No information is available about sex-related differences in unloading-induced cardiac atrophy. We aimed to compare the course of unloading-induced cardiac atrophy in intact (without gonadectomy) male and female rats, and in animals after gonadectomy, to obtain insight into the influence of sex hormones on this process. Heterotopic heart transplantation (HT((x)) was used as a model for heart unloading. Cardiac atrophy was assessed as the weight ratio of heterotopically transplanted heart weight (HW) to the native HW on days 7 and 14 after HTx in intact male and female rats. In separate experimental groups, gonadectomy was performed in male and female recipient animals 28 days before HT(x) and the course of cardiac atrophy was again evaluated on days 7 and 14 after HT(x). In intact male rats, HT(x) resulted in significantly greater decreases in whole HW when compared to intact female rats. The dynamics of the left ventricle (LV) and right ventricle (RV) atrophy after HT(x) was quite similar to that of whole hearts. Gonadectomy did not have any significant effect on the decreases in whole HW, LV, and RV weights, with similar results in male and female rats. Our results show that the development of unloading-induced cardiac atrophy is substantially reduced in female rats when compared to male rats. Since gonadectomy did not alter the course of cardiac atrophy after HTx, similarly in both male and female rats, we conclude that sex-linked differences in the development of unloading-induced cardiac atrophy are not caused by the activity of sex hormones.

Department of Cardiovascular Surgery Institute for Clinical and Experimental Medicine Prague Czech Republic

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Roger VL. Epidemiology of heart failure. A contemporary perspective. Circ Res. 2021;128:1421–1434. doi: 10.1161/CIRCRESAHA.121.318172. PubMed DOI

Savarese G, Becher PM, Lund LH, Seferovic P, Rosano GMC, Coats AJS. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res. 2023;118:3272–3287. doi: 10.1093/cvr/cvac013. PubMed DOI

Petrie MC, Dawson NF, Murdoch DR, Davie AP, McMurray JJ. Failure of women's hearts. Circulation. 1999;99:2334–2341. doi: 10.1161/01.CIR.99.17.2334. PubMed DOI

Cook JL, Grady KL, Colvin M, Joseph SM, Brisco MA, Walsh MN genVAD Working Group. Sex differences in the care of patients with advanced heart failure. Circ Cardiovasc Qual Outcomes. 2015;8(Suppl 2):S56–S59. doi: 10.1161/CIRCOUTCOMES.115.001730. PubMed DOI

Westerman S, Wenger NK. Women and heart disease, the underrecognized burden: sex differences, biases, and unmet clinical and research challenges. Clin Sci. 2016;130:551–563. doi: 10.1042/CS20150586. PubMed DOI

Bolijn R, Onland-Moret NC, Asselbergs FW, van der Schouw YT. Reproductive factors in relation to heart failure in women: A systematic review. Maturitas. 2017;106:57–72. doi: 10.1016/j.maturitas.2017.09.004. PubMed DOI

Clayton JA, Gaugh MD. Sex as a Biological Variable in Cardiovascular Diseases: JACC Focus Seminar 1/7. J Am Coll Cardiol. 2022;79:1388–1397. doi: 10.1016/j.jacc.2021.10.050. PubMed DOI

DeFilippis EM, Beale A, Martyn T, Agarwal A, Elkayam U, Lam CSP, Hsich E. Heart Failure Subtypes and Cardiomyopathies in Women. Circ Res. 2022;130:436–454. doi: 10.1161/CIRCRESAHA.121.319900. PubMed DOI PMC

Vogel B, Acevedo M, Appelman Y, Bairey Merz CN, Chieffo A, Figtree GA, Guerrero M, et al. The Lancet women and cardiovascular disease Commission: reducing the global burden by 2030. Lancet. 2021;397:2385–2438. doi: 10.1016/S0140-6736(21)00684-X. PubMed DOI

McDonagh TA, Metra M, Adamo M, Gardner S, Baumbach A, Böhm M, Burri H, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42:3599–3726. doi: 10.1093/eurheartj/ehab368. 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

Reue K, Wiese CB. Illuminating the Mechanisms Underlying Sex Differences in Cardiovascular Disease. Circ Res. 2022;130:1747–1762. doi: 10.1161/CIRCRESAHA.122.320259. PubMed DOI PMC

Frigerio M. Left Ventricular Assist Device: Indication, Timing, and Management. Heart Fail Clin. 2021;17:619–634. doi: 10.1016/j.hfc.2021.05.007. PubMed DOI

