Developmental Hypoxia Increases Susceptibility to Cardiac Ventricular Arrhythmias in Adult Offspring

Abstract

Ventricular arrhythmias are the leading cause of sudden cardiac death. It is well-established that environmental factors contribute to the origin and penetrance of ventricular arrhythmic disorders. However, to our knowledge, no studies have considered the role of the intrauterine environment. In this study, we investigated the long-term effects of fetal hypoxia on ventricular arrhythmia susceptibility. Pregnant Wistar rats were assigned to normoxia (21% O2) or hypoxia (13% O2 between gestational days 6-20), and offspring were raised to 6 months. Hearts were isolated and loaded with the fluorescent calcium- and voltage-sensitive indicators, Rhod-2 and RH237, respectively. Optical mapping was performed while the left ventricle was burst paced (10-20hz) to induce arrhythmias. Hearts isolated from adult offspring exposed to fetal hypoxia were more susceptible to arrythmia during burst pacing, compared to controls. This phenotype was associated with prolonged Ca2+ transients and action potentials, an increased frequency of Ca2+ waves and delayed after depolarisations, as well as lower gene and protein expression of the sarcoplasmic reticulum Ca2+ ATPase. Collectively, our data shows that fetal hypoxia can programme ventricular arrhythmia sensitivity in adulthood, driven by abnormalities in excitation-contraction coupling. This is the first evidence that some ventricular arrhythmias may have a developmental origin, highlighting pregnancy as a potential window for early preventive intervention.