Previous studies have demonstrated that modest, physiologically relevant increases in maternal cortisol in late gestation result in enlargement of the fetal heart. In this study, we investigated the role of mineralocorticoid receptor (MR) or glucocorticoid receptor (GR) in this enlargement. Ewes with single fetuses were randomly assigned at w120 days of gestation to one of four groups: maternal cortisol infusion (1 mg/kg per day, cortisol); maternal cortisol infusion with fetal intrapericardial infusion of the MR antagonist (MRa) potassium canrenoate (600 mg/day; cortisolCMRa); maternal cortisol infusion with fetal intrapericardial infusion of the GR antagonist (GRa) mifepristone (50 mg/day, cortisolCGRa); and maternal saline infusion (control). At w130 days of gestation, fetal heart to body weight ratio and right ventricular (RV) and left ventricular (LV) free wall thicknesses were increased in the cortisol group when compared with control group. Fetal hearts from the cortisolCMRa group weighed significantly less, with thinner LV, RV, and interventricular septum walls, when compared with the cortisol group. Fetal hearts from the cortisolCGRa group had significantly thinner RV walls than the cortisol group. Fetal arterial pressure and heart rate were not different among groups at 130 days. Picrosirius red staining of fetal hearts indicated that the increased size was not accompanied by cardiac fibrosis. These results suggest that physiologic increases in maternal cortisol in late gestation induce fetal cardiac enlargement via MR and, to a lesser extent, by GR, and indicate that the enlargement is not secondary to an increase in fetal blood pressure or an increase in fibrosis within the fetal heart.

We have previously found that modest chronic increases in maternal cortisol result in an enlarged fetal heart. To explore the mechanisms of this effect, we used intrapericardial infusions of a mineralocorticoid receptor (MR) antagonist (canrenoate) or of a glucocorticoid receptor (GR) antagonist (mifepristone) in the fetus during maternal infusion of cortisol (1 mg·kg⁻¹·day⁻¹). We have shown that the MR antagonist blocked the increase in fetal heart weight and in wall thickness resulting from maternal cortisol infusion. In the current study we extended those studies and found that cortisol increased Ki67 staining in both ventricles, indicating cell proliferation, but also increased active caspase-3 staining in cells of the conduction pathway in the septum and subendocardial layers of the left ventricle, suggesting increased apoptosis in Purkinje fibers. The MR antagonist blocked the increase in cell proliferation, whereas the GR antagonist blocked the increased apoptosis in Purkinje fibers. We also found evidence of activation of caspase-3 in c-kit-positive cells, suggesting apoptosis in stem cell populations in the ventricle. These studies suggest a potentially important role of corticosteroids in the terminal remodeling of the late gestation fetal heart and suggest a mechanism for the cardiac enlargement with excess corticosteroid exposure.