Varshney AS, DeFilippis EM, Cowger JA, Netuka I, Pinney SP, Givertz M. Trends and Outcomes of Left Ventricular Assist Device Therapy: JACC Focus Seminar. J Am Coll Cardiol. 2022;79:1092–1107. doi: 10.1016/j.jacc.2022.01.017. PubMed DOI

Shah P, Yuzefpolskaya M, Hickey GW, Breathett K, Wever-Pinzon O, Ton V-K, Hiesinger W, et al. Twelfth Interagency Registry for Mechanically Assisted Circulatory Support Report: Readmissions After Left Ventricular Assist Device. Ann Thorac Surg. 2022;113:722–737. doi: 10.1016/j.athoracsur.2021.12.011. PubMed DOI PMC

Tseliou E, Lavine KJ, Wever-Pinzon O, Topkara VK, Meyns B, Adachi I, Zimpfer D, et al. Biology of myocardial recovery in advanced heart failure with long-term mechanical support. J Heart Lung Transplant. 2022;41:1309–1323. doi: 10.1016/j.healun.2022.07.007. PubMed DOI

Kanwar MK, Selzman CH, Ton V-K, Miera O, Cornwell WK, 3rd, Antaki J, Drakos S, Shah P. Clinical myocardial recovery in advanced heart failure with long-term left ventricular assist device support. J Heart Lung Transplant. 2022;41:1324–1334. doi: 10.1016/j.healun.2022.05.015. PubMed DOI PMC

Boulet J, Mehra MR. Left ventricular reverse remodeling in heart failure: remission to recovery. Structur Heart. 2021;5:466–481. doi: 10.1080/24748706.2021.1954275. DOI

Gruen J, Caraballo C, Miller PE, McCullough M, Mezzacappa C, Ravindra N, Mullan CW, et al. Sex Differences in Patients Receiving Left Ventricular Assist Devices for End-Stage Heart Failure. JACC Heart Fail. 2020;8:770–779. doi: 10.1016/j.jchf.2020.04.015. PubMed DOI

Wever-Pinzon O, Drakos SG, McKellar SH, Horne BD, Caine WT, Kfoury AG, Li DY, et al. Cardiac Recovery During Long-Term Left Ventricular Assist Device Support. J Am Coll Cardiol. 2016;68:1540–1553. doi: 10.1016/j.jacc.2016.07.743. PubMed DOI

Shah P, Psotka M, Taleb I, Alharethi R, Shams MA, Wever-Pinzon O, Yin M, et al. Framework to Classify Reverse Cardiac Remodeling With Mechanical Circulatory Support: The Utah-Inova Stages. Circ Heart Fail. 2021;14:e007991. doi: 10.1161/CIRCHEARTFAILURE.120.007991. PubMed DOI PMC

Burkhoff D, Topkara VK, Sayer G, Uriel N. Reverse Remodeling With Left Ventricular Assist Devices. Circ Res. 2021;128:1594–1612. doi: 10.1161/CIRCRESAHA.121.318160. PubMed DOI PMC

Diakos NA, Selzman CH, Sachse FB, Stehlik J, Kfoury AG, Wever-Pinzon O, Catino A, et al. Myocardial atrophy and chronic mechanical unloading of the failing human heart: implications for cardiac assist device-induced myocardial recovery. J Am Coll Cardiol. 2014;64:1602–1612. doi: 10.1016/j.jacc.2014.05.073. PubMed DOI

Pokorný M, Cervenka L, Netuka I, Pirk J, Koňařík M, Malý J. Ventricular assist devices in heart failure: how to support the heart but prevent atrophy? Physiol Res. 2014;63:147–156. doi: 10.33549/physiolres.932617. PubMed DOI

Heckle MR, Flatt DM, Sun Y, Mancarella S, Marion TN, Gerling IC, Weber KT. Atrophied cardiomyocytes and their potential for rescue and recovery of ventricular function. Heart Fail Rev. 2016;21:191–198. doi: 10.1007/s10741-016-9535-x. PubMed DOI

Brinks H, Tevaearai H, Mühlfeld C, Bertschi D, Gahl B, Carrel T, Giraud M-N. The contractile function is preserved in unloaded hearts despite atrophic remodeling. J Thorac Cardiovasc Surg. 2009;137:742–746. doi: 10.1016/j.jtcvs.2008.09.020. PubMed DOI

Brinks H, Giraud MN, Segiser A, Ferrié C, Longnus S, Ullrich ND, Koch WJ, et al. Dynamic patterns of ventricular remodeling and apoptosis in hearts unloaded by heterotopic transplantation. J Heart Lung Transplant. 2014;33:203–210. doi: 10.1016/j.healun.2013.10.006. PubMed DOI PMC

