Apnea in babies can cause hypertension in adulthood – 05/25/2023 – Health

Babies who go through periods of low oxygenation in the first months of life – resulting, for example, from episodes of apnea during sleep – tend to develop respiratory problems and high blood pressure already in their youth and throughout their adult life.

Researchers from Unesp (Universidade Estadual Paulista) demonstrated, for the first time, that in these cases the increase in blood pressure is due to a deregulation in the autonomic nervous system – which works involuntarily to control blood pressure, heartbeat and breathing , among other factors.

The study, published in the journal Sleep Research Society, was carried out in an animal model and demonstrated that increased blood pressure is associated with hyperactivity of neurons in the sympathetic nervous system (the branch of the autonomic nervous system that is activated in stressful situations).

“We found that rats that experienced episodes of intermittent hypoxia in the postnatal period had increased neuronal activity in the final part of the brainstem [bulbo] during young and adult life. This is probably due to an adaptation of the brain resulting from the period of low oxygenation during a critical phase of development. Among the adaptations is increased activity of the sympathetic autonomic nervous system, probably because of increased expression of a protein called hypoxia-inducible factor. [HIF-1α] in neurons of the medulla”, says Daniel Zoccal, professor at the Faculty of Dentistry of Araraquara (FOAr-Unesp).

According to the researcher, the greater expression of the HIF-1α protein by the neurons of the medulla generates a series of alterations in the reading of other genes that, among several actions, control cell activity. As a consequence, neurons with higher expression of HIF-1α showed greater activity, resulting in smaller blood vessels and, therefore, higher blood pressure. This phenomenon corresponds to what scientists call epigenetics, that is, biochemical changes in cells caused by environmental stimuli that promote the activation or silencing of genes without causing changes in the individual’s genome.

In addition to demonstrating for the first time the mechanisms involved in the relationship between episodes of low oxygenation in postnatal life and hypertension in youth and adulthood, the work, supported by FAPESP, may bring about important clinical consequences.

“Although hypertension has a high prevalence – around 30% of the world’s population – its origin still needs to be better understood. It is only known that there is a risk associated with factors such as obesity, sedentary lifestyle, kidney problems and salt consumption, for example. With the finding, we can investigate new treatments”, says Zoccal to Agência Fapesp.

The discovery also sheds light on the importance of the first years of an individual’s life for the development of diseases. “It is necessary to look more carefully at the breathing of babies even as a way to prevent the development of disease in adult life”, she says. Episodes of apnea in newborns may occur more frequently in premature infants, when the central nervous system and respiratory system are not yet fully mature, or in babies with adenoid or tonsil hyperplasia, some anatomical deformity, or obesity.

For the researcher, describing the whole process of how arterial hypertension occurs due to low oxygenation in the postnatal period (up to about two years of age in humans) can also help in the search for treatment for those patients who do not respond well to medications antihypertensives – about 20% of hypertensive patients.

Previous studies had already demonstrated that hypertensive patients, especially those who do not respond to drug treatment, have an increase in electrical activity at the interface between sympathetic nerves and blood vessels. “The blood vessels of these individuals have a smaller caliber, which results in an increase in blood pressure”, he says.

LOW OXYGENATION

In the study, researchers induced hypoxia in rats during the first ten days of life. During this period, the animals underwent short-term hypoxia episodes, with a reduction in oxygen from 21% to 6% for 30 seconds. This happened every nine minutes during the animals’ sleeping period.

The simulation generated six episodes of sleep apnea per hour, which is equivalent to one case of moderate sleep apnea. “In the clinic, there are cases of severe apnea in which the patient experiences 30 or even 60 episodes per hour”, explains the researcher.

After two weeks, the simulations performed over eight hours a day ceased and the animals began to breathe normally. When the animals completed 40 and 90 days of life – which in humans would be comparable to 13-16 and 40-50 years respectively –, the researchers evaluated physiological parameters such as blood pressure and heart rate.

At both ages, rats that experienced periods of intermittent hypoxia in the postnatal phase showed a consistent increase in blood pressure – between 10 and 20 millimeters of mercury (mmHg) above the control group. According to the results, the mean blood pressure in young rats was 84±7 mmHg in the control group, while in the group that underwent intermittent hypoxia it was 95±5 mmHg. The average for adult animals was 103±10 mmHg for the control group and 121±9 mmHg for the group that experienced episodes of low oxygenation. It is worth noting that blood pressure indices in both rodents and humans are similar.

“In the study, we did not evaluate when the animals became hypertensive, we only verified that in the young phase the rats already presented alterations related to blood pressure and, in the adult phase, they were hypertensive”, explains the researcher.

After concluding that intermittent hypoxia generated an increase in blood pressure in the animals, the researchers went to investigate the contribution of the sympathetic nervous system in this process.

It is worth remembering that the autonomic nervous system is divided into two parts: the sympathetic and parasympathetic systems. In general, the sympathetic system is responsible for changes in the body in alert situations, preparing the body to face or flee a threat. Therefore, it involves greater expenditure of energy. It is up to this branch to increase heart rate and blood pressure, release adrenaline, dilate the bronchi, dilate the pupils, increase perspiration. The parasympathetic nervous system, on the other hand, normalizes the functioning of internal organs after the alert situation.

By placing electrodes in contact with the sympathetic nerves of young rats, the researchers observed that the animals that went through intermittent hypoxia had a greater amount of electrical impulses traveling through the sympathetic nerves compared to the animals that did not go through episodes of low oxygenation. In adult rodents, a pharmacological approach was used, which obtained the same result as in the study with young rats.

“We used a drug that inhibits the actions of the sympathetic nervous system and, depending on the response of the drop in blood pressure, it was possible to infer that the sympathetic activity was increased”, he says.

The Unesp researchers also analyzed the activity of neurons in the medulla, a region of the brain that controls the body’s vegetative functions, such as heartbeat, breathing and sympathetic activity for blood vessels.

“We focused our analysis on the ventral surface of the medulla, an essential region to generate sympathetic activity and maintain blood pressure at normal values. [em humanos cerca de 12/8 mmHg]. And we observed that among the animals that had undergone postnatal intermittent hypoxia, there is a higher rate of firing of neurons in this region. This showed a dysfunction in this group of the medulla, caused by exposure to intermittent hypoxia, which maintains increased sympathetic activity, raising blood pressure”, he explains.

The researchers also observed that, in addition to showing greater activity, the neurons of the sympathetic nervous system expressed more of the HIF-1α protein. “This discovery allowed us to associate this entire process with a possible epigenetic cause”, he says.

Zoccal points out that the HIF-1α protein was studied by the winners of the 2019 Nobel Prize in Medicine. The laureates discovered that when oxygen levels are low, the amount of this factor increases and induces cellular adaptations that ensure cell survival and the body during hypoxic conditions. On the other hand, the concentration of HIF-1α decreases when oxygen levels are normal.

The study focused on the effects of postnatal intermittent hypoxia on blood pressure resulting from sympathetic nervous system dysfunction. However, it is known that changes in this system can lead to other changes. This is because sympathetic activity controls many body functions, including body temperature and, consequently, metabolism.

“In another study that we published, using the same experimental model, we noticed that animals that undergo hypoxia had lower weight than the control group, which may be a consequence of the increase in sympathetic activity. We also observed that these animals began to present respiratory irregularities, with an unusual pattern of acceleration and deceleration of breathing at rest.

The article Sympathetic dysregulation induced by postnatal intermittent hypoxia can be read at:

And the study Postnatal intermittent hypoxia enhances phrenic and reduces vagal upper airway motor activities in rats by epigenetic mechanisms is available at: