Abstract
BackgroundLong QT syndrome type 3 (LQT3) is caused by gain-of-function mutations in the SCN5A gene, which encodes the α subunit of the cardiac voltage-gated sodium channel. LQT3 patients present bradycardia and lethal arrhythmias during rest or sleep. Further, the efficacy of β-blockers, the drug used for their treatment, is uncertain. Recently, a large multicenter LQT3 cohort study demonstrated that β-blocker therapy reduced the risk of life-threatening cardiac events in female patients; however, the detailed mechanism of action remains unclear.ObjectivesThis study aimed to establish LQT3-human induced pluripotent stem cells (hiPSCs) and to investigate the effect of propranolol in this model.MethodAn hiPSCs cell line was established from peripheral blood mononuclear cells of a boy with LQT3 carrying the SCN5A-N1774D mutation. He had suffered from repetitive torsades de pointes (TdPs) with QT prolongation since birth (QTc 680 ms), which were effectively treated with propranolol, as it suppressed lethal arrhythmias. Furthermore, hiPSCs were differentiated into cardiomyocytes (CMs), on which electrophysiological functional assays were performed using the patch-clamp method.ResultsN1774D-hiPSC-CMs exhibited significantly prolonged action potential durations (APDs) in comparison to those of the control cells (N1774D: 440 ± 37 ms vs. control: 272 ± 22 ms; at 1 Hz pacing; p < 0.01). Furthermore, N1774D-hiPSC-CMs presented gain-of-function features: a hyperpolarized shift of steady-state activation and increased late sodium current compared to those of the control cells. 5 μM propranolol shortened APDs and inhibited late sodium current in N1774D-hiPSC-CMs, but did not significantly affect in the control cells. In addition, even in the presence of intrapipette guanosine diphosphate βs (GDPβs), an inhibitor of G proteins, propranolol reduced late sodium current in N1774D cells. Therefore, these results suggested a unique inhibitory effect of propranolol on late sodium current unrelated to β-adrenergic receptor block in N1774D-hiPSC-CMs.ConclusionWe successfully recapitulated the clinical phenotype of LQT3 using patient-derived hiPSC-CMs and determined that the mechanism, by which propranolol inhibited the late sodium current, was independent of β-adrenergic receptor signaling pathway.
Highlights
Congenital long QT syndrome (LQT) is an inherited arrhythmogenic disease, associated with lethal arrhythmic events and sudden cardiac death
The proband was a 1-day-old infant who exhibited severe bradycardia at 27 weeks of gestation (Kato et al, 2014). His surface electrocardiogram showed an extremely prolonged QT interval (QTc 680 ms) with functional atrio-ventricular block and repeated TdPs immediately after his birth. He was suspected of long QT syndrome and propranolol was administered to suppress TdPs
A large clinical study demonstrated the efficacy of β-blockers on patients with Long QT syndrome type 3 (LQT3) (Wilde et al, 2016); FIGURE 4 | Late sodium current in control and N1774D-hiPSC-CMs. (A) Representative traces of sodium currents in the absence and presence of 20 μM tetrodotoxin (TTX)
Summary
Congenital long QT syndrome (LQT) is an inherited arrhythmogenic disease, associated with lethal arrhythmic events and sudden cardiac death. Patients with LQT1 and LQT2 suffer from cardiac events that occur during exercise or emotional stress (Schwartz et al, 2001, 2012) They are usually treated with β-blockers, as they are highly effective in reducing cardiac event and mortality rates (Schwartz et al, 2001; Priori et al, 2004). Patients with LQT3 experience cardiac events during rest or sleep (Schwartz et al, 2001, 2012), and β-blocker therapy has resulted less effective or even harmful in preventing those cardiac events, according to small cohort studies and the clinical features of LQT3 (Moss et al, 2000; Schwartz et al, 2001; Priori et al, 2004). A large multicenter LQT3 cohort study demonstrated that β-blocker therapy reduced the risk of life-threatening cardiac events in female patients; the detailed mechanism of action remains unclear
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