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

Abstract

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.

Fig. 1

An outline of the set of experiments in male and female Lewis rats performed for evaluation of the effectiveness of hormonal substitution with steroid hormones of the opposite sex. BS indicates blood sampling from the tail vein.

Fig. 2

An outline of the set of experiments evaluating the course of cardiac atrophy after heterotopic heart transplantation (HT_X) in Lewis rats after castration and exposed to substitution of steroid hormones of the opposite sex.

Fig. 3

An outline of the set of experiments evaluating the course of cardiac atrophy after heterotopic heart transplantation (HT_X) to Lewis rat recipients of the sex opposite to that of the donor’s heart.

Fig. 4

Plasma levels of testosterone (A) and estradiol (B) in the series of studies evaluating the effectiveness of hormonal substitution with steroid hormones of the opposite sex. ^*P<0.05 compared with basal values (day −30, i.e. before castration). ^#P<0.05 compared with the values of intact female at the same time point. ^@ P<0.05 compared with the values of intact male at the same time point.

Fig. 5

Effects of either substitution of steroid hormones of the opposite sex in castrated animals or heterotopic heart transplantation (HT_x) into the recipient of the sex opposite to that of the donor’s heart on the course of cardiac atrophy in response to mechanical heart unloading induced by (HT_x) in male and female Lewis rats. Data are expressed as percent decreases compared with the native heart: (A) changes in whole heart weight, (B) changes in left ventricle weight, (C) changes in right ventricle weight. ^*P<0.05 compared with male animals.

Fig. 6

Effects of either substitution of steroid hormones of the opposite sex in castrated animals or heterotopic heart transplantation (HT_x) into the recipient of the sex opposite to that of the donor’s heart on the course of the whole heart weight to tibia length ratio over 14 days after heterotopic heart transplantation (HT_x) in male and female Lewis rats. (A) values in native (i.e. orthotropic) heart, (B) values in transplanted (i.e. heterotopic) heart. ^*P<0.05 compared with male animals.

Fig. 7

Effects of either substitution of steroid hormones of the opposite sex in castrated animals or heterotopic heart transplantation (HT_x) into the recipient of the sex opposite to that of the donor’s heart on the course of myocyte size change in the left ventricle in response to mechanical heart unloading induced by heterotopic heart transplantation (HT_x) in male as well as in female Lewis rats. Data are expressed as percent decreases compared with the native heart: (A) changes in cardiomyocyte length, (B) changes in cardiomyocyte width, (C) changes in cardiomyocyte length to width ratio. ^*P<0.05 compared with male animals.