Étude des œstrogènes sur la repolarisation cardiaque et de la grossesse sur l’électrocardiographie chez la souris

Tamoxifen is a selective estrogen receptor modulator widely used in the treatment and prevention of breast cancer from more than 20 years. Other studies have reported that acute exposure to tamoxifen can reduce cardiac K+ currents. However, in vivo tamoxifen is largely metabolized and most of its activity is attributable to its major metabolite, 4- hydroxytamoxifen (4OH-tamoxifen). In our first study, we investigated the acute effects of 4OH-tamoxifen on cardiac K+ currents in mice. Using the patch-clamp technique, we found that, as with tamoxifen, short-term exposure to 4OH-tamoxifen reduced K+ currents in the mouse ventricle even in the presence of the selective oestrogen receptor antagonist, ICI-182,780, or the inhibitor of RNA synthesis, actinomycin D. These results suggest an inhibition independent of the intracellular oestrogen receptor and the protein synthesis. However, women receiving long-term tamoxifen therapy do not experience cardiac arrhythmias although acute perfusion of tamoxifen has been shown to inhibit cardiac K+ currents. This observation suggests that chronic tamoxifen treatment does not negatively modulate cardiac K+ currents. Therefore, in order to investigate the absence of cardiac arrhythmias in women, we examined the effects of long term tamoxifen therapy associated with low level of estrogen on ventricular K+ currents and channels expressed in mouse and guinea pig heart. Female mice and guinea pigs were treated with placebo or tamoxifen pellets for 60 days. Our results show an increase of the densities of K+ currents and the expression of their channels. Conditions with high oestrogen levels are associated with reduced K+ currents both in the heart and the uterus. Thus, conceivably, tamoxifen might prevent the inhibitory effects of oestrogen on K+ channels by blocking the oestrogen receptors, which would explain the reported increase in K+ currents. These findings could contribute to explain the absence of cardiac arrhythmia with long-term tamoxifen therapy. These association estrogen- tamoxifen and estrogen receptor lead us to study the influence of estrogens and estrogen receptors on ventricular repolarization. Accordingly, we assessed the involvement of estrogens and ER on K+ currents in mouse using ovariectomised (OVX), ER-knockout (ERKOα) or ERβ-knockout (ERKOβ) female mice. These experiments show that the absence of estrogen is associated with an increase of the density of the Ca2+-independent transient outward, Ito, the mRNA and protein expression of Kv4.3. These results vi obtained with ERKO mice suggest that estrogens regulate ventricular repolarization and ER mediates this effect. The last part of this thesis was to determine whether pregnancy elicits a change in the heart rate in mice and whether pregnancy-related changes are due to the cardiac conduction system rather than a change in autonomic tone. Our results revealed that pregnancy accelerates the resting heart rate and the AV node conduction time in the presence and absence of autonomic nervous system input suggesting an intrinsic mechanism. Moreover, Hormonal changes that occur during pregnancy are likely to be involved in these adaptations of the heart to pregnancy. These studies provide a new insight to understand the hormonal regulation of cardiac electrophysiology.

Keyphrases: tamoxifen, estrogen, estrogen receptor, electrophysiology, repolarization, pregnancy, arrhythmia