Using confocal microscopy, we studied Ca2+ sparks and waves in isolated saponin-permeabilized ventricular myocytes from two CPVT mouse models (Casq2-/-, RyR2-R4496C+/-), wild-type (c57bl/6, WT) mice, and WT rabbits (New Zealand white rabbits).
Adeno-associated virus-mediated CASQ2 delivery rescues phenotypic alterations in a patient-specific model of recessive catecholaminergic polymorphic ventricular tachycardia.
Interestingly CPVT has been linked to mutations in genes encoding the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2): two fundamental proteins involved in regulation of intracellular Ca(2+) in cardiac myocytes.
A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel.
These data, combined with our previous findings, show that RYR2 mutations are present in at least 6/16 (38%) of the catecholaminergic polymorphic ventricular tachycardia families, while CASQ2 mutations must be a rare cause of CPVT.
LCSD conferred short-term suppression but less than optimal long-term suppression of exercise-induced ventricular arrhythmia among CASQ2-associated CPVT patients.
Approximately 50% of CPVT cases are caused by dominant mutations in the cardiac ryanodine receptor (RYR2) gene, <5% of cases are accounted for by recessive mutations in cardiac calsequestrin (CASQ2) or Triadin (TRDN).
Moreover, our report of the first splicing abnormalities in CASQ2 caused by intronic mutation or synonymous change underlines the absolute necessity to perform extensive molecular analysis for genetic diagnosis and counseling of CPVT.
In conclusion, patients with CASQ2-associated CPVT should be recommended to receive ICDs to prevent sudden death when medical therapy is not effective.
In conclusion, these additional three CASQ2CPVT families suggest that CASQ2 mutations are more common than previously thought and produce a severe form of CPVT.
The disease has a heterogeneous genetic basis, with mutations in the cardiac Ryanodine Receptor channel (RyR2) gene accounting for an autosomal-dominant form (CPVT1) in approximately 50% and mutations in the cardiac calsequestrin gene (CASQ2) accounting for an autosomal-recessive form (CPVT2) in up to 2% of CPVT cases.
A missense mutation in CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel.
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).
Electrocardiographic characteristics of VPCs during ST in 16 calsequestrin-2 (CASQ2) mutation carriers CPVT patients were compared with that in 36 healthy subjects.
We additionally investigated how CPVT (catecholaminergic polymorphic ventricular tachycardia) mutations affect CASQ2 structure and its molecular behaviour when exposed to different metal ions.
These in vitro and in silico data suggest a regulatory role of CASQ2 on cytosolic Ca(2+) and hERG channels which may contribute to the etiology of CPVT.