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Expand Up @@ -6,32 +6,30 @@ This readme accompanies the paper "Glycophorin C in carotid atherosclerotic plaq

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### Abstract.
**Introduction**<br/>
The accumulation of erythrocyte membranes within an atherosclerotic plaque may contribute to the deposition of free cholesterol and thereby the enlargement of the necrotic core. Erythrocyte membranes can be visualized and quantified in the plaque by immunostaining for the erythrocyte marker glycophorin C. We therefore hypothesized, that glycophorin C is a marker for plaque vulnerability and may therefore reflect intraplaque hemorrhage (IPH), vulnerability of plaques and predict pre-procedural neurological symptoms.
**Introduction** The accumulation of erythrocyte membranes within an atherosclerotic plaque may contribute to the deposition of free cholesterol and thereby the enlargement of the necrotic core. Erythrocyte membranes can be visualized and quantified in the plaque by immunostaining for the erythrocyte marker glycophorin C. We therefore hypothesized, that glycophorin C is a marker for plaque vulnerability and may therefore reflect intraplaque hemorrhage (IPH), vulnerability of plaques and predict pre-procedural neurological symptoms.

**Methods**<br/>
We quantified glycophorin C in human atherosclerotic plaque samples from 1,819 consecutive asymptomatic and symptomatic patients undergoing carotid endarterectomy from the Athero-Express Biobank with the slideToolKit.
**Methods** We quantified glycophorin C in human atherosclerotic plaque samples from 1,819 consecutive asymptomatic and symptomatic patients undergoing carotid endarterectomy from the Athero-Express Biobank with the slideToolKit.

**Results**<br/>
The prevalence of IPH was 62.4%, and the prevalence of pre-procedural neurological symptoms was 87.1%. The percentage glycophorin staining was significantly higher in male patients compared to female patients (median 7.15 (IQR:3.37, 13.41) versus median 4.06 (IQR:1.98, 8.32), p<0.001). Quantified glycophorin C was associated with IPH (OR 1.90; 95% CI 1.63, 2.21; p=<0.001) when corrected for clinical confounders. Glycophorin C was significantly associated with ipsilateral pre-procedural neurological symptoms (OR:1.27, 95%CI:1.06-1.41, p=0.005), and upon sex-stratified analyses, specifically in male patients (OR 1.37; 95%CI 1.12, 1.69; p=0.003), but not in female patients (OR 1.15; 95%CI 0.77, 1.73; p=0.27). Glycophorin was associated with classical features of a vulnerable plaque, such as a larger lipid core (OR 1.85; 95%CI 1.60, 2.15; p<0.001), a higher macrophage burden (OR 1.87; 95%CI 1.63, 2.14; p<0.001), less calcifications (OR 0.81; 95%CI 0.71, 0.91; p<0.001), a lower collagen and SMC content (OR 0.70; 95%CI 0.60, 0.82; p<0.001 and OR 0.60; 95%CI 0.52, 0.68; p<0.001, respectively). There were marked sex differences, in male patients glycophorin was associated with calcifications and collagen (OR 0.75; 95%CI 0.64, 0.87; p<0.001 and OR 0.65; 95%CI 0.53, 0.79; p<0.001, respectively) while these associations were not found in female patients.
**Results** The prevalence of IPH was 62.4%, and the prevalence of pre-procedural neurological symptoms was 87.1%. The percentage glycophorin staining was significantly higher in male patients compared to female patients (median 7.15 (IQR:3.37, 13.41) versus median 4.06 (IQR:1.98, 8.32), p<0.001). Quantified glycophorin C was associated with IPH (OR 1.90; 95% CI 1.63, 2.21; p=<0.001) when corrected for clinical confounders. Glycophorin C was significantly associated with ipsilateral pre-procedural neurological symptoms (OR:1.27, 95%CI:1.06-1.41, p=0.005), and upon sex-stratified analyses, specifically in male patients (OR 1.37; 95%CI 1.12, 1.69; p=0.003), but not in female patients (OR 1.15; 95%CI 0.77, 1.73; p=0.27). Glycophorin was associated with classical features of a vulnerable plaque, such as a larger lipid core (OR 1.85; 95%CI 1.60, 2.15; p<0.001), a higher macrophage burden (OR 1.87; 95%CI 1.63, 2.14; p<0.001), less calcifications (OR 0.81; 95%CI 0.71, 0.91; p<0.001), a lower collagen and SMC content (OR 0.70; 95%CI 0.60, 0.82; p<0.001 and OR 0.60; 95%CI 0.52, 0.68; p<0.001, respectively). There were marked sex differences, in male patients glycophorin was associated with calcifications and collagen (OR 0.75; 95%CI 0.64, 0.87; p<0.001 and OR 0.65; 95%CI 0.53, 0.79; p<0.001, respectively) while these associations were not found in female patients.

**Conclusion**<br/>
Quantified glycophorin C was independently associated with the presence of IPH, symptomatic preprocedural symptoms in male, and with a more vulnerable plaque composition in both women and men. Which strengthens the hypothesize that plaque glycophorin C is a marker of plaque vulnerability.

**Keywords**<br/>
Atherosclerosis, Carotid endarterectomy, Glycophorin, Intraplaque hemorrhage, Plaque instability, Sex.
**Conclusion** Quantified glycophorin C was independently associated with the presence of IPH, symptomatic preprocedural symptoms in male, and with a more vulnerable plaque composition in both women and men. Which strengthens the hypothesize that plaque glycophorin C is a marker of plaque vulnerability.

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### Data availability
Data as shared through DataverseNL. DOI: https://doi.org/10.34894/08TUBV
Data as shared through [DataverseNL](https://doi.org/10.34894/08TUBV).

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### Acknowledgements
This work was supported by the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON-GENIUS-2 to GP and SWvdL). We are thankful for the support of the ERA-CVD program ‘druggable-MI-targets’ (grant number: 01KL1802), the EU H2020 TO_AITION (grant number: 848146), EU H2020 Taxinomisis (grant number 755320 JM, GP, GJB DdK), and the Leducq Fondation ‘PlaqOmics’.
Dr. Sander W. van der Laan is funded through EU H2020 TO_AITION (grant number: 848146), EU HORIZON NextGen (grant number: 101136962), EU HORIZON MIRACLE (grant number: 101115381), and HealthHolland PPP Allowance ‘Getting the Perfect Image’.

We are thankful for the support of the Netherlands CardioVascular Research Initiative of the Netherlands Heart Foundation (CVON 2011/B019 and CVON 2017-20: Generating the best evidence-based pharmaceutical targets for atherosclerosis [GENIUS I&II]), the ERA-CVD program ‘druggable-MI-targets’ (grant number: 01KL1802), and the Leducq Fondation ‘PlaqOmics’. The research for this contribution was made possible by the AI for Health working group of the EWUU alliance (https://aiforhealth.ewuu.nl/).

Plaque samples are derived from carotid endarterectomies as part of the [Athero-Express Biobank Study](https://pubmed.ncbi.nlm.nih.gov/15678794/) which is an ongoing study in the UMC Utrecht.

Plaque samples are derived from carotid endarterectomies as part of the [Athero-Express Biobank Study](http:www/atheroexpress.nl) which is an ongoing study in the UMC Utrecht.
### Disclosures
Dr. Sander W. van der Laan has received Roche funding for unrelated work.

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