Paradoxical Effect of Increased Diastolic Ca 2+ Release and Decreased Sinoatrial Node Activity in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia

• DOI: 10.1161/circulationaha.111.075382
• Publication Date: 2012-06-19T03:57:24Z
• Authors: Patricia Neco; Angelo G. Torrente; Pietro Mesirca; Esther Zorio; Nian Liu; Silvia G. Priori; Carlo Napolitano; Sylvain Richard; Jean-Pierre Benitah; Matteo E. Mangoni; Ana María Gómez
• Keywords: Male; Patch-Clamp Techniques; MESH: Mice, Mutant Strains; [SDV]Life Sciences [q-bio]; Action Potentials; MESH: Adrenergic beta-Agonists; MESH: Isoproterenol; MESH: Ryanodine Receptor Calcium Release Channel; Mice; 0302 clinical medicine; Increased Diastolic Ca2+; MESH: Animals; MESH: Action Potentials; MESH: Aged; MESH: Middle Aged; Adrenergic beta-Agonists; Middle Aged; 3. Good health; MESH: Calcium; MESH: Sarcoplasmic Reticulum; Female; MESH: Sinoatrial Node; Adult; MESH: Mutation; 610; In Vitro Techniques; MESH: Calcium Signaling; Mouse model; 03 medical and health sciences; MESH: Mice, Inbred C57BL; MESH: Patch-Clamp Techniques; Animals; Humans; Calcium Signaling; MESH: Mice; Exercise; Aged; MESH: In Vitro Techniques; MESH: Humans; Isoproterenol; MESH: Adult; MESH: Male; Mice, Mutant Strains; Mice, Inbred C57BL; Disease Models, Animal; MESH: Exercise; Mutation; MESH: Tachycardia, Ventricular; Calcium; Catecholaminergic Polymorphic Ventricular Tachycardia; MESH: Disease Models, Animal; MESH: Female

Background— Catecholaminergic polymorphic ventricular tachycardia is characterized by stress-triggered syncope and sudden death. Patients with catecholaminergic polymorphic ventricular tachycardia manifest sinoatrial node (SAN) dysfunction, the mechanisms of which remain unexplored.

Methods and Results—

We investigated SAN [Ca 2+ ] i handling in mice carrying the catecholaminergic polymorphic ventricular tachycardia–linked mutation of ryanodine receptor (RyR2 R4496C ) and their wild-type (WT) littermates. In vivo telemetric recordings showed impaired SAN automaticity in RyR2 R4496C mice after isoproterenol injection, analogous to what was observed in catecholaminergic polymorphic ventricular tachycardia patients after exercise. Pacemaker activity was explored by measuring spontaneous [Ca 2+ ] i transients in SAN cells within the intact SAN by confocal microscopy. RyR2 R4496C SAN presented significantly slower pacemaker activity and impaired chronotropic response under β-adrenergic stimulation, accompanied by the appearance of pauses (in spontaneous [Ca 2+ ] i transients and action potentials) in 75% of the cases. Ca 2+ spark frequency was increased by 2-fold in RyR2 R4496C SAN. Whole-cell patch-clamp experiments performed on isolated RyR2 R4496C SAN cells showed that L-type Ca 2+ current ( I Ca,L ) density was reduced by ≈50%, an effect blunted by internal Ca 2+ buffering. Isoproterenol dramatically increased the frequency of Ca 2+ sparks and waves by ≈5 and ≈10-fold, respectively. Interestingly, the sarcoplasmic reticulum Ca 2+ content was significantly reduced in RyR2 R4496C SAN cells in the presence of isoproterenol, which may contribute to stopping the “Ca 2+ clock” rhythm generation, originating SAN pauses.

Conclusion—

The increased activity of RyR2 R4496C in SAN leads to an unanticipated decrease in SAN automaticity by a Ca 2+ -dependent decrease of I Ca,L and sarcoplasmic reticulum Ca 2+ depletion during diastole, identifying subcellular pathophysiological alterations contributing to the SAN dysfunction in catecholaminergic polymorphic ventricular tachycardia patients.