Metabolomics and perinatal cardiology

Roberta Pintus, Angelica Dessì, and Vassilios Fanos

Perinatal programming of heart function

In recent years in medical history, a new fascinating hypothesis, which is being confirmed by a growing number of studies, has been proposed: the Developmental Origins of Health and Disease (DOHaD). It states that any adverse event that may occur in the perinatal period can shape the health status of an individual, making that individual less or more prone to develop a specific pathology, i.e., metabolic syndrome or cardiovascular diseases. It states that there is “a response by a developing organism to a specific challenge (event) during a critical time window that alters the trajectory of development qualitatively and/or quantitatively with resulting persistent effects on phenotype” (1).

For example, from animal studies, it has been found that if dexamethasone is administered to pregnant rats in a particular time window, their male offspring would display an increased systolic blood pressure (2).

Among adverse effects that may occur in the perinatal period, there are the pre- and periconceptional environment, preterm birth, intrauterine growth restriction, maternal diabetes, and hyperoxia. These may exert their effects via epigenetic changes such as DNA methylation/deacetylation or phosphorylation that may result in modifications of the phenotype. It has been demonstrated that being born prematurely or with intrauterine growth restriction (IUGR) or with an extremely low birth weight are risk factors for compromised heart function leading to cardiovascular diseases later in life (3,4). Already in 1915, autopsy findings showed that among 140 young soldiers killed during World War I, about 46% displayed atherosclerotic plaques in the coronary arteries (5). Low birth weight is a risk factor for cardiovascular disease: the lower the weight, the higher is the mortality risk in adulthood due to coronary heart disease. It seems to increase the hypertension risk as well. There is what is called “developmentally programmed hypertension” due to the altered vascular structure or function (6).

Moreover, our group found a significant QT interval prolongation in young adults born preterm with extremely low birth weight, which is related to sudden death (7).

In IUGR fetuses, some echocardiographic findings may indicate those at risk of developing hypertension at 6 months of age (8).

Even maternal diet may influence the perinatal programming of heart function of the neonate. It is well known from the results of the investigation on adults born during the Dutch Famine of 1944–1945. Caloric restriction during the first trimester may lead to cardiovascular disease and hypertension together with dyslipidemia and obesity that are risk factors of compromised heart function.

There are several crucial time points for heart development in fetuses and neonates. From 16 up to 35 weeks, the linear increase in heart tissue volume is due entirely to cardiomyocite proliferation (9). Furthermore, during late prenatal or early postnatal life, there is a switch from hyperplastic to hypertrophic cellular growth (10).

Nevertheless, IUGR is a more significant risk factor than preterm birth for later systolic hypertension. Among children born preterm, those that are also small for gestational age are at increased risk of arterial stiffness and metabolic dysfunction (11). In IUGR neonates, there is an altered cardiovascular remodeling. The IUGR heart is by definition the “less efficient heart.” This is induced in response to the stress condition in utero, that persists as a permanent feature in postnatal life. These neonates can be affected by dilated cardiomyopathy-like heart remodeling, vascular dysfunction, increased blood pressure, increased carotid intima-media thickness, and decreased sarcomere length. Furthermore, their heart may show persistent aortic wall thickening during infancy, and they may present reduced brachial flow-mediated vasodilation in adulthood, confirming the hypothesis of perinatal programming of heart diseases (12,13).

In case of perinatal hypoxia/asphyxia, in animal models of hypoxia/reoxygenation-induced myocardial lesions, the severity of the damages is due to interindividual variability and not to oxygen concentration. Animals displayed different lesions: interstitial edema and wavy fibers, hypereosinophilia of cardiomyocites, coagulative necrosis, and cytoplasmic vacuolization of the cardiomyocites (14).

Due to interindividual variability, even in humans according to the DOHaD hypothesis, being able to detect those fetuses and neonates at risk of developing cardiovascular disease, it is extremely important for the physician to intervene as soon as possible and ameliorate the outcomes and the quality of life of these small patients.

Metabolomics: A tool to investigate the present and predict the future

In this context, metabolomics could be a very useful tool to investigate the present and predict the future. Metabolomics is one of the newest omics sciences that through the analysis of the metabolites content in biofluids such as saliva, blood, sweat, and amniotic fluid can provide a picture of the metabolic state of an individual (even neonates and fetuses) in physiological and pathological conditions.

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