Terra Steven G, Pauly Daniel F, Lee Craig R, Patterson J Herbert, Adams Kirkwood F, Schofield Richard S, Belgado Bernadette S, Hamilton Karen K, Aranda Juan M, Hill James A, Yarandi Hossein N, Walker Joseph R, Phillips Michael S, Gelfand Craig A, Johnson Julie A
Department of Pharmacy Practice, University of Florida, Gainsville, FL 32610, USA.
Clin Pharmacol Ther. 2005 Mar;77(3):127-37. doi: 10.1016/j.clpt.2004.10.006.
beta-Blockers require careful initiation and titration when used in patients with heart failure. Some patients tolerate beta-blocker therapy initiation without difficulty, whereas in other patients this period presents clinical challenges. We tested the hypothesis that polymorphisms at codons 389 (Arg389Gly) and 49 (Ser49Gly) of the beta(1)-adrenergic receptor would be associated with differences in initial tolerability of beta-blocker therapy in patients with heart failure. We also tested whether polymorphisms in the beta(2)-adrenergic receptor, G-protein alpha s subunit (G(s)alpha), and cytochrome P450 (CYP) 2D6 genes or S-metoprolol plasma concentrations were associated with beta-blocker tolerability.
Sixty-one beta-blocker-naive patients with systolic heart failure were prospectively enrolled. Patients began taking 12.5 to 25 mg metoprolol controlled release/extended release with titration every 2 weeks (as tolerated) to 200 mg/d or the maximum tolerated dose over a period of 8 to 10 weeks. Decompensation was the composite of death, heart failure hospitalization, increase in other heart failure medications, or need to discontinue metoprolol. End points were assessed during the titration period.
The overall rate of decompensation was not different between the codon 49 or 389 genotypes. However, a significantly greater percentage of patients with the Gly389 variant required increases in heart failure medications as compared with Arg389 homozygotes (48% versus 14%, respectively; P = .006). Similarly, patients with the Ser49 homozygous genotype were significantly more likely to require increases in concomitant heart failure therapy as compared with Gly49 carriers (41% versus 11%, respectively; P = .03). Neither CYP2D6 genotypes nor metoprolol pharmacokinetics differed between patients with and those without a decompensation event. There was no association between the beta(2)-adrenergic receptor or G(s)alpha polymorphisms with decompensated heart failure.
Patients with the Gly389 variant and Ser49Ser genotype were significantly more likely to require increases in heart failure medications during beta-blocker titration and thus may require more frequent follow-up during titration.
β受体阻滞剂用于心力衰竭患者时，起始用药和剂量滴定需谨慎。一些患者能顺利耐受β受体阻滞剂治疗起始阶段，而其他患者在此阶段会面临临床挑战。我们检验了如下假设：β1肾上腺素能受体第389位密码子（Arg389Gly）和第49位密码子（Ser49Gly）的多态性与心力衰竭患者β受体阻滞剂治疗初始耐受性差异相关。我们还检验了β2肾上腺素能受体、G蛋白αs亚基（G(s)α）、细胞色素P450（CYP）2D6基因的多态性或S - 美托洛尔血浆浓度是否与β受体阻滞剂耐受性相关。
前瞻性纳入61例既往未使用过β受体阻滞剂的收缩性心力衰竭患者。患者开始服用12.5至25mg美托洛尔控释/缓释制剂，每2周（根据耐受情况）滴定剂量至200mg/d或在8至10周内达到最大耐受剂量。失代偿定义为死亡、因心力衰竭住院、增加其他心力衰竭药物治疗或需要停用美托洛尔的综合情况。在滴定期间评估终点事件。
第49位或第389位密码子基因型患者的总体失代偿率无差异。然而，与Arg389纯合子相比，携带Gly389变异的患者需要增加心力衰竭药物治疗的比例显著更高（分别为48%和14%；P = 0.006）。同样，与Gly49携带者相比，Ser49纯合基因型患者更有可能需要增加伴随的心力衰竭治疗（分别为41%和11%；P = 0.03）。发生失代偿事件的患者与未发生失代偿事件的患者之间，CYP2D6基因型和美托洛尔药代动力学均无差异。β2肾上腺素能受体或G(s)α多态性与失代偿性心力衰竭之间无关联。
携带Gly389变异和Ser49Ser基因型的患者在β受体阻滞剂滴定期间更有可能需要增加心力衰竭药物治疗，因此在滴定期间可能需要更频繁的随访。
