title: Mechanisms of acquired long QT syndrome in patients with propionic academia.
abstract: Propionic 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.
  
  
  
  The 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.
  
  
  
  Voltage 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.
  
  
  
  Acute 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.
  
  
  
  Acute reduction of IKs by PROP metabolites may be responsible for APD prolongation and acqLQTS observed in PROP patients.
authors: Department of Cardiology and Angiology I, Heart Center University of Freiburg, Freiburg, Germany.
authors: Ilona
authors: I
authors: Bodi
authors: Center of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany.
authors: Sarah C
authors: SC
authors: Grünert
authors: Nanion Technologies, Munich, Germany.
authors: Nadine
authors: N
authors: Becker
authors: Nanion Technologies, Munich, Germany.
authors: Sonja
authors: S
authors: Stoelzle-Feix
authors: Center of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany.
authors: Ute
authors: U
authors: Spiekerkoetter
authors: Department of Cardiology and Angiology I, Heart Center University of Freiburg, Freiburg, Germany.
authors: Manfred
authors: M
authors: Zehender
authors: Department of Cardiology and Angiology I, Heart Center University of Freiburg, Freiburg, Germany.
authors: Heiko
authors: H
authors: Bugger
authors: Department of Cardiology and Angiology I, Heart Center University of Freiburg, Freiburg, Germany.
authors: Christoph
authors: C
authors: Bode
authors: Department of Cardiology and Angiology I, Heart Center University of Freiburg, Freiburg, Germany. Electronic address: katja.odening@uniklinik-freiburg.de.
authors: Katja E
authors: KE
authors: Odening
mesh_terms: D000818:Animals; D006329:Heart Conduction System / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D008133:Long QT Syndrome / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology; D043586:Methylmalonyl-CoA Decarboxylase / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D056693:Propionic Acidemia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D011817:Rabbits; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000517:prevention & control
chemical_list: D024642:Potassium Channels, Voltage-Gated; D043586:Methylmalonyl-CoA Decarboxylase
keywords: Arrhythmia; Long QT syndrome; Patch clamp; Propionic acidemia; Repolarizing cardiac ion channels