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RCT·ophthalmology, nutrition, cardiology, endocrinology, clinical trial·PMC10017302

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

Hypertension (Dallas, Tex. : 1979) · 13 authors, 8 centres

AI SUMMARY

FIDELITY 100%

POPULATIONMale Wistar rat pups treated from postnatal day 1 (P1) to P6

INTERVENTIONDexamethasone (0.5, 0.3, 0.1 mg/kg/day IP on P1-P3) plus pravastatin (10 mg/kg/day IP on P1-P6)

COMPARISONDexamethasone alone, pravastatin alone, and saline control

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TL;DR

In a rat model of prematurity, neonatal dexamethasone treatment caused hypertension, cardiac dysfunction, and impaired vascular reactivity at weaning, mediated by reduced nitric oxide bioavailability and sympathetic hyper-reactivity. Adding pravastatin to dexamethasone normalized these cardiovascular adverse effects without diminishing the beneficial pulmonary maturational and anti-inflammatory effects of glucocorticoids. This suggests that combined statin and glucocorticoid therapy may be safer than glucocorticoids alone for treating preterm birth.

Full summary

4,686 CHARS

**Background:** Preterm birth is commonly treated with glucocorticoids to accelerate lung maturation and reduce respiratory distress, but these drugs have adverse off-target effects on the developing cardiovascular system, including hypertension, endothelial dysfunction, and cardiac remodeling. Accumulating evidence suggests that glucocorticoids impair nitric oxide (NO) bioavailability, which can lead to sympathetic hyper-reactivity and cardiovascular dysfunction. Statins, through their pleiotropic effects, increase NO bioavailability by inhibiting GTPases that degrade eNOS and Akt. This study tested the hypothesis that combining dexamethasone with pravastatin would preserve the pulmonary benefits of glucocorticoids while protecting the cardiovascular system.

**Methods:** Time-mated pregnant Wistar rats delivered at term. Male pups were assigned to four groups: control (saline), dexamethasone (0.5, 0.3, 0.1 mg/kg/day IP on P1-P3), dexamethasone+pravastatin (same dexamethasone plus pravastatin 10 mg/kg/day IP on P1-P6), and pravastatin alone (same dose on P1-P6). One male per litter was used per outcome. At P21, in vivo cardiovascular function was assessed under urethane anesthesia (basal arterial pressure, heart rate, heart rate variability). Isolated hearts were studied using Langendorff preparation (basal and post-ischemia function). Femoral artery reactivity was measured by wire myography (constriction to phenylephrine, endothelium-dependent relaxation to methacholine, with and without L-NAME to determine NO-dependent and NO-independent components). Histology was performed on perfusion-fixed hearts, aortas, and lungs (Masson Trichrome, H&E). Molecular analyses (Western blot) measured cardiac 4-hydroxynonenal and Hsp70 (oxidative stress), and pulmonary SP-C and SP-D (surfactant proteins). Circulating NO species (NOx) and C-reactive protein (CRP) were measured. Statistical analysis used 2- or 3-way ANOVA with Student-Newman-Keuls post hoc test; significance at P<0.05.

**Key Results:** Dexamethasone treatment significantly increased basal mean arterial pressure (control: 60±2 mmHg; dexamethasone: significantly higher, P<0.05) and decreased heart rate variability (lower RMSSD, higher LF/HF ratio, P<0.05), indicating sympathetic dominance. Circulating NOx fell from 22.3±2.2 μM in controls to significantly lower levels in dexamethasone-treated pups (P<0.05). Isolated hearts from dexamethasone-treated pups showed lower left ventricular developed pressure, coronary flow, dP/dtmax, and dP/dtmin (P<0.05 vs control). Femoral arteries from dexamethasone-treated pups exhibited increased sensitivity to phenylephrine (leftward shift) and impaired endothelium-dependent relaxation to methacholine (rightward shift), with a significant reduction in the NO-dependent component (P<0.05). Dexamethasone also caused asymmetric growth restriction (increased ponderal index, brain:liver ratio, head diameter:body weight ratio) and reduced absolute heart and liver weights. Combined dexamethasone+pravastatin restored arterial pressure, heart rate variability, circulating NOx, cardiac function, and vascular reactivity to control levels (P<0.05 vs dexamethasone alone). Importantly, pravastatin did not blunt dexamethasone-induced pulmonary maturation: secondary crest formation, SP-C and SP-D expression, and reduced lung tissue:air space ratio were similar in dexamethasone and dexamethasone+pravastatin groups (both P<0.05 vs control). CRP levels were similarly reduced in both dexamethasone groups (P<0.05 vs control). Pravastatin alone decreased circulating NOx and impaired endothelium-dependent relaxation, but also promoted lung maturation indices.

**Clinical Implications:** This study provides preclinical evidence that adding pravastatin to a clinically relevant course of neonatal dexamethasone protects against glucocorticoid-induced cardiovascular dysfunction (hypertension, cardiac impairment, vascular endothelial dysfunction, sympathetic dominance) while preserving the beneficial pulmonary maturational and anti-inflammatory effects. The findings suggest a potential therapeutic strategy to improve the safety of postnatal glucocorticoid therapy in preterm infants. The authors note limitations: only male pups were studied, outcomes were measured at weaning (not adulthood), and in vivo function was assessed under anesthesia. Future studies in larger animal models (e.g., preterm sheep) and in both sexes are needed before clinical translation. The perspective is also raised that combined antenatal glucocorticoid and statin therapy might similarly protect the fetal cardiovascular system in pregnancies threatened with preterm birth.

PICO

PPOPULATION

Male Wistar rat pups treated from postnatal day 1 (P1) to P6

IINTERVENTION

Dexamethasone (0.5, 0.3, 0.1 mg/kg/day IP on P1-P3) plus pravastatin (10 mg/kg/day IP on P1-P6)

OOUTCOME

Postnatal growth, in vivo cardiovascular function (arterial pressure, heart rate variability), isolated cardiac function (Langendorff), peripheral vascular reactivity (wire myography), cardiac and vascular histology, markers of oxidative stress, circulating NO species and CRP, and pulmonary maturation indices (secondary crests, surfactant proteins C and D)

STUDY TYPE

RCT

SPECIALTY

ophthalmology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10017302

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

Hypertension (Dallas, Tex. : 1979)

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ABSTRACT

Background: 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. Methods: 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. Results: 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. Conclusions: Therefore, combined glucocorticoid and statin therapy may be safer than glucocorticoids alone for the treatment of preterm birth.

CITATION EXPORT

Andrew D. Kane, Emilio A. Herrera, Youguo Niu et al.. Combined Statin and Glucocorticoid Therapy for the Safer Treatment of Preterm Birth. Hypertension (Dallas, Tex. : 1979). (2023). https://doi.org/10.1161/HYPERTENSIONAHA.122.19647

AUTHORS

13 · 8 CENTRES

Andrew D. Kane, Emilio A. Herrera, Youguo Niu, Emily J. Camm, Beth J. Allison, Deodata Tijsseling, Ciara Lusby, Jan B. Derks, Kirsty L. Brain, Inge M. Bronckers, Christine M. Cross, Lindsey Berends, Dino A. Giussani

Department of Physiology, Development and Neuroscience, University of Cambridge, United Kingdom (A.D.K., E.A.H., Y.N., E.J.C., B.J.A., C.L., K.L.B., C.M.C., D.A.G.).
Laboratory of Vascular Function & Reactivity, Pathophysiology Program, ICBM, Faculty of Medicine, Universidad de Chile, Santiago, Chile (E.A.H.).
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia (E.J.C., B.J.A.).
Perinatal Center, University Medical Center, Utrecht, the Netherlands (D.T., J.B.D.).
Institute of Metabolic Science, University of Cambridge Metabolic Research Laboratories, Addenbrooke’s Hospital, Cambridge, United Kingdom (L.B.).
Department of Obstetrics and Gynecology, Radboud University Nijmegen Medical Centre, the Netherlands (I.M.B.).
The Cambridge BHF Centre for Research Excellence, Cambridge, United Kingdom (Y.N., D.A.G.).
The Cambridge Strategic Research Initiative in Reproduction, Cambridge, United Kingdom (Y.N., D.A.G.).