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    • Safe Ca antagonists are already used clinically

    2018-11-08

    Safe Ca2+ antagonists are already used clinically, and convincing (albeit limited) evidence supports their use in LQTS diseases that resist conventional pharmacotherapy (Iseri and French, 1984; Jackman et al., 1990; Komiya et al., 2004). However, physicians appear hesitant to prescribe Ca2+ antagonists in LQTS for fear of triggering vasodilation, bradycardia, and further arrhythmias. Conversely, evidence from animal models favors these agents (Bailie et al., 1988; Guo et al., 2007; Thomas et al., 2007; Yamada et al., 2008). One study suggested that mere 5 mV shifts in ICa activation or inactivation voltage might abolish EADs (Madhvani et al., 2011). Direct injection of MgSO4 also terminates TdP effectively, but this is unsuitable for daily therapy (Johnson et al., 2001; Viskin, 1999). Interestingly, Mg2+ may be efficacious because it blocks both ICa and SR Ca2+ release, but little is known about what controls the level of this ion intracellularly (Eisner et al., 1998; Iseri and French, 1984; Wang et al., 2004). Compared to other types of LQTS, LQT3 is the most lethal (Bankston et al., 2007; Terrenoire et al., 2013; Zareba et al., 1998). Our results suggest that the LQT3 phenotype can be complex, depending directly on mutant Na+ channels, and partly on other conductances. ICa made up most of the measurable late inward current in LQT3 iPS-CM, substantiating the possibility that blocking this current (for which persistence is known) could be specifically useful in LQT3 (Linz and Meyer, 2000; Thomas et al., 2007). However, doubts have been expressed about whether studies using stem cell-derived myocytes are directly applicable to real-life medicine, because such PX-478 2HCl are acknowledged to be relatively immature (Doss et al., 2012; Lieu et al., 2009). On the other hand, immaturity and spontaneous beating in stem cell-derived myocytes has not prevented the successful development of assays for arrhythmogenesis, with some producing traces similar to ours (Abassi et al., 2012; Chang et al., 2012; Terrenoire et al., 2013). Because we could not fully constrain automaticity by electrical pacing, future studies would be aided by fuller elucidation of the underlying mechanisms or uncovering which transcription factors are required for complete iPS-CM differentiation. Another issue relates to the choice of appropriate controls in a disease with incomplete penetrance, as highlighted by our finding that LQT2 iPS-CM were relatively resistant to nifedipine compared to the other genotypes. Mitigating this, when we exposed control myocytes to HERG blockers, the resulting marked AP prolongation modeled LQTS in the absence of a genetic modification. Moreover, in the present studies and in some published findings, patient-derived iPS-CM lines exhibited exaggerated LQTS phenotypes as compared to clinical experience—though electrotonic and other passive effects alter the observable disease manifestations in organized tissue. Other groups found mild LQTS phenotypes, even in isogenic LQTS lines, and we found less dramatic AP prolongations in large colonies >100 myocytes (Bellin et al., 2013; Itzhaki et al., 2011; Matsa et al., 2011). Because microcluster control APDs closely matched published values from intact ventricles (Khan et al., 2010; Terrenoire et al., 2013), we suspect that a more hyperpolarized MDP may have produced a more physiologically appropriate resting state, evidenced by a generally large Vmax for AP upstrokes (see Table S1). Arguably, this led to heightened responses to LQTS mutations and to torsadogenic drugs. Initially, we obtained MDP no deeper than −65 mV (similar to other studies), but as our differentiation technique improved, the myocytes matured developmentally (Bellin et al., 2013; Doss et al., 2012; Itzhaki et al., 2011; Zhang et al., 2012). Moreover, isolated myocytes are likely to show more severe phenotypes due to the lack of compensatory mechanisms present in the native circulatory system. Finally, in validating the functionally syncytial nature of myocyte microclusters, we were also able to show that brief APs were associated invariably with brief [Ca2+]i transients, and vice versa.