Endothelial Function and T-Lymphocyte Subsets in Patients with Overlap Syndrome of Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnea
Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) are prevalent respiratory disorders frequently encountered in clinical practice. When these conditions coexist, the term overlap syndrome (OS) is applied. OS is associated with heightened risks of cardiovascular complications, reduced quality of life, and increased mortality compared to either condition alone. This study investigated the prevalence of cardiovascular comorbidities in OS patients and explored potential mechanisms linking endothelial dysfunction, systemic inflammation, and immune dysregulation to these outcomes.
Study Design and Participant Characteristics
The study enrolled 25 patients with stable COPD, 25 with OSA, 25 with OS, and 20 healthy controls. Participants were recruited from Tianjin Medical University General Hospital between January and December 2017. Diagnostic criteria for COPD included post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) <70%, while OSA was defined as an apnea-hypopnea index (AHI) ≥5 events/hour. OS patients met both criteria, with FEV1% predicted between 30%–80% and AHI ≥15/hour. Exclusion criteria eliminated other causes of airflow limitation or sleep-disordered breathing.
Demographic data showed no significant differences in age, sex distribution, or smoking history across groups. However, body mass index (BMI) was higher in OSA (30.15 ± 2.50 kg/m²), COPD (27.13 ± 1.50 kg/m²), and OS (28.14 ± 2.00 kg/m²) groups compared to controls (24.40 ± 3.23 kg/m²). Pulmonary function tests confirmed airflow obstruction in COPD and OS groups (FEV1/FVC: 58.89 ± 8.42% and 57.47 ± 9.21%, respectively), contrasting with normal values in OSA and controls. Polysomnography revealed elevated AHI in OSA (27.90 ± 5.95/hour) and OS (29.93 ± 4.58/hour) groups.
Cardiovascular Comorbidities
A striking finding was the elevated prevalence of hypertension and coronary heart disease (CHD) in OS patients. Hypertension affected 60% (15/25) of OS patients, significantly higher than OSA (20%, 5/25), COPD (36%, 9/25), and controls (0%). Similarly, CHD prevalence in OS (36%, 9/25) exceeded OSA (12%, 3/25), COPD (16%, 4/25), and controls (0%). Stroke incidence trended higher in OS (20%, 5/25) but did not reach statistical significance. These results highlight OS as a distinct clinical entity with amplified cardiovascular risks compared to isolated COPD or OSA.
Endothelial Dysfunction and Inflammatory Markers
Endothelial dysfunction was assessed via soluble vascular cell adhesion molecule-1 (sVCAM-1), a marker of endothelial activation. OS patients exhibited the highest sVCAM-1 levels (20.25 ± 2.50 ng/mL), surpassing COPD (15.80 ± 1.80 ng/mL), OSA (12.30 ± 1.20 ng/mL), and controls (8.50 ± 0.90 ng/mL). Tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine, followed a similar pattern: OS (128.50 ± 10.20 pg/mL) > COPD (95.60 ± 8.40 pg/mL) > OSA (75.30 ± 6.50 pg/mL) > controls (30.20 ± 3.10 pg/mL). These findings suggest synergistic endothelial injury and inflammation in OS, likely driven by cumulative hypoxia-reoxygenation cycles from OSA and chronic airway inflammation from COPD.
T-Lymphocyte Subset Abnormalities
Flow cytometry revealed significant immune dysregulation in OS. CD4+ T-helper cell percentages were markedly reduced in OS (28.14 ± 2.00%) versus COPD (32.50 ± 2.50%), OSA (35.60 ± 3.20%), and controls (40.20 ± 3.50%). Conversely, CD8+ cytotoxic T-cells were elevated in OS (35.90 ± 2.80%) compared to other groups (COPD: 30.80 ± 2.20%; OSA: 28.50 ± 2.00%; controls: 25.10 ± 1.80%). The CD4+/CD8+ ratio, a key indicator of immune balance, was lowest in OS (0.78 ± 0.10) versus COPD (1.05 ± 0.12), OSA (1.25 ± 0.15), and controls (1.60 ± 0.20). These imbalances suggest compromised cellular immunity and heightened cytotoxic activity in OS, potentially exacerbating endothelial damage.
Correlations Between Immune Dysfunction and Endothelial Injury
Pearson correlation analysis revealed strong inverse relationships between CD4+/CD8+ ratios and both sVCAM-1 (r = −0.77, P < 0.05) and TNF-α (r = −0.83, P < 0.05). This indicates that diminished T-cell immune regulation correlates with worsening endothelial dysfunction and systemic inflammation. Mechanistically, activated CD8+ T-cells may directly damage vascular endothelium through cytotoxic effects, while reduced CD4+ cells impair anti-inflammatory responses, creating a vicious cycle of inflammation and vascular injury.
Pathophysiological Implications
The study underscores OS as a high-risk phenotype for cardiovascular disease. Intermittent hypoxia from OSA induces oxidative stress and sympathetic activation, while COPD-related chronic inflammation promotes endothelial adhesion molecule expression. Together, these pathways amplify leukocyte-endothelial interactions, fostering atherosclerosis. The observed T-cell subset shifts further compound this process: CD8+ cytotoxicity may accelerate plaque instability, while low CD4+/CD8+ ratios reflect systemic immune exhaustion, reducing capacity to mitigate vascular damage.
Clinical and Therapeutic Considerations
These findings advocate for integrated management of OS beyond conventional COPD or OSA therapies. Screening for cardiovascular comorbidities in OS patients is crucial, given their heightened prevalence. Biomarkers like sVCAM-1 and TNF-α could help monitor endothelial health, while CD4+/CD8+ ratios might identify patients at highest cardiovascular risk. Therapeutically, interventions targeting endothelial protection (e.g., statins, antioxidants) and immune modulation (e.g., low-dose immunosuppressants) warrant exploration in OS.
Study Limitations and Future Directions
While the study provides novel insights, limitations include its cross-sectional design, which precludes causal inferences. The small sample size (n=25 per patient group) may limit generalizability, though statistical significance was achieved for primary outcomes. Longitudinal studies tracking endothelial and immune parameters against cardiovascular events in OS cohorts are needed. Additionally, mechanistic research should clarify whether T-cell subset alterations are drivers or bystanders in OS-related vascular pathology.
In conclusion, this work establishes OS as a distinct clinical syndrome characterized by exacerbated endothelial dysfunction, inflammatory hyperactivity, and cellular immune dysregulation compared to isolated COPD or OSA. The interplay between cytotoxic T-cell dominance and endothelial injury mechanisms offers a plausible explanation for the elevated cardiovascular morbidity in OS patients. These insights pave the way for targeted therapeutic strategies to mitigate multisystem complications in this vulnerable population.
doi.org/10.1097/CM9.0000000000000312
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