Le remodelage cardiaque lors de la gestation chez la rate : implication du récepteur aux minéralocorticoïdes et altérations par un supplément sodique

Pregnancy is characterized by marked hemodynamic and metabolic changes, which have consequences on the heart. The adaptation of the heart to this physiological situation requires a remodeling of its structure, and consequently functioning adjustments. Mechanisms responsible for these adaptations are largely unknown. However, this knowledge is essential for the understanding of cardiovascular complications, such as gestational hypertension (GH), which represents a risk for the mother and the fœtus. To characterize cardiac adaptations to pregnancy, our experimental approach consisted in studying this remodelling at the level of left ventricle cardiomyocytes. Therefore, our first objective was to determine structural and functional modifications of cardiomyocytes in pregnant rats to be able to identify their variations in GH. In pregnant rats, structural remodelling of cardiomyocytes was characterized by a proportional volume expansion. GH was induced by a high sodium supplement (0.9% NaCl). In hypertensive rats, we observe significant cell volume shrinkage. The study of functional modifications elicited a strong relationship between metabolic adaptations and cell contractility. According to our results, in pregnant rats cardiomyocyte contractility was increased in presence of energy substrates lactate and pyruvate. This effect was weaker in the cells from hypertensive rats. This suggested modifications of the excitation-contraction coupling, in which L-type calcium currents (ICa-L) play an important role. Unexpectedly, lactate and pyruvate induced a significant increase in ICa-L only in hypertensive rats.  In pathological conditions, mineralocorticoid receptors (MR) have been shown to mediate structural as well as functional remodelling of the heart. Our study is the first to investigate MR involvement in cardiac remodelling during pregnancy. Thus, our second objective was to determine MR involvement in cardiomyocyte remodelling. For this study, pregnant rats were treated with potassium canrenoate of (20 mg / kg / day), a MR antagonist. Our results revealed that MR inhibition during the pregnancy elicited a significant decrease of cell volume. MR inhibition has also affected metabolism and cellular functioning relationship. Indeed, plasma concentration of lactate was lower, which was in correlation with its blunted effect on cell contractility.  In women, pregnancy-induced hypertrophy is associated with changes in electrical properties of the heart. Indeed, repolarisation is prolonged, which is characterised by a longer duration of QTc interval on the electrocardiogram. Regulation mechanisms involved in this adaptation are still largely unknown. Our third objective was therefore to determine the role of MR in the adaptation of repolarisation to pregnancy. Pregnancy induced a prolongation in QTc interval, which correlates with a decrease in potassium currents Ito and IK1. MR inhibition prevented QTc interval prolongation and the lowering of Ito.  Our study gives a new insight of pregnancy-induced cardiac hypertrophy, which is provided by investigations at the cellular level. Our results demonstrate that pregnancy and GH are characterised by opposite remodellings. Moreover, in pregnancy the contractile function is dependent on metabolic adaptations. This is all the more glaring in GH as metabolic alterations induced modifications of electric properties to maintain contractile functioning. Furthermore, our work reveals MR involvement in the regulation of morphology, metabolism/contractility relationship, and repolarisation. By improving the knowledge of hypertrophy during pregnancy, this work contributes to improve the understanding of pregnancy-induced cardiac complications.

Keyphrases: coeur, pregnancy, cardiomyocytes, hypertrophic remodelling, mineralocorticoid receptors, glucose metabolism, ionic currents