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..
Cardiol J. 2016;23(5):573-582. doi: 10.5603/CJ.a2016.0050. Epub 2016 Jul 21.
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).
In an exploratory cohort (n = 11), patients started on ivabradine were genotyped and the HR reduction was studied.
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 CYP3A41F and CYP3A41B were found in one patient each and CYP3A4*1G was presented in 3 patients.
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.
伊伐布雷定是一种选择性的窦性心动过缓药物，可抑制 If。在心力衰竭（HF）患者中，伊伐布雷定可降低再住院和死亡率的风险。平均心率（HR）降低 8-10 次/分，尽管临床试验显示个体间存在差异。本研究旨在鉴定与药物代谢（CYP3A4）相关基因或与药物靶点（HCN4）相关基因中伊伐布雷定引起的 HR 降低相关的变异。
在一项探索性队列研究（n = 11）中，对开始服用伊伐布雷定的患者进行基因分型，并研究 HR 降低情况。
治疗后平均 HR 降低 18.10 ± 12.26 次/分。3 例患者的 HR 降低≥15 次/分，7 例患者的 HR 降低>5 次/分且<15 次/分。在 HCN4 基因中检测到 4 个同义变异，L12L、L520L、P852P 和 P1200P，频率分别为 0.045、0.045 和 0.681。此外，在 1 例患者中发现 CYP3A41F 和 CYP3A41B，在 3 例患者中发现 CYP3A4*1G。
这是第一项使用探索性药物遗传学方法的研究，试图解释伊伐布雷定 HR 降低的个体间差异。然而，为了确定 HCN4 和 CYP3A4 基因变异在伊伐布雷定反应中的作用，还需要进行更多的研究。