Rakusan K, Heron MI, Kolar F, Korecky B. Transplantation-induced atrophy of normal and hypertrophic rat hearts: effect on cardiac myocytes and capillaries. J Mol Cell Cardiol. 1997;29:1045–1054. doi: 10.1006/jmcc.1996.0350. PubMed DOI

Soloff LA. Atrophy of myocardium and its myocytes by left ventricular assist device. Circulation. 1999;100:1012. doi: 10.1161/circ.100.9.1011/-b. PubMed DOI

Tsuneyoshi H, Oriyanhan W, Kanemitsu H, Shiina R, Nishina T, Matsuoka S, Ikeda T, Komeda M. Does the beta2-agonist clenbuterol help to maintain the myocardial potential to recover during mechanical unloading? Circulation. 2005;112(Suppl):I51–I56. doi: 10.1161/CIRCULATIONAHA.104.525097. PubMed DOI

Birks EJ, Tansley PD, Hardy J, George RS, Bowles CT, Burke M, Banner NR, et al. Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med. 2006;355:1873–1884. doi: 10.1056/NEJMoa053063. PubMed DOI

Navaratnarajah M, Siedlecka U, Ibrahim M, van Doorn C, Soppa G, Gandhi A, Shah A, et al. Impact of combined clenbuterol and metoprolol therapy on reverse remodeling during mechanical unloading. PLoS One. 2014;9:e92909. doi: 10.1371/journal.pone.0092909. PubMed DOI PMC

Didié M, Biermann D, Buchert R, Hess A, Wittköpper K, Christalla P, Döker S, et al. Preservation of left ventricular function and morphology in volume-loaded versus volume-unloaded heterotopic heart transplants. Am J Physiol Heart Circ Physiol. 2013;305:H533–H541. doi: 10.1152/ajpheart.00218.2013. PubMed DOI

Liu Y, Maureira P, Gauchotte G, Falanga A, Marie V, Olivier A, Groubatch F, et al. Effect of chronic left ventricular unloading on myocardial remodeling: Multimodal assessment of two heterotopic heart transplantation techniques. J Heart Lung Transplant. 2015;34:594–603. doi: 10.1016/j.healun.2014.11.015. PubMed DOI

Oriyanhan W, Tsuneyoshi H, Nishina T, Matsuoka S, Ikeda T, Komeda M. Determination of optimal duration of mechanical unloading for failing hearts to achieve bridge to recovery in a rat heterotopic heart transplantation model. J Heart Lung Transplant. 2007;26:16–23. doi: 10.1016/j.healun.2006.10.016. PubMed DOI

Muranaka H, Marui A, Tsukashita M, Wang J, Nakano J, Ikeda T, Sakata R. Prolonged mechanical unloading preserves myocardial contractility but impairs relaxation in rat heart of dilated cardiomyopathy accompanied by myocardial stiffness and apoptosis. J Thorac Cardiovasc Surg. 2010;140:916–922. doi: 10.1016/j.jtcvs.2010.02.006. PubMed DOI

Fu X, Segiser A, Carrel TP, Tevaearai HT, Most H. Rat heterotopic heart transplantation model to investigate unloading-induced myocardial remodeling. Front Cardiovasc Med. 2016;3:34. doi: 10.3389/fcvm.2016.00034. PubMed DOI PMC

Benke K, Sayour AA, Mátyás C, Ágg B, Németh BT, Oláh A, Ruppert M, et al. Heterotopic Abdominal Rat Heart Transplantation as a Model to Investigate Volume Dependency of Myocardial Remodeling. Transplantation. 2017;101:498–505. doi: 10.1097/TP.0000000000001585. PubMed DOI

Pokorný M, Mrázová I, Malý J, Pirk J, Netuka I, Vaňourková Z, Doleželová Š, et al. Effects of increased myocardial tissue concentration of myristic, palmitic and palmitoleic acids on the course of cardiac atrophy of the failing heart unloaded by heterotopic transplantation. Physiol Res. 2018;67:13–30. doi: 10.33549/physiolres.933637. PubMed DOI

Pokorný M, Mrázová I, Kubátová H, Piťha J, Malý J, Pirk J, Maxová H, et al. Intraventricular placement of a spring expander does not attenuate cardiac atrophy of the healthy heart induced by unloading via heterotopic heart transplantation. Physiol Res. 2019;68:567–580. doi: 10.33549/physiolres.933936. PubMed DOI

