Preventing future heart disease before birth

By Lucy Hamer

Cardiovascular disease remains the leading cause of mortality in adults, claiming over 17 million deaths per year (Mensah et al., 2019), yet current treatment options are still limited to improving symptoms rather than attenuating disease development (Botting et al., 2020). It has been widely stated that the focus on cardiovascular disease research needs to be shifted from treatment to prevention (University of Cambridge, 2020) – but this is no easy feat, particularly when the onset of cardiovascular disease can’t be attributed to a single defining cause. Whilst smoking, diabetes and obesity are all risk factors for heart problems (National Health Service, 2020), researchers have identified that suboptimal uterine conditions program a predisposition to cardiovascular disease into the unborn fetus (Thompson et al., 2018), suggesting that heart disease prevention needs to start before birth.

Developmental programming describes the process by which the environment experienced during foetal development can inflict irreversible phenotypic changes onto the fetus, which can have lifelong influences on the offspring’s health. Interactions between the fetus and the womb control important gene expression signatures, affecting how well the offspring is able to cope with challenges as an adult (Huang et al., 2019). A common pregnancy complication with a powerful impact on long-term cardiovascular health is chronic fetal hypoxia, a term given to fetal oxygen deprivation. Low oxygen levels are caused by increased resistance in the placental blood vessels (Giussanin, 2016), which can occur due to placental infection, pre-eclampsia, gestational diabetes or maternal obesity (Huang et al., 2019). As a result of reduced oxygenation, fetal growth is compromised (Pereira & Chandraharan, 2017) which is associated with poor neonatal outcome and endothelial dysfunction. No effective treatments currently exist for chronic fetal hypoxia (Botting et al., 2020).

By adapting to hypoxic conditions experienced in the womb, the fetal heart becomes more vulnerable to subsequent metabolic challenges (Thompson et al, 2019). Oxygen deprivation causes a state of oxidative stress to arise in the mitochondria of fetal cells which impairs mitochondrial function (Bautista, 2020). Cardiac mitochondria are particularly susceptible to damage, with devastating effects. Alterations to the function of cardiac mitochondria in the fetus damages the contractile properties of the heart, predisposing the offspring to cardiovascular dysfunction in later life (Thompson et al, 2019). Oxidative stress in circulation also injures fetal blood vessels (Botting et al., 2020). These hypoxia-induced damages to fetal cardiovascular health program an increased risk of hypertension, coronary artery disease and heart dysfunction into the offspring (Thompson et al, 2019).

The need to block the programming effects of chronic fetal hypoxia on fetal cardiovascular health has already been recognised, with some researchers beginning work to identify potential therapeutic pathways. Brain et al. performed experiments with Welsh Mountain sheep to investigate whether maternal treatment with antioxidant vitamin C was capable to protect fetal heart and blood vessels from hypoxia-induced damage. Whilst this treatment successfully restored normal fetal growth patterns and prevented the offspring from experiencing systemic hypertension in adult life (Brain et al, 2019), the therapeutic doses of vitamin C were too high to be suitable for human treatment. Treatment also impaired the fetal brain-sparing response (Botting et al., 2020); a protective physiological response which ensures the brain experiences sufficient blood flow during periods of acute stress such as transient oxygen deprivation (Di Mascio et al., 2020). In response to reduced oxygen supply, cardiac output to the brain is enhanced via vasodilation and blood flow to peripheral structures is limited via vasoconstriction (Giussanin, 2016). Periods of acute hypoxia are common, occurring as a result of transient compression of the umbilical cord (Botting et al., 2020), and inadequate defences can lead to cognitive disability (Giussanin, 2016), making the fetal brain-sparing response vital for fetal health. It was hypothesised that the mechanism by which maternal vitamin C treatment weakens fetal brain-sparing is by enhancing NO bioavailability, which combats the ability of peripheral vessels to constrict (Botting et al., 2020).

Recently, MitoQ has been proposed as a promising alternative. MitoQ is a mitochondria-targeted antioxidant, developed by Professor Mike Murphy of the University of Cambridge MRC-Mitochondrial Biology Unit (University of Cambridge, 2020). Most antioxidants struggle to penetrate the double-walled membrane of mitochondria, but the ubiquinone antioxidant component of MitoQ is covalently bonded to a lipophilic cation which allows it to accumulate effectively in the mitochondrial matrix (Smith & Murphy, 2010). MitoQ has previously been examined for it’s therapeutic properties, including as a potential treatment for age-related vascular dysfunction, in which it promisingly reduced mitochondrial ROS levels in old mice (Rossman et al., 2010). Clinical trials in humans have demonstrated that long-term administration of MitoQ inflicts no serious side effects (Smith & Murphy, 2010), and it has also been hypothesised that maternal treatment with MitoQ will have no damaging effects on the fetal brain-sparing response, as it does not interfere with peripheral vasoconstriction (Botting et al., 2020).

It was previously unknown whether MitoQ would be a viable treatment to protect a fetus from hypoxia-induced cardiovascular dysfunction, but a recent investigation by Botting et al. shed some light onto this. Preliminary experiments confirmed that offspring born from pregnancies complicated by chronic fetal hypoxia were more likely to experience systemic hypertension as an adult, as a result of a weakened cardiovascular system. Subsequently, the potential of MitoQ to block this damage was assessed, and the results were encouraging. MitoQ treatment both restored fetal growth and protected against the effects of hypoxia on fetal cardiovascular function, whilst fetal brain-sparing responses remained unaffected. Additionally, adult offspring from these treated hypoxic pregnancies exhibited no signs of programmed hypertension and instead had cardiovascular health similar to offspring from healthy pregnancies. Experiments with chicken embryos demonstrated that MitoQ treatment protects fetal cardiovascular health by blocking hypoxia-induced increases in oxidative stress in cardiac mitochondria, inhibiting impairments to contractility (Botting et al., 2020).

Whilst this study poses MitoQ as an attractive candidate to protect offspring of pregnancies complicated by chronic fetal hypoxia from cardiovascular problems later in life, there are a number of questions that still need to be deliberated. The main limitation of this investigation is that male and female offspring were used exclusively for different experiments, so the study lacked any comparison of the effects of MitoQ treatment on offspring of the opposite sex. Sex differences exist in the pathophysiology, clinical presentation and management of numerous cardiovascular diseases so are important to address in any related investigation (Regitz-Zagrosek et al., 2016). In addition, Thompson et al. recently proposed that fetal hypoxia impairs the function of cardiac mitochondria in a sex-dependent manner (Thompson et al., 2018), so it is therefore probable that male and female offspring will respond differently to MitoQ treatment.

Chronic fetal hypoxia, a relatively common pregnancy complication, exerts devastating impacts on the health of the fetus that do not end at birth. Fetal cardiovascular health is severely impaired, with life-long impacts, but recent research suggests that maternal treatment with antioxidants may help to combat hypoxia-induced cardiovascular dysfunction. However, further experimentation is required to translate these findings to humans. Sheep and humans share similar tempos of cardiovascular development but it has previously been recognised that sheep are not perfect models of human pregnancy (Barry & Anthony, 2008). Additional considerations, such as the most appropriate doses and time-frames for MitoQ treatment, need to be identified before these preventative approaches can become common-place.

References:

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