Mechanisms of acquired long QT syndrome in patients with propionic academia

BackgroundPropionic acidemia (PROP) is a rare metabolic disorder caused by deficiency of propionyl-CoA carboxylase. PROP patients demonstrate QT prolongations associated with ventricular tachycardia and syncopes. Mechanisms responsible for this acquired long QT syndrome (acqLQTS) are unknown.ObjectiveThe aim of the study was to investigate acute and chronic effects of metabolites accumulating in PROP patients on major repolarizing potassium currents (IKs and IKr) and their channel subunits.MethodsVoltage clamp studies were performed in CHO-KCNQ1/KCNE1 or HEK-KCNH2 cells to determine effects of propionic acid (PA; 1–10 mM), propionylcarnitine (PC; 25 µM–10 mM), methylcitrate (MC; 25 µM–10 mM), 0.2 M phosphate buffer (PB), or patient serum on IKs and IKr currents. Metabolite effects on action potentials were recorded in current clamp mode in human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CM). Protein expression of α- and β-subunits of IKs (KCNQ1/KCNE1) and IKr (KCNH2) was evaluated with Western blots.ResultsAcute application of PA, PC, MC, and patient serum had no direct effect on net IKr densities (and KCNH2 expression), although it changed IKr gating kinetics. In contrast, PA, PC, MC, and patient serum all reduced IKs-tail (−67% ± 4.2%, −27% ± 6.7%, −16% ± 6.3%, −42.8% ± 5.15; P < .001) and IKs-end pulse currents. PA significantly prolonged action potential duration (APD) in hiPSC-CM and QT interval in wild-type but not in LQT1 rabbits lacking IKs. Moreover, PC and MC (1 mM) decreased KCNQ1 protein expression (relative density: 0.58 ± 0.08 and 0.16 ± 0.05; P < .01). Chronic exposure to 10 mM PA, in contrast, increased KCNQ1 5.4-fold (P < .001) owing to decreased protein degradation.ConclusionAcute reduction of IKs by PROP metabolites may be responsible for APD prolongation and acqLQTS observed in PROP patients.