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A novel mechanism of ACE inhibition–associated enhanced platelet reactivity: disproof of the ARB-MI paradox?

  • Pharmacodynamics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

ACE inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are important drugs in cardiovascular disease. However, little is known about which of these drug class is to be preferred. First analyses show that the blockade of the renin-angiotensin-aldosterone system (RAAS) influences platelet reactivity. Therefore, we evaluated the effects of ACEI and ARB on platelet reactivity and thrombin generation.

Methods

We conducted a time series analysis in 34 patients. We performed light transmission aggregometry (LTA) to evaluate platelet reactivity. Results are given as maximum of aggregation (MoA). Thrombin generation was measured as endogenous thrombin potential (ETP) via calibrated automated thrombogram. Flow cytometry was used to analyze protease-activated receptor (PAR)-1 expression.

Results

ACEI treatment significantly increased platelet reactivity already 4 h after initiation of treatment (prior vs. 4 h post ACEI: MoA 41.9 ± 16.2% vs. 55.2 ± 16.7%; p = 0.003). After switching from ACEI to ARB treatment, platelet reactivity decreased significantly (3 months after switching: MoA 34.7 ± 20.9%; p = 0.03). ACEI reduced endogenous thrombin potential significantly from before to 3 months after ACEI (ETP 1527 ± 437 nM × min vs. 1088 ± 631 nM × min; p = 0.025). Platelet thrombin receptor (PAR1) expression increased from 37.38 ± 10.97% before to 49.53 ± 6.04% after ACEI treatment (p = 0.036).

Conclusion

ACEI enhanced platelet reactivity. This can be reversed by changing to ARB. The mechanism behind RAAS influencing platelet function seems to be associated with PAR-1 expression.

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Data availability

Data are made available upon request.

Code availability

Not applicable.

Abbreviations

ACEI:

Angiotensin-converting enzyme inhibitor

ARB:

Angiotensin II receptor blocker

AT2:

Angiotensin receptor subtype 2

ETP:

Endogenous thrombin potential

LTA:

Light transmission aggregometry

MI:

Myocardial infarction

MoA:

Maximum of aggregation

PAR:

Protease-activated receptor

RAAS:

Renin-angiotensin-aldosterone system

TRAP:

Thrombin receptor activating peptide

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Acknowledgments

We gratefully acknowledge the excellent technical assistance of Kirsten Bartkowski and Kerstin Freidel.

Funding

Part of this work was supported by the Deutsche Forschungsgemeinschaft (LE 940/7-1 to A.P.; SFB1116 to A.P.) and the Forschungskommission of the Heinrich Heine University Medical School (No. 16-2014 and; No. 46-2016 to L.D.).

Author information

Author notes

  1. Carolin Helten and Philipp Mourikis contributed equally to this work.

Authors and Affiliations

  1. Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Düsseldorf, Düsseldorf, Germany

    Carolin Helten, Philipp Mourikis, Lisa Dannenberg, René M’Pembele, Kajetan Trojovsky, Aysel Ayhan, Verena Veulemans, Malte Kelm, Tobias Zeus & Amin Polzin

  2. Institute of Pharmacology and Clinical Pharmacology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Christina Kohlmorgen, Maria Grandoch & Thomas Hohlfeld

  3. Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, Essen, Germany

    Bodo Levkau

  4. Institute of Molecular Medicine III, University Hospital Düsseldorf, Düsseldorf, Germany

    Bodo Levkau

  5. Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany

    Tobias Petzold

  6. Klinik für Kardiologie, Pneumologie und Angiologie, Universitätsklinikum Düsseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany

    Amin Polzin

Authors
  1. Carolin Helten
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  2. Philipp Mourikis
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  3. Lisa Dannenberg
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  4. René M’Pembele
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  11. Tobias Petzold
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  12. Thomas Hohlfeld
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  13. Malte Kelm
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  14. Tobias Zeus
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  15. Amin Polzin
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Contributions

A.P. and T.H. designed the study, interpreted data and wrote the manuscript. C.H., P.M., L.D., R.M., K.T. and A.A. collected the samples, interpreted data and wrote the manuscript. M.G., C.K., B.L., V.V., T.P., T.Z. and M.K. supervised the study and revised the manuscript.

Corresponding author

Correspondence to Amin Polzin.

Ethics declarations

Ethics committee approval

The study conformed to the Declaration of Helsinki and was accepted by the University of Düsseldorf Ethics Committee (n° 5505R).

Conflict of interest

The authors declare that they have no conflict of interest.

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Key messages

What is already known about this subject?

• Influence of RAAS inhibitors on platelet reactivity is unknown so far.

What does this study add?

• ACE inhibitors enhanced platelet reactivity. However, this can be reversed by changing to ARB.

How might this impact on clinical practice?

• Patients with enhanced ischemic risk may get ARB as preferred RAAS inhibitor.

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Helten, C., Mourikis, P., Dannenberg, L. et al. A novel mechanism of ACE inhibition–associated enhanced platelet reactivity: disproof of the ARB-MI paradox?. Eur J Clin Pharmacol 76, 1245–1251 (2020). https://doi.org/10.1007/s00228-020-02915-y

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  • DOI: https://doi.org/10.1007/s00228-020-02915-y

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