

Cung TT, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D, Bonnefoy-Cudraz E, et al. Cyclosporine before PCI in Patients with Acute Myocardial Infarction. N Engl J Med. 2015;373:1021–1031. doi: 10.1056/NEJMoa1505489. PubMed DOI

Javadov S, Jang S, Parodi-Rullán R, Khuchua Z, Kuznetsov AV. Mitochondrial permeability transition in cardiac ischemia-reperfusion: whether cyclophilin D is a viable target for cardioprotection? Cell Mol Life Sci. 2017;74:2795–2813. doi: 10.1007/s00018-017-2502-4. PubMed DOI PMC

Milerova M, Drahota Z, Chytilova A, Tauchmannova K, Houstek J, Ostadal B. Sex difference in the sensitivity of cardiac mitochondrial permeability transition pore to calcium load. Mol Cell Biochem. 2016;412:147–154. doi: 10.1007/s11010-015-2619-4. PubMed DOI

Milerova M, Charvatova Z, Skarka L, Ostadalova I, Drahota Z, Fialova M, Ostadal B. Neonatal cardiac mitochondria and ischemia/reperfusion injury. Mol Cell Biochem. 2010;335:147–153. doi: 10.1007/s11010-009-0251-x. PubMed DOI

Bernardi P, Di Lisa F. The mitochondrial permeability transition pore: molecular nature and role as a target in cardioprotection. J Mol Cell Cardiol. 2015;78:100–106. doi: 10.1016/j.yjmcc.2014.09.023. PubMed DOI PMC

Regitz-Zagrosek V, Gebhard C. Gender medicine: effects of sex and gender on cardiovascular disease manifestation and outcomes. Nat Rev Cardiol. 2023;20:236–247. doi: 10.1038/s41569-022-00797-4. PubMed DOI PMC

Hellgren T, Blöndal M, Jortveit J, Ferenci T, Faxén J, Lewinter C, Eha J, Lõiveke P, Marandi T, Ainla T, Saar A, Veldre G, Andréka P, Halvorsen S, Jánosi A, Edfors R. Sex-related differences in the management and outcomes of patients hospitalized with ST-elevation myocardial infarction: a comparison within four European myocardial infarction registries. Eur Heart J Open. 2022;2:oeac042. doi: 10.1093/ehjopen/oeac042. PubMed DOI PMC

Aggarwal NR, Patel HN, Mehta LS, Sanghani RM, Lundberg GP, Lewis SJ, Mendelson MA, Wood MJ, Volgman AS, Mieres JH. Sex differences in ischemic heart disease: advances, obstacles, and next steps. Circ Cardiovasc Qual Outcomes. 2018;11:e004437. doi: 10.1161/CIRCOUTCOMES.117.004437. PubMed DOI

Regitz-Zagrosek V, Kararigas G. Mechanistic pathways of sex differences in cardiovascular disease. Physiol Rev. 2017;97:1–37. doi: 10.1152/physrev.00021.2015. PubMed DOI

Shi W, Sheng X, Dorr KM, Hutton JE, Emerson JI, Davies HA, Andrade TD, Wasson LK, Greco TM, Hashimoto Y, Federspiel JD, Robbe ZL, Chen X, Arnold AP, Cristea IM, Conlon FL. Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation. Dev Cell. 2021;56:3019–3034.e3017. doi: 10.1016/j.devcel.2021.09.022. PubMed DOI PMC

Deegan DF, Nigam P, Engel N. Sexual Dimorphism of the Heart: Genetics, Epigenetics, and Development. Front Cardiovasc Med. 2021;8:668252. doi: 10.3389/fcvm.2021.668252. PubMed DOI PMC