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CH-FIT trial

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Congenital heart defects (CHDs) are prevalent birth defects and affect nearly 1.8 in 100 live births worldwide.1 In Australia, it is 1 in 100. Maternal obesity and/or diabetes mellitus is causally associated with foetal cardiac hypertrophy2 that is noted as one of most common cardiac malformations occurring in birth. About 50 per cent of women are overweight or obese at their reproductive ages.3

Apart from that, it is also found that fructose and sucrose (a disaccharide of glucose and fructose) are hypertrophic stimuli in the heart independent of the insulinogenic effects and occurring outside of the diabetes state.4 Sucrose/table sugar is sourced from sugar cane and beets, and if not added as a sweetener by consumers, is added routinely in processed foods. Today, with a high urban population, we consume more processed and ultra-processed food, and certain locales such as the US have dramatically high levels of added high fructose corn syrup.

These obesogenic diets and pro-hypertrophic saccharides raise huge concerns of maternal diet and the impact on foetal heart development during gestation. In collaboration with Prof Fatima Crispi and her team in Barcelona, Spain, we have secured blood plasma samples from 1,200 pregnant women who underwent a parallel-group randomised clinical trial. This was an intervention study, where one third of the cohort underwent usual care, another third Mediterranean dietary intervention, and the third cohort mindfulness-based stress reduction.

The outcome from this clinical trial reveals that these structured interventions, either on the Mediterranean diet or mindfulness-based stress reduction, significantly reduced the risk of small-for-gestational-age newborns. This is a major finding, as we know that intra-uterine-growth-restriction (IUGR) is a major risk factor for lifelong poor health, cardiovascular risk, metabolic disease, and shorter lifespan. We also know that the intra-uterine period is a time of major cardiac plasticity where the heart is most vulnerable to insults that lead to long term impact on cardiac structure and function.

We first want to understand what salutary effects preventing IUGR had on the heart. We would also like to understand what specific macro and micronutrients in the Mediterranean diet are protective and promote healthy baby heart development. One technique we employ allows us to trace the carbon and nitrogen sources of the diets, whereby “healthy” and “unhealthy” dietary sources can be determined. Isotope ration mass spectrometry can provide information on food origins and dietary patterns by accurately measuring isotope ratios of carbon 13 over 12, and nitrogen 15 over nitrogen 14, called delta 13C and delta 15 nitrogen, respectively. In general, an increased carbon isotope ratio correlates with highly processed food and high nitrogen isotope ratio corresponds to unhealthy animal protein sources.5

We are determined to draw a detailed map of metabolomic and lipidomic changes in response to the maternal diet that is either Mediterranean or regular diet, as well as the relationships to foetal heart development. We plan to analyse both maternal blood plasma and foetal cord blood plasma in depth using liquid chromatography-tandem mass spectrometry (LCMS) to sensitively and simultaneously detect thousands of molecules, including lipids, metabolites and intermediates that play in central carbon metabolism, energy metabolism, oxidative stress, inflammation, extracellular homeostasis, and drug-drug interactions.

We are undertaking a major collaborative program with cardiac developmental biologists, experts in developmental programming, dietary science expertise, and biostatisticians. Prof Jean Yang and her team have created a new biostatistical program for multilayered dietary data that can cluster all omics features based on their response to nutrition intake and the multiple dimensions of analyses as well as other experimental factors including foetal echocardiograph images and microbiome data.

It is critical to highlight that this cohort is unique, with comprehensive dietary data, maternal and foetal anthropomorphy, biochemistry, metabolic, cardiac, blood, and gut microbiome data. The foetal cardiac data is super refined using both echocardiography and cardiac MRI. We will also validate signals in an emerging cohort in Sydney called Baby1000.

The outcome from this meta-analysis will provide information for improved pregnancy management and potentially reduce congenital heart diseases and other related disorders, thus resulting in better health for offspring and their later lives. This work has major potential for uncovering fundamental human biology: paired with preclinical mechanistic work isolating a relationship between sucrose ingestion, 1-carbon metabolism, and pathogenic cardiac hypertrophy, this work has the potential to reframe the provenance of human hypertrophic cardiomyopathy, which is poorly understood. We believe hypertrophic cardiomyopathy in adults arises to a large degree in utero due to processes set in place during this period of major plasticity far in advance of the adult phenotype. This work also has major potential for framing policy for maternal diet and cardiac development.

References

  1. The Lancet Child & Adolescent Health, 2017
  2. Basu and Garg 2018 and Gandhi, Zhang et al. 1995; Meijboom, 2007
  3. Ng, Fleming et al. 2014
  4. Mirtschink, Krishnan et al., Nature, 2015
  5. Martinelli, 2020

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