open access

Vol 23, No 5 (2016)
BASIC SCIENCE AND EXPERIMENTALNTAL CARDIOLOGY - ORIGINAL ARTICLES
Published online: 2016-07-20
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Analysis of variants in the HCN4 gene and in three single nucleotide polymorphisms of the CYP3A4 gene for association with ivabradine reduction in heart rate: A preliminary report

Lucía Núñez, María G. Crespo-Leiro, Grecia M. Marrón-Liñares, Natalia Suarez-Fuentetaja, Eduardo Barge-Caballero, María Jesús Paniagua-Martín, Raquel Marzoa-Rivas, Zulaika Grille-Cancela, Javier Muñiz-García, Jose Manuel Vazquez-Rodriguez, Manuel Hermida-Prieto
DOI: 10.5603/CJ.a2016.0050
·
Pubmed: 27439367
·
Cardiol J 2016;23(5):573-582.

open access

Vol 23, No 5 (2016)
BASIC SCIENCE AND EXPERIMENTALNTAL CARDIOLOGY - ORIGINAL ARTICLES
Published online: 2016-07-20

Abstract

Background: Ivabradine, a selective bradycardic drug, inhibits the If. In patients with heart failure (HF), ivabradine reduces the risk of rehospitalization and mortality. The average heart rate (HR) reduction is 8–10 beats, although clinical trials reveal interindividual variability. The aim of the study is to identify variants associated with HR reduction produced by ivabradine in genes involved in the drug metabolism (CYP3A4) or related to the drug target (HCN4).

Methods: In an exploratory cohort (n = 11), patients started on ivabradine were genotyped and the HR reduction was studied.

Results: The mean HR reduction after the treatment was 18.10 ± 12.26 bpm. The HR reduction was ≥ 15 bpm in 3 patients and > 5 and < 15 bpm in 7 patients. Four synonymous variants, L12L, L520L, P852P, and P1200P, were detected in the HCN4 gene (frequency = 0.045, 0.045, and 0.681, respectively). Moreover, the CYP3A4*1F and CYP3A4*1B were found in one patient each and CYP3A4*1G was presented in 3 patients.

Conclusions: This is the first study using an exploratory pharmacogenetic approach that attempts to explain interindividual variability in ivabradine HR reduction. However, more research must be undertaken in order to determine the role of variants in HCN4 and CYP3A4 genes in response to ivabradine.

Abstract

Background: Ivabradine, a selective bradycardic drug, inhibits the If. In patients with heart failure (HF), ivabradine reduces the risk of rehospitalization and mortality. The average heart rate (HR) reduction is 8–10 beats, although clinical trials reveal interindividual variability. The aim of the study is to identify variants associated with HR reduction produced by ivabradine in genes involved in the drug metabolism (CYP3A4) or related to the drug target (HCN4).

Methods: In an exploratory cohort (n = 11), patients started on ivabradine were genotyped and the HR reduction was studied.

Results: The mean HR reduction after the treatment was 18.10 ± 12.26 bpm. The HR reduction was ≥ 15 bpm in 3 patients and > 5 and < 15 bpm in 7 patients. Four synonymous variants, L12L, L520L, P852P, and P1200P, were detected in the HCN4 gene (frequency = 0.045, 0.045, and 0.681, respectively). Moreover, the CYP3A4*1F and CYP3A4*1B were found in one patient each and CYP3A4*1G was presented in 3 patients.

Conclusions: This is the first study using an exploratory pharmacogenetic approach that attempts to explain interindividual variability in ivabradine HR reduction. However, more research must be undertaken in order to determine the role of variants in HCN4 and CYP3A4 genes in response to ivabradine.

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Keywords

heart failure, ivabradine, HCN4, CYP3A4, pharmacogenetic

About this article
Title

Analysis of variants in the HCN4 gene and in three single nucleotide polymorphisms of the CYP3A4 gene for association with ivabradine reduction in heart rate: A preliminary report

Journal

Cardiology Journal

Issue

Vol 23, No 5 (2016)

Pages

573-582

Published online

2016-07-20

DOI

10.5603/CJ.a2016.0050

Pubmed

27439367

Bibliographic record

Cardiol J 2016;23(5):573-582.

Keywords

heart failure
ivabradine
HCN4
CYP3A4
pharmacogenetic

Authors

Lucía Núñez
María G. Crespo-Leiro
Grecia M. Marrón-Liñares
Natalia Suarez-Fuentetaja
Eduardo Barge-Caballero
María Jesús Paniagua-Martín
Raquel Marzoa-Rivas
Zulaika Grille-Cancela
Javier Muñiz-García
Jose Manuel Vazquez-Rodriguez
Manuel Hermida-Prieto

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