Paradoxical effect of increased diastolic Ca2+ release and decreased sinoatrial node activity in a mouse model of catecholaminergic polymorphic ventricular tachycardia

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

Research output: Contribution to journalArticle

Abstract

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]i handling in mice carrying the catecholaminergic polymorphic ventricular tachycardia-linked mutation of ryanodine receptor (RyR2) and their wild-type (WT) littermates. In vivo telemetric recordings showed impaired SAN automaticity in RyR2 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]i transients in SAN cells within the intact SAN by confocal microscopy. RyR2 SAN presented significantly slower pacemaker activity and impaired chronotropic response under β-adrenergic stimulation, accompanied by the appearance of pauses (in spontaneous [Ca]i transients and action potentials) in 75% of the cases. Ca spark frequency was increased by 2-fold in RyR2 SAN. Whole-cell patch-clamp experiments performed on isolated RyR2 SAN cells showed that L-type Ca current (ICa,L) density was reduced by ? 50%, an effect blunted by internal Ca buffering. Isoproterenol dramatically increased the frequency of Ca sparks and waves by ? 5 and ? 10-fold, respectively. Interestingly, the sarcoplasmic reticulum Ca content was significantly reduced in RyR2 SAN cells in the presence of isoproterenol, which may contribute to stopping the "Ca clock" rhythm generation, originating SAN pauses. Conclusion-: The increased activity of RyR2 in SAN leads to an unanticipated decrease in SAN automaticity by a Ca-dependent decrease of ICa,L and sarcoplasmic reticulum Ca depletion during diastole, identifying subcellular pathophysiological alterations contributing to the SAN dysfunction in catecholaminergic polymorphic ventricular tachycardia patients.

Original languageEnglish
Pages (from-to)392-401
Number of pages10
JournalCirculation
Volume126
Issue number4
DOIs
Publication statusPublished - Jul 24 2012

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Sinoatrial Node
Ryanodine Receptor Calcium Release Channel
Isoproterenol
Sarcoplasmic Reticulum
Polymorphic catecholergic ventricular tachycardia
Diastole
Syncope
Sudden Death
Confocal Microscopy
Adrenergic Agents
Action Potentials

Keywords

  • arrhythmias
  • calcium
  • cardiac
  • polymorphic catecholaminergic ventricular tachycardia
  • sinoatrial node

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Paradoxical effect of increased diastolic Ca2+ release and decreased sinoatrial node activity in a mouse model of catecholaminergic polymorphic ventricular tachycardia. / Neco, Patricia; Torrente, Angelo G.; Mesirca, Pietro; Zorio, Esther; Liu, Nian; Priori, Silvia G.; Napolitano, Carlo; Richard, Sylvain; Benitah, Jean Pierre; Mangoni, Matteo E.; Gómez, Ana María.

In: Circulation, Vol. 126, No. 4, 24.07.2012, p. 392-401.

Research output: Contribution to journalArticle

Neco, Patricia ; Torrente, Angelo G. ; Mesirca, Pietro ; Zorio, Esther ; Liu, Nian ; Priori, Silvia G. ; Napolitano, Carlo ; Richard, Sylvain ; Benitah, Jean Pierre ; Mangoni, Matteo E. ; Gómez, Ana María. / Paradoxical effect of increased diastolic Ca2+ release and decreased sinoatrial node activity in a mouse model of catecholaminergic polymorphic ventricular tachycardia. In: Circulation. 2012 ; Vol. 126, No. 4. pp. 392-401.
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abstract = "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]i handling in mice carrying the catecholaminergic polymorphic ventricular tachycardia-linked mutation of ryanodine receptor (RyR2) and their wild-type (WT) littermates. In vivo telemetric recordings showed impaired SAN automaticity in RyR2 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]i transients in SAN cells within the intact SAN by confocal microscopy. RyR2 SAN presented significantly slower pacemaker activity and impaired chronotropic response under β-adrenergic stimulation, accompanied by the appearance of pauses (in spontaneous [Ca]i transients and action potentials) in 75{\%} of the cases. Ca spark frequency was increased by 2-fold in RyR2 SAN. Whole-cell patch-clamp experiments performed on isolated RyR2 SAN cells showed that L-type Ca current (ICa,L) density was reduced by ? 50{\%}, an effect blunted by internal Ca buffering. Isoproterenol dramatically increased the frequency of Ca sparks and waves by ? 5 and ? 10-fold, respectively. Interestingly, the sarcoplasmic reticulum Ca content was significantly reduced in RyR2 SAN cells in the presence of isoproterenol, which may contribute to stopping the {"}Ca clock{"} rhythm generation, originating SAN pauses. Conclusion-: The increased activity of RyR2 in SAN leads to an unanticipated decrease in SAN automaticity by a Ca-dependent decrease of ICa,L and sarcoplasmic reticulum Ca depletion during diastole, identifying subcellular pathophysiological alterations contributing to the SAN dysfunction in catecholaminergic polymorphic ventricular tachycardia patients.",
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T1 - Paradoxical effect of increased diastolic Ca2+ release and decreased sinoatrial node activity in a mouse model of catecholaminergic polymorphic ventricular tachycardia

