Alterations in Adult Rat Heart after Neonatal Dexamethasone Therapy

Abstract

Glucocorticoid treatment in preterm babies to prevent chronic lung disease causes myocardial hypertrophy and increased myocardial protein content. Although these changes are thought to be transient, there is evidence that dexamethasone (DEX) induces permanent myocardial abnormalities as well. We investigated whether a therapeutic course of neonatal DEX in rat pups produces anatomic and biochemical alterations in rat hearts during adult life. Twenty-four rat pups were treated with DEX on d 1, 2, and 3 (0.5, 0.3, and 0.1 g/g) of life, with doses proportional to those used in preterm babies. Twenty-four control pups were treated with saline. At d 7, wk 8, or wk 45 (n ϭ 8 per group) rats were killed. The anatomic parameters measured were body weight (Bw, in grams), heart (myocardial) weight (Hw, in milligrams), and the Hw:Bw ratio. Myocardial total protein (Prot) and DNA content were determined, and the Prot:DNA ratio was calculated. Histopathology and morphometry were performed on 45-wk-old rat hearts. In DEX-treated rat pups, at d 7, Bw and Hw were lower and the Hw:Bw ratio was increased. DNA content was lower, Prot higher, and Prot:DNA ratio was increased. In 8-wk-old rats Bw, Hw, DNA content, Prot content or Prot:DNA ratio did not differ between groups, but the Prot:DNA ratio still tended to be higher in DEX-treated rats. In 45-wk-old rats Hw and Hw:Bw ratio were significantly lower and Prot:DNA ratio higher in DEX-treated rats. Histopathologic analysis showed larger cardiomyocyte volume, length, and width, indicating hypertrophy, and increased collagen, indicating early degeneration of individual myocytes. In conclusion, neonatal DEX treatment in rat pups causes a permanent decrease in heart weight, as well as hypertrophy and early degeneration of cardiomyocytes during adulthood. (Pediatr Res 52: 900-906, 2002) Abbreviations Bw, body weight DEX, dexamethasone GC, glucocorticoid Hw, heart weight Prot, total protein SAL, saline Chronic lung disease is a common outcome in extremely preterm neonates with severe respiratory distress syndrome and carries a high incidence of morbidity and mortality. Inflammation is an important factor in its pathogenesis. Because of their antiinflammatory properties GCs, particularly DEX, resulted in an impressive decrease in chronic lung disease (1, 2). Consequently GCs are frequently used and have become indispensable in all neonatal intensive care units in the Western world, especially inasmuch as an alternative therapy is not available at present. Despite the short-term benefits of GCs, major concern has emerged now because recent experimental studies report long-lasting adverse effects of perinatal GC treatment in later life, such as lifetime changes in cardiovascular function and reprogramming of the neuroendocrine system (3-5). Benediktsson et al. (6) reported that GC exposure during the perinatal period leads to hypertension during adult life, possibly related to a GC-induced reprogramming of the hypothalamic-pituitary-adrenal axis. Neonatal GCs also altered the epinephrine a...

Effect of neonatal dexamethasone exposure on growth and neurological development in the adult rat

“…Previous studies have reported neonatal glucocorticoid effects in rats using various regimens of dexamethasone administration (5,7,20,28,53,54). In the present protocol, dexamethasone was administered over a longer period (P3 through P6) in tapering doses in an attempt to mimic the longer treatment regimen cited by many neonatal intensive care units (17).…”

“…It is not designed to evaluate the effects of a 2-day, four-dose dexamethasone protocol used in many neonatal units for treatment of refractory hypotension but rather to provide a tapering dose of dexamethasone during a postnatal age in the rat that corresponds to the neurodevelopmental time point at which human premature infants have historically received prolonged glucocorticoid therapy for CLD (46 -48). This is in contrast to animal models that use short courses or single doses of dexamethasone (5,7,20,28,53,54).…”

Dexamethasone treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids

“…A major motivation for this therapy is the promotion of surfactant production and lung maturation and to induce closure of the ductus arteriosus (6,34,43,45,47). Dexamethasone decreases the duration of ventilatory support and lowers the incidence of chronic lung disease (13,23,33,50).Dexamethasone therapy, however, may lead to unfavorable long-term sequelae, including decreases in neuromotor and cognitive function (4,15,30,36,37,55), and may also lead to left ventricular abnormalities and metabolic dysfunction (5,14,17,24). A report of lipid intolerance in infants treated with dexamethasone highlights this potential for long-term metabolic dysfunction (2).…”

“…Dexamethasone therapy, however, may lead to unfavorable long-term sequelae, including decreases in neuromotor and cognitive function (4,15,30,36,37,55), and may also lead to left ventricular abnormalities and metabolic dysfunction (5,14,17,24). A report of lipid intolerance in infants treated with dexamethasone highlights this potential for long-term metabolic dysfunction (2).…”

Long-term cardiovascular effects of neonatal dexamethasone treatment: hemodynamic follow-up by left ventricular pressure-volume loops in rats

“…The development of these systems has been studied in the rat (30), but very few data are available for the (preterm) human situation. Thus, although species differences may be of influence, this model is frequently used, and several effects of dexamethasone treatment found in humans, including early transient hypertrophy, were also found in the rat model (11,22,27,34).…”