Pregnancy as a cardiac stress model

Abstract

Cardiac hypertrophy occurs during pregnancy as a consequence of both volume overload and hormonal changes. Both pregnancy- and exercise-induced cardiac hypertrophy are generally thought to be similar and physiological. Despite the fact that there are shared transcriptional responses in both forms of cardiac adaptation, pregnancy results in a distinct signature of gene expression in the heart. In some cases, however, pregnancy can induce adverse cardiac events in previously healthy women without any known cardiovascular disease. Peripartum cardiomyopathy is the leading cause of non-obstetric mortality during pregnancy. To understand how pregnancy can cause heart disease, it is first important to understand cardiac adaptation during normal pregnancy. This review provides an overview of the cardiac consequences of pregnancy, including haemodynamic, functional, structural, and morphological adaptations, as well as molecular phenotypes. In addition, this review describes the signalling pathways responsible for pregnancy-induced cardiac hypertrophy and angiogenesis. We also compare and contrast cardiac adaptation in response to disease, exercise, and pregnancy. The comparisons of these settings of cardiac hypertrophy provide insight into pregnancy-associated cardiac adaptation.

Keywords: Hormones; Molecular signatures; Physiological cardiac hypertrophy; Pregnancy; Signalling pathways.

Figure 1

Morphometric alterations in response to various stimuli. See detailed information in Section 3.

Figure 2

Circulating sex hormones during pregnancy in mice. (A) Serum progesterone levels in mice during pregnancy. Progesterone increases in early pregnancy and decreases slightly in mid-pregnancy and reach its peak value in 15–16 days of pregnancy.^,– (B) Serum oestradiol levels in mice during pregnancy. Values from previous studies.^, Day of gestation is grouped together based on previous reports to show the pattern of changes of hormones. Values are means ± SEM.

Figure 3

A simplified schematic view of signalling pathways in the heart. Red arrows represent signalling molecules that are altered during pregnancy. See detailed information in Section 8.

Figure 4

Signalling pathways in pregnancy-induced cardiac hypertrophy. Pregnancy is associated with prolonged cardiac volume overload and changes in hormonal milieu, which results in cardiac hypertrophy. Increased progesterone level in early pregnancy activates calcineurin. This increase in calcineurin activity transiently initiates pathways, such as Akt and its downstream targets, and ERK1/2 that are responsible for the development of physiological hypertrophy. Calcineurin inhibition by CsA treatment in early pregnancy blocks Akt and ERK1/2 activation, and blocks pregnancy-induced cardiac hypertrophy. A specific inhibitor of MEK 1 (PD98059), which is immediately upstream of ERK1/2, blocks progesterone-mediated isolated neonatal myocyte hypertrophy.