Sleep Apnea Leads to Low Oxygen, High Inflammatory Factors in CTEPH

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by Steve Bryson PhD |

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Adults with chronic thromboembolic pulmonary hypertension (CTEPH) experience more breathing stoppages during sleep (apnea), lower blood oxygen, and higher levels of pro-inflammatory proteins in the blood than people with idiopathic pulmonary arterial hypertension who have similar pulmonary artery pressure, a sleep study reported.

A low nighttime blood oxygen level was found to predict high levels of the inflammatory signaling protein TNF-alpha

The study, “Nocturnal Hypoxemia and High Circulating TNF-α Levels in Chronic Thromboembolic Pulmonary Hypertension,” was published in the journal Internal Medicine

Abnormally high pressure in the lungs’ blood vessels, caused by the formation of blood clots, is the hallmark of CTEPH. 

Sleep-disordered breathing, also known as sleep apnea, is a condition whereby a person stops breathing during sleep, resulting in lower oxygen levels. 

Studies have linked sleep apnea to various forms of pulmonary hypertension, but research exploring sleep apnea in people with CTEPH is lacking. Further, sleep apnea also is associated with proteins that cause inflammation in people with systemic heart failure, but little is known about the levels in CTEPH patients. 

“The association between [sleep apnea] and inflammation in CTEPH has been undefined,” the researchers wrote. 

To learn more, researchers at Chiba University, in Japan, conducted a sleep study involving 41 adults with CTEPH. Their goal was to investigate the association between the severity of sleep apnea, pressure in the blood vessels of the lungs, and levels of pro-inflammatory immune signaling proteins in the blood.

The patients, including 23 women and 18 men, ranged in age from 55 to 73. As a comparison, a group of 12 adults with idiopathic pulmonary arterial hypertension (IPAH) was recruited. IPAH is a rare form of pulmonary hypertension with an unknown cause (idiopathic). That group had two men and 10 women, ages 40 to 60.

Sleep apnea was measured using a device called WatchPAT 200, a portable, wrist-worn monitoring device validated for recording heart rate, blood pressure, body movements, and the level of oxygen in the blood — also called oxygen saturation (SpO2), which is usually above 95%. 

Right-heart catheterization — using a small hollow tube guided to the heart — was performed to measure the blood pressure within the heart and the pulmonary arteries of the participants. 

Blood samples were collected in the early morning to measure the levels of the inflammatory proteins (cytokines) TNF-alpha, interleukin (IL)-6, pentraxin3 (PTX3), and P-selectin. Control blood samples also were obtained from patients who experienced a blood clot in the pulmonary arteries (pulmonary thromboembolism or PTE) without pulmonary hypertension.

Before the start of the sleep study (baseline time point), there were no marked differences in the average SpO2 between the CTEPH (100%) and IPAH (99.5%) groups. During the test, the mean SpO2 was 94% in CTEPH patients and 95% in those with IPAH. The minimum SpO2 was 86% in those with CTEPH and 89% in IPAH patients.

The median (middle) apnea-hypopnea index (AHI) — a measure of sleep apnea severity calculated based on the number of breathing stoppages per hour — was 16.6 in CTEPH patients and 3.3 in those with IPAH. 

Likewise, the oxygen desaturation index (ODI), which measures the number of times per hour SpO2 levels drop, was 6.6 in those with CTEPH and 0.7 in IPAH patients. The average minimum SpO2 was significantly lower, and the overall SpO2 tended to be lower in the CTEPH group compared with the IPAH group.  

Further, the light sleep time, as estimated by the WatchPAT results, was longer in the CTEPH group while the sleep efficacy was lower compared with the IPAH group.

Together, “these results imply that CTEPH patients tend to have poor-quality sleep,” the researchers wrote. 

Tests measuring the blood pressure in the heart and pulmonary arteries found that the average nocturnal SpO2 levels were lower in those with high-average pulmonary artery pressure and pulmonary vascular resistance — the resistance against blood flow. There was no correlation between SpO2 and pulmonary measurements in IPAH patients.

In the CTEPH group, the TNF-alpha, PTX3, and P-selectin levels were higher than those in the control group. No significant differences were detected in the IL-6 levels.

Higher TNF-alpha levels significantly correlated with lower average SpO2 and higher ODI values in CTEPH patients. 

PTX3 and P-selectin levels also were elevated in the IPAH group; however, these protein levels did not significantly correlate with the WatchPAT measurements.

A statistical analysis found that only the average SpO2 was an independent predictive risk factor for high TNF-alpha.

“In conclusion, we showed that CTEPH patients had worse [sleep-disordered breathing] than IPAH patients,” the researchers wrote. “CTEPH patients had also high serum TNF-α levels, and the [nighttime] mean SpO2 was the most important predictive factor.”

“Further investigations focused on [nighttime low oxygen levels] and the TNF-α level may provide novel insight into the [underlying causes] and new therapeutic strategies for CTEPH,” the team concluded.