# Impact Of Obstructive Sleep Apnoea Syndrome Severity On The Mechanisms Of Aortic Valve Atherosclerosis

P Petit, F Bennani, E Lemarié, M Destors, S Baillieul, T Ngo, O Chavanon, J

Pépin, A Briancon-Marjollet, R Tamisier

► To cite this version:

P Petit, F Bennani, E Lemarié, M Destors, S Baillieul, et al.. Impact Of Obstructive Sleep Apnoea Syndrome Severity On The Mechanisms Of Aortic Valve Atherosclerosis. ATS Congress, May 2025, San Francisco, United States. hal-05290661

HAL Id: hal-05290661

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Submitted on 30 Sep 2025

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# Impact Of Obstructive Sleep Apnoea Syndrome Severity On The Mechanisms Of Aortic Valve Atherosclerosis

P. Petit¹,², F. Bennani², E. Lemarié¹, M. Destors¹,², S. Baillieul¹,², T. Ngo², O. Chavanon¹,², J. Pépin¹,², A. Briancon-Marjollet¹,², R. Tamisier¹,²

¹Grenoble Alpes University, HP2, Inserm 1300, Grenoble, France, ²CHU Grenoble Alpes, Grenoble, France

## Background

* Obstructive sleep apnea (OSA) is a common chronic condition that is independently associated with cardiovascular disease (CVD), including **calcific aortic valve disease (CAVD)**.

* The pathophysiological stimuli triggered by OSA are intermittent hypoxia, inflammation and mechanical stress.

* The mechanisms of CAVD include **autophagy**, **inflammation**, **oxidative stress** and **calcification**.

* This study aimed to **assess the hypothetical association of OSA and hypoxia on these CAVD mechanisms**.

## Methods

* Patients scheduled for surgical aortic valve replacement were prospectively enrolled in the "Multimorbidity Apnea Respiratory failure Sleep" database after signing a written consent form and completed a full polysomnography.

* Native aortic valves were harvested post-operatively and divided into 3 sections according to their macroscopic morphology (healthy, intermediate and calcified valve tissue).

* Quantification of gene and protein expression was performed by RT-qPCR and Western blot, respectively. Factors associated with transcriptional and translational expression were investigated in a multivariate analysis.

## Results

* Patients were predominantly men with a sex ratio of 18/31 with a median age of 68 [64 ; 73] years old, Epworth of 6 [3 ; 8], asthenia pichot scale of 4 [1 ; 9], snoring analogic scale of 3 [2 ; 5] and 8 (25,8%) patients with a nocturia of more than 1 voids/night. No significant difference was found between these.

* Of the **31 patients** included, **18 had moderate to severe OSA (AHI≥15/h)**, no significant difference was found in comorbidity prevalence.

<table><caption>Table 1. Characteristics of the study population.</caption><thead><tr><th></th><th>Non OSA Patients (AHI&lt;15/h), n=13</th><th>OSA Patients ((AHI≥15/h), n=18</th><th>Missing data</th><th>P-value</th></tr></thead><tbody><tr><td>BMI, kg/m²</td><td>24 [23.6 ; 25.8]</td><td>27.3 [25.3 ; 35.3]</td><td>0</td><td>&lt;0.01</td></tr><tr><td>CRP, mg/L</td><td>1 [0.8 ; 1.2]</td><td>2.3 [1.2 ; 7.2]</td><td>11 (35.5)</td><td>0.03</td></tr><tr><td>HbA1c, %</td><td>5.5 [5.3 ; 5.5]</td><td>5.8 [5.6 ; 5.9]</td><td>11 (35.5)</td><td>&lt;0.01</td></tr><tr><td>Glycemia, mmol/L</td><td>5 [4.9 ; 5.3]</td><td>5.8 [5.5 ; 6.5]</td><td>13 (41.9)</td><td>0.02</td></tr><tr><td>AHI, events/h</td><td>6.3 [5.6 ; 8.5]</td><td>30.5 [25.9 ; 39.8]</td><td>0</td><td>&lt;.01</td></tr><tr><td>T90, % of TST</td><td>0.3 [0 ; 0.7]</td><td>3.8 [1.2 ; 7.1]</td><td>2 (6.5)</td><td>0.02</td></tr><tr><td>ODI, events/h</td><td>7.2 [4.8 ; 7.8]</td><td>29.4 [24.4 ; 31.3]</td><td>2 (6.5)</td><td>&lt;.01</td></tr><tr><td>Mean SaO2</td><td>93.1 [93 ; 94]</td><td>92.5 [92 ; 94]</td><td>2 (6.5)</td><td>0.17</td></tr><tr><td>Minimal SaO2</td><td>88 [85 ; 90]</td><td>82 [78 ; 86]</td><td>3 (9.7)</td><td>&lt;.01</td></tr><tr><td>EEG Sleep architecture</td><td colspan="3">No significant difference</td><td></td></tr><tr><td>Parameters of cardiac echography</td><td colspan="3">No significant difference</td><td></td></tr><tr><td>Bicuspidia, n (%)</td><td>11 (84.6)</td><td>4 (22.2)</td><td>0 (0)</td><td>&lt;0.01</td></tr><tr><td>No healthy valve tissue</td><td colspan="3">61%</td><td></td></tr><tr><td>PaO2, kPa</td><td>12.4 [11.8 ; 13.1]</td><td>11.5 [10.6 ; 12.1]</td><td>12 (38.7)</td><td>0.04</td></tr></tbody></table>

Results are presented as median [interquartile range] or number of subjects (%). T90, time spent below a SaO2 of 90%; AHI, apnoea hypopnea index; SaO2, oxygen saturation of arterial blood; PaO2, arterial oxygen pressure; ODI, oxygen desaturation index of 3%.

