A human pluripotent stem cell model of catecholaminergic polymorphic ventricular tachycardia recapitulates patient-specific drug responses.
A human pluripotent stem cell model of catecholaminergic polymorphic ventricular tachycardia recapitulates patient-specific drug responses.
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DOI：
10.1242/dmm.026823
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发表时间：
2016-09-01
影响因子：
4.3
通讯作者：
Xu C
中科院分区：
文献类型：
--
作者：
Preininger MK;Jha R;Maxwell JT;Wu Q;Singh M;Wang B;Dalal A;Mceachin ZT;Rossoll W;Hales CM;Fischbach PS;Wagner MB;Xu C
虽然β受体阻滞剂可用于消除儿茶酚胺能多形性室性心动过速（CPVT）患者的应激诱导的室性心律失常，但这种治疗在约25%的病例中不成功。从这些患者中产生的诱导多能干细胞衍生的心肌细胞（iPSC-CM）有可能用于研究这种现象，但它们是否能重现患者对β受体阻滞剂的特异性药物反应仍是未知数。本研究评估了是否可以使用患者来源的CPVT iPSC-CM在体外观察到个体中β-受体阻滞剂治疗的不足。1例CPVT患者在2型心脏ryanodine受体（RyR 2）中发现了一种新的突变，在氟卡尼治疗期间，纳多洛尔β阻滞期间持续性室性心律失常被消除。从该患者和两个对照个体产生的iPSC-CM表达相当水平的兴奋-收缩基因，但是肌浆网Ca 2+渗漏和负荷关系的评估显示在CPVT iPSC-CM中细胞内Ca 2+稳态改变。与对照iPSC-CM相比，β-肾上腺素能刺激增强了CPVT中的自发Ca 2+波和过度频繁、大且延长的Ca 2+火花，从而验证了疾病表型。根据患者的体内反应，β-肾上腺素能刺激期间的纳多洛尔治疗实现了可忽略的Ca 2+波频率降低，并且未能挽救CPVT iPSC-CM中的Ca 2+火花缺陷。相反，氟卡尼降低了Ca 2+波的频率和振幅，并将Ca 2+火花的频率、宽度和持续时间恢复到基线水平。通过概括与体外β受体阻滞剂治疗相比，CPVT个体对氟卡尼的反应改善，这些数据提供了新的证据，证明iPSC-CM可以捕获患者特异性药物反应的基本成分。编辑选择：临床上观察到的对β-阻滞剂和氟卡尼治疗的儿茶酚胺能多形性室性心动过速的药物反应差异可以使用患者来源的iPSC-心肌细胞体外建模。
Although β-blockers can be used to eliminate stress-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), this treatment is unsuccessful in ∼25% of cases. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from these patients have potential for use in investigating the phenomenon, but it remains unknown whether they can recapitulate patient-specific drug responses to β-blockers. This study assessed whether the inadequacy of β-blocker therapy in an individual can be observed in vitro using patient-derived CPVT iPSC-CMs. An individual with CPVT harboring a novel mutation in the type 2 cardiac ryanodine receptor (RyR2) was identified whose persistent ventricular arrhythmias during β-blockade with nadolol were abolished during flecainide treatment. iPSC-CMs generated from this patient and two control individuals expressed comparable levels of excitation-contraction genes, but assessment of the sarcoplasmic reticulum Ca2+ leak and load relationship revealed intracellular Ca2+ homeostasis was altered in the CPVT iPSC-CMs. β-adrenergic stimulation potentiated spontaneous Ca2+ waves and unduly frequent, large and prolonged Ca2+ sparks in CPVT compared with control iPSC-CMs, validating the disease phenotype. Pursuant to the patient's in vivo responses, nadolol treatment during β-adrenergic stimulation achieved negligible reduction of Ca2+ wave frequency and failed to rescue Ca2+ spark defects in CPVT iPSC-CMs. In contrast, flecainide reduced both frequency and amplitude of Ca2+ waves and restored the frequency, width and duration of Ca2+ sparks to baseline levels. By recapitulating the improved response of an individual with CPVT to flecainide compared with β-blocker therapy in vitro, these data provide new evidence that iPSC-CMs can capture basic components of patient-specific drug responses. Editors' choice: Clinically observed drug response differentials to β-blocker and flecainide treatment in catecholaminergic polymorphic ventricular tachycardia can be modeled in vitro using patient-derived iPSC-cardiomyocytes.
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影响因子：
9
作者：
通讯作者：
--
影响因子：
23.9
作者：
Miller JD;Ganat YM;Kishinevsky S;Bowman RL;Liu B;Tu EY;Mandal PK;Vera E;Shim JW;Kriks S;Taldone T;Fusaki N;Tomishima MJ;Krainc D;Milner TA;Rossi DJ;Studer L
通讯作者：
Studer L
影响因子：
37.8
作者：
JAMES, FW;KAPLAN, S;SARWAR, CJ
通讯作者：
SARWAR, CJ
影响因子：
20.1
作者：
Jiang, DW;Wang, RW;Chen, SRW
通讯作者：
Chen, SRW
影响因子：
20.1
作者：
Iyer, Vivek;Hajjar, Roger J.;Armoundas, Antonis A.
通讯作者：
Armoundas, Antonis A.