Authors’ reply

Patoulias et al1 have made an interesting point, highlighting a possible impact of hypoxia-inducible factor-1α (HIF-1α) on the development and manifestation of cardiovascular diseases (CVDs), which are the main comorbidities in patients with obstructive sleep apnea (OSA).2 This association has a strong pathophysiological basis, as HIF-1α is responsible for the activation of multiple genes involved in angiogenesis and vascular resistance, most notably vascular endothelial growth factor and endothelin 1.3

To assess whether individuals with a history of CVD had increased serum HIF-1α protein levels, we performed a supplementary analysis to evaluate a diagnostic value of this parameter in OSA.4 Cardiovascular diseases included heart failure, myocardial infarction, cardiomyopathy, and cardiac arrythmias.

We found that the serum HIF-1α protein level was increased in individuals with CVD (n = 18), both in the evening (median, 1071.2 pg/ml [interquartile range [IQR], 640.4–1637 pg/ml] vs 1504.9 pg/ml [IQR, 899.2–2337.9 pg/ml]; P = 0.049) and in the morning (median, 1193 pg/ml [IQR, 622.5–1662.9 pg/ml] vs 1694.4 pg/ml [IQR, 1071.5–2022.5 pg/ml]; P = 0.045), as compared with patients without history of CVD (n = 42).

Furthermore, in the study group, evening and morning serum HIF-1α protein levels correlated with the apnea–hypopnea index (AHI; r = 0.37, P = 0.001 and r = 0.362, P = 0.001, respectively) and body mass index (BMI; r = 0.259, P = 0.018 and r = 0.276, P = 0.011, respectively).

To assess the effect of confounding variables, the analysis of covariance (ANCOVA) was performed with serum HIF-1α protein levels as a dependent factor, the presence of CVD as an independent factor, and AHI and BMI as covariates.In the applied ANCOVA model, only the presence of CVD differentiated serum HIF-1α protein levels in the evening and in the morning: F = 4.737, P = 0.032 and F = 5.477, P = 0.022, respectively. Covariates did not affect the observed differences in serum HIF-1α protein levels in the evening and in the morning, which remained significant (P = 0.034 and P = 0.035, respectively).

This additional analysis showed that OSA patients with CVD have increased serum HIF-1α protein levels, both in the evening and in the morning, independently of AHI and BMI. The results suggest the involvement of HIF-1α in the development and manifestation of CVD. However, as stated by Patoulias et al,1 large prospective studies are needed to corroborate these findings. Our research can be perceived as a pilot study, especially that the diagnosis of CVD was based only on patient history and no additional examinations were performed to confirm it. Moreover, the effect of continuous positive air pressure treatment5 should be assessed in relation to serum HIF-1α protein levels and comorbid CVD, including its severity, to show all aspects of this complex issue.