Natural History and Risk Stratification in Andersen-Tawil Syndrome Type 1

J Am Coll Cardiol. 2020 Apr 21;75(15):1772-1784. doi: 10.1016/j.jacc.2020.02.033.

Abstract

Background: Andersen-Tawil Syndrome type 1 (ATS1) is a rare arrhythmogenic disorder, caused by loss-of-function mutations in the KCNJ2 gene. We present here the largest cohort of patients with ATS1 with outcome data reported.

Objectives: This study sought to define the risk of life-threatening arrhythmic events (LAE), identify predictors of such events, and define the efficacy of antiarrhythmic therapy in patients with ATS1.

Methods: Clinical and genetic data from consecutive patients with ATS1 from 23 centers were entered in a database implemented at ICS Maugeri in Pavia, Italy, and pooled for analysis.

Results: We enrolled 118 patients with ATS1 from 57 families (age 23 ± 17 years at enrollment). Over a median follow-up of 6.2 years (interquartile range: 2.7 to 16.5 years), 17 patients experienced a first LAE, with a cumulative probability of 7.9% at 5 years. An increased risk of LAE was associated with a history of syncope (hazard ratio [HR]: 4.54; p = 0.02), with the documentation of sustained ventricular tachycardia (HR 9.34; p = 0.001) and with the administration of amiodarone (HR: 268; p < 0.001). The rate of LAE without therapy (1.24 per 100 person-years [py]) was not reduced by beta-blockers alone (1.37 per 100 py; p = 1.00), or in combination with Class Ic antiarrhythmic drugs (1.46 per 100 py, p = 1.00).

Conclusions: Our data demonstrate that the clinical course of patients with ATS1 is characterized by a high rate of LAE. A history of unexplained syncope or of documented sustained ventricular tachycardia is associated with a higher risk of LAE. Amiodarone is proarrhythmic and should be avoided in patients with ATS1.

Keywords: KCNJ2; genetics; inherited arrhythmias; life-threatening arrhythmic events; sudden cardiac death.

MeSH terms

  • Adolescent
  • Adrenergic beta-Antagonists / therapeutic use
  • Adult
  • Amiodarone / administration & dosage
  • Amiodarone / adverse effects
  • Andersen Syndrome / complications*
  • Andersen Syndrome / genetics
  • Andersen Syndrome / therapy
  • Anti-Arrhythmia Agents / administration & dosage
  • Anti-Arrhythmia Agents / adverse effects
  • Arrhythmias, Cardiac / etiology*
  • Arrhythmias, Cardiac / therapy
  • Child
  • Child, Preschool
  • Databases, Factual
  • Death, Sudden, Cardiac / epidemiology
  • Defibrillators, Implantable
  • Electrocardiography
  • Female
  • Genetic Testing
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Muscle Weakness / etiology
  • Mutation
  • Potassium Channels, Inwardly Rectifying / genetics
  • Risk Assessment*
  • Syncope / etiology
  • Syncope / therapy
  • Tachycardia, Ventricular / etiology
  • Tachycardia, Ventricular / therapy
  • Young Adult

Substances

  • Adrenergic beta-Antagonists
  • Anti-Arrhythmia Agents
  • KCNJ2 protein, human
  • Potassium Channels, Inwardly Rectifying
  • Amiodarone