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.
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.
authors.forename: Lucía
authors.initials: L
authors.lastname: Núñez
authors.forename: María G
authors.initials: MG
authors.lastname: Crespo-Leiro
authors.forename: Grecia M
authors.initials: GM
authors.lastname: Marrón-Liñares
authors.forename: Natalia
authors.initials: N
authors.lastname: Suarez-Fuentetaja
authors.forename: Eduardo
authors.initials: E
authors.lastname: Barge-Caballero
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Paniagua-Martín
authors.forename: Raquel
authors.initials: R
authors.lastname: Marzoa-Rivas
authors.forename: Zulaika
authors.initials: Z
authors.lastname: Grille-Cancela
authors.forename: Javier
authors.initials: J
authors.lastname: Muñiz-García
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Vazquez-Rodriguez
authors.affiliation: Grupo de investigación en Cardiología. Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas. Universidade da Coruña (UDC). Spain.. mhermida@udc.es.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hermida-Prieto
mesh_terms: D000328:Adult; D000368:Aged; D001552:Benzazepines / Q000008:administration & dosage*; D002317:Cardiovascular Agents / Q000008:administration & dosage; D054815:Cyclic Nucleotide-Gated Cation Channels; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics* / Q000378:metabolism; D000077550:Ivabradine; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000235:genetics*
chemical_list: D001552:Benzazepines; D002317:Cardiovascular Agents; D054815:Cyclic Nucleotide-Gated Cation Channels; C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009124:Muscle Proteins; D015221:Potassium Channels; D000077550:Ivabradine; D012313:RNA; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: CYP3A4; HCN4; heart failure; ivabradine; pharmacogenetic