Combined Statin and Glucocorticoid Therapy for the Safer Treatment of Preterm Birth

Prematurity is strongly associated with poor respiratory function in the neonate. Rescue therapies include treatment with glucocorticoids due to their anti-inflammatory and maturational effects on the developing lung. However, glucocorticoid treatment in the infant can increase the risk of long-term...

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Bibliographic Details
Published in:Hypertension (Dallas, Tex. 1979) Tex. 1979), 2023-04, Vol.80 (4), p.837-851
Main Authors: Kane, Andrew D, Herrera, Emilio A, Niu, Youguo, Camm, Emily J, Allison, Beth J, Tijsseling, Deodata, Lusby, Ciara, Derks, Jan B, Brain, Kirsty L, Bronckers, Inge M, Cross, Christine M, Berends, Lindsey, Giussani, Dino A
Format: Article
Language:English
Subjects:
Anti-Inflammatory Agents
Dexamethasone
Female
Glucocorticoids - adverse effects
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects
Infant, Newborn
Infant, Premature
Original
Premature Birth - prevention & control
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Summary:Prematurity is strongly associated with poor respiratory function in the neonate. Rescue therapies include treatment with glucocorticoids due to their anti-inflammatory and maturational effects on the developing lung. However, glucocorticoid treatment in the infant can increase the risk of long-term cardiovascular complications including hypertension, cardiac, and endothelial dysfunction. Accumulating evidence implicates a molecular link between glucocorticoid excess and depletion of nitric oxide (NO) bioavailability as a mechanism underlying the detrimental effects of postnatal steroids on the heart and circulation. Therefore, combined glucocorticoid and statin therapy, by increasing NO bioavailability, may protect the developing cardiovascular system while maintaining beneficial effects on the lung. We investigated combined glucocorticoid and statin therapy using an established rodent model of prematurity and combined experiments of cardiovascular function in vivo, with those in isolated organs as well as measurements at the cellular and molecular levels. We show that neonatal glucocorticoid treatment increases the risk of later cardiovascular dysfunction in the offspring. Underlying mechanisms include decreased circulating NO bioavailability, sympathetic hyper-reactivity, and NO-dependent endothelial dysfunction. Combined neonatal glucocorticoid and statin therapy protects the developing cardiovascular system by normalizing NO and sympathetic signaling, without affecting pulmonary maturational or anti-inflammatory effects of glucocorticoids. Therefore, combined glucocorticoid and statin therapy may be safer than glucocorticoids alone for the treatment of preterm birth.
ISSN:0194-911X
1524-4563
DOI:10.1161/HYPERTENSIONAHA.122.19647