Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited 
disease characterized by adrenergically mediated polymorphic ventricular 
tachycardia leading to syncope and sudden cardiac death. The autosomal dominant 
form of CPVT is caused by mutations in the RyR2 gene encoding the cardiac 
isoform of the ryanodine receptor. In vitro functional characterization of 
mutant RyR2 channels showed altered behavior on adrenergic stimulation and 
caffeine administration with enhanced calcium release from the sarcoplasmic 
reticulum. As of today no experimental evidence is available to demonstrate that 
RyR2 mutations can reproduce the arrhythmias observed in CPVT patients. We 
developed a conditional knock-in mouse model carrier of the R4496C mutation, the 
mouse equivalent to the R4497C mutations identified in CPVT families, to 
evaluate if the animals would develop a CPVT phenotype and if beta blockers 
would prevent arrhythmias. Twenty-six mice (12 wild-type (WT) and 14RyR(R4496C)) 
underwent exercise stress testing followed by epinephrine administration: none 
of the WT developed ventricular tachycardia (VT) versus 5/14 RyR(R4496C) mice 
(P=0.02). Twenty-one mice (8 WT, 8 RyR(R4496C), and 5 RyR(R4496C) pretreated 
with beta-blockers) received epinephrine and caffeine: 4/8 (50%) RyR(R4496C) 
mice but none of the WT developed VT (P=0.02); 4/5 RyR(R4496C) mice pretreated 
with propranolol developed VT (P=0.56 nonsignificant versus RyR(R4496C) mice). 
These data provide the first experimental demonstration that the R4496C RyR2 
mutation predisposes the murine heart to VT and VF in response caffeine and/or 
adrenergic stimulation. Furthermore, the results show that analogous to what is 
observed in patients, beta adrenergic stimulation seems ineffective in 
preventing life-threatening arrhythmias.