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Deciphering Genetic Variants of Warfarin Metabolism in Children With Ventricular Assist Devices

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Abstract

Warfarin is prescribed in patients with ventricular assist devices (VADs). Dosage depends on several factors including the underlying genotype. These include polymorphisms of genes encoding cytochrome P450 enzymes, the main ones being CYP2C9, VKORC1, and CYP4F2. The objectives of this study were to evaluate the prevalence of CY2CP9 1*2*3*, VKORC1, and CYP4F2 in children with VADs and the time to reach the target international normalized ratio. We performed a retrospective/prospective study in children with VADs. We recorded polymorphisms, disease, type of VAD, ethnicity, age, gender, height, weight, INR values, bleeding, and thromboembolic episodes. Informed consent was obtained. We enrolled 34 children (19 male, 15 female), with a median age of 2 years (range 0.3–17 years) and median weight of 6.9Kg. The Berlin Heart was the most commonly implanted VAD (22/34; 64%), and the most common diagnosis was dilated cardiomyopathy. Statistical analysis confirmed a significant partial correlation with VKORC1 CC (p = 0.019). The CYP2C9*2 CT genotype showed a late rise in target INR values (p = 0.06), while the CYP2C9*2 CC showed a tendency toward an early INR rise (p = 0.024). We provide new information on the contribution of the warfarin polymorphisms in children with VAD implantation. Pharmacogenomic dosing for children using warfarin has the potential to improve clinical care in VAD patients. Patients with the CYP2C9*2 CT genotype may need more time or higher doses to reach target INR, while clinicians may need to be aware of the potential for a rapid rise in INR in patients with the CYP2C9*2 CC genotype.

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Data Availability

Data and materials are deposited in a data repository and are available from the authors upon request.

Abbreviations

CMP:

Cardiomyopathy

DMD:

Duchenne muscular dystrophy

INR:

International normalized ratio

NTC:

No template control

SNP:

Single-nucleotide polymorphism

VAD:

Ventricular assist device

VKORC1 :

Vitamin K epoxide reductase

VK1:

Vitamin K1

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Acknowledgements

We thank the children and families who participated in this study for helping us to better understand this complex condition. We acknowledge that this work is part of a good clinical practice program, “cardiogenetic assessment of children with heart diseases.” We thank Daniela Corbo and Elisa Del Vecchio for logistic support. This study is part of the “ricerca corrente” project of the Cardiac Intensive Care Unit of our Institute (2016).

Funding

Not applicable.

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Author notes

  1. Anwar Baban and Francesca G. Iodice contributed equally to this work.

Authors and Affiliations

  1. The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart - ERN GUARD-Heart. Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children Hospital and Research Institute, Piazza Sant’Onofrio 4 – 00165, Rome, Italy

    Anwar Baban, Marianna Cicenia & Fabrizio Drago

  2. Paediatric Cardiac Anesthesia and Intensive Care Unit, Bambino Gesu’ Children Hospital, Rome, Italy

    Francesca G. Iodice, Luca Di Chiara & Giuseppina Testa

  3. Heart Failure, Transplant and Mechanical Assistance Program Unit, Bambino Gesù Children Hospital, Rome, Italy

    Arianna Di Molfetta & Antonio Amodeo

  4. Department of Infectious Diseases, Istituto Superiore Di Sanità, Rome, Italy

    Caterina Rizzo

  5. Genetics and Rare Diseases Research Division, Bambino Gesù Children Hospital, Rome, Italy

    Emanuele Agolini & Antonio Novelli

Authors
  1. Anwar Baban
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  2. Francesca G. Iodice
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  3. Arianna Di Molfetta
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  8. Antonio Novelli
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  9. Luca Di Chiara
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Contributions

AB, FI, and AA conceived the project, drafted the manuscript, and confirmed final version, and they are clinicians who cared for the children. EA and AN are molecular geneticists who designed and undertook molecular analysis. ADM, MC, CR, FD, LDC, G, and AA are clinicians who cared for the children. All authors revised the manuscript and approved the final version.

Corresponding author

Correspondence to Anwar Baban.

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Conflict of interest

All authors declare that they have no conflict of interest.

Consent to participate

Written informed consent was obtained from all parents or caregivers of patients enrolled in the study.

Ethical Approval

This study received approval from Bambino Gesù Children’s Hospital and Research Ethics Committee and was conducted according to the Declaration of Helsinki guidelines.

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Baban, A., Iodice, F.G., Di Molfetta, A. et al. Deciphering Genetic Variants of Warfarin Metabolism in Children With Ventricular Assist Devices. Pediatr Cardiol 42, 1082–1087 (2021). https://doi.org/10.1007/s00246-021-02585-2

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  • DOI: https://doi.org/10.1007/s00246-021-02585-2

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