Sleep Apnea in Babies and Adulthood Hypertension

Newborn kids who have low levels of oxygen in their bodily tissues (hypoxia) as a result of sleep apnea, for example, are more likely to have respiratory problems and hypertension (high blood pressure) later in life, and these problems may last the remainder of their lives.
According to researchers at So Paulo State University (UNESP) in Brazil, hypertension in these circumstances is caused by dysregulation of the autonomic nervous system, which controls involuntary physiological activities such as heart rate and respiration, as well as blood pressure.

The study’s findings were published in the journal SLEEP.

The study used an animal model to show that hypertension was connected with activation of neurons in the sympathetic nervous system, which is the branch of the autonomic nervous system that responds to stress.

“We discovered that rats that experienced episodes of intermittent hypoxia in the postnatal period displayed higher levels of neuronal activity in the lower part of the brainstem [i.e. the medulla oblongata] in youth and adulthood.

This may reflect adaptations of the brain to low levels of oxygen during a critical stage of development, including heightened activity of the sympathetic autonomic nervous system, probably due to increased expression of a protein called hypoxia-inducible factor 1 alpha [HIF-1α] in medulla neurons,” said Daniel Zoccal, last author of the article and a professor at the Araraquara Dental School (FOAr-UNESP).

According to Zoccal, increased HIF-1 expression by medulla neurons causes changes in the “reading” of other genes that control cellular activity. As a result, neurons that express more HIF-1 become more active, causing blood vessels to narrow and blood pressure to rise. This is an epigenetic phenomena because it is induced by biochemical changes in cells caused by environmental stimuli that activate or mute genes without affecting the genome.

The research could lead to substantial clinical breakthroughs in addition to the first-ever demonstration of the mechanisms involved in the link between intermittent low levels of oxygen in the neonatal period due to sleep apnea and hypertension in youth and adulthood.

“Although the prevalence of hypertension is high at about 30% of the world population, its origins are still poorly understood. All we know is that there’s a risk associated with factors such as obesity, sedentary lifestyles, kidney problems and consumption of salt, for example. The results of our study will serve as a basis for the development of novel therapies,” Zoccal told Agência FAPESP.

The discovery also highlights the importance of experiences during infancy to the development of diseases. “We must take greater care with babies’ breathing to prevent the development of disease in adulthood,” he stressed. Sleep apnea is quite common in newborns and can be more common in premature infants with immature central nervous and respiratory systems, babies with larger adenoids or tonsils, obese infants, and babies with other anatomical abnormalities.

Describing the full mechanism of hypoxia-induced hypertension in human infants up to roughly two years of age can also help with the development of medicines for the 20% or so of hypertensive individuals who do not respond well to antihypertensive drugs, according to Zoccal.

Previous research showed that electrical activity in the interface between sympathetic nerves and blood vessels is heightened in patients with high blood pressure, and especially those who do not respond to medicational treatment. “They have narrower blood vessels, which raises their blood pressure,” he said.

Chronic intermittent hypoxia after birth
In the study, rats were subjected to postnatal chronic intermittent hypoxia for the first ten days after birth. The hypoxic episodes were brief, with oxygen levels dropping from 21% to 6% for 30 seconds every 10 minutes while they slept. This resulted in six bouts of sleep apnea every hour, which is similar to a moderate case of sleep apnea.

“In the clinic, there are cases of severe apnea where the patient experiences 30 or even 60 episodes per hour,” Zoccal said.

The researchers ceased producing hypoxia after two weeks, and the mice were able to breathe properly. The researchers assessed physiological measures such as blood pressure and heart rate in rats aged 40 and 90 days, which corresponds to humans aged 13 to 16 years and 40 to 50 years.

Subjected to postnatal intermittent hypoxia, rats of both ages had persistently increased blood pressure—between 10 and 20 millimeters of mercury (mmHg) greater than the control group. Blood pressure in young rats averaged 847 mmHg in the control group and 955 mmHg in the hypoxia group, according to the findings. The averages for adult rats were 10310 mmHg and 1219 mmHg, respectively. It should be noted that blood pressure values in rats and humans are comparable.

“In the study, we didn’t analyze when animals became hypertense but confirmed that young rats already displayed alterations relating to blood pressure and were hypertense in adulthood,” Zoccal said.

Following their discovery that intermittent hypoxia increased blood pressure, the researchers set out to explore the sympathetic nervous system’s role in this process.

A bit of explanation is required here. As previously stated, the sympathetic nervous system is a subset of the autonomic nervous system. The parasympathetic nervous system is the other.

In response to danger or a threat, the sympathetic nervous system assists the body in activating its “fight or flight” response. Energy expenditure rises as the heart rate and blood pressure rise, adrenalin is released, muscles tense and relax, the bronchi and pupils dilate, breathing speeds up, and sweat glands activate. Once the threat has passed, the parasympathetic nervous system returns the internal organs to normal.

When the researchers implanted electrodes on sympathetic nerves in young rats, they found that the animals subjected to intermittent hypoxia had more electrical impulses than the control group. They employed a pharmacological technique on adult rats that produced the same results as the studies on young rats. We administered a drug that inhibits the actions of the sympathetic nervous system, and depending on the drop in blood pressure, it was possible to infer that sympathetic activity was augmented,” Zoccal said.

The researchers also looked at neural activity in the medulla oblongata, which controls autonomic activities like sneezing, breathing, and heart rate, as well as sympathetic vasomotor tone and blood pressure.

“Our analysis focused on the ventral surface of the medulla, a key region for sympathetic activity to keep blood pressure at normal levels [about 12/8 mmHg in humans]. We found a higher firing rate for neurons in this region among the animals that had experienced postnatal intermittent hypoxia, pointing to dysfunction in this portion of the medulla due to exposure to hypoxia, which keeps sympathetic activity higher and raises blood pressure,” Zoccal said.

They also found that neurons in the sympathetic nervous system expressed more HIF-1α. “This discovery enabled us to associate the entire process with a possible epigenetic cause,” he said.

The 2019 Nobel Prize in Physiology or Medicine was granted to three scientists for their discovery of how cells sense and adapt to oxygen supply, and investigations of HIF-1 were a crucial component of their work, according to Zoccal. They observed that when oxygen levels are low, the protein levels rise, generating changes that ensure cell and organism survival in hypoxic environments. When the supply of oxygen is normal, HIF-1 levels decrease.

The study focused on the effect of postnatal intermittent hypoxia on blood pressure due to sympathetic nervous system dysfunction, but changes in this system are known to cause other changes because sympathetic activity regulates many functions in the organism, including body temperature and thus metabolism.

“In another study we published, using the same experimental model, the body weight of the animals that experienced hypoxia was lower than that of the control group, possibly owing to increased sympathetic activity. We also noted respiratory irregularities, with an abnormal pattern of acceleration and deceleration of resting pulmonary ventilation. In sum, these animals not only have high blood pressure but may also suffer from respiratory problems and probably from metabolic alterations as well,” Zoccal said.

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