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β-Amyloid and mitochondrial-derived peptide-c are additive predictors of adverse outcome to high-on-treatment platelet reactivity in type 2 diabetics with revascularized coronary artery disease

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Abstract

Background and aims

Increased β-amyloid and decreased mitochondrial-derived peptide (MOTS-c), are reported in diabetes. We investigated their additive value to high on-clopidogrel platelet reactivity (HPR) for adverse outcome in type 2 diabetics after recent revascularization.

Patients and methods

In 121 type II diabetics, treated with clopidogrel and aspirin, (93 males, mean age 67.2 years) we measured: (a) maximum platelet aggregation to adenosine diphosphate (ADP) by light transmission aggregometry (LTAmax), (b) malondialdehyde (MDA), as oxidative stress marker, (c) MOTS-c, (d) β-amyloid blood levels. Cardiac death and acute coronary syndromes (MACE) were recorded during 2 years of follow-up.

Results

Out of 121 patients, 32 showed HPR (LTAmax > 48%,). At baseline, HPR was associated with β-amyloid > 51 pg/ml (p = 0.006) after adjusting clinical variables, HbA1c, MOTS-c, MDA and medication. During follow-up, 22 patients suffered a MACE. HPR, β-amyloid > 51 pg/ml and MOTS-c < 167 ng/ml were predictors of MACE (relative risk 3.1, 3.5 and 3.8 respectively, p < 0.05) after adjusting for confounders and medication. There was significant interaction between HPR and β-amyloid or MOTS-c for the prediction of MACE (p < 0.05). Patients with HPR and β-amyloid > 51 mg/dl or HPR and MOTS-c concentration < 167 ng/ml had a fourfold higher risk for MACE than patients without these predictors (relative risk 4.694 and 4.447 respectively p < 0.01). The above results were confirmed in an external validation cohort of 90 patients with diabetes and CAD.

Conclusions

Increased β-amyloid or low MOTS-c are additive predictors to high on-clopidogrel platelet reactivity for adverse outcome in diabetics with CAD during 2-years follow-up. Clinical Trial Registration-URL: https://www.clinicaltrials.gov. Unique identifier: NCT04027712.

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Acknowledgements

We thank Hellenic Diabetes Association (https://www.ede.gr/) for the financial support, which was critical for the completion of the study.

Funding

Hellenic Diabetes Association (https://www.ede.gr/), prize for young investigators.

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Authors and Affiliations

Authors

Contributions

II contributed to the study design data analysis and writing of the manuscript. KK contributed to data analysis and writing of the manuscript. GK, CV and FK contributed to patient recruitment and analysis of patients’ clinical characteristics. KS and PP contributed to patient recruitment of the validation cohort. EK and MT carried out the platelet function tests and analysis. MT and IA performed the bio markers measurement and analysis. EM and AP performed the MOTS-c and diabetic biomarkers assessment and analysis. MT and KK and PP carried out the 2-year follow up. DA, GD, VL and JP critically reviewed the manuscript and contributed to the scientific analysis of the results. AET contributed to study design, analysis of the results and critically reviewing of the manuscript. All authors discussed the results and contributed to the final manuscript.

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Correspondence to Ignatios Ikonomidis.

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Ikonomidis, I., Katogiannis, K., Kyriakou, E. et al. β-Amyloid and mitochondrial-derived peptide-c are additive predictors of adverse outcome to high-on-treatment platelet reactivity in type 2 diabetics with revascularized coronary artery disease. J Thromb Thrombolysis 49, 365–376 (2020). https://doi.org/10.1007/s11239-020-02060-4

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