title: Accelerated sinus rhythm prevents catecholaminergic polymorphic ventricular tachycardia in mice and in patients.
abstract: BACKGROUND
  Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) genes. Sinoatrial node dysfunction associated with CPVT may increase the risk for ventricular arrhythmia (VA).
  
  
  OBJECTIVE
  To test the hypothesis that CPVT is suppressed by supraventricular overdrive stimulation.
  
  
  RESULTS
  Using CPVT mouse models (Casq2(-/-) and RyR2(R4496C/+) mice), the effect of increasing sinus heart rate was tested by pretreatment with atropine and by atrial overdrive pacing. Increasing intrinsic sinus rate with atropine before catecholamine challenge suppressed ventricular tachycardia in 86% of Casq2(-/-) mice (6/7) and significantly reduced the VA score (atropine: 0.6±0.2 versus vehicle: 1.7±0.3; P<0.05). Atrial overdrive pacing completely prevented VA in 16 of 19 (84%) Casq2(-/-) and in 7 of 8 (88%) RyR2(R4496C/+) mice and significantly reduced ventricular premature beats in both CPVT models (P<0.05). Rapid pacing also prevented spontaneous calcium waves and triggered beats in isolated CPVT myocytes. In humans, heart rate dependence of CPVT was evaluated by screening a CPVT patient registry for antiarrhythmic drug-naïve individuals that reached >85% of their maximum-predicted heart rate during exercise testing. All 18 CPVT patients who fulfilled the inclusion criteria exhibited VA before reaching 87% of maximum heart rate. In 6 CPVT patients (33%), VA were paradoxically suppressed as sinus heart rates increased further with continued exercise.
  
  
  CONCLUSIONS
  Accelerated supraventricular rates suppress VAs in 2 CPVT mouse models and in a subset of CPVT patients. Hypothetically, atrial overdrive pacing may be a therapy for preventing exercise-induced ventricular tachycardia in treatment-refractory CPVT patients.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-0575, USA.
authors.forename: Michela
authors.initials: M
authors.lastname: Faggioni
authors.forename: Hyun Seok
authors.initials: HS
authors.lastname: Hwang
authors.forename: Christian
authors.initials: C
authors.lastname: van der Werf
authors.forename: Ineke
authors.initials: I
authors.lastname: Nederend
authors.forename: Prince J
authors.initials: PJ
authors.lastname: Kannankeril
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Björn C
authors.initials: BC
authors.lastname: Knollmann
mesh_terms: D000328:Adult; D000818:Animals; D001285:Atropine / Q000494:pharmacology / Q000627:therapeutic use; D001919:Bradycardia / Q000235:genetics / Q000503:physiopathology; D002110:Caffeine / Q000633:toxicity; D020013:Calcium Signaling / Q000502:physiology; D002155:Calsequestrin / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D002304:Cardiac Pacing, Artificial; D005080:Exercise Test; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007545:Isoproterenol / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D019837:Ryanodine Receptor Calcium Release Channel / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D012849:Sinoatrial Node / Q000503:physiopathology; D013563:Sympathectomy, Chemical; D017180:Tachycardia, Ventricular; D014630:Vagus Nerve / Q000187:drug effects / Q000503:physiopathology; D018879:Ventricular Premature Complexes / Q000209:etiology / Q000517:prevention & control; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: C443109:CASQ2 protein, human; D002155:Calsequestrin; D019837:Ryanodine Receptor Calcium Release Channel; C514388:casq2 protein, mouse; D002110:Caffeine; D001285:Atropine; D007545:Isoproterenol