An important complication of prolonged support of the left ventricle with an assist device when implanted in patients with heart failure is unloading-induced cardiac atrophy. Our recent study suggested that sex-linked differences in the development of atrophy induced by heterotopic heart transplantation (HTX) do exist, however, the role of the environmental conditions dependent on plasma concentrations of sex hormones remains elusive. We aimed to compare the course of HTX-induced cardiac atrophy in male and female rats after gonadectomy with substitution of steroid hormones of the opposite sex. In a separate series of experiments, we evaluated the course of unloading-induced cardiac atrophy in the female heart transplanted into a male recipient and vice versa. Cardiac atrophy was assessed as the ratio of the transplanted heart weight to native heart weight (HW), which was determined 14 days after HTX. In female rats, studied in both experimental variants, HTx resulted in significantly smaller decreases in whole HW when compared to those observed in male rats exposed to the same experimental conditions (-9 ± 1 and - 11 + 1 vs. -44 ± 2 and -42 ± 2 %, p?0.05 in both cases). The dynamic of changes in left and right ventricle was similar as in the whole HW. Our results show that the process of unloading-induced cardiac atrophy exhibits important sex-linked differences and that attenuation of this process in female rats cannot be simply ascribed to the protective effects of estradiol or to the absence of deleterious actions of testosterone. Keywords: Cardiac atrophy, Sex differences, Gonadectomy, Hormonal substitution, Heterotopic heart transplantation, Mechanical heart unloading.

Dept Cardiovasc Surgery Inst Clin Exp Med Prague Czech Republic

Zobrazit více v PubMed

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, et al. 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, 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

Mehra MR, Nayak A, Desai AS. Life-Prolonging Benefits of LVAD Therapy in advanced heart failure: a clinician’s action and communication aid. JACC Heart Fail. 2023;11:1011–1017. doi: 10.1016/j.jchf.2023.05.013. PubMed DOI

Brinks H, Tevaearai H, Mühlfeld C, et al. The contractile function is preserved in unloaded hearts despite atrophic remodeling. J Thorac Cardiovasc Surg. 2009;137:742–6. doi: 10.1016/j.jtcvs.2008.09.020. PubMed DOI

Diakos NA, Selzman CH, Sachse FB, 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;64:1602–12. doi: 10.1016/j.jacc.2014.05.073. PubMed DOI

Miyagawa S, Toda K, Nakamura T, et al. Building a bridge to recovery: the pathophysiology of LVAD-induced reverse modeling in heart failure. Surg Today. 2016;46:149–154. doi: 10.1007/s00595-015-1149-8. PubMed DOI

Pokorný M, Cervenka L, Netuka I, et al. Ventricular assist devices in heart failure: how to support the heart but prevent atrophy? Physiol Res. 2014;63:147–56. doi: 10.33549/physiolres.932617. PubMed DOI

Brinks H, Giraud MN, Segiser A, et al. Dynamic patterns of ventricular remodeling and apoptosis in hearts unloaded by heterotopic transplantation. J Heart Lung Transplant. 2014;33:203–10. doi: 10.1016/j.healun.2013.10.006. PubMed DOI PMC

Heckle MR, Flatt DM, Sun Y, et al. Atrophied cardiomyocytes and their potential for rescue and recovery of ventricular function. Heart Fail Rev. 2016;21:191–8. doi: 10.1007/s10741-016-9535-x. PubMed DOI

Pham BN, Chaparro SV. Left ventricular assist device recovery: does duration of mechanical support matter? Heart Fail Rev. 2019;24:237–244. doi: 10.1007/s10741-018-9744-6. PubMed DOI

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

Pamias-Lopez B, Ibrahim ME, Pitoulis FG. Cardiac mechanics and reverse remodelling under mechanical support from left ventricular assist devices. Front Cardiovasc Med. 2023;10:1212875. doi: 10.3389/fcvm.2023.1212875. PubMed DOI PMC

Drakos SG, Badolia R, Makaju A, et al. Distinct Transcriptomic and Proteomic Profile Specifies Patients Who Have Heart Failure With Potential of Myocardial Recovery on Mechanical Unloading and Circulatory Support. Circulation. 2023;147:409–424. doi: 10.1161/CIRCULATIONAHA.121.056600. PubMed DOI PMC

Chrysakis N, Xanthopoulos A, Magouliotis D, et al. Myocardial Recovery. Diagnostics (Basel) 2023;13:1504. doi: 10.3390/diagnostics13081504. PubMed DOI PMC

