Editorials |
From the Unit of Cardiac Physiology, University of Manchester, UK.
Correspondence to D. A. Eisner, Unit of Cardiac Physiology, University of Manchester, 3.18 Core Technology Facility, 46 Grafton St, Manchester M13 9NT, United Kingdom. E-mail eisner{at}man.ac.uk
See related article, pages 298–306
| Introduction |
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| Diastolic Calcium Release and Arrhythmias |
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| Cathecholiminergic Polymorphic Ventricular Tachycardia |
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| Normal function of CSQ |
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| CSQ Mutations and Generation of DADs |
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The clear picture that emerges from all of these studies is that decreased levels of CSQ are central to pathogenesis of arrhythmias in patients with CSQ mutations and that different compensatory changes induced by different mutations (ie, changes in other SR Ca-handling proteins) determine the severity of the phenotype. In the light of this conclusion, one can also hypothesize that some individuals heterozygous for CSQ mutations develop arrhythmias because they are not able to achieve normal levels of CSQ in their SR.
It has become increasingly clear that catecholamines cause arrhythmias in CPVT mainly because they increase SR Ca content up to the threshold for diastolic Ca release. An area that still needs to be clarified is what are the effects of catecholamines on mutant RyR and CSQ? Recent studies have suggested that catecholamines directly increase the activity of RyR.16 It is still unclear whether mutant RyRs respond differently to catecholamines. In the case of CSQ, it is not known whether catecholamines have any effects on its affinity for Ca or its capacity to bind triadin and inhibit RyR. Understanding of these factors would help us to find new treatments for CPVT. A recent study has clearly demonstrated that most VT is CPVT is mainly generated in the His-Purkinje system.17 It would be extremely interesting and useful to establish whether the alteration in Ca handling produced by RyR and CSQ mutations ventricular myocytes are also present in His bundle cells.
Finally, with the development of agents that stabilize RyR and increase threshold for diastolic Ca release,18,19 it will be very interesting to see whether these agents are effective in reducing arrhythmias in mice with CSQ mutations.
| Acknowledgments |
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British Heart Foundation.
Disclosures
None.
| Footnotes |
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| References |
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Related Article:
Circ. Res. 2008 103: 298-306.
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