Mattia Pasquinucci, Marco Scaglione, Sofia Mezzalira, Luisa Bonsembiante, Mariaelena Zaffina, Pietro Pogacnik, Sara Bondanza, Ramona Marini, Maria E. Derchi, Davide Meneghesso
San Bassiano Hospital. Hôpital Universitaire Necker-Enfants Malades. University of Padua. IRCCS Istituto Giannina Gaslini.
Università degli Studi Gugliemo Marconi.
Italy and France
Frontiers in Cardiovascular Medicine
Front Cardiovasc Med 2026; 13:
DOI: 10.3389/fcvm.2026.1900356
Abstract
Background: Pediatric pulmonary hypertension (PH) is traditionally managed under a strict hemodynamic paradigm, often overlooking systemic metabolic and nutritional drivers. This review introduces the “Cellular Deprivation Model” to evaluate how specific micronutrient deficiencies and metabolic blocks accelerate pulmonary vasculopathy.
Methods: A systematic, PRISMA-compliant search was conducted in PubMed/MEDLINE for literature published between January 2000 and April 2026. Keywords intersected pediatric PH with malnutrition, avitaminosis, iron deficiency, and inborn errors of metabolism. Out of 401 unique records, 115 articles were synthesized across clinical and mechanistic tracks.
Results: Acquired deficiencies (including ascorbic acid, thiamine, iron, folate, and cobalamin deficiencies) and inherited disorders of vitamin metabolism (such as Cobalamin C deficiency and folate metabolism disorders) converge on common pathophysiological pathways: the hypoxia-inducible factor (HIF) axis, causing normoxic pseudo-hypoxia, and endothelial nitric oxide synthase (eNOS) uncoupling via tetrahydrobiopterin depletion. In low- and middle-income countries (LMICs), these cellular blocks form a positive socio-hemodynamic feedback loop with congenital heart disease, accelerating vascular media hypertrophy and reducing surgical operability. Strikingly, these nutrition-driven vascular phenotypes demonstrate rapid, complete reversibility upon metabolic rescue.
Conclusion: Standardized biochemical testing for micronutrients faces severe economic and cold-chain barriers in resource-limited settings. We propose a pragmatic shift toward universal empirical metabolic pre-conditioning-utilizing standardized, low-cost iron, vitamin C, thiamine, and folate regimens-for at-risk pediatric populations. This strategy aims to bypass advanced diagnostic delays, expand surgical operability windows, and mitigate perioperative mortality.
Category
Class V. Pulmonary Hypertension Associated with Hematological, Systemic, Metabolic, Nutritional and Other Disorders
Class I. Pulmonary Hypertension Associated with Congenital Cardiovascular Disease
Environmental Factors Associated with Pulmonary Vascular Disease
Review Articles Concerning Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes