Mp Bal

Histopathological Changes of the Heart After Neonatal Dexamethasone Treatment: Studies in 4-, 8-, and 50-Week-Old Rats

Dexamethasone (Dex), for prevention of chronic lung disease in preterm infants, showed potential negative long-term effects. Studies regarding long-term cardiovascular effects are lacking. We investigated possible histopathological myocardial changes after neonatal Dex in the young and adult rat heart. Rats were treated with Dex on d 1, 2, and 3 (0.5, 0.3, and 0.1 mg/kg) of life. Control-pups received saline. At 4, 8, and 50 wk after birth rats were killed and anatomic data collected. Heart tissue was stained with hematoxylin and eosin, Cadherin-periodic acid schiff, and sirius red for cardiomyocyte morphometry and collagen determination. Presence of macrophages and mast cells was analyzed. Cardiomyocyte length of the Dex-treated rats was increased in all three age groups, whereas ventricular weight was reduced. Cardiomyocyte volumes were increased at 50 wk indicating cellular hypertrophy. Collagen content gradually increased with age and was 62% higher in Dex rats at 50 wk. Macrophage focus score and mast cell count were also higher. Neonatal Dex affects normal heart growth resulting in cellular hypertrophy and increased collagen deposition in the adult rat heart. Because previous studies in rats showed premature death, suggesting cardiac failure, cardiovascular follow-up of preterm infants treated with glucocorticoids should be considered.

Neonatal glucocorticosteroid treatment causes systolic dysfunction and compensatory dilatation in early life : Studies in 4-week-old prepubertal rats

Glucocorticosteroid treatment is widely used to prevent chronic lung disease in premature infants. Recent studies in adult rats, treated with dexamethasone in the neonatal period, report negative long-term effects on the heart and severely reduced life expectancy. We treated neonatal rats with dexamethasone and studied cardiac function after 4 wk (prepubertal age) to investigate whether the late effects as previously described are preceded by detectable alterations in cardiac function at a younger age. Male rat pups (n = 12) were injected intraperitoneally with dexamethasone on d 1, 2, and 3 (0.5, 0.3, and 0.1 μg/g) of life. Control pups (n = 10) received saline. At 4 wk the animals were anesthetized, and a pressure-conductance catheter was introduced into the left ventricle to measure pressure-volume loops. Cardiac function was measured and pressure-volume relations were determined to quantify intrinsic systolic and diastolic function. Subsequently, hearts were excised for histologic examination. Compared with saline-treated animals, dexamethasone-treated rats had a reduced ventricular weight (270 ± 40 versus 371 ± 23 mg, p < 0.001) and reduced systolic function (end-systolic elastance: 1.24 ± 0.43 versus 2.50 ± 1.39 mm Hg/μL, p = 0.028). Cardiac output was maintained and end-diastolic volume was increased (84 ± 23 versus 59 ± 19 μL, p = 0.012) indicating a state of compensatory dilatation. Heart rate, diastolic function, and systemic vascular resistance were unchanged. Neonatal dexamethasone treatment causes cardiac alterations that can be detected in the prepubertal period and that may precede severe cardiac dysfunction later in life. If our findings are confirmed in humans, this may have consequences for a large patient population and cardiac screening at young age may be indicated to enable secondary prevention.

Neonatal Dexamethasone Treatment in the Rat Leads to Kidney Damage in Adulthood

Recently, concern has been raised that corticosteroid treatment of preterm neonates might be associated with adverse effects later in life, including early development of hypertension. Here, we investigate the impact of neonatal dexamethasone (Dex) treatment on early renal cell proliferation and nephron number. We analyzed mitotic activity in renal cortex of rat pups neonatally treated with Dex. Nephron number was measured and possible renal damage was quantified by counting inflammatory foci, ED-1 positive cells (macrophages), and the desmin score (activated podocytes). Mitotic activity was 34 and 29% lower on d 2 and 4 in Dex-treated rats compared with saline-treated controls. The number of glomeruli was lower at 4 wk, but nephron size was unchanged after Dex treatment, as calculated from glomerular density and (lower) body- and kidney weight. At wk 50, the glomerular number was significantly lower in Dex-treated rats, whereas body and kidney weight were the same as in Sal controls. Dex rats also showed more kidney damage, manifested by a ∼3.5-fold increase in inflammation foci/mm2 and in ED-1 positive cells/mm2 and a ∼4.3-fold increased desmin score. Temporary suppression of mitotic activity during neonatal Dex treatment leads to reduction of nephron number and more kidney damage later in life.

Long-Term Effects of Perinatal Glucocorticoid Treatment on the Heart

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.

Delayed Peripheral Auditory Maturation in Small for Gestational Age Infants; a Matched Control Study of Click Evoked Otoacoustic Emissions

Delayed Peripheral Auditory Maturation in Small for Gestational Age Infants; a Matched Control Study of Click Evoked Otoacoustic Emissions