Mechanisms and management of congenital and acquired long QT syndromes.
The long QT syndromes can be divided into congenital and acquired forms. Early afterdepolarizations have been identified as triggering mechanisms for both congenital and acquired QT syndromes but reentry may play a role in the perpetuation of the ventricular tachycardia, torsade de pointes. Studies of the ionic mechanisms of early afterdepolarizations have implicated L-type Ca2+ current, persisting Na+ current, and Na+:Ca2+ exchange current related to Ca2+ loading. Different ionic mechanisms may be operative in early afterdepolarizations occuring at different levels of membrane potential in the setting of prolonged repolarization by blocking K+ currents or maintaining non-inactivating Ca2+ or Na+ currents or in early afterdepolarizations due to adrenergic stimulation. In the congenital long QT syndromes, two mutations have recently been discovered in the genes SCN5A and HERG which encode respectively the Na+ channel and a K+ channel conducting the current IKr. It is postulated that the SCN5A mutation leads to a problem with inactivation of Na+ current. In the case of the HERG mutation, the K+ current appears to be diminished. In the case of the acquired long QT syndromes, the therapeutic challenge is to maintain the prolonged repolarization but to interrupt the arrhythmogenic cascade. Current therapies for torsades de pointes include speeding of the heart rate, which enhances K+ current, and Ca2+ blockers or Mg, also a Ca2+ blocker. In the congenital long QT syndromes, therapy in the past has been directed toward reducting adrenergic influence either by betablockade or left cardiac sympathectomy. Recent discoveries open other possibilities such as Na+ channel blockers and methods to increase IKr such as elevation of extracellular K+.
Lazzara
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Cardiovascular Section, University of Oklahoma, Health Sciences Center, Oklahoma City 73104, USA.
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006329:Heart Conduction System / Q000503:physiopathology*; D006801:Humans; D008133:Long QT Syndrome / Q000151:congenital / Q000503:physiopathology* / Q000628:therapy*; D009154:Mutation; D010138:Pacemaker, Artificial; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics; D013562:Sympathectomy; D013564:Sympathetic Nervous System / Q000503:physiopathology
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D015222:Sodium Channels