* In healthy valve tissue, decreased Beclin-1 gene expression in the minimal SaO2 <88% group (p<0.05) reflects **impaired autophagy under severe hypoxia in the early phase of CAVD**.

<figure><img src="image_1.png" /><figcaption>Figure 1. Beclin 1 gene expression in healthy, intermediate and calcified valve tissue: according to OSA status, AHI, and SaO2 min < 88% vs. ≥88%.</figcaption></figure>

* In the more advanced intermediate and calcified stages, decreased protein expression of P62 in severe OSA compared to non-OSA (p=0.03) reflects increased autophagy in these patients.

<figure><img src="image_2.png" /><figcaption>Table 2. Gene expression according to the macroscopic morphology of each valve tissue.</figcaption></figure>

<table><thead><tr><th>Gene</th><th>Entire population, N=80</th><th>Healthy valve tissue, N=18 (22.5%)</th><th>Intermediate valve tissue, N=31 (38.75%)</th><th>Calcified valve tissue, N=31 (38.75%)</th><th>P-value</th></tr></thead><tbody><tr><td>hBeclin-1</td><td>0.5 [0.3; 0.8]</td><td>0.6 [0.5; 0.8]</td><td>0.6 [0.5;0.8]</td><td>0.3[0.2;0.5] ($^*$)</td><td>&lt;.001</td></tr><tr><td>hCD68</td><td>0.9 [0.6; 1.4]</td><td>0.8 [0.4; 0.9]</td><td>1.2[0.9;1.8] ($^*$)</td><td>0.8[0.4;1.4] ($^*$)</td><td>0.001</td></tr><tr><td>hCOX2</td><td>0.3 [0.1; 0.6]</td><td>0.6 [0.5; 0.8]</td><td>0.4[0.3;0.7]</td><td>0.1[0.1;0.2] ($^*$)</td><td>&lt;.001</td></tr><tr><td>hIL6</td><td>0.7 [0.4; 1.5]</td><td>0.6 [0.4; 0.8]</td><td>0.7[0.5;1.8]</td><td>0.9[0.6;2]</td><td>0.087</td></tr><tr><td>hIL1β</td><td>1.7 [0.9; 3]</td><td>0.5 [0.2; 1]</td><td>1.8[1.1;3.5] ($^*$)</td><td>2.3[1.4;3.7] ($^*$)</td><td>&lt;.001</td></tr><tr><td>hTGFβ1</td><td>0.7 [0.5; 1]</td><td>0.8 [0.5; 0.9]</td><td>1[0.7;1.4] ($^*$)</td><td>0.5[0.3;0.7] ($^*$)</td><td>&lt;.001</td></tr><tr><td>hTNFα</td><td>1 [0.5; 1.6]</td><td>0.6 [0.3; 1]</td><td>1.5[1;2.1] ($^*$)</td><td>0.7[0.4;1.2] ($^*$)</td><td>&lt;.001</td></tr><tr><td>hNOX2</td><td>1.7 [0.8; 3.5]</td><td>0.7 [0.4; 1]</td><td>3.6[1.9;5.9] ($^*$)</td><td>1.4[0.7;2.1] ($^*$)</td><td>&lt;.001</td></tr><tr><td>hSOD3</td><td>0.8 [0.4; 1.4]</td><td>0.7 [0.4; 1.1]</td><td>1.5[0.8;2] ($^*$)</td><td>0.5[0.4;0.9] ($^*$)</td><td>&lt;.001</td></tr><tr><td>hOCN</td><td>1.5 [1; 4.5]</td><td>1 [0.3; 1.2]</td><td>1.6[1;3.8] ($^*$)</td><td>4.2[1.3;24.9] ($^*$)</td><td>&lt;.001</td></tr><tr><td>HOPN</td><td>3.3 [0.9; 13.5]</td><td>0.6 [0.3; 1.3]</td><td>2.2[0.9;6.5] ($^*$)</td><td>16.4[5.2;37.7] ($^*$)</td><td>&lt;.001</td></tr><tr><td>hRUNX2</td><td>0.7 [0.5; 1]</td><td>0.6 [0.5; 0.9]</td><td>0.8[0.6;1]</td><td>0.7[0.4;1]</td><td>0.325</td></tr><tr><td>hBMP2</td><td>0.6 [0.3; 0.9]</td><td>0.7 [0.5; 0.9]</td><td>0.7[0.4;1.3]</td><td>0.3[0.2;0.6] ($^*$)</td><td>&lt;.001</td></tr></tbody></table>

Gene expression assessed by RT-qPCR, variations measured using the ddCT method. Results presented as median [IQR]. Significant difference from (S) morphologically healthy valve tissue group, ($^*$) intermediate valve tissue group.

<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /></figure>

* In calcified valve tissue, Beclin-1 gene expression was reduced in the entire population (p<0.001), suggesting a deregulation of autophagy, independent of OSA status.

The pro-calcifying state of the OSA patients was evident at the morphological and transcriptional level by the increase in osteocalcin gene expression associated with the desaturation index (ODI, p=0.02).

OSA did not affect inflammation or oxidative stress.

<figure><img src="image_6.png" /></figure>