The objective of this study was to determine the ontogenetic profiles in left and right ventricle of genes implicated in cardiac growth, including mineralocorticoid (MR) and glucocorticoid (GR) receptor, 11 beta-hydroxysteroid dehydrogenase (11β-HSD) 1 and 2 and genes of the angiotensin system and insulin-like growth factor (IGF) family. Samples from left and right ventricles (LV, RV) were collected from hearts of sheep fetuses at 80, 100, 120, 130, and 145 days of gestation and from newborn lambs. Quantitative real-time PCR was performed to determine the MR, GR, 11β-HSD 1 and 2, angiotensin converting enzyme (ACE) 1 and 2, IGF1, IGF2, IGF receptors IGF-1R and IGF-2R, and IGF-binding proteins (IGFBP) 2 and 3. In the LV, MR and GR both decreased toward term. In the RV, MR and GR expression did not decrease, but both 11β-HSD 1 and 2 mRNA levels increased after birth. ACE1 expression in LV and RV sharply increases just before parturition, whereas ACE2 decreased in the LV and RV in late gestation. IGF2, IGF2R, and IGFBP2 expression levels substantially decreased in late gestation in LV and RV; IGF2R also decreased with age in LV. These patterns suggest that reduced expression of genes related to IGF and angiotensin II action occur as proliferative activity declines and terminal differentiation occurs in the late gestation fetal heart. KeywordsHeart; Fetus; MR; GR; 11βHSD1; 11βHSD2; IGF1; IGF2; IGF1R; IGF2R; IGFBP2; ACE1; ACE2; AT1R; AT2R; Cortisol; Angiotensin; Angiotensinogen Results and discussionThis study reveals ontogenetic patterns of expression of several genes implicated by other investigators to play a role in either proliferative or hypertrophic cardiac growth. There is a pronounced increase in fetal heart growth in the last third of gestation, paralleling a similar exponential growth of the fetus (Burrell et al., 2003;Jonker et al., 2007). At the same time as the heart increases in both total weight and left and right ventricle wall mass, an increasing number of myocytes terminally differentiate. This process results in decreasing numbers of mononucleate cardiomyocytes, and increasing numbers of binucleate or multinucleate myocytes which are unable to undergo further cell division (Burrell et al., 2003;Jonker et al., 2007). A similar pattern of decreasing proliferative activity near term has also been described for the human fetus (Huttenbach et al., 2001). Some differences in this pattern have been identified in the left ventricle as compared to the right ventricle; the number of proliferating (Jonker et al., 2007). In contrast the number of myocytes that are enlarged due to terminal differentiation is greater in the right ventricle than in the left ventricle, particularly from day 130 to term, and right ventricular myocytes are on average greater in volume than are those in the left ventricle. Several factors have been identified as regulators of proliferation in the fetal heart in late gestation, these include cortisol (Giraud et al., 2006), IGFs (Liu et al., 1996;Sundgren et al., 2003a), and ...

Moderately elevated maternal cortisol levels late in gestation cause enlargement of the fetal sheep heart. We have used quantitative real-time PCR to examine expression of candidate genes in fetal hearts from mothers in whom cortisol levels were increased (by infusion of 1 mg cortisol.kg(-1).day(-1)) or decreased (by adrenalectomy and replacement to 0.5 mg cortisol.kg(-1).day(-1)) from 115 to 130 days gestation. Control ewes were not treated with steroid. Expression of mineralocorticoid receptor (MR), glucocorticoid receptor (GR), 11beta-hydroxysteroid dehydrogenases 1 and 2 (11beta-HSD1 and -2), IGF I and II, IGF receptors 1 and 2 (IGF-1R and IGF-2R), endothelial nitric oxide synthase, VEGF, myotrophin, angiotensinogen, the angiotensin receptors 1 and 2 (AT1R and AT2R), and the angiotensin converting enzymes 1 and 2 were measured. MR mRNA abundance in fetal hearts was found to be similar to that in adult kidney and hippocampus. Although there were no significant changes in most genes, 11beta-HSD2 and IGF-1R expression were significantly decreased in the high cortisol group and 11beta-HSD2 expression negatively correlated to left ventricular wall thickness. There was also a significant change in the ratio of AT receptor expression, with increased AT2R and decreased AT1R in the high cortisol group. MR, GR, and 11beta-HSD1 immunoreactivity was found in cardiomyocytes and cardiac blood vessels in 126-128 day fetal sheep; in contrast 11beta-HSD2 staining was predominantly in blood vessels. These results indicate that cortisol could indeed act in the fetal heart to induce enlargement and suggest that the renin-angiotensin system may play a role.

Cortisol is a stress-response hormone that is important for survivability in fight or flight situations. Hypercortisolism is a state of chronically elevated cortisol levels due to a failure to return to, or maintain baseline levels. It is a condition that is often undiagnosed and can aid in the development of many physiological and psychological health problems. Some of the health ailments associated with hypercortisolism include metabolic syndrome, decreases in bone mineral density, and depression. Chronic stress and sleep deprivation are two common causes of hypercortisolism, both areas of concern within the submarine community. This review discusses the etiology of hypercortisolism and the likelihood of submariner vulnerability to the condition along with health problems associated with it. Lastly, strategies to prevent chronic elevation of cortisol and mitigate the potential health risks associated with the condition are covered.