University of Manchester
Programming of Ventricular Arrhythmia by Fetal Hypoxia
Sudden death from cardiac arrhythmia is a major cause of mortality in the UK and Western world. We have recently shown oxygen deprivation during fetal development increases ventricular arrhythmia susceptibility in adulthood. This discovery suggests that some cardiac arrhythmias may have a developmental origin, and it provides us with a unique opportunity to intervene and prevent the risk of arrhythmia in adulthood even before a person is born. In this interventional project, we are integrating radiotelemetry, cardiac optical mapping and fluorescence microscopy to understand the mechanisms driving arrhythmia susceptibility in offspring from hypoxic pregnancies, and we are developing a therapy to protect against it. The overarching hypothesis for our study is that fetal hypoxia programmes offspring ventricular arrhythmia sensitivity in adulthood, and maternal MitoQ therapy can protect against it.
How does fetal hypoxia programme ventricular arrhythmia sensitivity?
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We are investigating whether hypoxic pregnancy increases arrhythmic susceptibility in adult rat progeny.
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Time-mated Wistar rats were assigned to Normoxia (21% O2) or Hypoxia (13% O2). Chronic hypoxia was induced via hypoxia chamber between GD6-20 (Term=23d). At 4 months of age offspring were humanely killed (CO2 inhalation). qRT-PCR was performed from frozen heart tissue isolated from the left ventricle.
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Optical mapping was performed on Langendorff perfused hearts. Hearts were loaded with intracellular calcium indicator (Rhod-2) and voltage sensitive dye (RH237). Following dye infusion, the left ventricle was burst paced from the apex at increasing frequencies (10-20hz) to induce arrhythmias. Hearts from hypoxic pregnancies become arrhythmic at an earlier stage of the burst protocol than Normoxic animals.
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Calcium homeostasis was disrupted by prenatal hypoxia with an increase in Ca2+ transient decay times and increased duration of the action potential compared to Normoxic animals. qRT-PCR revealed key components of the excitation-contraction coupling pathway were significantly altered within hypoxic hearts.
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These data support the developmental programming of an increased risk of cardiac arrhythmia in adult offspring of hypoxic pregnancy. Abnormal calcium handling programmed in offspring of hypoxic pregnancy resulting in an increased susceptibility to adrenergic stimulation and thereby increased arrhythmic events may include underlying mechanism. Prolonged action potentials and Ca2+ transient decay times as seen in the hypoxic hearts after burst pacing are a common feature associated with heart disease and in line with an increased risk to a ‘second hit".