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, et al. Does the beta2-agonist clenbuterol help to maintain the myocardial potential to recover during mechanical unloading? Circulation. 2005;112(Suppl):I51–6. doi: 10.1161/CIRCULATIONAHA.104.525097. PubMed DOI

Birks EJ, Tansley PD, Hardy J, et al. Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med. 2006;355:1873–84. doi: 10.1056/NEJMoa053063. PubMed DOI

Navaratnarajah M, Siedlecka U, Ibrahim M, 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

Hu D, Li H, Yu H, et al. Clenbuterol Prevents Mechanical Unloading-Induced Myocardial Atrophy via Upregulation of Transient Receptor Potential Channel-3. Int Heart J. 2023;64:901–909. doi: 10.1536/ihj.21-129. PubMed DOI

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;29:1045–54. doi: 10.1006/jmcc.1996.0350. PubMed DOI

Navaratnarajah M, Siedlecka U, Ibrahim M, 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, 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:H533–41. doi: 10.1152/ajpheart.00218.2013. PubMed DOI

Liu Y, Maureira P, Gauchotte G, 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, et al. 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, et al. 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;140:916–22. doi: 10.1016/j.jtcvs.2010.02.006. PubMed DOI

Fu X, Segiser A, Carrel TP, et al. 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, 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, 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, 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, et al. Isovolumic loading of the failing heart by intraventricular placement of a spring expander attenuates cardiac atrophy after heterotopic heart transplantation. Biosci Rep. 2018;38:BSR20180371. doi: 10.1042/BSR20180371. PubMed DOI PMC

McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42:3599–3726. PubMed

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

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

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

Kolesár DM, Kujal P, Mrázová I, Pokorný M, Škaroupková P, Sadowski J, Červenka L, Netuka I. Sex-linked differences in cardiac atrophy after mechanical unloading induced by heterotopic heart transplantation. Physiol Res. 2024;73:9–25. doi: 10.33549/physiolres.935217. PubMed DOI PMC

Ostadal B, Netuka I, Maly J, et al. Gender differences in cardiac ischemic injury and protection--experimental aspects. Exp Biol Med (Maywood) 2009;234:1011–9. doi: 10.3181/0812-MR-362. 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

Ono K, Lindsey ES. Improved technique of heart transplantation in rats. J Thorac Cardiovasc Surg. 1969;57:225–9. 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, et al. 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

Shawky NM, Reckelhoff JF, Alexander BT, Yanes Cardozo LL. Insights Into the Cardiomodulatory Effects of Sex Hormones: Implications in Transgender Care. Hypertension. 2023;80:1810–1820. doi: 10.1161/HYPERTENSIONAHA.123.19501. PubMed DOI PMC

de Blok CJ, Wiepjes CM, van Velzen DM, et al. Mortality trends over five decades in adult transgender people receiving hormone treatment: a report from the Amsterdam cohort of gender dysphoria. Lancet Diabetes Endocrinol. 2021;9:663–670. doi: 10.1016/S2213-8587(21)00185-6. PubMed DOI

Getahun D, Nash R, Flanders WD, et al. Cross-sex Hormones and Acute Cardiovascular Events in Transgender Persons: A Cohort Study. Ann Intern Med. 2018;169:205–213. doi: 10.7326/M17-2785. PubMed DOI PMC

Jackson SS, Brown J, Pfeiffer RM, et al. Analysis of Mortality Among Transgender and Gender Diverse Adults in England. JAMA Netw Open. 2023;6:e2253687. doi: 10.1001/jamanetworkopen.2022.53687. PubMed DOI PMC

Prajapati C, Koivumäki J, Pekkanen-Mattila M, Aalto-Setälä K. Sex differences in heart: from basics to clinics. Eur J Med Res. 2022;27:241. doi: 10.1186/s40001-022-00880-z. PubMed DOI PMC

DeFilippis EM, Nikolova A, Holzhauser L, Khush KK. Understanding and Investigating Sex-Based Differences in Heart Transplantation: A Call to Action. JACC Heart Fail. 2023;11:1181–1188. doi: 10.1016/j.jchf.2023.06.030. PubMed DOI

Drury ER, Wu J, Gigliotti JC, Le TH. Sex differences in blood pressure regulation and hypertension: renal, hemodynamic, and hormonal mechanisms. Physiol Rev. 2024;104:199–251. doi: 10.1152/physrev.00041.2022. PubMed DOI PMC