Pokorný M, Mrázová I, Šochman J, Melenovský V, Malý J, Pirk J, Červenková L, et al. Isovolumic loading of the failing heart by intra-ventricular placement of a spring expander attenuates cardiac atrophy after heterotopic heart transplantation. Biosci Rep. 2018;38:BSR20180371. doi: 10.1042/BSR20180371. PubMed DOI PMC

Ono K, Lindsey ES. Improved technique of heart transplantation in rats. J Thorac Cardiovasc Surg. 1969;57:225–229. doi: 10.1016/S0022-5223(19)42744-X. PubMed DOI

Vaněčková I, Husková Z, Vaňourková Z, Cervenka L. Castration has antihypertensive and organoprotective effects in male but not in female heterozygous Ren-2 rats. Kidney Blood Press Res. 2011;34:46–52. doi: 10.1159/000322618. PubMed DOI

Koblihová E, Mrázová I, Vaňourková Z, Maxová H, Ryska M, Froněk J. Sex-linked differences in the course of thioacetamide-induced acute liver failure in Lewis rats. Physiol Res. 2020;69:835–845. doi: 10.33549/physiolres.934499. PubMed DOI PMC

Kolár F, Papousek F, MacNaughton C, Pelouch V, Milerová M, Korecky B. Myocardial fibrosis and right ventricular function of heterotopically transplanted hearts in rats treated with cyclosporin. Mol Cell Biochem. 1996;163–164:253–260. doi: 10.1007/BF00408666. PubMed DOI

Benes J, Jr, Melenovsky V, Skaroupkova P, Pospisilova J, Petrak J, Cervenka L, Sedmera D. Myocardial morphological characteristics and proarrhythmic substrate in the rat model of heart failure due to chronic volume overload. Anat Rec (Hoboken) 2011;294:102–111. doi: 10.1002/ar.21280. PubMed DOI

Obayashi M, Yano M, Kohno M, Kobayashi S, Tanigawa T, Hironaka K, Ryouke T, Matsuzaki M. Dose-dependent effect of ANG II-receptor antagonist on myocyte remodeling in rat cardiac hypertrophy. Am J Physiol. 1997;273:H1824–H1831. doi: 10.1152/ajpheart.1997.273.4.H1824. PubMed DOI

Yin FC, Spurgeon HA, Rakusan K, Weisfeldt ML, Lakatta EG. Use of tibial length to quantify cardiac hypertrophy: application in the aging rat. Am J Physiol. 1982;243:H941–H947. doi: 10.1152/ajpheart.1982.243.6.H941. PubMed DOI

Vanourková Z, Kramer HJ, Husková Z, Vanecková I, Opocenský M, Certíková Chábová V, Tesar V, et al. AT1 receptor blockade is superior to conventional triple therapy in protecting against end-organ damage in Cyp1a1-Ren-2 transgenic rats with inducible hypertension. J Hypertens. 2006;24:2465–2472. doi: 10.1097/01.hjh.0000251909.00923.22. PubMed DOI

Kala P, Gawrys O, Miklovič M, Vaňourková Z, Škaroupková P, Jíchová Š, Sadowski J, et al. Endothelin type A receptor blockade attenuates aorto-caval fistula-induced heart failure in rats with angiotensin II-dependent hypertension. J Hypertens. 2023;41:99–114. doi: 10.1097/HJH.0000000000003307. PubMed DOI PMC

Wilder J. Basimetric approach (law of initial value) to biological rhythms. Ann N Y Acad Sci. 1962;98:1211–1220. doi: 10.1111/j.1749-6632.1962.tb30629.x. PubMed DOI

Kolár F, MacNaughton C, Papousek F, Korecky B. Systolic mechanical performance of heterotopically transplanted hearts in rats treated with cyclosporin. Cardiovasc Res. 1993;27:1244–1247. doi: 10.1093/cvr/27.7.1244. PubMed DOI

Schaefer A, Schneeberger Y, Schulz S, Krasemann S, Werner T, Piasecki A, Höppner G, et al. Analysis of fibrosis in control or pressure overloaded rat hearts after mechanical unloading by heterotopic heart transplantation. Sci Rep. 2019;9:5710. doi: 10.1038/s41598-019-42263-1. PubMed DOI PMC

Frangogiannis NG. Cardiac fibrosis. Cardiovasc Res. 2021;117:1450–1488. doi: 10.1093/cvr/cvaa324. PubMed DOI PMC

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

Sex-Linked Differences in Cardiac Atrophy After Heterotopic Heart Transplantation: No Direct Relation to the Actions of Sex Steroid Hormones