Long-term effects of perinatal glucocorticoid treatment on the heart

Abstract

Long-term effects of perinatal glucocorticoid treatment on the heart Chronic lung disease in the extremely preterm baby is still a major complication in neonatal intensive care medicine. Perinatal (ante- and neonatal) glucocorticoids are widely used to prevent severe infant respiratory syndrome and to reduce chronic lung disease. The aim of this thesis was to describe the histopathological, functional and hemodynamic impact of antenatal and neonatal glucocorticoid treatment on the developing and adult heart. The glucocorticoid dexamethasone is widely used in preterm infants for the prevention of chronic lung disease. However, major concern has arisen about the long-term sequelae of this therapy. Glucocorticoid treatment in preterm babies to prevent chronic lung disease causes myocardial hypertrophy and hypertension. Although these changes are thought to be transient, there is evidence that dexamethasone induces permanent myocardial abnormalities as well. In the studies described in this thesis long-term cardiovascular side effects were investigated in a rat model. Rats were treated neonatally with dexamethasone in dosages comparable to those used in neonates and compared to a control group. Found was that neonatal treatment with dexamethasone significantly shortens life span in rats, notably by 25% in males and by 18% in females. Histopathological examination of dexamethasone treated animals showed signs of end stage cardiac failure and end stage renal disease. Already at young adult age, dexamethasone treated rats showed symptoms of hypertension that increased with age. Thus, a brief period of glucocorticoid treatment during early life results in untimely death presumably due to cardiovascular and renal disease later in life. Neonatal dexamethasone treatment causes a temporary suppression of cardiomyocyte proliferation in the rat pup, which eventually leads to a reduced number of cardiomyocytes and hypertrophy of these cardiomyocytes during adult life. Furthermore it causes in rat pups a permanent decrease in heart weight, as well as hypertrophy of cardiomyocytes and increased interstitial collagen during adulthood. The combination of lower heart weight and hypertrophy also strongly suggests that the number of cardiomyocytes will be reduced. Taken together these findings may indicate early ageing of the heart. In a follow-up study at school age (7-10 years) of children who had been born prematurely and treated ante- and/or neonatally with glucocorticoids to reduce chronic lung disease no significant differences were found between groups for blood pressure, heart rate, myocardial performance, intima-media thickness or biochemical parameters (BNP, N-Terminal proBNP). However, these children were still young as compared to the data obtained from the animal experiments, assuming that the results of the rat studies can be extrapolated to humans. Furthermore the normal human heart has a large reserve capacity and in the present study no challenge of the cardiovascular system was applied. In future follow-up studies, tests challenging the cardiovascular system should be applied (such as stress echocardiography) and also more sophisticated echocardiographic techniques such as tissue Doppler imaging should be employed. Moreover, possible alterations may occur later in life. For instance, the large reserve capacity of the heart might be affected unfavourably. If necessary, secondary prevention might be offered to alleviate or to cure clinical symptoms of cardiovascular disease. The rate of successful treatment will improve when the symptoms are detected as early.