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Cardiac atrophy is the most common complication of prolonged application of the left ventricle (LV) assist device (LVAD) in patients with advanced heart failure (HF), obviously, it is a consequence of LVAD-induced mechanical unloading. Previous studies employing heterotopic heart transplantation (HTx) as a model of heart unloading after LVAD implantation discovered sex-linked differences in the course of unloading-induced in the healthy hearts. It remains to be clarified if sex-related differences are present in the failing hearts after heterotopic HTx. Therefore, we first compared the course of unloading-induced cardiac atrophy in the failing hearts in intact (without gonadectomy) male and female rats, and in animals after gonadectomy, to explore the influence of sex hormones on this process. Second, we examined if the animal's sex modifies the effects of increased isovolumic loading of the LV on the course of unloading-induced cardiac atrophy. Heterotopic abdominal heart transplantation (HTx) was used as a rat model of heart unloading. HF was induced by volume overload achieved by creation of aorto-caval fistula. Increased isovolumic loading was obtained by implantation of specially designed three-branch spring expander into the LV. The degree of cardiac atrophy was assessed as the whole heart weight (HW) ratio of the heterotopically transplanted to the native control heart. We found that decreases in HW after HTx were similar in intact male and female rats, similarly in intact and gonadectomized animals. Implantation of the expander significantly and comparably reduced decreases in HW in male and in female rats. We conclude that there are no sex-linked differences in the development of unloading-induced cardiac atrophy in the failing hearts. Our results also show that enhanced isovolumic heart loading obtained using the spring expander attenuates the development of unloading-induced cardiac atrophy in the failing hearts; the degree of attenuation is similar in both sexes. Key words Heart failure " Cardiac atrophy " Sex differences " Heterotopic heart transplantation " Mechanical heart unloading.