Maternal obesity accelerates cardiomyocyte maturation and programs adult heart dysfunction in offspring

Abstract

Rationale: Maternal obesity increases cardiovascular risk in offspring, but the developmental mechanisms linking early-life metabolic stress to adult heart dysfunction remain poorly understood, and whether maternal obesity alters the postnatal maturation of the cardiomyocyte itself has not been addressed. Objective: To determine whether maternal high-fat diet alters the developmental trajectory of postnatal cardiomyocyte maturation and its functional consequences in adult offspring. Methods: In a rat model of maternal high-fat diet, longitudinal echocardiographic and invasive hemodynamic phenotyping were combined with transcriptomic, lipidomic, and ultrastructural analyses across four postnatal stages. Results: Offspring exposed to maternal high-fat diet displayed accelerated postnatal cardiac maturation, with premature activation of contractile, calcium-handling and metabolic gene programs, concentric hypertrophy, and enhanced systolic performance in juvenile life. This precocious maturation was not sustained: by adulthood, ejection fraction and intrinsic myocardial contractility progressively declined, coinciding with disorganization of sarcomeres, intercalated discs, and excitation-contraction coupling proteins, in the absence of fibrosis, lipid accumulation or major mitochondrial respiratory dysfunction. Conclusions: These findings reveal accelerated cardiomyocyte maturation as a developmental mechanism linking maternal obesity to long-term cardiac vulnerability, with cardiomyocyte cytoarchitecture disruption emerging as an early hallmark that precedes overt systolic failure. Key words: Maternal obesity, DOHaD, postnatal cardiac maturation, cardiomyocyte cytoarchitecture, systolic dysfunction