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Developmental Vascular Biology
Developmental Vascular Biology
Developmental immaturity in vascular adrenergic receptor expression and function is important to consider in the context of preterm neonates, with alpha-1 receptors showing age-specific gene regulation and beta receptors (especially β₂ and β₃) exhibiting reduced density or altered responsiveness at lower gestational ages. Receptor maturation by gestational age:
Alpha-1 adrenergic receptors (α₁AR) in cerebral arteries undergo maturation: premature fetuses (e.g., ~96 days gestation in lambs, ~0.65 term) show unique activation of pro-inflammatory and angiogenesis pathways (e.g., 33 exclusive pathways) upon stimulation, versus fewer changes in near-term fetuses (~140-145 days). Pial artery constriction to norepinephrine decreases progressively from preterm fetus to newborn to adult, indicating evolving vascular tone regulation.
Beta receptors are underdeveloped in preterm hearts: lower β-adrenoceptor density in fetal/near-term (e.g., rabbits/mice at 2/3 gestation) vs term, with β₂ contributing more to inotropy in neonatal rat myocytes (via cAMP) but minimal in adults. β₃-ARs are upregulated in hypoxia (fetal environment) to promote vasodilation/angiogenesis; preterm birth exposes immature vessels to hyperoxia, downregulating β₃ and risking vascular pathologies like PDA, ROP, NEC.
References:
Preterm (<29-32w GA) show reduced response to catecholamines due to low receptor density/endogenous stores
The developmental biology of the neonate plays a critical role in how the infant responds to both the disease and its treatment. For example, the maturation of alpha and beta-adrenergic receptors is dependent on gestational age, with extremely preterm infants often displaying alpha dominance and less beta-receptor maturity. This means that a drug like dopamine, which is the most widely used and studied medication in neonatology, may function differently in a micro-preemie than it does in a term infant. Furthermore, neonates often present with competing physiologies, such as a low systemic vascular resistance state coupled with high pulmonary vascular resistance due to a reactive vascular bed. Clinicians must also account for the presence of open fetal channels, such as the ductus arteriosus, which can complicate cardiac output and oxygenation through right-to-left shunting.
Figure from open-source article: Agakidou E, Chatziioannidis I, Kontou A, Stathopoulou T, Chotas W, Sarafidis K. An Update on Pharmacologic Management of Neonatal Hypotension: When, Why, and Which Medication. Children (Basel). 2024 Apr 19;11(4):490. doi: 10.3390/children11040490. PMID: 38671707; PMCID: PMC11049273.
This is our approach at the NeoCardioLab regarding prematurity in the first week of life. However, this may not be adaptable or appropriate for your context of care. Please read our disclaimer.
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Important Note: Cardiac disturbances in the most immature infants are often secondary to adverse cardio-respiratory interactions. The first priority is to reassess respiratory status and ventilatory strategy, with close attention to mean airway pressure (MAP) and any degree of hyperinflation, as these infants are extremely sensitive to even modest increases in MAP. Hyperinflation can occur at MAPs as low as 8–9 cmH₂O and significantly affect both pulmonary vascular resistance and systemic venous return. Similarly, ventilatory settings that drive PaCO₂ into the normal range may exacerbate left-to-right ductal shunting, and in such cases mild permissive hypercapnia (PaCO₂ 50–60 mmHg) may be preferable. Once these cardio-respiratory contributors are addressed, it is essential to avoid polypharmacy and to target a single physiologic pathway rather than layering multiple drugs without a clear mechanistic rationale. An Echo/TnECHO assessment can help define the predominant mechanism and guide more precise therapy to avoid multiple agents being introduced, but only once the respiratory care has been optimized. Finally, after optimizing respiratory status, if a patient is still considered to have cardiovascular instability requiring pharmacologic support, it is important to avoid piling on multiple agents. An ineffective drug should be discontinued before introducing another, rather than adding therapies without evidence of benefit.
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