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Programming of Cardiac Myocyte Calcium Cycling Pathways by Fetal Hypoxia
Lead Researcher:  Dr Mitchell Lock

Developmental hypoxia is common in complicated pregnancy and it can programme cardiac abnormalities in the offspring.  Adult offspring from hypoxic pregnancies have impaired cardiac systolic/diastolic function as well as enhanced cardiac responsiveness to sympathetic stimulation; a state reminiscent of early stage heart failure.  The mechanistic basis for the programmed cardiac dysfunction in these individuals is unknown, but maternal treatment with antioxidants in hypoxic pregnancy can prevent it. 

Several lines of evidence suggest that prenatal hypoxia alters the intrinsic cellular properties of the cardiomyocyte, particularly calcium homeostasis.  This study investigated whether maladaptive cardiomyocyte calcium handling is the cellular basis for cardiac dysfunction in adult offspring of hypoxic pregnancy.  Further, we investigated whether maternal treatment with melatonin is a suitable antioxidant candidate with translational potential for human therapy. 

How Did Fetal Hypoxia Affect Cardiac Myocyte Calcium Handling?

Effects of fetal hypoxia on calcium cycling
  • Offspring from hypoxic pregnancy had altered cardiac myocyte calcium cycling, including:

    • A reduction in the ventricular systolic calcium transient amplitude

    • A decrease in contractility

    • A decrease in the velocity of contraction.

    • Slower rate of decay of the calcium transient, evidenced by significant changes in DT50, DT90 and Tau

  • The mechanism driving the reduction in calcium transient amplitude is unknown, but it could include reduced sarcolemmal calcium flux, decreased sarcoplasmic reticulum (SR) calcium release, and/or increased calcium buffering.

  • The mechanism driving the slowed rate of decay of the calcium transient could include changes in SERCA or PLB expression, or NCX activity 

  • Importantly, melatonin was successful in preventing most of the changes in cardiac myocyte calcium handling

  • This supports the use of maternal antenatal treatment with melatonin as an effective therapy with good human translational potential for protection against heart disease in offspring of hypoxic pregnancy.

Relevant Papers

Giussani DA (2021) Breath of Life: Heart Disease Link to Developmental Hypoxia. Circulation.   26;144(17):1429-1443. doi: 10.1161/CIRCULATIONAHA.121.054689. Epub 2021 Oct 25. PMID: 34694887; PMCID: PMC8542082.

Galli GLJ, Lock MC, Smith KLM, Giussani DA, Crossley DA 2nd (2022) Effects of Developmental Hypoxia on the Vertebrate Cardiovascular System. Physiology (Bethesda). 2023 Mar 1;38(2):0. doi: 10.1152/physiol.00022.2022. Epub 2022 Nov 1. PMID: 36317939.

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