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Rescuing cardiac automaticity in L‐type Cav1.3 channelopathies and beyond
Author(s) -
Mesirca Pietro,
Bidaud Isabelle,
Mangoni Matteo E.
Publication year - 2016
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp270678
Subject(s) - sss* , sick sinus syndrome , sinoatrial node , bradycardia , sinus bradycardia , cardiology , medicine , atrioventricular node , atrial fibrillation , population , heart rate , tachycardia , blood pressure , environmental health
Pacemaker activity of the sino‐atrial node generates the heart rate. Disease of the sinus node and impairment of atrioventricular conduction induce an excessively low ventricular rate (bradycardia), which cannot meet the needs of the organism. Bradycardia accounts for about half of the total workload of clinical cardiologists. The ‘sick sinus’ syndrome (SSS) is characterized by sinus bradycardia and periods of intermittent atrial fibrillation. Several genetic or acquired risk factors or pathologies can lead to SSS. Implantation of an electronic pacemaker constitutes the only available therapy for SSS. The incidence of SSS is forecast to double over the next 50 years, with ageing of the general population thus urging the development of complementary or alternative therapeutic strategies. In recent years an increasing number of mutations affecting ion channels involved in sino‐atrial automaticity have been reported to underlie inheritable SSS. L‐type Ca v 1.3 channels play a major role in the generation and regulation of sino‐atrial pacemaker activity and atrioventricular conduction. Mutation in the CACNA1D gene encoding Ca v 1.3 channels induces loss‐of‐function in channel activity and underlies the sino‐atrial node dysfunction and deafness syndrome (SANDD). Mice lacking Ca v 1.3 channels ( Ca v 1.3 −/− ) fairly recapitulate SSS and constitute a precious model to test new therapeutic approaches to handle this disease. Work in our laboratory shows that targeting G protein‐gated K + ( I KACh ) channels effectively rescues SSS of Ca v 1.3 −/− mice. This new concept of ‘compensatory’ ion channel targeting shines new light on the principles underlying the pacemaker mechanism and may open the way to new therapies for SSS.