AU - Neco, Patricia

AU - Torrente, Angelo G.

AU - Mesirca, Pietro

AU - Zorio, Esther

AU - Liu, Nian

AU - Priori, Silvia G.

AU - Napolitano, Carlo

AU - Richard, Sylvain

AU - Benitah, Jean Pierre

AU - Mangoni, Matteo E.

AU - Gómez, Ana María

PY - 2012/7/24

Y1 - 2012/7/24

N2 - 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]i handling in mice carrying the catecholaminergic polymorphic ventricular tachycardia-linked mutation of ryanodine receptor (RyR2) and their wild-type (WT) littermates. In vivo telemetric recordings showed impaired SAN automaticity in RyR2 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]i transients in SAN cells within the intact SAN by confocal microscopy. RyR2 SAN presented significantly slower pacemaker activity and impaired chronotropic response under β-adrenergic stimulation, accompanied by the appearance of pauses (in spontaneous [Ca]i transients and action potentials) in 75% of the cases. Ca spark frequency was increased by 2-fold in RyR2 SAN. Whole-cell patch-clamp experiments performed on isolated RyR2 SAN cells showed that L-type Ca current (ICa,L) density was reduced by ? 50%, an effect blunted by internal Ca buffering. Isoproterenol dramatically increased the frequency of Ca sparks and waves by ? 5 and ? 10-fold, respectively. Interestingly, the sarcoplasmic reticulum Ca content was significantly reduced in RyR2 SAN cells in the presence of isoproterenol, which may contribute to stopping the "Ca clock" rhythm generation, originating SAN pauses. Conclusion-: The increased activity of RyR2 in SAN leads to an unanticipated decrease in SAN automaticity by a Ca-dependent decrease of ICa,L and sarcoplasmic reticulum Ca depletion during diastole, identifying subcellular pathophysiological alterations contributing to the SAN dysfunction in catecholaminergic polymorphic ventricular tachycardia patients.

AB - 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]i handling in mice carrying the catecholaminergic polymorphic ventricular tachycardia-linked mutation of ryanodine receptor (RyR2) and their wild-type (WT) littermates. In vivo telemetric recordings showed impaired SAN automaticity in RyR2 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]i transients in SAN cells within the intact SAN by confocal microscopy. RyR2 SAN presented significantly slower pacemaker activity and impaired chronotropic response under β-adrenergic stimulation, accompanied by the appearance of pauses (in spontaneous [Ca]i transients and action potentials) in 75% of the cases. Ca spark frequency was increased by 2-fold in RyR2 SAN. Whole-cell patch-clamp experiments performed on isolated RyR2 SAN cells showed that L-type Ca current (ICa,L) density was reduced by ? 50%, an effect blunted by internal Ca buffering. Isoproterenol dramatically increased the frequency of Ca sparks and waves by ? 5 and ? 10-fold, respectively. Interestingly, the sarcoplasmic reticulum Ca content was significantly reduced in RyR2 SAN cells in the presence of isoproterenol, which may contribute to stopping the "Ca clock" rhythm generation, originating SAN pauses. Conclusion-: The increased activity of RyR2 in SAN leads to an unanticipated decrease in SAN automaticity by a Ca-dependent decrease of ICa,L and sarcoplasmic reticulum Ca depletion during diastole, identifying subcellular pathophysiological alterations contributing to the SAN dysfunction in catecholaminergic polymorphic ventricular tachycardia patients.

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