Genetic mechanisms of atrial fibrillation: impact on response to treatment.
Genetic mechanisms of atrial fibrillation: impact on response to treatment.
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DOI：
10.1038/nrcardio.2013.53
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发表时间：
2013-06
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--
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心房颤动（AF）是临床实践中观察到的最常见的持续性心律失常，但患者对治疗的反应差异很大。目前抑制房颤的药物治疗效果不完全且不可预测，并存在致心律失常和非心脏毒性的重大风险。房颤治疗的有限成功部分是由于基础基质的异质性、疾病机制的个体间差异以及我们无法预测个体患者对治疗的反应。在这篇综述中，我们讨论了对药物治疗反应的变异性也受到房颤潜在遗传底物的影响的证据。房颤易感性的增加是通过不同的遗传机制介导的，包括心房动作电位持续时间的调节，传导减慢，细胞间通讯受损，以及新的机制，例如调节在AF发病机制中重要的信号蛋白。然而，由于对与常见AF易感基因座相关的潜在机制缺乏了解，缺乏前瞻性的、有充分把握的研究，以及确定抗疟疾药物疗效的挑战。然而，显而易见的是，需要适当设计的基因型导向临床试验。
Atrial fibrillation (AF) is the most-common sustained arrhythmia observed in clinical practice, but response to therapy is highly variable between patients. Current drug therapies to suppress AF are incompletely and unpredictably effective and carry substantial risk of proarrhythmia and noncardiac toxicities. The limited success of therapy for AF is partially the result of heterogeneity of the underlying substrate, interindividual differences in disease mechanisms, and our inability to predict response to therapies in individual patients. In this Review, we discuss the evidence that variability in response to drug therapy is also conditioned by the underlying genetic substrate for AF. Increased susceptibility to AF is mediated through diverse genetic mechanisms, including modulation of the atrial action-potential duration, conduction slowing, and impaired cell-to-cell communication, as well as novel mechanisms, such as regulation of signalling proteins important in the pathogenesis of AF. However, the translation of genetic data to the care of the patients with AF has been limited because of poor understanding of the underlying mechanisms associated with common AF-susceptibility loci, a dearth of prospective, adequately powered studies, and the challenges associated with determining efficacy of antiarrhythmic drugs. What is apparent, however, is the need for appropriately designed, genotype-directed clinical trials.
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